Process for preparation of mek inhibitors

PROCESS FOR PREPARATION OF MEK INHIBITORS BACKGROUND OF THE INVENTION

The present invention is a divisional application divided out of Israel Patent Application No. 189900 filed March 3, 2008 and antedated as of October 5, 2006.

Field of the Invention [0001] This invention relates to certain inhibitors of MEK which are useful in the treatment of hyperproliferative diseases, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds. [0003] Improvements in the specificity of agents used to treat cancer is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms.

[0004] Protein kinases are enzymes that catalyze the phosphorylation of proteins, in particular, hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell differentiation and proliferation; i.e., virtually all aspects of cell life in one-way or another depend on protein kinase activity. Furthermore, abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).

[0005] Protein kinases can be categorized as receptor type or non-receptor type. Receptor-type tyrosine kinases have an extracellular, a transmembrane, and an intracellular portion, while non-receptor type tyrosine kinases are wholly intracellular. They are comprised of a large number of transmembrane receptors with diverse biological activity. In fact, about 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily, designated the HER subfamily, is comprised of EGFR (HER 1), HER2, HERS, and HER4. Ligands of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamily includes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II. In addition, there is the FLK family, which is comprised of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-I), fetal 1 liver kinase-4 (FLK-4) and the fins-like tyrosine kinase-1 (flt-1). The PDGF and FLK families are usually considered together due to the similarities of the two groups. For a detailed discussion of the receptor-type tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994.

[0006] The non-receptor type of tyrosine kinases is also comprised of numerous subfamilies, including Src, Frk, Btk, Csk, AbI, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further sub-divided into varying receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of the non-receptor type of tyrosine kinases, see Bolen, Oncogene, 8:2025-2031 (1993.

[0007] Since protein kinases and their ligands play critical roles in various cellular activities, deregulation of protein kinase enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. In addition to oncological indications, altered kinase signaling is implicated in numerous other pathological diseases. These include, but are not limited to: immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases. Therefore, both receptor and non-receptor protein kinases are attractive targets for small molecule drug discovery.

[0008] One particularly attractive goal for therapeutic use of kinase modulation relates to oncological indications. For example, modulation of protein kinase activity for the treatment of cancer has been demonstrated successfully with the FDA approval of Gleevec® (imatinib mesylate, produced by Novartis Pharmaceutical Corporation of East Hanover, NJ) for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers. Gleevec is a selective AbI kinase inhibitor.

[0009] Modulation (particularly inhibition) of cell proliferation and angiogenesis, two key cellular processes needed for tumor growth and survival (Matter A. Drug Disc Technol 2001 6, 1005-1024), is an attractive goal for development of small-molecule drugs. Antiangiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated v ascularization, including ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. As well, cell antiproliferative agents are desirable to slow or stop the growth of tumors.

[0010] One particularly attractive target for small-molecule modulation, with respect to antiangiogenic and antiproliferative activity is MEK. Inhibition of MEKl (MAPK/ERK Kinase) is a promising strategy to control the growth of tumors that are dependent on aberrant 2 ERK/MAPK pathway signaling (Solit et al., 2006; Wellbrock et al., 2004). The MEK-ERK signal transduction cascade is a conserved pathway which regulates cell growth, proliferation, differentiation, and apoptosis in response to growth factors, cytokines, and hormones. This pathway operates downstream of Ras which is often upregulated or mutated in human tumors. It has been demonstrated that MEK is a critical effector of Ras function. The ERK/MAPK pathway is upregulated in 30% of all tumors and oncogenic activating mutations in K-Ras and B-Raf have been identified in 22% and 18% of all cancers respectively (Allen et al., 2003; Bamford S, 2004; Davies et al., 2002; Malumbres and Barbacid, 2003). A large portion of human cancers, including 66% (B-Raf) of malignant melanomas, 60% (K-Ras) and 4% (B-Raf) of pancreatic cancers, 50% of colorectal cancers (colon, in particular, K-Ras: 30%, B-Raf: 15%), 20% (K-Ras) of lung cancers, 27% (B-Raf) papillary and anaplastic thyroid cancer, and 10-20% (B-Raf) of endometriod ovarian cancers, harbor activating Ras and Raf mutations. It has been shown that inhibition of the ERK pathway, and in particular inhibition of MEK kinase activity, results in anti-metastatic and anti-angiogenic effects largely due to a reduction of cellcell contact and motility as well as downregulation of vascular endothelial growth factor (VEGF) expression. Furthermore, expression of dominant negative MEK, or ERK reduced the transforming ability of mutant Ras as seen in cell culture and in primary and metastatic growth of human tumor xenografts in vivo. Therefore, the MEK-ERK signal transduction pathway is an appropriate pathway to target for therapeutic intervention.

[0011] Accordingly, the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases, particularly MEK, is desirable as a means to treat or prevent disease states associated with cancer and is an object of this invention.

SUMMARY OF THE INVENTION

[0012] The following only summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.

[0013] This invention provides compounds that inhibit, regulate and/or modulate the signal transduction of kinases, particularly MEK. The compounds of the invention are certain azetidin-l-yl(2-(2-fluorophenylamino)cyclic)methanones derivatives that are useful in the treatment of hyperproliferative diseases, such as cancer, in humans. This invention also provides methods of making the compound, methods of using such compounds in the treatment of hyperproliferative diseases in humans and to pharmaceutical compositions containing such 3 compounds.

[0014] In one aspect, the invention provides a compound of Formula I:

<img img-format="tif" img-content="drawing" file="IL229136AD00021.tif" id="idf0001" />

I or a pharmaceutically acceptable salt or solvate, thereof, wherein A, X, R1, Rz, R\ R4, RD, R° and R7 are as defined in Group A, Group B, Group C, or Group D:

Group A: A is arylene optionally substituted with one, two, three or four groups selected from R10, R12, R14, and R16 where R10, R12, R14 and R16 are independently hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, -NHS(O)2R8, -CN, -C(O)R8, -C(O)OR8, -C(O)NR8R8 and -NR8C(O)R8; X is alkyl, halo, haloalkyl, or haloalkoxy; R1, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, -NR8R8, -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8 , -C(O)R8, -C(O)OR8, -C(O)NR8R8 , -NR8C(O)OR8 , -NR8C(O)NR8 R8\ -NR8C(O)OR8 , -NR8C(O)R8 , -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(aNH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycioalkyl, optionally substituted 4 heterocycloaikyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, -OR8, -NR8R8’, -NR8S(O)2R9, -CN, -S(O),nR5, -C(O)R8, -C(O)OR8, -C(O)NR8R8&gt;NR8C(O)NR8,R8,&gt;NR8C(O)ORs’ and -NR8C(O)Rr ; or one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R5 and R6 together with the carbon to which they are attached form C(O) or C(=NOH); m is 0, 1, or 2; *7 R is hydrogen, halo or alkyl; R8, Rs and R8 are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloaikyl; where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloaikyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxya)kyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, optionally substituted cycloalkyl, optionally substituted cyclo alkyloxycarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkyloxycarbonyl, nitro, cyano, optionally substituted heterocycloaikyl, optionally substituted heteroaryl, -S(O)nR31 (where n is 0, 1, or 2 and R3i is optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloaikyl, or optionally substituted heteroaryl), -NR34SO2R34a (where R34 is hydrogen or alkyl and R34a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloaikyl), -SO2NR35R35a (where R35 is hydrogen or alkyl and R353 is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloaikyl), -NR32C(O)R32a (where R32 is hydrogen or alkyl and R32a is alkyl, alkenyl, alkoxy, or cycloalkyl), -NR30R30 (where R30 and R30 are independently hydrogen, alkyl, or hydroxyalkyl), and -C(O)NR33R33a (where R33 is hydrogen or alkyl and R33a is alkyl, alkenyl, alkynyl, or cycloalkyl); R9 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloaikyl; where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloaikyl are independently optionally susbstituted with one, two, three, four, or five groups selected from halo, hydroxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, and dialkylamino; 5 R25 and R25b are independently hydrogen, alkyl, alkenyl, optionally sbnstituted cycloalkyl, or optionally substituted aryl; and R25a is hydrogen, alkyl, or alkenyl;

Group B: A is heteroarylene optionally substituted with one, two, three, or four groups selected from Ri0, Riz, Ri4, R16 and R19 where R10, R12, R14 and R16 are independently hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, alkoxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkylsulfonylamino, alkylcarbonyl, alkenylcarbonyl, aikoxycarbonyl, alkenyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or alkylcarbonylamino; where R19 is hydrogen, alkyl, or alkenyl; and where each alkyl and alkenyl, either alone or as part of another group within R10, R12, R14, Ri6, and R19 is independently optionally substituted with halo, hydroxy, or alkoxy; X is alkyl, halo, haloalkyl, or haloalkoxy; R1, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, -NR8R8, -OR8, -NHS(O)2R8, -CN, -S(O)mR8, ~S(O)2NRsR8’, -C(O)Rs, -C(O)OR8, -C(O)NR8R8’, -NR8C(0)OR8', -NR8C(O)NRs’R8”, -NR8C(O)OR8’, ~NRsC(O)R\ ~CH2N(R25)(NR25aR23b), -CH2NR25C(-NH)(NR25aR25b), -CH2NR25C(“NH)(N(R25a)(NO2))} -CH2NR25C(=NH)(N(R23s)(CN)), -CH2NR25C(-NH)(R25), -CH2NR25C(NR25aR25b)-CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heleroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, -OR8, -NRSR8, -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, ~C(O)OR8, -C(O)NRSR8’, -NR8C(O)NR8Rs”j -NR8C(O)OR8’ and -NR8C(O)R8; or one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R3 and R6 together with the carbon to which they are attached form C(O) or C(=NOH); m is 1 or 2; R7 is hydrogen, halo or alkyl; and R8, R8 and R8’ are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and 6 heterocycloalkyl, where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, -S(O)nR3i (where n is 0,1, or 2 and R31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), -NR36S(0)2.R36;! (where R36 is hydrogen, alkyl, or alkenyl and R36a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), ~S(O)2NR37R37a (where R37 is hydrogen, alkyl, or alkenyl and R37a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted heteroaryl, -NHC(O)R32 (where R32 is alkyl, alkenyl, alkoxy, or cycloalkyl) and -NR30R30 (where R30 and R30’ are independently hydrogen, alkyl, or hydroxyalkyl), and -C(O)NHR33 (where R33 is alkyl, alkenyl, alkynyl, or cycloalkyl);

Group C: A is

I ww

Y1 I o (a) where Ri0 is hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, ~NHS(O)2R8, -CN, -C(O)RS, -C(O)OR8, -C(O)NR8R8’ and -NR8C(O)R8’; R10a is hydrogen, alkyl, or alkenyl; Y1 is-CH-or-N-; X is alkyl, halo, haloalkyl, or haloalkoxy; R1, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, -NRSR8, -OR8, -NHS(O)2R8, -CN, ~S(O)mR8, -S(O)2NR8R8’, -C(O)R8, -C(O)OR8, -C(O)NR8Rs’, ~NR8C(O)OR8’, -NR8C(O)NR8’R8” ~NR8C(O)OR8’, -NR8C(O)R8’,

<img img-format="tif" img-content="drawing" file="IL229136AD00022.tif" id="idf0002" />

7 -CH2N(R25)(NR25aR25b)&gt; -CH2NR2sC(=NH)(NR25aR25b), -CH2NR2SC(=NH)(NCR2Si,)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR23aR25i&gt;CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, -OR8, -NRSR8, -NR8S(O)2R9, -CN, -S(O)mR\ -C(O)R8, -C(O)OR8, -C(O)NR8R8&gt;NR8C(O)NR8’Rs’&gt;NR8C(O)OR8' and -NR8C(O)R8; or one of R1 and R2 together with the carbon to which they are attached, R and R together with the carbon to which they are attached, and R and R6 together with the carbon to which they are attached form C(O) or C(=NOH); m is 1 or 2; R7 is hydrogen, halo or alkyl; and R8, R8’ and Rr are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, -S(O)nR31 (where n is 0,1, or 2 and R31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), -NR36S(O)?R36a (where R36 is hydrogen, alkyl, or alkenyl and R36a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), -S(O)2NR37R37a (where R37 is hydrogen, alkyl, or alkenyl and R373 is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted heteroaryl, -NHC(O)R32 (where R32 is alkyl, alkenyl, alkoxy, or cycloalkyl) and -NR30R30 (where 8 R30 and R30 are independently hydrogen, alkyl, or hydroxyalkyl), and -C(0)NHR33 (where R33 is alkyl, alkenyl, alkynyl, or cycloalkyl); or

Group D: A is

»/VW

<img img-format="tif" img-content="drawing" file="IL229136AD00023.tif" id="idf0003" />

o (c) R40 and R40a are independently hydrogen or alkyl; X is alkyl, halo, haloalkyl, or haloalkoxy; R3, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, -NR8RS, -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)ORs, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR!’R8", -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR2SaR23b),-CH2NR25C(=NH)(NR2J’R25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH^’C^NHXNCR^XCN)), -CH2NR2SC(=NH)(R25), -CH2NR25C(NR25aR23b)=CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heteroeycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heteroeycloalkyl, optionally substituted aryl, optionally substituted arylaikyl, optionally substituted heteroaryl, -ORS, -NRSR8, -NR8S(O)?R9, -CN, ~S(O)mR9, -C(O)RS, -C(O)ORS, -C(O)NR8R8&gt;NRSC(O)NR8 R8’&gt;NRsC(O)ORs’ and ~NRSC(O)RS’; or one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R5 and R6 together with the carbon to which they are attached form C(O) or C(~NOH); m is 1 or 2; R7 is hydrogen, halo or alkyl; and 9 § g&gt; * R , R and Rg-&gt; are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloaikyl, where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, ~S(O)nR31 (where n is 0, 1, or 2 and R31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloaikyl, or optionally substituted heteroaryl), -NR36S(O)2R36:i (where R36 is hydrogen, alkyl, or alkenyl and R36a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloaikyl, or optionally substituted heteroaryl), -S(O)2NR37R37a (where R37 is hydrogen, alkyl, or alkenyl and R37a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloaikyl, or optionally substituted heteroaryl), optionally substituted cycloalkyl, optionally substituted heterocycloaikyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted hetero aryl, -NHC(O)R32 (where R32 is alkyl, alkenyl, alkoxy, or cycloalkyl) and -NR3OR30 (where R30 and R30’ are independently hydrogen, alkyl, or hydroxyalkyl), and -C(O)NHR33 (where R33 is alkyl, alkenyl, alkynyl, or cycloalkyl).

[0015] A second aspect of the Invention provides a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutically acceptable salt or solvate tberof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0016] In a third aspect, the invention is directed to a method of inhibiting MEK comprising administering to a patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable carrier, excipient, or diluent.

[0017] In a fourth aspect, the invention comprises a method of inhibiting MEK in a cell, comprising contacting a cell with a compound of Formula I or a pharmaceutically acceptable salt or solvate therof, or with a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, excipient, or diluent.

[0018] A fifth aspect of the Invention provides a method for treating a disease, disorder, or syndrome which method comprises administering to a patient a compound of Formula I or 10 a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, excipient, or diluent. (0019] A sixth aspect of the invention is directed to a process of preparing a compound of

Formula I, comprising: (a) reacting an intermediate of formula 19:

<img img-format="tif" img-content="drawing" file="IL229136AD00024.tif" id="idf0004" />

19 where X1 is OH or halo, specifically chloro or fluoro, and all other groups are as defined in the Summary of the Invention for a compound selected from Group A, Group B, Group C, and Group D; with an intermediate of formula 17:

<img img-format="tif" img-content="drawing" file="IL229136AD00025.tif" id="idf0005" />

17 where R1, R2, R3, R4, R5, and R6 are as defined in the Summary of the Invention for a compound selected from Group A, Group B, Group C, and Group D; and (b) optionally separating indiividual isomers; and (c) optionally modifying any of the R1, R2, R3, R4, R5, and R6 groups.

[0020] A seventh aspect of the invention is directed to a process of preparing intermediates of formula 3, 4, 5,6,10, and 13, comprising: (a) reacting an intermediate of formula 2(a):

<img img-format="tif" img-content="drawing" file="IL229136AD00026.tif" id="idf0006" />

with R4M (where R4M is a Grignard reagent or organometallic species and R4 is as defined in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D); with R4’CH2NO2 (where R4’ is hydrogen or alkyl optionally substituted as described for R4 in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D); with R4:R4”C(O) (R4? is alkyl optionally substituted as described for R4 in the Summary of 11 the invention for a compound of Group A, Group B, Group C, or Group D and R4” is hydrogen or R4’); with R’R”CHP(Ph)3 (where R’ and R” are independently hydrogen, alkyl, alkenyl, aryl, or heteroaryl and the alkyl, alkenyl, aryl, and heteroaryl are optionally substituted as described for R4 in the Sumnmary of the Invention for a compound of Group A, Group B, Group C, or Group D); with a chiral oxazolidinone auxiliary and subsequent treatment with a base, such as lithium hydroxide, in aqueous hydrogen peroxide; or with a N-protected hetero cycioalkyl group where Pl is Boc and P2 is CBz or P1 is CBz and P2 is Boc; to yield the intermediates of formula 3,4, 5, 6,12, and 13, respectively:

OH J--R4

A p (3); OH Mo2 'jfj"R4'

OH OH

<img img-format="tif" img-content="drawing" file="IL229136AD00027.tif" id="idf0007" />

Rl zA"R,! N- (6);

HO

<img img-format="tif" img-content="drawing" file="IL229136AD00028.tif" id="idf0008" />

CO2H z

Rf (10); and

<img img-format="tif" img-content="drawing" file="IL229136AD00029.tif" id="idf0009" />

(b) optionally further reacting 6 with /v-CPBA to form an epoxide and further opening the epoxide with an amine of formula NHRSR8 to yield an intermediate of formula 8: OH nr8r8' ,__/ N· 8 where P is a N-protecting group and R8 and R8’ are as defined in the Summary of the

Invention for a compound of Group A, Group B, Group C, or Group D; 12 (c) optionally further subjecting 10 to a Curtius rearrangement and subsequent treatment to yield an intermediate of formula 12: OH NH2 12 where P is a N-protecting group and R' is an alkyl group such as methyl or ethyl; (d) optionally further resolving individual isomers; and (e) optionally modifying any of the Rs, R2, R3, R4, R5, and R6 groups. DETAILED DESCRIPTION OE THE INVENTION Abbreviations and Definitions [0021] The following abbreviations and terms have the indicated meanings throughout:

Abbreviation Meaning Ac acetyl br broad °C degrees Celsius CBZ CarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dt doublet of triplet DAST (diethylamino)sulfur trifluoride DCM dichloromethane DIPEA XA-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF MV-dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide EDCI l-(3“dimethylaminopropyl) ethylcarbodiimide El Electron Impact ionization Et ethyl g gram(s) GC gas chromatography hor hr hour(s) HBTU 2-(1 H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOAc acetic acid HOBt hydroxybenzotriazole HPLC high pressure liquid chromatography L liter(s) LDA lithium diiospropylamide LHMDS lithium hexamethyldisilazide M molar or molarity 13 m multiplet MCPBA meta-chloroperbenzoic acid Me methyl mg milligram(s) MHz megahertz (frequency) min minute(s) mL milliliter(s) mM millimolar mmol millimole(s) mol mole(s) MS mass spectral analysis N normal or normality nM nanomolar NMM W-methylmorpholine NMR nuclear magnetic resonance spectroscopy PyBOP benzotriazole-1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate q quartet RT room temperature s singlet S“ secondary t- tertiary t or tr triplet 1 rir tetrahydrofuran pL microliter(s) pM micromole(s) or micromolar [0022] The symbol means a single bond, means a double bond, ’ means a triple bond, and means a single bond and optionally a double bond. When chemical structures are . depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four.

[0023] When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four, For example, in the structure on the left-hand side of the schematic below there are nine hydrogens implied. The nine hydrogens are depicted in the right-hand structure. Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogens as substitution (expressly defined hydrogen), for example, -CH2CH2-. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures. 14 {00241 formula: rf

<img img-format="tif" img-content="drawing" file="IL229136AD000210.tif" id="idf0010" />

a group “R” is depicted as “floating” on a ring system, as for example in the

<img img-format="tif" img-content="drawing" file="IL229136AD000211.tif" id="idf0011" />

then, unless otherwise defined, a substituent “R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.

[0025] if a group “R” is depicted as floating on a fused ring system, as for example in the formulae:

<img img-format="tif" img-content="drawing" file="IL229136AD000212.tif" id="idf0012" />

then, unless otherwise defined, a substituent “R” may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the -NH- in the formula above), implied hydrogen (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, “X” equals -CH-) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the “R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula depicted above, when y is 2 for example, then the two “R’s” may reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring. (0026] When a group “R” is depicted as existing on a ring system containing saturated carbons, as for example in the formula: where, in this example, “y” can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two “R’s” may reside on the same carbon, A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an “annular” carbon). In another example, two R’s on the same carbon, 15 including that carbon, may form a ring, thus creating a spirocyclic ring (a “spirocyclyl” group) structure with the depicted ring as for example in the formula:

<img img-format="tif" img-content="drawing" file="IL229136AD000213.tif" id="idf0013" />

(0027] “Acyl” means a ~C(O)R radical where R is optionally substituted alkyl, optionally substituted alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, hetero aralkyl, heterocycloalkyl, or heterocycloalkylalkyl, as defined herein, e.g,, acetyl, benzoyl, trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like. (0028] “Acylamino” means a -NRR’ group where R is acyl, as defined herein, and R? is hydrogen or alkyl. (0029] “Administration” and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.), “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents. (0030] “Alkenyl” means a means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to 6 carbon atoms which radical contains at least one double bond, e.g., ethenyl, propenyl, l-but enyl, 1-pent en.yl, l-hex enyl and the like.

[0031] “Alkenylcarbonyl” means a -C(O)R group where R is alkenyl, as defined herein.

[0032] “Alkenyloxycarbonyl” means a -C(O)OR group where R is alkenyl, as defined herein.

[0033] “Alkoxy” means an -OR group where R is alkyl group as defined herein. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like. Lower-alkoxy refers to groups containing one to six carbons, [0034] “Alkoxyalkyl” means an alkyl group, as defined herein, substituted with at least one, preferably one, two, or three, alkoxy groups as defined herein. Representative examples include methoxymethyl and the like, [0035] “Alkoxycarbonyl” means a -C(O)OR group where R is alkyl as defined herein. [0036] “Alkoxycarbonylamino” means a -NR’R” group where Rs is hydrogen, alkyl, hydroxy, or alkoxy and R” is alkoxycarbonyl, as defined herein. 16 [0037] “Alkyl” means a linear saturated monovalent hydrocarbon radical of one to eight carbon atoms or a branched saturated monovalent hydrocarbon radical of three to eight carbon atoms, e.g,, methyl, ethyl, propyl, 2-propyk butyl (including all isomeric forms), or pentyl (including all isomeric forms), and the like.

[0038] “Alkylamino” means a -NHR radical where R is alkyl as defined herein, or an f N-oxide derivative, or a protected derivative thereof, e.g., methylamino, ethylamino, v-propyiamino, &amp;amp;o~propylamino, π-butylamino, Ro-butylamino, fer/~butylamino, or methylamino-N-oxids, and the like.

[0039] “Alkyl aminoalkyl” means an alkyl group substituted with one or two alkylamino groups, as defined herein.

[0040] “Alkylaminocarbonyl” means a -C(O)R group where R is alkylamino, as defined herien, [0041] “Alkylcarbonyl” means a -C(O)R group where R is alkyl, as defined herein.

[0042] “Alkylcarbonylamino” means a -NRR’ group where R is hydrogen or alkyl as defined herein and R’ is alkylcarbonyl, as defined herein.

[0043] “Alkytcarbonyloxy” means an -OC(O)R group where R is alkyl, as defined herein.

[0044] “Alkylsulfonylamino” means a -NRS(O)2R’ group where R is hydrogen or alkyl as defined herein, and R’ is alkyl, as defined herein.

[0045] “Alkynyl” means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn yl and the like.

[0046] “Aminoalkyl” means an alkyl group substiuted with at least one, specifically one, two or three, amino groups.

[0047] “Aminocarbonyl” means a -C(O)NH2 group.

[0048] “Aryl” means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. Representative examples include phenyl, naphthyl, and indanyl, and the like, [0049] “Arylene” means a divalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Representative examples include phenylene, naphthylene, and indanylene, and the like. 17 [0050] “Arylalkyl” means an alkyl group, as defined herein, substituted with one or two aryl groups, as defined herein. Examples include benzyl, phenethyl, and the like.

[0051] “Carboxy ester” means a ~C(O)OR group where R is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyi, aryl or arylalkyl, each of which is defined herein. Representative examples include methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl, and the like, [0052] “Cycloalkyi” means a monocyclic or fused bicyclic, saturated or partially unsaturated (but not aromatic), monovalent hydrocarbon radical of three to ten carbon ring atoms. Fused bicyclic hydrocarbon radical includes bridged ring systems. Unless stated otherwise, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. One or two ring carbon atoms may be replaced by a -C(O)-, -C(S)-, or -C(~NH)“ group. More specifically, the term cycloalkyi includes, but is not limited to, cyclopropyl, cyciobutyl, cyclopentyl, cyclohexyl, cyclohexyi, or cyclohex enyl, and the like.

[0053] “Dialkylamino” means a -NRR’ radical where R and R’ are alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, MN-methylpropylamino or ΛζΛ’-mcthylethylammo, and the like.

[0054] “Dialkylammoalkyl” means an alkyl group substituted with one or two dialkylamino groups, as defined herein.

[0055] “Dialkylaminocarbonyl” means a -C(O)R group where R is dialkylamino, as defined herien.

[0056] “Fused-polycyclic” or “fused ring system” means a polycyclic ring system that contains fused rings and, unless otherwise indicated, can contain bridged rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ting atom of the fused-polycyclic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (/. e. saturated ring structures) can contain two substitution groups. 18 (0057] “Haloalkoxy” means an -OR’ group where R’ is haloalkyl as defined herein, e.g., trifluoromethoxy or 2&gt;2,2-trifluoroethoxy; and the like.

[0058] “Halogen” or “halo” means fluoro, chloro, bromo and iodo.

[0059] “Haloalkyl” means an alkyl group, as defined herein, that is substituted with one or more halogens, preferably one to five halo atoms. Representative examples include trifiuoromethyl, difluoromethyl, l-chloro fluoro-ethyl, and the like.

[0060] “Heteroaryl” means a monocyclic, fused hicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O)„- (n is 0, 1, or 2), -N-, -N(RX)-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(™NH)- group. R.x is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting, &amp;#970;η particular, when the point of valency is located on the nitrogen, Rx is absent. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazoiyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-17f-mdol~2-yl or 2,3-dihydro-17/-indol yl, and the like), isoindolyl, indolinyi, isoindolinyl, benzimidazolyl, benzodioxol yl, benzofuranyl, cinnolinyl, indolizinyl. naphthyridin yl, phthalazin yl, phthalazin yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrabydroisoquinolinyl (including, for example, tetrahydroisoquinolin yl or tetrahydroisoquinolin yl, and the like), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin yl or pyrrolo[3,2-c]pyri din yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the derivatives thereof, orN-oxide or a protected derivative thereof.

[0061] “Hetero arylene” means a monocyclic, fused bicyclic, or fused tricyclic, divalent radical of 5 to 14 ring atoms containing one or more, preferably one, two, three, or four ring heteroatoms independently selected from -O-, -S(O)n- (n is 0,1, or 2), -N-, -N(R19)-, and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any nonaromatic rings comprising a bicyclic or 19 tricyclic radical may be replaced by a -C(0)-, -C(S)-, or -C(~NH)- group. R19 is hydrogen, alkyl, or alkenyl. Unless stated otherwise, the valencies may be located on any atom of any ring of the heteroarylene group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, Rx is absent. More specifically, the term heteroaryl includes, but is not limited to, thien-diyl, benzo[Rjisoxazol-diyl, benzo[R]isothiazol-diyl, IH~ indazol-diyl (optionally substituted .at the NI position with R19), benzo [ifjoxazol-diyl, benzo[c(|thiazol-diyl, l/i-benzo[R]imidazol-diyl (optionally substituted at the NI position with Ri9), l/Rbenzo[Rj[l,2.3]triazol-diyl (optionally substituted at the NI position with R19), imidazo[l,2-iz]pyridin-diyl, cinnolin-diyl, qumolin-diyl, pyridin-diyl, l-oxido-pyridin-diyl, [l,2,4]triazolo[4,3~a]pyridin-diyl, and 2,3-dihydroimidazo[l,2-a]pyridin-diyl, and the like. [0062J “Heteroeycloalkyl” means a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group of 3 to 8 ring atoms or a saturated or partially unsaturated (but not aromatic) monovalent fused bicyclic group of 5 to 12 ring atoms in which one or more, specifically one, two, three, or four ring heteroatoms independently selected from 0, S(O)n (n is 0, 1, or 2), N, N(Ry) (where Ry is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms being carbon. One or two ring carbon atoms may be replaced by a ~C(O)“, -C(S)~, or -C(=NH)- group. Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. When the point of valency is located on a nitrogen atom, Ry is absent. More specifically the term heteroeycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-l//-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazmyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and the derivatives thereof and N~oxide or a protected derivative thereof, [0063] “Hydroxyalkyi” means an alkyl, as defined herein, substituted with at least one, preferably one, two, or three, hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl) methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, l-(hydroxymethyl)-2~hydroxyethyl, 2,3-dihydroxybutyI, 20 3,4-dihydroxybutyl and 2-(hydroxymethyl) hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1 -(hydroxyrnethyI) hydroxyethyl, and the like.

[0064] “Hydroxyamino” means a -'NH(OH) group.

[0065] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. “Optionally substituted ” refers to all subsequent modifiers in a term. So, for example, in the term “optionally substituted arylCug alkyl,” both the “C|_g alkyl” portion and the “aryl” portion of the molecule may or may not be substituted, A list of exemplary optional substitutions is presented below in the definition of “substituted.” [0066] “Optionally substituted alkoxy” means an -OR radical where R is optionally substituted alkyl as defined herein. Representative examples include -OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH(NH2)CH3, and the like.

[0067] “Optionally substituted alkyl” means an alkyl radical, as defined herein, optionally substituted with one or more group(s), specifically one, two, three, four, or five groups, independently selected from alkyl carbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylaminocarbonyl, alkoxy, aikenyloxy, halo, hydroxy, hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy, -S(0)o_2-alkyl, ~S(0)o-2~aIkenyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, -NRcS(O)2~alkyl (where Rc is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, aikenyloxy, or cyanoalkyl), alkylaminocarbonyloxy. dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkyl amincalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino, alkyl aminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and -C(O)NRaRb (where Ra and Rb are independently hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy, aikenyloxy, or cyanoalkyl).

[0068] “Optionally substituted aryl” means an aryl group, as defined herein, which is optionally substituted with one, two, three, four, of five groups selected from halo, haloalkyl, haloalkoxy, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycioalkyl, optionally substituted heterocyclo alkyl, optionally substituted heteroaryl, -C(O)NR’R” (where R’ is hydrogen or 21 aikyl and R” is hydrogen, aikyl, aryl, heteroaryl, or heterocycloalkyl), -NR’C(O)R” (where R’ is hydrogen or alkyl and R” is alkyl, aryl, heteroaryl, or heterocycloalkyl), and ~NHS(O)2R’ (where R’ is alkyl, aryl, or heteroaryl), [0069] ‘Optionally substituted arylalkyl means an alkyl group substituted with one or two optionally substituted aryl group(s) as defined herein.

[0070] “Optionally substituted arylalkyloxy” means an -OR group where R is optionally substituted arylalkyl, as defined herein.

[Θ071] “Optionally substituted arylalkyloxycarbonyl” means a -C(O)R group where R is optionally substituted arylalkyloxy, as defined herein.

[0072] “Optionally substituted aryloxy” means an -OR group where R is optionally substituted aryl, as defined herein.

[0073] “Optionally substituted aryloxycarbonyl” means a -C(O)R group where R is optionally substituted aryloxy as defined herein.

[0074] “Optionally substituted cycloalkyl” means a cycloalkyl radical, as defined herein, that is optionally substituted with one, two, three, or four groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkoxy, oxo, hydroxy, cyano, nitro, amino, mono(Cj~C6)alkyl amino, dialkylamino, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl dialkylaminoalkyl, carboxy, carboxy ester, cycloalkyl, hydroxyalkyl, -C(O)NR/R” (where R’ is hydrogen, alkyl, hydroxy, or alkoxy and R” is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), optionally substituted heterocycloalkyl, optionally substituted heteroaryl, -NR’C(O)R” (where R’ is hydrogen or alkyl and R” is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O)2R’ (where R’ is alkyl, aryl, or hetercyclyl), [0075] “Optionally substituted cycloalkyloxycarbonyl” means a -C(O)OR group where R is optionally substituted cycloalkyl as defined herein.

[0076] “Optionally substituted heteroaryl” means a heteroaryl group, as defined herein, optionally substituted with one, two, three, four, or five groups selected from halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, heteroaryl, optionally substituted aryl, -C(O)NR’R” (where R’ is hydrogen or alkyl and R” is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), ~NR’C(O)R” (where R’ is hydrogen or alkyl and R” is alkyl, aryl, heteroaryl, or heterocycloalkyl), and -NHS(O)2R’ (where R’ is alkyl, aryl, or heteroaryl).

[0077] “Optionally substituted heterocycloalkyl” means a heterocycloalkyl ring, as defined herein, optionally substituted with one, two, three, four, or five groups selected from 22 halo, haloalkyl, haloalkoxy, hydroxy, oxo, alkyl, alkenyl, alkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, arylalkyloxy carbonyl, cyclo alkyloxycarbonyl, cycloalkylalkyloxycarbonyl, ~C(O)NR’R” (where R’ is hydrogen or alkyl and R” is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl), ~NR’C(O)R” (where R’ is hydrogen or alkyl and R” is alkyl, aryl, heteroaryl, or heterocycloalkyl), amino, alkylamino, dialkylamino, and -NHSfOfiR’ (where Rf is alkyl, aryl, or heteroaryl).

[0078] "Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7-aza-bicyclo[2.2.l]heptane, and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class “saturated bridged ring system.” [0079] “Spiro”, “Spirocyclyl” or “spiro ring” refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below, a ring atom of a saturated bridged ring system (rings B and B’), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.

<img img-format="tif" img-content="drawing" file="IL229136AD000214.tif" id="idf0014" />

[0080] “Yield” for each of the reactions described herein is expressed as a percentage of the theoretical yield.

[0081] “Patient” for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a specific embodiment the patient is a mammal, and in a more specific embodiment the patient is human.

[0082] “Kinase-dependent diseases or conditions" refer to pathologic conditions that depend on the activity of one or more protein kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities including proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activities include tumor growth, the pathologic neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is 23 involved such as ocular diseases (diabetic retinopathy, age-related macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).

[0083] While not wishing to be bound to theory, phosphatases can also play a role in "kinase-dependent diseases or conditions” as cognates of kinases; that is, kinases phosphorylate and phosphatases dephosphorylate, for example protein substrates. Therefore compounds of the invention, while modulating kinase activity as described herein, may also modulate, either directly or indirectly, phosphatase activity. This additional modulation, if present, may be synergistic (or not) to activity of compounds of the invention toward a related or otherwise interdependent kinase or kinase family. In any case, as stated previously, the compounds of the invention are useful for treating diseases characterized in part by abnormal levels of cell proliferation (/. e. tumor growth), programmed cell death (apoptosis), cell migration and invasion and angiogenesis associated with tumor growth, [0084] “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.

[0085] “Cancer” refers to cellular-proliferative disease states, including but not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular 24 carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis defornians), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal Glands: neuroblastoma. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above-identified conditions.

[0086] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19.

[0087] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifiuoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic 25 acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesul fonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy ene-'l -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylic acid and the like, [0088] Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, hut are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, W-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0089] “Prodrug” refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cyeloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six 26 carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0090] " Metabolite" refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8.sup.th Ed., Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.

[0091] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.

As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art.

Embodiments of the Invention [0092] In one embodiment of the Invention, R7 is halo and all other groups are as defined in the Summary of the Invention for Group A, Group B, Group C, or Group D. In a more specific embodiment, R7 is iodo or bromo. In an even more specific embodiment, R7 is iodo. 27

Yet even more specifically, the compound is that where R? is iodo or bromo and all other groups are as defined in the Summary of the Invention for Group A.

[0093] In another embodiment of the Invention, X is halo and all other groups are as defined in the Summary of the Invention for Group A, Group B, Group C, or Group D. In a more specific embodiment, X is fluoro or chloro. In an even more specific embodiment, X is fluoro. Yet even more specifically, the compound is that where X is fluoro or chloro and all other groups are as defined in the Summary of the Invention for Group A.

[0094] In another embodiment of the Invention, R7 and X are halo and all other groups are as defined in the Summary of the Invention for Group A, Group B, Group C, or Group D. More specifcally, R7 is iodo and X is fluoro. Even more specifically, the compound is that where R7 is iodo and X is fluoro and all other groups are as defined in the Summary of the invention for Group A, [0095] In another embodiment of the Invention, R1, R2, R5, and R6 are hydrogen and all other groups are as defined in the Summary of the Invention for Group A, Group B, Group C, or Group D. More specifically, R1, R2, R5, and R6 are hydrogen and all other groups are as defined in the Summary of the Invention for Group A.

[0096] In another embodiment of the Invention, the compound of Formula I is selected from Group A where all groups are as defined in the Summary of the Invention.

[0097] In another embodiment of the invention (Al), X and R7 are halo and all other groups are as defined in the Summary of the Invention for a compound of Group A.

[0098] In another embodiment (A2), the compound of Fonnula I is selected from Group A where Rw and R12 are independently hydrogen or halo. In a more specific embodiment, R10 and Ri2 are independently hydrogen or fluoro. More specifically, R10 is 3-fluoro and R12 is hydrogen. In another more specific embodiment, R10 and R12 are fluoro, more specifically, 3-fluoro and 4-fluoro, 4-fluoro and 5-fluoro, or 4-fluoro and 6-fluoro, [0099] In another embodiment of the invention (A3), the compound is that where R1, R2, R5 and R6 are hydrogen and all other groups are as defined in the Summary of the Invention for Group A.

[00100] In another embodiment (A4), the compound of Formula I is selected ftom Group A where X, R7, and A are as defined in the Summary of the Invention; and one of R1, R2, R3, R4, R5, and R6 is halo, nitro, -NRSR8’, -OR8, -NHS(O)2Rs, -CN, -S(O)mRs, -S(O)2NR8R8’, -C(O)R8, -C(O)ORs, -C(O)NRsR8', -NRsC(O)OR8’, -NR8C(O)NRsR8”, -NR8C(O)OR8’, -NR8C(O)Rs&gt;, -CH2N(R25)(NR25aR25b), ~CH2NR25C(~NH)(NR23aR25b), -CH2NR25C(-NH)(N(R25a)(NO2)), 28 -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(-NH)(R25), -CH2NR25C(NR25aR25b)~CH(NO2), alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycioalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NR8RS&gt;, -NRsS(O)2R9, -CN, ~S(O)mR9, -C(O)RS, -C(O)OR8, -C(O)NR8Rs&gt;NR8C(O)NR8’Rs,’-NRsC(O)OR8, and ~NR8C(O)Rs ; and the others of R1, R2, R3, R4, R5, and R6 are as defined in the Summary of the Invention; or one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R5 and R6 together with the carbon to which they are attached forms C(O) or C(“NOH); and the others of R1, R2, R3, R4, R5, and R6 are as defined in the Summary of the Invention.

[00101] In a more another embodiment of the Invention (A5), the compound of Formula I is selected from Group A where X, R7, and A are as defined in the Summary of the Invention; and R3 is halo, nitro, -NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8’, -C(O)R8, -C(O)ORS, -C(O)NRSR8’, -NR8C(O)OR8’, -NR8C(O)NR8'R8’’, -NR8C(O)OR8', -NRSC(O)R8', -CH2N(R2S)(NR2S“R25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R23a)(NO2)),-CH2NR25C(=NH)(N(R2Sa)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycioalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NR8R8’, -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)ORS, -C(O)NR8R8’,-NRsC(O)NR8’R8” -NRsC(O)OR8’ and -NR8C(O)R8&gt;; and R4 is as defined in the Summary of the Invention; or R3 and R4 together with the carbon to which they are attached form C(O) or C(=NOH); and R1, R2, R5 and R0 are as defined in the Summary of the invention. 29 [00102] A more specific embodiment of embodiment A5 is that where R1, R2, R5 and R6 are hydrogen, [00103] In another embodiment of the Invention (A6). the compound of Formula I is selected from Group A where X. R7, and A are as defined In the Summary of the Invention; and R3 and R4 are independently halo, nitro, -NR8R8', -OR8, -NHS(O)2Rs, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8’, -NR8C(O)OR8’, -NR8C(O)NR8'R8”, -NR8C(O)OR8’, -NR8C(O)R8', -CH2N(R25)(NR25“R25b), -CH2NR25C(=NH)(NR2S“R2Sb), -CH2NR2SC(=NH)(N(R2Sa)(NO2)), -CH2NR25C(=NHXN(R25a)(CN)))-CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloaikyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloaikyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloaikyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, ~NR8R8, -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C^NRV^^CCONR8^8”, -NR8C(O)OR8’ and -NR8C(O)R8’; or R3 and R4 together with the carbon to which they are attached form C(O) or C(”NOH); R1, R2, R5 and R6 are are as defined in the Summary ofthe Invention.

[00104] A more specific embodiment of embodiment A6 is that where R3, R2, R5 and R6 are hydrogen.

[00105] In another embodiment of the Invention (A7), the compound of Formula I is selected from Group A where X and R7 are halo; A is phenylene optionally substituted with R30 and R12 where Rw and R12 are independently hydrogen or halo; R1, R2, R5 and R6 are hydrogen; R3 is hydrogen and R4 is -NR8R8’ (where R8 is hydrogen, hydroxy, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocycloaikyl and R8’ is hydroxy, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocycloaikyl), -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8’, -C(O)R8, -C(O)OR8, -C(O)NR8R8’, -NR8C(O)OR8\ -NR8C(O)NR8’R8”, -NR8C(O)OR8’, -NR8C(O)R8’, alkenyl, and alkynyl; where the alkenyl and alkynyl are optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted 30 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NR8R8’, ~NR8S(O)2R9, -CN, -S(O)mR9, ~C(O)R8, -C(O)OR8, -C(O)NR8R8&gt;NR8C(O)NR8’R8’&gt;NR8C(O)OR8’ and -NRaC(O)R8’; or R3 and R4 together with the carbon to which they are attached form C(O) or C(~NOH); m, R8 , and R9 are as defined in the Summary of the Invention for a compound of Group A; and unless otherwise specified in this embodiment, R8 and R8’ are as defined in the Summary of the Invention for a compound of Group A.

[00106] In another embodiment of the Invention (A8), the compound of Formula I is selected from Group A where R3 is hydrogen, halo, hydroxy, alkoxy, or amino. More specifically, R is hydrogen, fluoro, hydroxy, methoxy, or amino. Even more specifically, R is hydrogen or hydroxy. Yet even more specifically, R3 is hydroxy.

[00107] In a more specific embodiment of embodiment A8, X and R7 are halo; A is phenylene optionally substituted with R10 and Ri2 where R10 and R12 are independently hydrogen or halo; R1, R2, R5 and R6 are hydrogen; and R4, is as defined in the Summary of the Invention for a compound of Group A.

[00108] Another specific embodiment of the Invention (A9) is that where the compound of Formula I is selected from Group A where R1, R2, R5 and R6 are hydrogen; R3 is hydrogen, halo, hydroxy, alkoxy, or amino; and R4 is heterocycloalkyl, heteroaryl, or alkyl substituted with -NR8R8’ where R8 and R8’ and all other groups are as defined in the Summary of the Invention for a compound of Group A.

[00109] Another specific embodiment of embodiment A9 is that where R4 is alkyl substituted with -NR8R8’ where R8 and R8’ and all other groups are as defined in the Summary of the Invention for a compound of Group A. Specifically, the compound is of Formula 1(a) or 1(b):

<img img-format="tif" img-content="drawing" file="IL229136AD000215.tif" id="idf0015" />

where R3 is as defined in A9; X, R7, R8, R8’, Rw, Ri2, R*\ and Ri6 are as defined in the Summary of the Invention for a compound of Group A. 31 [00110] Another specific embodiment of embodiment A9 is that where R4 is hetero cyclo alkyl.

[00111] in a specific embodiment of embodiment A9, the compound is that where X and R7 are halo; A is phenylene optionally substituted with R10 and Ri2 where R10 and R12 are independently hydrogen or halo; R3 is hydroxy; and R4 is alkyl substituted with -NR8R8 or R4 is heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyi, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, -OR8, -NRSR8’, -NR8S(O)2R9, -CN, ~S(O)mR9, -C(O)RS, -C(O)OR8, -C(O)NR8R8’, ~NRsC(O)NRs’Rr, -NR8C(O)OR8’ and -NR8C(O)R8’; and where m, R3, R8, R8’, R8’’, and R9 are as defined in the Summary of the invention for a compound of Group A.

[00112] in another embodiment of the Invention (A 10), the compound of Formula &amp;#938; is selected from Group A where R4 is a) hydrogen; b) -CH2N(R25)(NR25aR25b); c) -CH2NR25C(~NH)(NR25aR25fa); d) -CH2NR25C(“NH)(N(R25a)(NO2)); e) -CH2NR25C(-NH)(N(R25a)(CN)); f) -CH2NR2SC(-NH)(R25); g) -CH2NR2sC(NR25itR25b)~CH(NO2); h) alkyl; i) alkyl substituted with one or two -OR8 where R8 is hydrogen, aryl, or alkyl where the alkyl is substituted with one or two hydroxy; j) alkyl substituted with one, two, or three halo; k) alkyl substituted with nitro; l) alkyl substituted with -S(O)mR9 (where m is 0 and R9 is aryl); m) alkyl substituted with optionally substituted heterocycloalkyl; n) alkenyl; o) -NR8R8’ (where R8 and Rs&gt; are independently hydrogen; alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl substituted with one or two -NR30R30 where R30 and R30’ are independently hydrogen, alkyl, or hydroxyalkyl; alkyl 32 substituted with optionally substituted heteroaryl; or alkyl substituted with optionally substituted cycloalkyl); p) -C(O)NR8R8 (where R8 is hydrogen, alkyl, or alkenyl; and Rs&gt; is hydrogen; hydroxy; alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl substituted with optionally substituted heterocycloalkyl; alkyl substituted with -NR30R30’ where R30

*1 AT and R are independently hydrogen, alkyl, or hydroxyalkyl; or optionally substituted alkoxy); q) -NR8C(O)ORS (where R8 and R8 are independently hydrogen, alkyl, or alkenyl); r) alkyl substituted with ~NR8R8’ (where R8 is hydrogen, alkyl, alkenyl, alkynyl, or alkyl substituted with one or two hydroxy; and R8 is hydrogen; hydroxy; alkoxy; alkyl; alkenyl; alkynyl; optionally substituted alkoxy; alkyl substituted with one or two hydroxy; alkyl substituted with one or two alkoxy; alkyl substituted with -NR30R30 where R30 and R30 are independently hydrogen, alkyl, or hydroxyalkyl; alkyl substituted with one or two hydroxy and one or two -NR R where R and R are independently hydrogen, alkyl, or hydroxyalkyl; alkyl substituted with one, two, three, four, or fiye halo; alkyl substituted with optionally substituted cycloalkyl; alkyl substituted with optionally substituted aryl; alkyl substituted with one or two hydroxy and one optionaiiy substituted aryl; alkyl substituted with optionally substituted heterocycloalkyl; alkyl substituted with optionally substituted heteroaryl; heteroaryl; aryl; aryl substituted with one or two hydroxy; aryl substituted with one or two alkoxy; aryl substituted with one or two halo; aryl substituted with one or two -NR32C(O)R32a where R32 is hydrogen or alkyl and R32a is alkyl, alkenyl, alkoxy, or cycloalkyl; aryl substituted with -NR34SO2R34a where R34 is hydrogen or alkyl and R34a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl substituted with one or two hydroxy; cycloalkyl substituted with one or two hydroxy and one or two hydroxyalkyl; cycloalkyl substituted with one or two alkoxy; cycloalkyl substituted with carboxy; cycloalkyl substituted with ~C(O)NR33R33a where R33 is hydrogen or alkyl and R33a is alkyl, alkenyl, alkynyl, or cycloalkyl; alkyl substituted with -C(O)NR33R33a where R33 is hydrogen or alkyl and R33° is alkyl, alkenyl, alkynyl, or cycioalkyl; cycloalkyl substituted with optionally substituted cycioalkyl; heterocycloalkyl; heterocycloalkyl substituted with alkyl; heterocycloalkyl substituted with alkoxycarbonyl; heterocycloalkyl substituted with optionally substituted arylalkyl; heterocycloalkyl substituted with one or two hydroxy; heterocycloalkyl substituted with one or two alkoxy; heterocycloalkyl 33 substituted with one or two hydroxyalkyl; heterocycloalkyl substituted with one or two hydroxy, one or two alkoxy, and one or two hydroxyalkyl; alkyl substituted with optionally substituted aryloxy; alkyl substituted with -S(O)nR31 where n is 0 and R3i is alkyl; alkyl substituted with carboxy; alkyl substituted with alkoxycarbonyl; or alkyl substituted with -NR32C(O)R32a where R32 is hydrogen or alkyl and R32a is alkyl, alkenyl, alkoxy, or cycioalkyl); s) -NR8C(O)R8 (where R8 is hydrogen, alkyl, or alkenyl; and R8’ is hydrogen; alkyl; alkyl substituted with one or two hydroxy; alkyl substituted with optionally substituted heterocycloalkyl; alkyl substituted with -NR30R30&gt; where R30 and R30 are independently hydrogen, alkyl, hydroxyalkyl, or alkenyl); t) cycioalkyl; u) cycioalkyl substituted with -NRSR8’ where R8 and R8’ are independently hydrogen, alkyl, or alkenyl; v) heierocycloalkyl; w) heierocycloalkyl substituted with -NR3R8’ where R8 and R8 are independently hydrogen, alkyl, or alkenyl; x) hetero cycioalkyl substituted with one or two alkyl; y) heterocylcloalkyl substituted with ~C(O)OR8 where R8 is alkyl or alkenyl; z) alkyl substituted with ~NR8C(O)R8’ (where R8 is hydrogen, alkyl, or alkenyl and R8 is alkyl; alkenyl; or alkyl substituted with alkoxy, aryl, and one, two, or three halo); aa) heteroaryl; bb) heteroaryl substituted with -NRSR8’ where R8 and R8’ are independently hydrogen, alkyl, or alkenyl; alkyl substituted with optionally substituted heteroaryl; cc) alkyl substituted with -NR8S(O)2R9 where R8 is hydrogen, alkyl, or alkenyl and R9 is alkyl or alkenyl; dd) alkyl substituted with ~NR8C(O)OR8’ where R8 and R8’ are independently hydrogen, alkyl, or alkenyl; ee) alkyl substituted with one aryl and one -NR8R8 where R8 and R8 are independently hydrogen, alkyl, or alkenyl; or ft) alkyl substituted with one or two -OR8 (where R8 is hydrogen) and one or two ~NR8R8 where R8 and R8’ are independently hydrogen, alkyl, or alkenyl.

[00113] Even more specifically, R4 is hydrogen, -CH2N(H)(NHCH3), -CH2NHC(=NH)(NH2), -CH2NHC(=NH)(NHNO2), -CH2NHC(-NH)(NHCN), -CH2NHC(-NH)(phenyl), -CH2NHC(NH2)-CH(NO2)9 methyl, ethyl, hydroxymethyl, 34 2.3-dihydroxypropyl, 3-hydrOzXy methyl-prop yk 77-(1 -methoxy-prop~2-yl)~aminomethyl, A'-Cethoxypropyri-aminomethyl, M-(ethoxyethyl)-aminomethyI, 77-(2,2-dimethoxyethyl)-aminomethyl, 77-(methoxyethyl)-aminomethyl, 77-(isopropxyethyl)-aminomethyl, trifluoromethyl, 1-nitro-ethyl, 1-methyl nitro-ethyl, 1-nitro-propyl, 3-methyl-l-nitro-butyl, phenylthiomethyl, allyl, ethenyl, 2-methylthio-ethylaminomethyl, 3-methylthio-propylaminomethyl, N“(W-butoxycarbonyiaminopropyl)-aminomethyl,77-(l-carboxyethyi)-aminomethyl, 77-(1 J?-earboxyefhyl)-aminomethyl, //-(LS-carbaxy ethyl)-aminomethyl, 77-(1-methoxycarbonylethyO-aminomethyl, ~NH2, -NH(CH2)3CH3, -NHCH3, -NH(CH2CH3), -NHCH2CH(CH3)2, -NHCH2CH2OH, -NHCH2CH2CH2NH2, -N(CH3)CH2CH2(heteroaryl), -NHCH2(cycloalkyI), -C(O)NH2, -C(O)NHOH, -C(O)NH(OCH2CH(OH)CH2OH), -C(O)NH(CH2)3CH3, -C(O)NHCH2CH=CH2, -C(O)NHCH2CH3, -C(O)NHCH2CH2OH, -C(O)NHCH2CH(OH)CH2OH, -C(O)NHCH2CH2CH(OH)CH2OH, -C(O)NHCH2CH2(piperidin-l-yl), -C(O)NH(phenyl), -C(O)NHCH2CH2N(CH2CH3)2, -NHC(O)OC(CH3)3, -NHC(O)OCH3, azetidinylmethyl, pyrrolidinylmethyl, 3-hydroxy-pyrrolidinylmethyl, 2-(methoxymethyl)-pyrrolidinyimethyl, 26L(meihoxymetbyl)-pyrroiidinyhnethyl, 2J?-(methoxymethyl)-pyrrolidinylmethyl, morpholinylmethyl, hydroxypiperidinylmelhyl, 4-alkyl-piperazinylmethyl, 4-alkyl-homopiperazinylmethyl, 4-(heterocycloalkyl)-piperidinylmethyl,4-(dialkylaminoalkyl)-piperazinylmethyl,77-hydroxyaminomethyl, 77-methoxyaminomethyl, 77-ethoxyaminomethyl, 77-ethylaminomethyl, l-(/7-ethyl-amino)-ethyl, 77,77-diethylaminomethyl, 77,77-dimethylaminomethyl, aminomethyl, 1-amino-ethyl, IF-amino-ethyl, 15-amino-ethyl, l_(methylamino)-ethyl, 1-(77,77-dimethylamino)-ethyl, 1-amino methyl-ethyl, 1-aminopropyl, 15-aminopropyl, lR-aminopropyl, 77-(n-propyl)-aminomethyl, 77-(isopropyl)-aminomethyI, 2-(77-isopropylamino)-ethyl, 3-(77-isopropylamino) methyl-prop yl, 1 -(77-ethyl-amino)-propyl, l-(77,77-diethyI-amino)-propyl} 1-aminobutyl, 1-amino-isobutyl, 77-(2-aminoethyl)~ aminomethyl, 77-(n-butyl)-aminomethyl, 77-isobutylaminomethyl, Zeri-butylaminomethyl, 1 -(V/7-butylamino)-ethyl, xac'-butylaminomethyl, 77-(2-methyl~but yl)-aminomethyl, 77-(3,3-dimethyl-butyl)-aminomethyl,77-(3-methylbut yl)-aminomethyl, 77-(2-methylbutyl)-aminomethyl, 77-(pent~3-yl)-ammomethyl, n-pentylaminomethyl, isopentylaminomethyl, .^c-pentylaminomethyl, neopentylaminomethyl, 77-(2,2,4-trimethyl-pent-4~yl)-aminomethyl, 77-(2-ethyl-butyl)-ammomethyl, 77-aliyl-ammomethyl, 3-methyl-but- l-yn ylaminoraethyl, 77-(2,3-dihydroxypropyloxy)-aminomethyl, 77-cyclopropylaminomethyl, 77-cyclobutylaminomethyI, 77-cyclopentylammomethyl,77-cyclopenten yiannnomethyl, 7V-(l(&amp;amp;S)-hydroxy-cyclopent yl)-aminomethyl,77-(15-hy&lt;froxy-cyclopent yl)- 35 aminomethyl, A'-(lR-hydroxy-cyclopent yl)-aminomethy], #-(l(R6&gt;hydroxy-l -methyl-cyclopent yl)-aminomethyl, Λ^Ι Ahydroxy-l -methy l-cyclopemt~2-yl)-aminomethyl? 77-( 1R~ hydroxy-1 -methyl-cyclopent yl)-aminomethyl, 77-(3,4-dihydroxy-eyclopentyl)-aminomethyl, W-(l-hydroxymethyl-cyclopent~l-yl)-aramomethyl, 77-(2,3-dihydroxy~4-hydroxymethybcyclopentyl)-aminomethyl, 77-(1 (A^-methoxy-cyclopent yl)-aminomethyl, 77-(1 iS'-methoxy-cyclopent y l)-aminomethyl, 77-( 17?-methoxy-cy clopent yl)-aminomethyl, 77-(1 -carboxy-cyclopentyl)-aminomefhyl, 77-cyclohexylamwomethyI, /7-(1 (7?,5)-hydroxy-cyclohex yl)-aminomethyl,77-(c&amp;amp; hydroxy-cyclohexyl)-aminomethyl, N-(trans-A-hydroxy-cyelohexyl)-affiinomethy], 1 -[A7-(6'/,s' hydroxy-cyclohexyi)-amino]'-ethyl, 1-[T7-(/raz75 hydroxy-cyclohexyl)-amino]“ethyl, 77-(1 (7?)-hydroxy-cyclohex~2-yl)~ aminomethyl, 77-( 1 (5)~hydroxy-cyclohex yl)-aminomethyl, 77-( 1 -hydroxymethyl-cyclohexyl)-aminomethyl, 77~(2-cyclohexyl-cyclohexyl)-ammomethyl, 77- {(2λ,35,4Λ,67?) (hydroxymethyl)-3,4-dihydroxy methoxy-tetrahydro-277“pyran yl}-aminomethyl, 77-(cycloheptyl)-aminomethyl,77-(cyclooctyl)-aminomethyl, [(lr,3r,57?,77?)- tricyclo[3.3.1.1 ~3,7~]dec~2-ylamino]methyl, /7-[l~(cycIopropylaminocarbonyl)-cyclopentyl]~ aminomethyl, -CH2NHC(CH3)2C(O)NH(cyclohexyl), -CH2NHC(CH3)2C(O)NH(CH2CH3), 77-( 1 -benzyloxy-cyclopent yl)-aminomethyl, 77-(cyclopropylmethyl)-arainomethyi, 77-(cyclohexylmethyl)-aminomethyl, 77-(1 -cyclohexylethyl)-aminomethyl, 77-(imidazolyl)-aminomethyl, 77-(l,3,5-triazinyl)-aminomethyl, /7-(5-hydroxy-pyrazol yl)-aminomethyl, 77-(5-methyl-pyrazol yl)-aminomethyl,77~(benzimidazolyl)-aminomethyl, 77-(pyrimidin yl)“ aminomethyl, 77-(pyridin yl)-aminomethyl, 77-(pyridin yl)-aminomethyl, 77-(pyridin yl)-aminomethyl, 77-indan- 1-yl-aminomethyl, 77-indan yl-aminomethyl, phenylaminomethyl,77-(2-hydroxyphenyi)-aminomethyl, 77-(3-hydroxyphenyl)-aminomethyl, 77-(4-hy droxyphenyl)-aminomethyl, 77-(2-methoxyphenyl)-aminomethyl, 77-(3-methoxyphenyl)-aminom ethyl, 77-(4-methoxyphenyl)-aminomethyl,77-(2-fhiorophenyl)-aminomethyl, 77-(3-fluorophenyl)-aminomethyl, 77~(4-fluorophenyl)-aminomethyl, 77-(2-chlorophenyl)-aminomethyl, 77- (3 -chlorophenyl)~aminomethyl, 77-(4-chlorophenyl)-aminomethyl, 77-(3 -methylcarbonylamino-phenyl)-aminomethyl, 77-(4-methylcarbonylammo-phenyl)-aminomethyl, 77-(2-aminophenyl)~aminomethyl, 77-(3-aminophenyl)-aminomethyI, 77-(4-aminophenyl)-aminomethyl,77-(2-methylsuifonylaminophenyl)-aminomethyl,77-(3-methylsulfonylaminophenyl)-aminomethyl, 77-(4-methylsulfonylaminophenyl)-ammomethyl, 77-(2-flnoro hydroxy-phenyl)-ammomethyl,77-(3-fluoro hydroxy-phenyl)-aminomethyl, 77-(benzy 1)- aminomethyl, 77-(2-hy droxyphenylmethyl)-aminomethyl, 77-(3 -hydroxyphenylmethyl)-aminomethyl, 77-(4~hydroxyphenylmethyl)-aminomethyl, 77-(2-(77- 36 methylpiper azin-1 -yl)-phenylmethyl)-aminomethyl3 W“(4-alkyI~phenethyl)~aminomethyl, /7-( 1 -hydroxy-3 -phenyl-pr0p yl)-aminoniethyl&gt; /7-(pyn'oHdin ylmethyl)-aminomethyl, /7-(/V-alkyl-pyrrolidinyimethyl)-aminomethyl, A'AV-alkyi-pynOlidinylethyl)-aminomelhyl, //-(pyrrolidmylpropyl)-ammomethyl, /7-(1,1 -dimethyl pyrrolidin-l -yl~ethyl)-aminomethyk N- (tetrahydrofur anylmethy l)-aminomethy k /7-(tetrahydro-2ZZ~pyran ylmethyl) -aminomethyl,/7-(tetrahydro-2H-pyranylethyl)-ammomethyl,/\/-(piperidin ylmethyl)~ ami nomethyl, A-(/7-methy lpiper idin y Imethyi)-aminomethyl, NAN-tert- butoxycarbonyipiperidin yimethyl)-aminomethyl} //-(/7-methylimidazol ylmethyl)-aminornethyl, 77-(77-methylimidazol ylmethyl)-aminomethyl, /7-[2-(imidazol~4-yl)-ethyl] -aminomethyl, /V-[3-(imidazolyl)-propyl3 -aminomethyl, /7-(pyridin ylethyl)-aminomethyl, /7-(pyridin ylethyl)-aminomethyI, Ar-(thien ylethyl)-aminomethyk N-(furan ylethyl)-aminomethyl,/7-(5-methyl“l,3,4“Oxadiazol“2-ylmethyl)-aminomethyl, /7-(2-indolm~3-ylethyl)-aminomethyl, 2-(ΑζΛ-dimethylamino)-ethy.laminomethyl, 2-(/7, /V-dimethylamino) methyl-ethylaminomethyl, 3-aminopropylammomethyl, 3-(/7, /V-dimethylamino)-propylaminomethyl, 3-(/7,M-diethylamino)-propylaminomethyl, /7-(/7,^- diisopropylaminoethyl)-aminomethyl,/7-(/7,/7-dimethyiaminobutyl)-aminomelhyl,77-(3-hydroxypropyl)-aminomethyl, /7-(2~hydroxypropyl)-aminomethyl, /7-(1,2-dihydroxypropyl)-aminomethyl, /7-(1 -amino hydroxy~prop yl)-aminomethyl, /7-(/7-ethoxycarbonyl-piperidin yl)-aminomethyl,/7-(Mbenzylpiperidin yl)-aminomethyl, //-(homopiperi din yl)-aminomethyl, //-(//-benzylpyrrolidin~3~yl)-aminomethyl,//-(//-ethylpiperidin yl)aminomethyl, 2,2,2-trifiuoroethylaminomethyl, 3,3,3-trifluoropropylaminomethyl, 2,2,3,3,3-pentafluoropropylaminomethyl, -ClLNCCiUCITOH)?, “CH2N(CH3)(CH2CH2OH), -CH2NH(CH2CH2OH), -CH2NH(CH2CH2CH2CH2OH), -CH2N(CH3)(/7-methyl-pyrfolidin yl), -CH2NH(C(CH3)2CH2OH), -NHC(O)CH(CH3)2, -NHC(O)CH2N(CH2CH3)2, -NHC(O)CH2NH(CH3), ~NHC(O)H, -NHC(0)CH2CH(OH)CH2OH, -NHC(O)CH2NH2, -NHC(O)CH2N(CH2CH2OH)2,-NHC(O)CH2CH2N(CH2CH2OH)2,-NHC(O)CH2(4-alkyi-piperazinyl), -NHC(O)CH2(piperidinyl), //-(phenyloxyethyl)-aminomethyi, cyclopentyl, l-amino-cyclopentyl, (myramj~2-ainmo-cyclopentyh (c7'yfrau0j amino-cyclopentyk cTs~2~ amino-cyclopentyl, 0YU7,s' mnino-cyclopentyk (c/y/ramj hydroxy-cycIohexyI, cis hydroxy-cyclohexyl, GYw,y hydroxy-cyclohexyl, (6v'y/w/wj aniino-cyclohexyl, cis amino-cyclohexyl, ?m?v2~amino~cyclohexyl, azetidin yl, pyrrolidinyl, //-alkyl-pyrrolidinyl, 3-(dialkylamino)-pyrrolidinyl, piperidinyl, 2-methyl-piperidin yl, N-tert-butoxycarbonylptperidm~2-yl, piperazinyl, -CH2NHC(O)CH3, ~CH(CH3)NHC(O)CH3, ~CH(CH3)NHC(O)C(OCH3)(CF3)phenyI, pyrrol yi, pyrrol yl, pyrrol yl, imidazol yl, 37 imidazoI yl, imidazol yl, imidazol yl, M-methyl-imidazol^-yl, 5-methyl-imidazol~2~yk l,2,4-triazoI yl, thiazol yl, 2-aminopyrimidin -yl, pyridinyl, benzimidazolyl, imidazol- l-ylmethyl, imidazol ylmethyl, triazolylmethyl, (5-ammo~3-methyipyrazol~l-yl)“methyl, phenoxymethyl, methylsulfonylaminomethyl, R(methoxycarbonylajnino)-ethyL 1-amino- I-phenyl-methyl, or l-amino hydroxy-propyl.

[00114] A more specific embodiment of embodiment A10 is that wherein X and R7 are halo; A is phenylene optionally substituted with R10 and R12 where R10 and R12 are independently hydrogen or halo; R1, R2, R5 and R6 are hydrogen; and R3 is hydrogen, halo, hydroxy, alkoxy, or amino.

[00115] A more specific embodiment of embodiment A10 is that where R3 is hydrogen and R4 is a) hydrogen; b) ~NR8Rs’ (where Rs and R8 are independently hydrogen; alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl substituted with one or two -NR30R30 where R30 and R30’ are independently hydrogen, alkyl, or hydroxyalkyl; alkyl substituted with optionally substituted heteroaryl; or alkyl substituted with optionally substituted cycloalkyl); c) -C(O)NRSR8’ (where R8 is hydrogen, alkyl, or alkenyl; and Rs is hydrogen; hydroxy; alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl substituted with heterocycloaikyl; alkyl substituted with -NR3GR30 where R30 and R30 are independently hydrogen, alkyl, or hydroxyalkyl; or optionally substituted alkoxy); d) ~NR8C(O)OR8’ (where Rs and R8’ are independently hydrogen, alkyl, or alkenyl); e) -NRSC(O)R8’ (where R8 is hydrogen, alkyl, or. alkenyl; and R8 is hydrogen; alkyl; alkyl substituted with one or two hydroxy; alkyl substituted with optionally substituted heterocycloaikyl; alkyl substituted with -NR3OR30 where R30 and R30 are independently hydrogen, alkyl, hydroxyalkyl, or alkenyl); f) alkyl; g) alkyl substituted with one or two -OR8 (where R8 is hydrogen); h) alkyl substituted with -NR8R8’ (where R8 is hydrogen, alkyl, alkenyl, alkynyl, or alkyl substituted with one or two hydroxy; and R8’ is hydrogen; alkyl; alkenyl; alkynyl; alkyl substituted with one or two hydroxy; heterocycloaikyl substituted with alkyl; or alkyl substituted with -NR30R30’ where R30 and R30’ are independently hydrogen, alkyl, or hydroxyalkyl); 1) heterocycloaikyl; or 38 j) heterocycloalkyl substituted with -NRSR8’ (where R8 and R8’ are independently hydrogen, alkyl, or alkenyl).

[00116] Even more specifically, R3 is hydrogen and R4 is hydrogen, hydroxymethyl, -NH2, -NH(CH2)3CH3, -NHCH3, -NH(CH2CH3), -NHCH2CH(CH3)2, -NHCH2CH2OH, -NHCH2CH2CH2NH2, -N(CH3)CH2CH2(pyridin yI), -NHCH2(cyclopropyl), ~NHCH2(cyclopentyl), -NHCH2(cyclohexyl), ~C(O)NHOH, -C(O)NH(OCH2CH(OH)CH2OH), -C(O)NH(CH2)3CH3, -C(O)NHCH2CH-CH2, -C(O)NHCH2CH3, -C(O)NHCH2CH2OH, -C(0)NHCH2CH(OH)CH2OH, -C(O)NHCH2CH2CH(OH)CH2OH, -C(O)NHCH2CH2(piperidin~l~yl), -C(O)NH(phenyl), -C(O)NHCH2CH2N(CH2CH3)2, /V-(isopropyl)-aminomethyl, MMdimethylaminomethyl, N~ (2-aminoethyl)-aminomethyl, -NHC(O)OC(CH3)3, -NHC(O)OCH3, -NHC(O)CH(CH3)2, -NHC(O)CH2NH2, -NHC(O)CH2N(CH2CH3)2, -NHC(O)CH2NH(CH3), -NHC(O)H, -NHC(O)CH2CH(OH)CH2OH,-NHC(O)CH2N(CH2CH2OH)2, -NHC(O)CH2CH2N(CH2CH2OH)2,-NHC(O)CH2(4-alkyl-piperazinyl), -NHC(O)CH2(piperidinyl), pyrrolidinyl, 3-(dialkylamino)-pyrroIidinyl, piperidinyl, 2-methyl-piperidin yl, A-methylpiperidin yl, or piperazin vl, [00117] A more specific embodiment of embodiment A10 is that where R3 is alkoxy and R4 is alkyl substituted with -NR8R8’ (where R8 and R8’ are independently hydrogen, alkyl, or alkenyl). More specifically, R3 is methoxy and R4 is alkyl substituted with -NR8R8 (where R8 and R8’ are independently hydrogen, alkyl, or alkenyl).

[00118] A more specific embodiment of embodiment A10 is that where R3 is halo and R4 is alkyl substituted with -NRSR8’ (where R8 and R8’ are independently hydrogen, alkyl, or alkenyl). More specifically, R3 is fluoro and R4 is alkyl substituted with -NR8R8 (where R8 and R8 are independently hydrogen, alkyl, or alkenyl).

[00119] A more specific embodiment of embodiment A10 is that where R3 is amino and R4 is alkyl substituted with -NR8R8 (where R8 and R8 are independently hydrogen, alkyl, or alkenyl).

[00120] A more specific embodiment of embodiment A10 is that where R3 is hydroxy and R4 is a) hydrogen; b) -CH2N(R25)(NR25aR25b); c) -CH2NR25C("NH)(NR25aR25b); d) -CH2NR25C(=NH)(N(R25a)(NO2)); e) -CH2NR25C(-NId)(N(R25a)(CN)); 39 f) -CH2NR25C(=NH)(R2S); g) -CH2NR25C(NR25aR25b)=CH(NO2); h) alkyl; i) alkenyl; j) alkyl substituted with one or two -OR8 where R8 is hydrogen, aryl, or alkyl where the alkyl is substituted with one or two hydroxy; k) alkyl substituted with one, two, or three halo; l) aikyl substituted with nitro; m) alkyl substituted with -S(O);r,R9 (where m is 0 and R9 is aryl); n) alkyl substituted with optionally substituted hetero cycloalkyl; o) alkyl substituted with -NR8R8 (where R8 is hydrogen, alkyl, alkenyl, alkynyl, or alkyl substituted with one or two hydroxy; and R8’ is hydrogen; hydroxy; alkoxy; alkyl; alkenyl; alkynyl; optionally substituted alkoxy; alkyl substituted with one or two hydroxy; alkyl substituted with ~NR30R30’ where R30 and R30 are independently hydrogen, alkyl, or hydroxyalkyl; alkyl substituted with one or two hydroxy and one or two -NR30R30’ where R30 and R30’ are independently hydrogen, alkyl, or hydroxyalkyl; heterocycloalkyl substituted with alkyl, alkoxycarbonyl, or optionally substituted arylalkyl; alkyl substituted with one, two, three, four, or five halo; alkyl substituted with optionally substituted cycloalkyl; alkyl substituted with optionally substituted aryl; alkyl substituted with one or two hydroxy and one optionally substituted aryl; alkyl substituted with optionally substituted heterocycloalkyl; alkyl substituted with optionally substituted heteroaryl; heteroaryl; aryl; aryl substituted with one or two hydroxy; aryl substituted with one or two alkoxy; aryl substituted with one or two halo; aryl substituted with one or two -NR C(O)R where R is hydrogen or alkyl and R32a is alkyl, alkenyl, alkoxy, or cycloalkyl; aryl substituted with -NR34SO2R34a where R34 is hydrogen or alkyl and R34a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl substituted with one or two hydroxy; cycloalkyl substituted with one or two hydroxy and one or two hydroxyalkyl; cycloalkyl substituted with one or two alkoxy; cycloalkyl substituted with carboxy; cycloalkyl substituted with ~C(O)NR33R33a where R33 is hydrogen or alkyl and R33a is alkyl, alkenyl, alkynyl, or cycloalkyl; cycloalkyl substituted with optionally substituted cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted with one or two hydroxy; heterocycloalkyl substituted with one or two alkoxy; heterocycloalkyl substituted with one or two hydroxyalkyl; heterocycloalkyl 40 substituted with one or two hydroxy, one or two alkoxy, and one or two hydroxyalkyl; alkyl substituted with -C(O)NR33R33a where R33 is hydrogen or alkyl and R33a is alkyl, alkenyl, alkynyl, or cycloalkyl; alkyl substituted with optionally substituted aryloxy; alkyl substituted with -S(O)nR3! where n is 0 and R3i is alkyl; alkyl substituted with carboxy; alkyl substituted with alkoxycarbonyl; or alkyl substituted with -NR32C(O)R32a where R32 is hydrogen or alkyl and R32tl is alkyl, alkenyl, alkoxy, or cycloalkyl); p) heterocycloaikyl; q) -C(O)NRSR8 (where R8 is hydrogen, alkyl, or alkenyl; and R8 is hydrogen; alkyl; alkyl; alkenyl; or substituted with one or two hydroxy;); r) alkyl substituted with -NR8C(O)R8’ (where R8 is hydrogen, alkyl, or alkenyl and R8 is alkyl; alkenyl; or alkyl substituted with alkoxy, aryl, and one, two, or three halo); s) cycloalkyl; t) cycloalkyl substituted with -NRSR8 where R8 and R8 are independently hydrogen, alkyl, or alkenyl; u) cycloalkyl substituted with -C(O)NR33R33a where R33 is hydrogen or alkyl and R33a is alkyl, alkenyl, alkynyl, or cycloalkyl; v) heterocycloaikyl; w) heterocycloaikyl substituted with one or two alkyl; x) heterocylcloalkyl substituted with -C(O)OR8 where Rs is alkyl or alkenyl; y) heteroaryl; z) heteroaryl optionally substituted with -NRSR8 where R8 and R8 are independently hydrogen, alkyl, or alkenyl; aa) alkyl substituted with optionally substituted heteroaryl; bb) alkyl substituted with -NR8S(O)2R9 where R8 is hydrogen, alkyl, or alkenyl and R9 is alkyl or alkenyl; cc) alkyl substituted with -NR8C(O)OR8’ where R8 and R8’ are independently hydrogen, alkyl, or alkenyl; dd) alkyl substituted with one aryl and one -NRSR8’ where Rs and R8 are independently hydrogen, alkyl, or alkenyl; or ee) alkyl substituted with one or two -OR8 (where Rs is hydrogen) and one or two -NR8R8’ where Rs and R8 are independently hydrogen, alkyl, or alkenyl.

[00121] Even more specifically, R3 is hydroxy and R4 is hydrogen, -CH2N(H)(NHCH3), -CH2NHC(~NH)(NH2), -CH2NHC(=NH)(NHNO2), -CH2NHC(=NH)(NHCN), 41 -CH2NHC(=NH)(phenyl), -€Η2ΝΗΟ(ΝΗ2)-ΟΗ(ΝΟ2), methyl, ethyl, hydroxymethyl, 2,3-dihydroxypropyl, 3-hydroxy methyl-prop yl, 7/-(1 -methoxy-prop-2~yl)-aminomethyl, 7/-(ethoxypropyl)-aminomethyl,7/-(ethoxyethyl)-aminomethyl,7/-(2,2-dimethoxyethyl)-aminomethyl, 7/-(methoxy ethyl)-aminomethyl, 7/-(isopropxyethyl)-aminomethyl, trifluoromethyl, 1-nitro-ethyl, 1-m ethyl nitro-ethyl, 1-nitro-propyl, 3-methyl nitro-butyl, phenylthiomethyl, allyl, ethenyl, 2-methylthio-ethylaminomethyl, 3-mefhylthio-propylaminomethyl, 7/-(Zcr/-butoxycarbonylaminopropyl)-aminomethyl, 7/-(1 -carboxyethyl)-aminomethyl, A-(17v-earboxyethyl)-aminomethyl, A-flF-carboxyethyL-aminomethyl, 7/-(1-methoxycarbonylethyl)-aminomethyl, azetidinylmethyl, pyrrolidinylmethyl, 3-hydroxy-pyrrolidinylmethyl, 2-(methoxymethyl)-pyrroiidinyImethyl, 2&gt;S'-(methoxymethyl)-pyrrolidinylmethyl, 27?-(methoxymethyl)-pyrroiidinylmethyl, morpholinylmethyl, 4-hydroxypiperidinylmethyl, 4-methyl-piperazinylmethyl, 4-methyl-homopiperazinylmethyl, 4-(piperidinyl)-piperidinyImethyl, 4- [2-(7/,7/-diethylamino)-ethyl] -piperazinylmethyl, 7/-hydroxyaminomethyl, TZ-methoxyaminomethyl, TZ-ethoxyaminomethyl, TZ-ethylaminomethyl, 1 -(7V-ethyl-amino)-ethyl, 7/ N-diethylaminomethyl, 7/,7/-dimethylaminomethyl, aminomethyl, 1-amino-ethyl, 17i-amino-ethyl, lS-amino-ethyl, 1-(methylamino)-ethyl, 1-(7/,7/-dimethylamino)~ethyl, 1-amino methyl-ethyl, 1-aminopropyl, 15'-aminopropyl, Ιλ-aminopropyl,//-(n-propyl)-aminomethyl, 7/-(isopropyl)-aminomethyl, 2-(7/-isopropylamino)-ethyl, 3-(7/-isopropylamino) methyl-prop yl, 1 -(//-ethyl-amino)-propyl, 1 -(7/, M-diethyl-amino)-propyl, 1-aminobutyl, 1-amino-isobutyl, 7/-(n-butyl)-aminomethyl, 7/-isobutylaminomeihyl, /eH-butylaminomethyl, l-(/ez7-butylaniino)-ethyl. ^ec-butylaminomethyl, 7/-(2-methyl-but yl)-aminomethyl, 7/-(3,3-dimethyl-butyl)-aminomethyl, 7/-(3-methylbut yl)-aminomethyl, 7/-(2-methylbutyl)-aminomethyl, 7/-(pent yI)-aminomethyl, n-pentylaminomethyl, isopentylaminomethyl, sac-pentylaminomethyl, neopentylaminomethyl, 7/-(2,2,4-trimefhyl-pent-4~yl)-aminomethyl, 7/-(2-ethyl-butyl)-aminomethyl, //-allyl-aminomethyl, 3-methyi-but-l~yn ylaminomethyl, 7/-(2,3-dihydroxypropyloxy)-ami nomethyl, TZ-cyclopropylaminomethyl, //-cyclopentylaminomethyl, 7/-cyclopenten ylaminomethyl, 7/-(l(7?,S)-hydroxy-cyclopent yl)-aminomethyl, 7/-(15-hydroxy-cyclopent yl)-aminomethyl, 7/-( 17?-hydroxy-cyclopent yl)-aminomethyl, 7/-(1 (7?, 5) -hydroxy-1 -methyl-cyclopent~2-yl)-aminomethyl, 7/-(1 S-hydroxy-1 -methyl-cyclopent yl)-aminomethyl, 7/-( 17?-hydroxy-1 -methyl-cyclopent yl)-aminomethyl, 7/-(3,4-dihydroxy-cyclopentyl)-aminomethyl,7/-(l-hydroxymethyl-eyclopent-l-yl)-aminomethyl, 7/-(2,3-dihydroxy hydroxymethyI-cyclopentyl)-aminomethyl,7/-(l(72j)S)-methoxy-cyclopent yl) -aminomethyl, 7/-(1 (S'-methoxy-cyclopent yl)-aminomethyl, 7/-(1 TTrn ethoxy 42 cyclopent-2qd)~aminomethyl, Ai-(l-carboxy-cyclopentyl)-aminomethyl, /V-cyclohexylaminomethyh #Xl(/h5)-hydroxy-cyclohex~2-yl)-ammomethyl., #-(1 (Rf hydroxy-cyclohex yl)-aminomethyl, A^l (5)-hydroxy~cyclohex-2~yl)-aminomethyl, N~(c/s hydroxy~cyelohexyl)-aminomethyh #-(ira^^ hydroxy-eyclohexyl)-aminomethyl, 1 -[#-(c/A hydroxy-cyclohexyl)-amino]-ethyb l-[AL(/zwM' hydiOxy-cyclohexyl)-amino]“ ethyl, #-(1-hydroxymethyl-cyclohexyl)-aminomethyl, Ar-(2-cyclohexyl-cyclohexyl)-aminomethyl, #-{(2R,35,4R,6R) (hydroxymethyl)-3,4-dihydroxy inethoxy-tetrahydro-2#-pyran- 5-yl} -aminomethyl, #-(cycloheptyl)-aminomethyl, #-(cyclooetyl)-aminomethyl, [(lr,3r,5R,77?)-tricyclo[3,3.1 .l#3,7~]dec ylammo]methyl, A-(l-benzyloxy-cyclopent yl)-aminomethyh Ar-[1-(cyclopropy laminocarbonyl)-cyclopentyl]-aminomethyl, -CH2NHC(CH3)2C(O)NH(cyclohexyl), -CH2NHC(CH3)2C(O)NH(CH2CH3), tV-(cyclopropylmethyl)-aminomethyL,jV“(cyclohexylmethyl)-aminomethyl, N~( 1 -cyclohexylethyl)-aminomethyh #~(imidazolyl)~aminomethyl, N~( 1,3,5-triazinyl)-aminomethyl, A7-(5-hy dr ox y-pyrazol yl)-aminomethyl, AL(5-methyl-pyrazol yl)-aminomethyl, #-(benzimidazolyl)-aminomethyl, Ar-(pyi-imidin yl)-aminomethyl, yV-(pyridin yl)-aminomethyl, A'-(pyridin yl)-aminomethyl, #-(pyridin yl)-aminomethyh AMndan-l~yl~ammom ethyl, #-mdan yl-aminomeihyl, phenyl aminomethyl, #-(2-hydroxyphenyl)™aminomethyl,#-(3-hydroxyphenyl)-aminomethyl,#~(4-hydroxyphenyl)-aminomethyl, #-(2~methoxyphenyl)-aminomethyl, #~(3-methoxyphenyl)-aminomethyl, #-(4-methoxyphenyl)-aminomethyl, A-(2-fiuorophenyl)-aminomethyh A'-(3-fluorophenyl)-aminomethyl, A'-(4-fluorophenyl)-aminomethyl, #-(2-chlorophenyl)-aminomethyl, #-(3-chlorophenyl)~aminomethyl, A-(4-chlorophenyl)-aminoinethyl, A-(3-methylcarbonylamino-phenyl)-aminomethyl, #-(4-methylcarbonylamino-phenyl)-aminomethyl,#-(2~ aminophenyl)~aminomethyl, #-(3-aminophenyl)-am mom ethyl, #-(4-aminopheny 1)-aminomethyl, #-(2-methylsnlfonylaminophenyl)-aminomethyl, #-(3 - methylsulfonylaminophenyl)-aminomethyl, #-(4-methylsulfonylaminophenyl)~aminomethyl, #-(2-fluoro~4-hydroxy-phenyl)-aminomethyl, #-(3~fluoro hydroxy~phenyl)-aminomethyI, #-(benzyl )-aminomethyl, #-(2-hydroxyphenylmethyl)-aminomethyl, #-(3- hydroxyphenylmethyl)-aminomethyl, #-(4-hydroxyphenylmethyl)-aminomethyl,#-(2-(#-methylpiperazin-1 -yl)-phenylmethyl)-aminomethyl, #-(4-methyl-phenethyl)-aminomethyl, #-(1 -hydroxy~3-phenyl-prop yl)-aminomethyl, #-(pyrrolidin ylmethyl)~aminomethyl, #-(#-ethyl-pyrrolidinylmethyl)-aminomethyl,#-(#-methyl-pyrrolidin ylethyl)-aminomethyl, #-(pyrrolidinylpropyl)-aminomethyl, #-(1,1 -dimethyl pyrrolidin-l -yl-ethyl)-aminomethyl, #~(tetrahydroforanylmethyl)-aminomethyl, #-(tetrahydro-2ff-pyran ylmethyl)- 43 aminomethyl, A7(tetrahydro-2/7-pyranylethyl)-aminomethyl,Ar-(piperidin ylmethyl)-aminomethyl, A/'-(yV-methylpiperidin -yImethyl)“aminomethyl,Az’-(A'“/ez7-butoxycarbonylpiperidin ylmethyl)-aminoniethyl, AfoV-methylimidazol-S-ylmethyl)-aininomethyl, JV-(A''-methyHmidazoh4-ylmethyl)--aminomethyl5 ;V-[2-(imidazoh4-yl)-ethylj-aminomethyl, A'r“[3-(lmidazolyl)-propyl]-aminomethykA/'-(j3yridin ylethyl)-aniinomethyl, 7V-(pyridin ylethyl)-aminomethyk ;V-(thien ylethyl)-aminomethyl, AY-(furan ylethyl)-aminomethyl, AL(5-methyl-l,3,4-oxadiazoh2-ylmethyl)-aminomethyl, yV-(2-indolin ylethyl)-aminomethyl, 2-(/7,77-dimethylammo)-ethylaminomethyl, 2-(77,77-dimethylamino)-1 -methyl-ethylaminomethyl, 3-ammopropylaminomethyl, 3-(77,77-dimethylamino)-propylaminomethyl, 3 -(/7,/7-diethylamino)-propylaminomethyl, /7-(77,77-diis opropylaminoethyl)- aminomethyl, N-(N, 77-dimethylaminobntyl)-aminomethyl, 3-hydroxypropylaminomethyl, N~( 1,2-dihydroxypropyl)-aminomethyl, 77-( 1 -amino hydroxy-prop yl)-aminomethyI, 77-(77-ethoxycarhonyl-piperidin yl)-aminomethyl,/7-(77-benzylpiperidin yl)-aminomethyl, 77-(homopiperidin-3 -yl)-aminomethyl, 77-(77-benzylpyrrolidm yl)-aminomethyl, 77-(77-ethylpiperidin yl)aminomethyl, 2,2,2-trifluoroethylammomethyl, 3,3,3-triflnoropropylaminomethyl, 2,2,3,3,3-pentafluoropropylammomethyl, -CH2N(CH2CH2OH)2, -CH2N(CH3)(CH2CH2OH), -CH2NH(CH2CH2OH), -CH2NH(CH2CH2CH2CH2OH), -CH2NH(C(CH3)2CH2OH), -CH2N(CFI3)(77-methyl-pyrrolidin-3 -yl), -C (O)NH2, ~C (O)NHCH2CH™CH2, ~C(O)NHCH2CH(OH)CH2OH, 77-(phenyloxyethyl)-ammomethyl, -CH2NHC(O)CH3, -CH(CH3)NHC(O)CH3, -CH(CH3)NHC(O)C(OCH3)(CF3)phenyl, cyclopentyl, 1-amino-cyclopentyl, (c/Vra/7s) amino-cyclopentyl, (mdram) amino-cyclopentyl, cw amino-cyclopentyl, Zram amino-cydopentyl, (c/y/ram)-2~hydroxy-cyclohexyl, c/s hydroxy-cyclohexyl, //w/7.v hydrox.y-cyclohexyL (cay/rams) amino-cyclohexyi, c/sU-amino-cyclohexyl, ira/w ammo-cyclohexyl, azeti din yl, pyrrolidinyl, 77-methyI-pyrrohdm yl, 77-ethyl-pyrrolidin yI, 3-(dimethylammo)~pyrrolidinyI, piperidinyk 2-methyl-piperidin yl, 77-methylpiperidin yl, 77-/erZ~butoxycarbonylpiperidm yl, piperazin yl, pyrrol yl, pyrrol yl, pyrrol yl, imidazol-l-yl, imidazol yl, imidazol yl, imidazol yl, 77-methyl-imidazol yl, 5-methyl-imidazol yI, l,2,4-triazol yl, thiazol yl, 2-aminopyrimidin yl, pyridin yl, pyridin yl, pyridin~4~yl, benzimidazolyl, imidazol ylmethyl, imidazol ylmethyl, triazol-l-ylmethyl, (5-ammo methyl-pyrazol yl)-methyl, phenoxymethyl, 2-hydroxyethyloxymethyl, methylsulfonylaminometbyl, 1-(methoxycarbonylamino)-ethyl, 1-amino-l-phenyl-methyl, or l-amino hydroxy-propyl. 44 [00122] Another specific embodiment of the Invention (All) is that where the compound of Formula I is selected from Group A where R3 and R4 together with the carbon to which they are attached form C(O) or C(~NOH), More specifically, X and R7 are halo; A is phenylene optionally substituted with Ri0 and R12 where R30 and Ri2 are independently hydrogen or halo; R\ R2, R5 and R6 are hydrogen; and R3 and R4 together with the carbon to which they are attached form C(O) or C(~NOH).

[00123] Another specific embodiment of the Invention (A 12) is that where the compound of Formula I is selected from Group A where X and R7 are halo; A is phenylene optionally substituted with R10 and Ri2 where Ri0 and R12 are independently hydrogen or halo; and R1, R2, R4, R5 and R6 are hydrogen, [00124] Another specific embodiment of the invention (A 13) is that where the compound of Formula I is selected from Group A where A is phenylene.

[00125] Another specific embodiment of the Invention (A 14) is that where the compound of Formula I is selected from Group A where R1 is hydrogen and R2 is alkyl substituted with -NRSR8’ where Rs and Rs’ and all other groups are as defined in the Summary of the Invention for a compound of Group A, [00126] Another specific embodiment of the Invention (A15) is that where the compound of Formula I is selected from Group A where A is phenylene; R7 is iodo or bromo; X is fluoro or chloro; and R1, R2, R5, and R6 are hydrogen; and Rw, R12, R14, and R16 are independently hydrogen or fluoro. More specifically, R10 is 3-fluoro and R12, R14, and R16 are hydrogen or halo; R30 is 3-fluoro, R12 is 4-fiuoro, and R14 and R16 are hydrogen; R10 is 4-fluoro, R32 is 5-fluoro, and R34 and R16 are hydrogen; Ri0 is 4-fluoro, R12 is &amp;#972;-fluoro, and R14 and R16 are hydrogen; or R12 is 4-fluoro and R10, R14, and R16 are hydrogen.

[00127] In another embodiment of the invention is a compound of Formula selected form Group A where R3 is hydroxy and R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NR8R8 (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycioalkyl where the cycioalkyl is optionally substituted with groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Specifically, R3 is hydroxy and R4 is heterocycloalkyl or alkyl, where the alkyl is optionally substituted with -NR8R8&gt; (where R8 is hydrogen or alkyl and R8’ is hydrogen, alkyl, or cycioalkyl where the cycioalkyl is optionally substituted with groups independently selected from hydroxy and alkyl), [00128] In another embodiment of the Invention (BI) the compound of Formula I is selected from Group B where all groups are as defined in the Summary of the Invention. 45 [00129] In another embodiment of the invention (B2), X and R7 are halo; and all other groups are as defined in the Summary of the Invention for a compound of Group B. Specifically, X is fluoro or chloro and R7 is iodo or bromo.

[00130] In another embodiment of the invention (B3), the compound is selected from Group B where R3 is halo, nitro, -NR8R8’, -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8’, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)ORs’, -NR8C(O)NRs’R8’’, -NRsC(O)OR8’, -NR8C(O)R8’, -CH2N(R2s)(NR2SaR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR2SC(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR2SC(=NH)(R25), -CH2NR25C(NR25aR2Sb)=CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NR8R8’, -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NRSR8', -NR8C(O)NR8’R8", -NR8C(O)OR8’ and -NR8C(O)R8' and R4 is as defined in the Summary of the Invention; or RJ and R4 together with the carbon to which they are attached form C(O) or CfrNOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B. More specifically, R1, R2, R5 and R6 are hydrogen; and X and R7 are halo, [00131] In another embodiment of the invention (B4), the compound is selected from Group B where R3 and R4 are independently halo, nitro, -NR8R8, -OR8, -NHS(O)2R8, -CN, -S(O)raR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8’, -NR8C(O)NR8'R8'', -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)),-CH2NR25C(=NH)(R23), -CH2NR23C(NR23aR23b)=CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NRsC(O)NR8’R8”, -NR8C(O)OR8' and -NR8C(O)R8’; or R3 and R4 together 46 with the carbon to which they are attached form C(O) or C(=NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B. More specifically, R1, R2, R5 and R6 are hydrogen; and X and R7 are halo.

[00132] In another embodiment of the invention (B5), A is heteroarylene selected from thien-diyl, benzo[AJisoxazol-diyl, benzofr/Jisothiazol-diyl, 1 A-indazol-diyl (optionally substituted at the NI position with R39 where R19 is as defined in the Summary of the Invention for a compound of Group B), benzo [tfjoxazol-diyl, benzo [i/Jthiazol-diyl, 1#~ benzo[d]imidazol-diyl (optionally substituted at the NI position with R19 where R39 is as defined in the Summary of the Invention for a compound of Group B), 1/A benzo [t/|[ 1,2,3]triazol~diyl (optionally substituted at the NI position with R19 where R39 is as defined in the Summary of the Invention for a compound of Group B), imidazo[l,2-tfjpyridin-diyl, cinnolin-diyl, quinolin-diyl, pyridin-diyl, 1-oxido-pyridin-diyl, [l,2,4]friazolo[4,3-a]pyridin~diyl, and 2,3-dihydroimidazo[l,2-a]pyridin-diyl; and A is further optionally substituted with one, two,'three, or four groups selected from R30, Ri2, R34, and R16 where R10, R12, R14, and R36 and all other groups are as defined in the Summary ofthe Invention for a compound of Group B. More specifically A is selected from thien-3,4-diyl, benzo[d]isoxazol“5,6-diyl, benzo[d]isothiazol~5,6-diyl, l/Aindazol-5,6-diyl (optionally substituted at the NI position with R39 where R39 is alkyl or alkenyl), benzo[A]oxazoL5fi-diyl, benzo[ri}thiazol-5,6-diyl, l#-benzo[d]imidazol-5,6-diyl (optionally substituted at the NI position with R19 where R19 is alkyl or alkenyl), li/Abenzo[ri][l,2,3]triazol-5,6-diyl (optionally substituted at the NI position with R39 where R19 is alkyl or alkenyl), imidazo[l,2-&lt;?]pyridin-5,6-diyl, cinnolin-6,7~diyl, quinolin-6,7-diyl, pyridin-3,4-diyl, 1-oxido-pyridin~3,4-diyl, [l,2,4]triazolo[4,3-a]pyridin~6,7-diyl, and 2,3~dihydroimidazo[l,2~ a]pyridin-6,7-diyl.

[00133] In another embodiment of the Invention (B6), the compound of Formula I is selected from Group B where A is thien-diyl and X, R3, R2, R3, R4, R5, R6, R7, R30, and R12 are as defined in the Summary of the Invention for a compound of Group B. More specifically A is thien~3,4-diyl; R10 and R12 are hydrogen; X and R7 are halo; and R1, R2, R5, and R6 are hydrogen. Even more specifically, X is fluoro or chloro; R7 is iodo or bromo; R3 is hydrogen or hydroxy; and R4 is -NR8R8 (where R8 and R8 are independently hydrogen or alkyl), heterocycloaikyl, heteroaryl (optionally substituted with alkyl), or alkyl where die alkyl is optionally substituted with ~NR8R8 (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl). 47 [00134] In another embodiment (B7), the compound is of Formula 1(c) or 1(d)

<img img-format="tif" img-content="drawing" file="IL229136AD000216.tif" id="idf0016" />

where X, R1, R2, R3, R4, R5, R6, R7, R10, R12 and R34 are as defined in the Summary of the Invention for a compound of Group B, More specifically, R3, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and R10, R12, and R14 are independently hydrogen, halo, or alkyl. Even more specifically, X is fluoro or chloro and R7 is iodo or bromo; Ri0 is hydrogen or halo, more specifically hydrogen or fluoro; R32 is hydrogen; Ri4 is hydrogen or alkyl; and R3 is hydroxy. Yet even more specifically, R4 is heterocycloaikyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with ~NRSRS’ (where Rs is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, 1 (7&lt;0)-amino~ethyL l(/?)-amino-ethyl, 1 (jS)-amino-ethyl, 1 (Ri$)-(methylamino)~ethyl, l(R)-(methylamino)-ethyl, 1 (5)-(methylamino)-ethyl, 1 (R, S)-(dimethylamino)-ethyl, 1 (R)~(dimethylamino)~ethyl, 1 (5&gt;(dimethylamino)-ethyl, 1 (R 0)-(3,4-ds-dihydroxy-cyclopentylamino)~ethyl, 1 (R)-(3,4-ds-dihydroxy-cyclopentylamino)-ethyl, or 1 (5)-(3,4-cE-dihydiOxy-cyclopentylamino)-ethyl. [00135] In another embodiment of the Invention (B8), the compound is of Formula 1(e) or 1(f):

<img img-format="tif" img-content="drawing" file="IL229136AD000217.tif" id="idf0017" />

where X, R1, R2, R3, R4, R5, R6, R7, R30, R12 and R14 are as defined in the Summary of the Invention for a compound of Group B. More specifically, R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and R10, R12, and R14 are independently hydrogen, halo, or alkyl. Even more specifically, X is 48 fluoro or chloro and R7 is iodo or bromo; R10 is hydrogen or halo, more specifically hydrogen or fluoro; R12 and Ri4 are hydrogen; R3 is hydroxy; and R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NRSR8’ (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycioalkyl where the cycioalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

[00136] In another embodiment of the Invention (B9), the compound is of Formula 1(g) or 1(h):

<img img-format="tif" img-content="drawing" file="IL229136AD000218.tif" id="idf0018" />

where X, R1, R2, R3, R4, R5, R6, R7, R10, R]2, R14, and R19 are as defined in the Summary of the Invention for a compound of Group B.

[00137] In a more specific embodiment of embodiment B9, the compound is of formula 1(g) or 1(h) where R3 is halo, nitro, -NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8’, -C(O)R8, -C(O)OR8, -C(O)NRSR8', -NR8C(O)OR8', -NRsC(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR2Si'R25b), -CH2NR2SC(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)),-CH2NR25C(=NH)(N(R25!1)(CN)), -CHzNR^^NH)^25), -CH2M&lt;25C(NR25aR25b&gt;=CH(NO2)&gt; cycioalkyl, heteroaryl, or heterocycloalkyl; where the cycioalkyl, heteroaryl, and heterocycloalkyl are optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycioalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8',-NR8C(O)NR8'R8'',-NR8C(O)OR8' and -NR8C(O)R8’; and R4 is as defined in the Summary of the Invention; or R3 and R4 together with the carbon to which they are attached form C(O) or C(™NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B. 49 [00138] In a more specific em bodiment of embodiment B9, the compound Is of formula 1(g) or 1(h) where R3 is hydroxy and all other groups are as defined in the Summary of the Invention for a compound of Group B, [00139] In a more specific embodiment of embodiment B9, the compound is of formula 1(g) or 1(h) where R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; R10, R12, and R14 are independently hydrogen, halo, or alkyl; and R19 is hydrogen or methyl. Even more specifically, X is fluoro or chloro and R7 is iodo or bromo; R/° is hydrogen or halo, more specifically hydrogen or fluoro; R12 and Rl4 are hydrogen; R3 is hydroxy; and R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NR8R8 (where Rs is hydrogen or alkyl and Rs is hydrogen, alkyl, or cycioalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

[00140] In another embodiment of the Invention (BIO), the compound is of Formula I(i) or I0)&lt;

<img img-format="tif" img-content="drawing" file="IL229136AD000219.tif" id="idf0019" />

R4

<img img-format="tif" img-content="drawing" file="IL229136AD000220.tif" id="idf0020" />

I®; 10); where X, R1, R2, R3, R4, R5, R6, R7, R10, R12 and R14 are as defined in the Summary of the Invention for a compound of Group B. More specifically, R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and R10, R12, and R14 are independently hydrogen, halo, or alkyl. Even more specifically, X is fluoro or chloro and R7 is iodo or bromo; R10 is hydrogen or halo, more specifically hydrogen or fluoro; R12 and R14 are hydrogen; R3 is hydroxy; and R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NR8R8' (where R8 is hydrogen or alkyl and R8’ is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. 50 [00141} In another embodiment of the Invention (BI 1), the compound is of Formula I(k) or I(m):

<img img-format="tif" img-content="drawing" file="IL229136AD000221.tif" id="idf0021" />

where X, R1, R2, R3, R4, R5, R6, R7, R10, R32 and R14 are as defined in the Summary of the Invention for a compound of Group B, More specifically, R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and R10, R52, and R14 are independently hydrogen, halo, or alkyl. Even more specifically, X is fluoro or chloro and R7 is iodo or bromo; R10 is hydrogen or halo, more specifically hydrogen or fluoro; R12 and R14 are hydrogen; R3 is hydroxy; and R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NR8R8 (where R8 is hydrogen or alkyl and Rs’ is hydrogen, aikyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl.

[00142] In another embodiment of the Invention &lt;B12), the compound is of Formula I(n) or I(o):

<img img-format="tif" img-content="drawing" file="IL229136AD000222.tif" id="idf0022" />

where X, R1, R2, R3, R4, R5, R6, R7, R30, R12, Rt4, and R19 are as defined in the Summary of the Invention for a compound of Group B.

[00143] In a more specific embodiment of embodiment BI2, the compound is of formula I(n) or I(o) where R7 is halo or alkyl; and all other groups are as defined in the Summary of the Invention for a compound of Group B. More specifically, R7 is iodo or bromo.

[00144] In a more specific embodiment of embodiment BI2, the compound is of formula I(n) or I(o) where X is halo, haloalkyl, or haloalkoxy; and all other groups are as defined in' 51 the Summary of the Invention for a compound of Group B. More specifically, X is halo.

Even more specifically X is fluoro or chloro, [00145] In a more specific embodiment of embodiment BI2, the compound is of formula I(n) or I(o) where R3 is halo, nitro, -NRSR8’, -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NRSC(O)OR8', -NRsC(O)NR8,R8", -NRsC(O)OR8’, -NR8C(O)Rs’, -CH2N(R25)(NR25aR2Sb), -CH2NR25C(=NH)(NR25aR2Sb), -CH2NR25C(=NH)(N(R2Sa)(NO2)),-CH2NR25C(=NH)(N(R25“)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR23b)=CH(NO2), alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryi, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycioalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR , -NRSR8’, -NRsS(O)2R9; -CN, -S(O)mR9, -C(O)R8, -C(O)0R8, -C(O)NRSR8', -NR8C(O)NR8'R8” -NR8C(O)OR8' and -NRSC(O)R8'; and R4 is as defined in the Summary of the Invention; or R3 and R4 together with the carbon to which they are attached form C(O) or C(=NOH); and unless otherwise indicated, R8 and R8’ are as defined in the Summary of the Invention; and all other groups are as defined in the Summary of the Invention for a compound of Group B. [00146] In a more specific embodiment of embodiment BI 2, the compound is of formula I(n) or l(o) where R19 is alkyl; R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and R10, R12, and R14 are independently hydrogen or halo. Even more specifically, R19 is methyl; X is fluoro or chloro and R7 is iodo or bromo; Ri0 is hydrogen or fluoro; R12 and R14 are hydrogen; and R3 is hydroxy. Yet even more specifically, R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NR8R8 (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycioalkyl where the cycioalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, l(R5)-amino-ethyl, l(R)-amino-ethyl, 1(δ&gt; amino-ethyl, 1 (RS)-(methylamino)-ethyl, l(R)-(methylamino)-ethyl, 1 (S)-(methylamino)-ethyl, l(RS)-(dimethylamino)-ethyl, 1 (R)-(dimethylamino)-ethyl, l(S)-(dimethylamino)-ethyl, 1 (R 5)-(3,4-cis-dihydroxy- 52 cyclopentylamino)-ethyl, 1 (72)-(3.4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1 (5)-(3.4-cis-dihydroxy-cyclopentylamino)-ethyl, [00147] In another embodiment of the Invention (B13), the compound is of Formula I(p):

<img img-format="tif" img-content="drawing" file="IL229136AD000223.tif" id="idf0023" />

where X, R3, R2, R3, R4, R5, R6, R7, Rw, R32, and R39 are as defined in the Summary of the Invention for a compound of Group B. More specifically, R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and R10 and Ri2 are independently hydrogen, halo, or alkyl. Even more specifically, X is fluoro or chloro; R7 is iodo or bromo; R10 is hydrogen or halo, more specifically hydrogen or fluoro; Ri2 is hydrogen; R19 is hydrogen or alkyl, more specifically hydrogen or methyl; R3 is hydroxy. Even more specifically, R4 is heterocycloaikyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NRSRS (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, l(7?,S)-amino~ethyl, l(72)-amino-ethyl, l(5)-amino-ethyl, i(75»S)-(methylamino)-eihyl51 (j?)-(methylamino)-ethyl, 1 (5)-(methylamino)-ethyl, 1 (7?,5)-(dimethylamino)-ethyl, 1 (7?)-(dim ethylamino)-ethyl, 1 (5)-(dimethylamino)-ethyl, 1 (72, 5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1 (72)-(3,4-cis-dihydroxy“cyclopentylamino)-ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl. [00148] In another embodiment of the Invention (B14), the compound is of Formula I(q):

<img img-format="tif" img-content="drawing" file="IL229136AD000224.tif" id="idf0024" />

53 where X, R1, R2, R3, R4, R5, R6, R7, Ri0, R12 R14, and R16 are as defined in the Summary of the Invention for a compound of Group B.

[00149] In a more specific embodiment of embodiment B14, the compound is of formula I(q) where R3 is halo, nitro, -NRSR8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -SCO^NRV, -C(O)R8, -C(O)OR8, -C(O)NR8R8’, -NR8C(O)OR8’, -NR8C(O)NRs,R8", -NR8C(O)OR8’, -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR2SaR25b), -CH2NR25C(=NH)(N(R25i)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR2SC(=NH)(R“), -CHaNR^CiNR^VCHCNOi), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NRSR8', -NRsS(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NRSR8', -NR8C(O)NR8’R8”, -NR8C(O)OR8’ and -NR8C(O)R8’; and R4 is as defined in the Summary of the Invention; or , R3 and R4 together with the carbon to which they are attached form C(O) or C(™NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B. [00150] In a more specific embodiment of embodiment B14, the compound is of fonnula I(q) where R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and R10, R12, R14, and R16 are independently hydrogen or halo. Even more specifically, R10 is halo and R12, R14, and R16 are hydrogen. Even more specifically, X is fluoro or chloro; R7 is iodo or bromo; R10 is chloro; and R3 is hydroxy. Even more specifically, R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NRSR8 (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycloaikyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, benzimidazolyl, 1 (R Y)-amino-ethyl&gt; 1 (//)-ami no-ethyl, l^-amino-ethyl, 1 (fo0)-(inethylamino)-ethyk 1 (^)-(methylamino)~ethyl, 1 (*S)-(methylamino)-etbyl, 1 (J?, 5)-(3,4-cis-dihydroxy- cyclopentylamino)-ethyl, 1 (/?)~(3,4-cis-dihydroxy-cyclopentylamino)~ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl. 54 WO 2007/04451.5 [00151] In another embodiment of the Invention (B15), the compound is of Formula l(r):

<img img-format="tif" img-content="drawing" file="IL229136AD000225.tif" id="idf0025" />

where X, R1, R2, R3, R4, R5, R6, R7, R10, R12 and Ri4 are as defined in the Summary of the Invention for a compound of Group B. More specifically, R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary ofthe Invention for Group B; RJ0 and R12 are independently hydrogen, halo, or alkyl; and R14 is hydrogen, halo, alkyl, or amino. Even more specifically, X is fluoro or chloro; R7 is iodo or bromo; R10 is hydrogen or halo, more specifically hydrogen or fluoro; R12 is hydrogen; Ri4 is hydrogen, alkyl, or amino, more specifically hydrogen, methyl, or amino; R is hydroxy. Even more specifically, R is heterocycloaikyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NR8R8 (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, l(7?,6)-amino-ethyl, 1 (/?)~amino-ethyl, l(5)-amino-ethyl, 1(Λ Y)-(methylamino)-ethyl, l(F)-(methylamino)-ethy], 1 (5)-(mefhylammo)-ethyl, 1 (/?, 5)-(3,4~cis“dihydroxy-cyclopentylamino)-ethyl, 1 (F)-(3,4-eis-dihydroxy- cyclopentylamino)-ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

[00152] In another embodiment of the Invention (B16), the compound is of Formula I(s):

<img img-format="tif" img-content="drawing" file="IL229136AD000226.tif" id="idf0026" />

where X, R3, R2, R3, R4, R5, R6, R7, R10, R12 and R14 are as defined in the Summary ofthe Invention for a compound of Group B, More specifically, R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and 55

Rw and R12 are independently hydrogen, halo, or alkyl; and RJ4 is hydrogen, halo, alkyl, or amino. Even more specifically, X is fluoro or chloro and R7 is iodo or bromo; Ri0 is hydrogen or halo, more specifically hydrogen or fluoro; R12 is hydrogen; R14 is hydrogen, methyl, or amino; R3 is hydroxy; and R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with ~NR8RS’ (where R8 is hydrogen or alkyl and Rs is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl, [00153] In another embodiment of the Invention (BI 8), the compound is of Formula l(u), I(v), I(w), orl(x):

<img img-format="tif" img-content="drawing" file="IL229136AD000227.tif" id="idf0027" />

where X, R1, R2, R3, R4, R5, R6, R7, Ri0, R12 and R14 are as defined in the Summary of the Invention for a compound of Group B.

[00154] In a more specific embodiment of embodiment B18, the compound is of formula I(u), I(v), I(w), or I(x) where R3 is halo, nitro, -NRSRS, -OR8, -NHS(O)2R8, -CN, -S(O)mR8, ~S(O)2NR8R8’, -C(O)R8, -C(O)OR8, -C(O)NRSR8’, -NRSC(O)OR8’, -NR8C(O)NR8R8”, -NRSC(O)OR8’, -NR8C(O)R8’, -CH2N(R25)(NR25aR25b), -CH2NR25C(-NH)(NR25aR25b), -CH2NR2SC(-NH)(N(R25a)(NO2)), -CH2NR25C(-NH)(N(R25a)(CN)), -CH2NR25C(-NH)(R25), -CH2NR25C(NR25aR25b&gt;CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted 56 heteroarylalkyl, -OR8, -NR8R8’, -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8Rs&gt;NR8C(O)NR8’R8’&gt;NR8C(O)OR8’ and -NR8C(O)R8’; and R4 is as defined in the Summary of the Invention for a compound of Group B; or R3 and R4 together with the carbon to which they are attached form C(O) or C(~NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B.

[00155] In a more specific embodiment of embodiment B18, the compound is of formula I(t), I(u), I(v), or I(w) where R3 and R4 are independently halo, nitro, -NR8R8*, -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NRsR8’, -C(O)R8, -C(O)OR8, -C(O)NR8R8’, -NR8C(O)OR8’, -NR8C(O)NRsR8”, ~NR8C(O)OR8’, -NR8C(O)R8’, -CH2N(R25)(NR25aR25b), -CH2NR25C(-NH)(NR25aR25b), -CH2NR25C(-NH)(N(R25a)(NO2))s ~CH2NR2SC(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R2S), -CH2NR25C(NR23aR25b)=CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteioarylalkyl, -OR8, -NR8R8’, -NR8S(O)2Rs, -CN, -S(O)mR9, -C(O)RS, -C(O)OR8, -C(O)NR8R8’, -NR8C(O)NR8R8", -NR8C(O)OR8' and -NR8C(O)R8’; or R3 and R4 together with the carbon to which they are attached form C(O) or C(~NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group B, [00156] In a more specific embodiment of embodiment B18, the compound is of formula I(u), I(v), I(w), or I(x) where R4 is heterocycloalkyl, heteroaryl (optionally substituted with aikyl), or alkyl where the alkyl is optionally substituted with -NR8R8 (where R8 is hydrogen or alkyl and R8’ is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl). More specifically, R4 is piperidinyl, pyrrolidinyl, l(R5)-amino-propyl, l(R)-amino-propyl, 1 (5)-amino-propyl, 1 (R5)-(methylamino)-propyl, 1 (R)-(methylamino)-propyl, l(5)-(methylamino)-propyl, 1 (R 5)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl, l(R)-(3,4-c/j-dihydroxy-cyclopentylammo)-propyl, or 1 (5)-(3,4-cis~dihydroxy-cyclopentyIamino)~ propyl.

[00157] In a more specific embodiment of embodiment B18, the compound is of formula I(u), I(v), I(w), or I(x) where R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3 and R4 are as defined in the Summary of the Invention for Group B; and R10, R12, and R14 are 57 independently hydrogen, halo, or alkyt Even more specifically, X is fluoro or chloro; R7 is iodo or bromo; R10 is hydrogen or halo, more specifically hydrogen or fluoro; R12 and R14 are hydrogen; and R3 is hydroxy. Even more specifically R4 is heteroeycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NR8R8’ (where Rs is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyt [00158] In another embodiment of the Invention (BI 9), the compound is of Formula I(cc)

<img img-format="tif" img-content="drawing" file="IL229136AD000228.tif" id="idf0028" />

where X, R1, R2, R3, R4, R5, R6, and R7 are as defined in the Summary of the Invention for a compound of Group B. Specifically, R1, R2, R5, and R6 are hydrogen; and X and R7 are halo. More specifically, X is fluoro or chloro; and R3 is hydrogen or hydroxy; R7 is iodo, or bromo. Even more specifically, R4 is heteroeycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NRSR8’ (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycloalkyl where the cyclo alkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, benzimidazolyk 77-methy l-benzimidazolyl, methylaminomethyl, 1(&amp;amp; ^-amino-ethyl, l(R)-amino-ethyk 1 (S)-ammo~ethyl, 1 (&amp;amp;5)-(methylamino)~ethyl, l(R)-(methylamino)-ethyk 1 (5)-(methyIaramo)~ethyl, 1 (R, S)-(dimethylamino)-ethy 1,1 (R)-(dimethylamino)-ethyl, l(S)&lt;d«nethylamino)-ethyi, l(A*S)-amino-propyl, l(i?)~amino~propyl, 1 (5)-amino-propyl, 1 (R, 5)-(methylamino)-propyl, 1 (R)-(inethylamino)-propyl. 1 (5)-(methylamino)-propyl, 1 (J?, S)-(dimethylamino)-propyl, 1 (77)-(diinethyIamino)-propyl, l(S)-(dimethylamino)-propyl, 1 (R, 5)-(3,4-cis-dihydroxy-eyclopentylamino)~ethyl, 1 (7?)-(3,4~cis-dihydroxy-cyciopentylamino)-ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

[00159] In a specific embodiment (Β 19a) of embodiment B19 is that where R4 is heteroeycloalkyl or alkyl where the alkyl is optionally substituted with -NR8R8 (where R8 is hydrogen or alkyl and R8’ is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally 58 substituted with one or two groups independently selected from hydroxy and alkyl). Specifically, R4 is piperidinyl, pyrrolidinyl, methylaminomethyl, l(7?f5)-amino-ethyl, 1 (/^-amino-ethyl, l(5)-amino-ethyl, l(&amp;amp;5)-(methylamino)-ethyl, 1 (7?)-(methylamino)-ethyl, l(5)-(methylammo)~ethyl, l(7?J5)-(dimethylamino)-ethyl, 1 (^)-(dimethylamino)-ethyl, 1 (5)-(dimethylanimo)-ethyl, l(7?,5)-amino-propyl, 1 (TQ-amino-propyl, 1 (5)-ammo-propyl, 1 (7( 5)-(methylamino)-propyl, 1 (7?)-(methylamino)-propy 1,1 (5)-(methylamino)-propyl, 1 (R 5)-(dimethylamino)-propyl, 1 (7?)-(dimethylamino)~propyl, 1 (5)-(dimethylamino)-propyI, 1 (R5)“(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1 (K)-(3,4-cis-dihydro xy-cyclopentylamino)-ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)~ethyl.

[00160] In another embodiment of the Invention (B20), the compound is of Formula I(dd)

<img img-format="tif" img-content="drawing" file="IL229136AD000229.tif" id="idf0029" />

where X, R\ R2, R3, R4, R5, R6, and R7 are as defined in the Summary of the Invention for a compound of Group B, Specifically, R1, R2, R5, and R6 are hydrogen; and X and R7 are halo. More specifically, X is fluoro or chloro; and R3 is hydrogen or hydroxy; R7 is iodo or bromo. Even more specifically, R4 is heierocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NRSR8’ (where R8 is hydrogen or alkyl and R8’ is hydrogen, alkyl, or cycioalkyl where the cycioalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl, l(/?,5)-amino-ethyl, l(7?)-amino-ethyl, 1 (5)-amino-ethyl, 1 (R5)-(methylamino)-ethyl, 1 (7?)-(methyIamino)-ethyl, 1 (5)-(mefhyiamino)-ethyl, 1 (R5)-(dimethyl amino)-ethyl, 1 (7?)-(dimethylamino)-ethyl, l(5)-(dimethylamino)-ethyl, l(7(5)-amino-propyl, l(7?)-amino-propyl, l(6)~amino-propyl, 1 (R5)-(methylamino)-propyl, l(7?)-(methylamino)-propyl, 1 (5)~(methylammo)~propyl, l(R5&gt;(dhn ethyl amino)-propyl, l(7?)-(dimethylamino)-propyl, 1 (iS)-(dimethylamino)-propyl, 1(7( 5)-(3,4-cis-dihydroxy~cyclopentylamino)~ethyl, 1 (A)-(3,4-cis-chhydroxy-cyclopentylaminomethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl. 59 [00161] In a specific embodiment (B20a) of embodiment B20 is that where R4 is heterocycloaikyl or alkyl where the alkyl is optionally substituted with -NR8R8’ (where R8 is hydrogen or alkyl and R8' is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl). Specifically, R4 is piperidinyl, pyrrolidinyl, methylaminomethyl, l(72,5)~amino-ethyi, l(7?)-amino-ethyl, 1 (5)-amino-ethyl, 1(72,5)-(methyl am ino)-ethyl, l(7?)-(methylamino)-ethyl, 1 (5)-(methylamino)-ethyl, 1 (R, 5)~(dimethylamino)-efhyl, 1 (72)-(dimethylamino)-ethyl, l(S)-(dimethylamino)-ethyl, l(72,5)-amino-propyl, l(72)-amino-propyl, l(5)-amino-propyl, 1 (λ, 5)-(methylamino)-propyl, 1 (72)-(methylamino)-propyl, 1 (5)-(methylamino)-propy 1, 1 (R, 5)-(dimethy lamino)-propyl, 1 (72)-(dimethylamino)-propyl, 1 (6)-(dimethylamino)-propyf, 1 (72,5)-(3,4-cis-dihydiOxy-cyciopentylamino)-ethyl, 1 (72)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

[00162] In one embodiment of the Invention (Cl), the compound of Formula I is selected hom Group C where all groups are as defined in the Summary of the Invention.

[00163] In another embodiment of the invention (C2), X and R7 are halo; and all other groups are as defined for a compound selected from Group C.

[00164] In another embodiment of the invention (C3), the compound is selected from Group C where R3 is halo, nitro, -NR8R8’, -OR8, -NHS(O)2Rs, -CN, -S(O)mR8, -S(O)2NR8R8’, -C(O)R8, -C(O)OR8, -C(O)NRSR8’, -NRsC(O)OR8', -NR8C(O)NR8'Rs", -NRsC(O)OR8', -NR8C(O)Rs’, -CH2N(R2S)(NR2SaR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R2Sa)(NO2)),-CH2NR25C(=NH)(N(R25a)(CN)),-CH2NR25C(=NH)(R2S), -CH2NR25C(NR25aR25b)=CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloaikyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloaikyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloaikyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NRSR8', -NR8S(O)2R5, -CN, -S(O)mR9, -C(O)R8, -C(O)ORS, -C(O)NR8R8’,-NR8C(O)NR8'R8”,-NR8C(O)OR8' and -NR8C(O)R8'; and R4 is as defined in the Summary of the Invention; or R3 and R4 together with the carbon to which they are attached form C(O) or C(=NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group C, More specifically, R1, R2, R5 and R6 are hydrogen; and X and R7 are halo. 60 [00165] In another embodiment of the invention (C4), the compound is selected from Group C where R3 and R4 are independently halo, nitro, “NR8R8’, -OR8, -NHS(O)2R8, “CN, -S(O)mR8, -S(O)2NR8R8’, ~C(O)R8, -C(O)OR8, -C(O)NRsR8&gt;, -NR8C(O)OR8’, -NR8C(O)NR8Rs”,-NR8C(O)OR8’, -NR8C(O)R8’,-CH2N(R25)(NR2SaR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(-NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR2SCO=NH)(R25), -CH2NR25C(NR25aR2Sb)=CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloaikyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloaikyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloaikyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NRSR8', -NR8S(O)2R’, -CN, -S(O)mR’, -C(O)RS, -C(O)0R8, -C(O)NR8R8', -NR8C(O)NR8’R8”, -NRSC(O)OR8’ and -NRSC(O)RS’; or R3 and R4 together with the carbon to which they are attached form C(O) or C(=NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group C. More specifically, Rl, R2, Rs and R6 are hydrogen; and X and R7 are halo.

[00166] In another embodiment of the invention (C5), A is

J

UWV

<img img-format="tif" img-content="drawing" file="IL229136AD000230.tif" id="idf0030" />

o and X, R1, R2, R3, R4, R5, R6, R7, R10, and R10a are as defined in the Summary of the invention for a compound of Group C. More specifically, R1, R2, R5, and R6 are hydrogen; X and R7 are halo; Ri0 is hydrogen or halo; and RlOs is alkyl. Even more specifically, X is fluoro or chloro; R3 is hydroxy; R7 is iodo or bromo; R10 is hydrogen or fluoro; and R10a is methyl. Even more specifically, R4 is heterocycloaikyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NRSR8 (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with aikyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, benzimidazolyl, N~ methyl-benzimidazolyl, methylaminomethyl, l(R5)-amino-ethyl, l(R)-amino-ethyl, 1 (iS)-ammo-ethyl, 1 (A5)-(methylamino)-ethyI, 1 (R)-(methylamino)-ethyI, 1 (S)-(methylamino)-ethyl, 1 (A 5)-(dimethy lamino)-ethyl, 1 (T)-(dimethylamino)-ethyl, 61 1 (5)-(dimethylamino)-et'hylJ l(R,50-amino-propyl, l(2?)-amino-propyl, 1 (^-amino-propyl, 1 (R(5)-(methylamino)-propyl, l(R)-(methylamino)-propyl, 1 (5)-(methylamino)-propyl, 1 (R,5)-(dimethylamino)-propyl, l(R)-(dimethylamino)-propyl, l(F)“(dimethylamino)-propyL 1(R,5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1 (R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1 (5)-(3,4-cis~dihydroxy-cyclopentylamino)-ethyl.

[001671 In another embodiment of the invention (C6), A is &amp;#943; ww

<img img-format="tif" img-content="drawing" file="IL229136AD000231.tif" id="idf0031" />

0 and X, R\ R2, R3, R4, R5, R6, R7, R30, and R10a are as defined in the Summary of the invention for a compound of Group C. More specifically, Rl, R2. R5, and R6 are hydrogen; X and R7 are halo; R10 is hydrogen or halo; and RIOa is alkyl. Even more specifically, X is fluoro or chloro; R3 is hydroxy; R7 is iodo or bromo; R10 is hydrogen or fluoro; and RWa is methyl. Even more specifically, R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NRSR8 (where R8 is hydrogen or alkyl and Rs is hydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, benzimidazolyl, N-methy Ibenzimidazolyl, l(/?,5)-amino-ethyls 1 (R)-amino-ethyl, 1 (5)-amino-ethyl, 1 (R 5)-amino-propyl, 1 (/fi-amino-propy 1. 1 (5)-ammo~propyl, 1 (R, 5)-(methylamino)“propyl, l(/?)-(methylamino)-propyl, l(5)-(methylamino)-propyl, 1 (R5)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl, 1 (R)-(3,4-cis~dihydroxy-cyclopentylamino)-piOpyl, 1 (5)-(3,4-ci s-dihydroxy-cyclopentylamino)-propyl, l(j?,5)-(3,4-cis-dihydroxy-cyclopentylamino)~ethyl, 1 (j?)-(3,4“cis-dihydroxy-cyclopentylamino)“efhyl, or 1 (5)~(3,4~cis-dihydroxy-cyc lopenty lamino)-ethyl. 62 WO 2007/0445.15 [00168} In another embodiment of the Invention (C7), the compound is of Formula I(y) or I(z):

<img img-format="tif" img-content="drawing" file="IL229136AD000232.tif" id="idf0032" />

I(z) where R1, R2, R5, and R6 are hydrogen; X and R7 are halo; R3, R4, R10, RI0\ and Y1 are as defined in the Summary of the Invention for a compound of Group C. In a more specific embodiment, X is fluoro or chloro; R7 is iodo or bromo; Ri0 is hydrogen, halo, or alkyl, more specifically hydrogen or halo; and RiOa is alkyl, more specifically methyl. Even more specifically R10 is hydrogen or fluoro; R3 is hydroxy; and R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with -NR8R8 (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cycioalkyl where the cycioalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl, [00169] In one embodiment of the Invention (D), the compound of Formula I is selected from Group D where all groups are as defined in the Summary of the Invention.

[00170] In another embodiment of the invention (DI), X and R7 are halo; and all other groups are as defined for a compound selected from Group D. 1 [00171] In another embodiment of the invention (D2), the compound is selected from Group D where R3 is halo, nitro, -NR8R8’, -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NRsC(O)OR8', -NR8C(O)NR8'R8”, -NR8C(O)OR8’, -NRsC(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR2SC(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R2Sa)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycioalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycioalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NRSR8’, -NR8S(O)2R9, -CN, -S(O)mR5, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8 '. -NR8C(O)OR8&gt; and -NR8C(O)R8'; and R4 is as defined in 63 the Summary of the Invention; or R3 and R4 together with the carbon to which they are attached form C(O) or C(~NOH); and all other groups are as defined in the Summary of the Invention for a compound of Group C. More specifically, R5. R2, R5 and R6 are hydrogen; and X and R7 are halo.

[00172] In another embodiment of the invention (D3), the compound is selected from Group D where R3 and R4 are independently halo, nitro, -NR8R8\ -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8’, ~C(O)Rs, -C(O)OR8, ~C(O)NR8R8’, -NR8C(O)OR8&gt;, -NR8C(O)NR8’R8’' -NR8C(O)ORb’, -NR8C(O)R8’, -CH2N(R25)(NR25aR25b), -CH2NR25C(-NH)(NR25aR2Sb), -CH2NR25C(-NH)(N(R25a)(NO2))5 -CH2NR25C(”NH)(N(R25a)(CN)), -CH2NR25C(-NH)(R25), -CH2NR25C(NR2SaR25b&gt;CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyi, heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyi, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyi, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8, -NRSR8, -NR8S(O)2R5, -CN, -S(O)mR9, -C(O)R8, -C(O)QR8, -C(O)NR8R8’, -NRsC(O)NR8'R8”, -NR8C(O)OR8’ and -NR8C(O)R8’; or R3 and R4 together with the carbon to which they are attached form C(O) or C(”NOH); and all other groups are as defined in the Summary of the invention for a compound of Group C. More specifically, R1, R2, R5 and R6 are hydrogen; and X and R7 are halo.

[00173] in another embodiment of the invention (D4), A is

<img img-format="tif" img-content="drawing" file="IL229136AD000233.tif" id="idf0033" />

where R40 is hydrogen or methyl (specifically, R40 is hydrogen) and all other groups are as defined in the Summary of the Invention. Specifically, R1, R2, R5, and R6 are hydrogen; X and R7 are halo; and R40 is hydrogen or methyl. More specifically, X is fluoro or chloro; and R3 is hydrogen or hydroxy; R7 is iodo or bromo. Even more specifically, R4 is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionally substituted with ~NR8R8 (where R8 is hydrogen or alkyl and R8’ is hydrogen, alkyl, or cycloalkyi where the cycloalkyi 64 WO 20()7/044515 is optionally substituted with one or two groups independently selected from hydroxy and alkyl) and the heteroaryl is optionally substituted with alkyl. Yet even more specifically, R4 is piperidinyl, pyrrolidinyl, benzimidazolyl, A-methyl-benzimidazolyl, methylaminomethyl, l(72,5)-ammo-ethyl, l(72)-amino~ethyl, l(5)-amino-ethyl, l(72,5)-(methylamino)-ethyl, l(72)-(methylamino)-ethyl, l(5)-(methylamino)-ethyl, 1 (72, 5)-(di methyl ami no)-ethyl, I(72)-(dnnethylamino)-ethyl, l(5)-(dimethylamino)-ethyl, 1(72,5)-am ino -propyl, 1 (^-amino-propyl, l(Sj-amino-propyl, 1 (72,5)-(m ethyl amino)-propyl, 1 ($)~(methylamino)-propyl, 1 (5)-(methylamino)-propyl, 1 (R, 5)-(dimethylamino)-propyl, 1 (R)-(dimethylamino)-propyl, l(5)-(dimethylamino)-propyl, 1(72,5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1(72)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylaraino)-ethyl. [00174] in a specific embodiment (D4a) of the invention of D4 is that where R4 is heterocycloalkyl or alkyl where the alkyl is optionally substituted with -NR8R8 (where R8 is hydrogen or alkyl and R8 is hydrogen, alkyl, or cyeloalkyl where the cyeloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl). Specifically, R4 is piperidinyl, pyrrolidinyl, methylaminomethyl, 1(72,5)-amino-ethyl, 1 (72)-amino-ethyl, 1 (5)-amino-ethy 1,1(72,5)-(methylamino)-ethyl, l(72)-(methylamino)-ethyl, l(5)-(methylamino)-ethyl, 1 (/2,5)-(dimethylamino)-ethyl, 1 (72)-(dimethylamino)~ethyl, l(5)-(dimethylamino)-ethyl, l(72f5)-amino-propyl, l(72)-amino-propyl, l(5)-amino-propyl, l(72,5)-(methylamino)-propyl, 1 (72)-(methylamino)-propyl, 1 (5)-(methylamino)-propyl, 1 (72, 5)-(dimethylamino)-propyl, 1 (72)-(dimethylamino)-propyl, 1 (5)-(dimethylamino)-propyl, 1 (72,5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, 1 (72)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or 1 (5)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

[00175] Another embodiment of the Invention (E) is directed to a Compound selected from Group A, Group B, and Group C where

Group A A is phenylene optionally substituted with one or two groups selected from Rw, R12, R14, and R16 where R10, R12, R14 and R16 are independently hydrogen or halo; X is halo; R1, R2, R5 and R6 are hydrogen; R3 is hydrogen, halo, hydroxy, alkoxy, or amino; R4 is hydrogen, -NR8R8', -C(O)NR8R8’, -NR8C(O)OR8&gt;, -NR8C(O)R8’, ~CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR253R25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(-NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkyl, alkenyl, 65 cycloalkyl, heterocycloalkyl, or heteroaryl; where the R4 alkyl is optionally substituted with one, two, or three groups independently selected from -OR8, halo, nitro, ~S(O)mR9, optionally substituted heterocycloalkyl, -NR8R8’, -NR8C(O)R8’, -NR8S(O)2R9, -NR8C(O)OR8, and aryl; where the R4 cycloalkyl is optionally substituted with one or two groups selected from -OR8 and -NRSR8’; where the R4 heterocycloalkyl is optionally substituted with one or two groups independently selected from alkyl and -C(O)OR8; and where the R4 heteroaryl is optionally substituted with -NR8R8’; or R3 and R4 together with the carbon to which they are attached form C(O) or C(:=NOH); m is 0; R7 is halo;

0 O I R and R are independently selected from hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, heteroaryl, and cycloaikyl; where the R8 and R8 alkyl are independently optionally substituted with one, two, or three groups indendently selected from hydroxy, -NR R (where R and R are independently hydrogen, alkyl, or hydroxyalkyl), optionally substituted heteroaryl, optionally substituted cycloaikyl), optionally substituted alkoxy, optionally substituted cycloaikyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, -C(O)NR33R33a (where R33 is hydrogen or alkyl and R33a is alkyl, alkenyl, alkynyl, or cycloaikyl), optionally substituted aryloxy, -S(O)nR31 (where n is 0 and R31 is alkyl), carboxy, alkoxycarbonyl, and -NR32C(O)R32a (where R32 is hydrogen or alkyl and R32a is alkyl, alkenyl, alkoxy, or cycloaikyl); or where the alkyl is optionally substituted with one, two, three, four, or five halo; where the R8 and R8 heteroaryl are independently optionally substituted with one or two groups indendently selected from amino and alkyl; where the R8 and R8 heterocycloalkyl are independently optionally substituted with one, two, or three groups indendently selected from alkyl, alkoxycarbonyl, optionally substituted arylalkyl, hydroxy, alkoxy, and hydroxyalkyl; where the R8 and R8 aryl are independently optionally substituted with one or two groups indendently selected from hydroxy, alkoxy, halo, -NR C(O)R (where R is hydrogen or alkyl and R32a is alkyl, alkenyl, alkoxy, or cycloaikyl), and -NR34SO2R34a (where R34 is hydrogen or alkyl and R34a is alkyl, alkenyl, cycloaikyl, aryl, heteroaryl, or heterocycloalkyl); and 66 where the R8 and R8’ cycioalkyl are independently optionally substituted with one, two, or three groups indendently selected from hydroxy, hydroxyalkyl, alkoxy, carboxy, ~C(O)NR33R33a (where R33 is hydrogen or alkyl and R33a is alkyl, alkenyl, alkynyl, or cycioalkyl), and optionally substituted cycioalkyl; and R9 is alkyl or aryl;

Group B A is thien-3,4“diyl, benzo[&lt;fjisoxazol-5,6-diyl, 177-indazol-5,6“diyl (optionaiiy substituted at the NI position with R19 where R19 is alkyl or alkenyl), benzo[J]oxazol-5,6-diyl, benzo[#]thiazol~5,6-diyl, 17Abenzo[d]imidazol-5,6-diyl (optionally substituted at the NI position with R39 where R19 is alkyl or alkenyl), 177-benzo[ri][l,2,3]triazol-5,0" diyl (optionally substituted at the NI position with R19 where R19 is alkyl or alkenyl), imidazo[l,2-a]pyridin-6,7-diyl, cinnolin-6,7-diyl, quinolin-6,7-diyl, pyridin-3,4-diyl, or l“oxido-pyridin~3,4“diyl; where A is optionally substituted with one, two, or three groups independently selected from R10, R12, R14, R16 and R19 where R10, R32, R34 and R16 are independently hydrogen, alkyl, halo, or amino; and R19 is hydrogen or alkyl; X is halo;

Rl, R2, R5 and R6 are hydrogen; R3 is hydrogen or hydroxy; R4 is -NR8R8’, heterocycloalkyl, heteroaryl, or alkyl; where the alkyl is optionally substituted with -NRSR8’ and where the heteroaryl is optionaly substituted with alkyl; R7 is halo; R8 is hydrogen or alkyl; and R8’ is hydrogen, alkyl, or cycioalkyl; where the cycioalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl;

Group C A is ww Y1 ?

O (a) where R10 is hydrogen or halo; R10a is hydrogen or alkyl; Y3 is-CH- or-Ns

<img img-format="tif" img-content="drawing" file="IL229136AD000234.tif" id="idf0034" />

67 X is halo; R1, R2, R5 and R6 are hydrogen; R3 is hydrogen or hydroxy; R4 is -NR8Rs , heteroeycloalkyl, heteroaryl, or alkyl; where the alkyl is optionally substituted with -NR8R8 and where the heteroaryl is optionaly substituted with alkyl; R7 is halo; R8 is hydrogen or alkyl; and R8 is hydrogen, alkyl, or cycloalkyl; where the cycloalkyl is optionally substituted with one or two groups independently selected from hydroxy and alkyl.

[00176] One embodiment of the invention provides a pharmaceutical composition which comprises a compound of Formula I selected from Group A, or a pharmaceutically acceptable salt or solvate therof and a pharmaceutically acceptable carrier, excipient, or diluent.

[00177] Another embodiment of the invention provides a pharmaceutical composition which comprises a compound of Formula I selected from Group B, or a pharmaceutically acceptable salt or solvate therof and a pharmaceutically acceptable carrier, excipient, or diluent. Specifically, the compound is of Formula 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), I(i), I(j), I(k), l(m), I(n), l(o), I(p), I(q), I(r), I(s), I(t), I(u), I(v), I(w), I(x), I(cc), or I(dd).

[00178] Another embodiment of the invention provides a pharmaceutical composition which comprises a compound of Formula 1 selected from Group C, or a pharmaceutically acceptable salt or solvate therof and a pharmaceutically acceptable carrier, excipient, or diluent.

[00179] Another embodiment of the invention provides a pharmaceutical composition which comprises a compound of Formula I selected from Group D, or a pharmaceutically acceptable salt or solvate therof and a pharmaceutically acceptable carrier, excipient, or diluent.

[00180] In another embodiment, the invention comprises a method of inhibiting MEK in a cell, comprising contacting a cell with a compound of Fonnula 1 selected from Group A or a pharmaceutically acceptable salt or solvate therof, or with a pharmaceutical composition comprising a therapeutically effective amount of a compound of Fonnula I selected from Group A and a pharmaceutically acceptable carrier, excipient, or diluent.

[00181] in another embodiment, the invention comprises a method of inhibiting MEK in a cell, comprising contacting a cell with a compound of Fonnula I selected from Group B or a pharmaceutically acceptable salt or solvate therof, or with a pharmaceutical composition 68 comprising a therapeutically effective amount of a compound of Formula &amp;#938; selected from Group B and a pharmaceutically acceptable carrier, excipient, or diluent.

[00182] In another embodiment, the invention comprises a method of inhibiting MEK in a cell, comprising contacting a cell with a compound of Formula 1 selected from Group C or a pharmaceutically acceptable salt or solvate therof, or with a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I selected from Group C and a pharmaceutically acceptable carrier, excipient, or diluent.

[00183] In another embodiment, the invention comprises a method of inhibiting MEK in a cell, comprising contacting a cell with a compound of Formula I selected from Group D or a pharmaceutically acceptable salt or solvate therof, or with a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I selected from Group D and a pharmaceutically acceptable carrier, excipient, or diluent.

[00184] Another embodiment of the invention provides a method for treating a proliferative disease which method comprises administering to a patient a compound of Formula &amp;#938; or a pharmaceutically acceptable salt or solvate therof, or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 1 and a pharmaceutically acceptable carrier, excipient, or diluent. In a specific embodiment, the disease is cancer. More specifically, the cancer is selected from malignant melanoma, colorectal cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, papillary and anaplastic thyroid cancer, and endometriod ovarian cancers.

[00185] One of ordinary skill in the art would understand that certain crystallized, protein-ligand complexes and their corresponding x-ray structure coordinates can be used to reveal new structural information useful for understanding the biological activity of kinases as described herein. As well, the key structural features of the aforementioned proteins, particularly, the shape of the ligand binding site, are useful in methods for designing or identifying selective modulators of kinases and in solving the structures of other proteins with similar features. Such protein-ligand complexes, having compounds of the invention as their ligand component, are an aspect of the invention.

[00186] As well, one of ordinary skill in the art would appreciate that such suitable x-ray quality crystals can be used as part of a method of identifying a candidate agent capable of binding to and modulating the activity of kinases. Such methods may be characterized by the following aspects: a) introducing into a suitable computer program, information defining a ligand binding domain of a kinase in a conformation (e.g. as defined by x-ray structure 69 coordinates obtained from suitable x-ray quality crystals as described above) wherein the computer program creates a model of the three dimensional structures of the ligand binding domain, b) introducing a model of the three dimensional structure of a candidate agent in the computer program, c) superimposing the model of the candidate agent on the model of the ligand binding domain, and d) assessing whether the candidate agent model fits spatially into the ligand binding domain. Aspects a-d are not necessarily carried out in the aforementioned order. Such methods may further entail: performing rational drug design with the model of the three-dimensional structure, and selecting a potential candidate agent in conjunction with computer modeling.

[00187] Additionally, one skilled in the art would appreciate that such methods may further entail: employing a candidate agent, so-determined to fit spatially Into the ligand binding domain, in a biological activity assay for kinase modulation, and determining whether said candidate agent modulates kinase activity in the assay. Such methods may also include administering the candidate agent, determined to modulate kinase activity, to a mammal suffering from a condition treatable by kinase modulation, such as those described above.

[00188] Also, one skilled in the art would appreciate that compounds of the invention can be used in a method of evaluating the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a kinase. Such a method may be characterized by the following aspects: a) creating a computer model of a kinase binding pocket using structure coordinates obtained from suitable x-ray quality crystals of the kinase, b) employing computational algorithms to perform a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the results of the fitting operation to quantify the association between the test agent and the computer model of the binding pocket.

Representative Compounds 70 [00189] Representative compounds of Fonnula 1 are depicted below. The examples are merely illustrative and do not limit the scope of the invention in any way. Compounds of the invention are named according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), international Union of Biochemistry and Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS). Names were generated using ACD/Labs naming software 8.00 release, product version 8,08.

Table 1

Cmpd No. Structure Name 1 _/0H Ki— OsZ F Η "V tsd 1-( {3.4-d ifluoro ['(2-fluoro iodophenyl)an«no]phenyl} -carbonyl)azetidin ol 2 ( rf° o^nJ 1-((3,4-dtfluoro-2~[(2~fluoro~4- iodopheny!)amino]pheny!}carbonyi) azeddin one 3 'oC &amp;#970; • o ° F 6-(azetidin"l~yicat,bonyi)“2,3“ difluoro-/V-(2-fluoro todophenyl)aniitne 4 OH CW F H A I-((3,4“difIuoro ((2-fIuoro-4“ iodophenyl)aminolphenyl}carbonyl) -3“(hydroxymetbyl)azetidin ol 71

Cmpd No. Structure Name 5 Εκ* Γ F o^NCr°'H F H y F l-({3,4“difiuoro [(2-fluoro iodopheny!)amino] phenyl} carbonyl) -3 -(trifluoromethy i)azetidin ο I 6 OH dA 05=/' ch2 P* 1-((3,4-difluoro [(2«fluoro iodophenyl)amino]phenyt)carbonyl) prop~2-en-l-ylazetidin-3“Ol 7 OH Γ~"^\-ΟΗ Π^ζΝ^ j HO^ F Η V, ,b"A 3-[l-({3,4-difiuoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidi n-3 -yl] propane-1,2-diol 8 oh3 Hoj^ Vn_,o p l-({3,4-difluoro ((2-fiuoro iodophenyl)anijno]phenyl}carbonyl) ethylazetidin ol 9 1 H | F 1 -({3,4-difiuoro [(2-iluoro-4~ !odophenyl)amino]phenyi}carbonyl) methyiazetidin-3“OJ 72

Crapd No. Structure Name 10 OH 0=211 &amp;#939; l-({3,4-difluoro-2~[(2-fluoro~4- iodophenyl)amino]phenyl} carbonyl) etlienyi azeiid in-3 -01 11 foA'0·»·0" F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyi) azetid in one oxime 12 FY fo [1-((3,4-difluoro [(2-fluoro io dophenyl)amino)phenyl} carbonyl) azetidin yi]methanol 13 \ F—A A H0Y YW F 1 -[ 1 -((3,4-difluorO“2-[(2-flaoro iodophenyl)amino]phenyl} carbonyl) hydroxyazetidin-3 -yl] ethane-1,2-diol 14 H2N^^ ury γ/ p Γ Η T ψΛ F 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino)phenyl)carbonyl) azeti d ln amine 15 Yk 0. r'G &amp;#910;° Λ-Y ZNH F HO 1-((3,4-difJuoro [(2“fiuoro iodophenyl)ammo]phenyl}carbonyl) -Λζ-hydroxy azeti d in e carboxamide 73

Cmpd No. Structure Name 16 Η n AA! 1J O-^CHa 0=¾^ CHj ,ΑΡ 1,1 -dimethy lethyl [1 -({3,4-d ifluoro [(2-fuoro~4- iodophenyl)amino]phenyl}carbonyl) azetkl in-3 -yl] carbamate 17 OH AJ Vn^o Γ Η 1 &lt;xA, F l-({3,4-difIuoro [(2-fiuoro~4-iodophenyl)amino]phenyl} carbonyl) “3-(pyrrolidin-l-ylmethyl)azetidin- 3-ol 18 gA F 3-[(diethyiamino)methyl]-l-({3}4- difiuorO“2“[(2-fluoro-4~ iodophenyJ)amino]phenyl}carbonyl) azetidin ol 19 OH 1 V-n^o T H T JA, F 1 -({3 )4-difluoro“2-((2“fluoro iodophenyl)am inoJphenyl} carbonyl) -3~[(dimethy lam mo)methyl] azetidm ol 20 &amp;#970; h AAf AU f F 0¾ tf-buty 1-1 -({3 54-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) azetidine-3 -carboxam ide 74

Cmpd No. Structure Name 21 q Γ&amp;#973;Λιη xi 5 F l-({3,4-difluoro [(2-ffuoro iodophenyl)amino]phenyl}carbonyl) -jV-prop en-l -ylazetidine carboxamide 22 | H 'π'νΤλ o F So, p N“[lX{3,4-difluoro-2~[(2“fluoro-4~ iodophenyl)ammo]phenyl}carbonyl) azetidin y!]-'2-methy!piOpanamide 23 H ΗγΝγ\ g Vnv0 Y H ? φζ&amp;#973;, F A"[l"({3,4-diftuoro-2“[(2“fiuoro~4-iodophenyl)aimno]phenyl} carbonyl) azetidin yljformamide 24 OH 0 F Xc F JV-[ 1 -({3,4-difluoro [(2-fiuoro iodophenyl)amino]phe'nyl}carbonyl) azetidin y 1)-3,4- dihydroxybutanamide 25 0 ΤΝγΟ p ¢¢6, F methyl [l-({3,4-difluoro [(2-fluoro iodophenyl)amino3phenyl}carbonyl) azetidin yl] carbamate 75

Cmpd No. Structure Name 26 H cxaA &amp;#912; Η &amp;#910; AS F //-butyi-1 -({3,4-ditiuoro [(2-fluoro iodophenyl)amino}pheny!}carbonyl) azetldin anitne 27 YNH* F H °y N-J i-({4~[(2-fluoro~4~ iodophenyl)amino] thienyI}carbonyl)azetidin amine 28 n hj/N-"7 p H AS F l-({3.4-difl«oiO-2~[(2-fiuoro iodophenyI)amino]phenyOcarbonyl) ((2S)-piperidin“2-yl3azetidin oi 29 AS 1 -({3,4-difluoro-2“[(2--iluorO“4- iodopbenyl)amino)pbenyl}carbonyl) -3~[(2#)-piperidin yl]azetidin~3-oi 30 , V3A 1 H 1 AS F 1 -({3,4-difiuoro [(2-fiuoro iodopbenyl)amino]phenyi}carbonyl) -3“pyrroUdin ylazetidin-3“Ol 31 (Λ&gt;1 -({3,4-difluoro [(2-fluoiO iodophenyl)annno}phenyl}carbonyi) ~3~pyrrolidin~2-yiazetidin~3“ol 76

Cmpd No. Structure Name F ο 3Λ3 F 32 HO \ F ovT/ H F (5)-1 -({3,4-difluoro [(2-ftuoro iodophenyl)aminojphenyl)carbonyl) -3 -pyrro i id &amp;#943;η ylazetid in-3 -ol 33 Ης^Η2 _ CX jLJ F 3-(aminomethyl)-l«({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) azetidin ol 34 OH f nh2 i H | Xc0 F 3-((15)-1 -aminoethyi3“l-({3s4-difluoro [(2-fluoro iodophenyl)aniino]phenyl}carbonyl)az etidin ο&amp;#943; 35 OH F 3 -[(17?)-1 -aminoethyl]-1 -({3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl }carbonyl)az etidin ο&amp;#943; 77

Cmpd No. Structure Name 36 OH I A Av F (3-(1-aminopropyI) hydroxyazetidin- l-yl)(3,4-difluoro-2~(2-fluor&lt;&gt; iodopheny lam i no)pheny Qmethanone 37 OH r-'-Ls— f °Y^\sh2 AW F (k)-{3“(l“arninopropyl)“3-hydroxyazetidin-l -y 1)(3,4-difiuoro (2-fiuoro-4·· iodophenylamino)phenyl)methanone 38 OH ΟγΝ^Α /.A F (5)-(3-( 1 -aminopr opyl)-3 - hydroxyazetidin-l-yQ(3,4-difluoro- 2-(2-fluoro tod ophenylam ino)pheny Qmethano ne 39 f H Y&lt;w° AY F l-({3,4-difluoro [(2-fiuoro iodopheny Qamino] phenyl} carbonyl)-yV-ethy 3 azeti d ine-3 -carboxam ide 40 F Y&lt;yM AM A:, HN-V-OH AA F 1 -({3,4-difluoro [(2-fluoro iodophenyl)am ino]phenyl} carbonyl)-#•(2 -hydroxyethy l)azetidine-3 -carboxamide 41 &amp;#938; h°AH° Αμ&amp;#902; a A ρΑγ &lt;,0 i-({3/1-difiuoro [(2-fhioro- iodophenyl)amino]phenyi}carbonyi)- N-(2-piperidm-l-yiethyI)azetidine carboxamide 78

Cmpd No. Structure Name 42 ck. nJ h 2Q F l-({3,4-difiuoro-2S(2-fluoiO'4" iodopheoyl)araino)phenyl}carbonyl)- N-phenylazetidine carboxamide 43 ovnJ h | i h ] F /V-[2-(diethylamsno)ethyl]-l“({3,4- diiluoro [(2-fluoro iodophenyl)amino]phenyi)carbonyi)az etidine carboxamide 44 F Η γ &amp;#973;# F 1-((3,4-difluoro [(2-fluoro io dopheny l)am &amp;#943; nojphenyl} carbonyl)# -(morphol in ylmethyl)azetid in ol 45 OH °H0 OxjJ F i H | ,σ;·&amp;#941; F 1-((1-((3,4-difluoro [(2-fluoro~4-iodophenyI)amino]phenyl}carbonyi) hydroxyazeti din-3 -y I]methy f} piperid in oi 46 ,H °\ ·Η % (°) F hVJ F 3-([bis(2- hydroxyethyl)amino]methyl ) ((3,4-diiluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl)az etidin ol 79

Cmpd No. Structure Name 47 z('V 0 '-'Νγ® p C/O, F /V-[b({3,4~difI«oro-2“[(2-fluoro-4~ iodophenyl)amino]phenyi}carbonyl)az et j d in-3 -yl] (4-methyipiperazan-1 - yOacetamide 48 ft F H°YNJ &amp;#973;ν F 1 -({3,4-difiuorO“2-[(2“fluoro iodophenyt)amino}phenyl)carbonyl) [(4-methyIpiperazin-l - yl)methyl]azetidin ol 49 H. / N ο \ 1 F H VJ Av ; F 1 “({3,4’'difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(4-methyH,4-diazepan-I-yi)ittethyi]azetid in-3 -o 1 50 OH rp NMT '—' I H 1 Λψ F &amp;#938; -({3,4“difIuoro [(2-fluoro iodophenyl)amino]phenyO carbonyl)-3 -{[methyl( 1 -methylpyrroHdin-3 -y Qamino'j methy l}azendin~3~ol 51 o v° F H°YnJ Nv F 3-(l#4'-bipiperidin-r-ylmethy3)-l' ({3 54-dtfluorO“2-[(2-fluoro-4“ iodophenyl)amino]phenyl}carbonyl)az etidin ol 80

Cmpd No. Structure Name 52 HOW ° h F WA F Λ4 H {3 /Fdif]uoro [(2-fi uoro iodophenyl)am tnojpheny 1} carbony I)az etidin-3 -yl] -jV,Y-bts(2“ hydroxyethyl)glycinam i de 53 &lt; 7 X^-N apE _ Ck-N-J I Μ 1 AM F 3-({4-{2-(diethy laminojethy l]p iperazin-1 -y!} mettiyO-H{3,4-difluoro-2“[(2-fluoro iodophenyl)amino]phenyi}carbonyl)az etidin-3 “ol 54 l~t 0 0 \ ) F HOYNJ Α&amp;#973; F 1 -({3,4-difluoro-2*l(2-f5uoro lo dophenyl)am ino]phenyl) carbonyt)-3 - EG- bydroxyethyl)(methyl)amino]methyl}a zetidin ot 55 G"Vv. o F 7W[1 -({3.4-djf]uoro [(2-fluoro-4~ iodophenyl)amino]phenyl}carbonyl)az etidin yl] piperidin-l-yiacetamide 56 o Ac, F 77-[l-({3,4~difluoro [(2-fluoro todophenyl)amtno]phenyl}carbonyl)az etidin y l]-X3~(2-hydroxyethy 1)-7/3 - methyi-beta-ataninamide 81

Cmpd No. Structure Name 57 OH S H Q V—N r u H j gA F //-(1-((3 &gt;4-di8uoro ((2-fluoro iodophenyi)amjno]pbenyl)carbonyl)az etid in yQ-/V3f/V3-b ls(2-bydroxyethyl)-beta-alaninamlde 58 '&amp;#902;-'&amp;#910;’Λ 0 VbiyO $o F /HH{M"difluoro-2“[(2~ftuoro-4" iodophenyi)amino]phenyl}carbonyl)az etid in y I J-/V2,/V2-d tethy Iglyc inam ide 59 H γλ p Λ’&amp;#943; F 1 -((3,4-diOuoro [(2~fluoro iodophenyl)amino]phenyl}carbonyl)~ //-methylazetidin amine 60 nCY~\ ry \ f V &amp;#910; zz F 1-(1-((3,4-difluoro [(2-fluoro iodophenyl)ammo]pheoyt}carbony!)az etidin yi]-N}/V-dimethyipyrrolidin amine 61 V.Z I a 1 0H ΛΑ F 2-((1-((3,4-difluoro [(2-fluoro-4~ iodophenyl)ammo]phenyl}carbonyl)az etidin y I] amino} ethanol 82

Cmpd No. Structure Name 62 ry 2 ex. nA Ai? F Ar~p-({3&gt;4-diflu0ro [(2-fluoro-4~ iodophenyi)am inojpheny &amp;#938;} carbonyi)az etidin yl]propane-l ,3-diamine 63 AVa 3-((dimethyIamino)methylj ((4-((2- nuorO"4-iodophenyl)amino] thienyi}carbonyl)azetidin~3 -ol 64 A 1 l-((3,4-difluoro ((2-fluoro iodophenyl)amino]phenyl}carbonyl)-N-methy]-A(2-pyridin ylethy I)azetid in-3 -amine 65 °Y^n" HN__” yr Aa F ^-(1-((3,4-4111^0 ((2-^11010 iodophenyi)amino]phenyi}carbonyi)az etid in-3 -ylJ-M-methylgfycinamide 66 H Ai&gt; F 1 -({3,4-difluoro-2“ ((2-fluoro iodophenyl)amino]phenyi}carbonyi)“ N-ethylazetid in-3 -am ine 83 I Cmpd No. Structure Name 67 JU Λ "Y Λγ F 1 -({3,4-difluorz&gt;2-[(2-fluoro iodophenyl)amino]phenyl}oarbonyl)- jV-(2-methylpropyI)azetidin amine 68 F Y-(cyclopropyJmethyl)-l -({3,4- difluoro-2~[(2-fluoro iod opheny l)am tnojp henyi} carbony!)az etidin amine 69 OyliT 1 &lt;Y = F Z/-(cycl ohexyimethy!)-1 -({3,4-difl uoro [(2-fluoro iodophenyi)amino]phenyl}carbonyi)az etidin amine 70 jY „ O^NU F Y F Y-(cycl opentyimethyl)-!-({3,4-difIuoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin amine 71 H ___ F H°YNJ &amp;#973;γ F 3-(azetidin-l-ylmetbyl)-! ~({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)az etidin ol 84

Cmpd No. Structure Name 72 Y/Q F l-({3„4-difluoro [(2-fluoro iodophenyl)amino]phenyi}carbonyl)- /7-((2,3- d ihydroxypropyl)oxy] azetid in e-3 -carboxamide 73 Y„„ ; h V&gt; Λγ F 2-({[l-((3,4“difiuoiO ((2-fluoro iodophenyi)am ino]phenyl} carbony l)az etidin yl] methyl} am ino)ethanoi 74 Λ Q. X lnh? &amp;#970; «vx F /7-((1-((3,4-difluoro [(2-fluoro iodophenyi)am inojpheny i} carbony l)az etidin yl]methyl}ethane-l,2-diamine 75 H h2n^YnVa δ f F 77-(1-((3,4-difluoro [(2-fluoro iod ophenyi)am ino] pheny 1} carbony l)az etidin y0glycinamide 76 I chi F t 6-((3- [(d imethylam ino)methyl]azeti d in-1 - yI}carbonyl)-2,3-diffuoro-/V-(2-fluoro- 4-iodophenyl)aniline 85

Cmpd No. Structure Name 77 H, u /::5 F 1-((3,4-difluoro j'(2~fluoro iodophenyl)amino]phenyl}carbonyl)“3“ {[(1- methyiethyI)amino]methyi}azetidin ol 78 q p-OH (JAA, F l-({3}4-difiuoro [(2-ftuoro iodophenyl)amino]phenyl}carbonyl)- jVR3,4~dihydroxybutyl)azetidine carboxamide 79 0 0h h -n/° f p 1 -({3,4-difluoro [(2“fluoro-4“ iodophenyl)amino]phenyl}carbonyl)-/V-(2s3“dihydroxypropyl)azetidine carboxamide 80 H r/'H F H°YnJ F 1 -({2,4-difluoro [(2-fiuoro iodophenyl)amino]phenyi}carbonyl)ax etidin amine 81 H r/'H r- o F Η γ Au F l-({4J5-difluoro [(2-f3uoro iodophenyi)amino]phenyi}carbonyl)az etidin amine 86

Cmpd No. Structure Name 82 H'o &amp;#906; F ΗθγΜ-Υ γγ F 1 -({3,4-d ifluoro [(2-fluoro iodophenyl)amino]phenyi) carbonyl)-3 -hydroxyazetidine carboxamide S3 "0 V Ν&amp;#910; F Η γ ,&amp;#973;γ F 6-{ [3-(aminomethyi) (methyloxy)azetidin-1 -y SI carbonyl} -2,3-d ifluoro-N-(2“fluoro iodophenyi)aniline 84 H-0 V . γ&amp;#970; r u θ r H γ YY F Ar-{[l-({3,4“difluoro ((2“fluoro iodophenyl)amino]phenyi}carbonyi) hydroxyazetidin - yljmethyl} acetamide 85 γ&amp;#910;νΑ CkzN-J H 1 H ? γ&amp;#973;, F 2,3-difluoro-Y-(2-fluoro iodophenyi) [(3-{[(l- methy lethy i)amino]methyl} azetidin-1 - yl)carbonyl]aniline 86 OH o^nY-n ,Χ&amp;#972; p l-GS^-difluoro^-f^-fluonM- iodophenyl)amino]phenyl}carfeonyl) [(ethylamino)methyl]azetidin ol 87

Cmpd No. Structure Name 87 V HbL | OH A Viy F qA F 1-((3,4-difluoro ((2-fluoro iodopheny l)am ino] phenyl} carbonyl)~3 -(2-((1- methylethyl)amino]ethyl}azetidjn“3-ol 88 hoACR An^o δ&amp;#972;. p 1-((3,4-difl uoro ((2-fluoro iodophenyl)amino]phenyl)carbonyl) (2-hydroxy-1,1 -dimethy lethyl)azetidin ol 89 1 Vnvo &amp;amp;Λ F l-({3,4-difluoro-2~[(2-fluoiO iodophenyl)amino]phenyl}carbonyl) (lsl-dimethyl“2-t(l-methyiethyl)am ino] ethyl} azetidin-3 -ol 90 \ nh2 n A-- N p SA F 1-((3,4-difluoro~2-((2-fiuoro iodophenyl)amino]phenyl}carbonyi) (t(i- methylethyl)amino]methyl} azetidln amine 91 OH &amp;#970; »χΑ AS F 3-[(cyclopropylamino)methyf|-l~ ({3,4-difluoro ((2-fluoro iodophenyl)aminojphenyi}carbonyl) azetid in ol 88

Cmpd No. Structure Name 92 OH F l-({3,4~difluoro-2~((2-fiuoro~4-iod ophenyl)am inojphenyl) carbonyl)~3 -{(0,2,2- trifluoroethyl)amino]methyl}azetidin- 3-oi 93 % Λ rPJ F HOYNJ A# F 1 “({3,4-djfiuoro ((2-fiuorO“4-iodopheny l)an™o3phenyl} carbonyl)~3-(l//-imidazol-l-ylmethyl)azetidin-3~oi 94 H. n rlJf- F Η F l“({3i4“difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyI) {((U- dimethylethyl)ammo] methyl jazetid in ol 95 OH F C0 F 3 -{(cycl opentyiamino)methy 1] -1 -({3,4-difluoro-2“((2-fluoro iodophenyi)amino]phenyl}carbonyl) azetidin ol 96 Lf 0 4 MM F h°ynJ Λ &amp;#973;ν p l-({3,4-difluoro-2~[{2-fluoro iodophenyi)amino]phenyi}carbonyi)-3~ hydroxy ~/V“prop en-1 -ylazetidine carboxamide 89

Cmpd No. Structure Name 97 HO OH H A E „γΑ AA F 1 •({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyi}carbony!)-7^-(2,3-dihydroxypropyl)-3 -hydroxyazetidine-3 -carboxamide 98 OH ; „ "At’· AV F 1 -({3,4-difiuoro [(2-fluoro iodophenyl)amino]phenyl}carbonyi) (lH-l,2,3-triazol-l-ylmethyl)azetidin oI 99 OH F l-({3,4~difluoro~2-[(2-fluoro iodopbenyl)amino3phenyi)carbonyl) {[(2,2- dimethylpropyl)amino]methyl}azetidin -3“Ol 100 H OH u-i^o i?:d, F 1 -({3,4-difluoro [(2-ftuoro iodophenyl)amino]phenyl}caxhonyi) [(propylamino)methyi]azeddin ol 101 V-N^O Am F l-({3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl}carbony!) ~3-{[(2- methylpropyl)amino]methyi}azetidi n ol 90

Cmpd No. Structure Name 102 % V f h°ynJ AV F 3-{[(cyclopropylmethyl)amino]meth yl} -1 -({3 54-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) azetidin ol 103 % &gt;? j3 A*"' F H°YNj AM F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(phenylmethyl)amino] methyl) azetidi n ο&amp;#943; 104 OH p θΑχ'ΗΑ n—. V F 3 - {[(eye lo hexy lmethy l)am i no Jmethy 1} -l-({3,4-difluoro [(2-fluoro iodophenyl)amino)phenyl)carbonyl)az etidin ol 105 V F Η &amp;#910; W F 3-[(butylamino)methyl]-l-({3,4- difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl)az etidin o! 106 A Η 0 F Η °γΝ J Av F 1 -({3,4-difluoro [(2-fluoro iodophenyI)aminoJphenyl)carbonyl) ({[(1 -ethylpyrrolidin yl)methyljamino}methyl)azetidin oi 91

Cmpd No. Structure Name 107 OH H n^°h _ 0;. ,N-J 1 H &amp;#910; Λα F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl} carbony 1)-3 -(K2- hydroxyethyl)amino]methyl}azetidin- 3-ol 108 0^-ΝΛ F 1-((3,4-difluoro [ (2-fluoro iodophenyl)amino]phenyl}carbonyl) (([2- (dimethylamino)ethyl]amino}methyl)a zetidin ol 109 A"y c U NA i-0 F Η Λ ' 1 1 H Λα F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(2-hydroxy-l,l- d imethy Iethy l)amino] methyl} azetidin 0/ 110 OH Η ,ΛΛ R1-' ΛΛ faJ F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl} carbony 1)- 3 -(([2-(4- methylphenyl)ethyl]amino}methyl)azet idin ol 111 OH H 1 H V.z F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]pheny 1} carbonyl)-3 -[(prop en-1 -ylam ino)methyl] azetidin ol 92

Cmpd No. Structure Name 112 OH H φΝΑ7 0^. nA 1 H T AA F 1-((3,4-difluoro [(2-fluoro iodophenyl)ami nojpheny 1} carb ony 1)-3 -({[2-(l-methylpyrrolidin yl)ethyl]amino}methyl)azetidin ol 113 oh t! f AA) &amp;#912; η &amp;#910; jrAxS .aa ρ&gt;ψ F 1 -({3,4 -d ifluoro [(2-fluoro iodophenyl)am inojpheny 1} carbonyl)-3 -[(2,3-dihydro-17/-inden y lam ino)methy 1] azetid in-3 -o 1 114 OH H LA ryAs O,&gt;ZNJ &amp;#912; H 1 xVko A-A AA F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(tetrahydrofuran ylmethyl)amino]methyl}azetidin ol 115 OH H „0 ν'^-Λ&amp;#908;ο &amp;#943;&amp;#910;η ,Λτ fAa F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -({[2-(tetrahydro-2 Apyran yl)ethyl]amino}methyl)azetidin ol 116 HO OH H 1 .V.A &amp;#912; H 1 Ay F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyI) ({[(!£ 25) hydroxy cyclopentyl] amino } methy l)aze tidin ol 93

Cmpd No. Structure Name 117 YY &amp;#912; h°ynJ^ k Λζψ F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbony 1)-3 -{[(1,1 -dimethy Iprop yn-l -y!)amino]methyI}azetidin ol 118 o OH H-- „ 0, ,N-./ T h T F 1 -({3,4-difluor o [(2-fiuoro iodophenyl)amino]phenyl}carbonyi) {[(3-pyrrolidin-l- ylpropyi)amino]methyI}azetidin ol 119 H \ OxzNJ ' F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) {[(1,2- dimethylpropyl)amino]methyl)azetidin 01 120 OH h Ox.nJ kA No - F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyI}carbonyl) ({[2-(177-imidazol yl)ethyl]amino}methyl)azetidin oi 121 OH H Οχ,ΝΑ ' f H 1 Γ&amp;#943; nyS ,/U FzU F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[l-methyl (methyioxy)ethyi]amino} methyi)azetid in ol 94

Cmpd No. Structure Name 122 OH H F o^nJ V AM &gt; F 1 -((3 54-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[3~ (ethyloxy)propy 1] amino} methy l)azetidi n ol 123 OH H ) o V } | H | z F l-({3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl} carbonyl) &lt;[(i- ethylpropyl)amino]methyl}azetidin ol 124 OH H F yTG Αα&amp;#902; ,Λ&gt; FKf F 1 -({3,4-difluoro f (2-fluoro iodophenyl)amino]phenyl} carbony 1)-3 -{[(33- d imethy lbuty 1) am ino ] methy 1} azetid in 01 125 OH H /,-, F GV F ethyl 4-({[l-({3,4-difluoro [(2-fluoro iodophenyl)aminojphenyl} carbonyl) -3 -hydroxyazetidin-3 -y Ijmethyl} amino)piperidine-1 -carboxylate 126 OH H F XV Γ&amp;#943;&amp;#910;&amp;#943; ,JU F l-({3,4-difluoro [(2-fluoro iodophenyl)aminojphenyl} carbony 1)-3 -{[(3- methylbutyl)aminojmethyl}azetidin ol 95

Cmpd No. Structure Name 127 HO &amp;#912; Η &amp;#910; Αχ F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]pheny 1} carbonyl)-3 - ({[2- (ethyloxy)ethy 1] amino} methy l)azetidin ol 128 OH H 5 „ ? ,Αχ ” F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[3- (dimethylamino)propyl]amino} methyl) azetidin ol 129 OH H F .jW &amp;#943; Η V (|ΥΝνη F 3 -[(cyclobuty lamino)methy 1 j ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 130 HO N"X__ F °VN H .yj F 3-({[3- (diethylamino)propyl]amino}methyl) ((3,4-difluoro [(2-fluoro iodophenyl)am inojphenyl} carbonyl)az etidin ol 1 131 H 0 H X-A F Η “A ( Αχ &lt;&amp;#912; F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[3-(177-imidazol-1 - yl)propy Ijamino} methyl)azetidin-3 -ol 96

Cmpd No. Structure Name 132 H '0 H &amp;#970; &amp;#938; yR Λ/ ' F 1-((3,4-difluoro [(2 -fluor o iodophenyl)amino]phenyl}carbonyl) ({[2- (methylthio)ethyljamino}methyl)azetid &amp;#912;η ol 133 H %% A F 1-((3,4-d ifluoro [(2-fluoro iodophenyl)amino]phenyl} carbony 1) (((1 -(pheny lmethyl)piper i d in yj]amino}methyl)azetidin ol 134 HO ο Y Η&amp;#910;&lt;\ 1 H 7 Ox Av F 3-(((2,2- bis(methy]oxy)ethyl]amino}methyl)-l-((3,4-difluoro [(2-fluoro iodophenyi)amino]phenyl}carbonyl)az etidin ol 135 p /-A F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -{[(1,1,3,3- tetramethylbutyl)amino]methyl}azetidi n oi 136 H. 0 H\ y rVyNV r nVJ F 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -{[(1,1- dimethylpropyl)amino]methyl}azetidin ol 97

Cmpd No. Structure Name 137 H 'OH. F H °VN J H o'i F 1-((3,4-d ifluoro [(2-fluoro iodophenyl)amino]phenyl) carbonyI)-3 -[(2,3-dihydro inden-l -y lam ino)methyl Jazetidin-3 -o 1 138 H OH. F H °yn0Lz Y AA f p λ' 1-((3,4-difluoro [(2-fluoro i odopheny l)amino ]phenyl} carbony 1)-3 -[({2- [(phenylmethyl)oxyjcyclopentyl) amino )methyl]azetidin ol 139 H 0 H p u 0&lt;^η&amp;#902; /-0 F Η γ H2N—/ h yA F 1 3-{[(3-amino hydroxypropybami noj methyl ) ((3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl) carbonyl)az etidin ol 140 O O. U-J ) HO AA F 1 -((3,4-difluoro [(2-fluoro &amp;#912;odophenyl)amino]phenyl)carbonyl) ( ([2-hydroxy-l- (phenylmethy])ethyl]amino}methyl)aze tidin ol 141 H, Ο H y--\ H /) ,&amp;#940;&amp;#902; F 3-[(cyclooctylammo)methyl] ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 98

Cmpd No. Structure Name 142 F 3 - {[ (1 -cy cl oh exy 1 ethyl) amino J methyl} -l-({3,4'difluoro ((2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 143 H r AM F 3 -[(cyclohepty lamino)methylj -1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etldin ol 144 H F H oyfCr V/γ MM F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbony 1)-3 -{((2-pyridin-3~ ylethyl)amino]methyl}azetidin ol 145 Η, o F HVJ MM F l-({3,4-difluoro [(2-fluoro iodopheny l)amino]phenyl} carbony 1)-3 - ({[3- (methylthio)propyl]amino} methyl)azeti din ol 146 H. Rv H 0 H &gt;-N mM F N-cy cl oh exy 1-JV~2~- {[ 1 -({3,4-difluor o [(2-fluoro iodophenyl)amino]pheny 1} carbonyl)-3 -hydroxyazetidin-3 -yl]methyl} methylalaninamide 99

Cmpd No. Structure Name 147 AS F 1 -((3,4-difIuoro~2-[(2-fluoro iodophenyl)amino]phenyl}carbonyl) {((tetrahydro-2/y-pyr an ylmethyl)amino]methyl}azetidin ol 148 H AS " F 1-((3,4-difluor o [(2-fluor 0 iodophenyl)amino]phenyl}carbonyl) (((3- hydr oxypropyl)amino] methyl} azetid &amp;#943;η ol 149 H 0 H A-A F Η °·γΝΑ γ&amp;#902; AS F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]pheny[}carbonyi) {((2-pyridin y lethy l)amino]methyl} azetid in-3 -ol 150 θ'" rA O AAA A-2 p H H AS F 1 -((3,4-dif!uoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({(1 -(phenylmethyl)pyrrolidin yl]amino}methyl)azetidin oi 151 θ.Η γΑν-α/Λ r , , Η γ Η AS F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[2-(2- th i eny 1) ethyl] am ino} methyl) azetidin-3 -oi 100

Cmpd No. Structure Name 152 h oAkA Mi F 3-[({2-[bis(l- methylethyl)amino]ethyl}amino)methy l]-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 153 .H 0 F H°V^ F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[2- (pheny &amp;#943; oxy) ethyl] am ino} methyl) azetid &amp;#943; n ol 154 H 0 H , Η Β ' &amp;#908; Ai F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]pheny 1} carbonyl)-3 -[(phenylamlno)methyl]azetidin ol 155 H 0 \ - F ΗνΑΜΗ Mi F 1 -({3,4"difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(2- hydroxypropyl)amino]methyl}azetidin- 3-ol 156 H F ,YN F 1 -({3,4-difluoro [(2-fluorO“4~ iodophenyl)amino]phenyI}carbonyl) [({2-[(l~ methylethyl)oxy]ethyl}amino)methyl]a zetidin ol 101

Cmpd No. Structure Name 157 ,H .si F 1 -({3,4-difluoro-2“[(2-fluoro iodophenyl)amino]phenyI}carbonyI) {[(l-ethylpiperidin yl)amino]methyl}azetidin ol 158 Κ· H Ck F Η γ Av F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl) carbony 1) ({f.2- (methyloxy)ethy l]amino} methy l)azetid in ο I 159 HO 0 W°' F hAV Av F 1 -({3,4-difluoro-2~[(2-fluoro i odophenyl)amino]phenyl} carbonyl)~3 -(1 -nitropropy l)azetidin-3 -ol 160 oh[ /γχ ovnJ aY F 3-(1 -aminoethyl)-1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 161 / AN H. H ( ) ? b /"S r'-L·' F H°YNJ Av F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[(1-methy lpiperidin yl)methyl]amino}methyl)azetidin ol 102

Cmpd No. Structure Name 162 f ' Ay F 1-((3,4-d ifluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[4- (dimethylamino)butyl]amino}methyl)a zetidin oI 163 H H 0 7 XiA A) Ay F 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino Jphenyl} carbonyl)-3 -{[(2-furan ylethyl)amino]methyl}azetidin ol 164 Η. H O'/ F ,γ&amp;#902; Ay F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl) carbonyl)-3 -{i-Kki- dimethylethyl)amino]ethyl}azetidin oi 165 H'o * C/ f h°ynJ Ay F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ([(2-ethylbutyl)amino]methy]}azetidin ol 166 o-H % F HOYNJ Ay F 1-((1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin-3 - yl]methyl}pyrrolidin ol 103

Cmpd No. Structure Name 167 o F Η V Xi F 1 -({3,4-difluoro [(2-fluoro io d opheny I)am inoj phenyl} carbony))-3 - ({(25) [(methyloxy)methyl]pyrrolidin-l- yl}methyl)azetidin ol 168 F l-({3,4-difluoro [(2-fIuoro iodophenyl)amino]phenyl}carbonyl) {[(2- hy dr oxypheny l)amino] methyl} azetidin- 3-oI 169 H &amp;#908; H F H Λα - F l-({3,4-difluoro~2-[(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(4- hydroxyphenyl)amino]methyl}azetidin- 3-oI 170 „"γ”7-ρ Λα κ"° F l-({3,4-difluoro [(2-fluoro iodophenyl)aminoj phenyl} carbonyl)-3 -&lt;L(3- hydroxyphenyl)amino]methyl}azetidin- 3-oi 171 H Λα F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(phenyloxy)methyl]azetidin oi 104

Cmpd No. Structure Name 172 H H &amp;#908; H I F Η °γΝ J XXh AX " F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) {[(lr,3r,5R7R&gt;- tricyclo[3.3.1.1 ~3,7~]dec ylamino]methyl}azetidin ol 173 H '0 H , .VA AX ‘ " F 3-({[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyI}carbonyl) hydroxyazetidin-3 - yl]methyl}amino)propane-l,2-diol 174 Η Χ"ΟΗ 0 I ANH F H°YNJ AX F 79-{[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]pheny 1} carbonyl)-3 -hydroxyazetidin yl]methyl)-L-alanine 175 H, F yyfAX) F Η γ A AX F 1 -({3,4-difluoro [(2-fluoro-4“ iodophenyl)amino]phenyl) carbonyl)-3 -[(pheny lthio)methyl] azetidin-3 -o 1 176 0 H -_AoH 0 4 χ-Α/ΝΗ F H°YnJ XX F /V-{ [1 -({3,4-difluoro [(2-fluoro iodopheny l)am inojphenyl) carbonyl)-3 -hydroxyazetidin yl]methyl)-D-alanine 105

Cmpd No. Structure Name 177 YNH F Η YN J Λγ F methyl 7V-{[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methyI}alaninate 178 H &amp;#908; H /Y^H , „°Y ° » A F 3-[({[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-3~ hydroxyazetidin-3 - yl]methyl} amino) oxy]propane-1,2-diol 179 N F V A) HN&gt; 'AQaiV&lt;xOH F 1 -({3,4 -d ifi uoro [(2-fluoro iodophenyl)amino]phenyi}carbonyl) ({[(5 -methyl-1,3,4-oxadiazol yl)methyl]amino}methyl)azetidin ol 180 F YyCAa --. F 1 ~({3,4~difluoro [(2-fluoro iodopheny l)amino] phenyl} carbonyl)-3 -{[(1~ methy ibuty l)am ino Jmethyl} azeti din-3 -ol 181 OH f : , ' F 1-((3 ,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(!- methylpropyl)amino]methyl}azetidin- 3-ol 106

Cmpd No. Structure Name 182 OH F : V : F 1-((3,4-difluoro ((2-fluoro iodophenyl)am inojphenyl} carbonyl)-3 -{[(2- methyIbutyl)amino]methyl}azetidin ol 183 OH F F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl) carbonyl)-3 -[(pentylamino)methyl]azetidin ol 184 F °vnJa ΛγυΛ N--A 3 -[(1S)~1 -aminoethyl]-1 -({ 8-fluoro [(2-fluoro iodophenyl)amino] imidazo[ 1,2- «]pyridin yl}carbonyl)azetidin ol 185 OH H Wv F o^nA \ 5, N-v 1 -({ 8-fluoro -7 - [(2-fluoro iodophenyl)amino]imidazo[l,2-z?]pyridm yl) carbony 1)-3 -[(15) (methylamino)ethyl]azetidin ol 186 HO γ-γ fA n-O hr H oA F N—v # (A 1 3 -[(cyclohexy lam ino)methyl] ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 107

Cmpd No. Structure Name 187 OH MM ( F 1 -((3,4-difl uoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -[l-(ethylamino)ethyl]azetidin ol 188 M FM M &amp;#943; 3-[(azepau y}amino)methyl]~l~({3s4- difluoro [(2-fIuoro iodophenyl)amino]phenyl}carbonyl)az etidin-3~o] 189 χ»μ&amp;#973; F Η °γΝ J ξ MM F l-({3,4-difluoro [(2-fIuoro iodophenyi)aminojphenyl}carbonyl) ({[2-(dimethylamino)-l - methylethyl]amino}methyl)azetidin ol 190 V H. NH M# F JV-cycl opropyl-1 -({(1 -({3,4-difluoro [(2-fluoro iodophenyl)aminoJphenyI}carbonyl) hydroxyazetidin-3' yl3methyl}amino)cyclopentanecarboxa mide 108

Cmpd No. Structure Name 191 HO h NJ H "IH U 0 G l-({334~difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[2-(2,3-dihydro-17/-indol yi)ethyl]amino}methyl)azetidin ol 192 HO Η O Gh F 77- ( [1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)~ 3 -hyd roxyazetid in-3 -yl] methy 1} -N-ethyl methylalaninamide 193 H &amp;#908; H / γ-ΗΗ'ν F Η °γΝ J F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -[(2-methylhydrazino)methyl]azetidin ol 194 H HO U-N^O K ' F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(hydroxyamino)methy 1] azetidin-3 -o 1 195 \ tl HO °'Or-A U-N-^O F 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(methyloxy)amino]methyl}azetidin- 3-ol 109

Cmpd No. Structure Name 196 tl HO O'NJA Sa, F 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyI) {[(ethy loxy)ammo]methy 1} azetid in-3 -ol 197 Γ H- H , X AS F l-({3,4-diiluoro [(2-fluoro iodophenyI)amino]phenyl}carbonyl) [ 1 -(ethy lamino)propyl]azetidin-3 -ol 198 H Ο H r .yX"^" AS F 3 -[(azetidin-3 -y lamino)methy 1]-1 -({3,4-difluoro [(2-fluoro iodophenyi)amino]pheny]} carbony))az etidin ol 199 H, 0 H s r u bA γ Η AS F l-({3,4-difluoro ((2-fluoro iodophenyl)amino] phenyl} carbonyl)-3 -[(l,3-thiazol ylamino)methyl]azetidin ol 200 OH H H AA) Λν yS nA 3-( 1 Ff-benzimidazol yl)-1 -({8-fluor o [(2-fluoro-4 -iodophenyl)amino] imidazof 1,2-a]pyridin yl}carbonyl)azetidin ol 110

Cmpd No. Structure Name 201 OH H F „vY BrY Ax 3-(l//-benzimidazol yl)-l-((7-[(4- bromo fluorophenyl)amino] fluoroimidazo[l,2-a]pyridin yl}carbonyl)azetidin ol 202 X Υυ 0 r- u F ri η AY |/\A F-YjY F 1,1 -dimethylethyl [3-({[1 -({3,4- difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin ylj methyl} am ino)propylj carbamate 203 H. HHY&gt; γ/Α-7 OYA F Η V &amp;#902;Α F 1-((3,4-difluoro ((2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -([(pyrrolidin ylmethy l)amino]methyl} azetidin-3 -ol 204 0 ,/A Λ F Y AA F 1,1 -d imethylethy 14-[( ([ 1 -((3,4-difluoro [ (2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxy azetidin-3 - yl]rnethyl}amino)methyl]piperidine-l- carboxylate 111

Cmpd No. Structure Name 205 F HOYNJ Mi F 1 -({3,4-d ifluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) ({[(2- hydroxyphenyl)methyl]amino}methyl) azetidin ol 206 H 0 H A pH F H°YNJ Mi F 1-((3,4-difluoro [(2-fluoro iodopheny l)amino]pheny 1} carbonyl)- 3 -({[(3- hy droxypheny l)methylj amino} methyl) azetidin ol 207 O-u A F Η°Μ Mi F 1 -((3,4-difluoro [(2-fluoro i od opheny 1) am ino] phenyl) carbony 1)-3 - ({[(4- hydroxyphenyl)methyl]amino}methyl) azetidin ol 208 H 0 tj H rM 0 F H °yNj vi F 1-((3,4-difluoro [(2-fluoro iodopheny I)amino]pheny I} car bony 1)-3 -{[(4- hyd r oxy b uty l)am i n o] methy 1} azeti din ol 112

Cmpd No. Structure Name 209 Aa F Η H Ay F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(2- hydroxyethyl)oxy]methyl}azetidin ol 210 HO OH H L· CY.N-J A y F 1 -({3,4 -difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) ({[(15,25) hydroxycyclohexyl]amino}methyl)azet idin ol 211 ,. H Aa Ay F 1-((3,4-difluoro -2 ~[(2-fluoro iodophenyl)amino]phenyl)carbonyl) {[(1,1 -d imethy 1-2 - pyrro 1 idin ylethyl)amino]methyl)azetidin ol 212 HO Η F HOYNJ Ay F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (([(1 -methy 1-1 //-imidazol yl)m ethyl] am ino} methy l)azeti d in-3 -o 1 213 HO H A&gt; rpA F Η °γΝ Ay F l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl) carbonyl)-3 -({[(1 -methyl-1 //-imidazol yl)methy 1] amino) methyl)azetidin-3 -ol 113

Cmpd No. Structure Name 214 H A Λα F 1 -({3,4-difluoro [(2-fluoro iodophenyl)am inojphenyl} carbonyl)-3 -({[(25) (methyloxy)cyclopenty ljammo} methyl )azetidin ol 215 X X.Λ ' F 3-{ [1,1 '-bi(cyclohexyl) yIamino]methyl}-l-({3,4~difluoro-2~ [(2-fluoro iodophenyl)aminojphenyl}carbonyl)az etidin ol 216 °h jTX Οχ,νΑ h 1 C X F l-({3,4-difluoro [(2-fluoro-4~ iodopheny!)amino]phenyl} carbony 1)-3 - ({[3- (methyloxy)phenyl]amino}methyl)azeti din-3 -ol 217 x „Y» f „Χγ^"Υ Λ&amp;#943;γ F l-({[l-({3,4-difluoro [(2-fluoro lodophenyl)amino]phenyl}carbonyl) hy dr oxy azetid in-3 - yl]methyl}ammo)cyclopentanecarboxyl ic acid 218 , Λ&amp;#940; ΛΑ F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(4- fluoropheny l)amino]methyl} azetidin-3 -ol 114

Cmpd No. Structure Name 219 . HO Av ογ H N , X - 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbor^yl) [(l,3,5-triazin y lamino)methyl]azetid in o 1 220 AV” OA F H 0 ,;'A 1-((3,4-d ifluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-3“ {[(trans hydroxycyclohexyl)amino]methyl}azet idin ol 221 HO r~~y V/V nA oV H oX 3 -[(cyclopent-3 -en-1 -y lamino)methy 1] ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 222 HO A\ id μ&amp;#910; v oM H ° X-A N-[4-( {[ 1 -((3,4-difluoro I (2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin-3 - yl]methyl}amino)phenyl]acetamide 223 HO &amp;#939;"fjYx / A H n F H A AA N-[3 -({[1 -((3,4-difluoro [(2-fluoro- 4-iodophenyl)amino]phenyl}carbonyl)~ 3-hydroxyazetidin yi]methyl}amino)phenyl]acetamide 115

Cmpd No. Structure Name 224 OH . F VnTv X X F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (l-methylpyrrolidin y!)azetidin ol 225 H 0 Η n rYA 7 F Η °γΝ'7 N‘NH Λυ F 1-((3,4-difluoro [(2-fluoro iodopheny l)am inojphenyl} carbonyl)-3 -[(177-1,2,4-triazol ylamino)methyl]azetidin ol 226 OH C / r YA X=X F 3-(1 -(diethylamino)propylj-l -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 227 YfN&lt;T0H F Y HO 0H aY F 3-(((1-((3,4-difluoro-2~[(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methy]}amino)- 5-(hydroxymethyl)cyclopentane-l,2- diol 228 H, F H Y - F l-((3,4-difluoro [(2~fluoro iodophenyl)amino]phenyl} carbonyI)-3 -piperidin ylazetidin~3-ol 116

Cmpd No. Structure Name 229 OH Η (.A X Aa? F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(3- fluorophenyl)amino]methyl} azetidin-3 -ol 230 F o aO /=» F ‘ 1 -({3,4 -difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (1 -methylpiperid in yl)azetid &amp;#943;η ol 231 h2n h ho HN V— ΝγγΟ A/ F 1 - {[ 1 -({3,4-difluoro [(2-fluoro~4-iodopheny l)amino] phenyl} carbonyl)-3 -hydroxyazetidin-3 -yljmethyl} guanidine 232 N U-N.0 _ H T H 1 ΦΑ F 1 -{[ 1 -({3,4-difluoro [(2-fluoro iodophenyl)aminoJphenyl}carbonyI) hydroxyazetidin yl]methyl} nitroguanidine 233 OH y x F 7V-{l-[l-({3,4-difluoro [(2-fluoro iodophenyl)aminojphenyl}carbonyl) hydroxyazetid in-3 -y 1 j ethyl} acetam i d e 117

Cmpd No. Structure Name 234 OH F Am m ,UM Mq (2RfN~{ 1 -[1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyI)-3 -hydroxyazetidin yl]ethyl}-3,3,3-trifluoro (methyloxy) phenylpropanamide 235 M"~NH m e Ox,nJ F l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(piperidm y lmethy l)amino]methy 1} azeti din-3 -o 1 236 % ? F H°M MM F 3 - {[(3 -aminopr opyl)amino jmethyl} -1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 237 Η. H MM o » M=M O nAA^N na F HVJ ( A F F i-({3,4-difluoro~2~[(2-fluoro-4~ iodophenyl)amino]phenyl}carbonyl) [({[2-(4-methylpiperazin-l -yl)phenyl]methyl}amino)methyl]azetid in ol 238 OH F ΟΥΝΤΗΝη ,MM 3~{[( 1,1 -dimethylethyl)amino]methyl} ((4-((2 -fluoro iodophenyl)amino]-3 -thieny 1} carbonyl)azetid in-3 -ο I _ 118

Cmpd No. Structure Name 239 HO OH H A F ovNcUnO V F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(2- hydroxy eye loh exy l)am ino] methyl} azet idin ol 240 OH f °yn/^hnAA V ' F 1 -({3,4-d ifluor o [(2 -fluor o iodophenyl)amino]phenyl}carbonyl) {[(2,2,3,3,3- pentafluoropropyl)amino]methyl}azeti din ol 241 OH A "A?" AA F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl]carbonyl) {[(3,3,3- trifluoropropyl)amino]methyl}azetidin- 3-ol 242 OH H p Az A vA, xH A FA/ F 7V-[3-({[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-3 -hydroxy azetid in-3 - yl]methyl}amino)phenyl]methanesuifo namide 243 H'o Η p f A" Ai F JV-{[1-({3,4-difluoro [(2-fluoro-4~ iodophenyl)amino]phenyl} carbonyl)-3 -hydroxy azetidin-3 - yl]methyl] methanesulfonamide 119

Cmpd No. Structure Name 244 OH H p&gt;ii (X .N-J N-NH &amp;#912; Η &amp;#910; AA F 3-({[ &amp;#943; -({3,4-d ifluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidm ylJrnethyl}amino)~ l/Z-pyrazol oI 245 HO Γ)-ΟΗ H F Η PH (1/?,25) ( {[1-((3,4 -difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methyl}amino)cyclopentane-l,2-diol 246 OH HO / Υγ&amp;#908; N H o^A F H 1-((3,4-difluoro [(2-fluoro iodophenyI)amino]phenyl}carbonyl) ({[1 -(hydroxymethyl)cyclohexyl]amino } methyl)azetidin ol 247 HO °Y Cl F Η M vA A F 3-{[(3-chlorophenyl)amino]methyl}-l- ({3,4-difluoro [(2-fluoro iodophenyl)aminojphenyl}carbonyl)az etidin ol 120

Cmpd No. Structure Name 248 HO oA f H Y, 3 - {[(4-chl oropheny l)amino] m ethyl} -1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 249 HO ,NH2 rAS 0 ν- γ ' =¥ 3-[(5-amino methyl-17/-pyrazol-l- yl)methyl]-l-({3,4-difluoro [(2- fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 250 HO ,Β-ΤΑ i\rNH o o^N \ r 1 -({ 3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(5 -methy 1 pyrazo 1-3 -yl)amino]methyl}azetidin ol 251 OH -.= / F 1-((3,4 -difluoro [(2-fluoro iodophenyl)am ino] phenyl }carbonyl) (1 -ethy lpyrrolid in yl)azetid in-3 -ol 252 OH hA"" r o^ nJ n &amp;#943;Υχ5 xfx F (27?)-7V-{(15)-l-[l-({354-difluoro [(2- fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]ethyl}-3,3,3- trifluoro (methyIoxy) phenylpropanamide 121

Cmpd No. Structure Name 253 HO cG ' F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (([4- (methyloxy)phenyljamino}methyl)azeti din ol 254 &amp;#912; η &amp;#910; /- Av F 3 -(1 -amino methylpropyl) -1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 255 H P N Γ~&amp;#905; F Η °γΝ AxaX nh* ,ΙΛν F 3-{[(4-aminophenyl)ammo]methyl} -1 -({3,4-difluoro [(2-fluoro i odophenyl)amino] phenyl} carbony l)az etidin ol 256 F Η V Dv F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ([(2-hydroxy methylcyclopentyl)amino]methyl}azeti din ol 257 ,.-"= Gc - F 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -(1-1(4- hydroxycyclohexyl)amino] ethyl} azetid in ol 122

Cmpd No. Structure Name 258 “Υγγ HO 0H γ H f AA F methyl (2xi)-2~deoxy ({[1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -hydroxyazetidin yl]methy]}amino)-beta-D-arabino-hexopyranoside 259 H. F Ηθγ&amp;#902;γ) AA F 1 -((3,4-difluoro [(2-fluoro iodophenyl)aminojphenyl}carbonyl) pyridin ylazetidin ol 260 H. ZOH F .MY AA F 1 -((3 A-difluoro^-^-fluoro-d-iodophenyljaminoJpheny 1} carbony 1)-3 -({Π- (hydroxymethyl)cyclopentyl]amino}me thyl)azetidin ol 261 =i-N H Ho N V-N.,0 &amp;#905; T H 1 AA F 1 -cyano-3 ~{[1 -({SA-difluoro^-fG-fluoroA- iodophenyOaminoJpbenyQcarbonyO-S-hy d roxy azetid in-3 -y I] methy 1} guanid ine 262 A n-x rY F H°YnJ ,ΑΑ F 6-((3- [(ethy lami no)methy 1] -3 -fluoroazetidin-1 -yl} carbonyl)-2,3 -difluoro-/V-(2-fluoro-4~ iodophenyl)aniline 123

Cmpd No. Structure Name OH o&lt; nTA no2 r 1 H 1 -({3,4-difluoro [(2-fluoro 263 fir "&amp;#943; iodophenyl)amino]phenyl}carbonyl) F^ .J (1 -nitroethyl)azetidin ol F H 0 H /¾^ c H°- Λ y-j/ iX l-({3,4-difluoro [(2-fluoro 1 \ F iodophenyl)amino]phenyl)carbonyl) 264 Λ A, {[(3-fluoro Jt hydroxyphenyl)amino]methyl}azetidin- F 3-oi H “A- 0 cP 1 -({3,4-difluoro [(2-fluoro F I H ill F iodopheny l)am inojpheny 1} carbonyi)-3 - 265 nA r &amp;#973; A, {[(2-fluoro 1 I hydroxyphenyl)amino]methy]} azetidin- Υ F F 3-oi A xnh2 Q; xxN-J 266 F I H r 3 -(1 -am inoethy 1)-1 -({8 -chloro [(2- x. Λχ fluoro fit γ &amp;#906; iodophenyl)amino]imidazo[l,2- Cl^ VN\ a]pyridin yl}carbonyl)azetidin ol IM OH O&lt; /A / NH F t H j z 1 -({3,4-difluoro [(2-fluoro 267 Ar Ax iodophenyl)amino]phenyl} carbonyl)-3 - ,χαΑ Λ J [ 1 -(methylamino)ethy 1] azetid in-3 -ol F 124

Cmpd No. Structure Name 268 OH A A 1 -({ 8-fluoro [(2-fluoro iodophenyl)amino]imidazo[l,2-«]pyridin yl}carbonyl) [(25)-piperidin yl]azetidin ol 269 OH H L·01-1 F ./A AbA A'^ fAA) nA 1 -( { 8-fluoro [(2-fluoro iodophenyl)amino]imidazo[l,2-a] pyridin yl} carbony 1)-3 - {(16)-1 -[(2-hydroxy methylcyclopentyl)amino]ethyl}azet idin o! 270 OH H , -,ββ f Η &amp;#910; N ΓΛΥ&amp;#943; ,UU fA^ F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyI) (1 /7-imidazol yl)azetidin ol 271 Η·η H 0 i /Ax F ΗθγΝ-ΓΟ AaA ,AA FAjY F 1 -({3,4 -d ifluoro-2~[(2-fluoro iodophenyl)amino]pheny 1} carbony 1) (l/7-pyrrol yl)azetidin ol 272 Ay &amp;#905; T Η I Ax F /V-{ 11 -({3,4-difluoro [(2-fluoro iodophenyl)aminojpheny 1} carbonyl)-3 -hydroxyazetldin yl]methyl}benzenecarboximidamide 125

Cmpd No. —--------’———— — --- Il — -., . « Structure ------------— Name 273 Ay ix F 3-({[(E)-l-amino nitroethenyl]amino)methyl)-l-({3,4- difluoro f(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 274 OH f ii y h)~o A F 1 -({3,4-difluoro [(2- fluoro iodophenyl)amino]pheny 1} carbonyl)-3 -(1 -methy 1-1 -nitroethyl)azetidin-3 -ol 275 OH p QvnA F „ V NH, F 3-(l-amino-l -methy lethy 1)-1 -({3,4-difluoro [(2-fluoro iodophenyl)amino}phenyl}carbonyl)az etidin ol 276 p „0 A AO XX F 3-[(l/f~benzimidazol ylamino)methyl]-l -({3,4-difluoro [(2-fluoro iodophenyl)aminojphenyl}carbonyl)az etidin ol 277 χχ-Χ F hV^ K XX F l-({3,4-difluoro [(2-fluoro-4~ iodophenyl)amino]phenyl}carbonyl) [(l/7-imidazol ylamino)methyl]azetidin ol 126

Cmpd No. Structure Name 278 Ax o.nJ Pp V Η I / vv F methy! {1 -[1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl) carbony 1) hydroxyazetidln yl]ethyl} carbamate 279 H H ° N ex nA 1Γ &amp;#943; F Η γ ΝΧγ/ w F 3-(17/-benzimidazol yl)-l-({3,4- difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 280 OH / F / J Η I AA F 1 -({3,4-d lfluoro [(2-fluoro iodophenyl)am ino]phenyl} carbonyl)-3 -[l-(dimethylamino)ethyl]azetidin ol 281 Λ-X fc! H9 T rxOA \^N ANV) X;. F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]pheny 1} carbony 1)-3 -[(pyrimidin ylamino)methyl]azetidin ol 282 H HO &amp;#943; \Y V-N^O X e F 1 -({3,4-difluoro-2~[(2-fluoro iodophenyl)amino]phenyl} carbonyl)-3 -[(pyrldin ylamino)methyl]azetidin ol 127

Cmpd No, Structure Name 283 /Y1 1 Y F l-({3,4-difluoro [(2-fluoro iodophenyl)amino]pheny 1} car bony 1)-3 -(l-methyI-17/-imidazol yl)azetidin ol 284 HO ,NH2 °YN 3-(l-ammobutyl)-l-({3,4~difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 285 F Λ-ΟΥ , Y ' 1 -{{2-fluoro [(2-fluoro iodophenyl)amino]pyridin yl}carbonyl) [(2S)-pyrrolidin yl]azetidin ol 286 OH f.va) AA nA 1 -({ 8-fluoro [(2-fluoro iodophenyl)amino] methylcinnolin y I} carbony 1) E(25)-piperidin“2“ylJazetidin ol 287 A:y ° F 3-[amino(phenyl)methylJ-l-({3,4- difluoro [(2~fluoro~4- iodophenyl)amino]phenyl}carbonyi)az etidin ol 128

Cmpd No. Structure Name 288 H H F Η MxM F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (5-methyl-l//-imidazol yl)azetidin-3~ ol 289 H'o p mAzA# n-Z MM F 1,1 -d imethy lethy 1 (28) [ 1 -({ 3,4- difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]piperidine-l- carboxylate 290 OH c, ηΜΑΟ Α&amp;#973; MS FXf F 1- ({2-[(4-bromo chlorophenyI)amino]-3,4-difluorophenyI}carbonyl) piperidin- 2- ylazetidin ol 291 H Q _ F yMM cFi F 3 - (&amp;#938; -am ino -3 -hydroxypropyl) ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 292 | H 1 H MM F 1-((3,4-difluoro [(2~fluoro iodophenyl)amino]phenyl}carbonyl) (lH-imidazol ylmethyl)azetidin ol 129

Cmpd No. Structure Name 293 ΠΟ Jfgjz / 3-(1 -aminocyclopentyl) ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 294 1 Η T NH2 AA F 3 -(2-aminocyc lohexy 1) ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)az etidin ol 295 OH . , mA 1 H ! NH2 aA F 3-(2-aminocyclopentyl)-l-({3,4- difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)- azetidin ol 296 HO Γ J fAAl o^nJ η aA, 1 -((4-fluoro-5~[(2-fluoro iodopheny l)aminoj-1 -methyl-1H-benzimidazoI y 1} carbonyl)-3 -piperidin ylazetidin ol 130

Cmpd No. Structure Name 297 ογ Of H .M, nA l-({5-[(4-bromo~2-chloropheny l)amino] fluoro-1 -methyl benzimidazoI yl}carbonyl) [(2S)-piperidin yl]azetidin ol 298 , .TA AA A 1 -({8-chloro [(2-fluoro iodophenyl)amino]imidazo[l ,2-aJpyridm yl}carbonyi) piperidin ylazetidin ol 299 A c/JA h A“i F 1- ({2-[(4-bromo fluorophenyl)aminoJ-3,4-difluorophenyl}carbonyl) piperidin- 2- ylazetidin oI 300 OH .JYQ F u A HNA nA A l-({7-[(4-bromo fluorophenyI)amino] fluoroirnidazo[l,2-&lt;7]pyridin yl}carbonyl) [(2S)-piperidin yl]azetidin ol 131

Cmpd No, Structure Name 303 H. πΜΜ F η °γΝ J NO, ' Ai F 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (3 -methyl-1 -nitrobutyl)azetidin-3 -ol 302 NFL HO jA 3-(2-aminopyrimidin yl)-l -((3,4-difluoro [(2“fluoro~4-iodophenyl)amino]phenyl}carbonyl)az eti din ol 303 f 1 OH H Cl Y Aoi ^Br VN l-({7-[(4-bromo chlorophenyl)aminoJ chloroimidazo[l,2-a]pyridin yl}carbonyl) piperidin~2-ylazetidin- 3-ol 304 o Ah F ΟγΝ-J AA iA 1 -((8-chloro [(2-fluoro iodophenyl)amino]imidazo[1,2-a]pyridin yI}carbonyl) [(2,5)“ piperidin yl]azetidin ol 132

Cmpd No. Structure Name 305 ci °-VnJ AfA l-({7-[(4-bromo chlorophenyl)amino] ch!oroimidazo[l,2-a]pyridin yI)carbonyi) [(2S)-piperidin yl] azetid in~3~o I 306 OH N==/ 1 -({4-fluoro [(2-fluoro iodophenyl)amino]-l-methyl benzimidazol yl}carbonyl) [(25)-piperidin yl]azetidin o! 307 Cl H ΟνΝ'"7 ''ΝΗ2 πο&amp;#902; 3-[(1 S)~ 1 -aminoethyl]-1 -({5-[(4-bromo chlorophenyl)amino] fluoro-l-methyl-lH-benzimidazol yl}carbonyl)azetidin ol 308 OH Cl H °γΝ'^ΗΝ- AXv l-({5-[(4-bromo chlorophenyl)amino] fluoro-l-methyl-lB-benzimidazol-h-y 1 ] carbony 1) [(1 iS) (methylam ino) ethyl] azeti d in-3 -o 1 133

Cmpd No. Structure Name H. o. ,A0 F I H X, - 4-[(4-bromo fluorophenyl)amino]- 309 Ji J ,N 3-fluoro ( {3-hydroxy [(2SJ-p iper idin y l]azetidin-1 - A 0 Br y 1} carbony l)pyridin-2(l B)-one F 0 HNA 4-[(2-fluoro iodophenyI)amino] 310 1 s 1 OH ({3-hydroxy [(26)-piperidin flV A yl]azetidin-l -yl) carbonyl)-1 - ,AJ I VA methyipyridin-2(l//)-one o Ci H γ °Y HNA &lt;A 4~[(2-fluoro~4-iodophenyl)amino)-5~ 311 i OH ({3-hydroxy [(2iS)-piperidin rA AA y l]azetidin-1 -yl} carbonyl)-1 - βγ&amp;#910;α (1 0 Νχ m ethy lpyr id in-2 (1Z/)-one OH._ ? HO cr On. A° a I (Γ Αγ yS [1 'p U, F and (±)-l -({3,4-difluoro [(2-fluoro 312 iodophenyl)amino]phenyl} carbonyl)-3 -[(hYWs) hydroxycyclohexyl]azetidin- Αλ "Λ 3-ol An A° η I r Αγ n A y &amp;#902;, F 134

Cmpd No. Structure Name 313 A F A F A, (3,4-difJuoro (2-fluoro-4~ iodophenylamino)phenyl)(3-hydroxy- 3-((15,25) hydroxycyclohexyl)azetidin-l -yl)methanone JA 314 A F •if F A (3,4-d ifluoro (2-fluoro-4~ iodophenylamino)phenyl)(3-hydroxy ((15,27?) hydroxycyclohexyl)azetidin-1 -yl)methanone 315 F ,Α“ψ 0An- V OH H k 4-[(2-fluoro iodophenyl)amino] ({3 -hydroxy-3 -[(15) (methy lamino)propyl]azetidm~l -yl}carbonyl)-l -methylpyridin-2(l//)-one O θΑΑγο H F I fiY .Nx iS "F AA, 316 F O'"tiyo h and F i (±)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(c«) hydroxycyclohexylJazetidin ol fjY Λ kxjx 'F AA, F 135

Cmpd No. Structure Name 317 0¾^° F Aa y-F aa, F (354-difluoro (2-fluoro iod ophenylamino)pheny 1)(3-hydroxy- 3-((15,271) hydroxycyclohexyl)azetidin-l -yl)methanone 318 Ptto F (3,4-difluoro (2-fluoro iodophenylamino)phenyl)(3-hydroxy ((1 R,2S) hydroxycycl ohexy l)azetid in-1 -yl)methanone 319 F vAy | H 1 OH F - 0 5-({3-[(lS)-l-(dimethylamino)ethyl] hydroxyazetidin-l-yl}carbonyl) [(2-fluoro iodophenyl)amino]-l-m ethy Ipyri d in-2 (177)-one 320 F AVTa 1 Η I OHH AA 0 4-[(2-fluoro iodophenyl)amino] ({3-hydroxy [(methylamino)methyl]azetidin-l“ yl}carbonyl)-l-methylpyridin- 2(ltf)-one 321 F VAP AA O 5-{[3-(1 J7-benzimidazol y 1) hydroxyazetidin-l-yl]carbonyl} [(4-bromo fluorophenyl)amino]-l-methy lpy r id i n-2 (177)-one 136

Cmpd No. Structure Name 322 ο'5 o 4~[(4-bromo fluorophenyl)amino]-5 - {[3 -hydroxy-3 -(1 -methy 1-1H-benzimidazol yl)azetidin-l-yljcarbonyl} -1 -methy lpyridin-2(177)-one 323 F 1 Η I OH H M 0 4- [(4-broino fluorophenyl)amino]- 5- ({3-hydroxy [(2S)-pyrrolidin yl]azetidin-l-yl}carbonyl)-l-methylpyridin-2(lfi)-one 324 pH __ ι Η I H AA l-({3-fluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl) [(2£)-piperidin-2~yl]azetidin ol 325 OH F 1 -({4-fluoro-2~[(2-fluoro iodophenyl)amino]phenyl}carbonyl) [ (25)-piperidin yl]azetidin oI 326 HO A\ Γ~1 hr &amp;#970; V " jYnyS 3X-'X fYV- O'N 1 -({6-[(4-bromo chlorophenyl)amino]-7 -fluoro-3 -methyl-1,2-benzisoxazol y 1} carbonyl)-3 -[(25)-piperidm yl]azetidin-3~ol 327 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl) (6-methylpiperidin yl)azetidin ol 137

Cmpd No. Structure Name OH ,—&lt; P ΟγχΝ·'-/ / aa F 328 oh^nh F VnV HN-k Vo F 1 -({3,4-difluoro l(2~fIuoro iodophenyl)amino]phenyl}carbonyl) -3 -p iperazin y lazetidi n-3 -ol 329 HN-"X p vVU -SY 0 5-[(2-fluoro iodophenyl)aminoJ ({3-hydroxy [(2S)-piperidin-2~ yljazetid in yl} carbony 1) methylpyridazin-3(277)-one 330 HNA f -ybY AV o 5-[(4-bromo chlorophenyl)aminoj ({3-hydroxy [(2iS)-piperidin yljazetidin-1 -yl) carbonyl) methylpyridazin-3 (2ff)~one 331 a C, ΥΥΟΗ AaA b/V ρΑγΥ 0 5-[(4-bronio chlorophenyl)amino] -4 -fluoro ( {3-hydroxy [(26)-pyrrolidin yl] azeti din yl} carbonyl) methylpyridazin-3(2/7)-one 138

Cmpd No. Structure Name 332 y-NH n, O^nQoH I H | 0 5-[(4-bromo chlorophenyl)amino] fluoro ({3-hydroxy [(2/?)-pyrrolidin yl]azetidin-l -yl}carbony!) methy!pyridazin-3(2//)-one 333 F OvnX&gt;XnH2 j H ( V OH Χχ o 6-({3-[(15)-l-aminoethyl] hydroxyazetidin-1 -yl} carbonyl) [(2-fluoro iodophenyl)amino] methylpyridazin-3 (2/7)-one 334 a h X'XXnh2 Ay U °H βγ-A Y- O 6-({3-[(15)-l-aniinoethyl] hydroxyazetidin-l-yl}carbonyl) [(4-br omo-2 -chi or oph enyl) am &amp;#943; n o] methy lpyridazin-3 (2jF7)-o ne 335 ? .OH ci ΧυΑχΑΧ JA X 0 5-[(4-bromo chloropheny l)amino] {[3 -((15)-1 -{[(3R4S)-3,4- dihydroxycyclopentyl]amino}ethyl)-3 -hydroxyazetidin -1 -yl] carbonyl} -2 -methylpyridazin-3 (2H)-on&amp;amp; 336 \ A1 F hyX?Xa 1 d 1 OH H V A X 0 5- [(4-bromo fluorophenyl)amino]- 6- [(3-hydroxy {(15)-l-[(2-hydroxy methylcyclopentyl)amino]propyl} az etidin-l-yl)carbonyl] methylpyridazin-3(2Z/)-one 337 \ F w °νΝ00NH2 ./A 0 6-({3-[(lS)-l-ammopropy]] hydroxyazetidin-l-yl}carbonyl) [(4-bromo fluorophenyl)amtno] methylpyridazin-3(277)-one 139

Cmpd No. Structure Name 338 HN-YY YX 0 6-{[3-(l//-benzimidazol yl) hydroxyazetidin-l-yl]carbonyl} [(2-fluoro iodophenyl)amino] methylpyridazin-3(2B)-one 339 F γ&amp;#970;Α” 0 5-[(2-fluoro iodophenyl)amino] {[3 -hydroxy-3 -(1 -methyl-1H-benzimidazol yl)azetidin-l-yl]carbonyl} methy!pyridazin-3(2//)-one 340 F ΑγΑλΥ &amp;#9633; X l-({2-fluoro [(2-fluoro iodophenyl)amino]pyridin yl}carbonyl) [(21S)-piperidjn yl] azetidin ol 341 f yvO/Sy , X. l-({3-[(2-fluoro iodophenyl)aminoJpyridin yl}carbonyl) [(2S)'piperidin yl] azetid in ol 342 F H°Y&lt;&gt;C0 .fX " 1 σ l-({3-[(2-fluoro iodophenyl)amino]-l-oxidopyridin y 1} carbonyl)-3 - [(25)-piper idin yl]azetidin ol 343 Λ Β Y YY no 1 -({2-fluoro [(2-fluoro bromophenyl)aminoJpyridin yl}carbonyl) [(2S)-piperidin yl] azetidin ol 140

Cmpd No. Structure Name 344 M &amp;#943; a ¥# Μ&amp;#973; 3- [(15)-l-aminopropyi]-l-({3-[(2-fluoro iodophenyl)amino]pyridin- 4- yl}carbonyl)azetidin o{ 345 l-({3-[(2-fiuoro iodophenyl)amino]pyridin yl}carbonyl) [(l 5) (methy3amino)propylJazetidin ol 346 oh (l/?,2S) ({(lS)-l“[l-({2-fluoro-3~ [(2-f3uoro iodophenyl)amino)pyridin y 1} carbonyl)-3 -hydroxyazetidin-3 -yl]propyl}amino)cyclopentane-l,2-diol 347 OH α H°vYO Βι-&amp;#902;^ F'l5U0 00 l-({7-[(4-bromo chloropheny l)amino]-8 -fluoro methylcinnolin yl}carbonyl) [(2S)-piperid in y 1] azetidin-3 -ol 348 OH f Η Y ™-Y MxY 80''-^ F’l#|0 NU l-({7-[(4-bromo fluorophenyl)amino] fluoro methylc innolin-6 -y 1) carbonyl)-3 -[(2S)-piperidin yl]azetidin oI 349 OH mNH, O^N-J \ 0004 0-0 y0 3-[(15)-l-aminoethyl]-l-({7-[(4- bromo fluorophenyl)amino]cinnolin yl} carbonyl)azetidin-3 -ol 141

Cmpd No. Structure Name 350 °h d AA bV"R &lt;fA A 1- ({7-[(4-bromo fluorophenyl)aminoJcinnolin-6~ yl}carbonyI) {(ll-l-[(2-hydroxy- 2- methylcyclopentyl)amino]ethyl}azet id in ol 351 F A aA ill A l-({7-[(4-bromo fluorophenyl)amino]cinnolin y 1} carbony 1)-3 - [(15)-1 -(dimethylamino)ethyl]azetidin ol 352 OH nMNH2 : 5., nA 3-((15)-1 -aminoethyl]-1 ~({5-[(2-fluoro iodophenyl)amino] l,2,3-benzolriazol yl}carbonyl)azetidin ol 353 OH \ F AA Al nA 3-[(15)-1 -(dimethy lamino)ethy 1]-1 -({5-[(2-fluoro iodophenyl)amino]~ 1 -methyl-&amp;#938;Η-1,2,3-benzotriazol yl) carbonyl)azetidin-3~ol 354 OH F Η°γΑΑΑ aA« nA 1-((5-((2-fluoro iodophenyl)amino]-17/-l ,2,3-benzotriazol yl}carbonyl) [(25)-piperidin yl]azetidin ol 355 oh F h0TN/^^ AynAi A AV nY l-((5-[(2-fluoro iodophenyl)amino]-1 -methyl-1H-I,2,3-benzotriazol yl}carbonyl)~3-[(25)-p iper idin yl] azetidin-3 -ol 142

Cmpd No. Structure Name 356 OH H 1&lt;OH F A n^n l-({5-[(2-fluoro iodophenyl)amino] l ,2,3-benzotriazol yl} carbonyl)-3 - {(15)-l-[(2-hydroxy methylcyclopentyl)amino]ethyl}azet idin ol 357 OH F CA/N-J \ nA 3 -[(15)-1 -aminoethyl] -1 -( {4-fluoro [(2-fluoro iodophenyl)amino] 1,2,3-benzotriazol y 1} carbony l)azetidin-3 -ol 358 OH F Η &amp;#910; HN-A &amp;#943;ιΥΝ/ιΥ &gt; F y NH nA 1 -({4-fluoro f(2-fluoro iodophenyl)amino] l,2,3-benzotr iazo &amp;#943; y 1} carbonyl)-3 -[(25)-piperidin yl]azetidin oi 359 OH f „ / t ,&gt;V hn^n o 5-({3-[(15)-l-aminoethyl] hydroxyazetidin-l -yl} carbonyl) [(2-fluoro iodopheny l)amino]pyr imidin-2( 177)-one 360 OH F /Akk) jtAyA HN^N O 6-[(2-fluoro iodophenyl)amino] ({ 3 -hydroxy-3 -[(25)-p iper i d in-2 -yl]azetidin-l-yl}carbonyl)pyrimidin-2(177)-one 361 OH f ,,/50 rVN/F ,AkA n^/Nh o 4-[(2-fluoro iodophenyl)amino] ({3-hydroxy [(2S)-piperidin yl]azetidin-l-yl}carbonyl)pyrimidin- 2(177)-one 143

Cmpd No. Structure Name 362 OH &amp;#943; ,Α/ ΝγΝΗ O 5-({3-[(15)-l-aminoethyl] hydroxyazetidin-1 -yl} carbonyl) [(2-fIuoro iodophenyI)amino]pyrimidin-2(l/7)- one

General Administration [00190] In one aspect, the invention provides pharmaceutical compositions comprising an inhibitor of MEK according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain other embodiments, administration may preferably be by the oral route. Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

[00191] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include carriers and adjuvants, etc.

[00192] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[00193] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, 144 antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.

[00194] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

[00195] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[00196] One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.

[00197] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution 145 retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[00198] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [00199] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for \ example, by dissolving, dispersing, etc., a compound(s) ofthe invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

[00200] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[00201] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.

[00202] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile 146 conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

[00203] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

[00204] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.

[00205] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention.

[00206] The compounds of the invention, or their pharmaceutically acceptable salts or hydrates, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.

[00207] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically 147 active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

[00208] Representative pharmaceutical formulations containing a compound of Formula I are described below in the Pharmaceutical Composition Examples.

UTILITY

[00209] Certain compounds of this invention have been tested using the assay described in Biological Example 1 and have been determined to be MEK inhibitors. As such compounds of Formula I are useful for treating diseases, particularly cancer in which MEK activity contributes to the pathology and/or symptomatology of the disease. For example, cancer in which MEK activity contributes to its pathology and/or symptomatology include malignant melanomas, colorectal cancer, pancreatic cancer, lung cancer, papillary and anaplastic thyroid cancer, and endometriod ovarian cancers, and the like.

[00210] Suitable in vitro assays for measuring MEK activity and the inhibition thereof by compounds are known in the art. For example, see WO 2006/061712 for measuring MEKl and MEK2 in vitro. For further details of an in vitro assay for measuring MEK activity see Biological Examples, Example 1 infra. Following the examples disclosed herein, as well as that disclosed in the art, a person of ordinary skill in the art can determine the inhibitory activity of a compound of this invention.

[00211] Assays for measurement of in vitro efficacy in treatment of cancer are known in the art. For example, see WO 2006/061712, for cell-based assays for colon cancer. In addition, cell-based tumor models are described in Biological Examples, Example 2 and 3 infra.

[00212] Suitable in vivo models for cancer are known to those of ordinary skill in the art (including WO 2006/061712). For further details of in vivo models for colorectal cancer, melanoma, breast adenocarcinoma, and lung anaplastic carcinoma, see Biological Example 4, infra.

GENERAL SYNTHESIS

[00213] Compounds of this invention can be made by the synthetic procedures described below. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon 148

Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[00214] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure and over a temperature range from about -78 0C to about 150 0C, more preferably from about 0 0C to about 125 0C and most preferably at about room (or ambient) temperature, e.g., about 200C. Unless otherwise stated (as in the case of an hydrogenation), all reactions are performed under an atmosphere of nitrogen.

[00215] Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups regenerate original functional groups by routine manipulation or in vivo. Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[00216] The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure. Compounds of Formula I that may be prepared through the syntheses described herein may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention. Some of the compounds of the invention may exist as tautomers. For example, where a ketone or aldehyde is present, the molecule may exist in the enol form; where an amide is present, the 149 molecule may exist as the imidic acid; and where an enamine is present, the molecule may exist as an imine. All such tautomers are within the scope of the invention.

[00217] The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. When compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable "protecting group" or "protective group". A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley &amp;amp; Sons,

Inc. 1991. The protected derivatives of compounds of Formula I can be prepared by methods well known in the art.

[00218] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) may be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization.

[00219] In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the 150 like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[00220] The chemistry for the preparation of the compounds of this invention is known to those skilled in the art.

[00221] An intermediate of Formula II:

<img img-format="tif" img-content="drawing" file="IL229136AD000235.tif" id="idf0035" />

II where R7, X, R10, R12, R14, and R16 are as defined in the Summary of the Invention for Group A can be prepared using procedures known to one of ordinary skill in the art. In particular, see (for example) US 7,019,033, WO 2002006213, WO 2003062191, WO 2003062189, WO 2002018319, W02001005392, WO 2000064856, WO 2001005392, WO 9901421, WO 2004056789, Davis, E. M. et al. Org. Process Res. &amp;amp; Dev. 2005, 9, 843-6, and Shapiro, N. et al. Synthetic Commun. 2005, 35, 2265-9. The following intermediates were prepared using similar procedures as described in the above references: 3,4-difluoro [(2-fluoro iodophenyl)amino]benzoic acid; 2-[(2-chloro iodophenyl)amino]-3,4-difluorobenzoic acid; 4-fluoro [(2-fluoro iodophenyl)amino]benzoic acid; 4,5-difluoro [(2-fluoro iodophenyl)amino]benzoic acid; and 2-[(4-bromo fluorophenyl)amino]-3,4-difluorobenzoic acid.

[00222] An intermediate of Formula 111(a) or 111(b) :

<img img-format="tif" img-content="drawing" file="IL229136AD000236.tif" id="idf0036" />

<img img-format="tif" img-content="drawing" file="IL229136AD000237.tif" id="idf0037" />

where R7, X, R10, R12, and R14 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular for formula 111(a), where R14 is amino or alkyl (particularly methyl); R10 is halo (particularly fluoro); R7 is hydrogen or halo (particularly bromo or chloro); X is halo (particularly chloro); and R12 is hydrogen see for example W02006030610, US2005049419, and US2005/0054701. 6-[(4-bromo chlorophenyl)amino] fluoro 151 methyl- l,2-benzisoxazole carboxylic acid was prepared using methods similar to those disclosed in W02006030610, US2005049419, and US2005/0054701.

[00223] An intermediate of Formula IV(a) or IV(b):

<img img-format="tif" img-content="drawing" file="IL229136AD000238.tif" id="idf0038" />

<img img-format="tif" img-content="drawing" file="IL229136AD000239.tif" id="idf0039" />

where R7, X, R10, R12, and R14 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art.

[00224] An intermediate of Formula V(a) or V(b):

<img img-format="tif" img-content="drawing" file="IL229136AD000240.tif" id="idf0040" />

where R7, X, R10, R12, R14, and R19 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular the halo precursor of V(a) can be prepared using, for example, W02003101968 and W02002083648. In particular the halo precursor of V(b) can be prepared using, for example, US2004192653, US2004180896, US2004176325. The halo precursors are then reacted with an appropriate aniline to yield the intermediates of Formula V(a) and V(b).

[00225] An intermediate of Formula VI(a) or VI(b) : 152

<img img-format="tif" img-content="drawing" file="IL229136AD000241.tif" id="idf0041" />

<img img-format="tif" img-content="drawing" file="IL229136AD000242.tif" id="idf0042" />

where R7, X, R10, R12, and R14 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, for VI(b) see for example W02000042022 and W02001005390.

[00226] An intermediate of Formula VII(a) or VII(b):

<img img-format="tif" img-content="drawing" file="IL229136AD000243.tif" id="idf0043" />

where R7, X, R10, R12, and R14 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. For intermediate VII(b) see, for example, W02001005390 and W02000042022.

[00227] An intermediate of Formula VIII(a) or VIII(b):

<img img-format="tif" img-content="drawing" file="IL229136AD000244.tif" id="idf0044" />

<img img-format="tif" img-content="drawing" file="IL229136AD000245.tif" id="idf0045" />

VHl(b) where R7, X, R10, R12, R14, and R19 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular for formula VIII(b) where R10 is halo (particularly fluoro), R12 is hydrogen, R14 is hydrogen, and R19 is hydrogen or alkyl (particularly methyl) or alkenyl (particularly allyl), see WO 05/023251, W02005 009975, and W02001005390 . In particular for VIII(a) where X is halo (particularly chloro or fluoro) or alkyl (particularly methyl), R7 is halo (particularly iodo, bromo, or chloro) or haloalkoxy (particularly trifluormethoxy), R10 is halo (particularly fluoro or chloro), R14 is hydrogen or alkyl (particularly methyl), and R19 is hydrogen or alkyl (particularly methyl), see for 153 example US 2004/0116710, WO 03/077914, WO 03/077855, WO 00/42022,

W02005009975, and W02001005390. The following intermediates were prepared using similar procedures described in US 2004/0116710, WO 03/077914, WO 03/077855, WO 00/42022, W02005009975, and WO2001005390: 5-[(4-bromo chlorophenyl)amino] fluoro-l-methyl-lH-benzimidazole- 6-carboxylic acid and 4-fluoro [(2-fluoro iodophenyl)amino]-l-methyl-1H-benzimidazole carboxylic acid.

[00228] An intermediate of Formula IX:

<img img-format="tif" img-content="drawing" file="IL229136AD000246.tif" id="idf0046" />

IX

where R7, X, R10, R12, R14, and R16 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, where R10 is hydrogen or halo (particularly chloro or fluoro); R12 is hydrogen; R14 is hydrogen, amino, alkylamino, or dialkylamino; R16 is hydrogen; X is halo (particularly chloro); and R7 is halo (particularly bromo) see for example WO 05/023759, US 2005/0054701, US 2006030610, US 2005049419, and US 2005049276. The following intermediates were prepared using similar procedures as those described in WO 05/023759, as well as US 2006030610 and US 2005/0054701 : 7-[(4-bromo chlorophenyl)amino] chloroimidazo[l ,2-a]pyridine carboxylic acid and 8-chloro [(2-fluoro iodophenyl)amino]imidazo[l,2-a]pyridine carboxylic acid. The following intermediates can be prepared using similar procedures described in the references given above: 8-Fluoro [(2-fluoro iodophenyl)amino]imidazo[l,2-a]pyridine carboxylic acid and 7-[(4-Bromo fluorophenyl)amino] fluoroimidazo[l,2-a]pyridine carboxylic acid.

[00229] An intermediate of Formula X(a) and X(b) : 154

<img img-format="tif" img-content="drawing" file="IL229136AD000247.tif" id="idf0047" />

where R7, X, R10, R12, and R14 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, where R10 is hydrogen, halo (specifically chloro), or alkyl (specifically methyl), R12 is hydrogen, and R14 is hydrogen, halo (specifically bromo), see for example WO 06/045514. To prepare the intermediate of Formula X(b), the nitrogen in the pyridine ring of X(a) can then be oxidized with an agent such as MCPBA or H2O2. The following X(a) and X(b) intermediates were prepared using similar methods as disclosed in WO 06/045514: 3-[(2-Fluoro iodophenyl)amino]pyridine carboxylic acid and 3-[(2-Fluoro iodophenyl)amino]pyridine carboxylic acid 1-oxide. The following X(a) intermediates can be prepared using similar methods as disclosed in WO 06/045514: 2-Fluoro [(2-fluoro iodophenyl)amino]pyridine carboxylic acid and 3-[(4-Bromo fluorophenyl)amino]pyridine -4 -carboxylic acid.

[00230] An intermediate of Formula XI(a):

<img img-format="tif" img-content="drawing" file="IL229136AD000248.tif" id="idf0048" />

<img img-format="tif" img-content="drawing" file="IL229136AD000249.tif" id="idf0049" />

where R7, X, R10, R12, and R14 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, where R10 is hydrogen, R12 is hydrogen or halo (particularly chloro or fluoro), R14 is amino or halo (particularly chloro), X is halo (particularly chloro), and R is halo (particularly bromo) see for example US 2005/0054701, US 200549419, and US 2006030610. The intermediate of Formula XI(b) can be prepared [00231] An intermediate of Formula XII: 155

<img img-format="tif" img-content="drawing" file="IL229136AD000250.tif" id="idf0050" />

XII where R7, X, R10, R12, R14, and R16 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, see for example WO 05/051302. The following intermediates can be prepared using similar methods as disclosed in WO 05/051302: 8-Fluoro [(2-fluoro iodophenyl)amino] methylcinnoline carboxylic acid; 7-[(4-Bromo chlorophenyl)amino] fluoro methylcinnoline carboxylic acid; 7-[(4-Bromo fluorophenyl)amino] fluoro methylcinnoline carboxylic acid; and 7-[(4-Bromo fluorophenyl)amino]cinnoline carboxylic acid.

[00232] An intermediate of Formula XIII: o

XIII where R7, X, R10, R10a, and Y1 are as defined in the Summary of the Invention for Group C can be prepared using procedures known to one of ordinary skill in the art, including for example the procedures in US 05/0256123, Wallace, E. M. et al. J. Med. Chem. 2006, 49, 441-4, WO 2005000818, and WO 2005051301 (where Y1 is carbon). 4-[(4-Bromo fluorophenyl)amino] fluoro-l-methyl oxo-l,6-dihydropyridine carboxylic acid was prepared using similar procedures to those disclosed in US 05/0256123 and WO 2005051301. 4-Chloro-l-methyl oxo-l,6-dihydropyridazine carboxylic acid was prepared using similar procedures to those disclosed in US 2005256123. The following intermediates can be prepared using the methods disclosed in the above references: 4-[(2-Fluoro iodophenyl)amino]-l-methyl oxo-l,6-dihydropyridine carboxylic acid; 4-[(4-Bromo chlorophenyl)amino]- 1 -methyl oxo- l,6-dihydropyridine carboxylic acid; 4-[(4-Bromo fluorophenyl)amino]-1 -methyl oxo-l,6-dihydropyridine-S-carboxylic acid; 156 4-[(4-Bromo chlorophenyl)amino]-l-methyl oxo-l,6-dihydropyridazine carboxylic acid; 4-[(4-Bromo chlorophenyl)amino] -5 -fluoro methyl oxo-l,6-dihydropyridazine-3 -carboxylic acid; and 4-[(4-Bromo fluorophenyl)amino]-l-methyl oxo-l,6-dihydropyridazine carboxylic acid.

[00233] An intermediate of Formula XIV:

<img img-format="tif" img-content="drawing" file="IL229136AD000251.tif" id="idf0051" />

where R7, X, R10, and R14 are as defined in the Summary of the Invention for Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, see for example WO 05/051302.

[00234] An intermediate of Formula XVI

<img img-format="tif" img-content="drawing" file="IL229136AD000252.tif" id="idf0052" />

XVI where X and R7 are as defined in the Summary of the Invention for a Compound of Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, see for example WO 2001005390 and WO 2000042022 for procedures that can be used to prepare the following: 5-[(2-Fluoro iodophenyl)amino]-lH-benzotriazole carboxylic acid; 5- [(2-Fluoro iodophenyl)amino]-l -methyl- lH-benzotriazole carboxylic acid; and 4-Fluoro-5 - [(2-fluoro -4 -iodophenyl)amino] -lH-benzotriazole -6 -carboxylic acid.

[00235] An intermediate of Formula XVII 157

<img img-format="tif" img-content="drawing" file="IL229136AD000253.tif" id="idf0053" />

where X and R7 are as defined in the Summary of the Invention for a Compound of Group B can be prepared using procedures known to one of ordinary skill in the art. In particular, see Example 29.

[00236] An intermediate of Formula XVIII(a) or XVIII(b)

<img img-format="tif" img-content="drawing" file="IL229136AD000254.tif" id="idf0054" />

<img img-format="tif" img-content="drawing" file="IL229136AD000255.tif" id="idf0055" />

XVIII(a) XVIII(b) where X, R7, R40, and R40a are as defined in the Summary of the invention for a Compound of Group D can be prepared using procedures known to one of ordinary skill in the art. In particular, the halo precursors to XVIII(a) and XVIII(b)

, CkOH O^OH halo. X .R40a halo. ^R40a ° and 0 , respectively can be prepared using procedures similar to those described in Machon and Dlugosz Acta Poloniae Pharmaceutica 1983,40(1), 1-6 and von Angerer, Science of Synthesis 2004,16, 379-572 (General Review written in English). The halo precursors are then reacted with

X

<img img-format="tif" img-content="drawing" file="IL229136AD000256.tif" id="idf0056" />

using procedures known to one of ordinary skill in the art and the synthetic methods disclosed herein. The following intermediates can be prepared as described above; 6-((2-fluoro iodophenyl)amino] oxo-l,2-dihydropyrimidine carboxylic acid and 4-((2-fluoro iodophenyl)amino] oxo-l,2-dihydropyrimidine carboxylic acid.

[00237] An intermediate of Formula XIX 158

<img img-format="tif" img-content="drawing" file="IL229136AD000257.tif" id="idf0057" />

where X and R7 are as defined in the Summary of the Invention for a Compound of Group C can be prepared using methods known to one of ordinary skill in the art. In particular see US 2005049276.

[00238] An intermediate of Formula XX

<img img-format="tif" img-content="drawing" file="IL229136AD000258.tif" id="idf0058" />

where X and R7 are as defined in the Summary of the Invention for a Compound of Group C can be prepared using methods known to one of ordinary skill in the art. In particular see US 2005049276.

[00239] The synthesis of azetidines substituted at the 3-position can be conveniently carried out according to Scheme 1:

Scheme 1

<img img-format="tif" img-content="drawing" file="IL229136AD000259.tif" id="idf0059" />

starting from the 77-diphenylm ethyl protected azeti din ol (1), readily prepared by reaction of epichlorohydrin and diphenylmethylamine (Chatter] ee, Shym S.; Triggle, D. J. Chemical Communications (London) 1968, 2, 93). Protecting group exchange, from Boc to CBz, on the azetidine is carried out according to literature protocols (Greene, T.W., Wuts, P.G. Protective Groups in Organic Synthesis, Wiley-Interscience) and subsequent oxidation to the azetidinone (2) where P is CBz provides a useful intermediate for the preparation of compounds of the invention. 159 [00240] For example, the ketone intermediates of formula 2 can be broadly functionalized at the 3-position according to Scheme 2.

Scheme 2

OH

<img img-format="tif" img-content="drawing" file="IL229136AD000260.tif" id="idf0060" />

Γ N- OH NO2

V (4)

An intermediate of formula (3), where R4 is as defined in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D can be prepared by reacting the intermediate 2 with Grignard reagents or other organometallic species of formula 17, such as organolithiums. Alternatively, the intermediate 2 can be reacted with nitroalkane anions of formula 18 prepared in-situ as in the Henry reaction (The Henry reaction, recent examples: Luzzio, F. A. Tetrahedron 2001, 57(6), 915-945) to give (4) where R4’ is hydrogen or alkyl optionally substituted as described for R4 in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D. Alternatively, the intermediate 2 can be reacted with ketone or aldehyde anions of fonnula 19 in a Claisen-type condensation to give (5) where R4’ is alkyl optionally substituted as described for R4 in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D and R4” is hydrogen or R4’. In addition, 2 can be reacted with Wittig reagents of formula 20 (where R’ and R” are independently hydrogen, alkyl, alkenyl, aryl, or heteroaryl and the alkyl, alkenyl, aryl, and heteroaryl are optionally substituted as described for R4 in the Sumnmary of the Invention for a compound of Group A, Group B, Group C, or Group D) to prepare intermediates of formula 6, which are also useful as precursors for compounds of the invention. 160 [00241] According to Scheme 3, intermediates of formula (6) where where (R’ and R” are hydrogen and P is a nitrogen-protecting group such as CBz or Boc)

Scheme 3 rf (6a)

w-CPBA NHRSR8' OH NR8R8' __/

<img img-format="tif" img-content="drawing" file="IL229136AD000261.tif" id="idf0061" />

<img img-format="tif" img-content="drawing" file="IL229136AD000262.tif" id="idf0062" />

can be further converted to the corresponding epoxide (7) and subsequent reaction with a suitable nitrogen base or other nucleophiles may be carried out to give access to a broad range of azetidin ol derivatives such as (8), where R8 and R8 are as defined in the Summary of the Invention.

[00242] In some cases the preparation of optically pure compounds is desired where the azetidine contains one or more stereo centers. Numerous techniques for the preparation of optically pure compounds through both resolution techniques and asymmetric synthesis are well known in the art. In one such case, an asymmetric synthesis methodology can be employed where an azetidine precursor of formula (2) is reacted with an intermediate of fonnula 21 where R’ is not hydrogen, as depicted in Scheme 4.

Scheme 4

<img img-format="tif" img-content="drawing" file="IL229136AD000263.tif" id="idf0063" />

One such useful approach makes use of Evans oxazolidinone methodology (Diastereoselective aldol condensation using a chiral oxazolidinone auxiliary. Gage, James R.; Evans, David A. Organic Syntheses .1990, 68, 83-91). The condensation of an azetidinone (2) with the a chiral oxazolidinone in the presence of a base such as LDA affords an intermediate oxazolidinone (9), where P is a nitrogen-protecting group such as CBz or 161

Boc, with diastereoselectivity. Treatment with lithium hydroxide in aqueous hydrogen peroxide gives carboxylic acid (10) which can be subject to Curtius rearrangement to provide the chiral oxazolidinone (11) then carried forward as required to a useful intermediate (12).

Further protecting group manipulation and derivatization as required can be employed to prepare compounds of Formula I.

[00243] Alternatively, a racemic mixture of an intermediate of formula (13), useful to prepare a compound of Formula I where R3 is hydroxy and R4 is heterocycloaikyl (in particular, where R4 is aN-protected piperidine), can be prepared according to Scheme 5. Scheme 5

<img img-format="tif" img-content="drawing" file="IL229136AD000264.tif" id="idf0064" />

In the reaction schemes P1 and P2 are orthogonal nitrogen-protecting groups. For example, P1 is Boc and P2 is CBz or P1 is CBz and P2 is Boc. The reaction is carried out in-situ by treating 22 to generate the lithated amine and by subsequently treating it with a ketone such as (2) according to the method of Peter Beak (Beak, Peter; Lee, Won Koo a-Lithioamine synthetic equivalents: syntheses of diastereoisomers from the Boc-piperidines. Journal of Organic Chemistry 1990, 55(9), 2578-80). The racemate (13) thus prepared can be resolved by functionalization, as depicted in Scheme 6, with a chiral acid such as the readily-available Mosher acid (14).

Scheme 6

<img img-format="tif" img-content="drawing" file="IL229136AD000265.tif" id="idf0065" />

The resulting diastereomeric esters (15) can be separated by chromatographic means and then carried forward individually as the enantiomerically pure intermediates (R)-(16) and (S)-(1.6). 162 [00244] Compounds of the Invention can be prepared by reacting an intermediate of

Formula II, 111(a), 111(b), IV(a), IV(b), V(a), V(b), VI(a), VI(b), VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a), XI(b), XII, XIII, XIV, XVI, XVII, XVIII(a), XVIII(b), XIX, or XX with intermediate 17 according to Scheme 7:

Scheme 7

<img img-format="tif" img-content="drawing" file="IL229136AD000266.tif" id="idf0066" />

<img img-format="tif" img-content="drawing" file="IL229136AD000267.tif" id="idf0067" />

R7

The reaction is carried out in a solvent such as DMF, THF, or DCM in the presence of a base such as DIPEA, V-methylmorpholine, DMAP, or triethylamine and optionally in the presence of a coupling agent such as PyBOP, HBTU, or EDCI.

[00245] Alternatively an intermediate of Formula II, 111(a), 111(b), IV(a), IV(b), V(a), V(b), VI(a), VI(b), VII(a), VII(b), VIIl(a), VIII(b), IX, X(a), X(b), XI(a), XI(b), XII, XIII, XIV, XVI, XVII, XVlII(a), XVIII(b), XIX, or XX can be converted into an aeid halide according to Scheme 8

Scheme 8 Π-ΧΧ

<img img-format="tif" img-content="drawing" file="IL229136AD000268.tif" id="idf0068" />

base ----

Compound of Formula I where X2 is halo, such as chloro or fluoro, and all other groups are as defined in the Summary of the Invention for a compound of Group A, Group B, Group C, or Group D. The reaction is carried out in a solvent such as dioxane, THF, or DCM In the presence of a base such as DIPEA, sodium bicarbonate. The acid halide of formula 18 can then be reacted with an azetidine intermediate of formula 17 to prepare a compound of Formula I.

Synthetic Examples [00246] Generally, the compounds listed below were identified by LC-MS, and/or isolated, and characterized by 1 H-NMR (most typically 400 MHz). Liquid chromatography-mass spectral (LC-MS) analyses were performed using at least one of: a Hewlett-Packard Series 1100 MSD, an Agilent 1100 Series LC/MSD (available from Agilent Technologies Deutschland GmbH of Waldbronn Germany), or a Waters 8-Channel MUX System (available 163 from Waters Corporation of Milford, Massachusetts). Compounds were identified according to either their observed mass [MH+] or [MNa+] ion (positive mode) or [MH‘] ion (negative mode). IH-NMR data for compounds was taken with a Varian AS400 Spectrometer (400MHz, available from Varian GmbH, Darmstadt, Germany). Starting materials and intermediates used to prepare a compound of the invention are either commercially available or can be prepared by one of ordinary skill in the art.

Reference 1 3,4-difluoro [(2-fluoro iodophenyl)amino] benzoyl fluoride

<img img-format="tif" img-content="drawing" file="IL229136AD000269.tif" id="idf0069" />

F (00247] To a stirred mixture of 3,4-difluoro [(2-fluoro iodophenyl)amino] benzoic acid (12 g, 30.5 mmol), prepared using procedures similar to those described in US 7,019,033, in dichioromethane (70 mL) at 0 °C was added pyridine (2.5 mL, 30.8 mmol) followed by dropwise addition of cyanuric fluoride (2.8 mL, 33.6 mmol). The reaction mixture was stirred at 0 °C for 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with dichioromethane (100 mL). The aqueous layer was extracted once with dichioromethane (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product as a brownish solid. Crude product was purified by flash chromatography (plug, 25% ethyl acetate in hexanes) to afford 3,4-difluoro [(2-fluoro iodophenyl)amino] benzoyl fluoride as a beige solid (11.8 g, 97% yield). *H NMR (400MHz, CD3OD): 8.41 (s, IH), 7.80-7.81 (m, IH), 7.52 (dd, IH), 7.43-7.47 (m, IH), 6.96-7.03 (m, 1H), 6.85-6.92 (m, IH).

Reference 2 2-[(4-bromo chlorophenyl)amino]-3,4-difluorobenzoic acid

<img img-format="tif" img-content="drawing" file="IL229136AD000270.tif" id="idf0070" />

[00248] To a solution of 2,3,4-trifluorobenzoic acid (1 g, 5.68 mmol) and 4-bromo chloroaniline (1.2 g, 5.68 mmol) in acetonitrile (10 mL) was added lithium amide (0.39 g, 164 17.04 mmol) and the reaction stirred at 60 °C for 1.5 hours. The mixture was cooled to room temperature and then to 0 °C and acidified with aq. hydrochloric acid. The obtained precipitate was collected by filtration and washed with cold water and dried in vacuo to afford 2-[(4-bromo chlorophenyl)amino]-3,4-difluorobenzoic acid (1.92 g, 94% yield) as a beige solid. MS (El) for Ci3H7BrClF2NO2: 363 (MH+).

[00249] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, 2-[(4-iodo fluorophenyl)amino] fluorobenzoic acid was prepared. MS (Ε&amp;#938;) for Ci3H8F2INO2: 376 (MH+).

Reference 3

Phenylmethyl l-oxa azaspiro[2.3]hexane~5-carboxylate

<img img-format="tif" img-content="drawing" file="IL229136AD000271.tif" id="idf0071" />

O

[00250] To a solution of azetidin oI hydrochloride in tetrahydrofuran (90 mL) and water (10 mL) was added triethylamine (15 mL, 0.106 mol) followed by slow addition of benzyl chlorofonnate (8.0 mL, 0.056 mol) at room temperature. The reaction mixture was stirred at room termperature for 16 hours then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 25-50% ethyl acetate in hexanes) to afford phenylmethyl 3-hydroxyazetidine carboxylate (3.56 g, 33% yield) as a clear and colorless oil. ’H NMR (400 MHz, CDC13): 7.36-7.31 (m, 5H), 5.09 (s, 2H), 4.64-4.57 (m, IH), 4.22 (dd, 2H), 3.88 (dd, 2H), 2.61 (d, IH, &gt;4.0 Hz). MS (El) for CnHi3NO3: 208 (MH+).

[00251] To a solution of phenylmethyl 3-hydroxyazetidine carboxylate (3.5 g, 0.0168 mol) in dichloromethane (100 mL) was added Dess-Martin periodinane (10.7 g, 0.0.25 mol) at room temperature and stirred for 5 h. The reaction mixture was quenched with 1:1 ratio of saturated aqueous sodium bicarbonate and IM sodium thiosulfate (200 mL) and then partitioned with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford phenylmethyl 3-oxoazetidine-1 -carboxylate (3.43 g, 99% yield) as a clear and colorless oil without further purification. NMR (400 MHz, CDClj): 7.39-7.31 (m, 5H), 5.17 (s, 2H), 4.77 (s, 4H). MS (El) for CnHuNO3: 205 (M+). [00252] A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol) and potassium /er/-butoxide (7.3 g, 0.0649 mol) in diethyl ether (140 mL) was stirred at room temperature for 20 min, and then heated to 35 °C for 1 h. To this bright yellow reaction 165 mixture was slowly added a dilute solution of phenylmethyl 3-oxoazetidine-l-carboxylate (3.33 g, 0.0162 mol) in diethyl ether (50 mL). The reaction mixture was stirred at 35 °C for 12 hours then filtered through a bed of ceiite and rinsed with ethyl ether. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 5-10% ethyl acetate in hexanes) to afford phenylmethyl 3-methylideneazetidine-l-carboxylate (2.46 g, 75% yield) as a clear and colorless oil). JH NMR (400 MHz, CDC13): 7.27-7.22 (m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (El) for Ci2Hi3NO2: 203 (M+).

[00253] To a solution of phenylmethyl 3-methylideneazetidine-l-carboxylate (2.46 g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (12.5 g, 0.0726 mol) at 0 °C. The reaction mixture was allowed to warm up to room temperature over a period of 12 hours then quenched with 1 M sodium thiosulfate 1 saturated aqueous sodium bicarbonate (1:1). The layers were separated and the organic layer was dried over anhydrous magnesium sulfate then concentrated. The residue was purified by flash chromatography (5-15% ethyl acetate in hexanes) to afford phenylmethyl l-oxa azaspiro[2.3]hexane carboxylate (2,2 g, 83% yield) as clear and colorless oil. !H NMR (400 MHz, CDC13): 7.37-7.29 (m, 5Η), 5.12 (s, 2H), 4.35-4.26 (m, 4Η), 2.85 (s, 2H). MS (El) for Ci2Hi3NO3: 220 (MH+).

Reference 4 4-(2-fluoro iodophenyIamino)-l-methyl oxo-l,6-dihydropyridazine carboxylic acid O;

.OH

[00254] 4-chloro-l-methyl oxo-l,6-dihydropyridazine carboxylic acid was prepared using procedures similar to those disclosed in US 2005256123.

[00255] To a solution of 4-chloro-l-methyI oxo-l,6-dihydropyridazine carboxylic acid (350 mg, 1.855 mmol) and 2-fluoro iodoaniline (1.06 g, 4.453 mmol) in tetrahydrofuran (13.3 mL) was sparged with nitrogen for 5 minutes followed by the slow addition of lithium bis(trimethylsilyl)amide, 1.0 M in THF (7.4 mL). The reaction mixture stirred for an additional 4 hours at room temperature. The mixture was quenched with 1 N HCl and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N 166 aqueous HCl. The aqueous layer was extracted (3x) with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford 4-(2-fluoro iodophenylamino)-l-methyl~6-oxo-l,6-dihydropyridazine- 3- carboxylic acid (939 mg, 100% yield). VlNMR (CDC13): 7.27 (dd, IH), 7.21 (d, IH), 6.54 (t, IH), 4.84 (broad s, 2H), 2.09 (s, IH), 1.26 (t, 3H); MS (El) for Ci2H9N3O3FI: 389 (MH+). [00256] A solution of 4-(2-fluoro~4-iodophenylamino)-l-methyl oxo- 1.6- dihydropyridazine carboxylic acid (939 mg, 2.413 mmol) in dichloromethane (60 mL) in the presence of dimethylformamide (8.0 mL) was cooled to 0 °C. Malonyl chloride (1.26 mL, 14.48 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was evaporated and partitioned between ethyl acetate and 1M aqueous ammonium chloride. The aqueous layer was extracted lx with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-(2-fluoro iodophenylamino)-l-methy 1 oxo-1,6-dihydropyridazine carbonyl chloride. This crude material was taken into the next step without further purification. MS (El) for CnHgbbCLClFI: 408 (MH+).

[00257] To a solution of 4-(2-fluoro iodophenylamino)-l-methyl oxo- 1.6- dihydropyridazine carbonyl chloride in methanol (15 mL) and benzene (12 mL) was added dropwise trimethylsilyl diazomethane (1 mL) and stirred at room temperature for 15 minutes. The reaction mixture was quenched with acetic acid and evaporated. The residue was partitioned between ethyl acetate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel chromatography column (7:3 hexanes/ethyl acetate) to afford methyl 4-(2-fluoro- 4- iodophenylamino)-l-methyl oxo-l,6-dihydropyridazine carboxylate (84.9 mg, 8.7% yield). ^NMR (CDC13): 7.49-7.56 (m, 3H), 7.12 (t, IH), 6.13 (d, IH), 4.00 (s, 3H), 3.83 (s, 3H); MS (El) for CAHiMAFI: 404 (MH+).

[00258] Methyl 4-(2-fluoro iodophenylamino)-l-methyl oxo-l,6-dihydropyridazine carboxylate (84.9 mg, 0.211 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (2.5 mL) and water (2.5 mL). Aqueous 2 M lithium hydroxide (200 pL) was added at room temperature. After 10 minutes, the reaction mixture was heated to 50 °C for 30 minutes and continued to stir at room temperature for 16 hours at which time the solvents were evaporated. The residue was made acidic with 2 M aqueous hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic layer separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 4-(2-fluoro iodophenylamino)-l- 167 methyl oxo-l,6-dihydropyridazine~3-carboxylic acid (54.0 mg, 66% yield), MS (El) for Ci2H9N3O3FI: 390 (MH+).

Reference 5 1,1-dimethylethyl 2-(3“hydroxy-l-{((phenylmethyl)oxy]carhoiiyl}azetidiii yl)piperidine-l-carboxylate

<img img-format="tif" img-content="drawing" file="IL229136AD000272.tif" id="idf0072" />

[00259] To a solution of 1,1-dimethylethyl piperidine carboxylate (0.50 g, 2.7 mmol) in anhydrous diethyl ether (9.0 mL) under anhydrous nitrogen gas was added tetramethylethane-l,2-diamine (0,41 mL, 2.7 mmol), and the solution was cooled to -78°C. To this solution was added (2-methylpropyl)lithium (2.1 mL, 1.4 M in cyclohexane, 3.0 mmol) in small portions. To this anion solution was added phenylmethyl 3-oxoazetidine-l-carboxylate (1.0 g, 5.4 mmol), prepared using procedures as described in Reference 3, in anhydrous ether (2.0 mL), while maintaining the internal temperature at less than -60°C. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether twice. The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.13 g (13%) of 1,1-dimethylethyl 2-(3 -hydroxy-1 - {[(phenylmethyl)oxy] carbonyl} azetidin yl)piperidine-1 - carboxylate. *H NMR (400 MHz, CDCb): 7.31 (m, 5H), 5.08 (s, 2H), 4.05 (d, 1H), 4.00 (d, 1H), 3.84 (d, 2H), 3.80 (broad s, 1H), 3.55 (broad s, 1H), 3.10 (broad s, 1H), 1.92 (m, 1H), 1.45-1.62 (m, 6H), 1.43 (s, 9H). MS (El) for C2,H3oN205: 335 (M-tBu), 315 (M-OtBu). EXAMPLE 1 1-((3,4-diiluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol

<img img-format="tif" img-content="drawing" file="IL229136AD000273.tif" id="idf0073" />

F 168 [00260] 3,4-Difluoro [(2-fluoro iodophenyl)amino]benzoic acid (2.1 g, 5.3 mmol), prepared using procedures similar to those in US 7,019,033, was taken into DMF (10 mL) followed by addition of PyBOP (2.6 g, 5.3 mmol) and the mixture was allowed to stir at room temperature over 15 minutes. Azetidin ol hydrochloride (870 mg, 8.0 mmol) and DIPEA (1.85 mL, 11.2 mmol) was then added and the mixture was allowed to stir an additional hour at room temperature. The mixture was then partitioned with ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was then washed with water (3x) then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography using ethyl acetate: hexanes (5:1) eluent afforded l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol (2.09 g, 87% yield) as a colorless amorphous solid. !H NMR (400 MHz, CDC13): 8.47 (s, 1H), 7.39 (dd, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.78 (m, 1H), 6.63-6.57 (m, 1H), 4.74-4.67 (m, 1H), 4.43- 4.39 (m, 2H), 4.20-3.96 (br d, 2H), 2.50 (d, 1H).

[00261] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the compounds in Examples l(a)-(e) were prepared. EXAMPLE 1(a). l-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}-carbonyl)azetidin yl]-A(77-diniethylpyrrolidin amine. The title compound was prepared by reacting 3,4-difluoro [(2-fluoro iodophenyl)amino]benzoic acid with7V-methyl-N-(2-(pyridin yl)ethyl)azetidin amine. The azetidine intermediate was prepared using procedures similar to those described in Abdel-Magid, et.al., Tetrahedron Letters 1990, 31(39), 5595 starting with ZerZ-butyl 3-oxoazetidine carboxylate, which itself was prepared as described in Example 3. The title compound: lH NMR (400 MHz, dg-DMSO): 8.56 (s, 1H), 7.58 (m, 1H), 7.38 (d, 1H), 7.31 (m, 1H), 7.16 (m, 1H), 6.67 (m, 1H), 4.16 (m, 1H), 3.97 (m, 2H), 3.77 (m, 1H), 3.26 (br s, 4H), 2.63 (m, 1H), 2.42 (br s, 6H), 1.99 (br s, 1H), 1.74 (br s, 1H). MS (El) for C22H24F3IN4O: 545 (MH+). EXAMPLE 1(b). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-A-methyl-A-(2~pyridin ylethyl)azetidm amine. The title compound was prepared by reacting 3,4-difluoro [(2-fluoro iodophenyl)amino]benzoic acid with l-(azetidin yl)-N,N-dimethylpyrrolidin amine. The azetidine intermediate was preparedusing procedures similar to those described in Abdel-Magid, et.al., Tetrahedron Letters 1990, 31(39), 5595 starting with ZerZ-butyl 3-oxoazetidine carboxylate, which itself was prepared as described in Example 3. The title compound: 3H NMR(400 MHz, CD3OD): 8.50 (d, 1H), 7.94 (t, 1H), 7.50-7.30 (m, 5H), 7.07 (q, 1H), 6.66- 6.61 (m, 1H), 4.52-4.48 (m, 2H), 4.31(s, 2H), 4.23- 169 4.18 (m, IH), 3.48- 3.46 (m, 2H), 3.17-3.13 (m, 2H), 2.88 (s, 3H); MS(EI) for C24H22F3IN4O: 567 (MH+). EXAMPLE 1(c). 6-(Azetidin-l-ylcarbonyl)-2,3-difluoro-/V-(2-fluoro iodophenyl)aniline: 3HNMR (400 MHz, CDC13): 8.57 (s, IH), 7.41-7.38 (dd, IH), 7.34-7.31 (dt, IH), 7.13-7.09 (m, IH), 6.83-6.77 (m, IH), 6.64-6.58 (m, IH), 4.27 (b, 2H), 4.18 (b, 2H), 2.38-2.30 (p, 2H); MS (Ε&amp;#938;) for Ci6H,2F3IN3O: 433 (MH+). EXAMPLE 1(d). [l-({3,4-Difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]methanol: ’H NMR (400 MFIz, CDC13): 8.52 (s, IH), 7.41-7.38 (dd, IH), 7.34-7.31 (dt, IH), 7.15-7.11 (m, IH), 6.83-6.77 (m, IH), 6.64-6.58 (m, IH), 4.29-4.20 (m, 2H), 4.09 (b, IH), 3.93 (b, IH), 3.82-3.81 (d, 2H), 2.89- 2.75 (m, IH); MS (El) for C17H14F31N2O2: 463 (MH+). EXAMPLE 1(e). l-({3,4-Difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidine carboxylic acid: 3HNMR (400 MHz, CDC13): 7.79 (b, 2H), 7.42-7.38 (dd, IH), 7.34-7.32 (dt, IH), 7.15-7.11 (m, IH), 6.89-6.83 (m, IH), 6.65-6.60 (m, IH), 4.46-4.29 (m, 4H), 3.55-3.47 (m, IH); MS (El) for Ci7H]2F3IN2O3: 477 (MH+). EXAMPLE 2 2V-[l-({3,4-Difluoro [(2-fluoro iodophenyl)ammo]phenyl}carbonyl)azetidin yl]- 2V2,/V2-diethylglycinamide

<img img-format="tif" img-content="drawing" file="IL229136AD000274.tif" id="idf0074" />

[00262] A solution of 3,4-difluoro [(2~fluoro iodophenyl)amino]benzoic acid (200 mg, 0.51 mmol), prepared using procedures similar to those in US 7,019,033, PyBOP (256 mg, 0.51 mmol), commercially available te/4-butyl azetidin ylcarbamate (131 mg, 0.77 mmol) and Λζ/V-diisopropylethylamme (180 pL, 1.02 mmol) in dimethyiformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was partitioned between 5% aqueous lithium chloride and ethyl acetate. The organic portion was washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford 1,1- 170 dimethylethyl [l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin- 3-yl]carbamate (225 mg, 80% yield) as a colorless oil. !H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.60-7.55 (m, 2H), 7.38 (d, 1H), 7.30-7.26 (m, 1H), 7.20-7.13 (m, 1H), 6.71-6.66 (m, 1H), 4.37-4.20 (m, 2H), 4.18-4.06 (m, 1H), 3.98-3.93 (m, 1H), 3.82-3.75 (m, 1H), 1.37 (s, 9H). MS (El) C21H21N3O3F3I: 548 (MH4).

[00263] A solution of 1,1 -dimethylethyl [ 1 -({3,4-difluoro-2~[(2-fluoro iodopbenyl)amino]phenyl}carbonyl)azetidin yl]carbamate (113 mg, 0.20 mmol) and trifluoroacetic acid (500 pL) in dichioromethane (2 mL) was added stirred at room temperature for one hour then was partitioned between saturated aqueous sodium bicarbonate, and dichloromethane. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a colorless residue which was purified by column chromatography eluting with 10% methanol in dichloromethane to afford l-({3,4-difluoro-2~[(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin amine (85 mg, 95% yield) as a white foam. *H NMR (400 MHz, CDC13): 8.53 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.46-4.39 (m, 2H), 3.98-3.75(br m, 4H); MS (El) for CieHi^jINjO: 448 (MH*).

[00264] A solution of l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin amine (100 mg, 0.22 mmol), PyBOP (131 mg, 0.25 mmol), MA-diisopropylethylamine (80 pL, 0.44 mol) and bromoacetic acid (35 mg, 0.25 mmol) in dimethylformamide (1 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the resultant residue was purified by column chromatography eluting with 80% ethyl acetate in hexanes to afford 2-bromo-Y-[l-({3,4-difluoro [(2-fluoro~4riodophenyl)amino]phenyl} carbonyl)azetidin yl] acetamide (102 mg, 82% yield) as a white foam. MS (El) for Cig^BrFsINaCt?: 568.

[00265] A solution of 2-bromo-A-[ 1 -({3,4-difluoro [(2-fluoro~4- iodophenyl)amino]phenyl}carbonyl)azetidin yl]acetamide (30 mg, 0.05 mmol) and Λζ/V-diethylamine (100 pL, excess) in dichloromethane (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and purified by preparative reverse phase HPLC (CH3CN/H2O with 0.1% TFA). isolated product was concentrated in vacuo to afford 77-(1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]-/V2,7V2~diethylglycinamide trifluoroacetate salt (13.0 mg, 38% yield) as a white solid. 3H NMR (400 MHz, CDCI3): 9.36 (br s, 1H), 9.25 (d, 1H), 8.60 (s, 1H), 7.60 (d, 1H), 7.40 (d, 1H), 7.33-7.27 (m, 1H), 7.22-7.15 (m, 1H), 171 6.73-6.66 (m, IH), 4.54-4.40 (m, 2H), 4.25-4.20 (in, IH), 4.04-3.82 (m, 4H), 3.17-3.12 (m, 4H), 1.18-1.15 (tn, 6H); MS (El) C22H24F3IN4O2: 561 (MH+).

[00266] Using the same or analogous synthetic techniques and/or substituting with alternative reagents, the compounds in Examples 2(a)-(n) were prepared. EXAMPLE 2(a). 1,1-Dimethylethyl [l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]carbamate: ’HNMR (400 MHz, CDCI3): 8.52 (br s, IH), 7.40 (dd, IH), 7.33 (dt, IH), 7.13-7.07 (m, IH), 6.80 (ddd, IH), 6.61 (ddd, IH), 5.01-4.88 (br, IH), 4.55-4.37 (br, 4H), 4.05 (br d, IH), 1.43 (s, 9H); MS (El) for C2,H21F3lN3O3S: 548 (MH+). EXAMPLE 2(b). l-({3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl}carbonyl)azetidin amine trifluoroacetate salt: 'H NMR (400 MHz, CDCb): 8.53 (s, IH), 7.39 (d, IH), 7.32 (d, IH), 7.13-7.09 (m, IH), 6.84-6.77 (m, IH), 6.63-6.57 (m, IH), 4.46-4.39 (m, 2H), 3.98-3.75(br m, 4H); MS (El) for C,6Hi3F3IN3O: 448 (MH+). EXAMPLE 2(c). A-[l-({3,4-difluoro [(2-fiuoro iodophenyl)amino]phenyl}carbonyl)azetidin yl] methylpropanamide: &amp;#905; NMR (400 MHz, DMSO): 8.60 (s, IH), 8.38 (d, IH), 7.59 (d, IH), 7.38 (d, IH), 7.32-7.28 (m, IH), 7.18-7.13 (m, IH), 6.72-6.66 (m, IH), 4.45-4.35 (m, IH), 4.18-3.77 (m, 4H), 2.36-2.28 (m, IH), 0.99 (d, 6H); MS (El) 02οΗ,9Ρ3ΙΝ3θ2: 518 (MIL). EXAMPLE 2(d). A-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yI]formamide: 'H NMR (400 MHz, DMSO): 8.69 (d, IH), 8.58 (s, IH), 8.02 (s, IH), 7.59 (d, IH), 7.39 (d, IH), 7.31-7.27 (m, IH), 7.19- 7.13 (m, IH), 6.70-6.66 (m, IH), 4.55-4.46 (m, IH), 4.42-4.36 (m, IH), 4.20-4.16 (m, IH), 4.01-3.97 (m, IH), 3.82-3.79 (m, IH); MS (El) C^HnFjINsOj: 476 (MH4). EXAMPLE 2(e). A-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]-3,4-dihydroxybutanamide: H NMR (400 MHz, DMSO): 8.60 (s, IH), 8.47 (d, IH), 7.59 (d, IH), 7.39 (d, IH), 7.31-7.28 (m, IH), 7.20- 7.14 (m, IH), 6.72-6.66 (m, IH), 4.45-4.35 (m, 2H), 4.18-4.14 (m, IH), 4.00-3.92 (m, IH), 3.84-3.78 (m, 2H), 3.31-3.18 (m, 2H), 2.38-2.18 (m, IH), 2.09-2.03 (m, IH); MS (El) C20Hi9F3IN3O4: 550 (MH+). EXAMPLE 2(f). methyl [l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]carbamate: 3H NMR (400 MHz, DMSO): 8.58 (s, IH), 7.84 (d, IH), 7.59 (d, IH), 7.39 (d, IH), 7.35-7.27 (m, IH), 7.20-7.13 (m, IH), 172 WO 2(107/1)44515 6.71-6.66 (m, IH), 4.38-4.25 (m, 2H), 4.17-4.12 (m, 1H), 4.00-3.97 (m, IH), 3.83-3.78 (m, 1H), 3.53 (s, 3H); MS (El) Ci8Hi5F3IN3O3: 506 (MH+). EXAMPLE 2(g). 77-(1-((3,4-difluoro [(2-fluoro iodophenyI)amino]phenyl}carbonyl)azetidin yl] (4-methylpiperazin-l-yl)acetamide trifluoroacetate salt: !H NMR (400 MHz, DMSO): 8.64 (s, IH), 8.54 (d, IH), 7.60 (d, IH), 7.39 (d, IH), 7.32-7.29 (m, IH), 7.21-7.15 (m, IH), 6.72-6.66 (m, IH), 4.54-4.28 (m, 2H), 4.19-4.15 (m, IH), 4.06-4.00 (m, IH), 3.91-3.84 (nt, IH), 3.44-3.24 (m, 2H), 3.16-2.92 (m, 6H), 2.78 (s, 3H), 2.62-2.50 (m, 2H); MS (El) C23H25F3IN5O2: 588 (MH+). EXAMPLE 2(h). 77-(1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]-77,77-bis(2-hydroxyethyl)glycinamide trifluoroacetate salt: ‘HNMR (400 MHz, DMSO): 9.19 (d, IH), 7.60 (d, IH), 7.41 (d, IH), 7.31-7.27 (m, IH), 7.21-7.15 (m, IH), 6.73-6.66 (m, IH), 4.51-4.40 (m, 2H), 4.23-4.18 (m, IH), 4.05-3.98 (m, 3H), 3.86-3.82 (m, IH), 3.75-3.69 (m, 3H), 3.32 (br s, 4H) C22H24F3IN4O4: 593 (MH+). EXAMPLE 2(i). 77-(1-( (3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl] piperidin-l-ylacetamide trifluoroacetate salt: ‘H NMR (400 MHz, DMSO): 9.20 (d, IH), 7.60 (d, IH), 7.41 (d, IH), 7.31-7.27 (m, IH), 7.21-7.15 (m, IH), 6.73-6.66 (ra, IH), 4.52-4.40 (m, 2H), 4.24-4.18 (m, IH), 4.05-4.00 (m, IH), 3.87-3.80 (m, 3H), 3.40-3.32 (m, 2H), 3.00-2.91 (m, 2H), 1.82-1.66 (m, 6H); MS (El) C23H24F3IN4O2: 573 (MH+). EXAMPLE 2(j). 77-[l-((3,4-difluoro [(2-fluoro iodophenyl)amiito(phenyl}carbonyl)azetidin yl(-N3-(2-hydroxyethyl)-N3-methyl-beta-alaninaniide hydrochloride: *H NMR (400 MHz, DMSO): 9.36 (br s, IH), 8.86 (d, IH), 8.60 (s, IH), 7.59 (d, IH), 7.39 (d, IH), 7.32-7.26 (m, IH), 7.21-7.14 (m, IH), 6.72-6.66 (m, IH), 5.35-5.33 (m, IH), 4.48-4.37 (m, 2H), 4.20-4.15 (m, IH), 4.02-3.96 (m, IH), 3.84-3.79 (m, IH), 3.74-3.68 (m, 2H), 3.42-3.06 (m, 4H), 2.75 (s, 3H), 2.65-2.60 (m, 2H); MS (El) C22H24F3IN4O3: 577 (MH+). EXAMPLE 2(k). 77-(1-( (3,4-difluoro [(2-fluoro iodophenyl)amxno]phenyl}carbonyl)azetidin yl]-N3,N3-bis(2-hydroxyethyl)-beta-alaninamide hydrochloride: 'H NMR (400 MHz, DMSO): 9.39 (br s, IH), 8.91 (d, IH), 8.61 (s, IH), 7.59 (d, IH), 7.39 (d, IH), 7.31-7.27 (m, IH), 7.21-7.14 (m, IH), 6.72-6.66 (m, IH), 5.31 (br s, 2H), 4.46-4.36 (m, 2H), 4.20-4.15 (m, IH), 4.02-3.97 (m, IH), 3.85-3.72 (m, 5H), 3.30-3.17 (m, 4H), 2.68-2.63 (m, 2H); MS (El) C23H26F3IN4O4: 607 (MH+). 173 EXAMPLE 2(m). W-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]-N2-methylglycinamide trifluoroacetate salt: 'H NMR (400 MHz, DMSO): 9.09 (d, 1H), 8.69 (br s, 2H), 8.60 (s, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.31-7.27 (m, 1H), 7.22-7.15 (m, 1H), 6.73-6.66 (m, 1H), 4.54-4.41 (m, 2H), 4.25-4.19 (m, 1H), 3.99-3.96 (m, 1H), 3.84-3.78 (m, 1H), 3.72-3.67 (m, 2H), 2.58-2.54 (m, 3H); MS (El) Ο,,Η,βΕιΙΝ,Λ: 519 (ΜΗ*). EXAMPLE 2(n). JV-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]glycinamide trifluoroacetate salt: *H NMR (400 MHz, DMSO): 8.59 (s, 1H), 8.46 (br s, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.32-7.28 (m, 1H), 7.20-7.13 (m, 1H), 6.72-6.66 (m, 1H), 4.49 (br s, 1H), 4.40-4.35 (m, 1H), 4.18-4.13 (m, 1H), 4.05-4.01 (m, 1H), 3.86-3.81 (m, 1H), 3.07 (s, 2H); MS (El) CMIY/WY 505 (ΜΗ*). EXAMPLE 3 l-({3,4-difhioro [(2-fluoro iodophenyI)amino]plienyI}carbonyl) (morpliolin- 4-yImethyl)azetidin ol

<img img-format="tif" img-content="drawing" file="IL229136AD000275.tif" id="idf0075" />

[00267] A mixture of 3-azetidinol hydrochloride (10 g, 91 mmol), di-ferributyl dicarbonate (18.8 g, 86.3 mmol) and sodium bicarbonate (15.3 g, 182 mmol) in dioxane:water (400 mL, 1:1) was stirred at room temperature for 15 hours. The organic portion was removed in vacuo and the aqueous portion was extracted with ethyl acetate three times. The combined organic portion was washed with 5% aqueous HCl, water, brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford 12.8 g, 74 mmol (81%) of 1,1-dimethylethyl 3-hydroxyazetidine-l-carboxylate as a colorless oil without further purification. *H NMR (400 MHz, DMSO): 5.62 (d, 1H), 4.40-4.33 (m, 1H), 4.02-3.95 (m, 2H), 3.62-3.54 (m, 2H), 1.37 (s, 9H). GC/MS for C8Hi5NO3: 173.

[00268] A solution of oxalyl chloride (545 pL, 6.36 mmol) in dichloromethane (25 mL) was cooled to -78 °C. While maintaining an internal temperature of -78 °C, the dropwise addition of DMSO (903 pL, 12.7 mmol) followed by 1,1-dimethylethyl 3-hydroxyazetidine- 174 1-carboxylate (1 g, 5.78 mmol in 30 mL of dichloromethane) and finally triethylamine (3.25 mL, 23.1 mmol in 20 mL of dichloromethane) was performed. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The reaction mixture was diluted with water and partitioned and the organic portion was washed twice with water. The combined aqueous portion was extracted once with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 893 mg, 5.20 mmol (90%) of 1,1-dimethylethyl 3-oxoazetidine-l-carboxylate as a colorless oil, which solidified upon standing. ’H NMR (400 MHz, DMSO): 4.67 (s, 4H), 1.42 (s, 9H). GC/MS forC8H13NO3: 171.

[00269] A mixture of potassium tor/-butoxide (15.5 g, 137 mmol) and methyltriphenylphosphine bromide (49 g, 137 mmol) in diethyl ether (300 mL) was stirred at room temperature for 1 hour, followed by the addition of 1,1-dimethylethyl 3-oxoazetidine carboxylate (10 g, 58 mmol in 100 mL diethyl ether). The mixture was stirred at 35 °C for 2 hours and then allowed to cool to room temperature. The mixture was filtered through a pad of celite, washing with diethyl ether. The filtrate was partitioned with water and washed twice with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil which was purified by column chromatography. Eluting with 10% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 9.80 g, 58 mmol (100%) of 1,1-dimethylethyl 3-methylideneazetidine carboxylate as a colorless oil. &amp;#905;. NMR (400 MHz, DMSO): 5.05-4.85 (m, 2H), 4.95-4.63 (m, 4H), 1.45 (s, 9H). GC-MS for C9Hi5NO2: 169.

[00270] To a solution of 1,1-dimethylethyl 3-methylideneazetidine carboxylate (2.96 g, 17.5 mmol) in chloroform (180 mL) was added 3-chloroperoxybenzoic acid (77%, 13.9 g, 62.0 mmol), and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate and saturated sodium bicarbonate solutions. The organic portion was isolated, dried over sodium sulfate, filtered and concentrated to give an oily residue which was then purified by flash chromatography (15-50% ethyl acetate-hexanes) to give 1,1-dimethylethyl l-oxa azaspiro[2.3]hexane earboxylate (1.65g, 51%), GC-MS for C9Hi5NO3: 185.

[00271] 1,1-Dimethylethyl l-oxa azaspiro[2.3]hexane carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 pL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then 175 concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in di chloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for 5 minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pFI &gt; 10 by addition of Biorad AG-IX hydroxide form resin. Filtration and concentration afforded 3-(morpholin ylmethyl)azetidin ol (11.6 mg, 24% yield) as a colorless oil. *H NMR (400 MHz, CD3OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2,57-2.55 (m, 4H).

[00272] 3-(Morpholin ylmethyl)azetidin ol (11.6 mg, 0.07 mmol) was taken into DMF (1 mL) followed by addition of DIPEA (35 pL, 0.21 mmol) and 3,4-difluoro [(2-fluoro iodophenyl)amino]benzoyl fluoride (28 mg, 0.07 mmol), prepared using procedures similar to those described in Reference 1, and the mixture was stirred for 30 minutes at room temperature. The solution was then concentrated in vacuo and the residue purified by preparative reverse phase HPLC. Lyophillization of the combined fractions gave 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (morpholin- 4-ylmethyl)azetidin ol trifluoroacetate salt (6.3 mg) as a colorless amorphous solid. !H NMR (400 MHz, CD3OD): 7.48 (d, IH), 7.36 (d, IH), 7.33-7.29 (m, IH), 7.08-7.02 (m, IH), 6.65-6.60 (m, IH), 4.39 (br d, IH), 4.24-4.18 (br, 2H), 4.08-3,96 (br m, 3H), 3.80 (br s, 2H), 3.51 (d, 2H), 3.40 (br s, 2H), 3.24 (br s, 2H).

[00273] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds were prepared. EXAMPLE 3(a). 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (pyrrolidin-l-ylmethyl)azetidin ol: MS (El) for C2iH2iF3IN3O2: 532 (MH+). EXAMPLE 3(b). 1-((1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)- 3- hydroxyazetidin yl]methyl}piperidin ol: MS (El) for C22H23F3IN3O3.· 562 (MH+). EXAMPLE 3(c). 3- {[bis(2-hydroxyethyl)amino]methyl} ((3,4-difluoro [(2-fluoro- 4- iodophenyl)amino]phenyl}carbonyl)azetidin ol: MS (El) for C2iH23F3IN3O4: 566 (MH+). EXAMPLE 3(d). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(4-methylpiperazin-l-yl)methyl]azetidin ol: MS (El) for C22H24F3IN4O2: 561 (MH+). EXAMPLE 3(e). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(4-methyl-l,4-diazepan-l-yl)methyl]azetidin ol: MS (El) for C23H26F3IN4O2: 575 (ΜΗ4). 176 EXAMPLE 3(f). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[methyl(l-methylpyrrolidin yl)amino]methyl}azetidin ol: MS (El) for C23H26F3IN4O2: 575 (MH4). EXAMPLE 3(g). 3-(1,4i-bipiperidm-r-ylmeihyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol: MS (El) for C27H32F3IN3O2: 629 (MH4). EXAMPLE 3(h). 3-({4-[2-(diethylamino)ethyl]piperazin-l-yl}rnethyl)-l -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyi}carbonyl)azetidin ol: MS (El) for C27H35F3IN3O2: 647 (MH4). EXAMPLE 3(i). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(2-hydroxyethyl)(methyl)amino]methyl}azetidin ol: MS (El) for C20H21F3IN3O3: 536 (MH4). EXAMPLE 3(j). 3-(azetidin-l-ylmethyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol: MS (El) for C2oH]9F3IN302: 518 (MH4). EXAMPLE 3(k). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(l-methylethyl)amino]methyl}azetidin ol: MS (El) for C2oH2iF3lN302: 520 (MH4). EXAMPLE 3(m). 3-(aminomethyl)-l-({354-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbony l)azetidin ol: MS (El) for Ci7Hi5F3IN3O2: 478 (MH4). EXAMPLE 3(n). N- {[ 1 -({ 3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl) hydroxyazetidin yl]methyl}acetamide: MS (El) for Ci9Hi7F3IN3O3: 520 (MH4). EXAMPLE 3(o). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(l,l-dimethylethyl)amino]methyl}azetidin ol·. MS (El) for C2iH23F3IN3O4: 534 (MH4). EXAMPLE 3(q). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(hydroxyamino)methyl]azetidin ol: *H NMR (400 MHz, d4-MeOH): 7.45 (2d, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 7.03 (m, 1H), 6.63 (m, 1H), 4.32 (d, 1H), 4.05 (dd, 2H), 3.85 (d, 1H), 3.00 (s, 2H); MS (El) for C]7Hi5F3IN3O3: 494 (MH4). EXAMPLE 3(r). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(methyloxy)amino]methyl}azetidin ol: *H NMR (400 MHz, d4-MeOH): 7.45 (2d, 1H), 7.35 (m, 1H), 7.27 (m, 1H), 7.04 (m, 1H), 6.62 (m, 1H), 4.26 (d, 1H), 4.08 (d, 1H), 4.00 (d, 1H), 3.84 (d, 1H), 3.30 (s, 3H), 3.00 (d, 2H); MS (Ε&amp;#938;) for CigH^FsINsOj: 508 (MH4). EXAMPLE 3(s). l-({3,4-difluoro [(2“fluoro iodophenyl)amino]phenyl}carbonyl) {[(ethyloxy)amino]methyl}azetidin ol: JH NMR (400 MHz, d4-MeOH): 7.45 (2d, 1H), 7.34 (m, 1H), 7.26 (m, 1H), 7.03 (m, 1H), 6.63 (m, 1H), 4.26 (d, 1H), 4.12 (d, 1H), 4.00 (d, 1H), 3.84 (d, 1H), 3.61 (dd, 2H), 3.00 (s, 2H), 1.06 (t, 3H); MS (Ε&amp;#938;) for C19H19F3IN3O3: 522 (MH4). 177 EXAMPLE 3(t). 1-( [1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methyl}guanidine acetate salt: !H NMR (400 MHz, cfi-MeOH): 7.46 (2d, 1H), 7.36 (m, 1H), 7.30 (m, 1H), 7.04 (m, 1H), 6.62 (m, 1H), 4.18 (d, 1H), 4.08 (d, 1H), 4.02 (d, 1H), 3.88 (1H)&gt; 3.40 (s, 2H); MS (El) for C18H17F3IN5O2: 520 (MH+). EXAMPLE 3(u). A-{[1-((3,4-difluoro-2~[(2-fhioro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methyl)benzenecarboximidamide hydrochloride: !H NMR (400 MHz, d4-MeOH): 7.70 (d, 3H), 7.58 (m, 2H), 7.46 (dd, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.04 (m, 1H), 6.62 (m, 1H), 4.28 (m, 1H), 4.15 (m, 2H), 3.96 (m, 1H), 3.78 (s, 2H); MS (El) for C24H20F3IN4O2: 581 (MH+). EXAMPLE 3(v). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(pyrimidin ylamino)methyl]azetidin ol hydrochloride: ’H NMR (400 MHz, d4-MeOH): 8.48 (s, 2H), 7.46 (2d, 1H), 7.36 (m, 1H), 7.28 (m, 1H), 7.04 (m, 1H), 6.85 (t, 1H), 6.61 (m, 1H), 4.24 (d, 1H), 4.06 (t, 2H), 3.87 (d, 1H), 3.75 (d, 2H); MS (Ε&amp;#938;) for C2iHi7F3lN5O2: 556 (MH+). EXAMPLE 3(w). 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(pyridin ylamino)methyl]azetidin ol hydrochloride: 3H NMR (400 MHz, d4-MeOH): 7.87 (dd, 1H), 7.85 (dd, 1H), 7.46 (2d, 1H), 7.36 (m, 2H), 7.06 (m, 2H), 6.89 (m, 1H), 6.61 (m, 1H), 4.53 (d, 2H), 4.46 (m, 1H), 4.28 (m, 1H), 4.16 (m, 1H), 3.96 (m, 1H); MS (El) for C22Hi8F3IN4O2: 555 (MH+). EXAMPLE 3(x). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)~3-f(ethylamino)methyl]azetidin ol: *H NMR. (400 MHz, dg-DMSO): 8.61 (s, 2H), 7,59 (d, 1H), 7.40 (d, 1H), 7.36-7.33 (m, 1H), 7.23-7.18 (m, 1H), 6.71 (s, 2H), 4.31-4.26 (m, 1H), 4.13-4.05 (m, 2H), 3.88-3.84 (m, 1H), 3.21 (br m, 2H), 2.97-2.90 (m, 2H), 1.19 (t, 3H). MS (El) for Ci9H19F3IN3O2: 506 (MH+). EXAMPLE 3(y). 3-[(cyclopropylamino)methyl] ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol: 3H NMR (400 MHz, de-DMSO): 8.99 (br s, 2H), 8.60 (s, 1H), 7.58 (d, 1H), 7.39 (d, 1H), 7.36-7.33 (m, 1H), 7.23-7.16 (m, 1H), 6.72 (s, 2H), 4.34-4.29 (m, 1H), 4.14-4.04 (m, 2H), 3.88-3.84 (m, 1H), 2.70-2.64 (m, 1H), 0.89 (br s, 2H), 0.74-0.69 (br s, 2H). MS (El) for C20H19F3IN3O2: 518 (MH+), EXAMPLE 3(z). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(2,2,2-trifluoroethyl)amino]methyl}azetidin ol: 3H NMR (400 MHz, d6-DMSO): 8.60 (s, 1H), 7.58 (d, 1H), 7.38 (d, 1H), 7.35-7.30 (m, 1H), 7.22-7.17 (m, 1H), 6.72-6.67 (m, 1H), 4.25-4.19 (m, 1H), 4.07-3.98 (m, 2H), 3.86-3.77 (m, 2H), 3.19-3.09 (m, 2H). MS (El) for Ci9Hi6F6IN3O2: 560 (MH+). 178 EXAMPLE 3(aa). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino3phenyl)earbonyl) (l/7-l,2,3-triazoi-l-ylmethyl)azetidin ol: ’HNMR (400 MHz, d6-DMSO): 8.55 (s, IH), 8.04 (s, IH), 7.66 (s, IH), 7.58 (d, IH), 7.39 (d, IH), 7.34-7.29 (m, IH), 7.22-7.15 (m, IH), 6.72-6.66 (m, IH), 6.29 (s, IH), 4.64 (s, 2H), 4.29-4.25 (m, IH), 4.13-4.09 (m, IH), 4.00-3.96 (m, IH), 3.77-3.73 (m, IH), 3.16 (d, IH). MS (El) for C19HI5F3IN5O2: 530 (ΜΗ4). EXAMPLE 3(bb). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-3~ {[(2,2-dimethylpropyl)amino]methyl}azetidin ol: JH NMR (400 MHz, di-DMSO): 8.61 (s, IH), 8.30 (s, 2H), 7.59 (d, IH), 7.39 (d, IH), 7.36-7.17 (m, 4H), 6.77-6.66 (m, 4H), 4.35-4.30 (m, IH), 4.16-4.08 (m, 2H), 3.92-3.87 (m, IH), 3.31-3.27 (m, 2H), 2.78-2.74 (m, 2H), 1.76 (s, 4H), 0.99 (s, 9H). MS (El) for C22H25F3iN3O2: 548 (MH+), EXAMPLE 3(cc). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[2-(4-methylphenyl)ethyl] amino} methy l)azetidin ol acetate salt: 3H NMR (400 MHz, CDCb): 8.48 (s, IH), 7.39 (dd, IH), 7.31-7.34 (m, IH), 7.08 (dd, 5H), 6.77-6.83 (m, IH), 6.58- 6.63 (m, IH), 4.20 (br s, IH), 4.01 (d, IH), 2.87 (t, 4H), 2.75 (t, 4H), 2.5 (br s, 2H), 2.33 (s, 3H), 2.08 (s, 2H). MS (Ε&amp;#938;) for C26H25F3IN3O2: 594 (M-H). EXAMPLE 3(dd). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbony 1) [(2,3-dihydro inden ylamino)m ethyl] azetidin ol acetate salt: ’H NMR (400 MHz, CDCI3): 8.48 (s, IH), 7.40 (dd, IH), 7.32-7.34 (m, IH), 7.15-7.22 (m, 4H), 7.10-7.14 (m, IH), 6.77-6.83 (m, IH), 6.58-6.64 (m, IH), 4.22 (br s, IH), 4.04 (d, IH), 3.57-3.63 (m, IH), 3.17 (dd, 2H), 2.94 (s, 2H), 2.75 (dd, 2H), 2.48 (br s, 4H), 2.08 (s, 2H). MS (El) for C26H23F3IN3O2: 592 (M-H). EXAMPLE 3(ee). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[(lS,2S) hydroxycyclopentyl]amino}methyl)azetidin ol acetate salt: 3H NMR (400 MHz, CD3OD): 7.46 (dd, IH), 7.33-7.37 (m, IH), 7.26-7.31 (m, IH), 7.00-7.08 (m, IH), 6.58- 6.65 (m, IH), 4.2 (t, IH), 3.86-4.06 (m, 4H), 2.92-3.10 (m, 3H), 2.00-2.10 (m, IH), 1.91-1.97 (m, 3H), 1.66-1.78 (m, 2H), 1.52-1.61 (m, IH), 1.32-1.44 (m, IH). MS (El) for C22H23F3IN3O3: 560 (M-H). EXAMPLE 3(ff). 1 -({3,4-difluoro [(2-fluoro iodophenyl)aniino]phenyl}carbonyl) {[(l,2-dimethylpropyl)amino]methyl}azetidin ol acetate salt: ’H NMR (400 MHz, CD3OD): 7.45 (dd, IH), 7.33-7.37 (m, IH), 7.26-7.31 (m, IH), 7.01-7.08 (m, IH), 6.59-6.64 (m, IH), 4.14-4.22 (m, IH), 3.98-4.06 (m, 2H), 3.84-3.90 (m, IH), 2.86-3.20 (m, 2H), 2.65 (br s, IH), 1.92 (s, 2H), 1.76-1.86 (m, IH), 1.06 (d, 3H), 0.91 (dd, 6H). MS (El) for C22H25F3IN3O2: 546 (M-H). 179 EXAMPLE 3(gg). l-({3,4-difluoiO [(2-fiuoiO iodophenyl)amino]phenyl}carbonyl) ({[ 1 -methy 1 (m ethy loxy) ethyl· jam ino) methyl)azetidin-3~ol acetate salt: !H NMR (400 MHz, CD3OD); 7.55 (dd, 1H), 7.33-7.36 (m, 1H), 7.26-7.31 (m, 1H), 7.01-7.09 (m, 1H), 6,59-6.65 (m, 1H), 4.14-4.22 (m5 1H), 3.96-4.06 (m, 2H), 3.85-3.92 (m, 1H), 3.40-3.48 (m, 1H), 3.34 (s, 3H), 2.90-3,15 (m, 3H), 1.94 (s, 3H), 1.11 (d, 3H). MS (El) for C2jH23F3iN3O3: 548 (M-H), EXAMPLE 3(hh). l-({3,4-difluoro~2“[(2-fluoro iodophenyl)araino]phenyl}carbonyl)-3“ {[(l-ethylpropyl)amino]methyl}azetidm~3~ol acetate salt: lH NMR (400 MHz, CD3OD): 7.45 (dd, 1H), 7.33-7.36 (m, 1H), 7.26-7.31 (m, 1H), 7.01-7.09 (m, 1H), 6.58-6.65 (m, &amp;#938;Η), 4,15-4.20 (m, 1H), 3.99-4.06 (m, 2H), 3.86-3,91 (ra, 1H), 2.94 (s, 2H), 2.55-2.63 (m, 1H), 1.92 (s, 2H), 1.48-1.58 (m, 4H), 0,92 (t, 6H). MS (El) for C^HzsFsWA: 546 (M-H). EXAMPLE 3(ii), 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (l/Mmidazol“l-ylmethyl)azetldin ol: *H NMR (400 MHz, CD3OD): 7.67 (brs, 1H), 7,48 (m, 1H), 7.36 (ra, 1H), 6.91 (br s, 1H), 6.63 (m, 1H), 4,25 (s, 2H), 4,22 (m, 1H), 4.02 (m,

2H), 3,82 (m, 1H). MS (El) for CzoH^RW 529 (MH J EXAMPLE 3(jj). 3-{[(cyclopropyhnethyl)araino]raethyl}-1 -({3,4-difluoro [(2-fluorO“4“ iodophenyl)amino3phenyl}carbonyl)azetidin ol: *H NMR (400 MHz, CD3OD),: 7.47 (m, 1H), 7.36 (ra, 1H), 7.31 (ra, 1H), 7.05 (ra, 1H), 6.62 (ra, 1H), 4.30 (m, 1H), 4.24 (m, 2H), 3,99 (ra, 1H), 3,66 (m, 2H), 2.91 (d, 2H), 1.08 (ra, 1H), 0.71 (ra, 2H), 0.40 (ra, 2H). MS (El) for C2sH2iF3lN3O2: 532 (MH+). EXAMPLE 3(kl&lt;). l-({3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl}cafbonyl) {[(phenylraethyl)amino]methyl}azetidin ol hydrochloride: NMR (400 MHz, CD3OD): 7.47 (m, 5H), 7.43 (ra, 1H), 7.35 (ra, 1H), 7.27 (ra, 1H), 7,04 (ra, 1H), 6.61 (m, 1H), 4.24 (m, 3H), 4.08 (ra, 2H), 3.96 (ra, 1H). MS (El) for C24H21F3IN3O2: 568 (MH+). EXAMPLE 3 (mm). 3-[(butylamrao)raethyl3-l“({3,4-difluoro“2-[(2“fluoro iodophenyl)amino3phenyl}carbonyl)azetidin-3~ol: *H NMR (400MHz, d6-DMSO): 8.56 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7,17 (q, 1H), 6,67 (dt, 1H), 4.04 (d, 1H), 3.88 (q, 2H), 3.69 (d, 1H), 2.59 (s, 2H), 1.90 (s, 2H), 1.22-1.33 (ra, 4H), 0.84 (t, 3H); MS (Ε&amp;#938;) for C2iH23F3IN3O2: 534 (MH*). EXAMPLE 3(nn). 1 -({3,4-difluoro“2-[(2-fluoro iodophenyl)araino]phenyl} carbonyl)~3-({[(l-ethylpyrrolidin yl)raethyl]araino}raethyl)azetidin ol: ‘HNMR(400MHz,dg-DMSO): 8.59 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.02 (t, 1H), 3.89 (q, 2H), 3.69 (d, 1H), 2.98 (s, 1H), 2.67-2.76 (ra, 1H), 2.62 (s, 1H), 2,39- 180

2.45 (m, IH), 2.29 (s, IH), 1.97-2.13 (m, 2H), 1.69 (s, IH), 1.54 (s, 3H), 0.97 (t, 3H); MS (El) for CmIWjRW 589 (MH+). EXAMPLE 3(oo). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl)-3~ {[(2-hydroxyethyl)amino]methyl}azetidin ol: 'H NMR (400MHz, d^-DMSO): 8.57 (s, IH), 7.57 (dd, IH), 7.37 (d, IH), 7.32 (t, IH), 7.18 (q, IH), 6.68 (dt, IH), 4.06 (d, IH), 3.87 (d, 2I-I), 3.70 (d, IH), 3.42 (t, 2H), 2.65 (s, 2H), 2.56 (dt, 2H). 1.91 (s, 2H); MS (El) for C19H19F3IN3O3: 522 (MH+). EXAMPLE 3(pp). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) ({[2-(dimethylamino)ethyl]amino}methyl)azetidin ol: ’H NMR (400MHz, di-DMSO): 8.58 (s, IH), 7.57 (dd, IH), 7.36 (d, IH), 7.31 (t, IH), 7.17 (q, IH), 6.68 (dt, IH), 4.02 (d, IH), 3.87 (t, 2H), 3.70 (d, IH), 2.62 (s, IH), 2.54 (t, IH), 2.23 (t, IH), 2.09 (s, 4H), 7.85 (s, 6H); MS (El) for C2iH24F3IN4O2: 549 (MH+). EXAMPLE 3(qq). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) (([2-(l-methylpyrrolidin yl)etliyl]amino}niethyl)azetidin oI·. 'H NMR (400MHz, dj-DMSO): 8.58 (s, IH), 7.57 (dt, IH), 7.36 (d, IH), 7.31 (t, IH), 7.17 (q, IH), 6.68 (dt, IH), 4.04 (d, IH), 3.89 (d, 2H), 3.79 (d, IH), 2.88-2.92 (m, IH), 2.61 (s, 2H), 2.15 (s, 3H), 1.93-2.04 (m, 2H), 1.75-1.83 (m, 3H), 1.54-1.70 (m, 3H), 1.20-1.37 (m, 2H); MS (El) for C24H28F3IN4O2; 589 (MH+). EXAMPLE 3(rr). 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(tetrahydrofuran ylmethyl)amino]methyl}azetidin ol: 'H NMR (400MHz, di-DMSO): 8.58 (s, IH), 7.57 (dd, IH), 7.37 (d, IH), 7.31 (t, IH), 7.14 (q, IH), 6.68 (dt, IH), 5.75 (s, IH), 4.03 (t, IH), 3.87 (t, 2H), 3.76 (q, IH), 3.68 (q, 2H), 3.54-3.58 (m, IH), 2.63 (s, 2H), 1.91 (s, 2H), 1.71-1.87 (m, 3H), 1.40-1.48 (m, IH); MS (El) for C22H23F3iN3O3: 562 (MH+). EXAMPLE 3(ss). 1-((3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl}carbonyl) {[(3-pyrrolidin-l-ylpropyl)amino]methyl}azetidin ol: *H NMR (400MHz, dj-DMSO); 8.58 (s, IH), 7.57 (dd, IH), 7.36 (d, IH), 7.31 (t, IH), 7.17 (q, IH), 6.68 (dt, IH), 4.04 (d, IH), 3.89 (d, 2H), 3.69 (d, IH), 2.60 (s, IH), 2.34-2.37 (m, 4H), 1.86 (s, 8H), 1.64 (s, 2H), 1.46-1.53 (m, IH); MS (El) for CmHmFjIN^: 589 (MH*)· EXAMPLE 3(tt). l-((3,4-difluoro [(2-fluoro iodophenyl)amino]pbenyl)oarbonyl) ({[2-(methyloxy)ethyl]amino)niethyl)azetidm ol: ’HNMR (400MHz, di-DMSO): 'H NMR (400MHz, ds-DMSO): 8.57 (s, IH), 7.57 (dd, IH), 7.37 (d, IH), 7.31 (t, IH), 7.17 (q, IH), 6.68 (dt, IH), 4.03 (d, IH), 3.86 (d, 2H), 3.70 (d, IH), 3.21 (s, 3H), 2.63 (s, 4H), 1.88 (s, 2H); MS (El) for C20H2i1;jIN3O3: 536 (MH+). 181 EXAMPLE 3(uu). 1-((3,4-diflnoro [(2-fluoro iodophenyl)atnino]phenyl}carbonyl) ({[(l-methylpiperidin yl)methyl]ainino}niethyl)azetidin ol: ’HNMR (400MHz, ds-DMSO): 8.58 (s. IH), 7.57 (d, IH), 7.37 (d, 1H), 7.31 (t, IH), 7.17 (q, IH), 6.68 (t, IH), 4.03 (d, IH), 3.89 (t, 2H), 3.69 (d, IH), 2.68 (d, 2H), 2.57 (s, IH), 2.34 (d, 2H), 1.88 (s, 4H), 1.73 (t, 2H), 1.57 (d, 2H), 1.23 (s, IH), 1.05 (q, 2H); MS (El) for ΟμΗΛΙΝ,Α: 589 (ΜΗ1). EXAMPLE 3(w). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)earbonyl) ({[4-(dimethylamino)butyl]amino}methyl)azetidin ol: *H NMR (400MHz, de-DMSO): 7.57 (dd, IH), 7.36 (d, IH), 7.31 (t, IH), 7.18 (q, IH), 6.68 (dt, IH), 4.03 (t, 2H), 3.88 (t, 2H), 3.70 (d, IH), 3.08 (s, IH), 2.60 (s, IH), 2.44-2.47 (m, 2H), 2.28-2.33 (m, IH), 2.07-2.16 (in, 6H), 1.29-1.35 (m, 4H); MS (El) for C23I-I28F3IN4O2: 577 (MH+). EXAMPLE 3(ww). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}cafbonyl) {[(2-furan yiethyl)amino]methyl}azetidin ol: *H NMR (400MHz, de-DMSO): 8.58 (s, IH), 7.57 (d, IH), 7.49 (s, IH), 7.36 (d, IH), 7.31 (t, IH), 7.17 (q, IH), 6.68 (t, IH), 6.33 (s, IH), 6.08 (s, IH), 5.72 (s, IH), 4.04 (d, IH), 3.87 (d, 2H), 3.70 (d, IH), 2.74 (d, 2H), 2.69 (d, 2H), 2.64 (s, 2H); MS (El) for C23H2iF3IN3O3: 572 (MH!). EXAMPLE 3(xx). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(2-ethylbutyl)amino]methy]}azetidin ol: !H NMR (400MHz, dg-DMSO): 8.58 (s, IH), 7.56 (dd, IH), 7.36 (d, IH), 7.31 (t, IH), 7.17 (q, IH), 6.67 (dt, IH), 4.03 (d, IH), 3.90 (d, 2H), 3.69 (d, IH), 2.58 (s, 2H), 2.37 (d, 2H), 1.17-1.27 (m, 5H), 0.78 (t, 6H); MS (El) for C23H27F3IN3O2· 562 (MH). EXAMPLE 3(yy). 1,1-dimethylethyl [3-(((1-((3,4-difluoro [(2-fluoro iodophenyI)amino]phenyl)carbonyl) hydroxyazetidin yl[methyl}amino)propyl]carbamate: 'HNMR (400MHz, d6-DMSO): 8.58 (s, IH), 7.57 (d, IH), 7.30-7.38 (m, 3H), 7.17 (q, IH), 6.82 (t, IH), 6.68 (dt, IH), 4.07 (d, IH), 3.89 (d, 2H), 3.70 (d, IH), 3.36 (s, 2H), 2.93 (q, 2H), 2.61 (s, 2H), 1.46 (t, 2H), 1.36 (s, 9H); MS (El) for C2SH30F3IN4O4: 635 (MH+). EXAMPLE 3(zz). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(pyrrolidin ylmethyl)amino)inethy!}azetidin ol· ’HNMR (400MHz, di-DMSO): 8.53 (s, IH), 7.58 (dd, IH), 7.37 (d, IH), 7.33 (d, IH), 7.18 (q, IH), 6.67 (dt, IH), 6.25 (s, IH), 4.07 (d, IH), 3.96 (q, 2H), 3.78 (s, 3H), 3.34 (s, 6H), 1.73 (s, IH), 1.35-1.39 (tn, IH); MS (El) for C22H24F3IN4O2: 561 (MH). EXAMPLE 3(aaa). 1,1-dimethylethyl 4-[({[l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methyl}amino)methyl]piperidine-l-carboxylate: ’H NMR (400MHz, cU-DMSO): 8.56 (s, 182 IH), 7.56 (dd, IH). 7-36 (d, IH), 7.30 (t, IH), 7.17 (q, IH), 6.68 (dt, IH), 4.03 (d, IH), 3.88 (t, 4H), 3.69 (d, IH), 2.58 (s, 2H), 2.35 (d, 2H), 1.60 (d, 2H), 1.47 (s, IH), 1.39 (s, 10H), 0.90 (q, 2H); MS (El) for CziHsAW),: 675 (MH4). EXAMPLE 3(bbb). 1-((3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl}carbonyl) ({[(2-hydroxyphenyl)methyl]amino}methyl)azetidin ol: 'HNMR (400MHz, cU-DMSO): 8.56 (s, IH), 7.54 (dd, IH), 7.35 (d, IH), 7.30 (t, IH), 7.17 (q, IH), 7.05 (t, 2H), 6.64-6.72 (m, 3H), 4.07 (d, IH), 3.90 (t, 2H), 3.78 (s, 2H), 3.72 (d, IH), 2.65 (s, 2H); MS (El) for C24H21F3IN3O3: 584 (MH4). EXAMPLE 3(ccc). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[(3-hydroxyphenyl)methyl]anuno}methyl)azetidin ol: *H NMR (400MHz, ds-DMSO): 8.58 (s, IH), 7.56 (d, IH), 7.35 (d, IH), 7.29 (t, IH), 7.16 (q, IH), 7.06 (t, IH), 6.64-6.72 (m, 3H), 6.60 (dd, IH), 4.07 (d, IH), 3.88 (t, 2H), 3.69 (d, IH), 3.60 (s, 2H), 2.58 (d, 2H); MS (El) for C24H21F3IN3O3: 584 (MH4). EXAMPLE 3(ddd). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[(4-hydroxyphenyl)methyl]amino}methyl)azetidin ol: !H NMR (400MHz, dg-DMSO): 8.57 (s, IH), 7.55 (dd, IH), 7.35 (d, IH), 7.27 (t, IH), 7.16 (q, IH), 7.06 (d, 2H), 6.64-6.70 (m, 3H), 4.04 (d, IH), 3.85 (t, 2H), 3.68 (d, IH), 3.55 (s, 2H), 2.56 (d, 2H); MS (El) for C24H21F3IN3O3: 584 (MH4), EXAMPLE 3(cee). 3-(((1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyI) hydroxyazetidin yl]methyl}amino) (hydroxymethyl)cyclopentane-l,2-diol: 'HNMR(400MHz, ds-DMSO): 8.60 (broads, IH), 7.57 (dd, IH), 7.37 (d, IH), 7.32 (t, IH), 7.16 (q, IH), 6.68 (t, IH), 4.06 (q, 2H), 3.86 (t, 3H), 3.72 (dd, IH), 3.60 (t, IH), 3.36-3.43 (m, 2H), 3.30 (dd, IH), 2.80 (q, IH), 2.62-2.72 (m, 2H), 1.88-1.95 (m, IH), 0.82-0.90 (m, IH); MS (El) for C23H25F3IN3O5: 608 (MH4). EXAMPLE 3(ffl). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyI}carbonyl) {[(piperidin vlmethyl)ammo]melhyI}azetidin ol: 'HNMR (400MHz, dj-DMSO); 8.59 (broad s, IH), 7.57 (dd, IH), 7.37 (d, IH), 7.30 (t, IH), 7.17 (q, IH), 6.68 (dt, IH), 4.03 (d, IH), 3.87 (d, 2H), 3.69 (d, IH), 3.01 (d, 2H), 2.59 (s, 2H), 2.43-2.56 (m, IH), 2.35 (d, 2H), 1.65 (d, 2H), 1.47 (s, IH), 1.07 (q, 2H); MS (El) for C23H26F3IN4O2: 575 (MH4). EXAMPLE 3(ggg). 3-([(3-aminopropyl)amino]methyl}-l-({3,4-difluoro [(2-fluoro iodophenyl)ainino]phenyl}carbonyl)azetidin ol: 'HNMR (400MHz, de-DMSO): 7.57 (dd, IH), 7.37 (d, IH), 7.31 (t, IH), 7.17 (q, 1H)„ 6.68 (dt, IH), 4.05 (d, IH), 3.88 (d, 2H), 3.69 (d, IH), 2.61 (t, 3H), 2.53-2.56 (m, IH), 1.49 (t, 1.49); MS (El) for C23H26F3IN4O2: 535 (MH4). 183 EXAMPLE 3(hhh). 1-((3,4-flifluoro [(2-fluoro iodophenyl)amino]phenyl}carboiiyl) [(([2-(4-methylpiperazin-l-yl)phenyl]methyl}amino)inethyl]azetidin ol: *HNMR (400MHz, ds-DMSO): 8.59 (broad s, 1H), 7.55 (dd, 1H), 7.34 (t, 2H), 7.28 (d, 1H), 7.13-7.20 (m, 1H), 7.05 (d, 1H), 6.99 (t, 1H), 6.66 (dt, 1H), 4.03 (d, 1H), 3.90 (t, 2H), 3.71 (d, 3H), 2.83 (s, 5H), 2.60 (s, 2H), 2.42 (s, 3H), 2.20 (s, 3H); MS (El) for Cz^iFalNjOj: 666 (MH4). EXAMPLE 3(iii), 3-[(lir-benzimidazol ylamino)methyl]-l-((3,4-difluoro [(2-fluoro iodophenyl)animo]phenyl}carbonyl)azetidm ol: *H NMR (400MHz, CDCb): 8.04 (s, 2H), 7.28-7.35 (m, 2H), 7.23-7.26 (m, 2H), 7.09-7.12 (m, 2H), 6.80 (q, 1H), 6.57-6.63 (m, 1H), 5.28 (broad s, 2H), 4.38 (s, 3H), 4.25 (s, 1H), 4.21 (d, 2H); MS (El) for C24Hi9F3INsO2: 594 (MH4). EXAMPLE 3(jjj). 1-((3,4-difluoro [(2-fluoro iodophenyI)ammo]phenyl}carbonyl) [(lH-imidazol ylamino)methyl]azetidin ol: ‘HNMR (400MHz, d6-DMSO): 12.12 (s, 1H), 8.68 (s, 1H), 7.57-7.61 (m, 3H), 7.36-7.41 (m, 2H), 7.19 (q, 1H), 6.99 (s, 1H), 6.91 (s, 1H), 6.71 (dt, 1H), 6.45 (s, 1H), 4.28 (d, 1H), 4.06 (d, 1H), 4.03 (d, 1H), 3.82 (d, 2H); MS (El) for C24HnF3rN5O2: 544 (MH4). EXAMPLE 3(kkk). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (2-((2,2,3,3,3-pentafluoropropyl)amino]ethyl}azetidin ol: ’HNMR,(400MHz, ds-j DMSO): 8.58 (br s, 1H), 7.56 (dd, 1H), 7.37 (dd, 1;H), 7.34-7.28 (m, l.H), 7.22-7.13 (m, 1H), 6.68 (ddd, 1H), 5.82 (br s, 1H), 4.06 (d, 1H), 3.91 (t, 2H), 3.70 (d, 1H), 3.40-3.25 (m, 2H), 2.76 (d, 2H), 2.40-2.31 (m, 1H); MS (El) for C2t,H16FsIN3O2: 610 (MH4). EXAMPLE 3(mmm). 1-((3,4-difluoro [(2-fltioro iodophenyl)amino]phenyl}carbonyl) (2-((3,3,3-trifluoropropyl)amino]ethyl}azetidin ol: *H NMR (400 MHz, dg-DMSO): 8.58 (br s, 1H), 7.57 (dd, 1H), 7.37 (dd, 1H), 7.34-7.28 (m, 1H), 7.22-7.13 (m, 1H), 6.68 (ddd, 1H), 5.76 (br s, 1H), 4.05 (d, 1H), 3.88 (d, 2H), 3.70 (d, 1H), 2.71 (t, 2H), 2.63 (s, 2H), 2.41-2.26 (m, 2H); MS (El) for C20HigF6IN3O2: 574 (MH4). EXAMPLE 3(nnn). 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(2,3-dihydro-l/7-inden-l-yIamino)methyl]azetidin ol acetate salt: *H NMR (400 MHz, DMSO): 8.61-8.56 (m, 1H), 7.55 (d, 1H), 7.37-7.07 (m, 8H), 6.71-6.64 (m, 1H), 4.16-4.05 (m, 2H), 3.98-3.85 (m, 2H), 3.72-3.68 (m, 1H), 2.90-2.82 (m, 1H), 2.74-2.64 (m, 2H), 1.91 (s, 3H), 1.73-1.63 (m, 1H); MS (El) for C26H23F31N3O2: 594 (MH4). EXAMPLE 3(ooo). 3-[(cyclooctylamino)methyl]-1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol acetate salt: ’H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.55 (d, 1H), 7.20-7.14 (m, 2H), 6.70-6.66 (m, 1H), 4.03-3.98 (m, 1H), 3.92- 184 3.86 (m, 2H), 3.72-3.67 (m, 1H), 2.60 (s, 2H), 1.90 (s, 3H), 1.64-1.22 (m, 15H); MS (El) for C25H29F3IN3O2: 588 (MH4). EXAMPLE 3(ppp). 3-[(cycloheptylamino)methyl]-l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol acetate salt: 'H NMR (400 MHz, DMSO): 8.55 (s, 1H), 7.55 (d, 1H), 7.36-7.28 (m, 2H), 7.21-7.14 (m, 1H), 6.70-6.66 (m, 1H), 4.04-4.00 (ni, 1H), 3.92-3.85 (m, 2H), 3.71-3.66 (m, 1H), 2.60 (s, 2H), 1.90 (s, 3H), 1.70-1.13 (m, 13H); MS (El) for 02^27^3^02: 574 (MH4). EXAMPLE 3(qqq). 1-((3,4-difluoro [(2-fluoro iodophenyl)atnino]phenyl}carbonyl) {[(2-pyridin yIethyl)aniino]methyl}azetidm ol acetate salt: *H NMR (400 MHz, DMSO): 8.58 (s, 1H), 8.42-8.37 (m, 2H), 7.62-7.54 (m, 2H), 7.38-7.27 (m, 3H), 7.21-7.14 (m, 1H), 6.71-6.66 (m, 1H), 4.06-4.02 (m, 1H), 3.90-3.86 (m, 2H), 3.72-3.68 (m, 1H), 2.80-2.64 (m, 6H), 1.90 (s, 3H); MS (El) for C24H22F3IN4O2: 583 (MH4). EXAMPLE 3(rrr)./V-cyclohexyl-N2-([l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]inethyl} methylalanmamide acetate salt: &amp;#905; NMR (400 MHz, DMSO): 8.66 (br s 1H), 8.55 (s, 1H), 7.93-7.90 (m, 1H), 7.58 (d, 1H), 7.40-7.31 (m, 2H), 7.24-7.17 (m, 1H), 6.71-6.66 (m, 1H), 6.60 (br s, 1H), 4.28-4.23 (m, 1H), 4.14-4.02 (m, 2H), 3.89-3.83 (m, 1H), 3.12 (br s, 2H), 1.90 (s, 3H), 1.74-1.42 (m, UH), 1.31-1.02 (m, 6H); MS (El) for C27H32F3IN4O3: 645 (MH+). EXAMPLE 3(sss). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(tetrahydro-2H-pyran ylmethyl)aimno]methyl}azetidm ol acetate salt: *H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.56 (d, 1H), 7.38-7.27 (m, 2H), 7.20-7.14 (m, 1H), 6.71-6.66 (m, 1H), 4.05-4.01 (tn, 1H), 3.91-3.78 (m, 4H), 3.71-3.67 (m, 1H), 3.25-3.18 (m, 2H), 2.60 (s, 2H), 2.36 (d, 2H), 1.90 (s, 3H), 1.57-1.50 (m, 3H), 1.13-1.02 (m, 2H); MS (El) for C23H25F3IN3O3: 576 (MH4). EXAMPLE 3(ttt). 1-((3,4-difluoro [(2~fluoro iodoplienyl)amino]phenyl}carbonyl) ({[2-(dimethylamino)-l-methyiethylJamino}metliyl)azetidin ol trifluoroacetate salt: *H NMR (400 MHz, DMSO): 8.59-8.54 (m, 1H), 7.56 (d, 1H), 7.38-7.28 (m, 2H), 7.21-7.13 (tn, 1H), 6.71-6.63 (m, 1H), 4.04-3.95 (m, 1H), 3.88-3.78 (m, 2H), 3.73-3.68 (m, 1H), 2.70-2.50 (m, 3H), 2.08 (s, 6H), 1.88 (s, 2H), 0.85-0.82 (m, 3H); MS (El) for C22H26F3IN4O2: 563 (MH4). EXAMPLE 3(uuu). W-cyclopropyl-l-(([l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methyl}amino)cyclopentanecarboxamide trifluoroacetate salt: *H NMR (400 MHz, DMSO): 8.80 (br s, 1H), 8.58 (s, 1H), 8.04 (s, 1H), 7.59 (d, 1H), 7.40-7.31 (m, 2H), 7.25- 185 7.16 (in, IH), 6.74-6.58 (m, 2H), 4.26-3.82 (m, 4H), 3.10 (br s, 2H), 2.69-2.64 (m, IH), 2.11-1.88 (m, 4H), 1.82-1.61 (m, 4H), 0.67-0.62 (m, 2H), 0.52-0.48 (m, 2H); MS (El) for C26H2BF3IN4O3: 629 (MH+). EXAMPLE 3(wv). N2-{[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}oarbonyl) hydroxyazetidin yl]inethyl}-/V-ethyl methylalahinamide acetate salt: ’H NMR (400 MHz, DMSO): 8.60 (s, 1H), 7.60-7.72 (m, IH), 7.56 (d, IH), 7.38-7.30 (m, 2H), 7.22-7.14 (m, IH), 6.69-6.63 (m, IH), 4.07-4.04 (m, IH), 3.95-3.90 (m, 2H), 3.72-3.68 (m, IH), 3.05-3.01 (m, 2H), 2.47 (br s, 2H), 1.90 (s, 3H), 1.09 (s, 6H), 0.94 (t, 3H); MS (El) for C23H26F3IN4O3: 591 (ΜΗ*). EXAMPLE 3(www). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(2-methylhydrazino)methyl]azetidin ol acetate salt: ’H NMR (400 MHz, DMSO): 8.54 (s, IH), 7.57 (d, IH), 7.38-7.30 (m, 2H), 7.19-7.12 (m, IH), 6.69-6.63 (m, IH), 4.04-4.01 (m, IH), 3.92-3.84 (m, 2H), 3.68-3.63 (m, IH), 2.55 (s, 2H), 2.39 (s, 3H), 1.90 (s, 3H); MS (El) for CuHnfoDW 507 (MIT). EXAMPLE 3(xxx). 3-[(azetidin ylammo)methyl]-l-((3,4-difluoro [(2-flisoro iodophenyl)amino)phenyl}earbonyl)azetidin ol acetate salt: *H NMR (400 MHz, DMSO): 7.57 (d, IH), 7.39-7.30 (m, 2H), 7.20-7.13 (m, IH), 6.70-6.65 (m, IH), 4.10-4.04 (m, IH), 3.90-3.83 (m, 2H), 3.78-3.67 (m, 3H), 3.61-3.53 (m, IH), 3.48-3.42 (m, 2H), 2.61-2.54 (m, 2H), 1.90 (s, 3H); MS (El) for C2oH2oF3IN402: 533 (MH4). EXAMPLE 3(yyy). 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]pbenyl) carbonyl) [(l,3-thiazol ylamino)methyl]azetidin ol acetate salt: !H NMR (400 MHz, DMSO): 8.60 (s, IH), 7.57 (d, IH), 7.38-7.28 (m, 2H), 7.20-7.13 (in, IH), 6.75 (d, IH), 6.70-6.64 (m, IH), 5.93 (d, IH), 4.26-4.22 (m, IH), 4.11-4.08 (m, IH), 4.00-3.88 (m, 3H), 3.74-3.70 (m, IH), 1.90 (s, 3H); MS (El) for C20H16F3IN4O2S: 561 (MH4·). EXAMPLE 3(zzz). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[3-(methyloxy)phenyl]amino}methyl)azetldin ol: 'H NMR (400 MHz, DMSO): 8,57 (s, IH), 7.56 (d, IH), 7.38-7.30 (m, 2H), 7.20-7.12 (m, IH), 6.95-6.91 (m, IH), 6.70-6.66 (m, IH), 6.21-6.17 (m, 2H), 6.14-6.10 (m, IH), 5.94 (s, IH), 5.49-5.44 (m, IH), 4.14-4.10 (m, IH), 3.98-3.93 (m, 2H), 3.78-3.75 (m, IH), 3.65 (s, 3H), 3.21 (d, 2H); MS (El) for C24H21F3IN3O3: 584 (MH+). EXAMPLE 3(ab). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[4-(methyloxy)phenyl]amino}methyl)azetidin ol: !H NMR (400 MHz, DMSO): 8.56 (s, IH), 7.58 (d, IH), 7.39-7.30 (d, 2H); 7.20-7.13 (m, IH), 6.71-6.66 (m, 3H), 6.55 (d, 2H), 5.93 186 (s, IH), 5.00-4.95 (m, IH), 4.14-4.08 (m, IH), 3.98-3.92 (m, 2H), 3.79-3.74 (in, IH), 3.63 (s, 3H), 3.13 (d, 2H); MS (El) for 584 (MlT). EXAMPLE 3(ac). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl) ({[2-(ethyloxy)ethyI]amino}methyl)azetidin ol: 'H NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.36-7.33 (d, IH), 7.31-7.26 (m, IH), 7.08-7.00 (q, iH), 6.65-6.58 (t, IH), 4.24-4.16 (d, IH), 4.08-3.98 (t, 2H), 3.92-3.85 (d, IH), 3.60-3.55 (t, 2H), 3.54-3.47 (q, 2H), 3.01-2.96 (s, 2H), 2.94-2.89 (t, 2H), 1.20-1.15 (t, 3H); MS (El) for C21H23F3IN3O3: 550 (MIT). EXAMPLE 3(ad). 3-({[2,2-bis(methyloxy)ethyl]anHno}niethyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol acetate salt: &amp;#905; NMR (400 MHz, CD3OD): 7.48-7.43 (d, 1H), 7.37-7.32 (d, IH), 7.30-7.24 (m, IH), 7.08-7.00 (q, IH), 6.65- 6.57 (t, IH), 4.48-4.42 (t, IH), 4,20-4.11 (d, IH), 4.02-3.93 (t, 2H), 3.86-3.80 (d, IH), 3.38-3.34 (s, 6H), 2.84-2.80 (s, 2H), 2.75-2.70 (d, 2H),1.93-1.87 (s, 3H); MS (El) for C21H23F3IN3O4: 566 (MH+). EXAMPLE 3(ae). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]pheiryl}carbonyl) {[(3-hydroxypropyl)amino]methyl}azetidin oI acetate salt: *HNMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.38-7.33 (d, IH), 7.32-7.26 (m, IH), 7.09-7.00 (q, IH), 6.66-6.58 (t, IH), 4.31-4.23 (d, IH), 4.16-4.05 (t, 2H), 3.99-3.89 (d, IH), 3.70-3.64 (t, 2H), 3.26-3.22 (s, 2H), 3.11-3.04 (t, 2H), 1.93-1.89 (s, 3H), 1.89-1.82 (t, 3H); MS (El) for CaJfeiFalNjOj: 536 (MI-T). EXAMPLE 3(af). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ([(2-pyridin ylethyl)amino]methyl)azetidin ol acetate salt: 'HNMR (400 MHz, CD3OD): 8.36-8.32 (d, 2H), 7.38-7.33 (d, IH), 7.26-7.14 (m, 3H), 7.00-6.91 (q, IH), 4.12-4.04 (d, IH), 3.96-3.88 (t, 2H), 3.80-3.73 (d, 2H), 2.92-2.74 (m, 6H), 1.87-1.84 (s, 3H); MS (El) for C24H22F3IN4O2: 583 (MH4). EXAMPLE 3(ag). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-3~ ({[l-(phenylmethyl)pyrrolidiii yl]amino}methyl)azetidin ol acetate salt: lH NMR (400 MHz, CD3OD): 7.47-7.24 (m, 8H), 7.08-7.00 (q, IH), 6.64-6.57 (t, IH), 4.19-4.11 (d, 1H), 4.05-3.81 (m, 5H), 3.52-3.44 (m, IH), 3.09-2.99 (m, 2H), 2.91-2.76 (m, 3H), 1.93-1.91 (s, 3H), 1.82-1.71 (m, IH); MS (El) for C28H28F3lN4O2: 637 (MH+). EXAMPLE 3(ah). 1-((3,4-difluoro [(2-fluoro iodophenyl)atnino]phenyl}carbonyl) ({[2-(2-thienyl)ethyl]amino}methyl)azetidin ol acetate salt: *H NMR (400 MHz, CD3OD): 7.47-7.42 (d, IH), 7.36-7.31 (d, IH), 7.30-7.24 (m, IH), 7.21-7.17 (d, IH), 7.08-7.00 (q, IH), 6.93-6.89 (t, 1H), 6.86-6.83 (d, IH), 6.64-6.57 (t, IH), 4.18-4.11 (d, IH), 4.01-3.93 (t, 2H), 187 3.85-3.78 (d, 1H), 3.04-2.97 (t. 2H), 2.92-2.87 (t, 2H), 2.82-2.78 (s, 2H), 1.92-1.87 (s, 3H); MS (El) for C23H2iF3IN3O2S: 588 (MH4). EXAMPLE 3(ai). 3-[({2-[bis(l-methylethyl)amino]ethyl}amino)methyl]-l-({3,4-difluoro [(2-fluoro iodophenyl)aiuino)phenyl}carbonyl)azetidin ol acetate salt: ’Η NMR (400 MHz, CDjOD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.18-4.13 (d, 1H), 4.06-3.98 (t, 2H), 3.88-3.82 (d, 2H), 3.57-3.47 (q, 2H), 3.05-2.99 (t, 2H), 2.92-2.85 (t, 4H), 1.92-1.88 (s, 3H), 1.28-1.22 (d, 12H); MS (El) for C25H32F3IN4O2: 605 (MH+). EXAMPLE 3(aj), 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyi) ({[2-(|-)henyloxy)ethyI'iamino}niethyl)azetidin ol acetate salt: ’H NMR (400 MHz, CD3OD): 7.36-7.31 (d,1H), 7.26-7.22 (d, 1H), 7.20-7.13 (m, 3H), 6.97-6.89 (t, 1H), 6,86-6.80 (m, 3H), 6.54-6.47 (t, 1H), 4.13-4.07 (d, 1H), 4.01-3,96 (t, 2H), 3.79-3.74 (d, 1H), 2.97-2.91 (t, 2H), 2.84-2,79 (s, 2H), 1.84-1.81 (s, 3H); MS (El) for C25H23F3IN3O3: 598 (MH4). EXAMPLE 3(ak). 1 -({3,4-difiuoro [(2~fluoroM4odopheny!)ammo]phenyl) carbony 1)-3 -{[(2~hydroxypropyl)amino]methyl}azetidin-3~ol acetate salt: Al NMR (400 MHz, CD3OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.27- 4.19 (d, 1H), 4.10-4,00 (m, 2H), 3.15-3.00 (t, 2H), 3.57-3.47 (q, 2H), 3.15-3.00 (t, 2H), 2.87-2.81 (d, 1H), 2.72-2.64 (t, 1H), 1.94-1.91 (s, 3H), 1.19-1.15 (d, 3H); MS (El) for C20H21F3lN3O3: 536 (MH4). EXAMPLE 3(am). 1-((3,4-difluoro [(2“fluoro iodophenyl)atnino]pbenyl)carbonyl) [((2-[(l-metbylethyl)oxy]ethyl)ammo)niethyl)azetidin ol acetate salt: Al NMR (400 MHz, CD3OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7,31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6,65- 6.58 (t, 1H), 4.21-4.13 (d, 1H), 4,04-3.95 (t, 2H), 3,88-3.82 (d, 1H), 3.64-3.51 (m, 3H), 2.89-2.84 (s, 2H), 2.83-2.77 (t, 2H), 1.91-1.89 (s, 3H), 1.15-1.12 (d, 6H); MS (El) for C22H25F3IN3O3: 564 (MH4). EXAMPLE 3 (an). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl) carbonyl)-3 -{[(l-ethylpiperidin yl)amino]rnethyl)azetidin ol acetate salt: &amp;#905; NMR (400 MHz, CD3OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65- 6.58 (t, 1H), 4.17-4.10 (d, 1H), 4.04-3.95 (t, 2H), 3.88-3,82 (d, 1H), 3.24-3.06 (m, 2H), 2.95-2.75 (m, 6H), 2,76-2.46 (m, 2H), 1.93-1,90 (s, 3H), 1.74-1.62 (m, 1H), 1.44-1.31 (m, 1H), 1.28- 1,20 (t, 3H); MS (El) for C24H28P3IN4O2: 589 (MH4). EXAMPLE 3(ao). 1-((3,4-difluoiO [(2-fluoro iodophenyl) aminojphenyl) carbonyl)-3~ (([(5-methyl“l,3,4-oxadiazoI“2-yl)methyl3amino}methyl)azetidin ol acetate salt: YlNMR (400 MHz, CD3OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 188 IH), 6.65-6.58 (t, IH), 4.20-4.13 (d, IH), 4.00-3.90 (t, 2H), 3.83-3.75 (d, IH), 2.84-2.78 (s, 2H), 2.53-2.48 (s, 2H), 1.93-1.87 (s, 3H); MS (El) for C2,Hi9F3IN5O3: 574 (ΜΗ4). EXAMPLE 3(ap). l-({3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl)carbonyl) {[(l-methylbuty])amino]methyl)azetidin ol acetate salt: 'H NMR (400 MHz, CD3OD): 7.48- 7.43 (d, IH), 7.38-7.33 (d, IH), 7.32-7.27 (m, IH), 7.09-7.01 (q, IH), 6.65-6.58 (t, IH), 4.25- 4.19 (d, IH), 4.12-4.02 (t, 2H), 3.96-3.90 (d, IH), 3.16-2.96 (m, 3H), 1.91-1.89 (s, 3H), 1.68-1.57 (m, IH), 1.49-1.29 (m, 3H), 1.23-1.18 (d, 3H), 0.99-0.92 (t, 3H); MS (El) for C22H25F31N3O2: 548 (MH1). EXAMPLE 3(aq). 1-((3,4-diftuoiO~2-{(2-fluoiO iodophenyl)amino]phenyl}carbonyl) {[(1 -methylpropyl)amino]methyl}azetidm ol acetate salt: NMR (400 MHz, CD3OD): 7.48- 7.43 (d, IH), 7.37-7.33 (d, IH), 7,32-7.26 (ra, IH), 7.09-7.01 (q, IH), 6.65-6.58 (t, IH), 4.27-4,20 (d, IH), 4.14-4.03 (t, 2H), 3.98-3.92 (d, IH), 3.20-3.16 (s, 2H), 3.07-2.97 (ra, IH), 1,91-1.89 (s, 3H), 1.80-1.70 (in, IH), 1.54-1.41 (ra, IH), 1.26-1.22 (d, 3H), 1.00-0.94 (t, 3H); MS (El) for C2iH23F3lN3O2: 534 (MH+). EXAMPLE 3(ar), 1 -({3,4~difluoro [(2-flnoro iodophenyl)amino3phenyl}carbonyl) {[(2-rnethy!butyl)amino] methyl (azetidin ol acetate salt: *H NMR (400 MHz, CD3OD): 7.48- 7.43 (d, IH), 7.37-7.33 (d, IH), 7.32-7,26 (ra, IH), 7.09-7.01 (q, IH), 6.65-6.58 (t, IH), 4.26- 4.19 (d, IH), 4.10-4.01 (t, 2H), 3,94-3.87 (d, IH), 3.05-2.99 (s, 2H), 2.77-2.70 (ra, IH), 2.61-2.54 (ra, IH), 1.91-1.89 (s, 3H), 1.73-1.61 (ra, IH), 1.49-1.39 (m, IH), 1.24-1.12 (m, IH), 0.94-0.84 (m, 6H); MS (El) for C22H25F31N3O2: 548 (MH+), EXAMPLE 3(as), I-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(pentylaraino)raethyl]azetidin oI acetate salt: ΓΗ NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.37-7.33 (d, IH), 7.32-7.26 (m, IH), 7.09-7.01 (q, IH), 6.65-6.58 (t, IH), 4,29-4.23 (d, IH), 4.15-4.05 (t, 2H), 3.98-3,90 (d, IH), 3.21-3,18 (s, 2H), 2.93-2.86 (ra, 2H), 1.91-1,89 (s, 3H), 1.70-1.60 (m, 2H), 1.42-1.29 (m, 4H), 0.97-0.90 (t, 3H); MS (El) for C22H25F3IN3O2: 548 (MH4'). EXAMPLE 3(at). 3-[(cyciohexylamino)raethyl]-1 ~({3,4-diflnoro [(2-fluoro iodophenyl)araino]phenyl)carbonyl)azetidin ol acetate salt: !H NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7,38-7.34 (d, IH), 7.33-7.27 (ra, IH), 7.09-7.01 (q, IH), 6.65-6.58 (t, IH), 4.25-4.19 (d, IH), 4,14-4.03 (t, 2H), 3.98-3.90 (d, IH), 3,21-3.18 (s, 2H), 2.93-2.86 (ra, IH), 2,07-2.00 Cd, 2H), 1.92-1.90 (s, 3H), 1.89-1.82 (d, 2H), 1.73-1.66 (d, IH), 1.42-1.14 (ra, 5H); MS (El) for C23H25F3IN3O2: 560 (MH4). EXAMPLE 3(au). 3-[(azepan ylaraino)methyl]-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol acetate salt: 3H NMR (400 MHz, CD3OD): 189 7.48- 7.43 (d, IH), 7.37-7,33 (d, IH), 7.32-7.26 (m, IH), 7.09-7.01 (q, IH), 6.65-6.58 (t, IH), 4.19-4.13 (d, IH), 4.05-3.95 (t, 2H), 3.90-3.81 (d, IH), 3.37-3.34 (s, 2H), 3.22-3.03 (m, 2H), 2.91-2.64 (m, 3H), 1.93-1.89 (s, 3H), 1.88-1.52 (m, 6H); MS (El) for C23H26F3IN4O2: 575 (MH4). EXAMPLE 3(av). 1 -((3,4-difluoro [(2-fluoro iodophenyl)amiiio]phenyl} carbonyl) ({[2-(2,3-dihydro indoI yI)ethyl]amino}metliyl)azetidin ol acetate salt: ’H NMR (400 MHz, CDjOD): 7.58-7.54 (d, IH), 7.48-7.43 (d, IH), 7.36-7.33 (d, IH), 7.31-7.26 (m, IH), 7.14-6.99 (m, 4H), 6.65-6.58 (t, IH), 4.25-4.19 (d, IH), 4.10-4.02 (t, 2H), 3.95-3.88 (d, IH), 3.23-3.03 (m, 9H), 1.94-1.92 (s, 3H); MS (El) for C27H26F3IN4O2: 623 (MH*). EXAMPLE 3(aw). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl) [(1,3,5-triazin ylammo)niethyl]azetidin ol acetate salt: 'H NMR (400 MHz, CD3OD): 8.48- 8.46 (s, IH), 8.36-8.34 (s, IH), 7.48-7.43 (d, IH), 7.37-7.33 (d, IH), 7.28-7.22 (m, IH), 7.06-6.98 (q, IH), 6.65-6.58 (t, IH), 4.24-4.18 (d, IH), 4.10-3.96 (t, 2H), 3.84-3.78 (d, IH), 3.69-3.67 (s, 2H), 1.99-1.97 (s, 3H); MS (El) for C2(,Hi6F3IN6O2: 557 (MH4). EXAMPLE 3(ax). 1-((3,4-difluoro [(2-fluoiO iodophenyl)amino]phenyl}carboiiyl) {[(4-hydroxycyclohexyl)amino]methyl}azetidin oI acetate salt: !H NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.37-7.33 (d, IH); 7.32-7.26 (m, IH), 7.09-7.01 (q, IH), 6.65- 6.58 (t, IH), 4.22-4.15 (d, IH), 4.08-3.99 (t, 2H), 3.93-3.87 (d, IH), 3.56-3.47 (m, IH), 3,.05-3.02 (s, 2H), 2.76-2.68 (m, IH), 2.03-1.96 (m, 4H), 1.93-1.89 (s, 3H), 1.35-1.23 (m, 4H); MS (El) for C23H25F3IN3O3: 576 (MH4). EXAMPLE 3(ay). 3-[(cyclopent en-l-ylamino)methyl]-l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol acetate salt: 'H NMR (400 MHz, CD3OD): 7.48- 7.43 (d, IH), 7.37-7.33 (d, IH), 7.32-7.26 (m, IH), 7.09-7.01 (q, IH), 6.65-6.58 (t, IH), 5.70-5.65 (s, 2H), 4.20-4.14 (d, IH), 4.03-3.95 (t, 2H), 3.90-3.81 (d, IH), 3.58-3.50 (m, IH), 2.90-2.86 (s, 2H), 2.68-2.58 (m, 2H), 2.26-2.16 (m, 2H), 1.93-1.89 (s, 3H); MS (El) for C22H2iF3IN3O2: 544 (MH+). EXAMPLE 3(az). N-[4-(([l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methyl}amino)plienyl)acetainide acetate salt: lH NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.37-7.33 (d, IH), 7.27-7.20 (m, 3H), 7.09-7.01 (q, IH), 6.65-6.55 (m, 3H), 4.22-4.16 (d, IH), 4.08-3.98 (t, 2H), 3.88-3.82 (d, IH), 3.28-3.24 (s, 2H), 2.08-2.05 (s, 3H), 2.91- 2.64 (m, 3H), 1.93-1.89 (s, 3H); MS (El) for C2SH22F3IN4O3: 611 (MH4). EXAMPLE 3(ba). A-[3-(([l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)~3 -hydroxyazetIdiii 190 yl]methyl}amino)phenyl]acetamide acetate salt: *H NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.36-7.33 (d, IH), 7.27-7.20 (m, IH), 7.04-6.96 (m, 3H), 6.72-6.68 (d, IH), 6.65- 6.58 (t, IH), 6.40-6.35 (d, IH), 4.24-4.18 (d, IH), 4.08-3.98 (t, 2H), 3.87-3.81 (d, IH), 3.28-3.25 (s, 2H), 2.10-2.07 (s, 3H), 1.97-1.95 (s, 3H); MS (El) for C23H22F3IN4O3: 611 (MH4). EXAMPLE 3(bc). (lR,2S) ({(l-({3(4-djfluoro [(2-flu&lt;w&gt;4- iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]methyl}amino)cyclopentane- 1,2-diol acetate salt: 'H NMR (400 MHz, DMSO): 8.58-8.54 (s, IH), 7.61-7.53 (d, IH), 7.39-7.28 (m, 2H), 7.21-7.13 (m, IH), 6.71-6.63 (t, IH), 5.58-5.64 (s, IH), 5.63-5.58 (s, IH), 4.06-4.01 (d, IH), 3.90-3.84 (t, 2H), 3.72-3.66 (d, IH), 3.31-3.26 (m, 3H), 2.61-2.57 (s, 2H), 2.46-2.36 (m, 2H), 2.02-1.93 (dd, 2H), 1.91-1.88 (s, 3H); MS (El) for C22H23F3IN3O4: 578 (MH4). EXAMPLE 3(bd). 1-((3,4-difluoro [(2-fluoro iodopbenyl)amino]phenyl)carbonyl) (([l-(hydroxyniethyl)cycloliexyl)aniino}methyl)azetidin ol acetate salt; ’ll NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.37-7.33 (d, IH), 7.32-7.26 (m, IH), 7.09-7.01 (q, IH), 6.65-6.58 (t, IH), 4.22-4.15 (d, IH), 4.08-3.99 (t, 2H), 3.89-3.83 (d, IH), 3.49-3.45 (s, 2H), 2.86-2.80 (s, 2H), 1.91-1.89 (s, 3H), 1.67-1.34 (m, 10H); MS (El) for C24H27F3IN3O3: 590 (MH4). EXAMPLE 3(be). 3-{[(3-chlorophenyl)amino]methyl) ((3,4-difluoro [(2-fluoro iodophenyl)aniino]phenyl)carbonyl)azetidin ol acetate salt: ’H NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.37-7.33 (d, IH), 7.32-7.26 (m, IH), 7.08-6.98 (m, 2H), 6.65-6.55 (m, 3H), 6.53-6.44 (d, IH), 4.22-4.15 (d, IH), 4.06-3.98 (t, 2H), 3.88-3.82 (d, IH), 3.27-3.24 (s, 2H), 1.91-1.89 (s, 3H); MS (El) for CjjHwCIFjINjOj: 588 (MH4). EXAMPLE 3(bf). 3-([(4-chlorophenyl)amino]methyl)-l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl)azetidin ol acetate salt: *H NMR (400 MHz, CD3OD): 7.45-7.40 (d, IH), 7.35-7.30 (d, IH), 7.28-7.22 (m, IH), 7.06-6.97 (m, 3H), 6.62-6.54 (m, 3H), 6.53-6.44 (d, IH), 4.22-4.15 (d, IH), 4.06-3.98 (t, 2H), 3.88-3.82 (d, IH), 3.26-3.22 (s, 2H), 1.96-1.94 (s, 3H); MS (El) for CjjHuClFjINjOz: 588 (MH4). EXAMPLE 3(bg). 3-[(5-amino methyl-lZf-pyrazol-l-yI)methyl]-l-({3,4-difhioro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol acetate salt: H NMR (400 MHz, CD3OD): 7.38-7.33 (d, IH), 7.28-7.24 (d, IH), 7.21-7.15 (m, IH), 6.98-6.90 (q, IH), 6.56- 6.49 (t, IH), 5.16-5.14 (s, IH), 4.36-4.30 (d, IH), 4.22-4.16 (d, IH), 3.99-3.97 (s, IH), 3.95-3.90 (d, IH), 3.77-3.71 (d, IH), 1.96-1.92 (s, 3H), 1.85-1.82 (s, 3H); MS (El) for C21H19F3IN5O2: 558 (MH4). 191 EXAMPLE 3(bli). 1 -({ 3,4-difluoro-2~[(2~fiuoiO~4-iodophenyl)amino]phenyl}carbonyl)-3~ {[(5-methyl· 17Z-pyrazol yl)amino]methyl} azetidin ol acetate salt: 1H NMR (400 MHz, CD3OD): 7.38-7.33 (d, 1H), 7.28-7.24 (d, IH), 7.21-7.15 (m, IH), 6.98-6,90 (q, 1H), 6.56- 6.49 (t, 1H), 5.22-5.19 (s, IH), 4.15-4.08 (d, IH), 4.02-3.88 (m, 2H), 3.75-3.68 (d, IH), 3.20- 3.18 (s, 2H), 2.07-2.05 (s, 3H), 1.85-1.82 (s, 3H); MS (El) for C2iHi9F3IN5O2: 558 (MH4"). EXAMPLE 3(bi). 3-[(diethylamino)methyl]-l-({3,4-difluoro [(2~fIuoro iodophenyl)amino)phenyl}carbonyl)azetidin ol: NMR (400 MHz, dg-DMSO): 8.54 (s, IH), 7.58-7,55 (dd, IH), 7.38-7.35 (dt, IH), 7.33-7.31 (m, IH), 7.22-7.15 (m, IH), 6.69-6.64 (m, IH), 5.56 (b, IH), 4.06-4,04 (d, IH), 3.90-3.88 (m, 2H), 3.72-3.69 (d IH), 2.51-2.49 (m, 6H), 0.86-0.83 (t, 6H); MS (El) for C2IH23F3IN3O2: 534 (MH+). EXAMPLE 3(bj). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}cai'boiiyl) [(dimethylamino)methyl]azetidin ol: 'H NMR (400 MHz, dg-DMSO): 8.56 (s, IH), 7.59-7.56 (dd, IH), 7.38-7.36 (dt, IH), 7.34-7.33 (m, IH), 7,21-7,14 (m, IH), 6,71-6.65 (bi, IH), 5.55 (b, IH), 4.07-4.05 (d, IH), 3.89-3.84 (t, 2H), 3.74-3.719 (d, IH), 2.46 (m, 2H), 2.19 (br s, 6H); MS (El) for Ci9H39F3IN3O2: 506 (MH4'). EXAMPLE 3(bk). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(2 -hydroxy-1,1 -dimethylethyl)amino]methyl} azeti din-3 -ol: A NMR (400MHz, CDC13): 8.40 (s, IH), 7,38 (dd, IH), 7.33-7.30 (m, IH), 7.12 (m, IH), 6.85-6.79 (m, IH), 6.63-6.57 (m, IH), 4.22-4.1 l(br m, 4H), 3.55 (s, 2H), 3.15 (s, 2H), 1.32 (s, 6H); MS (El) for C2iH23F3IN3O3: 550 (ΜΗ*). EXAMPLE 3(bra). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino) phenyl} carbonyl) [(prop-2~en-l-ylamino)methyl]azetidin ol): *H NMR (400MHz, CDC13): 8.47 (s, IH), 7.40 (dd, IH), 7.34-7.31 (m, IH), 7.12 (m, IH), 6.83-6.77 (in, IH), 6,64-6.59 (m, IH), 6.64- 6.59 (in, IH), 5.88-5.78 (m, IH), 5.00-5.12 (m, 2H), 4.13 (brm, 4H), 3.26 (d, 2H), 2.88 (d, 2H), 2.02 (s, IH); MS (El) for C2iHi9F3IN3O2: 518 (MH+). EXAMPLE 3(bn). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[2-(tetrahydro-2H-pyran~4-yl)ethyl]amino}methyl)azetidin ol): &amp;#905; NMR (400MHz, CDCI3): 8.45 (s, IH), 7.39 (dd, IH), 7,34-7.31 (m, IH), 7.14-7.10 (m, IH), 6.84-6.77 (m, IH), 6.63-6.58 (m, IH), 4,26-4.04 (m, 4H), 3,95 (dd, 2H), 3.35 (t, 2H), 2.92 (d, 2H), 2,67 (m, 2H), 1.40-1.25 (m, 8H); MS (El) for C24H27F3iN3O3: 590 (MH+). EXAMPLE 3(bo). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) {[(l,l-dimethylprop-2~yn-l-yl)amino]methyl} azetidin ol): *HNMR (400MHz, CDC13): 8.46 (s, IH), 7.39 (dd, IH), 7.33-7.30 (m, IH), 7.15-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.64- 192 6.58 (m, 1H), 4.20 (br, 1H), 4.07 (br, 1H), 2.92 (s, 2H), 1.58 (ra, 4H), 0.92 (dd, 6h); MS (El) for C22H21F3IN3O2: 572 (MH*). EXAMPLE 3(bp). l-({3,4-difluoro [(2-fluoro iodophenyi)ammo]phenyl}carbonyl) ({[2-(lZZ-imidazol yl)ethyl]ammo}methyl)azetidin ol): *HNMR (400MHz, CDCI3): 8.44 (s, 1H), 7.33-7.14 (m, 3H), 7.00 (m, 1H), 6.67 (dd, 1H), 6.59 (s, 1H), 6.44 (m, 1H), 3.93 (d, 2H), 2.75 (m, 2H), 2.60 (m, 1H), 2.42 (m, 1H) 2.02 (AcOH; s, 3H), 1.86 (m, 4H); MS (El) for C22H21F3IN3O2: 572 (MH+). EXAMPLE 3(bq). 1-((3,4-difIuoro [(2-fluoro iodophenyl)amino]phenyl) carbonyl) ({[3-(ethyloxy)propyl]amino)methyl)azetidin ol: lH NMR (400MHz, CDC13): 8.49 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7,14-7.10 (in, 1H), 6.83-6.76 (m, 1H), 6.64- 6.58 (m, 1H), 4.26-4.03 (br m, 4H), 3.53-3.44 (m, 4H), 2.92-2.73 (m, 4H), 1.72 (m, 2H) 1.18 (t, 3H); MS (El) for C22H23F3IN3O3: 564 (MH+). EXAMPLE 3(br). 1-((3,4-difiuoiO-2~[(2-fiuoiO“4-iodophenyl)amino]phenyl}carlxmyl) {[(3,3-dimethylbutyl)amino] methyl) azetidin ol: 1H NMR (400MHz, CDCI3): 8.46 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63- 6.58 (ni, 1H), 4.18 (br, 3H), 3.15 (s, 2H), 2.71 (m, 2H) 2.05 (AcOH; s, 3H), 1,43 (m, 2H), 0.90 (s, 9H); MS (El) for C23H27F3IN3O2: 562 (MH4). EXAMPLE 3(bs). 1-((3,4-difluoro [(2-flnoro iodophenyl)amino)phenyl)carbonyl) {[(3-methylbutyl)ammo]methyl)azetidm ol: &amp;#906;Η NMR (400MHz, CDC13): 8.46 (s, 1H), 7.39 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.63- 6.59 (m, 1H), 4.27-3.61 (br m, 6H), 2.98 (m, 2H), 2.72 (t, 2H) 2.05 (AcOH; s, 3H), 1.61 (m,!H), 1.43 (m, 2H), 0.90 (d, 6H); MS (El) for C22H25F3IN3O2: 547 (MH4"). EXAMPLE 3(bt). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) ({[3-(dimethylamino)propyl]amino)methyl)azetidin~3-oh MS (El) for C22H26F3IN4O2: 563 (MH+). EXAMPLE 3(bu), 1 -((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) (([3-(1 ff-imidazol-1 -yl)propyl]amino)methy l)azetidin~3-ol: lH NMR (400MHz, CDCI3): 8.46 (s, 1H), 7.53 (s, 1H), 7.40 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.09 (m, 1H), 7.05 (s, 1H), 6,89 (s, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4,24-4.00 (br m, 6H), 2.84 (m, 2H), 2.61 (m, 2H), 1.94 (m, 2H); MS (El) for C23H2IF3IN5O2: 586 (MH4’), EXAMPLE 3(bv). 1-((3,4-difluoro [(2-flnoro iodophenyl)amino]phenyl)carbonyl) ({[2-(methylthio)ethyl]amino) methyl)azetidin-3 -ol: ]H NMR (400MHz, CDCI3): 193 8.49 (s} 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H), 7.14-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.63-

6.59 (m, 1H), 4.26-4.03 (br m, 4H), 2.88 (s, 2H), 2.82 (t, 2H), 2.62 (t, 2H), 2.08 (s, 3H); MS (EI)forC23H21F3IN3O2S: 552 (MH+). EXAMPLE 3(bw). l-({3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl}carbonyl) {[(l,l,3,3-tetramethylbutyl)amino]methyl}azetidin ol: lHNMR (400MHz, CDC13): 8.49 (s, 1H), 7.38 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.64- 6.59 (m, 1H),4.25-4.01 (br m, 4H), 2.82 (s, 2H), 1.45 (s,2H), 1.15 (s, 6H), 0.90 (s, 9H); MS (El) for C2,Hj|F3INjO2: 590 (MH+). EXAMPLE 3(bx). L({3,4-difluoro-2‘-[(2-iluoro iodophenyl)amino]phenyl}carbonyl) {[(1,1 -dimethylpropyl)amino)methyl}azetidin-3*ol: NMR (400MHz, CDCI3): 8.50 (s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.15-7,11 (in, 1H), 6.83-6.77 (m, 1H), 6.65- 6.59 (ra, 1H), 4.27-4.01 (br ra, 4H), 2.82 (s, 2H), 1,46 (s, 2H), 1.08 (s, 6H), 0.89 (s, 3H); MS (El) for C22H21E3IN4O3: 548 (MH+). EXAMPLE 3(by). 3-{[(3-amino hydiOxypropyl)amino]methyl} -1 ~({3,4~difluoro [(2-fluoro-4”iodophenyl)amino]phenyl}carbonyl)azetidin ol: MS (El) for C23H22F3IK4O3: 551 (MH+). EXAMPLE 3(bz), 1 - {[ 1 -({3,4-difluoro [(2-fluoro~4-iodophenyl)amino]phenyi} carbonyl) hydroxyazetidm ylJmethyI}pyrrolidin-3~ol: MS (El) for C21H21F3IN3O3: 548 (MH4). EXAMPLE 3(ca). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-3~ ({(2S) [(methyloxy)raethyl]pyrrolidin-l-yl}methyl)azetidin ol: MS (El) for CzsBksWjCfi: 576 (MH4). EXAMPLE 3(eb). l-({3,4-difluoro~2-[(2~flnoro lodophenyl)amino]phenyl}carbonyl) {[(2-hydroxyphenyl)amino]methyl}azetidin~3-ol·. &amp;#905; NMR (400MHz, CDC13): 8.46 (s, 1H), 7.41 (dd, 1H), 7.35-7,30 (m, 1H), 7.15-7.11 (ra, 1H), 6.89-5,98 (m, 6H), 4.92 (s, 1H), 4.28-4.05 (br in, 4H), 3.44 (s, 2H); MS (El) for C23H]9F3IN3O3: 570 (MH+), EXAMPLE 3(cd), 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino)phenyl} carbonyl) {[(4-hydroxyphenyl)a«imo]methyl}azetidin~3~ol: lH NMR (400MHz, CDCI3): 8.46 (s, 1H), 7.78 (s, 1H), 7.40-7.05 (m, 4H), 6,72 (m, 1H), 6.62 (d, 1H), 6.50 (ra, 1H), 6.42 (d, 1H) 4,04-3.98 (m, 4H), 3.18 (s, 2H); MS (Ε&amp;#938;) for C23Hi9F3IN3O3; 570 (MH+). EXAMPLE 3(ce). 1 -({3,4-difluoro [(2-flnoro iodophenyl)araino3phenyl}carbonyl) {[(3-hydroxyphenyl)amino]methyl}azetidin ol: EHNMR (400MHz, CDCb): 8.52 (s, 1H), 8.22 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (ra, 1H), 7.14-7.11 (ra, 1H), 6.85 (dd, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (ra, 1H), 6.15 (d, 1H) 6.09-6.01 (ra, 3H), 4.16-3.95 (br m, 4H), 3.22 (d, 2H) 2.15 (AcOH; s, 3H); MS (El) for C23Hi9F3IN3O3; 570 (MH4). 194 EXAMPLE 3(cf), 1 -({ 3,4-difluoro [(2-{luoiO"44odophenyl)amino]phenyl} carbonyl)-3 -[(phenyloxy)methyl]azetidin ol: MS (El) for C23Hi8F3iN2O3: 555 (MH4). EXAMPLE 3(cg). 3-(((1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidm yl]niethyl}amino)propane~l}2- diol: MS (El) for 552 (MH+). EXAMPLE 3(ch). 1 -({3,4-difluo;O [(2-fluoiO-4“iodophenyl)aminojphenyl}carbonyl) [(phenylthio)methyl]azstidin ol: ‘H NMR (400MHz, CDCb): 8.46 (s, 1H), 7.45-7.23 (m, 5H), 7.14-7.05 (m, 1H), 6.78 (dd, 1H), 6.60 (m, 1H), 4.14-3.92 (br m, 4H), 3,33 (s, 2H); MS (El) for C23Hi8F3IN2O2: 571 (MH4). EXAMPLE 3(ci). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ([(4-hydroxybutyl)ainmo3inethyl}azetidin ol): ’H NMR (400MHz, CDC13): 8.43 (s, 1H), 7.38 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.26-4.04 (at, 4H), 3.61 (m, 2H), 2.96 (s, 2H), 2.73 (s, 2H); MS (El) for CjiH^jINjOj: 550 (MH4). EXAMPLE 3(cj). l-((3,4-difluoro [(2-fluoro iodophenyl)ainino]phenyl}carbonyl) ([(2-hydroxyethyl)oxy]methyl}azetidin ol: !H NMR (400MHz, CDC13): 8.51 (s, 1H), 7.39 (dd, 1H), 7.35-7.31 (m, 1H), 7.14-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.63- 6.59 (m, 1H), 4.21-4.05 (br m, 4H), 3.77 (m, 2H), 3.66 (m, 2H); MS (El) for CisH,sF3IN2O4: 523 (MH4). EXAMPLE 3(ck). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ({[(lS,2S) hydroxycyolohexyl]amino}methyl)azetidin ol): MS (El) for C23H2sF3IN3O3: 576 (MH4). EXAMPLE 3(cm). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ([(1,1 -dimethyl pyrrolidin-l -ylethyl)amino]methyl}azetidin ol: ’H NMR (400MHz, CDC13): 8.49 (s, 1H), 7.39 (dd, 1H), 7.34-7.29 (m, 1H), 7.14-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.64- 6.59 (m, 1H), 4.25-4.07 (br m, 4H), 2.88 (d, 2H), 2.62 (m, 4H), 2.58 (m, 2H), 1.78 (m, 4H), 2.05 (AoOH; s, 3H); MS (El) for CjsHjoFjOW 603 (MH4). EXAMPLE 3(cn). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (([(l-methyl-lif-imidazol yl)metliyl]aiiijno}mettiyl)azetidiii ol: *H NMR (400MHz, CDCb): 8.50 (s, 1H), 7.41-7.11 (m, 3H), 7.12 (m, 1H), 6.85-6.79 (m, 2H), 4.12-3.98 (brtn, 4H), 3.78 (s, 2H), 3.66 (s, 3H), 2.95 (s, 2H), 2.08 (AcOH; s, 4H) ,2.05 (AoOH; s, 3H); MS (El) for C22H2,F3IN5O2: 572 (MH4). 195 EXAMPLE 3(co), 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}cai'bonyl) ({[(3 -methyl-17/-imidazol yl)methyl}amino}methyl)azetidm ol: 3H NMR (400MHz, CDC13): 8.45 (s, 1H), 7.47 (s, 1H), 7.39 (dd, 1H), 7.33-7.30 (m, 1H), 7.15-7.10 (m, 1H), 6.91 (s, 1H), 6.87-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.18-4.02 (m, 4H), 3.3.80 (s, 2H)&gt; 3.62 (s, 3H), 2,90 (s, 1H), 2,05 (AcOH; s, 3H); MS (El) for C22H2iF31N5O2: 572 (MH+). EXAMPLE 3(cp). l-({3 ,4-difluoro~2-[(2-fluoro iodophenyl)amino3phenyl}carbonyl)"3-({[(2S) (methyl oxy)cyclopentyl] amino} methy l)azetidin ol): MS (El) for C23H25F31N3O3: 576 (MH+). EXAMPLE 3(cq). 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl} carbony 1) ({[(lR) hydroxycyclohexyl]amino}methyi)azetidin ol): MS (Ε&amp;#938;) for C23H25F31N3O3: 576 (MH+). EXAMPLE 3(cr). A-[3-({[l-({3,4-diiluoro [(2-fluoro iodophenyl)amino3phenyl}carbonyl) hydroxyazetidin yl]raethyl}amino)phenyl]methanesulfonamide: SHNMR (400MHz, CDC13): 7.33 (dd, 1H), 7.22 (m, 1H), 7.08 (dd, 1H), 6.83-6.77 (m, 1H), 6.03-5.98 (m, 2H), 6.64-6.59 (m, 1H), 4.08- 3.77 (br m, 5H), 2.88 (s, 3H); MS (El) for C24H22F3IN4O4S: 647 (MH+). EXAMPLE 3(cs). 3~{[(4-aminophenyl)aminoJmethyl}~l-({3,4~difiuoro [(2-£hxoro iodophenyl)amino]phenyI}carbonyl)azetidin ol: &amp;#905; NMR (400MHz. CDC13): 8.44 (s, 1H), 7.39 (dd, 1H), 7.34-7.30 (m, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.64- 6.53 (ra, 5H), 4.22-4.04 (br ra, 4H), 3.34 (s, 2H); MS (El) for C23H2oF3IN402: 569 (MH*). EXAMPLE 3(ct). l~({3/4-difiuorO“2-[(2-fluoro-4~iodophenyI)amino]phenyl}carbonyl) {[(2-hydroxy methylcyclopentyl)amino]methyl} azetidin-3 -ol: MS (El) for C23H2sF3IN303: 576 (ΜΗ4). EXAMPLE 3(cu). 3-[(cyclopentylamino)methyl]-1 -({3,4-difluoro [(2-fluoro~4-iodophenyl)amino]phenyl}carbonyl)azetidin ol: lH NMR (400 MHz, CD3OD): 7.44 (dd, 1H), 7.36-7.31 (m, 1H), 7.30-7.24 (ra, 1H), 7.09-6.99 (m, 1H), 6.64-6.57 (m, 1H), 4,17-4.10 (m,lH), 4.01-3,91 (m, 2H), 3.87-3.79 (m, 1H), 3.07-2.97 (m, 1H), 2.75 (s, 2H), 1.92-1.79 (ra, 2H), 1.75-1.62 (ra, 2H), 1.6M.47 (m, 2H), 1.37-1.22 (ra, 2H). MS (El) for C22H23F3IN3O2: 546 (MH4) EXAMPLE 3(cv). 3-{[(cyelohexylmethyl)araino]methyl} -1 -({3,4-difluoro [(2-fluoro iodophenyl)araino] phenyl }carbonyl)azetidin ol acetate (salt): 3H NMR (400 MHz, CD3OD): 7.46 (dd, 1H), 7.39-7.32 (ra, 1H), 7.31-7.25 (m, 1H), 7.11-6.99 (ra, 1H), 6.67-6.57 (ra, 1H), 4.27-4,15 (m, 1H), 4.12-3.97 (ra, 2H), 3,96-3.85 (ra, 1H), 3 (s,2H), 2.62 (d, 2H), 196 1.90 (s, 3H), 1.82-1.45 (m, 6H), 1.40-1.07 (m, 3H), 1.04-0.80 (m, 2H). MS (El) for CmHjvFsINjOz: 574 (MH+). EXAMPLE 3(cw). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(propylamino)methyI]azetidm ol: *H NMR (400 MHz, d6-DMSO): δ 8.56 (s, IH), 7.57 (dd, IH), 7.37 (dd, IH), 7.32 (m, IH), 7.18 (m, 1H), 6.67 (m, IH), 4.03 (d, IH), 3.89 (m, 2H), 3.69 (d, IH), 2.59 (s, 2H), 2.42 (t, 2H), 1.90 (s, 3H), 1.32 (m, 2H), 0.81 (t, 3H); MS (El) for C20H21F3IN3O2: 520 (MH+). EXAMPLE 3(cx). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino Jphenyl} carbonyl) {[(2-methylpropyl)amino]methyl}azetidin ol: !H NMR (400 MHz, de-DMSO): δ 8.56 (s, IH), 7.56 (dd, 1H), 7.36 (dd, 1H), 7.31 (m, IH), 7.18 (m, IH), 6.67 (m, IH), 4.02 (d, IH), 3.89 (m, 2H), 3.70 (d, IH), 2.57 (s, 2H), 2.27 (d, 2H), 1.91 (s, 3H), 1.55 (ra, IH), 0.79 (d, 6H); MS (El) for C21H23F3IN3O2: 534 (MH+). EXAMPLE 3(cy). methyl (2xi) deoxy (([l-((3,4-difluoro [(2-fluoro iodophenyl)aminoJphenyl}carbonyl) hydroxyazetidin yl]methyl}amino)-beta-D-arabino-hexopyranoside: ’H NMR (400 MHz, d4-methanol, ~3:1 mixture of anomers): δ 7.46 (d, IH), 7.34 (d, IH), 7.28 (ra, IH), 7.04 (q, 1H),'6.62 (m, IH), 4.19-5.92 (m, 4H), 3.87-3.78 (m, 2H), 3.68 (ra, IH), 3.56-3.18 (m, 5H), 2.99-2.82 (m, 3H), 2.56 (in, 0.25H), 2.29 (m, 0.75H) MS (BI) for C24H27F3IN3O7: 652 (M-H). EXAMPLE 3(cz). 3-({[3-(diethylammo)propyl]amino}methyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)arainoJphenyl}carbonyl)azetidin ol acetate salt: *H NMR (400 MHz, CD3OD): 7.48-7.43 (d, IH), 7.38-7.33 (d, IH), 7.32-7.26 (m, IH), 7.09-7.00 (q, IH), 6.66- 6.58 (t, IH), 4.24-4.16 (d, IH), 4.11-3.99 (t, 2H), 3.92-3.85 (d, IH), 3.10-3.02 (m, 8H), 2.99-2.96 (s, 2H), 2.92-2.87 (t, 2H), 1.93-1.87 (s, 3H), 1.27-1.20 (t, 6H); MS (El) for C24H30F3IN4O2: 591 (MH4)· EXAMPLE 4 l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-/V-(2- hydroxyethyI)azetidine carboxamide

<img img-format="tif" img-content="drawing" file="IL229136AD000276.tif" id="idf0076" />

197 [00274] To a solution of l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyi}carbonyl)azetidine carboxylic acid (15 mg, 0.03 mmol), prepared using procedures similar to those in Example 1, in ;VyV-dimethylformamide (2.00 mL) was added HBTU (38 mg, 0.10 mmol). The mixture was stirred for 15 minutes at room temperature followed by the addition of 2-aminoethanol (3.6 pL, 0.06 mmol) and//-methylmorpholine (110 pL, LOO mmol). The mixture was allowed to stir at room temperature for 3 d, then diluted the mixture with chloroform (20 mL), and washed with water (30 mL). The aqueous phase was back extracted with chloroform (10 mL). The combined organic phases were dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by high pressure liquid chromatography to afford the title compound (9.20 mg, 58%) as tire trifluoroacetic acid salt: NMR (400MHz, CDCL): 8.54 (s, IH), 7.41-7,37 (m, IH), 7.34-7.31 (m, IH), 7.18-7.14 (m, IH), 6.85-6.77 (m, IH), 6.64- 6.58 (m, IH), 4.66 (br, IH), 4.40-4.24 (br, 3H), 3.83-3.23 (br m, 7H), 1.18 (t, 3H); MS (El) for C19H17F3IN3O3*. 542 (MNa+).

[00275] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 4(a): 1 -({3,4-difluoro [(2-fiuoro iodophenyl)amino]phenyl} carbonyl)-?/-(3,4-dihydroxybutyl)azetidine carboxamide: lHNMR (400 MHz, CDCI3): 8.55 (s, IH), 7.40 (dd, IH), 7,31-7.35 (m, IH), 7.14-7.18 (m, IH), 6.78-6.84 (m, IH), 6,59-6.65 (m, IH), 6.14 (br s, IH), 4.50-4.60 (m, IH), 4.20-4.40 (m, 3H), 3.60-3.80 (m, 3H), 3.40-3.52 (m, 2H), 3.20-3.32 (nr, 2H), 1.96 (br s, IH), L18-1.28 (m, 2H). MS (El) for CaiHaiFsINjO*: 562 (ΜΗ). EXAMPLE 4(b): V-butyl-l-({3,4-difluoro [(2-fluoro iodophenyi)amino)phenyl}carbonyl)azetidine~3-carboxamide: ^1 NMR (400MHz, CDCI3): 8.53 (s, IH), 7.39 (dd, IH), 7.33-7.31 (m, IH), 7.17-7.13 (m, IH), 6.83-6.77 (m, IH), 6.64- 6.58 (m, IH), 5.50 (m, IH), 4.57 (br, IH), 4.29 (br m, 3H), 3.27 (m, 3H), 1.49 (m, IH), 1.33 (m, 2H), 0.92 (t, 3H); MS (El) for CziHaiFslNrOa’. 532 (MH+), 554 (MNa+). 1 -({3,4-difluoro~2-[(2-fluoro iodophenyI)ammo]phenyi} carbonyl)-//-prop en-1 -yIazetidme carboxamide: *H NMR (400MHz, CUC13): 8.54 (s, IH), 7.39 (dd, IH), 7.34- 7.31 (m, IH), 7.17,7.12 (m, IH), 6.83-6.77 (m, IH), 6.64-6.58 (m, IH), 5.88-5.77 (m, IH), 5.57 (br, IH), 5.21-5.16 (m, 2H), 4.59 (br, IH), 4.30 (br m, 3H), 3.9 (tt, 2H), 3.32-3.25 (m, IH)); MS (El) for CzoH^lNsOj: 516 (MH+), 538 (MNa+). EXAMPLE 4(c): l-({3,4-difluoro [(2-fiuoro iodophenyl)amino]phenyl}carbonyl)-//-ethylazefidine carboxamide: 1'H NMR (400MHz, CDCI3): 8.54 (s, IH), 7.38 (dd, IH), 198 7.33-7.30 (π&gt;, IH),7.17-7.12 (m, IH), 6.83-6.77 (m, IH), 6.63-6.57 (m, IH), 5.55 (br s, IH), 4.57 (br s, IH), 4.28 (br m, IH), 3.36-3.29 (m, 2H), 3.27- 3.20 (m, IH), 1.15 (t, 3H); MS (El) for C19H17F3IN3O2: 504 (MH4), 526 (MNa4). EXAMPLE 4(d): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (2-hydroxyethyl)azetidine carboxamide: 'H NMR (400MHz, CDCI3): 8.50 (s, IH), 7.39 (dd, IH), 7.33-7.30 (m, IH),7.16-7.12 (m, IH), 6.84-6.77 (m, IH), 6.63-6.57 (m, IH), 4.57 (br, IH), 4.28 (br, 3H), 3.73 (t, 2H), 3.49-3.44 (m, 2H), 3.33-3.27 (m, IH), 2.18 (br, IH); MS (El) for C19H17F3IN3O3: 542 (MNa4). EXAMPLE 4(e): l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-lV-(2-piperidin-l-ylethyl)azetidjne oarboxamide: 'H NMR (400MHz, CDCI3): 11.28 (s, IH), 8.55 (s, IH), 7.38 (dd, IH), 7.33-7.30 (m, IH), 7.15-7.10 (m, IH), 6.82-6.76 (ra, IH), 6.63- 6.58 (m, IH), 4.42 (b, IH), 4.26 (br m, 3H), 3.68 (br s, 2H), 3.58 (br d, 2H), 3.36 (br m, 1H)3.17 (br s, IH), 2.63 (m, 4H), 1.92 (m, 5 H); MS (El) for C24H26F3IN4O2: 587 (MH4). EXAMPLE 4(f): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-Af- phenylazetidine carboxamide: *H NMR (400MHz, CDCI3): 8.52 (s, IH), 7.50 (d, IH), 7.41-7.27 (a, 4H), 7.16 (m, 2H), 6.85-6.78 (m, IH), 6.65-6.59 (m, IH), 4.37 (br, 3H), 3.43 (m, IH); MS (El) for (WjINjO!: 574 (MNa4). EXAMPLE 4(g): Af-[2-(diethylamino)ethyl]-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidine carboxamide: 'HNMR (400MHz, CDCI3): 11.43 (s, IH), 8.90 (s, IH), 8.55 (s, IH), 7.39 (dd, IH), 7.33-7.30 (m, IH), 7.15-7.10 (m, IH), 6.87-6.77 (m, IH), 6.63-6.58 (m, IH), 4.44-4.22 (m, 4H), 3.65 (m, 2H), 3.38 (m, IH), 3.19-3.13 (m, 5H), 1.33(t, 6H); MS (El) for C2iH2iF3IN3O2:575 (MH4). EXAMPLE 4(h): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-Ar- [(2,3-dihydroxypropyl)oxy]azetidine carboxamide: MS (El) for C2oHisF3IN305: 566 (MH4). EXAMPLE 4(i): 1-((3,4-Difluoro [(2-fiuoro iodophenyl)amino]phenyl}oarbonyl)-/V-(2,3-diliydroxypropyl)azetidine cafboxamide: 'H NMR (400 MHz, CDC13): 8.40 (br s, IH), 7.35 (dd, IH), 7.30 (br d, IH), 7.16-7.09 (m, IH), 6.89-6.76 (m, 2H), 6.58 (ddd, IH), 4.58-4.40 (br, IH), 4.27 (br t, 2H), 4.22-4.14 (br, IH), 4.08-3.12 (m, 5H), 2.18-1.82 (br, 2H); MS (El) for C2oHi9F3IN304: 550 (MH4). EXAMPLE 4(j): 1 -((3,4-Difluoro [(2-fluoro iodophenyl)amino]phenyI}carbonyI)-/V-hydroxyazetidine carboxamide: &amp;#905; NMR (400 MHz, CDC13): 8.23-8.10 (b, IH), 7.35-7.28 (m, 2H), 7.14-7.07 (m, IH), 6.86-6.80 (m, IH), 6.60-6.54 (m, IH), 4.52-4.38 (b, IH), 4.32-4.08 (m, 3H), 3.30-3.21 (m, IH); MS (El) forCi7Hi3F3IN303:492 (MH4)· 199 EXAMPLE 5 6-({3»[dimethylamino)methyi]azetidm-l-yl}carbonyl)“2,3-difluorO“7V“(2-fluoro-4“ iodopbeny])andine

<img img-format="tif" img-content="drawing" file="IL229136AD000277.tif" id="idf0077" />

[00276] A mixture of l-({3,4-difluoro [(2-fluoro- 44odophenyl)aminojphenyl}carbonyl)azetidine carboxylic acid (196 mg, 0.41 mmol), prepared using procedures similar to those in Example 1, triethylamine (58 pL, 0.41 mmol), PyBOP (213 mg, 0.41 mmol) and sodium borohydride (48 mg, 1.24 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the resultant residue was partitioned between 20% aqueous citric acid and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless residue that was purified by column chromatography. Eluting with 60% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 48 mg, 0.11 mmol (25%) of [l-({3,4“difhioro-2“[(2-fluorO“4~ iodophenyl)amino]phenyl}carbonyl)azetidin yl3methanol as a white solid. 3H NMR (400 MHz, CDC13): 7.44 (d, IH), 7.34 (d, IH), 7.28-7.23 (m, IH), 7.04-6.97 (m, IH), 4,26-4.18 (m, IH), 4.02-3.94 (m, 2H), 3.78-3.72 (ra, IH), 3.03 (d, 2H), 3.34 (s, IH), 2.80-2.71 (ra, IH). MS (El) for C17H14F3IN2O: 463 (MH4).

[00277] A solution of l-({3,4-difluoro [(2-fluoro- 4-iodophenyl)amino]phenyl}carbonyl)azetidin~3-yl]methanol (48 mg, 0.11 mmol), l,4-diazabicyclo[2.2.2]octane (18 mg, 0.16 mmol) and methanesulfonyl chloride (10 pL, 0.13 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 minutes. The mixture was then partitioned between water and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless residue which was purified by column chromatography. Eluting with 70% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 28 mg, 0,05 mmol (47%) of [1 -({3,4-difluoro [(2“fluoro iodophenyl)amino]phenyl)carbonyl)azetidin yl]methyl methanesulfonate as a colorless residue which was immediately dissolved in 200 ethylene glycol dimethyl ether (2 mL). To the solution was added dimethylamine (excess) and the solution was stirred in a seal tube at 50 °C for 15 hours. The reaction mixture was concentrated in vacuo, and the resultant residue was purified by preparative reverse phase HPLC. Isolated product was concentrated in vacuo to afford 12 mg, 0.02 mmol (40%) of 6-({3-[dimethylamino)methyl]azetidin-l-yl}carbonyl)-2,3-difluoro-Ar-(2-fiuoro iodophenyI)aniline acetate salt as a white solid. &amp;#905; NMR (400 MHz, DMSO): 8.54 (br s, IH), 7.58 (d, IH), 7.37 (d, IH), 7.33-7.28 (ra, IH), 7.18-7.12 (ra, IH), 6.70-6.64 (m, IH), 4.18-4.12 (ra, IH), 3.99-3.76 (ra, IH), 3.52-3.47 (ra, IH), 2.52-2.48 (ra, IH), 2,39 (d, 2H), 1.85 (s, 6H); MS (El) for C^H^INjO: 490 (MH+).

[00278] Using the same or analogous synthetic techniques and/or substituting with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 5(a): 2,3-difluoro-W-(2-fluoro iodophenyl) [(3-{[(l-methylethyl)amino) methyl} azetidin-1 -yl)carbonyl] aniline: 1H NMR (400 MHz, CDC13): 8,54 (s, IH), 7,40 (dd, IH), 7,31-7.33 (ra, IH), 7.11-7.15 (ra, IH), 6.76-6.82 (ra, IH), 6.58- 6.64 (ra, IH), 4.23-4,30 (m, 2H), 3.90-4.00 (ra, IH), 3.76-3.84 (ra, IH), 2.69-2.85 (m, 4H), 1.05 (d, 6H). MS (El) for C2oH2iF3IN30: 502 (M-H). EXAMPLE 5(b): 2-({[ 1-((3,4~difluoro-2~[(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin-2~yl]methyl}amino)ethanol; MS (El) for Ci9H19F3IN3O2: 506 (MH4). EXAMPLE 5(c): /V-{[l-({3,4-difluoro [(2-fiuoiO iodophenyl)amino]phenyl} car bony l)azetidin yl'Jmethyi} ethane- 1,2-diamxne: MS (Ε&amp;#938;) for C19H20F3IN4O: 505 (MH+). EXAMPLE 5(d): !6-({3- [diraethylaraino)methyl] azetidin-1 -yl} carbonyl)-2,3-difiuoiO-A'-(2-fluoro iodophenyl)aniline acetate salt: *H NMR (400 MHz, DMSO): 8.54 (br s, IH), 7.58 (d, IH), 7.37 (d, IH), 7.33-7.28 (m, IH), 7.18-7.12 (m, IH), 6.70-6.64 (ra, IH), 4.18-4.12 (m, IH), 3.99-3.76 (ra, IH), 3,52-3,47 (ra, IH), 2.52-2.48 (ra, IH), 2.39 (d, 2H), 1.85 (s, 6H); MS (El) for C[9Hi9F31N3O: 490 (MH4). 201 EXAMPLE 6 1-( {3,4-Difluor o [(2-fluoro iod opheny ljammo] phenyl} carb onyl)azetidin one

<img img-format="tif" img-content="drawing" file="IL229136AD000278.tif" id="idf0078" />

[00279] 1-((3,4~Difiuoro~2-[(2~fiuoro iodophenyl)amino]phenyl} carbonyI)azetidm ol (132 mg, 0.295 mmol)ures similar to those in Example 1, was dissolved in dichioromethane (8 mL) and cooled to 0 °C. Dess-Martin periodinane (187 mg, 0.441 mmol) was added and the mixture was stirred at ambient for 2 h, The mixture was quenched with saturated sodium bicarbonate solution; 10% sodium thiosulfate solution (1:1; 6 mL) and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 40-50% ethyl acetate in hexanes) gave l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidm one (122 mg, 0.273 mmol, 93% yield); !H NMR (400 MHz, CDCI3): 8.43 (br s, IH), 7.44-7.38 (m, IH), 7.36-7.32 (m, IH), 7,27-7.20 (ra, IH), 6,86 (ddd, IH), 6.64 (ddd, IH), 4.94-4.93 (m, 4H); MS (El) for Ci6Hi0F31N2O2: 447 (MH+). EXAMPLE 7 l-({3i4-Difiuoro [(2-fluoro-4“iodophenyl)amino]phenyl}carbonyl) (hydroxymethyl)azetidin ol

<img img-format="tif" img-content="drawing" file="IL229136AD000279.tif" id="idf0079" />

[00280] Methyl triphenylphosphoniura bromide (508 rag, 1.42 raraol) was treated with potassium /ert-butoxide (159 mg, L42mmol) in tetrahydrofuran (5 mL) at 0 °C for 10 minutes. 1-((3,4-Difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin one (270 rag, 0.605 mmol), prepared using procedures similar to those described in Example 6, was dissolved in tetrahydrofuran (2 rat) and was added to the mixture. The mixture was stirred at ambient for 15 h and then the mixture was filtered and the filtrate was partitioned 202 between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ethyl acetate in hexanes) gave 2,3 “difluorokV-(2“fluoro iodopheny 1) [(3 -methy lideneazetidi η-1 - yl)carbonyl]aniline (57 mg, 0.128 mmol, 21% yield): NMR (400 MHz, CDCb): 8.56 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7,18-7.12 (m, 1H), 6.86-6.76 (m, 1H), 6.62 (ddd, 1H), 5.14-5,00 (br, 2H), 4.74 (br d, 4H); MS (El) for Ci7H12F3IN2O: 445 (MH4).

[00281] 2,3-Difluoro-N-(2-fluoro iodophenyl) [(3-methyHdeneazetidin-l-yl)carbonyl]aniline (56 mg, 0.126 mmol) and 4-methylmorpholine N-oxide (44 mg, 0.376 mmol) were dissolved in acetone / water (4:1; 10 mL) and osmium tetroxide (4 wt.% in water; 0.7 mL) was added. The solution was stirred at ambient for 4 h, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatograph}'' (silica gel, 80% ethyl acetate in hexanes) and then reverse phase HPLC gave l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (hydroxymethyl)azetidin ol (17 mg, 0,036 mmol, 28% yield): 'll NMR (400 MHz, CDCb): 8.43 (br s, 1H), 7.40 (dd, 1H), 7,35-7.31 (m, 1H), 7.16-7.10 (m, 1H), 6,81 (ddd, 1H), 6.61 (ddd, 1H), 4,25-4.00 (m, 4H), 3.78 (s, 2H); MS 031) for CnHwFsIbW 479 (MH4). EXAMPLE 8 3-(2-3minopynmidin yl)-l-({3,4-difluoro [(2-fluoro iod op henyl) amino] phenyl} car bonyl)azetidin o!

<img img-format="tif" img-content="drawing" file="IL229136AD000280.tif" id="idf0080" />

[00282] To a solution of 4-iodo (methylthio)pyrimidine (2.00 g, 7.92 mmol) in tetrahydrofuran (4.00 ml) was added isopropylraagnesium chloride (815 mg, 7.92 mmol).

The mixture was allowed to stir for 1 h at 0 °C, followed by the addition of 1,1-dimethylethyl 3-oxoazetidiene-l-carboxylate (1.64 g, 9.60 mmol), prepared using procedures similar to 203 WO 2()07/044515 those described in Example 3. The reaction mixture was then allowed to warm to room temperature and stirred for 6h. The mixture was quenched with 1 N hydrochloric acid (10 mL) and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford 1,1-dimethylethyl 3-hydroxy [2-(methylthio)pyrimidin yl]azetidine-l-carboxylate (380 mg, 16%) as a yellow oil. lH NMR (400 MHz, CDC13): 8,62-8.59 (d, IH), 7.36-7.33 (d, IH), 5.14-5.11 (s, IH), 4.29-4.24 (d, 2H), 4.13-4,08 (d, 2H), 2,61-2.58 (s, 3H), 1.50-1.47 (s, 9H); MS (El) for C13Hi9N3O3S: 298 (MH+).

[00283] A solution of 1,1-dimethylethyl 3-hydroxy [2-(methylthio)pyrimidin yl]azetidine carboxylate (480 mg, 1.62 mmol), and 3-chloroperoxybenzoic (558 mg, 3,23 mmol) acid in dichloromethane (25 mL) was stirred at room temperature for 22 h. The reaction mixture was quenched with a saturated solution of sodium thiosulfate and the pH adjusted to 7 with sodium carbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The resulting crude 1,1-dimethylethyl 3-hydroxy“3-[2-(methylsulfonyl)pyrimidin-4~yl]azetidine-l-cafboxylate (524 mg, 98%) was used without further purification. !H NMR (400 MHz, CDC13): 9,01-8.97 (d, IH), 7.96-7.93 (d, IH), 4.57-4.53 (s, IH), 4.31-4,27 (d, 2H), 4,23-4.18 (d, 2H), 3.42-3.39 (s, 3H), 1.50-1.47 (s, 9H); MS (El) for Ci3Hi9N3O5S: 330 (MH*).

[00284] A solution of 1,1-dimethylethyl 3-hydroxy [2-(methylsu!fonyl)pyrimidin yl]azetidine-1 -carboxylate (215 mg, 0.652 mmol), and aqueous ammonia (7 mL, 28% solution) in dioxane (15 mL) within a sealed steel bomb cylinder was heated at 80°C for 4h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in dichloromethane and a solution of saturated sodium carbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The resulting crude 1,1-dimethylethyl 3-(2-aminopyrimidin yl) hydroxyazetidine carboxylate (140 mg, 100%) was used without further purification, ’ll NMR (400 MHz, CDCI3): 8.38-8.35 (d, IH), 6.97-6.94 (d, IH), 5.30-5.28 (s, 2H), 4,23-4.18 (d, 2H), 4.08-4.04 (d, 2H), 1.48-1.45 (s, 9H).

[00285] To a solution of 1,1-dimethylethyl 3-(2-arainopyrimidin yl) hydroxyazetidine carboxylate (140 mg, 0.524 mmol) in di chloromethane (10 ml) was added trifluoro acetic acid (3 ml). The reaction mixture was stirred for 2h at room temperature. The mixture was concentrated in vacuo. The resulting crude 3-(2-aminopyrimidm yl)azetidin ol (87 mg, 100%) was used without further purification. 204 [00286] A solution of 3,4-difluoro [(2-fluorO“4“iodophenyl)amino]benzoic acid (201 mg, 0.512 mmol), prepared using procedures similar to those described in US 7,019,033, 3- (2"aminopyrimidin yl)azetidin ol (87 mg, 0.52 mmol), benzotriazol-T-yl-oxy- tris(pyrrolidino)phosphonium hexafluoropbosphate (293 mg, 0,563 mmol) and A(JV-diisopropylethylamine (270 uL, 2.82 mmol) in AUV-dimeihylfonnamide (2 mL) was stirred at room temperature for 20h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the title compound 3“(2-annnopyrimidin yl)'-l-({3J4-¥ difluoro [(2-fluoro iodoplienyl)amino]phenyl}carbonyl)azetidiii ol (22 mg, 7%). H NMR (400 MHz, CD3OD): 8.23-8.20 (d, 1H), 7.48-7.43 (d, 1H), 7.35-7.32 (m, 2H), 7.09-7.00 (m, 1H), 6.88-6.84 (d, IH), 6.70-6.63 (t, IH), 4.59-4.54 (d, 1H), 4.45-4.40 (d, 1H), 4.23- 4.18 (d, IH), 3.04-3.99 (t, 1H); MS (El) for CjsHisDWV 542 (MH4).

[00287] Using the same or analogous synthetic techniques add substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 8(a): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}earbonyl) pyridin ylazetidin ol: *H NMR (400 MHz, CD3OD): 8.47 (m, 1H), 7.80 (m, IH), 7.65 (d, IH), 7.44 (m, IH), 7.33 (m, 3H), 7.04 (m, IH), 6.65 (m, IH), 4.61 (d, IH), 4.44 (d, IH), 4.29 (d, IH), 4.12 (d, IH). MS (El) for C21Hi5F3IN3O2: 526 (MH4). EXAMPLE 8(b): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl]carbonyl) (lH-imidazol yl)azetidin ol: *H NMR (400 MHz, CD3OD): 7.42 (m, IH), 7.37 (m, IH), 7.32 (m, IH), 7.02 (m, 3H),'6.63 (m, IH), 4.65 (d, IH), 4.42 (d, IH), 4.33 (d, IH), 4.16 (d, IH). MS (El) for C,9Hi4F3IN4O2: 515 (MH4). EXAMPLE 8(c): 3-(177-benzimidazol yl)-l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol: ’H NMR (400 MHz, CD3OD): 7.55 (brs, 2H), 7.42 (m, 2H), 7.33 (m, IH), 7.23 (m, 2H), 7.04 (m, IH), 6.65 (m, IH), 4.76 (d, IH), 4.57 (d, IH), 4.43 (d, IH), 4.25 (d, IH). MS (El) for C23Hi6F3IN4O2: 565 (MH4). EXAMPLE 8(d): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}earbonyl) (5-methyl-lff-imidazol yl)azetidin ol: 'H NMR (400 MHz, CDjOD): 7.41 (in, IH), 7.36 (m, IH), 7.31 (m, IH), 7.02 (m, IH), 6.67 (br s, IH), 6.63 (m, IH), 4.63 (d, 1H), 4.39 (d, IH), 4.30 (d, IH), 4.13 (d, IH), 2.18 (s, 3H). MS (El) for C20Hi6F3IN4O2: 529 (MH4). EXAMPLE 8(e): 1-((3,4-difluoro [(2-fluoro iodophenyI)amino]phenyl}carbonyl) prop en-l-ylazetidin ol: *H NMR (400 MHz, CDC13): 8.47 (br s, IH), 7.40 (dd, IH), 7.35-7.31 (m, IH), 7.15-7.10 (m, IH), 6.81 (ddd, IH), 6.62 (ddd, IH), 5.84-5.72 (m, IH), 205 5.27-5.20 (m, 2H), 4.22-3.94 (m, 4H), 2.52 (d, 2H), 2.25 (s, 1H); MS (El) for C19H11SF3IN2O2: 489 (MH*). EXAMPLE 8(i): 3-(1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yI]propane-l,2-diol: ‘HNMR(400 MHz, CDCI3): 8.43 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.16-7.10 (m, 1H), 6.82 (ddd, 1H), 6.61 (ddd, 1H), 4.31-3.91 (m, 5H), 3.68 (br d, 1H), 3.54-3.49 (m, 1H), 2.01-1.80 (m, 2H); MS (El) for C19H18F3IN2O4: 523 (MH4). EXAMPLE 8(g): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) ethenylazetidin ol: ]H NMR (400 MHz, CDCI3): 8.48 (br s, 1H), 7.40 (dd, 1H), 7.35-7.31 (m, 1H), 7.17-7.11 (m, 1H), 6.81 (ddd, 1H), 6.62 (ddd, 1H), 6.15 (dd, 1H), 5.39 (d, 1H), 5.28 (d, 1H), 4.30-4.10 (m, 4H); MS (El) for Ci8H,4F3lN2O2:475 (MH*). EXAMPLE 8(h): 1-(1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbony 1) hydroxyazetidin yl]ethane-l,2-diolhydrochloride: 'HNMR (400MHz, de-DMSO): 8.66 (d, 1H), 7.58 (dd, 1H), 7.38 (d, 1H), 7.33-7.27 (m, 1H), 7.17 (q, 1H), 6.74-6.65 (m, 1H), 4.50-3.58 (br, 3H), 4.29 (dd, 1H), 4.14 (dd, 1H), 3.87 (t, 1H), 3.66 (t, 1H), 3.56-3.32 (m, 3H); MS (El) for C18H16F3IN2O4: 509 (MH4). EXAMPLE 8(i): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl)carbonyl) ethylazetidin ol: 'H NMR (400 MHz, CDC13): 8.23 (br s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.15- 7.10 (m, 1H), 6.85-6.79 (m, 1H), 6.64-6.58 (m, lH), 4.14-3.94 (m, 4H), 1.78 (q, 2H), 0.96 (t, 3H); MS (El) for CisHwFslNjOj: 477 (MH+). EXAMPLE 8(j): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyI) methylazetidin ol: ‘HNMR (400 MHz, CDCI3): 8.31 (br s, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.15- 7.11 (m, 1H), 6.85-6.78 (m, 1H), 6.65-6.59 (m, 1H), 4.24-4.04 (m, 4H), 1.55 (s, 3H); MS (El) for C,7Hi4F3IN2O2·. 463 (MH1). EXAMPLE 8(lc): 3-(2-aminopyrimidin yl)-l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol acetate salt: *H NMR (400 MHz, CD3OD): 8.22-8.20 (d, 1H), 7.48-7,43 (d, 1H), 7.38-7.30 (m, 1H), 7.09-7.01 (q, 1H), 6.88-6.84 (d, 1H), 6.70-6.61 (t, 1H), 4.59-4.54 (d, 1H), 4.44-4.39 (d, 1H), 4.23-4.19 (d, 1H), 4.05-3.99 (d, 1H), 3.90-3.81 (d, 1H), 1.99-1.97 (s, 3H); MS (El) for C2oHlsF3I N5O2: 542 (MH*). EXAMPLE 8(m): 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (lif-pyrrol yl)azetidm ol: *H NMR (400 MHz, CD3OD): 7.37 (dd, 1H), 7.31-7.23 (m, 2H), 7.07-6.97 (m, 1H), 6.73-6,68 (m, 1H), 6.65-6.56 (m, 1H), 6.06-5.98 (m, 2H), 4.49-4.40 (m,lH), 4.32-4.18 (m, 2H), 4.15 4.07 (m, 1H). MS (El) for C20H15F3IN3O2: 514 (MH*) 206 EXAMPLE 8(n): l-({3.4-difluorO“2-[(2-fluoro iodophenyl)amino]phenyl}carbonyl) (l- methyl imidazol yl)azetidin ol: 'H NMR (400 MHz, CDjOD): 7.34 (dd, 1H),7.31- 7.25 (m, IH), 7.23-7.18 (m, IH), 7.11-7.09 (m, IH), 7.06-6.97 (m, IH), 6.89-6.86 (m, IH), 6.62-6.55 (m, IH), 4.88-4.80 (m, IH), 4.52-4.44 (m.lH), 4.38-4.30 (m, IH), 4.21-4.12 (m, IH), 3.68 (s, 3H). MS (El) for C2oHi6F3IN,|02: 529 (MH4). EXAMPLE 9 l-({3,4-difluoro [(2-fluoro-4“iodophenyI)ammo]phenyl}carbonyI) (trifiuoro methyl) azeti dm-3~ol

<img img-format="tif" img-content="drawing" file="IL229136AD000281.tif" id="idf0081" />

[00288] 1 -({3.4-difluoiO [(2-fluoiO iodophenyl)amino]phenyl} carbonyl)azetidin one (25 mg, 0.056 mmol), prepared using procedures described in Example 6, was taken into DMF (0.5 mL) followed by addition of (trifluoromethyl)trimethylsilane (40 pL, 0.28 mmol) and cesium carbonate (22 mg, 0.067mmol) and the mixture was stirred for one hour at room temperature. The mixture was partitioned with ethyl ether and water and the organic phase washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes :ethyl acetate 3:2 as eluent afforded l~({3,4-difluoro [(2-fluorO“4-iodophenyl)amino]phenyl}carbonyl)~3-(trifluoromethyl)azetidin ol (19.8 mg, 69% yield) as a colorless crystalline solid, ^LNMR (400 MHz, CDC13): 8,31-8.26 (br, IH), 7.40 (d, IH), 7.33 (d, IH), 7.13-7.10 (m, IH), 6.86-6,80 (m, IH), 6.65-6.60 (m, IH), 4,42 (br s, 2H), 4.18 (brs, 2H). MS(EI)forC17HnF6lN2O2: 517 (MH4). 207 EXAMPLE 10 l~({3/LdifluorO“2-[(2-fluoro-4~iodophenyI)amino]phenyI}earbonyl)azetidin~3-one oxime

<img img-format="tif" img-content="drawing" file="IL229136AD000282.tif" id="idf0082" />

OH

[00289] To a solution of l-({3,4-diflu0rO“2-[(2~fluoro iodophenyl) amino]phenyl} carbony l)azetidin-3~one (100 mg, 0.22 mmol), prepared using procedures similar to those described in Example 6, in dioxane (1.0 mL) was added hydroxylamine (0.10 mL, 50% solution in water, 1.5 mmol), and the resulting solution was heated at 60 °C for 18 h. The mixture was cooled to room temperature and the crude product was purified by reverse phase HPLC to afford 1-({3,4~difiuoro~2~[(2-fluoro«4-iodophenyl)amino]phenyl}carbonyl)azetidin one oxime (56 mg, 54% yield): 1HNMR (400MHz, CDCL), 8.43 (br s), 7.43-7.39 (m, 2H), 7.35-7.32 (dd,lH), 7,19-7.15 (m, IH), 6.87-6,81 (m,lH), 6.65-6.59 (m, IH), 4.89 (br s, 2H), 4.85 (br s, 2H); MS (El) for Ci6HHF3W)2:462 (MH+).

Example 11 7V-butyl-l-({3,4-difiuoro-2“[(2-iluoro iodophenyl)amino]phenyl}carbonyl)azetidin

<img img-format="tif" img-content="drawing" file="IL229136AD000283.tif" id="idf0083" />

[00290] To a solution of 1 -({3,4-difluoro [(2-fluoro iodophenyI)amino]phenyl}carbonyl)azetidin amine (0.09 M in acetonitrile, 500 uL, 0.045 mmol), prepared using procedures similar to those described in Example 2, was added triethylamine (20 pL, 0.135 mmol) and n-butylbromide (6.14 pL, 0.054 mmol) followed by additional acetonitrile (LO mL). The reaction mixture was stirred at room temperature for 16 h, at which time it was purified directly by reverse phase HPLC to afford the title compound (8.4 mg), !H NMR (400 MHz, CDCb): 8.50 (s, IH), 7.39 (dd, IH), 7.32 (dd, IH), 7.13-7,09 208 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.35 (br s, 2H), 4.00 (br s, 1H), 3.87 (br s, 1H), 3.74-3.68 (m, 1H), 3.20 (br s, 3.5H), 2.56 (t, 2H), 2.03 (s, 2H), 1.50-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.91 (t, 3H). MS (El) for C20H2iF3IN3O: 504 (MH+). EXAMPLE 12 l“({3,4“difluoro-2“j[(2-fluorO“4-iodophenyi)amrao]pheiiyi}carbonyl)-Ar“methyiazetidm“3- amine

NH

[00291] To a solution of l-({3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl} carbonyl) azetid in-3 -amine (0.10 M in acetonitrile, 1.0 mL, 0.09 mmol), prepared using procedures similar to those described in Example 2, in 1:1 ratio of methanol and tetrahydrofuran (2,0 mL) was added formaldehyde (37%wt, 6,7 pL, 0,09 mmol) followed by sodium cyanoborohydride (11.0 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h, at which time it was quenched with saturated aqueous ammonium chloride. The solution was then purified directly by reverse phase HPLC to afford the title compound (14.9 mg). lH NMR (400 MHz, CDC13): 8.13 (brs, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 7.09-7.04 (m, 1H), 6.84-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.46-4.33 (br m, 4H), 3.93 (br m, 1H), 2.64 (s, 3H). MS (El) for Ci7H,5F3IN3O: 462 (MH*).

[00292] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 12(a). 1-( { 3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl} carbonyl)-?/-methylazetidin amine: NMR (400 MHz, CDC13): 8.13 (br s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 7.09-7.04 (m, 1H), 6.84-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.46-4.33 (br m, 4H), 3.93 (br m, 1 FI), 2.64 (s, 3H). MS (El) for C,7Hi5F3IN3O: 462 (MH*). EXAMPLE 12(b). 2-{[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]amino}ethanol: *H NMR (400 MHz, CDC13): 8.20 (s, 1H), 7.36 (d, 1H), 7.30 (d, 1H), 7.13-7.09 (m, 1H), 6.85-6.79 (m, 1H), 6.61-6.55 (m, 1H), 4.43 (brm, 3H), 3.98 (brm, 1H), 3.87 (brm, 1H), 3.02 (brm, 1H), 1.24-1.20 (m, 1H). MS (El) for C18Hi7F3IN3O2:492 (MH*). 209 EXAMPLE 12(c). W-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin yl]propane-l,3-diamme: *H NMR (400 MHz, CDCI3): 8.51 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.33 (br s, 2H), 3.99 (br s, 1H), 3.84 (br s, 1H), 3.71-3.64 (m, 1H), 2.91 (t, 2H), 2.70-2.66 (m, 2H), 2.01 (s, 4H), 1.76-1.69 (m, 2H). MS (El) for C^HzoFjIYO: 505 (MH4). EXAMPLE 12(d). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)-jV-ethylazetidm amine: *H NMR (400 MHz, CDC13): 8.47 (s, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 7.13-7.09 (m, 1H), 6.83-6.77 (m, 1H), 6.62-6.57 (m, 1H), 4.49 (br s, 3H), 4.36 (br s, 2H), 4.08 (brs, 1H), 3.94 (brs, 1H), 3.77-3.72 (m, 1H), 2.69-2.63 (m, 2H), 1.99 (s,2H), 1.14 (t, 3H). MS (El) for C18H17F3IN30:476 (MH4). EXAMPLE 12(e). l-({3,4-difluoro [(2-fiuoro~4“iodophenyl)amino]phenyl}carbonyl)-A'-(2-methylpropyl)azetidin amine: ‘H NMR (400 MHz, CDC13): 8.50 (s, 1H), 7.38 (d, 11-1), 7.31 (d, 1H), 7.14-7.09 (m, 1H), 6.83-6.76 (m, 1H), 6.63-6.57 (m, 1H), 4.34 (br s, 2H), 4.00 (br s, 1H), 3.86 (br s, 1H), 3.71-3.66 (m, 1H), 3.42 (br s, 2H), 2.36 (d, 2H), 2.00 (s, 1H), 1.75- 1.65 (m, 1H), 0.91 (d, 6H). MS (El) for C20H21F3IN3O: 504 (MH4). EXAMPLE 12(f).iV-(cyclopropylmetbyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carboiiyl)azetidin amine: 'HNMR (400 MHz, CDCI3): 8.48 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 5.78 (s, 3H), 4.36 (br s, 2H), 4.10 (br s, 1H), 3.94 (br s, 1H), 3.81-3.75 (m, 1H), 2.49 (d, 2H), 2.01 (s, 4H), 0.94-0.86 (m, 1H), 0.53 (d, 2H), 0.13 (d, 2H). MS (El) for C20H19F3IN3O: 502 (MH4). EXAMPLE 12(g). W-(cyclohexylmethyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin amine: ’H NMR (400 MHz, CDCI3): 8,48 (s, 1H), 7.38 (dd, 1H), 7.31 (d, 1H), 7.13-7.08 (m, 1H), 6.83-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.55 (br s, 2H), 4.33 (br m, 2H), 4.02 (br s, 1H) 3.87 (br s, 1H), 3.71-3.65 (m, 1H), 2.38 (d, 2H), 1.74-1.68 (m, 4H), 1.46-1.36 (m, 1H), 1.27-1.12 (m, 3H), 0.94-0.84 (m, 2H). MS (El) for C23H25F3IN3O: 544 (MH4). EXAMPLE 12(h). W-(cyclopentylmethyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin amine: ’H NMR (400 MHz, CDCI3): 8.32 (s, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.11-7.07 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.44-4.37 (m, 3H), 4.02-3.96 (m, 1H), 2.84 (d, 2H), 2.54 (br s, 5H), 2.20-2.12 (m, 1H), 1.88- 1.81 (m, 2H), 1.68-1.54 (m, 4H), 1.24-1.15 (m, 2H). MS (El) for C22H23F3IN3O: 530 (MH4). 210 EXAMPLE 13 l-((2,4-difluoro [(2-fluoro iodopbenyI)ammo]phenyl}carboMyl)azetidin amine

<img img-format="tif" img-content="drawing" file="IL229136AD000284.tif" id="idf0084" />

<img img-format="tif" img-content="drawing" file="IL229136AD000285.tif" id="idf0085" />

[00293] 2,4,6-Trifluorobenzoic acid (643 mg, 3.65 mmol) and 2-fluoro-4~iodoaniline (1,0 g, 4.22 mmol) were taken into acetonitrile (30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) and the mixture was heated to 60 °C under a nitrogen atmosphere for one hour. On cooling to room temperature the mixture was added to 1 N aqueous hydrochloric acid (100 mL) and the precipitate formed was collected by filtration and washed once with water then hexanes and dried in vacuo to give 2,4-difluoro [(2-fluoro iodophenyl)amino]benzoic acid (849 mg, 59% yield) as a tan solid. 1 H-NMR (400 MHz, Dg-DMSO): 13.72 (br s, IH), 9.46 (s, IH), 7.75 (d, IH), 7.56 (d, IH) 7,28 (tr, IH), 6.73-6.67 (m, IH), 6.53 (d, IH).

[00294] 2,4-DifluorO“6-[(2-fluoiO iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 pL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes;ethyl acetate 3:1 as eluent afforded 1,1 -dimethylethyl [ 1 -({2,4-difluoro [(2~fluoro-4“ iodophenyl)amino]phenyl)carbonyl)azetidm yl]carbamate (125 mg) as a colorless oil. [00295] The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1-((2,4-difluoro- 6“[(2-fluoro-4“iodophenyl)amino]phenyI} carbonyl)azetidin-3 -amine 211 hydrochloride (58 mg, 48% overall yield). 'H-NMR (400 MHz, D6-DMSO): 8.67 (br s, 3H), 8.45 (s, IH), 7.71 (d, 1H), 7.54 (d, IH), 7.25 (tr, IH), 6.77 (tr, IH), 6.48 (d, IH), 4.28-4.23 (m, 2H), 4.13-4,06 (m, 3H), MS (El) for C16H13F3IN3O: 448 (MH+). EXAMPLE 14 l-({4?5“diiluor0 [(2-fluorO"4“iod0phe»yl)ainino]phenyl}carboiiyl)azetidiii amine

<img img-format="tif" img-content="drawing" file="IL229136AD000286.tif" id="idf0086" />

[00296] 2,4,5-Trifluorobenzoic acid (643 mg, 3.65 mmol) and 2-fluoro iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile (30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) and the mixture was heated to 60 °C under a nitrogen atmosphere for one hour. On cooling to room temperature the mixture was added to 1 N aqueous hydrochloric acid (100 mL) and the precipitate formed was collected by filtration and washed once with water then hexanes and dried in vacuo to give 4,5-difluoro [(2-fluoro iodophenyl)amino]benzoic acid (624 mg, 43% yield) as a tan solid. 1 H-NMR (400 MHz, Dg~ DMSO); 13.65 (br s, IH), 9.63 (s, IH), 7.84 (tr, IH), 7.71 (d, IH), 7.52 (d, IH), 7,32 (tr, IH), 7.03-6.98 (dd, IH).

[00297] 4,5-difluoro [(2“fluoro~4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137*rag, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 pL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1 -dimethylethyl [ 1 -({4,5-difluoro [(2-fluoro~4~ iodophenyl)amino]phenyl} carbony l)azetidin yl]carbamate (131 mg) as a colorless oil. The oil was taken into trifluoro acetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the 212 residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1-({4,5-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbony l)azetidin amine hydrochloride (67 mg, 55% overall yield). ’H-NMR (400 MHz, Ds-DMSO): 9.02 (s, IH), 8.54 (br s, 3H), 7.68 (dd, IH), 7.53-7.47 (ra, ZH), 7.22 (tr, IH), 7.16 (dd, IH), 4.60 (br s, IH), 4.23 (br s, 2H), 4.03 (br m, 2H). MS (El) for Cl6Hi3F3IN3O: 448 (MH+). EXAMPLE 15 1-((3,4-T)ifhioro-2“[(2-fiuoro iodophenyl)amino]phenyl}carbonyI)-;V“(2,3-dihydroxypropyl) hydroxy azetidin e carboxamide

<img img-format="tif" img-content="drawing" file="IL229136AD000287.tif" id="idf0087" />

[00298] l-(Diphenylmethyl)azetidin ol hydrochloride (2.75 g, 9.98 mmol), prepared using procedures similar to those described for Scheme 1 of the General Synthetic Section, 3A molecular sieves and 4-methylmorpholine (1.1 mL, 10.0 mmol) were suspended in dichioromethane (20 mL) at 0 °C, 4-MethylmorphoIine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammonium perruthenate (140 mg, 0.399 mmol) were added and the mixture was stirred at ambient for 24 h. The mixture was filtered through a plug of silica using 5% triethylamine in ethyl acetate as eluent. The filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 8:1 hexanes:ethyl acetate) gave 1 -(diphenylmethyl)azetidin one (871 mg, 3.68 mmol, 37% yield): Tl NMR (400 MHz, CDC13): 7.50-7.46 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, IH), 4.01 (s, 4H); MS (El) for C16Hi5NO: 238 (MH4).

[00299] l-(Diphenylmethyl)azetidin one (600 mg, 2.53 mmol), was dissolved in dichioromethane (1 mL) and treated with triethylamine (0.5 mL, 3.59 mmol) and trimethyisilylcyanide (0,8 mL, 6.01 mmol) at ambient for 2 h and then the mixture was concentrated in vacuo to afford l-(diphenylmethyI) [(trimethylsilyl)oxy]azetidine carbonitrile (774 mg, 2.30 mmol, 91% yield) as a yellow solid. l-(diphenyImefhyI) 213 [(trimethylsilyl)oxy]azetidine carbonitrile (250 mg, 0.744 mmol) was dissolved in dichloromethane (2 mL) at 0 °C and concentrated sulfuric acid (0.2 mL) was added dropwise. The mixture was stirred at ambient for 2 h and then was cooled to 0 °C and 25% ammonium hydroxide solution was added carefully dropwise to pH V0-11, The mixture was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a residue which was triturated with hexanes/ether to afford 1 -(diphenylmethy 1) hydroxyazetidine carboxamide (160 mg, 0.567 mmol, 76% yield) as an off-white solid: NMR (400 MHz, CDC13): 7.92 (br s, 1H), 7.39-7.34 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 5.61 (br s, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.50 (dd, 2H), 3.20 (dd, 2H); MS (El) for C17H18N2O2: 283 (MH4).

[00300] l-(Diphenylmethyl) hydroxyazetidine carboxamide (1.1 g, 3.90 mmol) was treated with 10% sodium hydroxide in ethanol (15 mL) and water (2 mL) at reflux for 2 h and then was concentrated in vacuo. The resiude was neutralized with 1 N hydrochloric acid (pH --7) and the precipitate was collected by filtration and lyophilized to afford 1-(diphenylmethyl) hydroxyazetidine carboxylic acid (assume 3.90 mmol) which was used without further purification: JH NMR (400 MHz, d6-DMSO): 7.45-7.40 (m, 4H), 7.31-7,25 (m, 4H), 7.21-7.15 (m, 2H), 4.52 (s, 1H), 3.46 (dd, 2H), 3.02 (dd, 2H); MS (El) for C17H17NO3: 284 (MH4).

[00301] 1-(Dipheny lmethy 1) hydroxy azeti dine carboxylic acid (assume 3.90 mmol) was suspended in methanol (40 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. 20 wt% Palladium hydroxide on carbon (100 mg) was added to the solution and the mixture was treated with hydrogen at 40 psi for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-hydroxyazetidine carboxylic acid hydrochloride which was dissolved in tetrahydrofuran (5 mL) and water (5 mL) and treated with potassium carbonate (1.615 g, 11.7 mmol) and di-Wbutyl dicarbonate (935 mg, 4.29 mmol) were added. The mixture was stirred at ambient for 17 h and then the mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate and then was acidified to pH ~3-4 and extracted twice more with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford l-{[(l,l-dimethylethyl)oxy]carbonyl) hydroxyazetidine carboxylic acid which was dissolved in DMF (3 mL). Benzotriazol yloxytris(pyrrolidino)phosphoniwn hexafluorophosphate (2,028 g, 3.90 mmol) and NJf-diisopropylethylamine (0.7 mL, 4.03 mmol) were added. The mixture was stirred at ambient 214 for 5 minutes and then allylamine (0.6 mL, 8.03 mmol) was added and the mixture was stirred for 17 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl 3-hydroxy [(prop~2-en~l-ylamino)carbonyl]azetidine~l-carboxylate (782 mg, 3,05 mmol, 78% yield from 1 -(diphenylmethyl)-3~hydroxyazetidine-3“Carboxamide), 1,1 -Dimethylethyl 3-hydroxy-3“[(pr0p“2“en“i“ylamino)carbonyl]azetidme4“carboxylate (782 mg, 3,05 mmol) was dissolved in methanol (10 mL) and 4 N hydrochloric acid in dioxane (2 mL, 8 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-hydiOxy-A7'-piOP~2-en-l-ylazetidine carboxamide hydrochloride (3.05 mmol). [00302] 3,4-Difluoro [(2-fluoro iodophenyl)amino]benzoic acid (1.20 g, 3.05 mmol), prepared using procedures similar to those described in US 7,019,033, 4“(dimethylamino)pyridine (1.20 g, 9,86 mmol) and l-(3-dimethylaminopropyl) ethylcarbodiimide hydrochloride (701 mg, 3,66 mmol) were dissolved in DMF (10 mL). The mixture was stirred at ambient for 5 minutes and then 3“hydroxy-Ar-prop en-l-ylazetidine carboxamide hydrochloride (3.05 mmol) in DMF (5 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 60-85% ethyl acetate in hexanes) and then reverse phase HPLC gave l-({3,4-difluoro [(2-fluoro iodophenyl) am ino] phenyl} carbony ]) hydroxyY-prop en yl azeti dine carboxamide (150 mg, 0.282 mmol, 9% yield): 3H NMR (400 MHz, d6-DMSO): 8.64 (br s, IH), 8.13 (t, IH), 7,58 (dd, IH), 7.38 (dd, IH), 7.34-7.28 (m, IH), 7.21-7.12 (m, IH), 6.84 (br s, IH), 6.72 (ddd, IH), 5.83-5,72 (m, IH), 5.10-4.99 (m, 2H), 4.38 (d, IH), 4.20 (d, IH), 4.02 (d, IH), 3.86 (d, IH), 3.73-3.68 (m, 2H); MS (El) for C20H17F3IN3O3: 532 (MH4).

[00303] I-({3s4-DifiuorO“2-[(2-fluorO“4-iodophenyl)amino]phenyl}carbonyl)-3~hydroxy-N-prop en-l -ylazetidine carboxamide (88 mg, 0.166 mmol) and 4-methylmorpholine N~ oxide (58 mg, 0.496 mmol) were dissolved in acetone / water (4:1; 10 mL) and osmium tetroxide (2,5 wt.% in water; 0.1 mL) was added. The solution was stirred at ambient for 15 h, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over 215 anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC gave 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl)-#-(2,3-dihydiOxypropy 1) hydroxyazetidine carboxamide (68 mg, 0.120 mmol, 72% yield): ]H NMR (400 MHz, d6-DMSO): 8.65 (br s, IH), 7.72 (t, IH), 7.58 (dd, IH), 7.41-7.36 (m, IH), 7.34-7,28 (m, IH), 7.21-7.12 (m, IH), 6.92 (br s, IH), 6.72 (ddd, IH), 5.00-4.10 (br, 2H), 5,10-4.99 (m, 2H), 4.39 (d, IH), 4.20 (d, IH), 4.02 (d, IH), 3.54-3.45 (m, IH), 3.34-3.21 (m, 2H), 3.06-2,96 (m, IH); MS (El) for C2oHi9F3IN305: 566 (MH+).

[00304] EXAMPLE 15(a). Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: l-({3,4-Dxfluoro-2~[(2-fluoro iodophenyl)amino]phenyl}carbonyl)-#-hydroxyazetidine carboxamide: 1H NMR (400 MHz, d6-DMSO): 8.63 (br s, IH), 7.58 (dd, IH), 7.42-7.36 (m, 3H), 7.34-7.28 (m, IH), 7.22-7.12 (m, IH), 6,76-6.68 (m, 2H), 4.39 (d, IH), 4.19 (d, IH), 4.00 (d, IH), 3.83 (d, IH); MS (El) for Ci7H13F3IN3O3: 492 (MH+), EXAMPLE 16 6-{[3“(aminomethyl) (methyloxy)azetidin-l-yl]carbonyI}-2,3-difluorO“iV-(2“fluoro io doph eny I)amline

<img img-format="tif" img-content="drawing" file="IL229136AD000288.tif" id="idf0088" />

[00305] Phenylmethyl l-oxa-5~azaspiro[2.3]hexane carboxylate (165 mg, 0.75 mmol), prepared using procedures similar to those described in Reference 3, in THF (1 mL) was added to anhydrous ammonia saturated in THF (10 mL) and the mixture was allowed to stir in a sealed vessel at room temperature over 24 hours. The solution was then concentrated and taken back into THF (1 mL) followed by addition of di-Zerr-butyldicarbonate (164 mg, 0.75 mmol) and stirred for one hour at room temperature. The mixture was then concentrated and the residue purified by silica gel flash chromatography using hexanes:ethyl acetate (1:1) as eluent to give phenylmethyl 3-[({[(l,l-dimethylethyl)oxy]carbonyl}amino)methyl]-3~ hydroxyazetidine carboxylate (16.5 mg, 7% yield) and unreacted epoxide (120 mg, 73% recovery). 1 H-NMR (400 MHz, CDC13): 7.34 (m, 5H), 5.10 (br, IH), 5.09 (s, 2H), 4.68 (s, IH), 3.90 (dd AB, 4H), 3.41 (d, 2H), 1.44 (s, 9H). 216 [00306] Phenylmethyl 3-[(([(l,l-dimethylethyl)oxy]carbonyl}amino)methyl] hydroxyazeddineV-carboxylate (16.5 mg, 0,05 mmol) and 10% Pd/C (8 mg) were taken into methanol (2 mL) and hydrogenated at ambient pressure over 12 hours. The catalyst was removed by filtration and the filtrate concentrated and dried in vacuo. The residue was taken into THF (1 mL) followed by addition of DIPEA (10 pL, 0.06 mmol) and 3,4-difluoro~2~[(2-fiuoro iodophenyl)amino]henzoyl fluoride (19.8 mg, 0.05 mmol), prepared using procedures similar to those described in Reference 1, and the solution was stirred at room temperature for 30 minutes. Concentration and purification of the residue by silica gel flash chromatography using hexanes :ethyl acetate (1:1.5) afforded 1,1-diinethylethyl ([1-((3,4-difiuoro-2 [(2-fluoro iodophenyl)ammo] phenyl} carbonyl)-3~hydroxyazetidine yl]methyl}carbamate (19 mg, 66% yield).

[00307] U-Dimethy3ethyl([l-((3,4-difluoro-2[(2-fluoro iodophenyl)amino]phenyl}carhonyl) hydiOxyazetidine yl]methyi}carbamate (8.0 mg, 0.014 mmol) and silver (I) oxide (12 mg, 0.05 mmol) were taken into methyl iodide (0.5 mL) and the mixture was brought to reflux for 4 hours. The suspension was then cooled to room temperature and diluted with an excess of ethyl ether then filtered. The filtrate was concentrated and purified by silica gel flash chromatography using hexanes:ethyl acetate (1:1) as eluent to give 1,1-dim ethyl ethyl ([1-((3,4-difluoro-2[(2-fiuoro iodophenyl)amino]phenyi}carbonyl)~3-(methyloxy)azetidine yl3methyl}carbamate (2 mg). The material was taken into TFA (0.5 mL) and allowed to stand for 5 minutes then concentrated in vacuo. The residue was azetroped twice from methanol (2 mL) and the residue dried in vacuo to afford 6-{[3-(ammomethyl) (methyloxy)azetidin-l-yl]carbonyl}- 2,3-difluoro-V-(2-fiuoro-4~iodophenyl)aniline trifluoroacetate salt (2.3 mg, 27% yield) as an amorphous solid. MS (El) for C18H17F3IN3O: 492 (MH*). EXAMPLE 17 1 -((3,4-difluor o [(2-fluoro iod ophenyl)ainino] pheny l}carbonyl)-3~{2-[(1-metliyiethvl)annno] ethyl} azetid &amp;#943;η ol 217 [00308] A solution of /eri-hutyl acetate (566 pL, 4.2 mmol) in THF (10 mL) was cooled to -78 °C. To the solution was added LHMDS (5.25 mL of a 1.0 M solution in hexanes, 5.25 mmol), and the resulting mixture was stirred for 20 min at -78 °C, To the solution was added l-(diphenylmethyl)azetidm one (500 mg, 2.1 mmol), prepared using procedures similar to those described in Example 15. After stirring for 1 h, saturated aqueous ammonium chloride was added, and the mixture was warmed to rt. Water and ether were added, and the resulting biphasic mixture was partitioned, The aqueous phase was extracted once with ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate) to provide 1,1-dimethylethyl [l-(diphenylmethyl) hydroxyazetidin y I] acetate as a pale yellow solid (644 mg, 1.8 mmol, 87% yield). NMR (400 MHz, CDC13): δ 7.40 (m, 4H), 7.26 (m, 4H), 7.19 (m, 2H), 4.40 (s, IH), 4.02 (s, IH), 3.15 (m, 2H), 3.05 (m, 2H), 2.83 (s, 2H), 1.45 (s, 9H).

[00309] To a solution of 1,1-dimethylethyl [l-(diphenylmethyl) hydroxyazetidin yl]acetate (333 mg, 0.94 mmol) in THF (3 mL) at 0 °C was added lithium aluminum hydride (940 pL of a 1.0 M solution in THF, 0.94 mmol). The mixture was stirred for 3 h 20 min while warming to rt. Water (36 pL) was added carefully to the solution, followed by 15% sodium hydroxide (36 pL) and more water (108 pL). The resulting precipitate was removed by filtration through ceiite, and the filtrate was concentrated to dryness yielding 1-(diphenylmethyi) (2-hydroxyethyl)azetidin ol (228 mg, 0.80 mmol, 85% yield) as a colorless syrup. *H NMR (400 MHz, CDC13): δ 7.38 (m, 4H), 7.26 (m, 4H), 7.19 (m, 2H), 4.37 (s, IH), 3.92 (m, 2I-I), 3.32 (m, 2H), 2.96 (m, 2H), 2.07 (m, 2H).

[00310] Palladium hydroxide (100 mg) was suspended in a solution of 1-(diphenylmethyl) (2-hydroxyethyl)azetidin-3~ol (228 mg, 0.80 mmol) in methanol (15 mL), and the mixture was subjected to an atmosphere of hydrogen at 50 psi for 4 h. The catalyst was then removed by filtration through ceiite, and the filtrate was concentrated in vacuo to provide 3-(2-hydroxyethyl)azetidin ol, This material was used in the subsequent reaction without purification. To a solution of 3,4-difluoro [(2-fluoro iodophenyl) amino] benzoic acid (314 mg, 0,80 mmol), prepared using procedures similar to those described in US 7,019,033, in DMF (4 mL) was added PyBOP (416 mg, 0.80 mmol) and triethylamine (223 pL, 1,6 mmol). Finally, the unpurified 3-(2-hydroxyethyl)azetidin ol was added, and the resulting mixture was stirred at rt for 16 h. Water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with once more 218 with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated m vacuo. The residue was purified by flash chromatography, eluting with ethyl acetate, to provide l-((3,4-difluoro-2“[(2“fluoro iodopheny l)amino]phenyl}carbonyl)~3-(2-hydroxyethyl)azetidin-3~ol as a colorless oil (303 mg, 0.62 mmol, 78% yield). *H NMR (400 MHz, CDC13): 8 8.46 (s, 1H), 7.39 (dd, 1H), 7.32 (m, 1H), 7.13 (m, 1H), 6.81 (m, 1H), 6.60 (m, 1H), 4.37 (br s, 1H), 4.28 (br m, 4H), 3.94 (br s, 2H), 2.19 (br s, 1H), 2.02 (m, 2H); MS (El) for CjjHwFjW),: 491 (M-H).

[00311] A solution of oxalyl chloride (13 pL, 0.15 mmol) in dichloromethane (1 mL) was cooled to -78 °C, and DMSO (22 pL, 0,31 mmol) was then added. To this mixture was added 1-((3,4-difluoro [(2-fiuoro iodophenyl)amino]phenyl}carbonyl) (2- hydroxyethyl)azetidin-3~ol (67.8 mg, 0.14 mmol) as a suspension in dichloromethane (1 mL). After stirring at -78 °C for 10 min, triethylamine (78 pL, 0.56 mmol) was added and the mixture was allowed to warm to rt, The solution was diluted with dichloromethane, and washed with 0.5 N HCl. The aqueous phase wash then extracted with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to provide [1-((3,4-difiuoro [(2-fluoro iodopheiiyl)amino]phenyl}carbonyl) hydiOxyazetidin-3“yl3acetaldehyde as a white solid (22.1 mg, 0.045 mmol, 32% yield). NMR (400 MHz, CDClj): S 9.82 (s, 1H), 8.46 (s, 1H), 7.39 (m, 1H), 7.33 (m, 1H), 7.11 (m, 1H), 6.81 (m, 1H), 6.61 (m, 1H), 4.32-3.96 (brm, 4H), 3.41 (t, 2H), 3.07 (s, 1H); MS (El) for Ci8H]4F3lN2O3: 491 (MH*), [00312] To a solution of [1-((3,4-difluoro [(2-fluoro iodophenyl)amino)phenyl}carbonyl) hydroxyazetidin yl]acetaldehyde (38.0 mg, 0.078 mmol) in 1,2-dichloroethane (1 mL) was added isopropylamine (27 pL, 0.31 mmol) followed by sodium triacetoxyborohydride (26 mg, 0.12 mmol). The mixture was stirred for 3 h before quenching with 1 drop of concentrated HCl. lire quenched mixture was concentrated to dryness, and then purified by preparative HPLC to provide l-({3,4-difluoro [(2-fiuoro iodophenyl)amino] phenyl} carbonyl) (2- [(1 -methy lethyl)amino]ethyl} azetidin ol (21.5 mg) as a pale yellow solid. lH NMR (400 MHz, d6-DMSO): δ 8.54 (s, 1H), 7.57 (dd, 1H), 7,38 (dd, 1H), 7,31 (m, 1H), 7.17 (m, 1H), 6.67 (tn, 1H), 4,02 (m, 1H), 3.89 (m, 2H), 3,71 (m, 1H), 2,70 (m, 1H), 2.63 (m, 2H), 1.86 (s, 3H), 1.75 (m, 2H), 0.97 (d, 6H); MS (El) for C2iH23F3IN3O2: 534 (MH*). EXAMPLE 18 219 l“({3,4“diiluoro-2“[(2“fluoro-4“iodophenyl)amino3phenyI}carbonyl)-3“{X,l“di&lt;nethy^" [(1-m ethy Iethyl)amin o] ethy!} azetid &amp;#943;π ol

<img img-format="tif" img-content="drawing" file="IL229136AD000289.tif" id="idf0089" />

[00313] To a solution of l~({3,4-difluoro~2-[(2~fiuoro iodophenyl)amino]phenyI}carbonyi)azetidin one (500 mg, 1.12 mmol), prepared using procedures similar to those described in Example 6, in dichloromethane (5 mL) cooled to 0 °C was added titanium tetrachloride (125 pL, 1.12 mmol). The dark brown solution was stirred at 0 °C for 45 minutes, followed by the addition of methyltrimethylsilyl dimethylketene acetal (550 pL, 2.24 mmol) at 0 °C. Upon addition the solution was allowed to warm to room temperature, and was stirred for 1 hour. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a, brown oil which was purified by column chromatography. Eluting with 10% diethyl ether in dichloromethane, the isolated product was concentrated in vacuo to afford 520 mg, 0.95 mmol (85%) of methyl 2-[l-({3,4-difluoro [(2-fluoro iodophenyi)amino]phenyl}carbonyl)-3~hydroxyazetidin yl] methylpropanoate as a white foam. NMR (400 MHz, CDC13): 8.34 (s, IH), 7.38 (d, IH), 7.31 (d, IH), 7.13-7.08 (m, IH), 6.85-6.77 (m, IH), 6.63-6.56 (m, IH), 4.26-4.20 (m, 2H), 4.13-4.09 (m, IH), 4.00-3.93 (m, IH), 3.70 (s, 3H), 1.23 (s, 6H), MS (El) for C21H20F3IN2O4: 547 (MET).

[00314] A solution of methyl 2-[l-({3,4-difluoro [(2-fluoro- 4-iodophenyl)amino]phenyl}carbonyl)~3-hydroxyazetidin yl] methylpropanoate (520 mg, 0.95 mmol) in 4N aqueous potassium hydroxide (5 mL) was stirred at 50°C for 1 hour. Using concentrated aqueous hydrochloric acid, the reaction mixture was acidified to pH 5, and then partitioned with ethyl acetate. The aqueous portion was extracted twice using ethyl acetate, and the combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 300 mg, 0.56 mmol (59%) of 2-[l-({3,4-difluoro· 2-[(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin“3-yl] methylpropanoic acid as a white solid. lH NMR (400 MHz, DMSO): 8.49 (s, IH), 7.57-7.52 220 («1, IH), 7.37-7.25 (m, 2H), 7.17-7.13 (m, IH), 6.68-6.58 (m, IH), 3.98-3.94 (m, 2H), 3.80- 3.77 (m, IH), 3.55-3.52 (m, IH), 0.88 (s, 6H). MS (El) for C20H18F3IN2O4:535 (MH).

[00315] To solution of 2-[I-({3?4-difluoro [(2-fluoro- 4-iodophenyl)amino]phenyI}carbonyl) hydroxyazetidin yl] methylpropanoic acid (300 mg, 0.56 mmol) in tetrahydrofuran (5 mL) was added triethylamine (80 pL, 0.56 mmol), followed by PyBOP (295 mg, 0.56 mmol) and finally sodium borohydride (64 mg, 1.68 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding 20% aqueous citric acid, and then partitioned with ethyl acetate. The organic portion was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a white solid which was purified by column chromatography. Eluting with 60% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 238 mg, 0,46 mmol (82%) of 1-((3,4-difluoro [(2~ fluoro-4“iodophenyl)amino]phenyl}carbonyl) (2-hydroxy~l,l-dimethylethyl)azetidin ol as a white solid. *H NMR (400 MHz, DMSO): 8.53 (s, IH), 7.57 (d, IH), 7.38-7.28 (m, 2H), 7.22-7.15 (m, IH), 6.70-6.64 (m, IH), 5.61 (s, IH), 4.57 (br s, IH), 4.30-4.27 (m, IH), 4.18-4.15 (m, IH), 3.80-3.77 (m, IH), 3.68-3.64 (m, IH), 3.25 (s, 2H), 0.76 (d, 6H); MS (El) for C20H20F3IN2O3: 521 (MH).

[003161 A mixture of 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl) carbonyl) (2-hydroxy~ 1,1 -dimethylethyl)azetidin ol (200 mg, 0,38 mmol) and Dess-Martin periodinane (240 mg, 0.57 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. 10% aqueous sodium thiosulfate (2 mL), and saturated aqueous sodium bicarbonate (2 mL) was added and the mixture was stirred at room temperature for 15 minute. The mixture was partitioned and the aqueous layer was extracted twice using di chloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, to afford a white solid which was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 100 mg, 0,20 mmol (53%) of 2-(1-((3,4-difluoro-2“[(2“fluoro iodophenyl)amino3phenyl}carbonyl) hydroxyazetidin yl] methylpropanal as a white solid, which was immediately dissolved in tetrahydrofuran (2 mL). i

To the solution was added isopropylamine (34 pL, 0.40 mmol), followed by triacetoxyborohydride (212 mg, 1.0 mmol). The solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and partitioned between 20% aqueous citric acid and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate, and the combined organic portion was washed with saturated aqueous sodium 221 bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by preparative reverse phase HPLC. The isolated product was concentrated in vacuo to afford 50 mg, 0,07 mmol (36%) of l-({3,4-difluoro [(2-fluorO“ 4-iodophenyl)amino]phenyl)carbonyl) {l,l-dimethyl [(l“ methylethyl)amino]ethyl}azetidin-3~ol acetate salt as a white solid. &amp;#905; NMR (400 MHz, DMSO): 8.47 (br s, 1H), 7.55 (d, 1H), 7.36-7.29 (m, 2H), 7.22-7.15 (m, 1H), 6,68-6.63 (m, 1H), 4,17-4.08 (m, 2H), 3.76-3.73 (m, 1H), 3.56-3.52 (m, 1H), 2.58-2.51 (m, 1H), 2.45-2.37 (m, 2H), 0.92 (t, 6H), 0.78 (d, 6H); MS (El) for C23H27F3IN3O2: 562 (MH4). EXAMPLE 19 1-({3,4-difluoro-2~[(2“fluoro iodophenyl)amino] phenyl) carbonyl) {[(l“ methylethyl)amino]methyi}azetidin amine

<img img-format="tif" img-content="drawing" file="IL229136AD000290.tif" id="idf0090" />

[00317] To a solution of the l-(diphenylmethyl) [(phenylmethyl)amino]azetidine- 3-carbonitrile (0.80 g, 2.2 mmol), prepared using procedures similar to those described in Kozikowski and Fauq Synlett 1991, 11, 783-4, in ethanol (30 mL) was added solid sodium hydroxide (7.5 mmol), and the resulting mixture was stirred at room temperature for 3 days, Water (6 mL) was added to the reaction mixture and stirring was continued at 90 °C for 2 h. The pH of the reaction mixture was adjusted to 5 with concentrated hydrochloric acid and a white solid precipitated. The mixture was cooled , diluted with water (50 mL) and the solid was collected, washed with water then dried in vacuo to give the l-(diphenylmethyl) [(phenylmethyl)amino]azetidine carboxylic acid (0.75g, 88% yield), MS (El) for C24H24N2O2: 373 (MH*).

[00318] To a mixture of l-(diphenylmethyl) [(phenylmethyl)amino]azetidme carboxylic acid (0.50 g, 1.34 mmol), ATV-diisopropylethylamine (0.47 mL, 2.68 mmol) in DMF (3 mL) was added l-benzotnazolyloxytripyrrolidinylphosphomum hexafluorophosphate (1.34g, 2,68 mol) and the resulting mixture was stirred at room temperature for 10 minutes. To this mixture was added 2-propylamine (0.22 mL, 2.68 mmol) and stirring was continued for 18 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 2% aqueous citric acid, 5% lithium chloride, and brine solutions (50 222 W Ο 2007/044515 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, eluting with 15-25% ethyl acetate-hexane) to give 1 -(diphenylraethyl)“N-(l-methylethyl) [(phenylniethyl)ammo]azetidine~3- carboxamide (0,51 g, 92% yield), MS (El) for C27H3iN3O: 414 (MH4).

[00319] To a solution of the L(diphenylmethyl)-AL(1 -methy lethyl) [(phenylmethyl)amino]azetidine carboxamide (0.40 g, 0.97 mmol) in tetrahydrofuran (10 mL) at room was added a solution of lithium aluminum hydride in tetrahydrofuran (1M, 2,90 mL, 2.90 mmol), and the resulting mixture was stirred at 50 °C for 3h. The reaction mixture was cooled to room temperature, quenched with 20% aqueous hydroxide solution (1 mL), diluted with ether (50 mL) and filtered. The filtrate was washed with brine solution (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, eluting with 5% methanol-dichloromethane) to give 1 -(d ipheny Imethy 1)-3 - {[(1 -methy lethyl)amino]methyl} -JV- (phenylmethyl)azetidin-3 - amine (0.35g, 90% yield), 'H NMR (400 MHz, CDC13): 7.42-7.14 (m, 15H), 4.34 (s, IH), 3.66 (s, 2H), 3.22-3.18 (d, 2H), 2.97 (s, 2H), 2.90-2.86(d, 2H), 2.68-2.62 (p, IH), 1.09-1.07 (d, 6H); MS (El) for C27H33N3: 400 (MH4).

[00320] To a solution of the l-(diphenylmethyl) {[(l-methylethyl)amino]methyl}-Y(phenyhnethyl)azetidin amine (0.35 g , 0.88 mmol) in methanol was added a solution of hydrogen chloride in dioxane (4 molar solution, 0.96 mL, 4.40 mmol) and the resulting mixture was concentrated to give a white solid which was taken back into methanol. To this solution were added palladium hydroxide (20% on carbon, 0.50 g, 0.19 mmol) and the resulting mixture shaken at 50 psi in a Parr apparatus for 3h. The reaction mixture was filtered and concentrated to give a solid, which was washed with ether and dried in vacuo to give 3-( [(1 -methylethyl)amino]methyl}azetidin amine hydrochloride as a white solid (0.18 g, 81% yield). MS (El) for C7H17N3: 144 (MH4).

[00321] To a mixture of the 3-{[(l-methylethyl)amino]methyl}azetidin amine hydrochloride (20 mg, 0.079 mmol) in saturated sodium bicarbonate solution (1.0 mL) and dioxane (1.0 mL) was added 3&gt;4~difluoro [(2-fluoro iodophenyl)amino]benzoyl fluoride (31 mg, 0.079 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3x5 mL). The combined extract was washed with water then brine solution (5 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by reverse phase HPLC to afford 1-((3,4-difluoiO [(2~fluoro~4-iodophenyl)amino]phenyl} carbonyI) ([(1 - 223 methylethyl)amino]meihyl}azetidin amine (15 mg, 37% yield). !H NMR (400 MHz, d4-Methanol): 7.46-7.43 (dd, 1H), 7.35-7.33 (dd, 1H), 7.31-7.27 (m, 1H), 7.08-7.01 (dd, 1H), 6,63, 6.58 (td, 1H), 4.09-4.07 (d, 1H), 3.91-3.85 (dd, 2H), 3.76-3.73 (d, 1H). 2.80-2.74 (m, 1H), 2.73 (s, 2H), 1,07-1.05 (d, 6H); MS (El) for C20H22F3IN4O: 519 (MH+). EXAMPLE 20 3-(l-ammo methy!propyl)-l-({3,4-difluoro-2~[(2-fiuoro iod op h enyl)ara in 0] ph enyl) carbony 1) azetidm ol

<img img-format="tif" img-content="drawing" file="IL229136AD000291.tif" id="idf0091" />

[00322] 1,1 -Dimethylethyl 3 -oxoazetidine-1 -carboxylate (677.2 mg, 3.96 mmol), prepared using procedures similar to those described in Example 3, was taken into 2-methyl-l-ntropropane (5 mL) then cooled to 0 °C followed by addition of potassium /m-butoxide (444 mg, 3.96 mmol) and the resulting mixture was allowed to warm to room temperature over 30 minutes, The mixture was partitioned with ethyl acetate and 0.5 N aqueous hydrochloric acid then once with water and brine then dried over anhydrous magnesium sulfate. Filtration and concentration afforded a residue (1.5 g) that was further purified by silica gel flash chromatography using 3:1 hexanes:ethyl acetate as eluent to give 1,1-dimethylethyl 3-hydroxy (2-methyl-l-mtropropyl)azetidine-l-carboxylate (730 mg, 67% yield) as a colorless crystalline solid. 'H-NMR (400 MHz, CDC13): 4.50 (d, 1H), 3.93 (dd AB, 2H), 3.85 (s, 2H), 3.58 (s, 1H), 2.54-2.48 (m, 1H), 1.44 (s, 9H), 1.04 (d, 6H).

[00323] 1,1-Dimethylethyl 3-hydroxy (2-methyl-l-nitropropyl)azetidine-l-carboxylate (105 mg, 0.38 mmol) was taken into methanol (1 mL) followed by addition of 4 N anhydrous hydrogen chloride in dioxane (1 mL) and the acidic solution was allowed to stand for 15 minutes at room temperature then concentrated and dried in vacuo to an amorphous residue. 3,4-Difluoro [(2-fluoro iodophenyl)amino]benzoic acid (150 mg, 0.38 mmol), prepared using procedures similar to those described in US 7,019,033, was taken into DMF (0.7 mL) followed by addition of PyBOP (198 mg, 0.38 mmol) and the solution was allowed to stir for 10 minutes at room temperature. The above amine hydrochloride salt and DIPEA (190 pL, 1.1 mmol) in DMF solution (0.7 mL) was added and the mixture was allowed to stir for one hour at room temperature. The mixture was partitioned with ethyl acetate and 0.5 N aqueous 224 hydrochloric acid and the organic phase washed three times with water then brine and dried over anhydrous magnesium sulfate. Filtration and concentration afforded a residue that was further purified by silica gel flash chromatography using 1.5:1 hexanes:ethyl acetate as eluent to give 1 -({3,4-difluoro [(2-fluoro-40odophenyl)amino]phenyl}carbonyl) (2-methyl-1 -nitropropyl)azetidin ol (189 mg, 90% yield) as an amorphous solid. ^H-NMR (400 MHz, CDC13): 8.41 (brs, IH), 7.41 (dd, IH), 7.34 (d, &amp;#938;Η), 7.09 (brm, IH), 6.81 (q, IH), 6.65-6.60 (m, IH), 4.49 (d, IH), 4.15-4.09 (m, 4H), 3.66 (s, IH), 2.56-2.46 (m, IH) 1.03 (d, 6H).

[00324] 1-((3,4-Difluoro“2-[(2-fluoro-4“iodophenyl)amino]phenyl}carbonyl)-3~(2-methyi- l-nitropropyl)azetidin ol (189 mg, 0.34 mmol) was taken into 4:1 THF:water (5 mL) followed by addition of iron powder (192 mg, 3,4 mmol) and ammonium formate (429 mg, 6.8 mmol) and the mixture was heated to reflux. After four hours additional aliquots of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) were added and the mixture was allowed to reflux an additional 12 hours, The mixture was cooled to room temperature and diluted with ethyl acetate then filtered. The filtrate was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate then the organic layer washed with brine and dried over anhydrous sodium sulfate. Filtration and, concentration afforded a residue that was -further purified by silica gel flash chromatography· using ethyl acetate to 10% methanol in dichloromethane as eluents to give a residue (36.5 mg) that was further purified by preparative reverse phase HPLC to give 3-(l-amino methylpropyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol trifluoroacetate salt (7.9 mg) as a colorless amorphous solid after lyophillization of the combined pure fractions. 3H-NMR (400 MHz, Dg-DMSO): 8.63 (s, IH), 7.58 (dd, IH), 7.37 (d, IH), 7.35-7.31 (m, IH), 7.17 (q, IH), 6.71-6.66 (m, IH), 4.23 (dd, IH), 4.03 (dd, IH), 3.80 (dd, IH), 3.66 (dd, IH), 2.34 (dd, IH), 1.79-1.70 (m, IH), 0.84-0.77 (m, 6H). MS (El) for C20H2iF3IN3O2: 520 (MH4).

[00325] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 20(a). 3-(l-aminoethyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol: &amp;#905; NMR (400 MHz, dg-DMSO): 8.56 (s, IH), 7.91 (br s, 2H), 7.58 (d, IH), 7.39 (d, IH), 7.36-7.32 (m, IH), 7.24-7.17 (m, IH), 6.72-6.65 (m, 2H), 4.33-4.29 (m, IH), 4.23-4.19 (m, IH), 4.16-4.14 (m, IH), 4.07-3.94 (m, IH), 3.82-3.77 (m, IH), 3.51-3.45 (m, IH), 1.15-1.12 (m, IH), 1.10-1.08 (m, &amp;#938;Η). MS (El) for CiSHi7F3IN3O2: 492 (MH4). 225 EXAMPLE 20(b). 1 ~({ 3,4-difiuoiO [(2-fiuoro iodophenyl)aniino]phenyl} carbonyl) [l-(ethylamino)ethyl]azetidin ol: 'H NMR (400 MHz, d6-DMSO): 8.61 (d, IH), 8.50 (s, IH), 8.20 (s, IH), 7.59 (d, IH), 7.39 (d, IH), 7.36-7.32 (m, IH), 7.24-7.17 (m, IH), 6.82 (s, IH), 6.74-6.67 (m, IH), 4.38 (d, IH), 4.27 (d, IH), 4.18 (d, IH), 4.06 (d, 2H), 3.99 (d, IH), 3.89 (d, IH), 3.82 (d, IH), 3.49-3.43 (m, IH), 3.04-2.80 (m, 4H), 1.21-1.12 (m, 6H). MS (El) for C2oH2IF3IN302: 520 (MH4). EXAMPLE 20(c). 1-( { 3,4-difiuoro [(2-fiuoro-4“iodophenyl)amino] phenyl [carbony 1) (1 -nitroethyl)azetidin ol: ’H NMR (400 MHz, ds-DMSO): 8.57 (d, IH), 7.58 (d, IH), 7.38 (d, IH), 7.37-7.33 (m, IH), 7.22-7.17 (ra, IH), 6.73-6.66 (m, IH), 6.57 (s, IH), 5.06-4.97 (m, IH), 4.54 (d, 0.5H), 4.37 (d, 0.5 H), 4.29 (d, 0.5H), 4.14 (d, 0.5 H), 4.05 (d, 0.5 H), 3.95 (d, 0.5H), 3.86 (d, 0.5H), 3.80 (d, 0.5H), 1.44-1.38 (m, 3H). MS (El) for C18Hi6F3IN3O4: 523 (MH4). EXAMPLE 20(d). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [l-(meBiylammo)ethyl]azettdin ol: *H NMR (400 MHz, d6-DMSO): 8.63-8.55 (ra, IH), 8.44-8.23 (m, IH), 7.79 (br s, 1H), 7.60 (d, IH), 7.39 (d, IH), 7.36-7.31 (m, IH), 7.24-7.17 (m, IH), 6.82 (br s, 0.5H), 6.73-6.65 (m, IH), 4.38-3.77 (m, 4H), 1.18-1.07 (m, 3H). MS (El) for CI9H19F3IN3O2: 505 (M4). EXAMPLE 20(e). methyl (1-(1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]ethyl}carbamate: HNMR (400 MHz, ds-DMSO): 8.59 (d, IH), 7.58 (d, IH), 7.41-7.05 (m, 4H), 6.72-6.64 (m, IH), 5.84 (d, 1H), 4.20 (d, 0.5H), 4.08-4.04 (m, IH), 3.92-3.85 (m, 1.5H), 3.76-3.71 (m, IH), 3.69-3.63 (m, IH), 3.46 (d, 2H), 0.99-0.95 (m, 3H). MS (El) for C20Hi9F31N3O4: 550 (MH4). EXAMPLE 20(i). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phetiyl}carbonyl) [l-(dimethylamino)ethyl]azetidin ol: ‘HNMR (400 MHz, d6-DMSO): 9.45 (s, IH), 8.61 (d, IH), 7.60 (d, IH), 7.39 (d, IH), 7.38-7.33 (m, IH), 7.24-7.18 (ra, IH), 7.05 (s, IH), 6.73-6.66 (m, IH), 4.48 (d, 0.5H), 4.36 (d, 0.5 H), 4.26 (d, 0.5H), 4.16-4.11 (m, IH), 4.00-3.94 (m, IH), 3.86 (d, 0.5H), 3.60-3.54 (m, IH), 2.75-2.70 (m, 3H), 2.66-2.62 (br s, 3H), 1.22 (dd, 3H). MS (El) for C2oH2,F3IN302: 520 (MH4). EXAMPLE 20(g). 1-((3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl}carbonyl) (l-nitropropyl)azetidin ol: ‘H NMR (400 MHz, CD3OD): 7.46 (m, 1H), 7.35 (m, IH), 7.28 (m, IH), 7.07 (m, IH), 6.61 (m, IH), 4.65 (m, IH), 4.44 (m, IH), 4.25 (m, IH), 4.02 (m, IH), 3.86 (m, IH), 2.04 (m, IH), 1.76 (m, IH), 0.94 (m, 3H). MS (El) for Ci9Hi7F3IN3O4: 536 (MH4). 226 EXAMPLE 20(h). 3-(l-aminopiOpyl)-l-({3,4-difluoiO ['(2“fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol: Yl NMR (400 MHz, CD3OD): 7.45 (m, 1H), 7,34 (m, IH), 7.28 (ra, IH), 7.05 (m, 1H), 6.61 (ra, 1H), 4.21 (m, IH), 4.09-3.86 (ra, 2H), 3.78 (m, 1H), 2.63 (m, 1H), 1.50 (ra, 1H), 1.24 (ra, 1H), 0.98 (ra, 3H). MS (El) for

CigHicONaCb: 506 (MH*). EXAMPLE 20(i). 1 -({3,4-diflnoro [(2-fluoro iodophenyl)araino]phenyl}carbonyl) [ 1 -(ethylamino)propyl]azetidin-3~ol: Yl NMR (400 MHz, CD3OD); 7.45 (m, 1H), 7.34 (ra, 1H), 7.28 (ra, 1H), 7.05 (ra, 1H), 6.61 (m, 1H), 4.23 (ra, 1H), 4,02 (m, 1H), 3.90 (ra, 1H), 3.79 (m, 1H), 2.70 (ra, 1H), 2.54 (m, 1H), 1.53 (m, 1H), 1.40 (ra, 1H), 1.05 (m, 3H), 0.95 (m, 3H). MS (Ε&amp;#938;) for C21H23E3IN3O2: 534 (MH*). EXAMPLE 20(j). 3“l l-(diethyIammo)piOpyl]-l-({3,4-difluoro [(2-fluoro lodophenyl)amino] phenyl }carbonyl)azeti din ol: *H NMR (400 MHz, CD3OD): 7.44 (ra, 1H), 7.33 (ra, 1H), 7.27 (m, 1H), 7.07 (m, 1H), 6.60 (ra, 1H), 4.21 (ra, 1H), 4.10 (m, IH), 4.03-3.70 (ra, 2H), 2.71-2.45 (ra, 5H), 1.67 (ra, 1H), 1.49 (m, 1H), 0.94 (m, 9H). MS (El) for C23H27F3IN3O2: 562 (MH*). EXAMPLE 20(k). 3-[amino(phenyl)raethyl] -1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidm ol):· MS (El) for C23H19F3IN3O2: 554 (MH*). EXAMPLE 20(m). 1 -({3,4-difiuoro [(2-fluoro iodophenyl)araino]phenyl}carbonyl) (3-methyl-l-nitrobntyl)azetidin ol): NMR (400MHz, CDCI3): 8.38 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (ra, 1H), 7.14-7.10 (ra, 1H), 6.84-6,77 (ra, 1H), 6.63-6.58 (ra, 1H), 4.68 (dd, 1H), 4.23-4.04 (br m, 4H), 2.13 (t, 2H), 1.64-1.44 (br m, 3H), 0,93 (d, 6H); MS (El) for C21H21F3IN3O4: 564 (MH*). EXAMPLE 20(n). 3-(l-arainobutyl)-l-({3,4-diflnoro [(2-fiuoro iodophenyl)amino]phenyl)carbonyl)azetidin ol acetate salt: Yl NMR (400 MHz, CD3OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d, IH), 7.32-7,26 (m, 1H), 7.09-7.00 (q, IH), 6.66-6.58 (t, 1H), 4.33-4.22 (d, 1H), 4.13-3.81 (ra, 3H), 3.17-3.09 (t, 1H), 1,93-1.89 (s, 3H), 1.89-1.82 (t, 3H), 1.56-1.24 (ra, 4H), 0.97-0.88 (t, 3H); MS.(EI) for C20H21F3IN3O2: 520 (MH*). EXAMPLE 20(o). 3-(l-aminocyclopentyl)-l-({3,4-difluoro [(2-flnoro iodophenyl)amino]phenyl}carbonyl)azetidin ol acetate salt: !H NMR (400 MHz, CDCI3): 8.27-8.21 (s, 1H), 7,42-7.36 (d, 1H), 7.34-7.29 (d, 1H), 7,15-7.09 (t, 1H), 7.09-7.01 (q, 1H), 6.88-6.79 (q, 1H), 6.63-6.53 (ra, 1H), 4.18-3.92 (ra, 4H), 2.12-2.08 (s, 3H), 2.06-1.70 (ra, 7H), 0.92-0.68 (ra, 4H); MS (Ε&amp;#938;) for CzftiFsINaCh: 532 (MH*). EXAMPLE 20(p). A-{l-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydiOxyazetidin yl]ethyl}acetamide: iH NMR (400 227 MHz, CDC13): 8.42 (s, IH), 7.41-7.38 (dd, IH), 7.34-7.32 (dt, IH), 7.12-7.09 (m, IH), 6.85- 6.78 (m, IH), 6.63-6.57 (m, IH), 5.76 (b, IH), 4.28-3.98 (ra, 5H), 2.00 (s, 3H), 1.20-1.19 (d, 3H); MS (Ε&amp;#938;) for C20Hi9F31N3O3: 534 (MH4), EXAMPLE 20(q). (2R)-7V-{l-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin“3“yl3ethyl}-3,353-trifluoiO-2~ (methyloxy) phenylpropanamide: JH NMR. (400 MHz, CDCB): 8.47 (s, IH), 7.45-7.40 (m, 5H), 7,33-7.31 (m, IH), 7,21-7.19 (m, IH), 7.12-7.05 (m, IH), 6.85-6.76 (m, IH), 6,63- 6,58 (m, IH), 4.20-3.99 (m, 5H), 3.36 (s, 1.5H), 3.34 (s,1.5H), 1.27-1.25 (d, 1.5H), 1.24-1.22 (d, L5H); MS (El) for C28H24F6IN3O4: 708 (MH4). EXAMPLE 20(r). (2R)Y-{(lR)-l-[l-({3,4-difluoro [(2-fluoro-4~ iodophenyI)amino]phenyl}carbonyl) hydroxyazetidm~3-yl]ethyl}-3,3,3-tnfluoro (methyloxy) phenylpropanamide: ]H NMR (400 MHz, CDCB): 8.49 (s, IH), 7.46-7.391 (m, 5H), 7.33-7.31 (m, IH), 7.21-7.16 (m, IH), 7.14-7.10 (m, IH), 6.85-6.79 (m, IH), 6.64- 6,58 (m, IH), 4.24-4.00 (m, 5H), 3.35 (s, 3H), 1.25-1.23 (d, 3H); MS (El) for C28H24F6IN3O4: 708 (MH4). EXAMPLE 20(s). l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (l -methyl-l-nitroethyl)azetidin ol: *HNMR (400 MHz, CDC13): 8.28 (s, IH), 7.4L7.38 (dd, IH), 7.34-7.32 (dt, IH), 7.14-7.10 (m, IH), 6.87-6,81 (m, IH), 6.64-6.59 (m, IH), 4.33-4.15 (m, 4H), 1.64 (s, 6H); MS (Ε&amp;#938;) for CI9Hi7F3IN3O4: 536 (MH4). EXAMPLE 20(t). 3-( 1 -amino-1 -methylethyl)-1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carhonyl)azetidin ol: NMR (400 MHz, CDCB): 8.30 (s, IH), 7.39-7.36 (dd, IH), 7.32-7,30 (dt, IH), 7.13-7.09 (m, IH), 6.85-6.79 (m, IH), 6.62-6.56 (m, IH), 4.25-3.97 (m, 4H), 1.14 (s, 6H); MS (El) for Ci9HI9F3IN3O2: 506 (MH4). EXAMPLE 21 l-({3,4-Difluoro [(2-fl«oro iodophenyl)amiao]phenyl}carbonyl)-3“{l“[(Zraws hydroxycyclohexyl)amino]ethyl}azetidin ol hydrochloride

<img img-format="tif" img-content="drawing" file="IL229136AD000292.tif" id="idf0092" />

<img img-format="tif" img-content="drawing" file="IL229136AD000293.tif" id="idf0093" />

[00326] Potassium A/7-butoxide (1.672 g, 14.9 mmol) and ethyltriphenylphosphonium bromide (5.538 g, 14.9 mmol) were stirred in ether (30 mL) at amibient for 1 h, 228 1,1-Dimethylethyl 3-oxoazetidine-l-carboxylate (954 mg, 6.0 mmol), prepared usmg procedures similar to those described in Example 3, was added and the mixture was 35 °C for 4,5 h. Mixture was filtered through celite and the solid was washed with ether. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ether in hexanes) gave LLdimethylethyl 3- ethylideneazetidine-l-carboxylate (506 mg, 2.76 mmol, 49% yield): NMR (400 MHz, CDCb): 5.37-5,28 (m, IH), 4.47-4,39 (m, 4H), 1.56-1.51 (m, 3H), 1.45 (s, 9H).

[00327] 1,1-Dimethylethyl 3-ethylideneazetidine-l-carhoxylate (506 mg, 2.76 mmol), and 4- methylmorpholine V-oxide (1,04 g, 8.89 mmol) were dissolved in acetone / water (4:1; 30 mL) and osmium tetroxide (2.5 wt,% in /-butanol; 0.2 mL) was added. The solution was stirred at ambient for 5 days, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The aqueous portion was extracted with ethyl acetate, The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave l,l-dimethylethyl 3-hydroxy (1-hydroxyethyl)azetidine-l-carboxylate (375 mg, 1.73 mmol, 63% yield): !H NMR (400 MHz, CDCb): 4.00-3,77 (m, 5H), 2.65 (br s, IH), 1.86, (br s, lid), 1.44 (s, 9H), 1.25 (d, 3H). [00328] 1,1 -Dimethylethyl 3-hydroxy (l -hydroxyethyl)azetidine-1 -carboxylate (200 mg, 0.922 mmol) was dissolved in methanol (5 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-(l-hydroxyethyl)azetidin ol hydrochloride (0.922 mmol).

[00329] 3,4-Difluoro [(2-fluoro iodophenyi)amino]benzoic acid (362 mg, 0.921 mmol), prepared using procedures similar to those described in US 7,019,033, 4-(dimethylamino)pyridine (337 mg, 2.76 mmol) and l-(3-dimethylaminopropyi)- 3- ethylcarbodiimide hydrochloride (212 mg, 1.11 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(l-hydroxyethyl)azetidin ol hydrochloride (0.922 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 80% ethyl acetate in hexanes) gave l-({3,4-difluoro [(2-fluoro- 4- iodophenyl)amino]phenyl}carbonyl)“3-(I-hydroxyethyI)azetidin oI (296 mg, 0.602 mmol, 65% yield): MS (El) for C^H^jINzOj·. 493 (MH*)· 229 [00330] 1 -({334-“Difluoro-2“[(2~fluoiO iodophenyI)amino]phenyl}carbonyl)- 3-(l-hydiOxyethyl)azetidin ol (267 mg, 0,543 mmol), was dissolved in dichloromethane (10 mL) and treated with 4~(dimethylamino)pyridine (80 mg, 0.661 mmol) and 2.4.6- triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) at ambient for 15 h. Triethylamine (0,076 mL, 0.545 mmol) was added and the mixture was stirred at ambient for 3 h and then at 35 °C for 4 h and then at ambient for a furhter 15 h. 2.4.6- Triisopropylbenzenesulfonyl chloride (110 mg, 0.363 mmol) was added and the mixture was stirred at 35 °C for 3 h and then 4-(dimethylamino)pyridine (80 mg, 0.661 mmol) was added and the mixture was stirred at 35 °C for 2 h. 2,4,6-

Triisopropylbenzenesulfonyl chloride (303 mg, 1,0 mmol) was added and the mixture was stirred at 35 °C for a furhter 18 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 30-50% ethyl acetate in hexanes) to give l-[l-({3,4-difluoro-2~[(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]ethyl 2.4.6- tris(l-methylethyl)benzenesulfonate (201 mg, 0.265 mmol, 49% yield): MS (El) for CssHjsFjINjOsS: 759 (MH4)· [00331] l~[l-({3,4-Difluoro-2“[(2~fluoro-4~iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin ylJethyl 2,4,6-tris(l-methylethyl)benzenesulfonate (194 mg, 0.256 mmol) was dissolved in tetrahydrofuran (2 mL) and was cooled to 0 °C. Sodium hydride (60 wt% dispersion in oil; 31 mg, 0.775 mmol) was added and the mixture was stirred at 0 °C for 15 minutes. The mixture was quenched with saturated sodium bicarbonate solution and partitioned with ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 2,3-difluoroW-(2-fhjoro iodophenyl)-6~[(2~methyl-1 -oxa azaspiro[2.3]hex yl)carbonyl]anilme (120 mg, 0.253 mmol, 99% yield): MS (Ε&amp;#938;) for 475 (MH4).

[00332] 2,3-Difluoro-Az-(2-fiuoro iodophenyl) [(2-methyl-l-oxa azaspiro[2.3]hex~5-yl)carbonyl]aniline (50 mg, 0.105 mmol) was dissolved in dimethylsulfoxide (0.8 mL) and treated with irans, cyciohexanolamine (70 mg, 0.609 mmol) with 100 W microwave power at 100 °C for 45 minutes. The mixture was purified by reverse phase HPLC and the clean fractions were combined, neutralized with saturated sodium bicarbonate solution and the organic solvent was removed in vacuo. The remaining aqueous residue was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was 230 treated with aqueous hydrochloric acid and then was lyophilized to afford l-({3,4-difluoiO [(2-fluoro iodophenyl)amino] phenyl} carbony 1) {1 -[(?rcms hydroxycyclohexyl)amino]ethyl}azetidin ol hydrochloride (36 mg, 0,058 mmol, 55% yield): 'H NMR (400 MHz, ds-DMSO): 8.61 (br s, 0.5H), 8.55 (br s, 0.5H), 8.49-8.33 (m, IH), 8.08-7.90 (m, IH), 7.59 (dd, IH), 7.39 (br d, IH), 7.37-7.30 (m, IH), 7.21 (br q, IH), 6.81 (br d, 1H), 6.77-6.65 (m, IH), 4.20 (br d, IH), 4.09-4.02 (m, IH), 3.97 (br d, IH), 3.93- 3.80 (m, IH), 3.62-3.47 (m, IH), 3.03-2.90 (m, IH), 2.07-1.93 (m, 2H), 1.93-1.77 (m, 2H), 1.54-1.06 (m, 8H); MS (El) for C24H27F3IN3O3: 590 (MH).

[00333] EXAMPLE 21(a). Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compound of the invention was prepared: 1 -({3,4-Difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) { 1-[(l,l-dimethylethyl)amino]ethyl}azetidin ol: SH NMR (400 MHz, de-DMSO); 8.63 (br s, 0.4H), 8.53 (br s, 0.6H), 7,56 (dt, IH), 7.40-7.34 (m, IH), 7.32-7.26 (ra, 1H), 7.25-7.13 (m, IH), 6.72-6.62 (ra, IH), 5,43 (br s, IH), 4,14-3.56 (m, 4H), 2.69-2.53 (m, IH), 1.00-0.85 (br, 12H); MS (El) for C^HssFsINsOz: 548 (ΜΗ*). EXAMPLE 22(a) and 22(b) l~({3,4-difluor0-2“[(2-fluoro-4~i0d0phenyI)annn0]phenyI}carbonyI) [(2R)-piperidin~2- yl]azetidra-3~ol

<img img-format="tif" img-content="drawing" file="IL229136AD000294.tif" id="idf0094" />

l-({3,4-diflu0r0 [(2-fluor0 i0d0phenyl)amin0]phenyl}carbonyl)“3“[(2S)-piperidin ylJazetidin ol

<img img-format="tif" img-content="drawing" file="IL229136AD000295.tif" id="idf0095" />

231 [0O334J To a solution of LI-dimethylethyl 2-(3-hydiOxy-l- {[(phenylmethyl)oxy]carbonyl}azetidin yl)piperidine-l-carboxylate (368 mg, 0.94 mmol), prepared using procedures similar to those described in Reference 5, in dichioromethane (5 mL) was added DMAP (115 mg, 0.94 mmol) and the resulting solution was cooled to 0°C. (7?)-(-)-oi-Methoxy-a~trifluoromethylphenyiacetyl chloride (105 pL, 0.56 mmol) was added to the solution by syringe and the mixture was allowed to warm to room temperature then stirred an additional 12 hours. The solution was then partitioned with saturated aqueous soldium bicarbonate and the organic phase dried over anhydrous magnesium sulfate then filtered and concentrated to an oily residue. Silica gel flash chromatography using hexanes:ethyl acetate 3:1 as eluent afforded the less polar 1,1-dimethylethyl (2/0 (1-{[(phenylmethyl)oxy] carbonyl} {[(2/0-3,3,3~trifluoro (methyloxy) phenylpropanoyl]oxy}azetidin yl)piperidine-l-carboxylate (27.5 mg, 5% yield), the more polar 1,1-dimethylethyl (20) (l-{[(phenyImethyl)oxy]carbonyl} {[(2/?)-3,3,3-trifluoro (methyloxy) plienylpropanoyl]oxy}azetidin yl)piperidme-l-carboxylate (105 mg, 19% yield) and starting material (253 mg, 69% recovery), [00335] The starting material thus recovered was taken into dichioromethane (3 mL) followed by addition of DMAP (115 mg, 0.94 mmol) and (70-(~)~a-methoxy-ct-trifiuoromethylphenylacetyl chloride (105 pL, 0.56 mmol) and the mixture was allowed to stir at room temperature over 12 hours. Proceeding as before afforded combined 1,1-dimethylethyl (2R)-2~(1 - {[(phenyl methy l)oxy] carbonyl} {[(270-3,3,3-trifluoro- 2- (methyloxy) phenylpropanoyl]oxy} azetidin-3 -yl)piperidine- 1-carboxylate (46,6 mg, 8% yield), the more polar 1,1-dimethylethyl (25) (l-{[(phenylmethyl)oxy]carbonyl} {[(2/2)-3,3,3-trifiuoro (methyloxy) phenylpropanoyl] oxy} azetidin-3 -yl)piperidine-1 -carboxylate (228 mg, 41% yield) and starting material (100,8 mg, 27% recovery).

[00336] The starting material thus recovered was taken into tetrahydrofuramdichloromethane (1:1,2 mL) followed by addition of DMAP (47 mg, 0.39 mmol) and (R)-(~)-a-mefhoxy-a-trifluoromethylphenylacetyl chloride (80 pL, 0.43 mmol) and the mixture was heated to 60 °C over 12 hours. Proceeding as before afforded combined less polar 1,1-dimethylethyl (2/?) (l-{[(phenylmethyl)oxy]carbonyl} {[(2/?)-3,3,3-trifluoro (methyloxy) phenylpropanoyl]oxy} azetidin-3 -yl)piperidine-1 -carboxylate (144 mg, 26 % yield). The chiral ester derivatives thus obtained were again subject to silica gel Hash chromatography using hexanes:ethyl acetate 3:1 as eluent to give the pure less polar 1,1 -dimethylethyl (2/0 (1 -{[(phenylmethyl)oxy]carbonyl} -3 [(270-3,3,3-trifluoro (methyloxy) phenylpropanoyl]oxy}azetidin yl)piperidine-l-carboxylate (122.8 mg, 22% 232 yield) and the more polar 1,1-dimethylethyl (26) (1 -{[(phenylmethyl)oxy] carbonyl} {[(2/2)-3,3,3-trifluoro (methyloxy)-2“phenylpropanoyl]oxy}azetidin-3~yl)piperidine~l-carboxylate (177.6 mg, 32% yield) both as colorless amorphous residues.

[00337J 1,1 -Dimethylethyl (2/2) ( 1 -{[(phenylmethyl)oxy3carbonyl} {[(2/2)-3,3,3- trifluoro (methyIoxy) phenylpropanoyl]oxy} azetidin-3~yl)piperidine-1 -carboxylate (122.8 mg, 0.21 mmol) was taken into methanol (4 mL) followed by addition of 1M aqueous sodium hydroxide (1 mL) and the resulting solution was stirred for one hour at room temperature. The solution was then partitioned with ethyl acetate and IN aqueous hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. The residue was purified by silica gel flash chromatography using hexanes:ethyl acetate 2:1 to give 1,1-dimethylethyl (2/2) (3-hydroxy-1 -([(phenylmethyl)oxy]carbonyl }azetidin yl)piperidine-l -carboxylate (60.8 mg, 81 % yield) a colorless amorphous solid. 1,1 -dimethylethyl (26) (3-hydroxy-1 -{[(phenylmethyl)oxy]carbonyl}azetidin yl)piperidine-l-carboxylate (87.4 mg, 75% yield) was prepared analogously.

[00338] 1,1 -Dimethylethyl (2/2) (3-hydroxy-1 -{[(phenylmethyl)oxy]carbonyl}azetidin~ 3-yl)piperidine-l-carboxylate (60.8 mg, 0.16 mmol) and 10% Pd/C (30 mg) were taken into methanol (2 mL) and the mixture hydrogenated at ambient pressure for one hour. The suspension was then filtered through a celite pad and concentrated then dried in vacuo to a colorless solid. The solid amine was taken into THF (1 mL) followed by addition of DIPEA (42 pL, 0.24 mmol) and 3s4-difluoro [(2-fluoro iodophenyl)amino]benzoyl fluoride (63 mg, 0.16 mmol), prepared using procedures similar to those described in Reference 1, and the mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and 1 N aqueous hydrochloric acid and the organic layer washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate 3:2 as eluent afforded 1,1 -dimethylethyl (2/2) [1-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]piperidine-l-carboxylate (74.9 mg, 74% yield) as an amorphous solid. 1,1-Dimethylethyl (2/2) (1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]piperidine-l-carboxylate &amp;#905; NMR (400 MHz, CDCI3): 8.53 (br s, 0.5H), 8.40 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.3l(dt, 1H), 7.17-7.14 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.587 (m, 1H), 4.24-3.90 (m, 4H), 3.37-3.23 (m, 1H), 2.90-2.80 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (El) for C2SH29F3IN3O4.· 576 (M-CiH?*). 233 [00339] 1,1-dimethylethyl (2R) [l~({3,4-difluoro [(2~fiuoro~4- iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]piperidine-l -carboxylate (74.9 mg, 0.12 mmol) was taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane (1 mL) and the solution was stirred at room temperature for one hour. The solution was then concentrated and the residue partitioned with chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium· sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using ethyl acetate then concentrated aqueous ammonia in chloroform and methanol (0.1:10:1) as eluents afforded l-({3,4-difluoro [(2-fluoro iodophenyl)amino] phenyl} carbony 1)-3 -[(2J?)-piperidm yl] azetidin-3 -ol (57.3 mg) as a colorless amorphous solid. The free base was taken into methanol (1 mL) then brought to about pH 1 by addition of 4 N HCl in dioxane and the solution concentrated. The residue was triturated with ethyl ether to afford a suspension. The solid was collected by filtration to afford l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(2R)-piperidin yl]azetidin ol hydrochloride salt (49 mg, 72% yield) as a colorless solid. Tl NMR (400 MHz, CDC13): 8.43-8.39 (d, 1H), 7.41-7,38 (dd, 1H), 7.33-7.3l(dt, 1H), 7.14- 7.10 (m, 1H), 6.84-6.80 (m, 1H), 6.63-6.57 (m, 1H), 4.12-3.99 (m, 4H), 3.10-3.08 (d, 1H), 2.72-2.69 (d, 1H), 2.64-2.62 (m, IH), 1.61-1.58 (m, 2H), 1.36-1.16 (m, 4H); MS (El) for- . C2tH2iF3lN3O2: 532 (MH+).

[00340] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 22(c). 1,1-dimethylethyl (2S) [l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]piperidine-l-carboxylate: NMR (400 MHz, CDC13): 8.52 (br s, 0.5H), 8,39 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.3l(dt, 1H), 7.17-7.12 (m, 1H), 6.85-6.79 (m, 1H), 6.63-6.57 (m, 1H), 4.25-3.88 (m, 4H), 3.34-3.26 (m, 1H), 2.80-2,90 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (El) for C26H29F3IN3O4: 576 (M-C4H94). EXAMPLE 22(d). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(2S)-piperidin yl]azetidin ol hydrochloride: ]H NMR (400 MHz, d4-Methanol): 7.49- 7.46 (dd, 1H), 7.37-7.35(dt, 1H), 7.35-7.30 (m, IH), 7.10-7.04 (m, 1H), 6.64-6.59 (m, 1H), 4.39-4.32 (dd, IH), 4.21-4.18 (dd, 1H), 4.13-4.07 (m, 1H), 3.97-3.88 (dd, 1H), 3.57-3.32 (m, 1H), 3.02-2.96 (dd,lH), 1,90-1.50 (m, 7H); MS (El) for C2iH2IF3IN3O2: 532 (MH4). EXAMPLE 22(e). 1 -({2-[(4-bromo chlorophenyl)amino] -3,4-difluorophenyl }carbonyl) piperidin ylazetidm Ol acetate salt: 3H NMR (400 MHz, CD3OD): 7.56 (d, 1H), 7.29- 234 7.38 (m, 2H), 7.08-7.16 (m, IH), 6.64-6.70 (m, 1H), 4.30-4.40 (m, IH), 4.18-4.26 (m, 1H), 4.04-4.14 (m, 1H), 3.90-4.00 (m, 1H), 3.16-3.26 (m, 2H), 2.86-2.96 (m, 1H), 1.91 (s, 3H), 1.76-1.88 (m, 3H), 1.44-1.64 (m, 3H). MS (El) for C2,H2iBrClF2N3O2: 500 (M-H). EXAMPLE 22(f). l-((2-[(4-bromo fluorophenyl)amino]-3,4-difluorophenyl}carbonyl) piperidin ylazetidm ol acetate salt: ‘H NMR (400 MHz, DMSO): 8.52 (br s, 1H), 7.50 (d, 1H), 7.35-7.15 (m, 3H), 6.88-6.79 (m, 1H), 4.15-3.96 (m, 1H), 3.84-3.78 (m, IH), 3.68-3.63 (m, 1H), 2.95-2.88 (m, 1H), 2.48-2.40 (m, 2H), 1.71-1.42 (m, 3H), 1.25-1.14 (m, 2H), 1.03-0.90 (m, 1H); MS (El) for C2iH2iBrF3N3O2:485 (MH+). EXAMPLE 22(g). 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) pyrrolidin ylazetidm ol: 'H NMR (400 MHz, CD3OD): 7.45 (dd, 1H), 7.37-7.31 (m, 1H), 7.30-7.25 (m, 1H), 7.13-6.99 (m, 1H), 6.67-6.54 (m, 1H), 4.20-4.09 (m,lH), 4.08-3.91 (m, 2H), 3.88-3.79 (m, 1H), 3.27 (t, 1H), 2.99-2.89 (m, 1H), 2.88-2.81 (m, 1H), 1.93-1.67 (m, 3H), 1.55-1.42 (m, 1H). MS (El) for C20H,9F3IN3O2: 518 (MH+) EXAMPLE 22(h). 1-((3,4-difluoro [(2-fluoro iodoplienyl)amino]phenyl} carbonyl)-3 -(l-metbylpyrrolidin yl)azetidin ol acetate (salt): *HNMR (400 MHz, CD3OD): 7.46 (dd, 1H), 7.38-7.26 (m, 2H), 7.12-6.99 (m, 1H), 6.66-6.56 (m, 1H), 4.37-3.87 (m,4H), 2.94- 2.82 (m, 1H), 2.75-2.63 (m, 3H), 2.20-2.06 (m, 1H), 2.00-1.67 (m, 8H). MS (El) for C2,H2iF3IN3O2: 532 (MH4). EXAMPLE 22(&amp;#943;). 1 -({3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl}carbonyl) (l-ethylpyrroHdin yl)azetidin ol acetate (salt): ’ll NMR (400 MHz, CD3OD): 7.46 (d, 1H), 738-733 (m, IH), 732-7.27 (m, IH), 7.12-7.01 (m, IH), 6.66-6.57 (m, IH), 434-3.89 (m,4H), 3.57 (t, 1H), 3.51-3.40 (m, 1H), 3.28~2.81(m, 3H), 2.25-1.72 (m, 8H), 131-1.18 (m, 3H). MS (El) for C^H^INsCb; 546 (MH4). EXAMPLE 22(j). 1 -({4“fiuoro [(2-fluoro iodophenyl)amino'j ~ 1 -methyl-1 /7-benzimidazol yl}carbonyl) [(2S)-piperidin yl3azetidin ol acetate salt: *H NMR (400 MHz, d4-MeOH): 830 (s, 1H), 7.56 (s, IH), 7.42 (d, IH), 7.24 (d, 1H), 6.34 (m, IH), 4,20 (d, 2H), 3.92 (s, 3H), 3.38-3.24 (m, 3H), 3.08 (bs, IH), 2.88 (bs (IH), 1.90-1.70 (m, 3H), 1.66-132 (m, 3H); MS (El) for C23H24F2IN5O2: 568 (MH4). EXAMPLE 22(k), 1 -({7-fiuoro [(2-fluoro iodophenyl)ammo] -1 -methyl benzimidazol yl}carbonyI) [(2S)-pipendm~2-yl]azetidin-3~ol acetate salt: A NMR (400 MHz, d4-MeOH): 8.22 (s, IH), 7.60 (s, IH), 7,42 (d, IH), 7.26 (d, IH), 6.46 (m, IH), 4.21 (d, 2H), 4.06 (s, 3H), 3.88 (m, IH), 338-3.24 (m, 3H), 3.10 (bs, IH), 2,88 (bs (1/7), 1.88-1.70 (m, 3H), 1.64-1.28 (m, 3H); MS (El) for C23H24F2IN5O2: 568 (MH4). 235 EXAMPLE 22(m). 4-[(4-biOmo fluorophenyl)amino] fluoiO ( {3 ~hydroxy [(2S)-piperidin yl]azetidin-l-yl}carbonyl)-l-methylpyridin-2(lH)“one: MS (El) for C2|H23BrF2N403: 498 (MH+). EXAMPLE 22(n). l-({8-chIoro [(2-fluoro iodophenyl)amino]imidazo[l,2-a)pyridin yl}carbonyl) [(2S)-piperidin yl]azetidin ol: 'H NMR (400MHz, d6-DMSO): 8.79 (s, IH), 8.04 (d, IH), 7.91 (d, IH), 7.64 (dd, IH), 7.55 (d, IH), 6.95-7.02 (m, IH), 4.38 (d, IH), 4.15 (dd, IH), 3.99 (dd, IH), 3.72 (q, IH), 3.32-3.39 (m, IH), 3.00-3.12 (m, IH), 1.93 (t, 3H), 1.51-1.70 (m, 3H); MS (El) for C22H22C1FIN5O2: 532 (MH4). EXAMPLE 22(o). l-({7-[(4-bromo chloiOphenyl)amino’] chloroinndazo[l,2-a]pyridin- 6-yl)carbonyl) [(2S)-piperidin yl]azetidin oI: ‘H NMR (400MHz, d4-MeOH): 8.85 (s, IH), 8.06 (d, IH), 7.91 (d, IH), 7.71 (d, IH), 7.45 (d, IH), 7.01 (d, IH), 4.48 (d, IH), 4.10-4.27 (m, 2H), 3.87 (q, IH), 3.37 (d, 2H), 3.02 (s, IH), 1.88-1.94 (m, 3H), 1.58-1.69 (m, 3H); C22H22BrCI2N5O2: 540 (MH4). EXAMPLE 22(p). l-({6-[(4-biOmo chloiOphenyl)amino]“7-fluoro niethyl-l,2“ benzisoxazol yi}carbonyl) [(2S)-piperidin yl] azetidin ol: NMR (400MHz, CDC13): 8.50 (m, IH), 7.51 (d, IH), 7.42 (s, IH), 7.26 (dd, IH), 6.79 (dd, IH), 4.20-3.98 (br tn, 4H), 3,11 (d , IH), 2.77-2.50 (br m, 5H), 1.80-1.15 (br m, 6H); MS (El) for CzsHzjBrClFN^a: 537 (MH4), EXAMPLE 22(q). l-({3-fluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl) [(2S)-piperidin~2~yl] azetidin ol: jH NMR (400 MHz, d4-MeOH): 7,53 (2d, IH), 7.46 (m, 2H), 7.16 (t, IH), 6.86 (m, IH), 6,63 (m, IH), 4.36 (m, IH), 4.22 (ra, IH), 4.02 (ra, IH), 3.88 (ra, IH), 3.08 (d, IH), 2.66 (dd, IH), 2.56 (m, IH), 1.82 (bs, IH), 1.66 (d, IH), 1.58 (d, IH), 1.38 (m, 2H), 1.22 (ra, IH); MS (El) for C2iH22F2IN3O2: 514 (MH4). EXAMPLE 22(r). l-({4-fIuoro [(2-fiuoro iodophenyl)amino]phenyl} carbonyl) [(2S)-piperidin yl]azetidin ol: 3H NMR (400 MHz, dj-MeOH): 7.42 (2d, IH), 7.34-7.18 (ra, 4H), 6.46 (m, IH), 4.10 (m, 2H), 3.84 (m, 2H), 3.04 (d, IH), 2.52 (dd, 2H), 1.76 (bs, 0.5H), 1.58 (ra, 2.5H), 1.32 (m, 2H), 1.18 (m, 0.5H), 1.04 (m, 0.5H); MS (El) for C21H22F2IN3O2: 514 (MH4), EXAMPLE 22 (s). 5 - [(2-fluoro iodophenyl) amino] ( {3 -hydroxy-3 - [(2 S)-piperidin yl]azetidin-l-yl}carbonyl) methylpyridazin-3(2H)-one: 3H NMR (400MHz, dg-DMSO): 10.19 (s, IH), 7.78 (dd, IH), 7.59 (d, IH), 7.32 (t, IH), 5.95 (s, IH), 4.59 (q, IH), 4.13-4,27 (ra, 2H), 3,77 (d, IH), 3.62 (s, 3H), 3.02 (d, 2H), 2.71 (d, IH), 1.78 (s, IH), 1.68 (d, IH), 1.53 (d, IH), 1.32 (s, 2H), 1.17 (t, IH); MS (El) for C20H23FIN5O3: 528 (MH+). 236

Example 23 l"{[l“({3i4-difluoro-2“[(2-fluoro iodophenyl)ammo]pheiiyl}carbonyl)“3" hydroxyazetidin yl] methyl) “3-nitroguanid in e hydrochloride

<img img-format="tif" img-content="drawing" file="IL229136AD000296.tif" id="idf0096" />

<img img-format="tif" img-content="drawing" file="IL229136AD000297.tif" id="idf0097" />

Γ003411 To mixture of

F 2,3-difluoro-Ar-(2-fluoro-4“iodophenyl) (l“Oxa“5“ azaspiro[2,3]hex ylcarbonyl)aniline (0.15g, 0.33 mmol), prepared using procedures similar to those described in Example 21, and nitroguanidine (0.1 g, 1.00 mmol) in tetrahydrofuran (3.00 mL) an aqueous solution of sodium hydroxide (1,0 mL, 2.0 mmol) was added and the reaction mixture was stilted at 70 °C for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC. The fractions were collected, and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amdrphous residue, which was dissolved in methanol, and 4 N HCl in dioxane-'(80 pL, 0.33 mmol) was added to the solution, A white precipitate formed and was collected by filtration. The solid was washed with hexane, and dried to afford 76 mg (38%) l-{[l-({3,4~difiuoro [(2-fluoro-4b odophenyi)ammo]phenyi} carbonyl) YhydiOxyazetidinYyl] methyl) nitro guanidine hydrochloride. 'H NMR (400 MHz, tk-MeOH): 7.46 (2d, IH), 7.36 (m, IH), 7.29 (m, IH), 7.02 (m, IH), 6.63 (m, IH), 4.22 (m, IH), 4.01 (m, 2H), 3.86 (m, IH), 3.51 (d, 2H); MS (El) for C18HWF3INSO4: 565 (MH4).

[00342] EXAMPLE 23(a). Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: 1 -cyano {[ 1 -({3,4-difluoro [(2-fluoro iodophenyI)amino]phenyl}carbonyl)~3-hydroxyazetidin yI]methyl) guanidine hydrochloride. &amp;#905; NMR (400 MHz, d4-MeOH): 7.47 (2d, IH), 7.36 (m, IH), 7.27 (m, IH), 7.03 (m, IH), 6.63 (m, IH), 4.18 (m, IH), 3.98 (m, 2H), 3.80 (m, IH), 3.43 (s, 2H); MS (El) for Ci9Hi6F3IN6O2: 545 (MH4). 237 WO 2007/044515. EXAMPLE 24 6-( {3-[(e thylam in o)metliyl]-3~fluoroazetidin-l-yl} carbony 1)-2,3-(3 iflu0ro»/V-(2“flu0r0-4“ iodophenyl) aniline [00343] To 1,1 “dimethylethyl [(1-((3,4-difuoro [(2-fluoro- 4-iodophen.yl)amino]phenyl}carbonyl)“3-hydroxyazetidin yl]methyl}ethylcarbamate (27 mg, 0.044 mmol), prepared using procedures similar to those in Example 3 and followed by Boc-protection, in chloroform (2.5 mL) added DAST (11.8 pL, 0.089 mmol) and stirred for 3.5 hr at room temperature. Quenched with water (15 mL), partitioned phases and extracted aqueous phase with chloroform (2 X 15mL). The combined chloroform extracts were dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified on a silica gel column to afford 1,1-dimethylethyl [(1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) fluoroazetidin yl]methyl}ethylcarbamate (19.0 mg, 70%).

[00344] To the 1,1-dimethylethyl [(l-((3,4-difluoro [(2-fluoro

i odopheny l)amino] phenyl} carbonyl) fluoroazetidin yljmethyl}ethylcarbamate (19.0 mg, 0.031 mmol) in acetonitrile (1.0 mL) added a solution 4.ON hydrogen chloride in dioxane (1.0 mL). After l,5hr the solution was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to afford the title compound (4.30 mg, 27%), jH NMR (400MHz, CDCb): 8,25 (s, IH), 7.33 (dd, IH), 7.33-7.25 (m, IH), 7.18-7.14 (m, IH), 6.84-6.77 (m, IH), 6.63-6.58 (ra, IH), 4.33-4,05 (br m, 4H), 3.07-2.95 (br m, 2H), 2.65 (q, 2H), 1.08 (t, 3H); MS (Ei) for C19H1SF4IN3O: 508 (MH*). 238 EXAMPLE 25 3-(2-aminocyclohexyl)-l-({3,4-difluoro l(2-fluoro iodophenyl)amin0)phenyl}carbonyl)azetidin-3“oi

<img img-format="tif" img-content="drawing" file="IL229136AD000298.tif" id="idf0098" />

[00345] A solution of l-(trimethylsiloxy)cyclohexene (200 mg, 1,17 mmol) and benzyl 3-oxoazetidine carboxylate (289 mg, 1.41 mmol), prepared using procedures similar to those described in Reference 3, in tetrahydrofuran (3,90 mL) was cooled to -78 °C for 10 minutes followed by the addition of titanium tetrachloride (0.13 mL, 1.17 mmol). The reaction mixture stirred for an additional 5 hours at -78 °C. The mixture was quenched with aqueous sodium bicarbonate and the aqueous layer was extracted with ether (2x). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel chromatography column (3:2 hexanes/ethyl acetate) to afford benzyl 3-hydroxy (2-oxocyclohexyl)azetidine-l-carboxylate (328 mg, 37%) . *H NMR (CDC13): 7.28-7.34 (m, 5H), 5.08 (s, 2H), 4.02 (d, IH), 3.89 (d, 1Ι-&amp;#938;), 3.87 (s, IH), 3.55 (s, IH), 2.71 (q, IH), 2.29-2.43 (m, 2H), 2.11 (s, 2H), 1.95 (s, IH), 1.66 (d, 3H); MS (El) for C17H21NO4: 303 (MH+).

[00346] A solution of benzyl 3-hydroxy“3-(2-oxocyclohexyl)azetidine-l-carboxylate (100 mg, 330 mmol) in methanol (1.60 mL) in the presence of ammonium acetate (191 mg, 2.48 mmol was cooled to 0 °C for 1 hour. Sodium cyanoborohydride (81.5 mg, 1.30 mmol) was added and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 6 N hydrogen chloride (800 pL) and extracted with ethyl acetate. The aqueous layer was basified with aqueous sodium bicarbonate (pH 9) and extracted with dichioromethane. The combined organic portion was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford benzyl (2-aminocyclohexyl)“3~ hydroxyazetidine carboxylate (73,7 mg, 73%). MS (El) for Ci7H24N2O3: 305 (MH+). [00347] To a solution of benzyl (2-aminocyclohexy 1) hydroxyazetidine- 1-carboxylate (202 mg, 0.663 mmol) in dioxane-water (1:1, 2.5 mL) was added di-Zert-butyl dicarbonate (138 mg, 0.630 mmol) and solid sodium bicarbonate (112 mg, 1.33 mmol). The reaction mixture was stirred at room temperature for 2 hours and evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried 239 over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford benzyl 3-(2-terf~

butoxycarbonylamino)cyclohexyl) hydroxyazetidine-l-carboxylate (237 mg, 100%). A NMR (CH3OH): 7.15-7.21 (m, 5H), 5.45 (s, 0.5H), 5.20 (d, 0.5H), 4.95 (s, 2H), 4.81 (s, IH), 3.81 (d, 2H), 1.43-1.74 (m, 5H), 1.39 (s, IH), 1.31 (s, 11H), 1.20 (s, IH). MS (El) for C22H32N2O5: 405 (MH+).

[00348] A solution of benzyl 3-(2-tert-butoxycarbonylamino)cyclohexyl) hydroxyazetidine carboxylate (237 mg, 0.586 mmol) in ethyl acetate (2 mL) was hydrogenated over 10% palladium-carbon (200 mg, 0.586 mmol) at 40 psi for 16 hours. The reaction mixture was filtered and concentrated in vacuo to provide tert-butyl 2-(3-hydroxyazetidm yl)cyclohexylcarbamate (181 mg, 100%). NMR (CDC13): 5.10 (s, IH), 4.80 ((s, IH), 3.78-3.86 (m, IH), 3.61 (d, IH), 3.57 (s, IH), 3.36 (d, IH), 1.77 (s, 2H). 1.40-1.53 (m, IH), 1,36 (d, 9H), 1.25 (s, 2H). MS (El) for C14H20N2O3: 271 (MH+).

[00349] To a solution of tert-butyl 2-(3~hydroxyazetidin yl)cyclohexylcarbamate (181 mg, 0.669 mmol) and 3,4-difluoro (2-fluoro-4~iodophenylamino)benzoyl fluoride (265 mg, 0.669 mmol), prepared using procedures similar to those described in Reference 1, in tetrahydrofuran (2.2 mL) was added vYAMiisopropylethylamine (110 pL) at room temperature. After an hour, the reaction mixture was heated to 50 °C and stirred for 45 minutes, at which time it was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford /er/-butyl-2“(l-(3,4-difluoro (2-fluoro iodophenylamino)benzoyl) hydroxyazetidin yl)cyclohexylcarbamate. This crude material was taken into the next step without further purification, [00350] 7hr/-butyl (l-(3,4-difluoro (2-fluoro iodophenylamino)benzoyl)-3“ hydroxyazetidin yl)cyclohexylcarbamate was dissolved in a mixture of methanol (4 mL) and hydrogen chloride (4 M in dioxane) (3 mL). The solution was heated to reflux then cooled to room temperature and stirred for 16 hours. The reaction mixture was concentrated and purified by reverse phase HPLC. The purified fractions were evaporated to dryness and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil. Tlie residue was taken up in methanol (2 mL) and was added hydrogen chloride (4M in dioxane) (700 pL) and evaporated to dryness to afford die title compound 3-(2-aminocyclohexyl) ((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol hydrochloride (44.7 mg, 12%). 240 'H NMR (400MHz, d6-DMSO): 8.58 (d, IH), 7.59 (dd, IH), 7.54 (s, 2H), 7.38 (d, IH), 7.33 (t, IH), 7.16-7.25 (m, IH), 6.69 (dt, IH), 6.41 (s, IH), 4.26 (d, 0.5H), 4.17 (d, 0.5H), 4.04 (t, IH), 3.90 (t, IH), 3.79 (d, 0.5H), 3.65-3.73 (m, 0.5H), 3.45-3.51 (m, IH), 1.88 (s, IH), 1.65-1.88 (m, 2H), 1.47 (s, 4H), 1.16-1.37 (m, 2H); MS (El) for C22H23F3IN3O2: 546 (MH1)· [00351] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 25(c).3-(2-aminocyclopentyl)- 1 ~({3,4-difluoro~2-[(2~fluoro iodophenyi)amino]phenyl}carbonyl)azetidm ol; NMR (400MHz, ds-DMSO): 8.56 (d, IH), 7.82 (d, IH), 7.59 (td, IH), 7.45 (s, IH), 7.38 (d, IH), 7.30-7.35 (m, IH), 7.18-7.24 (m, IH), 6.68-6.72 (m, 1H0, 6.41 (s, 0.5H), 6.17 (s, 0.5H), 3.91-4.27 (m, 2.5H), 3.78-3.86 (m, IH), 3.65-3.73 (m, IH), 3.44-3.52 (m, 0.5H), 2.19-2.26 (m, IH), 1.54-1.94 (m, 5H), 1.30-1.39 (m, IH); MS (El) for C21H2iF3IN3O2: 532 (MH+). EXAMPLE 25(a) and EXAMPLE 25(b) (±)“l-({3,4-difluoro [(2-fluorO“4-iodophenyl)amino]phenyl}carbonyl)-3~[(trans) hydroxycyclohexyl] azetidin ol and (±)-1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl) [(cis) hydiOxycyclohexyljazetidin ol [00352] The compounds of examples 25a and 25b were synthesized starting from benzyl 3-hydroxy (2-oxycyclohenyl)azetidme-l-carboxylate prepared according to the procedure given in example 25, The ketone was reduced to give benzyl 3-hydroxy (2-hydroxycyclohexyl)azetidine-l-carhoxylate as a mixture of racemic diastereomers which were subjected to hydrogenation to afford 3-(2-hydroxycyclohexyl)azetidin ol. 3-(2-hydroxycyclohexy!)azetidin ol was then carried forward in a coupling step with 3,4-difluoro (2-‘fluoro iodophenylammo)benzoyl fluoride in the usual manner. The coupled material thus obtained was purified by preparative reverse phase HPLC where fraction 1 was tentatively assigned as (±)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(trans) hydroxycyclohexyl]azetidin ol (Example 25 a) and fraction 2 was tentatively assigned as (±)~ 1 -({3,4-difluoro [(2-fluoro~4-iodophenyl)amino]phenyl}carhonyl) [(cis) hydroxycyclohexyl]azetidin ol. EXAMPLE 25(a). First eluting fraction: NMR (400 MHz, cfr-MeOH): 7.44 (2d, IH), 7.34 (t, IH), 7.25 (m, IH), 7.03 (m, IH), 6.60 (m, IH), 4.46 (d, 0.5H), 4.28 (d, 0.5H), 4.22 (d, 0.5H), 3.98 (dd, IH), 3.89 (d, 0.5H), 3.85 (s, 0.5H), 3,77 (d, 0.5H), 3.56 (m, IH), 1.90 (m, IH), 1.46-1.74 (m, 4H), 0.98-1.32 (m, 4H); MS (Ε&amp;#938;) for C22H22F3IN2O3: 547 (MH*). 241 EXAMPLE 25(b). Second eluting fraction: 'H NMR (400 MHz, d4-MeOH): 7.44 (2d, 1H), 7.33 (d, 1H), 7.26 (m, 1H), 7.04 (m, 1H), 6.59 (dd, 1H), 4.20 (m, 1.5H), 4.19 (s, 0.5H), 4.00 (m, 1.5H), 3.86 (dd, 1H), 3.74 (d, 0.5H), 1.76 (m, 2H), 1.50-1.68 (m, 5H), 1.18-1.46 (m, 4H); MS (El) for CjjH^INzOj: 547 (MH4).

Example 26 3-(([(E)-l-amino nitroethenyl]ammo}methyl)-l-((3,4-difliioro [(2-flui)ro iodophenyl)ammo]phenyl}carbonyl)azetidm ol

<img img-format="tif" img-content="drawing" file="IL229136AD000299.tif" id="idf0099" />

[00353] A solution of 3-(aminomethyl)- 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol (0,24 g, 0,5 mmol), prepared using procedures similar to those described in Example 3, and commercially available 1,1-bis(methylthio) nitroethylene (0.083 g, 0,5 mmol) in ethanol (5 mL) was stirred at 70 °C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford 0.10 g, (39%) 1-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) (([(Z)-l-(methylthio)-2~ nitroethenyl]amino}methyl)azetidin ol. MS (El) for C20H18F3IN4O4S: 595 (MH*).

[00354] To a solution of (0.05 g 0.08 mmol) 1-((3,4-difluoro~2-[(2-fluoro iodopheny l)ammo] phenyl} carbonyl) ( {[(Z)~ 1 ~(methylthio) nitroethenyl]amino}methyl)azetidin ol in ethanol (2 mL) was added ammonium hydroxide (0.1 mL, 0.8 mmol) and the reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC, The fractions were collected and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was dissolved in methanol, and 4 N HCl in dioxane (40 pL, 0.16 mmol) was added to the solution. A white precipitate formed and was collected by vacuum filtration. The solid was washed with hexane, and dried to afford 42 mg (87%) 3-({[(E)-l-amino nitroethenyl]araino}methyl)-l-((3,4-difluoro [(2-242 fiuoro iodophenyl)amino]phenyl}carbonyl)azetidin ol hydrochloride. lHNMR (400 MHz, d4-MeOH): 7.58 (t, 0.5H), 7.44 (t, 0.5H), 7.36 (m, IH), 7.31 (m, IH), 7.04 (m, IH), 6,63 (m, IH), 3.90-4.30 (m, 4H) 3.72 (s, 2H); MS (El) for C19H17F3IN5O4: 564 (MH4). EXAMPLE 27 l-({3,4-difiu0ro“2“[(2-fl&lt;i0ro iodophenyl)amino]phenyl}carbonyl)“3-(lZlr-iinidazol-2“ yhnethyl)azetidm~3-ol

<img img-format="tif" img-content="drawing" file="IL229136AD0002100.tif" id="idf0100" />

[00355] A solution of 2-methyI“l-({[2-(trimethylsilyl)ethyl]oxy}methyl)-l/Y-imidazo]e (0.5 g, 2.3 mmol) (prepared using procedures similar to those described in Clader et. al. J, of Med, Chem, 1995, 38(10), 1600-7) in tetrahydrofuran (5 mL) was cooled to ~78 °C, and Yutyllithium was added (2.5 M in hexanes, 0.990 mL, 2.5 mmol), After 2 hours, 1,1-dimethylethyl 3-oxoazetidine-l-carboxylate (0.60 g, 3.5 mmol), prepared using procedures similar to those described in Example 3, in 2.0 mL tetrahydrofuran was added and the solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.37 g (41%) of 3-{[!-({[2-(trimethylsilyl)ethyl]oxy}methy 1)-lH-imidazol yl]methyl}azetidm oI: *H NMR (400 MHz, CDC13): 6.96-6.92 (m, IH), 5.23 (s, 2H), 3.98 (d, 2H), 3.79 (d, 2H), 3.52-3,47 (m, 2H), 3.13 (s, 2H), 1,43 (s, 9H), 0.94-0,88 (m, 2H), 0.00 (s, 9H).

[00356] 3-{ [ 1 -({[2-(trimethylsilyl)ethyl]oxy}methyl)- lH-imidazol yI]methyl}azetidin- 3-ol (0.19 g, 0,49 mmol) was dissolved in dichioromethane (1.5 mL) and trifluroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature overnight and the solvent was removed under vacuum to give 0.16 g of 3-(lH-imidazol~2-ylmethyl)azetidin ol trifluoroacetate salt (87%). The crude residue was used without further purification for the next step. 243 [00357] To a solution of 3-(l//-imidazol ylmethyl)azetidm ol trifluoroacetate salt (0.16 g, 0.42 mmol) and ^^-diisopropylethylamine (0.370 mL, 2.13 mmol) in tetrahydrofuran (2.0 mL) 3,4-difluoro [(2-fluoro iodophenyl)amino] benzoyl fluoride (0.17 g, 0.42 mmol), prepared using procedures similar to those described in Reference 1, was added and the reaction mixture was stirred for 3 hours at room temperature. The solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by reverse-phase HPLC followed by lyophilization of the pure fractions gave 0.032 g (13%) of 1 -({3,4-difluoro [(2-fluoro iodophenyl)ammo]phenyl} carbonyl) (1 /7Tmidazol ylmethyl)azetidin ol acetate salt: *H NMR (400 MHz, CD3OD): 7.45 (dd, IH), 7.38-7.33 (m, IH), 7.25-7.18 (m, IH), 7.08-6.96 (m, IH), 6.89 (s, 2H), 6.65-6.56 (m, IH), 4.33-4.22 (m, IH), 4.17-4.00 (m, 2H), 3.91-3.80 (m, IH), 3.08 (s, 2H), 1.96 (s, 3H). MS (El) for C20H16F3IN4O2: 529 (MH+). EXAMPLE 28 3-[( 17?)-1 -aminoethyl] -1 -({3,4-difluoro [(2-fluoro iodopbenyl)amino]phenyl}carbonyl)azetidin ol

<img img-format="tif" img-content="drawing" file="IL229136AD0002101.tif" id="idf0101" />

[00358] To a solution of diisopropylamine (6.5 mL, 46.3 mmol) in THF (200 mL) at -78 °C was added butyllithium (17 mL of a 2.5 M solution in hexanes, 42.5 mmol) over 5 min. The solution of lithium diisopropylamide was stirred for 15 min at-78 °C. A solution of (5) benzyl propionyl oxazolidinone (9.0 g, 38.6 mmol) in THF (100 mL) was added to the lithium diisopropylamide by addition funnel over 26 min. The reaction temperature was kept below -70 °C during the course of the addition. After the addition, the mixture was stirred for a further 30 min at -78 °C. Then phenylmethyl 3-oxoazetidine-l-carboxylate (9.5 g, 46.3 mmol) was added by addition funnel over 25 minutes as a solution in THF (100 mL). Again, the reaction mixture was kept below -70 °C during the reagent addition. After stirring for an additional 1 hour at -78 °C, the reaction mixture was quenched with saturated ammonium chloride solution and was then allowed to warm to rt. Water was added to dissolve any precipitated ammonium chloride, and ethyl acetate was added. The layers were partitioned, 244 and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (50% ethyl acetate: 50% hexanes) to provide phenylmethyl 3-hydroxy {(H?)-l-methyl oxo [(45) oxo (phenylmethyl)-l,3-oxazolidin yl]ethyl)azetidine“l-carboxylate as a white crystalline solid (6.03 g, 13.8 mmol, 36% yield). *H NMR (400 MHz, CDCl·,) δ 7.37 (m, 8H), 7.20 (d, 2Η), 5.12 (s, 2Η), 4.66 (m, 1Η), 4.27-4.20 (m, 2Η), 4.10 (q, 1Η), 4.03-3.93 (m, 3Η), 3.28 (dd, IH), 2.77 (dd, 1Η), 1.29 (d, 3Η).

[00359] A solution of lithium hydroxide monohydrate (1.16 g, 27.6 mmol) in 30% hydrogen peroxide (13.2 mL, 138 mmol) was prepared and was subsequently added slowly to a solution of phenylmethyl 3“hydroxy {(lR)-l-methyl oxo [(46) oxO“4-(phenylmethyl)-l,3-oxazolidin yl]ethyl}azetidine-l-carboxylate (6.03 g, 13.8 mmol) in THF (80 mL) and water (20 mL) at 0 °C. After the mixture was stirred for 1 h at rt, the hydrogen peroxide was quenched carefully with 1 M sodium sulfite (150 mL, 150 mmol).

The THF was removed in vacuo, and the mixture was then acidified to pH“2 with concentrated hydrochloric acid. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient, 5% methanol: 95% dichioromethane to 10% methanol: 90% dichioromethane) to provide (2λ) (3 -hydroxy-L{[(phenyImethyl)oxy] carbonyl} azetidin yl)propanoic acid as a colorless oil (2.77 g, 9.9 mmol, 72% yield). NMR (400 MHz, CDC13) δ 7.37-7.31 (m, 5H), 5.10 (s, 2H), 3.99 (s, 2H), 3.93 (s, 2H), 2.88 (q, IH), 1.28 (d, 3H); MS (El) for Ci4H17NO5: 280 (MH4).

[00360] To a solution of (2/7) (3 -hy droxy-1 [(pheny Imethy l)oxy] carbonyl) azetidin yl)propanoic acid (2.77 g, 9.9 mmol) in toluene (100 mL) was added triethylamine (1.52 mL, 10.9 mmol) followed by diphenyl phosphoryl azide (2,24 mL, 10,4 mmol). The mixture was heated to 80 °C for 2 h and was then cooled to rt. The volatile materials were removed in vacuo, and the residue was purified by column chromatography (gradient: 50% hexanes: 50% ethyl acetate up to 100% ethyl acetate). The desired product, (8/?) methyl oxo oxa-2,7-diazaspiro[3.4]octane-2~carboxylic acid phenylmethyl ester, was isolated as a viscous, colorless syrup (1.84 g, 6.6 mmol, 67% yield). !H NMR (400 MHz, CDC13) δ 7.39-7.32 (m, 5H), 5.66 (br s, IH), 5.12 (s, 2H), 4.34 (dd, IH), 4,30 (dd, IH), 4.17 (dd, IH), 4.05 (dd, IH), 3.98 (q, IH), 1.34 (d, 3H). 245 [00361] To a solution of (87?) methyl oxo- oxa-2.7-diazaspiro[3,4]octane carboxylic acid phenylmethyl ester (1.84 g, 6.6 mmol) in methanol (66 mL) was added wet 10% palladium on carbon (50% by mass, 500 mg). The resulting suspension was stirred under 1 atm of hydrogen for 1 h. The catalyst was then removed by filtration through celite.

The filtrate was concentrated in vacuo to provide (8/?) methyl-5“Oxa-2,7- diazaspiro[3.4]octan~6“one as a white solid (0.99 g, quantitative yield). NMR (400 MHz, CDCb) δ 5.23 (br s, IH), 4.07 (d, IH), 4.02 (d, IH), 3,92 (d, IH), 3.79 (d, IH), 3.58 (d, IH), 1.38 (d, 3H); MS (El) for C6Hi0N2O2: 143 (MH4).

[0Θ362] A solution of (8R)“8-methyl oxa-2,7-diazaspiro[3.4]octan one (937 mg, 6.6 mmol), acetic acid (0.756 mL, 13.2 mmol), and benzaldehyde (1.0 mL, 9.9 mmol) in methanol (65 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) at rt for 30 min. The mixture was then cooled to 0 °C, and 3 N hydrochloric acid (100 mL) was added. The methanol was then removed in vacuo. The resulting aqueous solution was washed with ethyl acetate. The ethyl acetate wash was back extracted with 1 N hydrochloric acid, and the aqueous acidic phases were combined and basified with potassium carbonate. The organic phase was discarded. The aqueous mixture was then extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired (8R) methyl (phenylmethyl) oxa-2,7-diazaspiro[3,4]octan-6~one was obtained in 93% purity as a milky colorless liquid (1.33 g, 5.73 mmol, 87% yield). MS (El) for C13H16N2O2: 233 (MH*).

[00363] To a solution of (8TY8-methyL2-(phenylmethy 1)-5x^xa-T,7~diazaspiro[3.4]octan- 6-one (1.33 g, 5.7 mmol) in dioxane (40 mL) and water (20 inL) was added barium hydroxide octahydrate (9.0 g, 28.5 mmol), and the mixture was heated to reflux for 2 h. After cooling to rt, the mixture was acidified with 3 N hydrochloric acid (10 mL) and dichloromethane (50 mL) was added. The biphasic mixture was treated with potassium carbonate (1.6 g, 11.4 mmol) and di-Wbutyl dicarbonate (2.11 g, 9.7 mmol). After stirring vigorously at rt for 17 h, solids were removed by filtration, and the layers were partitioned. The aqueous phase was extracted with dichloromethane, and the organic extracts were combined and dried over magnesium sulfate, filtered, and concentrated. The residue was taken up in methanol (60 mL) and was treated with potassium carbonate (3.0 g, 22 mmol) added in two portions over 4 h at reflux, After cooling, the methanol was removed in vacuo, and the residual solids were loaded directly on to a silica column. After purification (5% methanol: 95% dichloromethane), 1,1 -dimethylethyl {(12?)~1 -[3-hydroxy-1 -(phenylmethyl)azetidin 246 yl]ethyl}carbamate was obtained as a colorless syrup (1.07 g, 3.5 mmol, 62% yield), MS (EI) for CI7H26N2O3: 307 (MH*).

[00364] To a solution of 1,1-dimethylethyl {(17Q-l-[3-hydroxy-l-(phenylmethyl)azetidin yl)ethyl}carbamate (1.07 g, 3,5 mmol) in methanol was added wet 10% palladium on carbon (50% by mass, 250 mg). The resulting suspension was subjected to 1 atmosphere of hydrogen for 7 h, and an additional 250 mg of catalyst was added over the course of the reaction. The catalyst was then removed by filtration through celite. The filtrate was then concentrated in vacuo to provide 1,1-dimethylethyl [(l/?)-l-(3-hydroxyazetidin-3~ yl)ethyl]carbamate as a colorless syrup (800 mg, quantitative yield). MS (EI) for CioH2oN203: 161 (M - tort-butyl + H), [00365] To a solution of 1,1 -dimethylethyl [(!/?) (3-hydroxyazetidin-3 - yl)ethyl]carbamate (200 mg, 0.92 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (228 pL. 1.38 mmol) and 3,4-difluoro-2“[(2-fluoro-4“ iodophenyl)amino] benzoyl fluoride (prepared according to the procedures described in Reference 1) (363 mg, 0.92 mmol). The mixture was stirred at rt for 16 h, after which the volatile materials were removed in vacuo. The residue was purified by column chromatography (50% hexanes : 50% ethyl acetate) to provide 1,1-dimethylethyl {(1λ) [1 -({3,4-difluoro [(2~fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin-3~ yl]ethyl}carbamate as a colorless film (333 mg, 0.56 mmol, 61% yield). *H NMR (400 MHz, CDC13) δ 8.47 (br s, IH), 7.40 (dd, IH), 7.32 (d, IH), 7.12 (m, IH), 6.81 (m, IH), 6.61 (m, IH), 4.74 (brd, IH), 4.22 (d, IH), 4.15-4.07 (m, 2H),3.96 (br s, IH), 3.77 (m, IH), 1.43 (s, 9H), 1.18 (d, 3H); MS (EI) for C^HasWaCL: 536 (M - tort-butyl + H).

[00366] A solution of 1,1-dimethylethyl {(lA)-l-[l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl]ethyl}carbamate (333 mg, 0.56 mmol) in methanol (10 mL) was treated with hydrochloric acid (4 N in dioxane, 1,4 mL, 5.6 mmol) at 60 °C for 30 min. After cooling, the volatile materials were removed in vacuo to provide 3-[(l Λ) aminoethyl] ({3,4-difluoro [(2-fiuoro iodophenyl)amino]phenyl}carbonyl)azetidin ol hydrochloride as a white solid (285 mg, 0.54 mmol, 97% yield). ‘H NMR (400 MHz, DMSO-d6) δ 8.56 (s, IH), 7.83 (br s, 3H), 7.59 (dd, IH), 7.39 (d, IH), 7.34 (m, IH), 7.21 (q, IH), 6.69 (m, IH), 6.65 (s, IH), 4.25 (dd, IH), 4.10 (dd, IH), 3.98 (dd, IH), 3.80 (m, IH), 3.48 (m, IH), 1.11 (dd, 3H); MS (EI) for C18H17F3IN3O2: 492 (MH) [00367] To establish the enantiomeric excess (ee) of this material, 3 ~[(l/?)-l-aminoethyl] - l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin~3-ol 247 hydrochloride (21 mg, 0.040 mmol) was dissolved in dichloromethane (400 μΤ) and was treated with diisopropylethylamine (20 pL, 0.12 mmol) and (R) a-methoxy-a-(trifluoromethyl)phenylacetyl chloride at rt for 15 min. An aliquot was removed and was analyzed by chiral HPLC. The diastereomeric excess of (25)-N-((172) (1-((3,4-difluoro [(2-fluoro~4bodophenyl)amino]phenyl}carbonyl)~3“hydroxyazetidin~3~yl]ethyl}~3,3,3“ irifluoro (methyloxy)~2-phenylpropanamide was found to be 91%, and by extrapolation the ee of 3-[(11?) aminoethyl] ((3,4-difiuoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol was also assigned to be 91%.

[00368] Example 28a. Using the sequence described above, beginning with (/2) benzyl propionyl oxazolidinone, 3-((15)-1 -aminoethyl]-! -((3,4-difluoro ((2-fluoro iodophenyl)amino]phenyl}carbony!)azetidin ol was prepared using similar procedures except that the phenylmethyl 3-hydroxy {(15)-l-methyl oxo [(472) oxo (phenylmethyl)-l, 3-oxazoli din yl] ethyl} azeti dine-1 -carboxylate required additional recrystallizations from isopropanol. Using the same method described above in Example 28, 3-(( 15)-1 -aminoethyl] -1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol was determined to have 98,4% ee. ’H NMR (400 MHz, DMSO-d6) δ 8.56 (s, IH), 7.84 (br s, 3H), 7.59 (dd, IH), 7.39 (d, IH), 7.34 (m, IH), 7.21 (q, IH), 6.69 (m, IH), 6.65 (s, IH), 4.25 (dd, IH), 4.10 (dd, IH), 3.98 (dd, IH), 3.80 (m, IH), 3.48 (m, IH), 1.11 (dd, 3H); MS (Ε&amp;#938;) for 492 (MH1).

[00369] Example 28b. To 3-((15)-1 -aminoethyl] ((3,4-difluoro [(2-fluoro . iodophenyl)ammo]phenyl}carbonyl)azetidin ol (87.4 mg, 0.18 mmol), prepared using procedures similar to those described in Example 28, was added formaldehyde (37% aqueous, 14 mg, 0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol). The mixture was stirred for 3 h at rt, after which sodium borohydride (16 mg, 0.42 mmol) was added. Upon stirring an additional 1,25 h, more formaldehyde (37% aqueous, 1 drop) was added, and the mixture was stirred 3 days at rt. A further small spatula (-50 mg) of sodium borohydride was then added, and the mixture was stirred at rt for 30 min. After quenching with 1 N HCl, the reaction mixture was purified directly by preparative HPLC.

The clean material was converted to its hydrochloride salt to provide 1-((3,4-difluoro~2-[(2-fluoro iodophenyl)amino]phenyl}carbonyl) [(15)-l-(methylamino)ethyl]azetidin ol as a yellow solid (21,7 mg, 0.040 mmol, 22% yield). NMR (400 MHz, CD3OD) δ 7.47 (dd, IH), 7.36 (d, IH), 7.31 (m, IH), 7.06 (q, IH), 6.62 (dt, IH), 4,36 (dd, IH), 4.21-3.91 (m, 3H), 3.44 (q, IH), 2.66 (s, 3H), 1.29 (br m, 3H); MS (El) for CAHm: 506 (MH4). 248 EXAMPLE 29 3-{[(l,l-DimetbyIethyl)amino]methyl}-l-({4-[(2-fluoro iodophenyl)amino]

thienyl}carbonyI)azetidin oI

<img img-format="tif" img-content="drawing" file="IL229136AD0002102.tif" id="idf0102" />

<img img-format="tif" img-content="drawing" file="IL229136AD0002103.tif" id="idf0103" />

[00370] To a mixture of methyl 4-oxotetrahydrothiophene carboxylate (1.75 g, 11 mmol) (commercially available or prepared using procedures similar to those described in Rossy et. al. J. Org. Chem. 1980, 45(4), 617-2) in 15 mL of ethanol was added 2-fluoro iodoaniline (2.6 g, 11 mmol) followed by addition of several drops of acetic acid . The mixture was refluxed for 3 hrs. The mixture was cooled to room temperature and the product precipitated. This product was filtered off, washed with ethyl acetate, ether, dried in vacuo to afford the methyl 4-[(2-fluoiO iodophenyl)amino]-2,5-dihydrothiophene-3~carboxylate (1.7 g, 42%). 'HNMR(d6-DMSO):9.80 (s,lH), 7.71 (d, IH), 7.49 (dd, IH), 7.24 (t, IH), 4.10 (t, 2H), 3.79 (t, 2H), 3.69 (s, 3H); MS(EI) for C,2HnFINO2S: 380 (MH4).

[00371] To a mixture of methyl 4-[(2-fluorO“4“iodophenyl)amino]“2,5“dihydrothiophene carboxylate (1,2 g, 3.16 mmol) in 10 ml of anhydrous toluene was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (0.78 g, 3.16 mmol). The mixture was refluxed for 2 h. The mixture was cooled to 50 °C and concentrated in vacuo to dryness and cooled to room temperature. To the residue was added ethanol and the mixture was refluxed for several minutes, cooled to room temperature and light blue crystalline product was filtered off and dried in vacuo to afford methyl 4-[(2-fluoro iodophenyl) amino] thiophene carboxylate (0.74 g, 62%). ‘HNMR(d6-DMSO): 8.78 (s, IH), 8.42(d, IH), 7.64 (d, IH), 7.46 (d, IH), 7.37(t, IH), 7.14 (s, IH), 3.85(s, 3H); MS(EI) for CI2H9FINO2S: 378 (MH4). [00372] A mixture of methyl 4-[(2-fluoro iodophenyl)amino]thiophene carboxylate (0.74g, 1,96 mmol) in the solution of potassium hydroxide (0.3 g) in ethanol / water (4ml/4ml) was heated up to 60 °C and stirred at this temperature for 30 min. The mixture was cooled to room temperature, diluted with 4 ml of water and extracted with ether. The water layer was acidified with 1 N HCI to pH 2. the product precipitated and was filtered off, washed several times with water and dried in vacuo to afford 4-[(2-fluoro iodophenyl)amino] thiophene carboxylic acid (0.59 g, 83%). XH NMR (d6-DMSO): 13.20(s, IH), 9.13 (s, IH), 8.35 (d, IH), 7.62 (dd, IH), 7.48-7.38 (m, 2H), 7.11 (s, IH); MS(EI) for CnHyFINOaS: 362 (MH'). 249 [00373] 4~[(2~fluoro-4flodophenyl)ammo]thiophene carboxylic acid (200 mg, 0.551 mmol), 4-(dimethylamino)pyridine (202 mg, 1.65 mmol) and l~(3~dimethylaminopropyl) ethylcarbodiimide hydrochloride (127 mg, 0.662 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(hydroxymethyl) azetidin ol hydrochloride (72 mg, 0.516 mmol) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 20% citric acid. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with 5% lithium chloride, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was crystallized from dichloromethane to afford l-({4-[(2-fluoro iodophenyl)amino] thienyl}carbonyl) (hydroxymethyl)azetidin ol (247 mg, 0.551 mmol, quantitative yield) as off-white crystals: MS (El) for Ci5Hi4FfN2O3S: 449 (MH4).

[00374] 1 -({4-[(2-Fluoro iodophenyl)amino] thienyl} carbonyl)- 3-(hydroxymethyl)azetidin ol (247 mg, 0.551 mmol), was suspended in dichloromethane (10 mL) and treated with 4-(dimethylammo)pyridine (80 mg, 0.661 mmol), and 2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) at ambient for 15 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 30% ethyl acetate in hexanes) to give [l-({4-[(2-fluoro~4-iodophenyl)amino] thienyl}carbonyl)-3 -hy droxy azetidin yl] methyl 2,4,6-tris(l-methylethyl)benzenesulfonate (101 mg, 0.141 mmol, 26% yield): MS (El) for C30H36FIN2O5S2:715 (MH4).

[00375] [ 1 -({4-[(2-Fluoro iodophenyl)amino] thienyl} carbonyl) hydroxyazetidin~3-yl]methyl 2,4,6-tris(l-methylethyl)benzenesulfonate (101 mg, 0.141 mmol) was dissolved in tetrahydrofuran (2 mL) and was treated with sodium hydride (60 wt% dispersion in oil; 17 mg, 0.425 mmol) at ambient for 20 minutes. Tetrahydrofuran (2 mL) and Ze/V-butyl amine (0.1 mL) were added and the mixture was stirred at ambient for 16 h. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC and the clean fractions were combined, neutralized with saturated sodium bicarbonate solution and the organic solvent was removed in vacuo. The remaining aqueous residue was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-{[(l,l-dimethylethyl)amino]methyl}-l-({4-[(2-fluoro iodophenyl)amino] thienyl}carbonyl)azetidin~3-ol (8 mg, 0,016 mmol, 11% yield): 'H NMR (400 MHz, ds-DMSO): 9.64 (br, IH), 8.08 (d, IH), 7.59 (dd, IH), 7.44 250 (dd, 1H), 7.36 (t, 1H), 7.12 (d, 1H), 4.39 (d, 1H), 4.22 (d, 1H), 4.03 (d, 1H), 3.80 (d, 1H), 2.68 (br, 2H) 1.04 (s, 9H); MS (BI) for C19H23FIN3O2S: 504 (MH*).

[00376] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 29(a). 3-[(dimethylamino)methyl]-l-({4-[(2-fluoro iodophenyl)ammo] thienyl}carbonyl)azetidin-3~ol: *H NMR (400 MHz, CD3OD): 7.91 (d, 1H), 7.46- 7.41 (m, 2H), 7.33 (t, 1H), 7.00 (d, 1H), 4.66 (s, 1H), 4.49 (s, 1H), 4.30 (s, 1H), 4.15 (s, 1H), 3.54 (s, 1H), 3.17- 3,13 (m, 3H), 2.90 (s, 2H), 1.87- 1.83 (m, 3H); MS(EI) for CnEtaFINsOjS: 476 (MH*). EXAMPLE 29(b). l-({4-[(2-fluoro iodophenyl)amino] thienyl}carbonyl)azetidin amine: *H NMR (400 MHz, CD3OD): 7.90 (d, 1H), 7.46-7,41 (m, 2H), 7.31 (t, 1H), 6,99 (d, 1H), 4.47 (br.s, 2H), 4,22-4.16 (m, 2H); MS(EI) for Ci4H13FIN3OS: 418 (MH*). EXAMPLE 30 3-(l-ammoetliyl)-l-({8-chloro-7“[(2-fluoro-4“iodophenyl)ami»o]iraidazo[l,2-a]pyndm yI}carbonyl)azetidin ol

<img img-format="tif" img-content="drawing" file="IL229136AD0002104.tif" id="idf0104" />

[00377] To a suspension of sodium hydride (72 mg, 1.75 mmol, 60% wt) in tetrahydrofuran (1 mL) cooled to 0 °C was added nitroethane (125 pL, 1.75 mmol). The suspension was allowed to warm to room temperature and was stirred for 15 minutes, then cooled back to 0 °C, To the suspension was added dropwise a solution of 1,1-dimethylethyl 3-oxoazetidine-l-carboxylate (300 mg, 1.75 mmol, in 2 mL of tetrahydrofuran), prepared using procedures similar to those described in Reference 3. The suspension was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding 20% aqueous citric acid, and then was partitioned with ethyl acetate. The aqueous portion was extracted twice using ethyl acetate and the combined organic portion was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless oil that was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 250 mg, 1.02 mmol (58%) of 1,1-dimethylethyl 3-hydroxy (l-nitroethyl)azetidine-l-carboxylate as a 251 colorless oil. *H NMR (400 MHz, DMSO): 6.46 (s, IH), 5.01 (q, IH), 4.24-3.97 (m, 2H), 3.77-3.60 (m, 2H), 1.41 (d, 3H), 1.39 (s, 9H).

[00378] 1,1 -Dimethylethyl 3-hydroxy (1 -nitroethyl)azetidine-l -carboxylate was dissolved in methanol (5 mL) and treated with 4 N HCl in dioxane. The solution was briefly heated to reflux and then was concentrated in vacuo to afford 178 mg, 0.98 mmol (96%) of 3-(l-nitroethyl)azetidin ol hydrochloride as a white solid. Al NMR (400 MHz, DMSO): 9.30 (br s, IH), 8,96 (br s, IH), 5.12 (q, IH), 4.44-4,38 (m, IH), 4.22-4.17 (m, IH), 3.94-3.87 (m, IH), 3.85-3.77 (m, IH), 1.44 (d, 3H).

[00379] A solution of 8-chloro-7“[(2-fluoro iodophenyl)amino]imidazo[l,2-ii]pyridine“ 6-carboxylic acid (150 mg, 0.35 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), NN-diisopropylethy famine (300 pL, 1.74 mmol), PyBOP (180 mg, 0,35 mmol) and 3-(l-nitroethyl)azetidin ol hydrochloride (76 mg, 0.42 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was then partitioned between 5% aqueous lithium chloride, and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 20% aqueous citric acid, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with 5% methanol in dichloromethane, the isolated.product was concentrated in vacuo to afford 195 mg, 0.35 mmol (100%) of l-({8-chloro [(2-fiuoro iodophenyl)amino]imidazo[l,2-&lt;3]pyridin yl}carbonyl)“3-(l-nitroethyl)azetidin ol as a yellow foam. *H NMR (400 MHz, CDCI3): 8,28 (s, IH), 7.68 (s, IH), 7.59 (s, IH), 7.43 (d, IH), 7.31 (d, IH), 7.23 (br s, IH), 6.55-6.51 (m, IH), 6.02 (br s, IH), 4.79 (q, IH), 4.45-3.96 (4H), 1.56 (d, 3H). MS (El) for C2oHi9C1FIN604: 560 (MH+), [00380] To a solution of l-({8-chloro [(2-fluoro iodophenyl)amino3imidazo[l,2-Apyridm yl}carbonyI)~3-(l-nitroethyl)azetidm ol (195 mg 0.35 mmol) in tetrahydrofuran/water (5 mL, 4:1) was added iron powder (193 mg, 3.5 mmol) and ammonium formate (438 mg, 7.0 mmol). The mixture was stirred at 80°C for' 1 hour, then cooled to room temperature and filtered through a pad of ceiite. The ceiite was washed three times with boiling ethanol (20 mL). The filtrate was concentrated in vacuo and the residue was diluted with ethyl acetate. The precipitate which formed was filtered through a pad a ceiite and the filtrate was partitioned with water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow residue which was purified by preparative reverse phase HPLC, The isolated product was concentrated in vacuo to afford 252 WO 2007/04453.5 mg, 0.05 mmol (15%) of 3-(l-aminoethyl)-l-({8-chloro [(2-fluoro iodophenyl)ammo]imidazo[l,2-a]pyridin-6~yl}carbonyl)azetidin ol acetate salt as a white solid. 'H NMR (400 MHz, DMSO): 8.79 (s, IH), 8.00 (s, IH), 7.61 (s, IH), 7.54 (d, IH), 7.32 (d, IH), 6.54-6.48 (m, IH), 4.24-4.13 (m, IH), 3.98-3.84 (m, 2H), 3.61-3.56 (m, 1H), 2.83 (q, IH), 0.92-0.88 (m, 3H); MS (El) for C19H18CIFIN5O2: 530 (MH4). EXAMPLE 31 l-({8“Chloro-7“[(2-fl«oro-4“iodophenyl)ammo]imidazo[l,2-a]pyridin-6"yl}carbonyl)“3“

piperidin ylazetid»i“3~oI

<img img-format="tif" img-content="drawing" file="IL229136AD0002105.tif" id="idf0105" />

[00381] To a solution of 1,1 -dimethylethyl 2-(3-hydroxy-1 - {[(phemylmethyd)oxy]carboRyi}azetidm yl)piperidme-l-carboxylate (595 mg, 1.52 mmol), prepared using procedures similar to those described in Reference 5, in methanol (5 mL) was added catalytic palladium on carbon (5% wt). The heterogeneous mixture was stirred under a hydrogen gas atmosphere for 15 hours at ambient pressure and then was filtered. The filtrate was concentrated in vacuo to afford 385 mg, 1.50 mmol (98%) of 1,1-dimethylethyl 2-(3-hydroxyazetidin yl)piperidine-l-carboxylate as a colorless film without further purification. [00382] A solution of 8-chloro [(2“fluoro iodophenyl)amino]imidazo[l,2“«]pyridine“ 6-carboxyIic acid (78 mg, 0.18 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), 1,1-dimethylethyl 2-(3-hydroxyazetidin yl)piperidine-l-carboxylate (46,7 mg, 0.18 mmol), 4-(dimethylamino)pyridine (66 mg, 0.55 mmol), and finally l-(3-dimethylaminopropyl) ethylcarbodiimide hydrochloride (42 mg, 0.21 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was partition between 5% aqueous lithium chloride and ethyl acetate and the aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 1 N HCl, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with ethyl acetate, the isolated product was concentrated in vacuo to afford 101 mg, 0.15 mmol (83%) of 1,1 -dimethylethyl 2-(1-(( 8-chloro~7-[(2-fluoro iodophenyl)amino]imidazo[ 1,2- a]pyridin yl)carbonyl) hydroxyazetidin yl]piperidine-l-carboxylate as a white solid. 253 WO 2007/04451.5

The solid was immediately dissolved in methanol (5 mL) and 4 N HCl in dioxane was added. The solution was briefly heated to reflux and then was concentrated in vacuo. The resultant residue was purified by preparative reverse phase HPLC. Isolated product was concentrated in vacuo to afford 36 mg, 0.06 mmol (40%) of l-({8-chloro [(2-fiuoiO iodophenyl)amino]imidazo[l,2-a]pyridin yl}carbonyl) piperidin ylazetidin ol acetate as a white solid. 'H NMR (400 MHz, DMSO): 8.78 (s, IH), 8.19 (s, 0.5H), 8.15 (s, 0.5H), 8.00 (s, IH), 7.62 (s, IH), 7.55 (d, IH), 7.31 (d, IH), 6.54-6.49 (m, IH), 4.24-4.12 (m, IH), 3.97-3.86 (m, 2H), 3.63-3.56 (m, IH), 2.98-2.90 (m, IH), 2.50-2.40 (m, IH), 1.72-1.61 (m, IH), 1.56-1.43 (m, 2H), 1.32-1.14 (m, 2H), 1.07-0.94 (m, IH); MS (El) for C22H22CIFIN5O2: 570 (MH+).

[00383] Using the same or analogous synthetic techniques and/or substituting with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 31(a). 1 -({4-fluoro [(2-fluoro iodophenyl)amino]-1 -methy 1-1V-benzimidazol yl}carbonyl) piperidin ylazetidin ol acetate salt: !H NMR (400 MHz, DMSO): 8.35 (s, IH), 7.84-7.77 (m, IH), 7.54-7.49 (m, 2H), 7,25 (d, IH), 6.31-6.25 (m, IH), 4,04-3.92 (m, 2H), 3.90 (s, 3H), 3,86-3.78 (m, IH), 3.70-3.62 (m, IH), 2.94-2.85 (m, IH), 2.45-2.32 (m, 2H), 1.66-1,36 (m, 3H), 1.26-1,08 (m, 2H), 1.01-0,80 (m, IH); MS (El) for C23H24F2IN5O2: 568 (MH+). EXAMPLE 31(a). l-({7-[(4-bromo chlorophenyl)amino] chloroimidazo[l ,2-a]pyridin yl} carbony 1) piperidin ylazetidin ol acetate salt: ]H NMR (400 MHz, DMSO): 8.87 (s, IH), 8.29 (s, 0.5H), 8.21 (s, 0.5H), 8.04 (s, IH), 7.67-7.63 (m, 2H), 7.32 (d, IH), 6.59 (d, IH), 4.35-4.22 (m, IH), 4.08-3,98 (m, 2H), 3.72-3.67 (m, IH), 2.96-2,88 (m, IH), 2.50-2,44 (m, 2H), 1.66-1.42 (m, 3H), 1.26-1.17 (m, 2H), 1.04-0.94 (m, IH); MS (El) for C^HzsBrCbNsOz: 540 (MH*). EXAMPLE 32 3-(l-Amino hydroxypropyl)“l-({3i4-difluoro [(2-fluoro iodopbenyI)amino]phenyi}carbonyl)azetidin ol trifluoroacetate salt

<img img-format="tif" img-content="drawing" file="IL229136AD0002106.tif" id="idf0106" />

[00384] Potassium /m-butoxicie (1.393 g, 12,4 mmol) and [2-(l,3-dioxolan yl)ethyl]-triphenylphosphonium bromide (5.51 g, 12.4 mmol) were stirred in ether (30 mL) at amibient for 1 h. Phenylmethyl 3-oxoazetidine-l-carboxylate (1.025 g, 5,0 mmol), prepared using procedures similar to those described in Reference 3, was added and the mixture was stirred at 35 °C for 6 h and then at ambient for 4 days. Mixture was filtered through celite and the solid was washed with ether. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ether in hexanes) gave phenylmethyl 3-[2»(lYdioxolan yl)ethyhdene]azetidine-l-carboxylate (220 mg, 0.761 mmol, 15% yield): *H NMR (400 MHz, CDC13): 7.39-7.28 (m, 5H), 5.43-5.35 (ra, IH), 5.11 (s, 2H), 4.89 (t, IH), 4.56 (br d, 4H), 4.00-3.92 (m, 2H), 3.91- 3.83 (m,2H), 2.27 (br t, 2H).

[00385] Phenylmethyl 3-(2-(1,3-dioxolan yl)ethylidene]azetidine-l-carboxyIate (220 mg, 0.761 mmol), and 4-methylmorpholine N-oxide (287 mg, 2.45 mmol) were dissolved in acetone I water (4:1; 10 mL) and osmium tetroxide (4 wt,% in water; 0.05 mL) was added. The solution was stirred at ambient for 20 h, then was quenched with saturated sodium bisulfite (2 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave phenylmethyl 3- (2-( l,3-dioxolan yl)-l-hydroxyethyl] hydroxyazetidine- 1-carboxylate (244 mg, 0,755 mmol, 99% yield): 'l-Ι NMR (400 MHz, CDC13): 7.38-7.28 (m, 5H), 5.11-5.07 (m, 3H), 4.14-4.01 (m, 4H), 3.96-3.86 (m, 5H), 3.47 (d, IH), 2.97-2.94 (m, IH), 1.98-1.84 (m, 2H). [00386] Phenylmethyl 3-(2-(1,3 -dioxol an yl)-1 -hydroxyethyl] hydroxyazetidine-1 - carboxylate (235 mg, 0.728 mmol) was dissolved in methanol (5 mL) and treated with 5 wt% palladium on carbon (50 mg) under hydrogen at ambient for 1.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-(2-(1,3-dioxolan yl)-l -hydroxyethy 1]azetidin ol (0.729 mmol): MS (El) for CsHi5NO4: 190 (MH+).

[00387] 3,4-Difluoro~2-[(2-fluoro iodophenyl)amino] benzoic acid (287 mg, 0.730 mmol), prepared using procedures similar to those described in US 7,019,033, 4- (dimethylamino)pyridine (178 mg, 1,46 mmol) and l-(3-dimethylaminopropyl) ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 10 minutes and then 3-(2-(1,3-dioxolan yl)-l-hydroxy ethyl] azetidin ol (0.729 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. 255

The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, gradient 90% ethyl acetate in hexanes to 100% ethyl acetate) gave 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl) [2-(l,3-dioxolan yI)-l-hydroxyethyl]azetidin ol (148 mg, 0.262 mmol, 36% yield): MS (El) for C2iH20F3IN2O5: 565 (MH+).

[00388] 1 -({3.4-Difluoro [(2-fluoiO iodophenyl)amino]phenyl} carbonyl) [2-( 1,3- dioxolan yl)-l-hydroxyethyl]azetidin ol (148 mg, 0.262 mmol), was dissolved in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (38 mg, 0.31 mmol), triethylamine (0.036 mL, 0.262 mmol) and 2,4,6-trnsopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) at 35 °C for 15 h, 2,4,6-Triisopropylbenzencsulfonyl chloride (100 mg, 0.33 mmol) was added and the mixture was stirred at 35 °C for 3.5 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 40-50% ethyl acetate in hexanes and then 100% ethyl acetate) to give l-[l-({3,4~difluoro [(2-fluoro~4-iodophenyl)amino]phenyl}cai'bonyl) hydroxyazetidin yl]~2-(l,3-dioxolan yl)ethyl 2,4,6-tris(l-methylethyl)benzenesulfonate (30 mg, 0.0361 mmol, 14% yield): MS (El) for C36H42F3IN2O7S: 831 (MH4). ; [00389] l-[l-({3,4-Difluoro [(2-fluoro~4-iodophenyl)amino]phenyl}carbonyl) hydroxyazetidin yl] (1,3-dioxolan yl)ethyi 2,4,6-tris(l -methylethyl)benzenesulfonate (50 mg, 0.060 mmol) was dissolved in tetrahydrofuran (1 mL) and was cooled to 0 °C. Sodium hydride (60 wt% dispersion in oil; 7 mg, 0.18 mmol) was added and the mixture was stirred at 0 °C for 45 minutes. The mixture was quenched with saturated sodium bicarbonate solution and partitioned with ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 6-{[2-(l,3-dioxolan ylmethyl)-l-oxa azaspiro[2.3]hex yl]carbonyl}-2,3-difluoro-M(2-fluoro iodophenyl)aniline (31 mg, 0.057 mmol, 94% yield): MS (El) for C2iH18F3IN2O4: 547 (MH4).

[00390] 6~ {[2-(1,3-Dioxolan ylmethyl)-1 -oxa azaspiro [2,3] hex yl] carbonyl} - 2,3-difluoro-/V-(2-fluoro iodophenyl)aniline (31 mg, 0.057 mmol) was dissolved in dimethylformamide (0.5 mL) and sodium azide (20 mg, 0,308 mmol) was added. The mixture was stirred at ambient for 22 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with water, brine, then was dried over anhydrous 256 sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 3-ri-azido (l,3-dioxolan yl)ethyl]-l-({3?4-difluoro [(2- fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol (25 mg, 0.042 mmol, 74% yield): MS (El) for C2iHI9F3lN5O4: 590 (MH*).

[00391] 3-[l~Azido (l,3-dioxolan yI)ethyl]-l-((3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol (24 mg, 0.041 mmol) was dissolved in tetrahydrofuran (0.5 mL) and treated with 5% aqueous hydrochloric acid (0.5 mL) at ambient for 15 h. The misture was neutralised with saturated sodium bicarbonate solution and was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-azido-3~ [ 1 -({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl} carbonyl) hydroxyazetidm~3-yl]propanal (21 mg, 0.0385 mmol) which was suspended in ethanol (2 mL) and treated with sodium borohydride (5 mg, 0,132 mmol) at ambient for 2 h. The mixture was quenched with acetic acid (4 drops) and concentrated in vacuo. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 70-80% ethyl acetate in hexanes) gave 3-(l-azido hydroxypropyl)-l-((3,4-difluoro~2-[(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol (14 mg, 0.0255 mmol, 62% yield from 3-[l-azido (l,3~dioxolan yI)ethyl] ((3,4-difluoro [(2-fluoro iodophenyl)amino}phenyl}carbonyl)azetidin ol): !H NMR (400 MHz, CDC13): 8,33 (br s, IH), 7.40 (dd, IH), 7.32 (br d, IH), 7.13 (br t, IH), 6.83 (br q, IH), 6.61 (ddd, IH), 4.32-3.94 (m, 4H), 3,92-3.84 (m, IH), 3.82-3,71 (m, 2H), 2.56 (br, IH), 1.94 (br, 2H), 1.26 (br, IH); MS (El) for CwHi7F3IN5O3; 548 (MH+).

[00392] 3-(l-Azido hydroxypropyl)-l-({3,4-difluoro [(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidm ol (14 mg, 0.0255 mmol) was dissolved in tetrahydrofuran and water (1:1, 0,5 mL) and polymer supported triphenylphosphine (-3 mmol/g; 20 mg, 0.06 mmol) was added. The mixture was stirred at 55 °C for 1 h. Triphenylphosphine (10 mg, 0.038 mmol) was added and the mixture was stirred at 55 °C for 1.5 h. The mixture was filtered and the filtrate was purified by reverse phase HPLC to afford 3-( 1 -araino hydroxypropyl)-1 -((3,4-difiuoro [(2-fiuoro iodophenyl)amino]phenyl}carbonyl)azetidin ol trifluoroacetate salt (1.7 mg, 0.003 mmol, 10% yield): 'H NMR (400 MHz, CD3OD): 7.47 (dd, 1Η), 7.36 (br d, IH), 7.33-7.28 (m, 1Η), 7.05 (br q, IH), 6.62 (ddd, 1Η), 4.38-4.26 (m, IH), 4.18-4.00 (m, 2Η), 3.98-3.88 (m, 257 IH), 3.78-3.67 (m, 2H), 3,61-3.56 (m, IH), 1,87-1.70 (m, 2H); MS (El) for C^HigFjINsOj: 522 (MH4). EXAMPLE 33 l“({3,4-difiuoro-2“[(2-fluorO“4“iodophenyl)amino]phenyI}carbonyl) (6“ metbylpipendin yl)azetidiH“3-ol

<img img-format="tif" img-content="drawing" file="IL229136AD0002107.tif" id="idf0107" />

[00393] To a solution of #,#-diisopropylamme (1.6 mL, 11.2 mmol) cooled to -78 °C in THF (15 mL) was added a 2,5 M solution of n-BuLi in hexane (4.5 mL, 11.2 mmol) dropwise over 5 minutes and the mixture was stirred at this temperature for an addition 15 minutes. 6-methyl-l-(phenylmethyl)piperidine carbonitrile (2.4 g, 11.2 mmol) (prepared using procedures similar to those in Bonin et. al. Tet. Lett, 1982, 23(33), 3369-72) in THF (10 mL) was then added dropwise over 20 minutes and the reaction mixture was stirred for a further 30 minutes. Next a solution of 1,1-dimethylethyl 3-oxoazetidine-l-carhoxylate (1.3 g, 7.5 mmoL), prepared using procedures similar to those in Example 3, in THF (10 mL) was added dropwise over 30 minutes. The reaction mixture was gradually warmed to room temperature and allowed to stir overnight. The reaction mixture was quenched with 10% citric acid and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate then filtered and concentrated in vacuo to give crude product as yellow oil. Further purification by flash chromatography (30% ethyl acetate in hexanes) afforded 1,1-dimethylethyl 3-[2-cyano methyl-l-(phenylmethyl)piperidin~2-yl]-3“hydroxyazetidine-l-carboxylate as a pale yellow oil (0.2 g, 7% yield). *H NMR (400 MHz, CDC13): 7.17-7.40 (m, 5H), 4.42 (d, IH), 4.04-4.18 (m, IH), 3.83-4.00 (m, IH), 3.70-3.75 (m, 2H), 1.70-1.87 (m, 4H), 1.45 (s, 3H), 1.41 (s, 9H), 1.22-1.26 (m,lH), 1.13-1.18 (m, 2H); MS (El) for C22H3IN3O3: 386 (MH4).

[00394] To a stirred solution of 1,1-dimethylethyl 3-[2-cyano~6-methyl-l- (phenyhnethyl)piperidin yl] hydroxyazetidine-l-carboxylate (180 mg, 0.47 mmol) in ethanol (1 mL) was added acetic acid (53,5 pL, 0.94 mmol) followed by sodium cyanoborohydride (58.7 mg, 0.94 mmol) and the reaction mixture stirred at 70 °C overnight.

After cooling to room temperature the suspension was filtered through celite and the solid 258 washed with additional ethanol. The filtrate was concentrated in vacuo and taken up in ethyl acetate (30 mL). The organic layer was washed with 2 M sodium hydroxide solution. The sodium hydroxide layer was separated and washed with ethyl acetate (10 mL), The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give crude 1,1-dimethylethyl 3 -hydroxy-3 -[6-raethyH-(phenylmethyl)piperidm yl]azetidine-l-carboxylate as yellow oil (60 mg, 36% yield). Crude product was used further without purification. !H NMR (400 MHz, CDC13): 7.22- 7.35 (m, 5H), 4.08 (d, IH), 3.85-3.96 (m, 3H), 3.57 (d, IH), 3.33-3.36 (ra, IH), 2.91-3.06 (m, 2H), 1.63-1.70 (ra, 4H), 1.44 (s, 9H), 1.23 (d,3H), 1.05 (d, 2H); MS (El) for C2iH32N2O3: 361 (MH4).

[00395] To a solution of 1,1 -dimethylethyl 3-hydroxy [6-methyl-1 - (phenylmethyl)piperidin yl]azetidine-l-carboxylate (60 mg, 0.16 mmol) in methanol (0.5 mL) was added hydrogen chloride (4N in dioxane, 0.5 mL) and the reaction mixture stirred at 60 °C for one hour. The reaction mixture was cooled to room temperature and concentrated in vacuo and aezotroped 3 times from, methanol and diethyl ether. On drying the hydrochloride salt of 3-[6-methyl-l-(phenylmethyl)piperidin yl]azetidin ol was obtained as a dark brown residue (40 mg, 81% yield), which was used further without purification. lH NMR (400MHz, CD3OD): 7.58-7.63 (m, 2H), 7.47-7.49 (m, 3H), 4.78 (d, IH), 4.44-4.62 (m, 2H), 4.29 (s, 2H), 4.22-4.26 (m, IH), 4.12-4.18 (m, lid), 4.08 (s, 1H)~, 1.60-2.00 (ra, 8H), 1.48 (d, 3H); MS (El) for Ci6H25ClN2O: 261 (MH4).

[00396] To a solution of 3-[6-methyl-l-(phenylmethyl)piperidin yl]azetidin ol hydrochloride (40 mg, 0,13 mmol) in ethyl acetate (3 mL) was added acetic acid (0.5 mL) and Pd/C (50 mg) and the mixture was hydrogenated at 35 psi for 3 hours. The reaction mixture was filtered, through celite. The filtrate was concentrated in vacuo. The obtained residue was dissolved in a small amount of ethyl acetate and concentrated hydrochloric acid was added and the mixture was concentrated in vacuo to give the crude dihydrochloride salt of 3-[6-methylpiperidin yl]azetidin ol (20 mg, 54%). The crude product was used further without purification. *H NMR (400MHz, CD3OD): 4.20-4.40 (ra, IH), 4.00-4.10 (ra, IH), 3.60-3.90 (m, 2H), 1,50-2.00 (m, 6H), 1,45 (d, 3H), 1.26-1.30 (ra, IH); MS (El) for C9H20Cl2N2O: 171 (MH4), [00397] To a 0 °C solution of 3-[6-methylpiperidin yl]azetidin ol dihydrochloride (20 mg, 0.08 mmol) in DMF (1 mL) was added MN-diisopropylethylamine (42 pL, 0.26 mmol) followed by 3,4-difluoro [(2-fluoro iodophenyl)amino] benzoyl fluoride (32 mg, 0.08 mmol), prepared using procedures similar to those described in Reference 1, and the reaction 259 mixture stirred at 0 °C for 30 min. The mixture was diluted with acetonitrile and purified by preparative reverse phase HPLC (CH3CN/H2O with 0.1% TFA). Fractions were collected and lyophilized to give 1-({3,4-difluoro [(2“fluoro iodophenyl)amino]phenyl}carbonyl)- 3-(6-methyIpiperidin yl)azetidin-3“0l acetate salt (7 mg, 16% yield) as a white solid, &amp;#905; NMR (400MHz, CD3OD): 7.44-7.50 (m, 1H), 7.34-7.37 (m, 1H), 7.28-7.32 (m, 1H), 7,02-7.12 (m, 1H), 6.60-6.63 (m, 1H), 4.10-4.30 (m, 2H), 3.95-4.09 (m, 2H), 3.80-3.95 (m, 1H), 3.55-3.65 (m, 1H), 3.34-3.36 (m, 1H), 1.90 (s, 3H), 1.62-1.84 (m, 6H), 1.40-1.52 (m, 1H), 1.33 (d, 3H); MS (El) for C22H23F3IN3O2: 546 (MH*). EXAMPLE 34 l-({3i4-difluoro [(2-fluoro iodophenyl)amino]pbenyl}carboiiyl) piperaziii ylazetidin ο&amp;#970;

OH

NH

[00398] To a solution of commercially available l,4-bis(phenylmethyl)piperazine-2,5-dione (2.0 g, 6.8 mmol) in dry THF (50 mL) at -78 °C was added lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.4 mL, 6.8 mmol). The resulting reddish brown suspension was stirred for 23 min at -78 °C, and then a solution of 1,1-dimethylethyl 3-oxoazetidine carboxylate (770 mg, 4.5 mmol) in THF (10 mL) was added over 30 min by syringe pump. The mixture became a bright yellow solution as it was allowed to warm to room temperature over 3 hours. The mixture was quenched with saturated aqueous ammonium chloride. Water was added to dissolve precipitated salts, and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (60% ethyl acetate: 40% hexanes) to provide 1,1-dimethylethyl 3-(3,6-dioxo-l,4-bis(phenylmethyI)piperazin yl] hydroxyazetidine-l-carboxylate as a colorless foam (1.04 g, 2.23 mmol, 50% yield). 'H NMR (400 MHz, CDC13): 7.39-7.29 (m, 7H),

<img img-format="tif" img-content="drawing" file="IL229136AD0002108.tif" id="idf0108" />

260 S2006/039126 [00399] A·solution of 1,1-dimethylethyl 3-[3,6-dioxo-l,4-bis(phenylmethyl)piperazin yl]“3«hydroxyazetidine-l-carboxylate (1.04 g, 2.2 mmol) in methanol (10 mL) was treated with hydrogen chloride in dioxane (4 N, 5,5 mL, 22 mmol) at 60 °C for 25 min. After cooling to room temperature the solution was concentrated. Ethyl acetate and 2 N hydrochloric acid were added to the residue and the phases were separated. The organic phase was discarded. The aqueous phase was basified with 5 M sodium hydroxide and the resulting solution was extracted 4 times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (85% dichloromethane: 14% methanol: 1% aqueous ammonium hydroxide) to provide 3“(3-hydroxyazetidin yl)“l,4-bis(phenyImethyl)piperazine-2,5“dione as a colorless film (493 mg, 1.35 mmol, 61% yield). ^NMR (400 MHz, CDC13): 7.39-7.28 (m, 6H), 7.25-7.20 (m, 4H), 5.39 (d, IH), 4.80 (d, IH), 4.44 (d, IH), 4.36 (d, IH), 4.26 (d, IH), 4.11 (s, IH), 3.97 (d, 1H), 3.83 (d, IH), 3.71 (d, IH), 3.27 (m, 2H); MS (EI) for C21H23N3O3: 366 (MH*).

[00400] A solution 3-(3~hydroxyazetidin yl)-l,4-bis(phenylmethyl)piperazme-2,5-dione (493 mg, 1.35 mmol) in ethyleneglycol dimethylether (12 mL) was treated with sodium borohydride (511 mg, 13.5 mmol) followed by slow addition of boron trifluoride-diethyl etherate. The reaction mixture was then heated to reflux for 3 hours. After cooling to 0 °C, methanol (17 mL) was added followed by careful addition of concentrated hydrochloric acid (7 mL). The resulting mixture was heated to reflux for 70 minutes. After cooling to room temperature, insoluble residue was removed by filtration. The filtrate was concentrated to an aqueous mixture of about 10 mL in volume. This mixture was cooled to 0 °C and was then basified to pH 10 with 5 M sodium hydroxide (approximately 17 mL), Dichloromethane (10 mL) was then added followed by di-to/7-butyl dicarbonate (442 mg, 2.03 mmol). The mixture was warmed to room temperature and stirred for 15 minutes. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (70% hexanes: 30% ethyl acetate) to provide 1,1 -dimethylethyl 3- [ 1,4-bis(phenylmethyl)piperazin yl] -3 -hydroxyazetidine-1 -carboxylate as a white foam (408 mg, 0.93 mmol, 69% yield). ‘H NMR. (400 MHz, CDC13): 7.35-7.24 (m, 10H), 4.12 (br s, IH), 3.88 (d, IH), 3.78-3.65 (m, 4H), 3.53 (d, IH), 3.43 (d, IH), 3.21 (m, IH), 2.80 (br s, IH), 2.66 (m, IH), 2.57-2.37 (m, 4H), 1.41 (s, 9H); MS (EI) for C26H35N3O3: 438 (MH). 261 [00401] To a solution of 1,1-dimethy lethy I 3-[l,4-bis(phenylmethyl)piperazin yl] hydroxyazetidine carboxylate (408 mg, 0.93 mmol) in methanol (15 mL) was added 10% palladium on carbon (wet), and the resulting suspension was subjected to an atmosphere of hydrogen for 21 hours. The catalyst was removed by filtration through celite, and the filter cake was rinsed with methanol. The combined filtrate was concentrated to provide 1,1-dimethylethyl 3~hydroxy~3-piperazin yIazetidine-l-carboxylate as a brown syrup (227 mg, 0.88 mmol, 95% yield). ’H NMR (400 MHz, CDCb): 3.94-3.76 (m, 5H), 3.12 (m, IH), 3.01 (m, IH), 2.94-2.81 (m, 3H), 2.78-2.70 (m, 2H); MS (El) for C12H23N3O3: 258 (MH4), [00402] To a solution of 1,1-dimethylethyl 3-hydroxy piperazin ylazetidine-l-carboxylate (227 mg, 0.88 mmol) and MAMiisopropylethylamine (436 pL, 2.64 mmol) in THF (5 mL) was added 2-nitrobenzenesulfonyl chloride (195 mg, 0.88 mmol). The mixture was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane: 5% methanol) to provide 1,1 -dimethylethyl 3-hydroxy {4-[(2-nitrophenyl)sulfonyl]piperazin yl}azetidine-1 - carboxylate as a white foam (308 mg, 0.70 mmol, 79% yield). NMR, (400 MHz, CDCb): 7.98 (m, IH), 7.72 (m, 2H), 7.64 (m, IH), 3.96 (d, IH), 3.94 (d, IH), 3.85 (d, IH), 3.79 (d, IH), 3.79-3.73 (m, 2H), 3.11 (m, IH), 3.05 (dd, IH), 3.00 (br s, IH), 2.94 (dt, IH), 2.78 (dt, IH), 2.68 (dd, IH), 1.45 (s, 9H).

[00403] To a solution of 1,1-dimethylethyl 3-hydroxy {4-[(2- mtrophenyl)sulfonyl]piperazin yl}azetidme-l-carboxylate (308 mg, 0.70 mmol) in methanol (10 mL) was added HCI in dioxane (4 N, 1,75 mL, 7.0 mmol), and the mixture was heated to 60 °C for 30 minutes. The solution was concentrated to provide 3-{4-[(2-nitrophenyl)sulfonyl]piperazin yl}azetidin ol as a sticky white solid. This material was dissolved in dichloromethane (7 mL), To the solution was added MA^diisopropylethylamine (1.16 mL, 7,0 mmol) followed by 3,4-difluoro [(2-fluoro iodophenyl)amino]benzoyl fluoride (277 mg, 0.7 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 16 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane: 5% methanol) to provide l-({3,4-difluoro-2~[(2-fluoro iodophenyl)amino]phenyl}carbonyl) {4-[(2-nitrophenyI)sulfonyl]piperazin yl}azetidin ol as a pale yellow foam (453 mg, 0.63 mmol, 90% yield). *H NMR, (400 MHz, CDCb): 8.49 (s, IH), 7.96 (dd, IH), 7.71 (m, 2H), 7.53 (dd, IH), 7.39 (dd, IH), 7.33 (d, IH), 7.15 (m, IH), 6.84 (br s, IH), 6.62 (m, IH), 4.29-3.97 (br m, 4H), 3.79-3.62 (m, 3H), 3.26- 2.99 (br m, 3H), 2.92-2.62 (br m, 3H); MS (El) for C26H23F3lN5O6S: 718 (MH4). 262 [00404] To a solution of l-({3,4~difiuoro [(2-fiuoro iodophenyl)amino] phenyl} carbonyl) {4-[(2-nitrophenyl)sulfonyl]piperazin yl} azeti din 01 (139.4 mg, 0.19 mmol) in DMF (1 mL) was added potassium carbonate (79 mg, 0,57 mmol) and thiophenol (21 pL, 0.21 mmol). The mixture was stirred for 45 min at room temperature then quenched with water. The aqueous mixture was extracted twice with ethyl acetate, and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by preparative reverse phase HPLC to provide 1-({3,4-difiuoro [(2“fluoro iodophenyl)amino]phenyl}carbonyl) piperazin ylazetidin ol as a white solid (26.8 mg, 0.05 mmol). 'H NMR (400 MHz, CD3OD): 7.45 (dd, IH), 7.36 (m, IH), 7.32 (m, IH), 7.03 (m, IH), 6.62 (ddd, IH), 4.51 (brdd, IH), 4.31 (br dd, IH), 4.17-3.92 (m, 4H), 3.73-3.56 (m, 3H), 3.46 (br m, IH), 3.26 (m, IH); MS (El) for C20H20F3IN4O2: 533 (MH+). EXAMPLE 36 1,1-Dimethylethyl {(liS)-l“[l-({4-[(2-fluoro~4“iodophenyI)amino]-l-metliyl oxO“l,6-dihydropyridazin yl}carbonyl) hydroxvazetidin~3-yl]ethyl}carbarnate

<img img-format="tif" img-content="drawing" file="IL229136AD0002109.tif" id="idf0109" />

[00405] To a suspension of 4-[(2-fluoro iodophenyl)ammo]-l-methyl oxo-l,6- dihydropyridazme carboxylic acid (50 mg, 0,13 mmol) in DMF (2 mL), prepared using - similar procedures to those described in Reference 4, at room temperature was added 1-hydroxybenzotriazole (36.3 mg, 0,27 mmol) and l~(3-dimethylammopropyl)~3- ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol) and the reaction was stirred for 2 hours. 1,1-Dimethylethyl [(15) (3-hydroxyazetidin yl)ethyl] carbamate (30 mg, 0.13 mmol), prepared using procedures similar to those in Example 28, and triethylamine (0,04 mL) were added and the mixture was stirred for 15 hours. The reaction mixture was partitioned between saturated sodium chloride and ethyl acetate. The organic layer was washed with 5% lithium chloride solution, saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product as yellow oil. The oil was purified by column chromatography (silica gel, ethyl acetate) to afford 1,1-dimethylethyl {(15) (1- ({ 4- [(2-fiuoro io dophenyl)amino] -1 -methyl oxo-1,6-dihydropyridazin-3 -yl} carbonyl)-3 - 263 hy dr oxyazetidin ylj ethyl} carbamate as a yellow oil (55 mg, 73% yield): Yd NMR (400 MHz, CDC13): 10.24-10.23 (m, 1H), 7.52-7.50 (m, 2H), 7.12-7.07 (m, IH), 6.10-6.09 (m, IH), 5.13-5.09 (m, IH), 4.91-4.82 (m, IH), 4.60-4.39 (m, 2H), 4.10-4.08 (m, IH), 4.00-3.87 (m, 2H), 3.70 (d, 3H), 1.43 (s, 9H), 1.24-1.20 (m, 3H); MS (El) for C22H27FIN5O5: 588 (MH+).

[00406] Using the same or analogous synthetic techniques and substituting, as necessary, with alternative reagents, the following compounds of the invention were prepared: EXAMPLE 36(a). 1,1-Dimethylethyl {(15) [l-({5-[(4~bromo~2-chlorophenyl)amino] fluoro-1 -methyl-1 /7-benzimidazol yl} c arbony 1) hydroxyazetidin-3 -yl] ethyl} carbamate: ‘H NMR (400 MHz, CDCb): 7.95 (s, IH), 7.45-7.44 (m, IH), 7.33-7.27 (m, 2H), 7.15-7.12 (m, IH), 6.50-6.47 (m, IH), 4.82-4.74 (m, IH), 4.17-3.92 (m, 4H), 3.86 (s, 3H), 3.74-3.60 (m, IH), 1.40 (s, 9H), 1.11-1.06 (m, 3H). MS (El) for C25H28BrClFNsO4: 598 (MH4) with a chloro, bromo isotope pattern. EXAMPLE 36(b). 1,1-Dimethylethyl (25) [l-({5-[(4-bromo-2“Chlorophenyl)amino] fluoro-1 -methyl-1 W-benzimidazol yl} carbonyl) hydroxyazetidin yl]piperidine-l -carboxylate: MS (El) for C2sH32BrClFN5O4: 638 (Mlf ) with a chloro, bromo isotope pattern.

Example 37 6-({3-[(15)-l-ammoethyl) hydroxyazetidm-l-yl}carbonyl)-5~[(2-fluoro iodophenyl)ammo] methylpyndazin~3(2LZ)-one acetate salt HO =

<img img-format="tif" img-content="drawing" file="IL229136AD0002110.tif" id="idf0110" />

O

[00407] 1,1 -Dimethylethyl {(15)-1 -[ 1 -({4-[(2-fluoro iodophenyl)amino] -1 -methyl oxo-1,6-dihydropyridazin-3~yl) carhonyl) hydroxyazetidin yl]ethyl) carbamate (55 mg, 0.09 mmol), prepared using procedures similar to those described in Example 36, was taken up in methanol (2 mL) and hydrochloric acid (4N in dioxane, 1 mL, 4 mmol) was added and the reaction was stirred at 60 °C for 2 hours. The reaction mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 6-( {3-((15)-1 -aminoethyl) hydroxyazetidin-1 -yl} carbony l) [(2-fluoro 264 WO 2007/04451.5

iodophenyl)amino] metliylpyridazin~3(2H)--one acetate as yellow solid (40 mg, 87%). 1H NMR (400 MHz, CDC13): 10.17 (d, IH), 7.52-7.46 (m, 2H), 7.09 (t, IH), 6.13-6.12 (m, IH), 4.51-4.48 (m, 2H), 4.18-4.03 (m, 2H), 3.73 (d, 3H), 3.35-3.28 (m, IH), 3.22-2.80 (br, 3H), 1.21-1.19 (ra, 3H); MS (El) for Ci7H19F1N5O3: 488 (MH4).

[00408] Using the same or analogous synthetic techniques and/or substituting with alternative reagents, the following compounds of the invention were prepared:

Example 37(a). 3-((15)-1 -Aminoethyl]-1 -({5-((4-bromo chlorophenyl)amino] fluoro-l-methyl-l/Abenzimidazol yl} carbony l)azetidin~3~ol hydrochloride. MS (El) for C2oH2oBrClEN502’. 498 (MH4) with a chloro, bromo isotope pattern Example 37(b). 1 -({5-[(4-Bromo chlorophenyl)ammo] fluoro-1 -methyl-1/7-benzimidazoI yl}carbonyl) [(25)-piperidin yl]azetidin oi hydrochloride. *H NMR (400 MHz, CD3OD): 9.42 (s, IH), 7.97-7.96 (m, IH), 7.57 (s, IH), 7.30-7.27 (m, IH), 6.70- 6,66 (ra, IH), 4.60-4.55 (m, IH), 4.28 (t, IH), 4.19 (s, 3H), 4.13-3.98 (m, 2H), 3,38-3,32 (ra, 2H), 3,00 (t, IH), 1,86-1.30 (ra, 6H). MS (El) for Cxs^BrClFNjOz. HCl: 538 (MH4) with a chloro, bromo isotope pattern EXAMPLE 38 l-({3-[(2-fluoro iodopbeftyl)amino]pyridm yl}carb0nyl) [(2X)-pipendm ylJazetidin ol

<img img-format="tif" img-content="drawing" file="IL229136AD0002111.tif" id="idf0111" />

[00409] 3-[(2-FIuoro Iodophenyl)amino]pyridine carboxylic acid (200 mg, 0.559 mmol), prepared using procedures similar to those described in WO 2006/045514, was suspended in DMF (7 mL) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) and 1-(3-dimethylaminopropyl) ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol) were added. The mixture was stirred at ambient for 10 minutes and then triethylamine (0,078 mL, 0.559 mmol) was added. After a further 20 minutes, 1,1-dimethylethyl (25) (3-hy droxyazetidin yl)piperidine~l -carboxylate (143 mg, 0.559 mmol), prepared using similar procedures to those described in Example 22(a) and 22(b), and triethylamine (0.16 mL, 1.15 mmol) were added and the mixture was stirred for 15 hours. The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic portion was washed with 5% lithium 265 chloride and twice with saturated sodium bicarbonate, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 60-80% ethyl acetate in hexanes) to give 1,1-dimethylethyl (2jS)-2“[l-({3-[(2-fluoro iodophenyl)amino]pyridin yl}carbonyl)“3~hydroxyazetidin yl]piperidine-l-carboxylate (368 mg, 0.587 mmol, 74% yield): &amp;#905; NMR (400 MHz, CDC13): 8.73 (br m, IH), 8.62 (br s, IH), 8.14 (d, IH), 7.47 (dd, IH), 7.43-7.39 (m, IH), 7.20-7,12 (m, 2H), 4.38-4.21 (m, 2H), 4.16-4.01 (m, 2H), 4.01-3.88 (m, IH), 3.44-3.30 (m, IH), 2.98-2.83 (m, IH), 2.00-1.88 (m, IH), 1.71-1.50 (m, 6H), 1.44 (s, 9H); MS (El) for C25H30FIN4O4: 597 (MH*).

[00410] 1,1 -Dimethylethyl (2&lt;S) [l-((3-[(2-fluoro iodophenyl)ammo]pyridin yl}carbonyl) hydroxyazetidin yl]piperidme“l-carboxylate (24 mg, 0,040 mmol) was dissolved in methanol (2 mL) and treated with 4 N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at reflux for 20 minutes. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-((3-((2-fluoro~4-iodophenyl)amino]pyridin yl}carbonyl) [(2i$')-piperidin yl]azetidin ol acetate (14 mg, 0.025 mmol, 63% yield): !H NMR (400 MHz, d6~DMSO): 8.62 (br s, IH), 8.46 (s, IH), 8.18 (dd, IH), 7.65 (dd, IH), 7.45 (d, IH), 7.37 (t, IH), 7.16-7.08 (m, IH), 4.25 (dd, IH), 4.04 (dd, IH), 3.90 (t, IH), 3.70 (d, IH), 2.95 (br d, IH), 2.52-2.42 (m, 2H), 1.78-1.68 (m, IH), 1,57 (br t, IH), 1.47 (br d, IH), 1.35-1.13 (m, 2H), 1,10-0.96 (m, IH); MS (El) for C2oH22FIN402: 497 (MH*). EXAMPLE 39 l-({3-[(2-fluor0 i0d0phenyI)amiMoJ-l~0xid0pyridin~4-yI}carbonyl)~3~[(2X)-piperidin yl]azetidin ol

<img img-format="tif" img-content="drawing" file="IL229136AD0002112.tif" id="idf0112" />

<img img-format="tif" img-content="drawing" file="IL229136AD0002113.tif" id="idf0113" />

[00411] 1,1-Dimethylethyl (25) [l-((3-[(2-fiuoro iodophenyl)amino]pyridin yl}carbonyl) hydroxyazetidin yl]piperidine-l-carboxylate (80 mg, 0.134 mmol), prepared using procedures similar to those described in Example 38, was dissolved in dichloromethane (3 mL) and treated with 3-chloroperoxybenzoic acid (73% pure; 32 mg, 266 0.135 mmol) at ambient for 7 hours. 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) was added and the mixture was stirred for 15 hours. The mixture was purified by column chromatography (silica gel, 0-10% ethanol in ethyl acetate) to give 1,1-dimethylethyl (25) [ 1 -({3~[(2-fluoro iodophenyl)amino]-1 -oxidopyridin yl} carbonyl)-3 -hydroxyazetidin yl]piperidine-l-carboxylate (57 mg, 0.093 mmol, 69% yield): 3H NMR (400 MHz, CDC13): 9.38 (s, IH), 8.00 (s, IH), 7.68 (dd, IH), 7.51 (dd, IH), 7.46 (d, IH), 7.19 (br d, IH), 7.09 (t, IH), 5.78 (br, IH), 4.44-3.98 (m, 3H), 3.98-3.87 (m, IH), 3.49-3.39 (m, IH), 3,07-2.88 (ra, IH), 2.01-1.91 (ra, IH), 1.70-1.47 (m, 6H), 1.45 (s, 9H); MS (El) for C25H3oFIN405: 613 (MH4).

[00412] 1,1 -Dimethylethyl (25) [ 1 -((3-((2-fluoro iodophenyl)amino]-1 -oxidopyridin yl}carbonyl) hydroxyazetidin yl]piperidine-l-carboxylate (57 mg, 0.093 mmol) was dissolved in methanol (2 mL) and treated with 4N hydrochloric acid in dioxane (0,25 mL, 1 mmol) at 50 °C for 2.25 hours. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-((3-((2-fluoro-4“iodophenyl)amitto]-l-oxidopyridin yl}carbonyl)~3“[(2S)-piperidin yl]azetidin-3~ ol acetate (35 mg, 0.061 mmol, 66% yield): *H NMR (400 MHz, d6-DMSO): 7,83 (s, IH), 7.72 (dt, 2H), 7.55-7.51 (m, IH), 7.47-7.41 (m, IH), 7.24 (t, IH), 4.45-4.32 (ra, IH), 4.14-3.95 (m, 2H), 3.72 (d, IH), 2.97 (d, IH), 2.58-2.43 (ra, 2H), 1.80-1.73 (m, IH), 1.67-1.55 (ra, IH), 1.49 (br d, IH), 1.38-1.16 (ra, 2H), 1.16-1.01 (m, IH); MS (El) for C20H22FIN4O3: 513 (MH4). EXAMPLE 40 l-({3,4-difhior0 [(2-fiuoro iodophenyI)ammo]phenyl}earbonyl) [(15)-l- (methylaniino)ethyl]azetidin ol [00413] To 3-((15)-l-aminoethyl] (( 3,4-difluoro-2~[(2-fluoro iodophenyl)amino]phenyl}carbonyl)azetidin ol (87.4 mg, 0.18 mmol), prepared using similar procedures to those described in Example 28, was added formaldehyde (37% aqueous, 14 mg, 0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol). The mixture was stirred for 3 h at rt, after which sodium borohydride (16 mg, 0.42 mmol) 267 was added. Upon stirring an additional 1.25 h, more formaldehyde (37% aqueous, 1 drop) was added, and the mixture was stirred 3 days at rt. A further small spatula (-50 mg) of sodium borohydride was then added, and the mixture was stirred at rt for 30 min. After quenching with 1 N HCl, the reaction mixture was purified directly by preparative HPLC.

The clean material was converted to its hydrochloride salt to provide l-({3,4~difIuoro [(2-fiuoro-44odophenyl)amino]phenyl}carbonyl) [(liS')-l-(methylamino)ethyl]azetidin ol as a yellow solid (21.7 mg, 0.040 mmol, 22% yield). !HNMR (400 MHz, CD3OD) δ 7.47 (dd, IH), 7.36 (d, IH), 7.31 (m, IH), 7.06 (q, IH), 6.62 (dt, IH), 4.36 (dd, IH), 4.21-3.91 (m, 3H), 3,44 (q, IH), 2.66 (s, 3H), 1.29 (br m, 3H); MS (El) for Ci9Hi9F3IN3O2: 506 (MH*).

Biological Example 1 Biochemical Assay [00414] For a biochemical measurement of MEKl inhibitory activity, compounds of the invention were screened in a triple coupled cRaf-MEK-ERK2 assay using ALPHASCREEN (Registered Trademark of Perkin Elmer) technology (Perkin Elmer), The compound of the invention, 0.5 pL of 100% DMSO stock solution, is diluted into an assay buffer composed of 20 mM Tris (pH = 7.5), 10 mM magnesium chloride, 0.03% CHAPS and 1 mM DTT. Subsequently, 10 pL of substrate mixture is added composed of unactive MEKl (3 nM), ATP (50 pM), unactive ERK2 (4 nM), biotinylated MBP peptide (b-FFKNIVTPRTPPPSQGK, 1 pM) and antiphospho MBP peptide (0.5 nM). The mixture is then gently shaken for 30 minutes at room temperature followed by addition of active cRaf (5 pL at 0.5 nM) to initiate reaction. The mixture is then shaken for 100 minutes at room temperature then quenched by addition of 10 pL of a mixture of 5pg/mL streptavidin donor beads and 5pg/mL protein A acceptor beads in detection buffer (75 mM Hepes pH ~ 7,5, 300 mM sodium chloride, 120 mM EDTA, 0.3% BSA and 0.03% Tween), followed by incubation overnight and signal detection on an ALPHAQuest® (Registered Trademark of Perkin Elmer) plate reader (Perkin Elmer).

[00415] Compounds of the invention are inhibitors of MEK. The extent to which these compounds are MEK inhibitors can be determined by one of ordinary skill in the art. In particular, the compounds can he tested in the assay described in Biological Example 1.

When tested in that assay, certain compounds of the invention demonstrated the ability to bind to MEK. In one embodiment of the invention, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 4 pM or less. In another 268 embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 3 μΜ or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 2 μΜ or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 1.6 μΜ or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 1 μΜ or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.7 μΜ or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.3 μΜ or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.2 μΜ or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0.1 μΜ or less. In another embodiment, the MEK inhibitor is selected from the compounds in Table 1 having a MEK-binding affinity of about 0,05 μΜ or less.

Biological Example 2

Endogenous ERK Phosphorylation ELISA Assay (00416] MDA-MB-231T (ATCC), Calu-6 (ATCC), HCT 116 (ATCC), A2058 (ATCC), and A375 (ATCC) cells were seeded at 20000, 30000, 30000, 20000, and 30000 cells/well, respectively, onto black 96-well microtiter plates (Costar 3904), in DMEM (Cellgro) containing 10% FBS (Heat-Inactivated, Cellgro), 1% NEAA (Cellgro), and 1% Pen/Strep (Cellgro). SK-MEL-28 (ATCC) cells were seeded at 20000 cells/well in MEM (ATCC) containing 10% FBS (Heat-Inactivated, Cellgro), and 1% Pen/Strep (Cellgro), The cells were then incubated at 37°C, 5% CO2 for 24 h. Serum starvation was performed by replacing the medium with serum-free DMEM or MEM for an additional 24 h. Serial dilutions of test compounds in fresh serum-free medium in a final concentration of 0.3% DMSO (vehicle) were added to the cells and incubated for 1 h. Negative control wells were in serum-free medium + 0.3% DMSO only. After treatment, the medium was removed and cells were fixed with 4% formaldehyde, followed by quenching of endogenous peroxidases with 0.6% H2O2. Plates were then blocked (10% FBS, Cellgro) and incubated with mouse monoclonal anti-phospho-p44/42 MAPK, E10 (1:2000, Cell Signaling), followed by secondary antibody 269 (HRP-conjugated, goat anti-mouse IgG, 1:3000 from Jackson ImmunoResearch Laboratories, Inc). Washing of the plates was performed with PBS-T (0.1% Triton X-100) in between ail incubation steps, A luminol-based substrate solution was then added and plates read using the Victor Wallac machine, IC50 values were determined based on total ERK phosphorylation with compound treatment versus total ERK phosphorylation with 0.3% DMSO treatment alone.

Biological Example 3 BrdU Cell Proliferation Assay [00417] MDA-MB-231T (ATCC), Calu-6 (ATCC), HCT 116 (ATCC), A2058 (ATCC), A375 (ATCC), and Colo-205 (ATCC) cells were plated at densities of 2500, 3500, 3500, 2500, 3500, and 15000 cells/well onto 96-well microtiter plates (Cat# 3904, Costar), in DMEM (Cellgro) containing 10% FBS (Heat Inactivated, Cellgro), 1% Pen/Strep (Cellgro), and 1% NEAA (Cellgro). SK MEL-28 (ATCC) and WM 4 (ATCC) were plated at densities of 2000 and 6000 cells/well in MEM (ATCC) containing 10% FBS (Heat-Inactivated, Cellgro), and 1% Pen/Strep (Cellgro). The cells were incubated overnight at 37°C, 5% CO2 for 18 h. The next day, cells were treated with a serial dilution of compound in medium (containing a final concentration of 0.3% DMSO). Triplicate wells were used for each compound concentration. The control wells received 0.3% DMSO media. The cultures were incubated at 37°C, 5% CO2 for an additional 48 h, The cells were assayed for proliferation according to the “Cell Proliferation ELISA, Bromo Deoxyuridine (BrdU) (chemiluminescence) kit” from Roche. The cells were treated with the BrdU labeling solution and then fixed with FixDenat solution. Anti-BrdU-POD (PerOxiDase) conjugate was added to the cells, after which the plates were washed 3x with IX PBS. Substrate solution was added, and the plates were read for luminescence using the Victor Wallac machine. IC50 values were calculated based on the cell proliferation with compound treatment compared to the vehicle control.

Biological Example 4 In vivo mouse models [00418] Female athymic nude mice (NCr) 5-8 weeks of age and weighing approximately 20g were purchased from Taconic (Germantown, NY). Prior to initiation of a study, the animals were allowed to acclimate for a minimum of 48 h. During these studies, animals were provided food and water ad libitum and housed in a room conditioned at 70-75°F and 270 60% relative humidity. A 12 h light and 12 h dark cycle was maintained with automatic timers.

[00419] Colo-205 human colorectal carcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified, 5% CO2 atmosphere. On day 0. cells were harvested by trypsinization, and 3xl06 cells (passage #3, 92% viability) in 0.1 ml ice-cold Hank’s balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice.

[00420] A3 75 human melanoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified, 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 5xl06 cells (passage #8, &gt;99% viability) in 0.1 mL ice-cold Hank’s balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice, [00421] A2058 human melanoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified, 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 3x106 cells (passage #5, 80% viability) in 0.1 mL ice-cold Hank’s balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice.

[00422] MDA-MB-231 human breast adenocarcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified, 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and lxl06 cells (passage #6, &gt;99% viability) in 0.1 mL ice-cold Hank’s balanced salt solution were implanted subcutaneously into the mammary fat pad of 5-8 week old female athymic nude mice.

[00423] Calu-6 human lung anaplastic carcinoma cells were cultured in vitro in DMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone), Penicillin-Streptomycin and non-essential amino acids at 37 °C in a humidified, 5% CO2 atmosphere. On day 0, cells were harvested by trypsinization, and 5x106 cells (passage #8, 96% viability) in 0.1 mL ice-cold Hank’s balanced salt solution were implanted intradermally in the hind-flank of 5-8 week old female athymic nude mice, [00424] For subcutaneous or intradermal tumors, the mean tumor weight of each animal in the respective control and treatment groups was determined twice weekly during the study. 271

Tumor weight (TW) was determined by measuring perpendicular diameters with a caliper, using the following formula: tumor weight (mg) ® [tumor volume ™ length (mm) x width2 (mm2)]/2.

[00425] Percent inhibition of tumor growth (TGI) is determined with the following formula: X" 1 - (Xf-Xo) “X JYf-Xoi * too where Xo ~ average TW of all tumors on group day; Xf = TW of treated group on Day f; Yf = TW of vehicle control group on Day f [00426] If tumors regress below their starting sizes, then the percent tumor regression is determined with the following formula: (Xo-Xf) * 100

V Αβ

A A TGI is calculated individually for each tumor to obtain a mean ± SEM value for each experimental group. Statistical significance is determined using the 2-tailed Student’s t-test (significance defined as P&lt;0,05).

Pharmaceutical Composition Examples [00427] The following are representative pharmaceutical formulations containing a compound of Formula I.

Tablet Formulation

The following ingredients are mixed intimately and pressed into single scored tablets.

Ingredient Quantity per tablet, mg compound of this invention 400 Cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. 272

Ingredient Quantity per tablet, mg compound of this invention 200 lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oral administration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0,05 g granulated sugar 25,5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1,0 g Flavoring 0.035 mL Colorings 0.5 mg distilled water q.s. to 100 mL

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention sodium acetate buffer solution HCl (IN) or NaOH (1 M) water (distilled, sterile) 1.2 g 0.4 M 2.0 mL q.s. to suitable pH q.s.to 20 mL

[00428] All of the above ingredients, except water, are combined and heated to 60-70.degree, C. with stirring. A sufficient quantity of water at 60.degree. C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. to 100 g.

Suppository Formulation [00429] A suppository of total weight 2,5 g is prepared by mixing the compound of the invention with Witepsol.RTM. H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:

Ingredient Quantity per tablet; mg 273

Ingredient Quantity per tablet, mg compound of this invention 500 Witepsol® H-15 balance 274