WO2015069287A1

WO2015069287A1 - Compounds as tyrosine kinase modulators

Info

Publication number: WO2015069287A1
Application number: PCT/US2013/069337
Authority: WO
Inventors: Xialing Guo; Zhen Zhu
Original assignee: Allergan, Inc.
Priority date: 2013-11-08
Filing date: 2013-11-08
Publication date: 2015-05-14

Abstract

The present invention is directed to novel compounds of Formula I. The compounds of the present invention are potent tyrosine kinase modulators, and are suitable for the treatment and prevention of diseases and conditions related to abnormal activities of tyrosine kinase receptors.

Description

COMPOUNDS AS TYROSINE KINASE MODULATORS Inventors: Xialing Guo and Zhen Zhu CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation in part of U.S. Application Serial No. 13/673,437 filed November 9, 2012 which is a continuation in part of U.S. Application Serial No. 12/875,218, filed August 31, 2010, which claims priority under 35 U.S.C. 119(e) to United States Provisional Application Nos. 61 /239,603, filed on Sep 03, 2009, 61/306,616, filed on Feb 22, 2010, 61/356,699 filed on June 21, 2010 and 61/360,531 filed on July 01, 2010, all of which are expressly incorporated herein by reference in their entireties. FIELD OF THE INVENTION The present invention is directed to novel compounds with multiple aromatic

components capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. The present invention is also directed to methods of prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including but not limited to, cell growth disorders, metabolic disorders, blood vessel proliferative disorders, inflammatory disorders, neurodegenerative diseases and immune disorders. BACKGROUND OF THE INVENTION Protein tyrosine kinases (“PTKs”) play an important role in the control of cell growth and differentiation. PTKs comprise a large and diverse class of proteins having enzymatic activity. PTKs can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). For example, signal transduction mediated by receptor tyrosine kinases (“RTKs”) is initiated by extracellular interaction with a specific growth factor (i.e., a ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment). With respect to RTKs, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with RTKs have been identified and are divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack a catalytic domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each RTK is determined not only by its pattern of expression and ligand availability, but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors. The RTKs comprise a large family of transmembrane receptors with diverse biological activities. The intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses. At present, at least nineteen distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, is believed to be comprised of EGFR, HER2, HER3 and HER4. Ligands to the HER subfamily of receptors include epithelial growth factor (EGF), TGF- , amphiregulin, HB-EGF, betacellulin and heregulin. The second subfamily of RTKs, designated the insulin subfamily, is comprised of the INS-R, the IGF-1R and the IR-R. The third RTK subfamily, the“PDGF” family, includes the PDGF α and receptors, CSFIR, c- kit and FLK-II. Another subfamily of RTKs, identified as the FLK family, is believed to be comprised of the kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1). Each of these receptors was initially believed to be a receptor for hematopoietic growth factors. Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron). Because of the similarities between the PDGF and FLK subfamilies, the two subfamilies are often considered together. The known RTK subfamilies are identified in Plowman et al, 1994, DN&P 7(6): 334-339, which is incorporated herein by reference. The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual non- receptor tyrosine kinases, comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non- receptor tyrosine kinases is comprised of the largest number of PTKs, and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporated herein by reference. Many of the protein tyrosine kinases (PTKs), whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways leading to cellular signal cascades and pathogenic conditions such as cancer, psoriasis and hyper immune responses. In view of the importance of PTKs to the control, regulation and modulation of cell proliferation and the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify receptor and non-receptor tyrosine kinase“inhibitors” using a variety of approaches, including the use of mutant ligands (U.S. Patent No. 4,966,849), soluble receptors and antibodies (Kendall & Thomas, 1994, Proc. Nat’l Acad. Sci 90: 10705-09; Kim, et al, 1993, Nature 362: 841-844), RNA ligands (Jellinek, et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell 4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al, 1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (U.S. Patent No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. Cancer Res. 35: 2268). More recently, attempts have been made to identify small molecules which act as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT Application No. WO 92/20642), vinylene-azaindole derivatives (PCT Application No. WO 94/14808) and 1-cyclopropyl-4-pyridyl-quinolones (U.S. Patent No. 5,330,992) have been described generally as tyrosine kinase inhibitors. Styryl compounds (U.S. Patent No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0566 266 A1), seleoindoles and selenides (PCT Application No. WO 94/03427), tricyclic polyhydroxylic compounds (PCT Application No. WO 92/21660) and benzylphosphonic acid compounds (PCT Application No. WO 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer. In addition, other small molecules were studied as tyrosine kinase inhibitors, such as the compounds disclosed in U.S. Pat. Nos. 6,765,012; 6,541,504; 6,747,025; 5,792,783; 5,834,504; 5,883,113; 5,883,116 and 5,886,020, all of which are incorporated by reference in their entireties. The identification and use of compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine is one aspect of the present invention. SUMMARY OF THE INVENTION The present invention is directed to compounds represented by Formula I capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction, and uses of the compounds and compositions incorporating the compounds for disease treatment and prevention. The compounds of the present invention can be found in general Formula I:

Formula I

wherein X is selected from the group consisting of NR¹, O, S(O)_n; n is 0 or an integer of from 1 to 2; R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^I is selected from the group consisting of hydrogen, halogen, C₁ to C₈ alkyl, S(O)_fR⁴, (CR⁵R⁶)_dC(O)OR⁴, S(O)_f(CR⁵R⁶)_dC(O)OR⁴, (CR⁵R⁶)_dAr, NR⁴(CR⁵R⁶)_dAr, O(CR⁵R⁶)_dAr, S(O)_f(CR⁵R⁶)_dAr, (CR⁵R⁶)_dS(O)_fR⁴, NR⁴(CR⁵R⁶)_dS(O)_fR⁴, O(CR⁵R⁶)_d S(O)_fR⁴,

S(O)_f(CR⁵R⁶)_eS(O)_fR⁴, (CR⁵R⁶)_dC(O)N(R⁴)₂, NR⁴(CR⁵R⁶)_dC(O)N(R⁴)₂,

O(CR⁵R⁶)_dC(O)N(R⁴)₂, S(O)_f(CR⁵R⁶)_eC(O)N(R⁴)₂, (CR⁵ R⁶)_dOR⁴, S(O)_f(CR⁵R⁶)_dOR⁴, (CR⁵ R⁶)_dOSO₂R⁴, S(O)_f(CR⁵ R⁶)_eOSO₂R⁴, (CR⁵ R⁶)_dP(O)(OR⁴)₂, S(O)_f(CR⁵ R⁶)_eP(O)(OR⁴)₂, OC(O)(CR⁵R⁶)_dN(R⁴)₂, C(O)(CR⁵R⁶)_dN(R⁴)₂, C(O)N=S(O)R⁵ R⁶, NR²C(O)(CR⁵R⁶)_dN(R⁴)₂, (CR⁵R⁶)_dR⁵, S(O)_f(CR⁵R⁶)_dR⁵, HNC(O)R⁴, HN-C(O)OR⁴, (CR⁵R⁶)_dN(R⁴)_2, S(O)_f

(CR⁵R⁶)_dN(R⁴)₂, OC(O)OR⁴, (CR⁵R⁶)_dC(O)(CR⁵R⁶)_dR⁴, (CR⁵R⁶)_dC(O)(CR⁵R⁶)_dOR⁴, and (CR⁵R⁶)_dC(O)(CR⁵R⁶)_dN(R⁴)₂, wherein each R⁴ is independently selected from the group consisting of hydrogen, hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, (CR⁵R⁶)_d and N(R⁴)₂ may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N- methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be optionally substituted with up to three of R⁵; wherein R⁵ and R⁶ are independently selected from the group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl,

hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR⁵R⁶)_d and (CR⁵R⁶)_e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate; a is 0 or an integer of from 1 to 3; d is 0 or an integer of from 1 to 5; e is an integer of from 1 to 4; f is 0 or an integer of from 1 to 2; R^II is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR²R³)alkoxy, (NR²R³)alkenyl, (NR²R³)alkyl,

(NR²R³)carbonylalkenyl, and (NR²R³)carbonylalkyl, wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; b is 0 or an integer of from 1 to 2; Y is selected from the group consisting of: (1’)—(CH₂)g—O—(CH₂)h—;

(2’)—(CH₂)g—NR¹—(CH₂)h—;

(3’)—(CH₂)g—S(O)_n—(CH₂)h—;

(4’)—(CH₂)g—SO₂N R²—(CH₂)h—;

(5’)—(CH₂)g—NR²SO₂—(CH₂)h—;

(6’)—(CH₂)g— CO—(CH₂)h—;

(7’)—(CH₂)g— C(O)NR²—(CH₂)h—;

(8’)—(CH₂)g— NR²C(O )—(CH₂)h—;

(9’)—(CH₂)g—C≡C—(CH₂)h—;

(10’)—(CH₂)g— NR²C(O)NR³—(CH₂)h—;

(11’)—(CH₂)g—(CH₂)h—;

(12’)—(CH₂)g—CF₂—(CH₂)h—;

(13’)—(CH₂)g—CCl₂—(CH₂)h—;

(14’)—(CH₂)g—CHF—(CH₂)h—;

(15’)—(CH₂)g—CH(OH)—(CH₂)h—;

(16’)—(CH₂)g—CR²R³—(CH₂)h—;

(17’)—(CH₂)g—C═C—(CH₂)h—;

and (18’) a single bond;

wherein g is 0 or an integer of from 1 to 3; h is 0 or an integer of from 1 to 3; R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R² and R³ are independently selected from the group consisting of hydrogen, alkyl,

alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered cyclic ring; Ring A is selected from the group consisting of:

(i) Phenyl; (ii) Naphthyl; (iii) A 5 or 6 membered monocyclic heteroaryl group which have 1-5 heteroatoms independently selected from the group consisting of O, N and S; and (iv) An 8 to 10 membered bicyclic heteroaryl group which have 1-6 heteroatoms independently selected from the group consisting of O, N and S; Ring A can be illustrated but not limited to the following:

R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^III represents optionally 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₅ alkoxy, hydroxy, amino, C₁-C₅ alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro; Z is selected from the group consisting of (1’) (CH₂)_iN(R⁷)C(O)N(R⁸)(CH₂)_j; (2’) (CH ⁸

2)_iN(R⁷)C(S)N(R )(CH₂)_j; (3’) (CH₂)_iN(R⁷)C(O)_; (4’) C(O)N(R⁸)(CH₂)_j; (5’) (CH₂)_iN(R⁷)S(O)₂; and (6’) S(O)₂N(R⁸)(CH₂)_j; wherein i is 0 or 1; j is 0 or 1; R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl. Ring B is selected from the group consisting of:

(i’) Phenyl; (ii’) Naphthyl; (iii’) A 5 or 6 membered monocyclic heteroaryl group which have 1-3 heteroatoms independently selected from the group consisting of O, N and S; and (iv’) An 8 to 10 membered bicyclic heteroaryl group which have 1-3 heteroatoms independently selected from the group consisting of O, N and S;

Ring B can be illustrated but not limited to the following:

wherein R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR⁹R¹⁰; wherein R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl. Some embodiments of the present invention are included in the following paragraphs:

(1) A compound according to Formula I, including any tautomer, stereoisomer,

diastereoisomeric form, polymorphic form, crystal form, a solvate, a hydrate, a metabolite, a pharmaceutically acceptable salt or prodrug, mixture of different stereoisomers, and any mixture of different crystal forms. (2) A compound of Formula I in the form of a prodrug.

(3) The compound according to paragraph 1, wherein Z is selected from the group consisting of (CH₂)_iN(R⁷)C(O)_, C(O)N(R⁸)(CH₂)_j, (CH₂)_iN(R⁷)S(O)₂ and S(O)₂N(R⁸)(CH₂)_j. (4) The compound according to paragraphs 1– 3, wherein Y is selected from the group consisting of —(CH₂)g—O—(CH₂)h—;—(CH₂)g—NR¹—(CH₂)h—; —(CH₂)g—S(O)_n—(CH₂)h—;—(CH₂)g—SO₂N R²—(CH₂)h—;

—(CH₂)g—NR²SO₂—(CH₂)h—;—(CH₂)g— CO—(CH₂)h—;

—(CH₂)g— C(O)NR²—(CH₂)h—;—(CH₂)g— NR²C(O )—(CH₂)h—;

—(CH₂)g—C≡C—(CH₂)h—;—(CH₂)g— NR²C(O)NR³—(CH₂)h and a single bond. (5) The compound according to paragraphs 1– 4, wherein Ring A and Ring B are

independently selected from the group consisting of

(6) The compound according to paragraphs 1– 5, wherein Y is selected from the group

consisting of —(CH₂)g—(CH₂)h—;—(CH₂)g—CF₂—(CH₂)h—;—(CH₂)g—CCl₂— (CH₂)h—; —(CH₂)g—CHF—(CH₂)h—; —(CH₂)g—CH(OH)—(CH₂)h—; —(CH₂)g—CR²R³—(CH₂)h—; and—(CH₂)g—C═C—(CH₂)h—. (7) The compound according to paragraphs 1– 6, wherein X is NH.

(8) A compound selected from the group consisting of (1’) [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin- 2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetic acid;

(2’) methyl [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}

phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetate;

(3’) ({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)acetic acid;

(4’) methyl ({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)acetate;

(5’) 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3- carboxylic acid;

(6’) methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole- 3-carboxylate;

(7’) 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-N-hydroxy-1H-pyrrole-3-carboxamide;

(8’) 4-fluoro-N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypiperidin-1- yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide;

(9) N-(2,3-dihydroxypropyl)-5-[4-(3-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrole-3-carboxamide; (10) N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H- pyrrol-2-yl}pyridin-4-yl)oxy]benzamide;

(11’) 5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N- hydroxy-1H-pyrrole-3-carboxamide;

(12’) methyl 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate; (13’) 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrole-3-carboxylic acid;

(14’) N-ethyl-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxamide;

(15’) N-(2,3-dihydroxypropyl)-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2- yl)-1H-pyrrole-3-carboxamide;

(16’) 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxamide; (17’) N-hydroxy-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole- 3-carboxamide;

(18’) N-(3-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4- yl]oxy}phenyl)-3-methyl-2-furamide;

(19’) 5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrole-3-carboxylic acid;

(20’) methyl 5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrole-3-carboxylate;

(21’) 2,3-dihydroxypropyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)- 1H-pyrrole-3-carboxylate;

(22’) 5-[4-(3-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3- carboxylic acid;

(23’) methyl 5-[4-(3-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrole-3-carboxylate;

(24’) 2-hydroxyethyl 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2- yl]-1H-pyrrole-3-carboxylate;

(25’) 2-hydroxyethyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxylate;

(26’) 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole- 3-carboxylic acid;

(27’) methyl 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H- pyrrole-3-carboxylate;

(28’) 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylic acid;

(29’) methyl 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxylate;

(30’) N-[dimethyl(oxido)-lambda~4~-sulfanylidene]-5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide;

(31’) N-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4- yl]oxy}phenyl)-3-methyl-2-furamide;

(32’) 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid; (33’) methyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylate;

(34’) 3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide;

(35’) methyl 4-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-2- carboxylate;

(36’) 2-fluoro-5-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)benzamide; and (37’) 3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide. (9) The compound according to paragraph 1, wherein Z is (CH₂)_iN(R⁷)C(O)N(R⁸)(CH₂)_j or (CH₂)_iN(R⁷)C(S)N(R⁸)(CH₂)_j, provided that when Ring B is pyrazole, R^IV is not a phenyl or substituted phenyl.

(10) The compound according to paragraph 9, wherein Y is selected from the group

consisting of —(CH₂)g—O—(CH₂)h—;—(CH₂)g—NR¹—(CH₂)h—; —(CH₂)g—S(O)_n—(CH₂)h—;—(CH₂)g—SO₂N R²—(CH₂)h—; —(CH₂)g—NR²SO₂—(CH₂)h—;—(CH₂)g— CO—(CH₂)h—; —(CH₂)g— C(O)NR²—(CH₂)h—;—(CH₂)g— NR²C(O )—(CH₂)h—;

—(CH₂)g—C≡C—(CH₂)h—;—(CH₂)g— NR²C(O)NR³—(CH₂)h, and a single bond. (11) The compound according to paragraph 9, wherein Y is selected from the group consisting of —(CH₂)g—(CH₂)h—;—(CH₂)g—CF₂—(CH₂)h—;—(CH₂)g—CCl₂—(CH₂)h—; —(CH₂)g—CHF—(CH₂)h—; —(CH₂)g—CH(OH)—(CH₂)h—;—(CH₂)g—CR²R³— (CH₂)h—; and—(CH₂)g—C═C—(CH₂)h—. (12) The compound according to paragraphs 9– 11, wherein Ring A and Ring B are

independently selected from the group consisting of

(13) The compound according to paragraphs 9– 12, wherein X is NH. (14) The compound according to paragraphs 9– 12, wherein X is S. (15) The compound according to paragraphs 9-14, wherein R^I is selected from the group consisting of hydrogen, halogen, C₁ to C₈ alkyl, (CR⁵R⁶)_dC(O)OR⁴, (CR⁵R⁶)_dAr, NR⁴(CR⁵R⁶)_dAr, (CR⁵R⁶)_dC(O)N(R⁴)₂, NR⁴(CR⁵R⁶)_dC(O)N(R⁴)₂,

O(CR⁵R⁶)_dC(O)N(R⁴)₂, (CR⁵ R⁶)_dOR⁴, OC(O)(CR⁵R⁶)_dN(R⁴)₂, C(O)(CR⁵R⁶)_dN(R⁴)₂, C(O)N=S(O)R⁵ R⁶, NR²C(O)(CR⁵R⁶)_dN(R⁴)₂, (CR⁵R⁶)_dR⁵, HNC(O)R⁴, HN-C(O)OR⁴, (CR⁵R⁶)_dN(R⁴)_2, S(O)_f (CR⁵R⁶)_dN(R⁴)₂, OC(O)OR⁴, (CR⁵R⁶)_dC(O)(CR⁵R⁶)_dR⁴, (CR⁵R⁶)_dC(O)(CR⁵R⁶)_dOR⁴, and (CR⁵R⁶)_dC(O)(CR⁵R⁶)_dN(R⁴)₂, wherein each R⁴ is independently selected from the group consisting of hydrogen, hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, (CR⁵R⁶)_d and N(R⁴)₂ may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5- fluoropyrrolidine, piperidine, 6-fluoropiperidine, N-methylpiperazine, morpholine, 2,6- dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be optionally substituted with up to three of R⁵; wherein R⁵ and R⁶ are independently selected from the group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl,

hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR⁵R⁶)_d and (CR⁵R⁶)_e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl,

alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate.

(16) A compound of Formula II:

Formula II wherein

W is C or N;

X is selected from the group consisting of NR¹, O, and S(O)_n;

n is 0 or an integer of from 1 to 2; R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R⁵ and R⁶ are independently selected from the group consisting of hydrogen, halo, hydroxyl, C₁- C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate; R^II is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR²R³)alkoxy, (NR²R³)alkenyl, (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and (NR²R³)carbonylalkyl, wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; b is 0 or an integer of from 1 to 2; Y is selected from the group consisting of:

(1’)—(CH₂)g—O—(CH₂)h—; (2’)—(CH₂)g—NR¹—(CH₂)h—;

(3’)—(CH₂)g—S(O)_n—(CH₂)h—;

(4’)—(CH₂)g—SO₂N R²—(CH₂)h—;

(5’)—(CH₂)g—NR²SO₂—(CH₂)h—;

(6’)—(CH₂)g— CO—(CH₂)h—;

(7’)—(CH₂)g— C(O)NR²—(CH₂)h—;

(8’)—(CH₂)g— NR²C(O )—(CH₂)h—;

(9’)—(CH₂)g—C≡C—(CH₂)h—;

(10’)—(CH₂)g— NR²C(O)NR³—(CH₂)h—;

(11’)—(CH₂)g—(CH₂)h—;

(12’)—(CH₂)g—CF₂—(CH₂)h—;

(13’)—(CH₂)g—CCl₂—(CH₂)h—;

(14’)—(CH₂)g—CHF—(CH₂)h—;

(15’)—(CH₂)g—CH(OH)—(CH₂)h—;

(16’)—(CH₂)g—CR²R³—(CH₂)h—;

(17’)—(CH₂)g—C═C—(CH₂)h—;

and (18’) a single bond;

wherein

g is 0 or an integer of from 1 to 3;

h is 0 or an integer of from 1 to 3;

R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered cyclic ring; Ring A is selected from the group consisting of:

(i) Phenyl;

(ii) Naphthyl;

(iii) A 5 or 6 membered monocyclic heteroaryl group which have 1-5 heteroatoms independently selected from the group consisting of O, N and S; and (iv) An 8 to 10 membered bicyclic heteroaryl group which have 1-6 heteroatoms independently selected from the group consisting of O, N and S; Ring A can be illustrated but not limited to the following:

wherein

R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,

haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^III represents optionally 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₅ alkoxy, hydroxy, amino, C₁-C₅ alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro; Z is selected from the group consisting of (1’) (CH₂)_iN(R⁷)C(O)N(R⁸)(CH₂)_j;

(2’) (CH₂)_iN(R⁷)C(S)N(R⁸)(CH₂)_j;

(3’) (CH₂)_iN(R⁷)C(O)_;

(4’) C(O)N(R⁸)(CH₂)_j;

(5’) (CH₂)_iN(R⁷)S(O)₂;

and (6’) S(O) ⁸

2N(R )(CH₂)_j;

wherein

i is 0 or 1;

j is 0 or 1; R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl; Ring B is selected from the group consisting of:

(i’) Phenyl;

(ii’) Naphthyl;

(iii’) A 5 or 6 membered monocyclic heteroaryl group which have 1-3 heteroatoms

independently selected from the group consisting of O, N and S;

and (iv’) An 8 to 10 membered bicyclic heteroaryl group which have 1-3 heteroatoms independently selected from the group consisting of O, N and S; Ring B can be illustrated but not limited to the following:

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR⁹R¹⁰; wherein R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and any pharmaceutical acceptable salt or prodrug. (17) The compound according to paragraph 16, wherein Z is selected from the group

consisting of (CH₂)_iN(R⁷)C(O)_, C(O)N(R⁸)(CH₂)_j, (CH₂)_iN(R⁷)C(O)N(R⁸)(CH₂)_j and (CH₂)_iN(R⁷)C(S)N(R⁸)(CH₂)_j.

(18) The compound according to paragraphs 16– 17, wherein Y is selected from the group consisting of —(CH₂)g—O—(CH₂)h—;—(CH₂)g—NR¹—(CH₂)h—;

—(CH₂)g—S(O)_n—(CH₂)h—;—(CH₂)g—SO₂N R²—(CH₂)h—;

—(CH₂)g—NR²SO₂—(CH₂)h—;—(CH₂)g— CO—(CH₂)h—;

—(CH₂)g— C(O)NR²—(CH₂)h—;—(CH₂)g— NR²C(O )—(CH₂)h—; —(CH₂)g—C≡C—(CH₂)h—; —(CH₂)g— NR²C(O)NR³—(CH₂)h and a single bond. (19) The compound according to paragraphs 16– 18, wherein Ring A and Ring B are

independently selected from the group consisting of

(20) The compound according to paragraphs 16-19, wherein W is C. (21) A method of use of the compounds of paragraphs 1– 20, wherein the compounds are used as tyrosine kinase modulators; (22) Use of the compounds of paragraphs 1– 20 in the preparation of a medicament for the treatment or prevention of diseases or conditions related with unregulated tyrosine kinase activities, comprising administering a therapeutically effective amount of the compound of paragraphs 1– 20 together with a pharmaceutically acceptable carrier; (23) The use of paragraph 22, wherein the diseases or conditions are selected from the group consisting of cell growth and metabolic disorders, blood vessel proliferative disorders, inflammatory disorders, neurodegenerative diseases, and immune disorders. (24) The use of paragraphs 22– 23 wherein the diseases or conditions are selected from the group consisting of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders.

(25) The use of paragraphs 22– 23 wherein the conditions and diseases are wound healing or to alleviate transplant rejection. (26) A pharmaceutical composition comprising a therapeutic effective amount of a

compound according to paragraphs 1– 20 together with a pharmaceutically acceptable carrier which is suitable for systematic, parenteral, local or topical delivery. (27) The pharmaceutical composition of paragraph 26, which are in the form selected from the group comprising of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, ophthalmic solutions, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts or depots. (28) Use of the compounds of paragraphs 1-20 in the preparation of a medicament for the treatment of diseases and conditions, wherein the medicament contains pharmaceutical acceptable composition according to paragraphs 26 and 27. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a powder X-Ray Diffraction (XRPD) of Example 78; Fig 2 shows a powder X-Ray Diffraction (XRPD) of Example 69; Fig 3 shows a fluorescein angiography (blood-retinal barrier breakdown) of Example 121, Example 84 Sodium, Example 83, Example 78, Example 75 Sodium, Example 69, and Example 66; and Fig 4 shows a fundus photography (retinal vasodilation and vessel tortuosity) of Example 121, Example 84 Sodium, Example 83, Example 78, Example 75 Sodium, Example 69, and Example 66. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a series of compounds with multiple aromatic components useful as protein tyrosine kinase inhibitors. The compounds of the present invention are useful for treating diseases related to unregulated tyrosine kinase signal transduction, for example, cancer, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases. In particular, compounds of the present invention are useful for the treatment of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal

neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, transplant rejection, inflammation, neurodegenerative diseases and immune disorders.

1. Compounds of the Invention In one aspect of the invention, the compounds of the present invention can be represented by the general formula I:

wherein X is selected from the group consisting of NR¹, O, and S(O)_n; n is 0 or an integer of from 1 to 2; R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,

haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^I is selected from the group consisting of hydrogen, halogen, C₁ to C₈ alkyl, S(O)_fR⁴, (CR⁵R⁶)_dC(O)OR⁴, S(O)_f(CR⁵R⁶)_dC(O)OR⁴, (CR⁵R⁶)_dAr, NR⁴(CR⁵R⁶)_dAr, O(CR⁵R⁶)_dAr, S(O)_f(CR⁵R⁶)_dAr, (CR⁵R⁶)_dS(O)_fR⁴, NR⁴(CR⁵R⁶)_dS(O)_fR⁴, O(CR⁵R⁶)_d S(O)_fR⁴,

O(CR⁵R⁶) ⁶

dC(O)N(R⁴)₂, S(O)_f(CR⁵R⁶)_eC(O)N(R⁴)₂, (CR⁵ R )_dOR⁴, S(O)_f(CR⁵R⁶)_dOR⁴, (CR⁵ R⁶)_dOSO₂R⁴, S(O)_f(CR⁵ R⁶)_eOSO₂R⁴, (CR⁵ R⁶)_dP(O)(OR⁴)₂, S(O)_f(CR⁵

R⁶)_eP(O)(OR⁴)₂, OC(O)(CR⁵R⁶)_dN(R⁴)₂, C(O)(CR⁵R⁶)_dN(R⁴)₂, C(O)N=S(O)R⁵ R⁶, NR²C(O)(CR⁵R⁶)_dN(R⁴)₂, (CR⁵R⁶)_dR⁵, S(O)_f(CR⁵R⁶)_dR⁵, HNC(O)R⁴, HN-C(O)OR⁴, (CR⁵R⁶)_dN(R⁴)_2, S(O)_f (CR⁵R⁶)_dN(R⁴)₂, OC(O)OR⁴, (CR⁵R⁶)_dC(O)(CR⁵R⁶)_dR⁴,

(CR⁵R⁶)_dC(O)(CR⁵R⁶)_dOR⁴, and (CR⁵R⁶)_dC(O)(CR⁵R⁶)_dN(R⁴)₂, wherein each R⁴ is independently selected from the group consisting of hydrogen, hydroxyl, C₁-C₈ alkyl, aryl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, (CR⁵R⁶)_d and N(R⁴)₂ may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be optionally substituted with up to three of R⁵; wherein R⁵ and R⁶ are independently selected from the group consisting of hydrogen, halo, hydroxyl, C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR⁵R⁶ may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR⁵R⁶)_d and (CR⁵R⁶)_e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, C₁-C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate; a is 0 or an integer of from 1 to 3; d is 0 or an integer of from 1 to 5; e is an integer of from 1 to 4; f is 0 or an integer of from 1 to 2; R^II is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR²R³)alkoxy, (NR²R³)alkenyl, (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and (NR²R³)carbonylalkyl, wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; b is 0 or an integer of from 1 to 2; Y is selected from the group consisting of: (1’)—(CH₂)g—O—(CH₂)h—; (2’)—(CH₂)g—NR¹—(CH₂)h—; (3’)—(CH₂)g—S(O)_n—(CH₂)h—; (4’)—(CH₂)g—SO₂N R²—(CH₂)h—; (5’)—(CH₂)g—NR²SO₂—(CH₂)h—; (6’)—(CH₂)g— CO—(CH₂)h—; (7’)—(CH₂)g— C(O)NR²—(CH₂)h—; (8’)—(CH₂)g— NR²C(O )—(CH₂)h—; (9’)—(CH₂)g—C≡C—(CH₂)h—; (10’)—(CH₂)g— NR²C(O)NR³—(CH₂)h—; (11’)—(CH₂)g—(CH₂)h—; (12’)—(CH₂)g—CF₂—(CH₂)h—; (13’)—(CH₂)g—CCl₂—(CH₂)h—; (14’)—(CH₂)g—CHF—(CH₂)h—; (15’)—(CH₂)g—CH(OH)—(CH₂)h—; (16’)—(CH₂)g—CR²R³—(CH₂)h—; (17’)—(CH₂)g—C═C—(CH₂)h—; and (18’) a single bond. wherein g is 0 or an integer of from 1 to 3; h is 0 or an integer of from 1 to 3; R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,

haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered cyclic ring; Ring A is selected from the group consisting of:

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N. R^III represents optionally 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₅ alkoxy, hydroxy, amino, C₁-C₅ alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro; Z is selected from the group consisting of (1’) (CH₂)_iN(R⁷)C(O)N(R⁸)(CH₂)_j; (2’) (CH₂)_iN(R⁷)C(S)N(R⁸)(CH₂)_j; (3’) (CH₂)_iN(R⁷)C(O)_; (4’) C(O)N(R⁸)(CH₂)_j; (5’) (CH₂)_iN(R⁷)S(O)₂; and (6’) S(O)₂N(R⁸)(CH₂)_j; wherein i is 0 or 1; j is 0 or 1; R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl;

Ring B is selected from the group consisting of:

(i’) Phenyl; (ii’) Naphthyl; (iii’) A 5 or 6 membered monocyclic heteroaryl group which have 1-3 heteroatoms independently selected from the group consisting of O, N and S; and (iv’) An 8 to 10 membered bicyclic heteroaryl group which have 1-3 heteroatoms independently selected from the group consisting of O, N and S; Ring B can be illustrated but not limited to the following:

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^IV represents optionally 1-3 substituents, independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR⁹R¹⁰; wherein R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; In another aspect of the invention, the compounds of the present invention can be represented by the general formula II:

wherein

W is C or N;

X is selected from the group consisting of NR¹, O, and S(O)_n;

heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R⁵ and R⁶ are independently selected from the group consisting of hydrogen, halo, hydroxyl, C₁- C₈ alkyl, C₁-C₈ hydroxyalkyl, C₁-C₈ alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, and sulfonate; R^II is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR²R³)alkoxy, (NR²R³)alkenyl, (NR²R³)alkyl, (NR²R³)carbonylalkenyl, and (NR²R³)carbonylalkyl, wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; b is 0 or an integer of from 1 to 2; Y is selected from the group consisting of:

(1’)—(CH₂)g—O—(CH₂)h—;

(2’)—(CH₂)g—NR¹—(CH₂)h—;

(3’)—(CH₂)g—S(O)_n—(CH₂)h—;

(4’)—(CH₂)g—SO₂N R²—(CH₂)h—;

(5’)—(CH₂)g—NR²SO₂—(CH₂)h—;

(6’)—(CH₂)g— CO—(CH₂)h—;

(7’)—(CH₂)g— C(O)NR²—(CH₂)h—;

(8’)—(CH₂)g— NR²C(O )—(CH₂)h—;

(9’)—(CH₂)g—C≡C—(CH₂)h—;

(10’)—(CH₂)g— NR²C(O)NR³—(CH₂)h—;

(11’)—(CH₂)g—(CH₂)h—;

(12’)—(CH₂)g—CF₂—(CH₂)h—;

(13’)—(CH₂)g—CCl₂—(CH₂)h—;

(14’)—(CH₂)g—CHF—(CH₂)h—;

(15’)—(CH₂)g—CH(OH)—(CH₂)h—;

(16’)—(CH₂)g—CR²R³—(CH₂)h—;

(17’)—(CH₂)g—C═C—(CH₂)h—;

and (18’) a single bond;

wherein

g is 0 or an integer of from 1 to 3;

h is 0 or an integer of from 1 to 3;

(i) Phenyl;

(ii) Naphthyl;

(iii) A 5 or 6 membered monocyclic heteroaryl group which have 1-5 heteroatoms independently selected from the group consisting of O, N and S;

and (iv) An 8 to 10 membered bicyclic heteroaryl group which have 1-6 heteroatoms independently selected from the group consisting of O, N and S; Ring A can be illustrated but not limited to the following:

wherein

R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^III represents optionally 1-3 substituents independently selected from the group consisting of C₁-C₅ linear or branched alkyl, C₁-C₅ linear or branched haloalkyl, C₁-C₅ alkoxy, hydroxy, amino, C₁-C₅ alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro; Z is selected from the group consisting of (1’) (CH₂)_iN(R⁷)C(O)N(R⁸)(CH₂)_j;

(2’) (CH₂)_iN(R⁷)C(S)N(R⁸)(CH₂)_j;

(3’) (CH₂)_iN(R⁷)C(O)_;

(4’) C(O)N(R⁸)(CH₂)_j;

(5’) (CH₂)_iN(R⁷)S(O)₂;

and (6’) S(O)₂N(R⁸)(CH₂)_j;

wherein

i is 0 or 1;

j is 0 or 1;

R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl. Ring B is selected from the group consisting of:

(i’) Phenyl;

(ii’) Naphthyl;

(iii’) A 5 or 6 membered monocyclic heteroaryl group which have 1-3 heteroatoms independently selected from the group consisting of O, N and S;

wherein R¹ is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF₃, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R²R³), wherein R² and R³ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R²and R³ and may be taken together to form a 5-7 membered heterocyclic ring with N; R^IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR⁹R¹⁰; wherein R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

and including any pharmaceutically acceptable salt or prodrug. Unless otherwise indicated, reference to a compound should be construed broadly to include compounds, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, diastereoisomers, alternate solid forms, crystal forms, polymorphic forms, hydrates, solvates, metabolites, mixtures of stereoisomers, mixtures of crystal forms, non-covalent complexes, and combinations thereof, of a chemical entity of a depicted structure or a chemical name. Whenever there is a conflict between chemical name and its structure drawing, the structure drawing should be used to interpret the compound of the present invention. A pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt. A salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions). A "prodrug" is a compound, which when administered to the body of a subject (such as a mammal), breaks down in the subject's metabolic pathway to provide an active compound of Formula I. More specifically, a prodrug is an active or inactive "masked" compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject or patient. One common form of a prodrug is a masked carboxylic acid group. Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Prodrug preparation is well known in the art. For example,“Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.

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58

Additional compounds of the present invention are listed below.

3.1 Compound Synthesis and Characterization Preparation of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate

To a mixture of methyl-1H-pyrrole-3-carboxylate (5.0 g, 39.9 mmol), bis(pinacolato)diboron (5.37 g, 21.1 mmol), 4,4’-di-tert-butyl-2,2’-bipyridine (0.054 g, 0.20 mmol) and [Ir(OMe)(COD)]₂ (0.067 g, 0.099 mmol) was added cyclohexane (60 mL). The mixture stirred at 90°C for 5 hours. The mixture was cooled to room temperature and filtered, washing with ample amounts of water and twice with hexanes. The light orange solid was collected and dried in a vacuum oven at 55°C to afford methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrole-3-carboxylate (6.99 g, 70% yield). Preparation of 3-(2-Bromo-pyridin-4-yloxy)-benzoic acid

A mixture of 2-bromo-4-chloro-pyridine (200mg, 1.04mmol), methyl-3-hydroxybenzoate (158mg, 1.04mmol), cesium carbonate (507mg, 1.56mmol) in 10ml of anhydrous DMSO was heated at 66°C for 5 hours. The mixture was diluted with ethyl acetate (100ml), washed with brine (3x50ml), dried over Na₂SO₄ and evaporated to give a colorless oil. The oil was dissolved in MeOH (8ml), and 2M NaOH solution (4ml, 8mmol) was added. The mixture was heated at 60°C for 20 minutes, poured into 50ml of water, and acidified to pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give 3-(2-bromo-pyridin-4-yloxy)-benzoic acid as white solid. Yield: 170mg, 56%.

1H NMR (DMSO-d₆): 13.24 (br. s., 1H), 8.27 (d, J = 5.9 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.58 - 7.68 (m, 2H), 7.45 - 7.52 (m, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 5.7, 2.2 Hz, 1H) LR MS (ES-): 292 (M-H), 294 Preparation of 3-(2-Bromo-pyridin-4-yloxy)-N-m-tolyl-benzamide

A mixture of 3-(2-bromo-pyridin-4-yloxy)-benzoic acid (170mg, 0.58mmol), HATU (265mg, 0.69mmol),) m-toluidine (93mg, 0.87mmol) and N,N-diisopropylethylamine (164mg, 1.28mmol) in anhydrous DMF (10ml) was stirred at room temperature for 20 minutes. The mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 3-(2-Bromo-pyridin-4-yloxy)-N-m-tolyl-benzamide as off-white solid. Yield: 150mg, 68%.

1H NMR (DMSO-d₆): 10.18 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.50 - 7.60 (m, 2H), 7.45 (dd, J = 7.9, 1.8 Hz, 1H), 7.16 - 7.25 (m, 2H), 7.02 (dd, J = 5.7, 2.2 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 2.29 (s, 3H)

LR MS (ES+): 405 (M+Na⁺), 407

LR MS (ES-): 381 (M-H), 383 Preparation of 3-(2-Bromo-pyridin-4-yloxy)-N-(2-fluoro-5-methyl-phenyl)-benzamide

A mixture of 3-(2-bromo-pyridin-4-yloxy)-benzoic acid (200mg, 0.68mmol), HATU (312mg, 0.82mmol),) 2-fluoro-5-methylaniline (125mg, 1.0mmol) and N,N-diisopropylethylamine (193mg, 1.5mmol) in anhydrous DMF (10ml) was stirred at 60°C for 90 minutes. The mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 3-(2-bromo-pyridin-4-yloxy)-N-(2-fluoro-5-methyl-phenyl)-benzamide as off- white solid. Yield: 200mg, 74%. Example 1

[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]acetic acid

To a stirred solution of methyl [({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetate (110mg, 0.21mmol) in a mixture of solvents THF/MeOH (5ml/5ml) was added 1M NaOH solution (1ml, 1mmol). The mixture was stirred at room temperature for 1 hour, and poured into 100ml of water. 2M HCl was added until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give [({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]acetic acid as white solid. Yield: 100mg, 93%.

1H NMR (DMSO-d₆): 12.41 (br. s., 1H), 11.87 (br. s., 1H), 10.12 (s, 1 H), 8.42 (d, J = 5.6 Hz, 1H), 8.19 (t, J = 6.0 Hz, 1H), 7.95 - 8.04 (m, 2H), 7.63 (dd, J = 10.1, 8.7 Hz, 1H), 7.41 (dd, J = 3.1, 1.6 Hz, 1H), 7.35 (dd, J = 7.3, 1.8 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.09 - 7.18 (m, 2H), 7.04 (td, J = 5.3, 2.3 Hz, 1H), 6.81 (dd, J = 5.9, 2.3 Hz, 1H), 3.82 (d, J = 5.9 Hz, 2H), 2.27 (s, 3H)

LR MS (ES-): 505 (M-H) Example 2

methyl [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]- 1H-pyrrol-3-yl}carbonyl)amino]acetate

Similar procedure as Example 1.

1H NMR (DMSO-d₆): 11.95 (br. s., 1H), 10.12 (s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 8.33 (t, J = 5.9 Hz, 1H), 7.97 - 8.03 (m, 2H), 7.61 - 7.67 (m, 1H), 7.45 (br. s., 1H), 7.33 - 7.37 (m, 1H), 7.30 (s, 1H), 7.18 (br. s., 1H), 7.14 (dd, J = 10.3, 8.5 Hz, 1H), 7.02 - 7.08 (m, 1 H), 6.86 (br. s., 1H), 3.91 (d, J = 5.9 Hz, 2H), 3.61 (s, 3H), 2.27 (s, 3H)

LR MS (ES+): 521 (MH), 543 (M+Na⁺)

LR MS (ES-): 519 (M-H) Preparation of 4-(3-Aminophenoxy)-2-chloropyridine

To a mixture of 3-aminophenol (3.7 g, 34.09 mmol) in DMSO (50 mL) was added Cs2CO3 (30.7 g, 94.46 mmol). The mixture stirred for 10 minutes and then 2,4-dichloropyridine (5.0 g, 33.79 mmol) was added. The mixture was stirred at 120°C for 1.5 h. The mixture was cooled and diluted with water. The aqueous solution was extracted with EtOAc (3 x 100 mL). The organic extracts were combined, dried over MgSO4 and concentrated to afford a dark oil. The oil was purified via column chromatography, eluting with 30-40% EtOAc/hexanes, to afford 4- (3-Aminophenoxy)-2-chloropyridine (6.63 g, 89%) as a brown solid. Preparation of methyl 5-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate

A mixture of 4-(3-aminophenoxy)-2-chloropyridine (4.0 g, 18.13mmol), methyl-(5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (6.82 g, 27.16mmol) and Pd(PPh3)4 (4.20 g, 3.63mmol) was added to a thick walled reaction vessel and purged with N2. A solution of 2M K2CO3 (13.59 mL) was added, followed by DME (70 mL). The reaction vessel was sealed and the mixture stirred at 92°C for 18 h. The reaction vessel was cooled to room temperature and the mixture was filtered over celite, washing with EtOAc. The filtrate was concentrated and the resultant dark oil was purified via column chromatography, eluting with 40-80% EtOAc/hexanes to afford methyl 5-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3- carboxylate (2.85 g, 51% yield). Example 3

({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)acetic acid

Similar procedure as Example 1.

1H NMR (DMSO-d₆): 12.42 (br. s., 1H), 11.91 (br. s., 1H), 10.20 (s, 1 H), 8.41 (d, J = 5.6 Hz, 1H), 8.21 (t, J = 5.4 Hz, 1H), 7.76 (s, 1H), 7.65 - 7.73 (m, 2H), 7.36 - 7.47 (m, 2H), 7.26 (br. s., 1H), 7.12 (br. s., 1H), 6.86 - 6.98 (m, 1H), 6.77 (br. s., 1H), 6.56 (s, 1H), 3.81 (d, J = 5.9 Hz, 2H), 2.29 (s, 3H)

LR MS (ES-): 459 (M-H) Example 4

methyl ({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)acetate

Similar procedure as Example 3.

1H NMR (DMSO-d₆): 11.88 (br. s., 1H), 10.19 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 8.32 (t, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.65 - 7.72 (m, 2H), 7.36 - 7.44 (m, 2H), 7.23 (d, J = 2.1 Hz, 1H), 7.08 (br. s., 1H), 6.90 (d, J = 7.3 Hz, 1H), 6.75 (dd, J = 5.6, 1.8 Hz, 1H), 6.56 (s, 1H), 3.89 (d, J = 5.6 Hz, 2H), 3.60 (s, 3H), 2.29 (s, 3H)

LR MS (ES+): 475 (MH), 497 (M+Na⁺)

LR MS (ES-): 473 (M-H) Preparation of 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine

To a degassed (15 min, N₂) suspension of 2-chloro-4-iodopyridine (3.0 g, 12.53 mmol), 3- nitroaniline (1.82 g, 13.18 mmol), BINAP (0.39 g, 0.626 mmol) and Cs₂CO₃ (8.16 g, 25.04 mmol) in toluene (72 mL) was added Pd(OAc)₂ (0.084 g, 0.374 mmol). The reaction tube was sealed and the mixture stirred at 90°C for 18 h. The mixture was cooled to rt and filtered, washing with EtOAc. The orange/yellow solid collected was washed with CH₂Cl₂ until all the product washed through into the filtrate. The filtrate was concentrated to afford 2-Chloro-N-(3- nitrophenyl)pyridine-4-amine as a bright yellow solid. Additional product was collected from the solid collected upon concentration of the previous filtrate, after washing with CH₂Cl₂. No further purification. Total amount of product collected was 2.85 g (91% yield). Preparation of tert-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate

To a stirring solution of 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine (2.70 g, 10.82 mmol) in THF (45 mL) was added Et₃N (6.32 mL, 45.3 mmol). The mixture was cooled to 0°C, and DMAP (0.0135 g, 0.110 mmol) and BOC₂O (2.84 g, 12.99 mmol) were added. The mixture was warmed to rt and stirred for 18 h. The mixture was quenched with ice and diluted with water. Extracted with EtOAc (3 x 200 mL), washed with brine and water, dried (MgSO₄), and concentrated. A dark oil was afforded, which was passed through a pad of silica gel, eluting with 1:1 EtOAc/hexanes. Concentrated and dried under high vacuum to afford tert-Butyl 2- chloropyridin-4-yl(3-nitrophenyl)carbamate (3.65 g, 96.5% yield). Preparation of methyl 5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H- pyrrole-3-carboxylate

A mixture of tert-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate (3.65 g, 10.43 mmol), methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (5.48 g, 21.82 mmol), xantphos (0.72 g, 1.25 mmol) and Pd₂dba₃ (0.72 g, 0.79 mmol) was added to a thick walled reaction vessel and purged with N₂. A solution of 2M K₂CO₃ (8.76 mL) was added, followed by dioxane (67 mL). The reaction vessel was sealed and the mixture stirred at 105°C for 18 h. The reaction vessel was cooled to rt and the mixture was filtered over celite, washing with EtOAc. The filtrate was concentrated to afford a dark oil, which was purified via column chromatography eluting with 30-50% EtOAc/hexanes to afford methyl 5-(4-(tert- butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate (2.98 g, 65% yield) as an orange oil. Preparation of methyl 5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate

Methyl 5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate (0.40 g, 0.91 mmol) was taken up in toluene (38 mL) and SiO₂ (9.0 g) was added. The mixture stirred at reflux for 20 h. The mixture was cooled to rt and filtered over celite, washing with EtOAc. The filtrate was concentrated to a bright orange color. The solid was taken up in hexanes and filtered. The solid was then washed with CH₂Cl₂/hexanes to afford methyl 5-(4-((3- nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (0.15 g, 49% yield) as a bright yellow solid. Preparation of methyl 5-(4-((3-aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate

Methyl 5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.32 g, 3.9 mmol) was taken up in EtOAc/EtOH (1:1; 90 mL) and purged with N₂. Pd/C (10%, 0.145 g) was added and the mixture was stirred under an atmosphere of H₂ at rt for 18 h. The mixture was filtered over celite, washing with EtOAc/EtOH. The filtrate was concentrated, taken back up in EtOAc and filtered over celite again to remove any residual catalyst. The filtrate was concentrated again and taken back up in EtOAc. The solution was filtered and the filtrate was concentrated to afford a tan solid. The solid was washed with CH₂Cl₂/hexanes (1:2) and dried under high vacuum to afford methyl 5-(4-((3-aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.15 g, 96% yield) as a tan solid. Example 5

5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid

To a stirred solution of methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]- 1H-pyrrole-3-carboxylate (10mg, 0.024mmol) in a mixture of solvents THF/MeOH (5ml/5ml) was added 2ml of 1M NaOH (2mmol) solution. The mixture was heated in a 60°C bath for 16 hours, cooled to room temperature and poured into 100ml of water. 2M HCl was added until pH = 5. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-[4- ({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 2mg. Example 6

methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3- carboxylate

A mixture of 3-methyl-2-furoic acid (22 mg, 0.18mmol), HATU (73mg, 0.19mmol) and N,N- diisopropylethylamine (45mg, 0.35mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of methyl 5-(4-((3- aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (50mg, 0.16mmol). The mixture was stirred at room temperature for 3 hours and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give methyl 5-[4-({3-[(3-methyl-2- furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate as off-white solid. Yield: 10mg, 15%.

1H NMR (DMSO-d₆): 13.60 (br. s., 1H), 12.37 (br. s., 1H), 10.14 (s, 1 H), 8.15 (d, J = 6.5 Hz, 1H), 7.86 (t, J = 1.9 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.58 (br. s., 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.32 - 7.38 (m, 2H), 7.22 (br. s., 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 6.2, 2.1 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 3.71 (s, 3H), 2.32 (s, 3H)

LR MS (ES+): 417 (MH) LR MS (ES-): 415 (M-H) Example 7

5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N- hydroxy-1H-pyrrole-3-carboxamide

Similar procedure as Example 1.

1H NMR (DMSO-d₆): 11.85 (br. s., 1H), 10.56 (br. s., 1H), 10.12 (s, 1 H), 8.66 (br. s., 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.63 (t, J = 9.4 Hz, 1H), 7.30 - 7.40 (m, 2H), 7.27 (br. s., 1H), 7.10 - 7.18 (m, 1H), 7.01 - 7.10 (m, 2H), 6.75 - 6.85 (m, 1 H), 2.26 (s, 3H)

LR MS (ES+): 487 (M+Na⁺)

LR MS (ES-): 463 (M-H) Example 8

4-fluoro-N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol- 2-yl}pyridin-4-yl)oxy]benzamide

Similar procedure as Example 1.

LR MS (ES+): 533 (MH), 555 (M+Na⁺)

LR MS (ES-): 531 (M-H) Example 9

N-(2,3-dihydroxypropyl)-5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin- 2-yl]-1H-pyrrole-3-carboxamide

Similar procedure as Example 1.

1H NMR (DMSO-d₆): 11.83 (br. s., 1H), 10.11 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 7.0 Hz, 1H), 7.83 (t, J = 5.6 Hz, 1H), 7.77 (s, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.42 - 7.46 (m, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.09 - 7.16 (m, 2H), 7.02 - 7.06 (m, 1H), 6.76 (dd, J = 5.7, 2.5 Hz, 1H), 4.77 (d, J = 5.0 Hz, 1H), 4.53 (t, J = 6.0 Hz, 1H), 3.50 - 3.56 (m, 1H), 3.25 - 3.30 (m, 3H), 3.08 - 3.14 (m, 1H), 2.27 (s, 3H)

LR MS (ES+): 505 (MH), 527 (M+Na⁺)

LR MS (ES-): 503 (M-H) Example 10

N-(2-fluoro-5-methylphenyl)-3-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2- yl}pyridin-4-yl)oxy]benzamide

A mixture of 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H- pyrrole-3-carboxylic acid (50mg, 0.12mmol), HATU (55mg, 0.14mmol) and N,N- diisopropylethylamine (34mg, 0.26mmol) in anhydrous DMF (8ml) was stirred at room temperature for 10 minutes, followed by addition of (S)-3-pyrrolidinol (16mg, 0.18mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-fluoro-5-methylphenyl)-3-[(2- {4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]benzamide as white solid. Yield: 40mg, 69%.

1H NMR (DMSO-d₆): 11.91 (br. s., 1H), 10.12 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.32 - 7.51 (m, 3H), 7.26 (d, J = 6.7 Hz, 1H), 6.99 - 7.20 (m, 3H), 6.73 (dd, 1H), 4.91 (br. s., 1H), 4.30 (br. s., 1H), 3.76 (br. s., 2H), 3.50 (br. s., 2H), 2.28 (s, 3H), 1.86 (br. s., 2H)

LR MS (ES+): 501 (MH), 523 (M+Na⁺)

LR MS (ES-): 499 (M-H) Example 11

5-[4-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-hydroxy-1H- pyrrole-3-carboxamide

Similar procedure as Example 10.

1H NMR (DMSO-d₆): 11.84 (br. s., 1H), 10.56 (br. s., 1H), 10.10 (s, 1 H), 8.65 (br. s., 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.76 (br. s., 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.44 (dd, J = 7.9, 1.5 Hz, 1H), 7.35 (d, J = 6.7 Hz, 1H), 7.31 (br. s., 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.13 (dd, J = 10.3, 8.5 Hz, 1H), 7.01 - 7.07 (m, 2H), 6.75 (dd, J = 5.7, 2.2 Hz, 1H), 2.27 (s, 3H)

LR MS (ES+): 469 (M+Na⁺)

LR MS (ES-): 445 (M-H) Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester

4-Fluoro-3-hydroxybenzoic acid methyl ester (1.70 g, 10.0 mmol) was dissolved in

dimethylformamide (9 mL) under nitrogen at room temperature. Sodium hydride (60% oil dispersion, 0.48 g, 12 mmol) was added in portions over 30 min. The reaction was stirred for 90 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (1.58 g, 10.0 mmol) was added in small portions over 50 min. The reaction was stirred at room temperature for 17.5 h. Water (200 ml) was added and the mixture stirred until a brown lump formed. The water was decanted and the residue dissolved in EtOAc (150 mL). The solution was washed with brine, dried (MgSO₄), filtered and evaporated to give 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester. Yield: 3.10 g. Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid

3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester (2.81 g, 10.0 mmol) was dissolved in tetrahydrofuran (15 mL) and mixed with 2M lithium hydroxide (15 mL, 30 mmol). The suspension was stirred for 5 h. To the reaction was added water, then extracted with EtOAc. The aqueous layer was treated with 6M HCl (5 mL, 30 mmol) and then extracted with EtOAc (3x25 mL). The extract was dried (MgSO₄), filtered and evaporated to 3-(2-Chloropyridin-4- yloxy)-4-fluorobenzoic acid. Yield: 2.22 g, 83%. Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2-fluoro-5-methylphenyl)benzamide

A solution of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid (2.22 g, 8.29 mmol), 2-fluoro-5- methylaniline (1.56 g, 12.4 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU, 3.78 g, 9.95 mmol) and N-methylmorpholine (2.00 mL, 18.2 mmol) in dimethylformamide (22 mL) was heated at 90^oC for 2 h. The solvent was evaporated in vacuo at 50^oC. To the residue was added water resulting in a thick oil. The water was decanted and the oil dissolved in EtOAc then extracted twice with water, 1M hydrochloric acid and brine. The organic layer was dried (MgSO₄), filtered and evaporated to crude 6 (3.37 g). Trituration with dichloromethane (25 mL) gave 3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2- fluoro-5-methylphenyl)benzamide as white solid. Yield: 1.788 g, 58%. Example 12

methyl 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrole-3-carboxylate

A mixture of 3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2-fluoro-5-methylphenyl)benzamide (1.217 g, 3.25 mmol), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3- carboxylate (1.63 g, 6.50 mmol) and potassium carbonate (0.67 g, 4.87 mmol) in water (2.5 mL) and dioxane (15 mL) was purged with nitrogen for several minutes. To the mixture was added tetrakis-triphenylphosphine palladium(0) (0.18 g, (0.16 mmol). The reaction was sealed under nitrogen and heated at 100^oC for 15 h. The cooled reaction was mixed with dichloromethane and filtered through Celite. The red solution was evaporated. The resulting oil was dissolved in dichloromethane, put on a column of silica gel (80 g) and eluted with hexane/EtOAc (1:1) to afford methyl 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrole-3-carboxylate as white solid. Yield: 1.162 g, 77%. Example 13

5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrole-3-carboxylic acid

Similar procedure as Example 12.

1H NMR (DMSO-d₆): 12.03 (br. s., 1H), 11.85 (br. s., 1H), 10.11 (s, 1 H), 8.42 (d, J = 5.6 Hz, 1H), 7.98 (d, J = 6.2 Hz, 2H), 7.62 (t, J = 9.4 Hz, 1H), 7.43 (br. s., 1H), 7.30 - 7.39 (m, 2H), 7.08 - 7.19 (m, 2H), 7.04 (br. s., 1H), 6.79 (d, J = 3.2 Hz, 1H), 2.26 (s, 3H)

LR MS (ES-): 448 (M-H) Example 14

N-ethyl-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 31.

LR MS (ES+): 453 (M+Na⁺) Example 15

N-(2,3-dihydroxypropyl)-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxamide

Similar procedure as Example 31.

1H NMR (DMSO-d₆): 11.83 (br. s., 1H), 10.21 (s, 1H), 8.40 (d, J = 5.9 Hz, 1H), 7.85 (t, J = 6.0 Hz, 1H), 7.78 (s, 1H), 7.63 - 7.74 (m, 2H), 7.35 - 7.48 (m, 2H), 7.23 (d, J = 2.1 Hz, 1H), 7.10 (s, 1H), 6.85 - 6.96 (m, 1H), 6.75 (dd, J = 5.7, 2.2 Hz, 1H), 6.57 (s, 1H), 4.78 (d, J = 4.7 Hz, 1H), 4.53 (t, J = 5.9 Hz, 1 H), 3.48 - 3.61 (m, 1H), 3.24– 3.33 (m, 3H), 3.04 - 3.19 (m, 1H), 2.30 (s, 3H)

LR MS (ES+): 499 (M+Na⁺)

LR MS (ES-): 475 (M-H) Example 16

5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 31. ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 10.21 (s, 1H), 8.40 (d, J = 5.9 Hz, 1H), 7.77 (s, 1H), 7.65 - 7.74 (m, 2H), 7.31 - 7.48 (m, 3H), 7.23 (d, J = 1.2 Hz, 1H), 7.07 (br. s., 1H), 6.86 - 6.95 (m, 1H), 6.75 (d, J = 3.5 Hz, 2H), 6.57 (s, 1H), 2.30 (s, 3H)

LR MS (ES-): 401 (M-H) Example 17

N-hydroxy-5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxamide

Similar procedure as Example 31.

1H NMR (DMSO-d₆): 11.84 (br. s., 1H), 10.49 - 10.64 (m, 1H), 10.20 (s, 1H), 8.60 - 8.74 (m, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.65 - 7.81 (m, 3H), 7.41 (t, J = 7.9 Hz, 1H), 7.32 (br. s., 1H), 7.23 (s, 1H), 7.02 (br. s., 1H), 6.85 - 6.94 (m, 1H), 6.69 - 6.78 (m, 1H), 6.57 (s, 1H), 2.30 (s, 3H) LR MS (ES-): 417 (M-H) Example 18

N-(3-{ [2-(4-{ [(3R)-3-hydroxypyrrolidin-1 -yl]carbonyl}-1 H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl-2- furamide

Similar procedure as Example 31.

1H NMR (DMSO-d₆): 11.90 (br. s., 1H), 10.20 (s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.64 - 7.73 (m, 2H), 7.36 - 7.46 (m, 2H), 7.21 - 7.30 (m, 1H), 7.03 - 7.13 (m, 1H), 6.85 - 6.93 (m, 1H), 6.70 (dd, J = 5.7, 2.2 Hz, 1H), 6.57 (d, J = 1.5 Hz, 1H), 4.90 (br. s., 1H), 4.30 (m, 1H), 3.76 (m, 1H), 3.49 (m, 2H), 2.30 (s, 3H), 1.86 (m, 2H)

LR MS (ES-): 471 (M-H) Example 19

5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid

To a stirred solution of 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}- 1H-pyrrole-3-carboxylic acid methyl ester (140mg, 0.31mmol) in THF (8ml) was added 5M NaOH solution (1ml, 5mmol). The mixture was heated at 70°C for 3 hours, cooled to room temp, and poured into 100ml of water. 2M HCl was added until pH = 4. The precipitates were filtered, washed with water, and dried to give 5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)- phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid as white solid. Yield: 120mg, 92%. ¹H NMR (d₆-DMSO): 12.03 (br. s., 1H), 11.89 (br. s., 1H), 10.11 (s, 1 H), 8.42 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 7.3 Hz, 1H), 7.77 (s, 1H), 7.56 - 7.71 (m, 1H), 7.30 - 7.54 (m, 4H), 6.97 - 7.23 (m, 3H), 6.75 (dd, J = 5.6, 2.1 Hz, 1H), 2.28 (s, 3H)

LR MS (ES+): 454 (M+Na⁺)

LR MS (ES-): 430 (M-H) Example 20

5-{4-[3-(2-Fluoro-5-methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid methyl ester

A mixture of 3-(2-bromo-pyridin-4-yloxy)-N-(2-fluoro-5-methyl-phenyl)-benzamide (200mg, 0.50 mmol), methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (251mg, 1.0 mmol) and PdCl₂(dppf)·CH₂Cl₂ (10mg, 0.012 mmol) was added to a thick-walled reaction vessel and purged with N₂. A solution of 2M Na₂CO₃ (0.5 mL) was added, followed by DMSO (8 mL). The reaction vessel was sealed and the mixture stirred at 95°C for 16 h. The reaction vessel was cooled to room temperature and the mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified via column chromatography eluting with 30-40% EtOAc/hexanes to afford 5-{4-[3-(2-Fluoro-5- methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid methyl ester (150mg, 58% yield).

1H NMR (d₆-DMSO): 12.14 (br. s., 1H), 10.11 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.77 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.41 - 7.50 (m, 3H), 7.35 (s, 1H), 7.09 - 7.21 (m, 2H), 7.06 (dd, J = 5.1, 1.9 Hz, 1H), 6.76 (dd, J = 5.6, 2.3 Hz, 1H), 3.70 (s, 3H), 2.28 (s, 3H) LR MS (ES+): 468 (M+Na⁺)

LR MS (ES-): 444 (M-H) Example 21

Similar procedure as Example 25.

2,3-dihydroxypropyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylate Example 22

5-[4-(3-m-Tolylcarbamoyl-phenoxy)-pyridin-2-yl]-1H-pyrrole-3-carboxylic acid

Similar procedure as Example 19.

1H NMR (DMSO-d₆): 12.03 (br. s., 1H), 11.86 (br. s., 1H), 10.19 (s, 1 H), 8.42 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.50 - 7.69 (m, 3H), 7.32 - 7.46 (m, 3H), 7.21 (t, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.74 (dd, J = 5.6, 2.3 Hz, 1H), 2.28 (s, 3H) Example 23

5-[4-(3-m-Tolylcarbamoyl-phenoxy)-pyridin-2-yl]-1H-pyrrole-3-carboxylic acid methyl ester

Similar procedure as Example 20.

1H NMR (DMSO-d₆): 12.14 (br. s., 1H), 10.18 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.50 - 7.68 (m, 3H), 7.38 - 7.48 (m, 3H), 7.21 (t, J = 7.8 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 5.7, 2.2 Hz, 1H), 3.70 (s, 3H), 2.28 (s, 3H)

LR MS (ES+): 450 (M+Na⁺)

LR MS (ES-): 426 (M-H) Example 24

2-hydroxyethyl 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H- pyrrole-3-carboxylate

Similar procedure as Example 25.

1H NMR (d₆-DMSO): 12.13 (br. s., 1H), 10.13 (s, 1H), 8.43 (d, J = 5.9 Hz, 1H), 7.68 (d, J = 5.0 Hz, 1H), 7.56 - 7.64 (m, 2H), 7.40 - 7.52 (m, 3H), 7.14 (s, 1H), 7.03 (d, J = 5.0 Hz, 1H), 6.89 - 6.98 (m, 1H), 6.76 (dd, J = 5.7, 2.2 Hz, 1H), 4.83 (t, J = 5.9 Hz, 1H), 4.15 (t, J = 5.1 Hz, 2H), 3.64 (q, J = 5.6 Hz, 2H), 2.44 (s, 3H)

LR MS (ES+): 486 (M+Na⁺)

LR MS (ES-): 462 (M-H) Example 25

2-hydroxyethyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylate

A mixture of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylic acid (70mg, 0.17mmol), ethylene glycol (1ml), 1-ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride (EDC• HCl, 40mg, 0.21mmol) and 4- dimethylaminopyridine (DMAP, 10mg, 0.08mmol) in anhydrous DMF (10ml) was stirred at 70°C for 3 hours then room temperature for 16 hours. The mixture was poured into 100ml of water. Saturated NaHCO₃ solution was added until pH = 9. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3~4% MeOH/CHCl₃ to give 2-hydroxyethyl 5-(4-{3- [(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate as white solid. Yield: 40mg, 51%.

1H NMR (d₆-DMSO): 12.13 (br. s., 1H), 10.22 (s, 1H), 8.43 (d, J = 5.9 Hz, 1H), 7.79 (s, 1H), 7.70 (s, 2H), 7.36 - 7.54 (m, 3H), 7.13 (br. s., 1H), 6.86 - 6.97 (m, 1H), 6.72 - 6.80 (m, 1H), 6.59 (s, 1H), 5.75 (s, 1H), 4.83 (t, J = 5.3 Hz, 1H), 4.14 (t, J = 4.7 Hz, 2H), 3.58 - 3.69 (m, 2H), 2.32 (s, 3H)

LR MS (ES+): 470 (M+Na⁺)

LR MS (ES-): 446 (M-H) Example 26

5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid

Similar procedure as Example 32.

1H NMR (d₆-DMSO): 12.04 (br. s., 1H), 11.87 (s, 1H), 10.13 (s, 1H), 8.42 (d, J = 6.2 Hz, 1H), 7.68 (d, J = 4.7 Hz, 1H), 7.57 - 7.64 (m, 2H), 7.40 - 7.49 (m, 2H), 7.38 (dd, J = 3.2, 1.5 Hz, 1H), 7.05 - 7.09 (m, 1H), 7.03 (d, J = 5.0 Hz, 1H), 6.90 - 6.97 (m, 1H), 6.75 (dd, J = 5.7, 2.5 Hz, 1H), 2.44 (s, 3H)

LR MS (ES+): 442 (M+Na⁺)

LR MS (ES-): 418 (M-H) Example 27

methyl 5-[4-(3-{[(3-methyl-2-thienyl)carbonyl]amino}phenoxy)pyridin-2-yl]-1H-pyrrole-3- carboxylate

Similar procedure as Example 33.

1H NMR (DMSO-d₆): 12.12 (br. s., 1H), 10.10 (s, 1H), 8.35 - 8.45 (m, 1H), 7.65 (d, J = 5.0 Hz, 1H), 7.55 - 7.60 (m, 2H), 7.37 - 7.45 (m, 3H), 7.10 (s, 1H), 7.00 (d, J = 5.0 Hz, 1H), 6.87 - 6.93 (m, 1H), 6.73 (dd, J = 5.6, 2.3 Hz, 1H), 3.69 (s, 3H), 2.41 (s, 3H)

LR MS (ES+): 456 (M+Na⁺)

LR MS (ES-): 432 (M-H) Example 28

5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid

To a stirred solution of methyl 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2- yl)-1H-pyrrole-3-carboxylate

(20mg, 0.046mmol) in a mixture of solvents THF/MeOH (5ml/5ml) was added 3ml of 1M NaOH (3mmol) solution. The mixture was heated in a 72°C bath for 3 hours, cooled to room temperature and poured into 50ml of water. 2M HCl was added until pH = 4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-(4-{4-fluoro-3-[(3- methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid as light gray solid. Yield: 19mg, 100%.

LR MS (ES-): 420 (M-H) Example 29

methyl 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylate

Similar procedure as Example 33.

1H NMR (d₆-DMSO): 12.15 (br. s., 1H), 9.74 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.60 (dd, J = 6.4, 2.9 Hz, 1H), 7.34 - 7.50 (m, 3H), 7.02 - 7.18 (m, 2H), 6.75 (dd, J = 5.6, 2.3 Hz, 1H), 6.60 (d, J = 1.5 Hz, 1H), 3.72 (s, 3H), 2.31 (s, 3H)

LR MS (ES+): 458 (M+Na⁺)

LR MS (ES-): 434 (M-H) Example 30

N-[dimethyl(oxido)-lambda~4~-sulfanylidene]-5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 101.

1H NMR (d₆-DMSO): 11.83 (br. s., 1H), 10.20 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.65 - 7.72 (m, 2H), 7.37 - 7.45 (m, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.27 (dd, J = 2.9, 1.5 Hz, 1H), 6.96 - 6.99 (m, 1H), 6.87 - 6.92 (m, 1H), 6.71 (dd, J = 5.6, 2.3 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 3.35 (s, 6H), 2.30 (s, 3H)

LR MS (ES+): 501 (M+Na⁺)

LR MS (ES-): 477 (M-H) Example 31

N-(3-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4- yl]oxy}phenyl)-3-methyl-2-furamide

A mixture of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylic acid (60mg, 0.15mmol), HATU (68mg, 0.18mmol) and N,N-diisopropylethylamine (43mg, 0.33mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of (S)-3-pyrrolidinol (16mg, 0.18mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. 2M HCl was added dropwise until pH = 4~5. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-{[2-(4- {[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1 H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-methyl- 2-furamide as white solid. Yield: 40mg, 56%.

1H NMR (d₆-DMSO): 11.95 (br. s., 1H), 10.21 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.64 - 7.74 (m, 2H), 7.35 - 7.51 (m, 2H), 7.29 (br. s., 1H), 7.12 (br. s., 1H), 6.90 (dd, J = 8.1, 1.3 Hz, 1H), 6.73 (dd, J = 5.7, 2.2 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 4.20 - 4.36 (m, 1H), 3.66 - 3.88 (m, 2H), 3.42 - 3.60 (m, 3H), 2.30 (s, 3H), 1.66 - 2.03 (m, 2H)

LR MS (ES+): 495 (M+Na⁺)

LR MS (ES-): 471 (M-H) Example 32

5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid

To a stirred solution of methyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxylate (1.30g, 3.12mmol) in a mixture of solvents THF/MeOH (10ml/10ml) was added 2ml of 5M NaOH (10mmol) solution. The mixture was heated in a 68°C bath for 8 hours, cooled to room temperature and poured into 200ml of water. 2M HCl was added until pH = 3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-(4-{3- [(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid as white solid. Yield: 1.20g, 95%.

1H NMR (d₆-DMSO): 11.98 (br. s., 1H), 10.22 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.61 - 7.76 (m, 2H), 7.27 - 7.51 (m, 3H), 7.04 (br. s., 1H), 6.85 - 6.98 (m, 1H), 6.73 (dd, J = 5.7, 2.2 Hz, 1H), 6.59 (d, J = 1.5 Hz, 1H), 2.32 (s, 3H)

LR MS (ES-): 402 (M-H) Example 33

methyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate

A mixture of 3-methyl-2-furoic acid (490 mg, 3.88mmol), HATU (1.71 g, 4.5mmol) and N,N- diisopropylethylamine (1.0g, 7.8mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of methyl 5-[4-(3-aminophenoxy)pyridin-2- yl]-1H-pyrrole-3-carboxylate (1.0g, 3.24mmol). The mixture was stirred at 50°C for 2 hours and poured into 100ml of water. 2M HCl was added dropwise until pH = 4~5. The precipitates were filtered, washed with water and dried in vacuo to give methyl 5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate as white solid. Yield: 1.30g, 96%.

1H NMR (d₆-DMSO): 12.15 (br. s., 1H), 10.22 (s, 1H), 8.43 (d, J = 5.9 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.68 - 7.74 (m, 2H), 7.38 - 7.47 (m, 3H), 7.09 - 7.14 (m, 1H), 6.88 - 6.94 (m, 1H), 6.75 (dd, J = 5.6, 2.3 Hz, 1H), 6.59 (d, J = 1.5 Hz, 1H), 3.72 (s, 3H), 2.32 (s, 3H)

LR MS (ES+): 440 (M+Na⁺) LR MS (ES-): 416 (M-H) Example 34

3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide

5

A mixture of 3-methyl-2-furoic acid (60 mg, 0.48mmol), HBTU (198 mg, 0.52mmol) and N,N- diisopropylethylamine (129mg, 1.0mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of 3-{[2-(1H-pyrrol-2-yl)pyridin-4- yl]oxy}aniline (100mg, 0.40mmol). The mixture was stirred at 70°C for 3 hours and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3-5% MeOH/CHCl₃ to give 3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide as white solid. Yield: 52mg, 36%.

1H NMR (d₆-DMSO): 11.46 (br. s., 1H), 10.19 (s, 1H), 8.36 (d, J = 6.2 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.64 - 7.72 (m, 2H), 7.35 - 7.44 (m, 1H), 7.28 (d, J = 2.1 Hz, 1H), 6.86 - 6.91 (m, 1H), 6.81 - 6.86 (m, 1H), 6.68 - 6.74 (m, 1H), 6.65 (dd, J = 5.7, 2.5 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.06 - 6.13 (m, 1H), 2.30 (s, 3H)

LR MS (ES+): 360 (M+H)

LR MS (ES-): 358 (M-H) Example 35

methyl 4-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-2-carboxylate

Similar procedure as Example 33.

1H NMR (d₆-DMSO): 12.18 (br. s., 1H), 10.19 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.59 - 7.72 (m, 3H), 7.33 - 7.44 (m, 2H), 7.25 - 7.32 (m, 1H), 6.83 - 6.93 (m, 1H), 6.66 (dd, J = 5.6, 2.3 Hz, 1H), 6.57 (d, J = 1.2 Hz, 1H), 3.76 (s, 3H), 2.30 (s, 3H)

LR MS (ES+): 440 (M+Na⁺)

LR MS (ES-): 416 (M-H) Example 36

2-fluoro-5-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)benzamide

Similar procedure as Example 37.

1H NMR (d₆-DMSO): 11.44 (br. s., 1H), 10.47 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.76 - 7.86 (m, 2H), 7.46 (dd, J = 6.4, 2.1 Hz, 1H), 7.36 (ddd, J = 7.9, 5.3, 2.1 Hz, 1H), 7.13 - 7.27 (m, 4H), 6.80 - 6.87 (m, 1H), 6.66 - 6.73 (m, 1H), 6.60 (dd, J = 5.6, 2.3 Hz, 1H), 6.06 - 6.15 (m, 1H), 2.34 (s, 3H)

LR MS (ES+): 388 (M+H)

LR MS (ES-): 386 (M-H) Example 37

3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide

A mixture of 3-methyl-2-furoic acid (70mg, 0.55mmol), HATU (243mg, 0.64mmol),) tert-butyl 2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate (160mg, 0.46mmol) and N,N- diisopropylethylamine (148mg, 1.15mmol) in anhydrous DMF (10ml) was stirred at 45°C for 2 hours. The mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was dissolved in 5ml of methylene chloride, followed by addition of trifluoroacetic acid (3ml). The mixture was stirred at room temperature for 16 hours. The solvents were evaporated under reduced pressure. The residue was purified by reversed-phase chromatography with a gradient of 10~50% acetonitrile/water to give 3-methyl-N-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide as white solid. Yield: 56mg, 34%.

LR MS (ES+): 360 (M+H)

LR MS (ES-): 358 (M-H) Preparation of 4-((2-chloropyridin-4-yl)oxy)aniline

A stirred solution of 4-aminophenol (740mg, 6.8mmol) in anhydrous DMSO (8ml) was flushed with nitrogen and treated with 1M KOBu^t / THF solution (10ml, 10mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. 2,4-dichloropyridine (1.0g, 6.8mmol) was added and the mixture was heated at 60ºC for 30 minutes, cooled to room temperature and poured into 100ml of water. The resulting precipitates were filtered, washed with water and dried to give 4-((2-chloropyridin-4-yl)oxy)aniline as light brown solid. The material was used for the following reactions without further purification. Yield: 1.15g, 77%.

1H NMR (d₆-DMSO): 8.21 (d, 1H), 6.77 - 6.91 (m, 4H), 6.54 - 6.68 (m, 2H), 5.16 (s, 2H) Preparation of methyl 5-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate

A mixture of 4-((2-chloropyridin-4-yl)oxy)aniline (2.6 g, 11.78 mmol), methyl-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (6.0 g, 23.90 mmol) and Pd(PPh3)4 (2.72 g, 2.35 mmol) was added to a thick walled reaction vessel and purged with N₂. A solution of 2M K₂CO₃ (17.68 mL) was added, followed by DME (90 mL). The reaction vessel was sealed and the mixture stirred at 92°C for 18 h. The reaction vessel was cooled to room temperature and the mixture was filtered over celite, washing with EtOAc. The filtrate was concentrated to afford a dark oil, which was purified via column chromatography eluting with 40-80% EtOAc/hexanes to afford methyl 5-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole- 3-carboxylate (2.4 g, 65% yield). Example 38

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3- morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

LR MS (ES+): 573 (MH) Example 39

5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- hydroxy-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.82 (br. s., 1H), 10.55 (br. s., 1H), 9.05 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 2.3 Hz, 1H), 8.64 (br. s., 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.23 (t, J = 9.2 Hz, 1H), 7.98 (dd, J = 7.8, 1.9 Hz, 1H), 7.31 (br. s., 1H), 7.26 (dd, J = 11.7, 2.6 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 6.98 - 7.05 (m, 2H), 6.76 - 6.83 (m, 1H), 6.73 (dd, J = 5.7, 2.5 Hz, 1H), 2.25 (s, 3H)

LR MS (ES-): 478 (M-H) Example 40

{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2- thienyl)carbonyl]amino}acetic acid

To a stirred solution of methyl {[(4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate (60mg, 0.11mmol) in a mixture of solvents THF/MeOH (5ml/5ml) was added 1ml of 1M NaOH (l.0mmol) solution. The mixture was stirred at room temperature for 1 hour and poured into 100ml of water. 2M HCl was added until pH = 3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give {[(4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetic acid as white solid. Yield: 50mg, 86%.

1H NMR (DMSO-d₆): 12.61 (br s, 1H), 9.15 (s, 1H), 8.98 (t, J = 5.9 Hz, 1H), 8.43 - 8.48 (m, 2H), 8.40 (d, J = 1.5 Hz, 1H), 8.36 (d, J = 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.8 Hz, 1H), 7.50 - 7.58 (m, 2H), 7.40 (d, J = 2.3 Hz, 1H), 7.12 - 7.19 (m, 2H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.73 - 6.81 (m, 2H), 3.88 (d, J = 5.9 Hz, 2H), 2.25 (s, 3H)

LR MS (ES-): 519 (M-H) Example 41

methyl {[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 2-thienyl)carbonyl]amino}acetate

A mixture of 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}thiophene-2-carboxylic acid (100mg, 0.22mmol), HATU (100mg, 0.26mmol) and N,N- diisopropylethylamine (85mg, 0.66mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of glycine methyl ester hydrochloride (41mg, 0.33mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. 2M HCl was added dropwise until pH = 4~5. The precipitates were filtered, washed with water and dried in vacuo to give methyl {[(4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}acetate as white solid. Yield: 90mg, 78%.

1H NMR (DMSO-d₆): 9.17 (s, 1H), 9.10 (t, J = 5.9 Hz, 1H), 8.44 - 8.49 (m, 2H), 8.37 - 8.42 (m, 2H), 7.92 - 7.98 (m, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 2.1 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.75 - 6.84 (m, 2H), 3.98 (d, J = 5.9 Hz, 2H), 3.63 (s, 3H), 2.25 (s, 3H)

LR MS (ES+): 557 (M+Na⁺)

LR MS (ES-): 533 (M-H) Preparation of methyl 4-(4-(4-aminophenoxy)pyridine-2-yl)thiophene-2-carboxylate

A mixture of 4-(4-aminophenoxy)-2-chloropyridine (5.0 g, 22.66mmol), methyl-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (9.73 g, 36.25 mmol) and Pd(PPh3)4 (5.24 g, 4.53 mmol) was added to a thick walled reaction vessel and purged with N2. A solution of 2M K2CO3 (17.0 mL) was added, followed by dioxane (120 mL). The reaction vessel was sealed and the mixture stirred at 92°C for 18 h. The reaction vessel was cooled to room temperature and the mixture was filtered over celite, washing with EtOAc. The filtrate was concentrated and the resultant dark oil was purified via column chromatography, eluting with 40-60% EtOAc/hexanes to afford methyl 4-(4-(4-aminophenoxy)pyridine-2-yl)thiophene-2- carboxylate (6.1 g, 82% yield). Example 42

methyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}thiophene-2-carboxylate

To a stirred solution of methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]thiophene-2-carboxylate (500 mg, 1.53 mmol) in anhydrous THF (10ml) was added 2-fluoro-5-methyl-phenylisocyanate (255mg, 1.68mmol). The mixture was stirred at room temperature for one hour and poured into 200ml of water. The resulting precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3-5%

MeOH/CHCl₃ to give methyl 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylate as off- white solid. Yield: 560mg, 76%. ¹H NMR (DMSO-d₆): 9.14 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.41 - 8.47 (m, 2H), 8.33 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.48 - 7.57 (m, 3H), 7.13 (d, J = 9.1 Hz, 2H), 7.08 (dd, J = 11.4, 8.5 Hz, 1H), 6.76 - 6.81 (m, 1H), 6.74 (dd, J = 5.6, 2.3 Hz, 1H), 3.83 (s, 3H), 2.25 (s, 3H) LR MS (ES+): 500 (M+Na⁺)

LR MS (ES-): 476 (M-H) Example 43

(4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}- 5-oxopentanoic acid

To a stirred solution of tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}- 5-oxopentanoate (30mg, 0.046mmol) in 5ml of methylene chloride was added 2ml of TFA. The mixture was stirred at room temperature for 1 hour, and evaporated to dryness. The residue was dissolved in MeOH (3ml), which was added dropwise into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give (4S)-5- (ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}- 5-oxopentanoic acid as white solid. Yield: 20mg, 74%.

1H NMR (DMSO-d₆): 12.04 (br. s., 1H), 11.86 (br. s., 1H), 8.97 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 8.20 (t, J = 9.1 Hz, 1H), 7.82 (t, J = 5.6 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 1H), 7.46 (br. s., 1H), 7.12 - 7.29 (m, 5H), 6.99 - 7.04 (m, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.74 (d, J = 4.7 Hz, 1H), 4.31 (td, J = 8.6, 5.4 Hz, 1H), 2.97 - 3.11 (m, 2H), 2.26 (s, 3H), 2.17 - 2.25 (m, 2H), 1.87 - 1.98 (m, 1H), 1.74 - 1.84 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H)

LR MS (ES-): 601 (M-H) Example 44

tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}- 5-oxopentanoate

A mixture of (2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}- 5-oxopentanoic acid (80mg, 0.13mmol), HATU (57mg, 0.15mmol) and N,N- diisopropylethylamine (49mg, 0.38mmol) in anhydrous DMF (8ml) was stirred at room temperature for 10 minutes, followed by addition of 2M ethylamine in THF solution (0.1ml, 0.2mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. 2M HCl was added dropwise until pH = 5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 4~5% MeOH/CHCl₃ to give tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}- 5-oxopentanoate as white solid. Yield: 40mg, 48%.

1H NMR (DMSO-d₆): 11.83 (br. s., 1H), 8.95 (s, 1H), 8.56 (br. s., 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.20 (t, J = 9.1 Hz, 1 H), 7.81 (t, J = 5.3 Hz, 1 H), 7.77 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.23 - 7.30 (m, 2H), 7.18 - 7.23 (m, 2H), 7.12 - 7.18 (m, 2H), 6.98 - 7.04 (m, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.73 (dd, J = 5.6, 2.3 Hz, 1H), 4.27 - 4.35 (m, 1H), 3.01 - 3.08 (m, 2H), 2.26 (s, 3H), 2.17 - 2.23 (m, 2H), 1.87 - 1.95 (m, 1H), 1.78 (m, 1H), 1.34 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H) LR MS (ES+): 681 (M+Na⁺)

LR MS (ES-): 657 (M-H) Example 45

(2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}- 5-oxopentanoic acid

To a stirred solution of (S)-5-tert-butyl 1-methyl 2-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate (120mg, 0.19mmol) in a mixture of solvents THF/MeOH (5ml/5ml) was added 1ml of 1M NaOH (1mmol) solution. The mixture was stirred at room temperature for 30 minutes, and poured into 100ml of water. 2M HCl was added dropwise until pH = 4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give (2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}- 5-oxopentanoic acid as white solid. Yield: 100mg, 85%.

1H NMR (DMSO-d₆): 12.49 (br. s., 1H), 11.84 (br. s., 1H), 8.98 (s, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.20 (t, J = 9.1 Hz, 1 H), 7.89 (br. s., 1H), 7.42 (br. s., 1H), 7.28 (s, 1H), 7.25 (dd, J = 11.7, 2.6 Hz, 1H), 7.20 - 7.23 (m, 2H), 7.11 - 7.18 (m, 2H), 7.01 (dd, J = 9.0, 1.6 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.73 (dd, J = 5.6, 2.3 Hz, 1H), 4.23 - 4.34 (m, 1H), 2.23 - 2.28 (m, 2H), 2.26 (s, 3H), 1.95 - 2.03 (m, 1H), 1.80 - 1.88 (m, 1H), 1.35 (s, 9H)

LR MS (ES+): 654 (M+Na⁺)

LR MS (ES-): 630 (M-H) Example 46

(S)-5-tert-butyl 1-methyl 2-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate

A mixture of 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (500mg, 1.1mmol), HATU (500mg, 1.32mmol) and N,N- diisopropylethylamine (426mg, 3.3mmol) in anhydrous DMF (8ml) was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert-butyl 1-methyl ester hydrochloride (334mg, 1.32mmol). The mixture was stirred for another 10 minutes and poured into 200ml of water. 2M HCl was added dropwise until pH = 5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3~5% MeOH/CHCl₃ to give (S)-5-tert-butyl 1-methyl 2-{[(5-{4- [3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate as off-white solid. Yield: 380mg, 52%.

1H NMR (DMSO-d₆): 11.87 (br. s., 1H), 8.96 (s, 1H), 8.56 (br. s., 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.20 (t, J = 8.9 Hz, 1 H), 8.08 (d, J = 7.0 Hz, 1H), 7.44 (br. s., 1H), 7.23 - 7.29 (m, 2H), 7.18 - 7.23 (m, 2H), 7.11 - 7.17 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 7.0 Hz, 1H), 6.70 - 6.76 (m, 1H), 4.32 - 4.41 (m, 1H), 3.60 (s, 3H), 2.23 - 2.31 (m, 5H), 1.93 - 2.03 (m, 1H), 1.81 - 1.91 (m, 1H), 1.35 (s, 9H)

LR MS (ES+): 646 (MH), 668 (M+Na⁺)

LR MS (ES-): 644 (M-H) Example 47

bis(2-hydroxyethyl) 2-{[(5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate

Similar procedure as Example 131.

LR MS (ES+): 686 (M+Na⁺)

LR MS (ES-): 662 (M-H), 561 Example 48

3-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}propanoic acid

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.90 (br. s., 1H), 8.99 (s, 1H), 8.59 (br. s., 1H), 8.40 (d, J = 5.9 Hz, 1H), 8.22 (t, J = 9.0 Hz, 1 H), 7.90 - 7.96 (m, 1H), 7.40 (br. s., 1H), 7.25 - 7.30 (m, 2H), 7.21 (d, J = 7.0 Hz, 2H), 7.15 (t, J = 7.8 Hz, 2H), 7.03 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 7.0 Hz, 2H), 3.32 - 3.37 (m, 2H), 2.43 (t, J = 7.0 Hz, 2H), 2.26 (s, 3H)

LR MS (ES-): 516 (M-H) Example 49

2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}pentanedioic acid

1H NMR (DMSO-d₆): 12.43 (br. s., 2H), 11.89 (br. s., 1H), 8.97 (br. s., 1H), 8.57 (br. s., 1H), 8.39 (d, J = 5.3 Hz, 1H), 8.20 (t, J = 8.8 Hz, 1 H), 7.97 (d, J = 7.6 Hz, 1H), 7.46 (br. s., 1H), 7.11 - 7.31 (m, 4H), 7.02 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 7.0 Hz, 1H), 6.75 (br. s., 1H), 4.32 (br. s., 1H), 2.30 (t, J = 7.2 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H), 1.86 (m, 2H)

LR MS (ES-): 574 (M-H) Example 50

methyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylate

Similar procedure as Example 132

LR MS (ES+): 615 (MH), 637 (M+Na⁺)

LR MS (ES-): 613 (M-H) Example 51

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-{2- [(3S)-3-hydroxypyrrolidin-1-yl]-2-oxoethyl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

LR MS (ES+): 573 (MH), 595 (M+Na⁺)

LR MS (ES-): 571 (M-H) Example 52

N-{4-[(2,3-dihydroxypropyl)(methyl)amino]-4-oxobutyl}-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

1H NMR (DMSO-d₆): 11.70 - 11.82 (m, 1H), 9.24 (s, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 5.9 Hz, 1H), 7.93 - 7.98 (m, 1H), 7.85 (dt, J = 14.5, 5.5 Hz, 1H), 7.54 (d, J = 9.1 Hz, 2H), 7.34 (br. s., 1H), 7.10 - 7.15 (m, 3H), 7.08 (dd, J = 11.2, 8.5 Hz, 1H), 7.01 - 7.05 (m, 1H), 6.73 - 6.82 (m, 1H), 6.67 (dd, J = 5.6, 2.3 Hz, 1H), 4.87 (d, J = 5.3 Hz, 1H), 4.60 - 4.69 (m, 1H), 4.46 (t, J = 5.9 Hz, 1H), 3.55 - 3.65 (m, 2H), 3.20 - 3.27 (m, 2H), 3.10 - 3.19 (m, 2H), 2.96 (s, 1H), 2.79 (s, 2H), 2.27 - 2.35 (m, 1H), 2.24 (s, 3H), 1.62 - 1.72 (m, 2H)

LR MS (ES+): 619 (MH), 641 (M+Na⁺)

LR MS (ES-): 617 (M-H) Example 53

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3- hydroxypiperidin-1 -yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

LR MS (ES+): 637 (M+Na⁺)

LR MS (ES-): 613 (M-H) Example 54

N-{4-[(2,3-dihydroxypropyl)amino]-4-oxobutyl}-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

F

Similar procedure as Example 61.

1H NMR (DMSO-d₆): 11.77 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 5.9 Hz, 1H), 7.96 (dd, J = 7.9, 2.1 Hz, 1H), 7.84 (t, J = 5.6 Hz, 1H), 7.77 (t, J = 5.9 Hz, 1H), 7.51 - 7.57 (m, 2H), 7.33 (dd, J = 3.1, 1.6 Hz, 1H), 7.11 - 7.16 (m, 3H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 7.01 - 7.05 (m, 1H), 6.75 - 6.82 (m, 1H), 6.68 (dd, J = 5.7, 2.5 Hz, 1H), 4.68 (d, J = 5.0 Hz, 1H), 4.46 (t, J = 5.9 Hz, 1 H), 3.41 - 3.47 (m, 1H), 3.20 - 3.26 (m, 2H), 3.09 - 3.19 (m, 3H), 2.90 - 2.97 (m, 1H), 2.25 (s, 3H), 2.10 (t, J = 7.6 Hz, 2H), 1.66 (quin, J = 7.3 Hz, 2H)

LR MS (ES+): 605 (MH), 627 (M+Na⁺)

LR MS (ES-): 603 (M-H) Example 55

N-(4-amino-4-oxobutyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

1H NMR (DMSO-d₆): 11.92 (br. s., 1H), 9.20 (br. s., 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.95 (dd, J = 7.8, 1.9 Hz, 1H), 7.89 (br. s., 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.42 (br. s., 1H), 7.18 - 7.28 (m, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 11.4, 8.5 Hz, 1H), 6.78 (ddd, J = 7.5, 5.0, 2.2 Hz, 2H), 6.68 (br. s., 1H), 3.14 (q, J = 6.7 Hz, 2H), 2.25 (s, 3H), 2.05 (t, J = 7.5 Hz, 2H), 1.66 (quin, J = 7.3 Hz, 2H)

LR MS (ES+): 553 (M+Na⁺)

LR MS (ES-): 529 (M-H) Example 56

N-{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.83 (br. s., 1H), 9.15 (s, 1H), 8.46 (br. s., 1H), 8.36 (d, J = 5.9 Hz, 1H), 8.14 (t, J = 6.0 Hz, 1 H), 7.95 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 5.6 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 2H), 7.38 (br. s., 1H), 7.13 (d, J = 8.8 Hz, 3H), 7.03 - 7.11 (m, 2H), 6.75 - 6.82 (m, 1H), 6.69 (dd, J = 5.6, 2.3 Hz, 1H), 4.70 (d, J = 5.0 Hz, 1H), 4.47 (t, J = 5.7 Hz, 1 H), 3.76 (d, J = 5.6 Hz, 2H), 3.45 (dq, J = 11.2, 5.5 Hz, 1H), 3.16 - 3.27 (m, 3H), 2.93 - 3.00 (m, 1H), 2.25 (s, 3H) LR MS (ES+): 577 (MH), 599 (M+Na⁺)

LR MS (ES-): 575 (M-H) Example 57

5-(2,3-dihydroxypropyl) 1-methyl 2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate

Similar procedure as Example 58.

1H NMR (DMSO-d₆): 11.86 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.08 - 8.17 (m, 1H), 7.96 (dd, J = 7.9, 1.8 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.43 (br. s., 1H), 7.04 - 7.21 (m, 4H), 6.78 (dt, J = 5.7, 2.7 Hz, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 4.83 (d, J = 5.3 Hz, 1H), 4.58 (t, J = 5.7 Hz, 1H), 4.36 - 4.45 (m, 1H), 3.95 - 4.06 (m, 2H), 3.88 (dd, J = 11.0, 6.6 Hz, 1H), 3.60 (s, 3H), 3.28 - 3.35 (m, 2H), 2.40 (t, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.99 - 2.10 (m, 1H), 1.88 - 1.95 (m, 1H), 1.15 (t, J = 7.0 Hz, 1H)

LR MS (ES+): 664 (MH), 686 (M+Na⁺) Example 58

bis(2,3-dihydroxypropyl) 2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate

A mixture of 2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioic acid (60mg, 0.10mmol), glycerol (0.5ml), 1-Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride (EDC• HCl, 37mg, 0.19mmol) and 4- dimethylaminopyridine (DMAP, 5mg, 0.04mmol) in anhydrous THF (10ml) was stirred at 60°C for 3 hours. The mixture was cooled to room temperature, concentrated and purified by silica gel chromatography eluting with a gradient of 10~15% MeOH/CHCl₃ to give bis(2,3- dihydroxypropyl) 2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate as colorless oil. Yield: 40mg, 53%.

LR MS (ES+): 746 (M+Na⁺)

LR MS (ES-): 722 (M-H) Example 59

4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}-5-methoxy-5-oxopentanoic acid

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.98 (br. s., 1H), 9.19 (s, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.95 (dd, J = 7.8, 1.9 Hz, 1H), 7.53 - 7.57 (m, 2H), 7.47 - 7.52 (m, 1H), 7.24 (br. s., 1H), 7.19 (br. s., 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.72 - 6.81 (m, 2H), 4.38 (ddd, J = 9.5, 7.5, 5.3 Hz, 1H), 3.60 (s, 3H), 2.31 (t, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.95 - 2.05 (m, 1H), 1.82 - 1.93 (m, J = 14.0, 9.6, 7.0, 7.0 Hz, 1H)

LR MS (ES-): 588 (M-H) Example 60

N-[4-(ethylamino)-4-oxobutyl]-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

1H NMR (DMSO-d₆): 11.96 (br. s., 1H), 9.20 (s, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.95 (dd, J = 7.8, 1.9 Hz, 1H), 7.89 (br. s., 1H), 7.76 (t, J = 5.3 Hz, 1H), 7.53 - 7.58 (m, 2H), 7.44 (br. s., 1H), 7.23 (br. s., 1H), 7.13 - 7.19 (m, 3H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.75 - 6.84 (m, 2H), 3.11 - 3.17 (m, 2H), 3.01 (qd, J = 7.2, 5.6 Hz, 2H), 2.25 (s, 3H), 2.05 (t, J = 7.5 Hz, 2H), 1.66 (quin, J = 7.3 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H)

LR MS (ES+): 559 (MH), 581 (M+Na⁺)

LR MS (ES-): 557 (M-H) Example 61

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4-(3- hydroxypyrrolidin-1 -yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide

A mixture of 4-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoic acid (60mg, 0.11 mmol), HATU (50mg, 0.13mmol) and N,N- diisopropylethylamine (43mg, 0.33mmol) in anhydrous DMF (8ml) was stirred at room temperature for 10 minutes, followed by addition of (R)-3-pyrrolidinol (14mg, 0.16mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. 2M HCl was added dropwise until pH = 4~5. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- [4-(3-hydroxypyrrolidin-1-yl)-4-oxobutyl]-1H-pyrrole-3-carboxamide as white solid. Yield: 40mg, 59%.

1H NMR (DMSO-d₆): 11.97 (br. s., 1H), 9.31 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.95 (dd, J = 7.8, 1.9 Hz, 1H), 7.91 (d, J = 4.4 Hz, 1H), 7.54 - 7.59 (m, 2H), 7.42 - 7.48 (m, 1H), 7.24 (br. s., 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.05 - 7.10 (m, 1H), 6.78 (ddd, J = 7.5, 5.0, 2.2 Hz, 2H), 4.24 - 4.28 (m, 0H), 4.16 - 4.21 (m, 1H), 3.40 - 3.48 (m, 2H), 3.35 (ddd, J = 11.6, 8.4, 3.5 Hz, 1H), 3.25 - 3.30 (m, 1H), 3.14 - 3.25 (m, 4H), 2.25 (s, 3H), 2.23- 2.27 (m, 1H), 2.20 (t, J = 7.9 Hz, 1H), 1.84 - 1.92 (m, 1H), 1.75 - 1.82 (m, 1H), 1.65 - 1.73 (m, 2H)

LR MS (ES+): 601 (MH), 623 (M+Na⁺)

LR MS (ES-): 599 (M-H) Example 62

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[4- (hydroxyamino)-4-oxobutyl]-1H-pyrrole-3-carboxamide

Similar procedure as Example 61.

1H NMR (DMSO-d₆): 11.92 (br. s., 1H), 10.33 (s, 1H), 9.18 (s, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.95 (dd, J = 7.9, 1.8 Hz, 1H), 7.87 - 7.92 (m, 1H), 7.51 - 7.58 (m, 2H), 7.38 - 7.46 (m, 1H), 7.21 (br. s., 1H), 7.11 - 7.18 (m, 3H), 7.05 - 7.11 (m, 1H), 6.72 - 6.82 (m, 2H), 3.14 (q, J = 6.7 Hz, 2H), 2.25 (s, 3H), 1.96 (t, J = 7.6 Hz, 2H), 1.66 (quin, J = 7.3 Hz, 2H) LR MS (ES+): 547 (MH), 569 (M+Na⁺)

LR MS (ES-): 545 (M-H) Example 63

2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}pentanedioic acid

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 12.42 (br. s., 1H), 12.12 (br. s., 1H), 11.86 (br. s., 1H), 9.15 (s, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.93 - 8.01 (m, 2H), 7.51 - 7.58 (m, 2H), 7.44 (br. s., 1H), 7.18 (s, 1H), 7.11 - 7.16 (m, 3H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.75 - 6.82 (m, 1H), 6.69 (d, J = 3.8 Hz, 1H), 4.32 (ddd, J = 9.7, 7.9, 5.0 Hz, 1H), 2.30 (t, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.96 - 2.05 (m, 1H), 1.80 - 1.91 (m, J = 14.0, 9.8, 7.2, 7.2 Hz, 1H)

LR MS (ES-): 574 (M-H) Example 64

dimethyl 2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 12.27 (br. s., 1H), 9.33 (br. s., 1H), 8.50 - 8.57 (m, 1H), 8.44 (d, J = 6.2 Hz, 1H), 8.23 (d, J = 6.7 Hz, 1H), 7.95 (d, J = 6.5 Hz, 1H), 7.64 (br. s., 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.39 (br. s., 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 11.2, 8.2 Hz, 1H), 6.92 (br. s., 1H), 6.79 (d, J = 5.6 Hz, 1H), 4.35 - 4.43 (m, 1H), 3.60 (s, 3H), 3.55 (s, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.22 - 2.28 (m, 3H), 2.00 - 2.10 (m, 1H), 1.88 - 1.97 (m, 1H)

LR MS (ES+): 626 (M+Na⁺)

LR MS (ES-): 602 (M-H) Example 65

1-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]pyrrolidine-3-carboxylic acid

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 12.47 (br. s., 1H), 11.85 - 12.01 (m, 1H), 9.05 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 8.22 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.8, 1.9 Hz, 1H), 7.41 (br. s., 1H), 7.21 - 7.32 (m, 2H), 7.06 - 7.14 (m, 2H), 7.01 (dd, J = 9.0, 1.6 Hz, 1H), 6.79 (ddd, J = 7.6, 5.1, 1.9 Hz, 1H), 6.65 - 6.76 (m, 1H), 2.97 - 3.93 (m, 5H), 2.25 (s, 3H), 1.93 - 2.19 (m, 2H)

LR MS (ES+): 562 (MH), 584 (M+Na⁺)

LR MS (ES-): 560 (M-H) Example 66

4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoic acid

To a stirred solution of ethyl 4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoate (45mg, 0.078mmol) in 10ml of THF was added 3ml of 1M NaOH (3.0mmol). The mixture was heated at 60°C for 3 hours, cooled to room temperature and poured into 100ml of water. 2M HCl was added until pH = 5. The precipitates were filtered, washed with water, and dried to give 4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoic acid as grey solid. Yield: 40mg, 93%.

1H NMR (DMSO-d₆): 11.99 (br. s., 1H), 11.82 (br. s., 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.9, 2.1 Hz, 1H), 7.85 (t, J = 5.7 Hz, 1 H), 7.37 (br. s., 1H), 7.27 (dd, J = 11.7, 2.6 Hz, 1H), 7.19 (s, 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 2H), 7.02 (dd, J = 8.9, 1.6 Hz, 1H), 6.77 - 6.82 (m, 1H), 6.73 - 6.77 (m, 1H), 3.16 (q, J = 6.7 Hz, 2H), 2.25 (s, 3H), 2.22 (t, J = 7.3 Hz, 2H), 1.67 (quin, J = 7.2 Hz, 2H) LR MS (ES-): 548 (M-H) Example 67

ethyl 4-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoate

Similar procedure as Example 132. ¹H NMR (DMSO-d₆): 11.99 (br. s., 1H), 9.09 (d, J = 1.5 Hz, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.42 (d, J = 6.2 Hz, 1H), 8.26 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.8, 2.2 Hz, 1H), 7.86 - 7.94 (m, 1H), 7.46 (br. s., 1H), 7.25 - 7.34 (m, 2H), 7.22 (br. s., 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.87 (br. s., 1H), 6.76 - 6.82 (m, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.13 - 3.21 (m, 2H), 2.30 (t, J = 7.5 Hz, 2H), 2.25 (s, 3H), 1.70 (quin, J = 7.2 Hz, 2H), 1.14 (t, J = 7.04 Hz, 3H) LR MS (ES+): 578 (MH), 600 (M+Na⁺)

LR MS (ES-): 576 (M-H) Example 68

4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}butanoic acid

Similar procedure as Example 66.

1H NMR (DMSO-d₆): 12.00 (br. s., 1H), 11.82 (br. s., 1H), 8.97 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 8.21 (t, J = 9.1 Hz, 1 H), 7.85 (t, J = 5.7 Hz, 1 H), 7.37 (br. s., 1H), 7.24 - 7.29 (m, 2H), 7.17 - 7.23 (m, 2H), 7.13 - 7.17 (m, 1H), 7.10 (br. s., 1H), 7.02 (dd, J = 8.8, 1.8 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.75 (br. s., 1H), 3.16 (q, J = 6.7 Hz, 2H), 2.26 (s, 3H), 2.22 (t, J = 7.3 Hz, 2H), 1.67 (quin, J = 7.2 Hz, 2H)

LR MS (ES+): 532 (MH), 554 (M+Na⁺)

LR MS (ES-): 530 (M-H) Example 69

3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoic acid

Similar procedure as Example 66.

1H NMR (DMSO-d₆): 11.93 (br. s., 2H), 9.08 (br. s., 1H), 8.96 (d, J = 1.8 Hz, 1H), 8.41 (d, J = 5.9 Hz, 1H), 8.25 (t, J = 8.9 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.94 (br. s., 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 10.3 Hz, 1H), 7.24 (br. s., 1H), 7.17 (br. s., 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.83 (br. s., 1H), 6.76 - 6.81 (m, 1H), 3.33 - 3.38 (m, 2H), 2.44 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H)

LR MS (ES-): 534 (M-H) Example 70

N-ethyl-5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.98 (br. s., 1H), 9.11 (s, 1H), 8.67 (br. s., 1H), 8.41 (d, J = 5.9 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1 H), 7.87 (t, J = 5.0 Hz, 1H), 7.44 (br. s., 1H), 7.25 - 7.32 (m, 3H), 7.18 - 7.25 (m, 2H), 7.12 - 7.17 (m, 1H), 7.04 (dd, J = 9.0, 1.6 Hz, 1H), 6.85 (br. s., 1H), 6.79 (d, J = 7.3 Hz, 1H), 3.15 - 3.22 (m, 2H), 2.26 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H)

LR MS (ES+): 474 (MH), 496 (M+Na⁺)

LR MS (ES-): 472 (M-H) Example 71

{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}acetic acid

Similar procedure as Example 66.

1H NMR (DMSO-d₆): 11.84 (br. s., 1H), 9.23 (s, 1H), 8.73 (d, J = 1.5 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.18 (t, J = 9.1 Hz, 1H), 8.12 (t, J = 5.4 Hz, 1H), 7.38 (dd, J = 2.9, 1.8 Hz, 1H), 7.28 (s, 1H), 7.21 - 7.26 (m, 2H), 7.19 (d, J = 2.3 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.08 - 7.11 (m, 1H), 7.01 (dd, J = 9.0, 2.5 Hz, 1H), 6.78 (d, J = 7.3 Hz, 1H), 6.73 (dd, J = 5.9, 2.3 Hz, 1H), 3.78 (d, J = 5.9 Hz, 2H), 2.25 (s, 3H)

LR MS (ES-): 502 (M-H) Example 72

methyl {[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]amino}acetate

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.87 (br. s., 1H), 8.96 (s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 8.31 (t, J = 6.0 Hz, 1H), 8.20 (t, J = 9.1 Hz, 1H), 7.39 (dd, J = 3.2, 1.8 Hz, 1H), 7.24 - 7.29 (m, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.13 - 7.17 (m, 1H), 7.08 - 7.10 (m, 1H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.74 (dd, J = 5.9, 2.3 Hz, 1H), 3.90 (d, J = 5.9 Hz, 2H), 3.60 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 518 (MH), 540 (M+Na⁺)

LR MS (ES-): 516 (M-H) Example 73

1-(2-fluoro-4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol-2-yl)pyridin-4- yl]oxy}phenyl)-3-(3-methylphenyl)urea

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.87 (br. s., 1H), 8.97 (s, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 5.9 Hz, 1H), 8.18 (t, J = 9.1 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.18 - 7.30 (m, 4H), 7.12 - 7.17 (m, 1H), 7.08 (d, J = 18.8 Hz, 1H), 6.99 (dt, J = 7.6, 1.5 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 4.90 (d, J = 9.4 Hz, 1H), 4.30 (br. s., 1H), 3.68 - 3.82 (m, 2H), 3.42 - 3.54 (m, 2H), 2.26 (s, 3H), 1.72 - 1.97 (m, 2H)

LR MS (ES+): 516 (MH), 538 (M+Na⁺)

LR MS (ES-): 514 (M-H) Example 74

1-{2-fluoro-4-[(2-{4-[(3-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4- yl)oxy]phenyl}-3-(3-methylphenyl)urea

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.83 (br. s., 1H), 8.96 (s, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.19 (t, J = 9.1 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.27 (s, 1H), 7.19 - 7.25 (m, 2H), 7.15 (t, J = 7.8 Hz, 1H), 7.12 (br. s., 1H), 6.97 - 7.01 (m, 1H), 6.90 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.68 (dd, J = 5.7, 2.2 Hz, 1H), 4.87 (br. s., 1H), 4.04 (br. s., 1H), 3.85 (br. s., 1H), 3.41 - 3.52 (m, 1H), 3.07 (t, J = 10.1 Hz, 1H), 2.26 (s, 3H), 1.78 - 1.90 (m, 1H), 1.67 (td, J = 8.8, 4.7 Hz, 1H), 1.30 - 1.43 (m, 2H)

LR MS (ES+): 530 (MH), 552 (M+Na⁺)

LR MS (ES-): 528 (M-H) Example 75

5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxylic acid

Similar procedure as Example 134.

1H NMR (DMSO-d₆): 12.04 (br. s., 1H), 11.87 (br. s., 1H), 8.97 (br. s., 1H), 8.56 (br. s., 1H), 8.39 (d, J = 5.9 Hz, 1H), 8.20 (t, J = 9.1 Hz, 1 H), 7.36 (br. s., 2H), 7.19 - 7.30 (m, 3H), 7.12 - 7.17 (m, 1H), 7.08 (br. s., 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.73 (br. s., 1H), 2.26 (s, 3H)

LR MS (ES+): 469 (MH) Example 76

methyl 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxylate

Similar procedure as Example 135.

1H NMR (DMSO-d₆): 12.11 (br. s., 1H), 8.96 (s, 1H), 8.55 (s, 1H), 8.38 (d, J = 5.9 Hz, 1H), 8.19 (t, J = 9.1 Hz, 1H), 7.42 (dd, J = 3.1, 1.6 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1 H), 7.28 (s, 1H), 7.19 - 7.26 (m, 2H), 7.12 - 7.17 (m, 1H), 7.09 - 7.12 (m, 1H), 7.00 (dd, J = 9.1, 2.3 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.72 (dd, J = 5.6, 2.3 Hz, 1H), 3.69 (s, 3H), 2.26 (s, 3H) LR MS (ES+): 461 (MH), 483 (M+Na⁺)

LR MS (ES-): 459 (M-H) Example 77

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.92 (br. s., 1H), 9.20 (s, 1H), 8.48 (br. s., 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.92 (br. s., 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.43 (br. s., 1H), 7.20 (br. s., 1H), 7.11 - 7.17 (m, 3H), 7.08 (dd, J = 11.2, 8.5 Hz, 1H), 6.73 - 6.81 (m, 2H), 3.41 - 3.48 (m, 12H), 3.34 - 3.39 (m, 2H), 3.31 (q, J = 5.8 Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 622 (MH), 644 (M+Na⁺)

LR MS (ES-): 620 (M-H) Example 78

4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}butanoic acid

Similar procedure as Example 66.

1H NMR (DMSO-d₆): 11.83 (br. s., 1H), 9.17 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.95 - 8.02 (m, 1H), 7.88 (t, J = 5.6 Hz, 1H), 7.57 (d, J = 9.1 Hz, 2H), 7.38 (br. s., 1H), 7.16 (d, J = 9.1 Hz, 2H), 7.06 - 7.17 (m, 3H), 6.77 - 6.85 (m, 1H), 6.67 - 6.76 (m, 1H), 3.16 - 3.22 (m, 2H), 2.28 (s, 3H), 2.25 (t, J = 7.3 Hz, 2H), 1.70 (quin, J = 7.2 Hz, 2H)

LR MS (ES+): 532 (MH)

LR MS (ES-): 530 (M-H) Example 79

ethyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]amino}butanoate

Similar procedure as Example 132.

LR MS (ES+): 560 (MH), 582 (M+Na⁺)

LR MS (ES-): 558 (M-H) Preparation of 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine

2,4-Dichloropyrdine (4.44 g, 30.0 mmol) and potassium carbonate (8.28 g, 60.0 mmol) in dimethylformamide (60 mL) was purged with nitrogen for 10 min. 4-Aminothiophenol (3.76 g, 30.0 mmol) was added and the mixture stirred under nitrogen at room temperature for 18 h. Water (300 mL) was added and the slurry stirred for 30 min. The resulting solid was filtered, washed with water and vacuum dried at room temperature. Recrystallization from ethyl acetate (35 mL), filtered hot, then cooled gave 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (3.946 g, 56% yield). Preparation of 1-[4-(2-Chloro-pyridin-4-ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea

To a stirred solution of 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (300 mg, 1.27 mmol) in anhydrous THF (10ml) was added 2-fluoro-5-methyl-phenylisocyanate (210mg, 1.39mmol). The mixture was stirred at 60°C for 5 hours, and poured into 100ml of water. The precipitates were filtered, washed with water (50ml), and dried to give the crude, which was purified by silica gel chromatography eluting with 2-3% MeOH/CHCl₃ to give 1-[4-(2-Chloro-pyridin-4- ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea as white solid. Yield: 410mg, 83%. ¹H NMR (DMSO-d₆): 9.37 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 5.9 Hz, 1H), 7.89 - 8.01 (m, 1H), 7.58 - 7.70 (m, 2H), 7.47 - 7.59 (m, 2H), 7.10 (dd, J = 11.4, 8.2 Hz, 1H), 6.94 - 7.03 (m, 2H), 6.82 (dd, J = 4.8, 2.2 Hz, 1H), 2.26 (s, 3H) Example 80

5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H- pyrrole-3-carboxylic acid

To a stirred solution of methyl 5-(4-{[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylate (86mg, 0.18mmol) in a mixture of solvents THF/MeOH (5ml/5ml) was added 2ml of 1M NaOH (2mmol) solution. The mixture was heated in a 66°C bath for 7 hours, cooled to room temperature and poured into 100ml of water. 2M HCl was added until pH = 3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-(4-{[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 73mg, 88%. ¹H NMR (DMSO-d₆): 12.01 (br. s., 1H), 9.37 (s, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 7.95 (s, 1H), 7.44 - 7.68 (m, 5H), 7.36 (br. s., 1H), 7.10 (dd, J = 11.1, 8.5 Hz, 1H), 6.94 (br. s., 1H), 6.81 (br. s., 1H), 6.69 (d, J = 5.3 Hz, 1H), 2.26 (s, 3H)

LR MS (ES-): 461 (M-H) Example 81

3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}propanoic acid

Similar procedure as Example 66.

1H NMR (DMSO-d₆): 12.12 (br. s., 1H), 11.81 (br. s., 1H), 9.15 (s, 1H), 8.46 (br. s., 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.92 (t, J = 5.3 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.35 (br. s., 1H), 7.13 (dd, J = 6.6, 2.2 Hz, 3H), 7.08 (dd, J = 11.2, 8.5 Hz, 1H), 7.04 (br. s., 1H), 6.75 - 6.82 (m, 1H), 6.70 (d, J = 3.2 Hz, 1H), 3.32 - 3.41 (m, 2H), 2.43 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 518 (MH), 540 (M+Na⁺)

LR MS (ES-): 516 (M-H) Example 82

4-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoic acid

To a stirred solution of methyl 4-{S-methyl-N-[(5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]sulfonimidoyl}butanoate (5mg, 0.0087mol) in MeOH (3ml) was added 1M NaOH (0.5ml, 0.5mmol). The mixture was stirred at room temperature for 30 minutes, and poured into 30ml of water. 2M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried to give 4-{S-methyl-N-[(5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]sulfonimidoyl}butanoic acid as off-white solid. Yield: 5mg, 100%.

LR MS (ES+): 576 (MH), 598 (M+Na⁺)

LR MS (ES-): 574 (M-H) Example 83

1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]pyrrolidine-3-carboxylic acid

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 12.04 (br. s., 1H), 9.16 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.93 - 7.99 (m, 1H), 7.54 (d, J = 9.1 Hz, 2H), 7.41 (br. s., 1H), 7.33 (br. s., 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.75 - 6.82 (m, 1H), 6.72 (br. s., 1H), 2.98 - 3.93 (m, 5H), 2.25 (s, 3H), 1.93 - 2.19 (m, 2H)

LR MS (ES+): 544 (MH), 566 (M+Na⁺)

LR MS (ES-): 542 (M-H) Example 84

{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}acetic acid

Similar procedure as Example 66.

1H NMR (DMSO-d₆): 12.42 (br. s., 1H), 11.85 (br. s., 1H), 9.15 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 5.9 Hz, 1H), 8.21 (t, J = 6.0 Hz, 1H), 7.90 - 8.03 (m, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.38 (br. s., 1H), 7.02 - 7.21 (m, 5H), 6.74 - 6.84 (m, 1H), 6.70 (dd, J = 5.6, 2.3 Hz, 1H), 3.82 (d, J = 5.9 Hz, 2H), 2.26 (s, 3H)

LR MS (ES+): 504 (MH), 526 (M+Na⁺)

LR MS (ES-): 502 (M-H) Example 85

methyl {[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]amino}acetate

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 12.00 (br. s., 1H), 9.18 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.29 - 8.44 (m, 2H), 7.97 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 9.1 Hz, 2H), 7.46 (br. s., 1H), 7.02 - 7.27 (m, 5H), 6.79 (d, J = 2.1 Hz, 2H), 3.91 (d, J = 6.2 Hz, 2H), 3.61 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 518 (MH), 540 (M+Na⁺)

LR MS (ES-): 516 (M-H) Example 86

1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]piperidine-4-sulfonic acid

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 12.41 (br. s., 1H), 9.24 (s, 1H), 8.46 - 8.53 (m, 2H), 7.91 - 7.98 (m, 1H), 7.54 - 7.64 (m, 3H), 7.45 (br. s., 1H), 7.30 (br. s., 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 11.2, 8.2 Hz, 1H), 7.02 (br. s., 1H), 6.75 - 6.82 (m, 1H), 4.29 (br. s., 2H), 3.52 (br. s., 2H), 2.48 - 2.56 (m, 1H), 2.25 (s, 3H), 1.93 (d, J = 12.6 Hz, 2H), 1.45 (br. s., 2H)

LR MS (ES+): 616 (M+Na⁺)

LR MS (ES-): 592 (M-H) Example 87

methyl 4-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoate

Similar procedure as Example 101.

LR MS (ES+): 590 (MH), 612 (M+Na⁺) Example 88 methyl 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)- 1H-pyrrole-3-carboxylate

A mixture of 1-[4-(2-Chloro-pyridin-4-ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea (410mg, 1.06 mmol), methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3- carboxylate (532mg, 2.12 mmol) and PdCl₂(dppf)·CH₂Cl₂ (10mg, 0.012 mmol) was added to a thick-walled reaction vessel and purged with N₂. A solution of 2M Na₂CO₃ (1.0 mL) was added, followed by DMSO (10 mL). The reaction vessel was sealed and the mixture stirred at 95°C for 16 h. The reaction vessel was cooled to room temperature and the mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified via silica gel chromatography eluting with 2-5% MeOH/CHCl₃ to afford methyl 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)- 1H-pyrrole-3-carboxylate as off-white solid. Yield: 100mg, 20% yield.

LR MS (ES+): 477 (MH), 499 (M+Na⁺) Example 89

N-methyl-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.88 (br. s., 1H), 8.89 (s, 1H), 8.69 (s, 1H), 8.37 (d, J = 5.9 Hz, 1H), 7.82 (d, J = 4.4 Hz, 1H), 7.52 - 7.58 (m, 2H), 7.37 (br. s., 1H), 7.27 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.18 (br. s., 1H), 7.11 - 7.15 (m, 3H), 7.08 (br. s., 1H), 6.71 - 6.80 (m, 2H), 2.67 (d, J = 4.7 Hz, 3H), 2.25 (s, 3H)

LR MS (ES+): 442 (MH), 464 (M+Na⁺) LR MS (ES-): 440 (M-H) Example 90

1-{4-[(2-{4-[(3-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]phenyl}-3-(3- methylphenyl)urea

Similar procedure as Example 132.

LR MS (ES+): 512 (MH), 534 (M+Na⁺)

LR MS (ES-): 510 (M-H) Example 91

1-{4-[(2-{4-[(3-hydroxypyrrolidin-1-yl)carbonyl]-1H-pyrrol-2-yl}pyridin-4-yl)oxy]phenyl}-3- (3-methylphenyl)urea

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.88 (br. s., 1H), 8.74 (s, 1H), 8.58 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.99 - 7.39 (m, 8H), 6.78 (d, J = 7.0 Hz, 1H), 6.62 (dd, J = 5.6, 2.3 Hz, 1H), 4.91 (br. s., 1H), 4.31 (br. s., 1H), 3.67 - 3.87 (m, 2H), 3.49 (br. s., 2H), 2.26 (s, 3H), 1.88 (br. s., 2H)

LR MS (ES+): 520 (M+Na⁺) Example 92 N-(2,3-dihydroxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 11.86 (br. s., 1H), 8.78 (s, 1H), 8.61 (s, 1H), 8.37 (d, J = 5.9 Hz, 1H), 7.87 (t, J = 5.7 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.41 (br. s., 1H), 7.05 - 7.32 (m, 7H), 6.75 (dd, J = 17.7, 6.6 Hz, 2H), 3.49 - 3.61 (m, 1H), 3.22 - 3.35 (m, 3H), 3.04 - 3.18 (m, 1H), 2.26 (s, 3H) LR MS (ES+): 524 (M+Na⁺) Example 93

N-ethyl-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole- 3-carboxamide

Similar procedure as Example 132.

1H NMR (DMSO-d₆): 12.09 (br. s., 1H), 8.98 (s, 1H), 8.76 (s, 1H), 8.42 (d, J = 5.9 Hz, 1H), 7.91 (br. s., 1H), 7.45 - 7.65 (m, 3H), 7.05 - 7.38 (m, 7H), 6.82 - 6.94 (m, 1H), 6.78 (d, J = 7.6 Hz, 1H), 3.09 - 3.27 (m, 2H), 2.26 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H)

LR MS (ES+): 478 (M+Na⁺)

LR MS (ES-): 454 (M-H) Example 94

5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3- carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO,300MHz): 11.81 (br. s., 1H), 8.76 (s, 1H), 8.59 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 9.1 Hz, 2H), 7.37 (br. s., 2H), 7.28 (s, 1H), 7.19 - 7.26 (m, 1H), 7.09 - 7.18 (m, 4H), 7.04 (br. s., 1H), 6.78 (d, J = 7.3 Hz, 2H), 6.69 (dd, J = 5.4, 1.9 Hz, 1H), 2.26 (s, 3H) LR MS (ES+): 428 (MH), 450 (M+Na⁺)

LR MS (ES-): 426 (M-H) Example 95

N-hydroxy-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO,300MHz): 11.98 (br. s., 1 H), 10.62 (br. s., 1 H), 8.87 (s, 1 H), 8.68 (s, 1 H), 8.41 (d, J = 5.6 Hz, 1 H), 7.58 (d, J = 9.1 Hz, 2H), 7.04 - 7.46 (m, 8H), 6.80 (d, J = 7.6 Hz, 2H), 2.28 (s, 3H)

LR MS (ES+): 444 (MH), 466 (M+Na⁺)

LR MS (ES-): 442 (M-H) Example 96

5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxylic acid

Similar procedure as Example 134.

1H NMR (d₆-DMSO,300MHz): 12.04 (br. s., 1H), 11.88 (br. s., 1H), 9.08 (s, 1H), 8.97 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.25 (t, J = 9.2 Hz, 1 H), 8.01 (d, J = 7.6 Hz, 1H), 7.38 (s, 2H), 7.27 (dd, J = 11.9, 2.5 Hz, 1H), 6.95 - 7.18 (m, 3H), 6.78 - 6.88 (m, 1H), 6.74 (dd, J = 5.6, 2.1 Hz, 1H), 2.28 (s, 3H)

LR MS (ES+): 465 (MH), 487 (M+Na⁺)

LR MS (ES-): 463 (M-H) Example 97

N-[dimethyl(oxido)-lambda~4~-sulfanylidene]-5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide Similar procedure as Example 101.

1H NMR (d₆-DMSO,300MHz): 11.82 (none, 1H), 11.83 (br. s., 1H), 8.76 (s, 1H), 8.60 (s, 1H), 8.37 (d, J = 5.9 Hz, 1H), 7.56 (d, J = 9.1 Hz, 2H), 7.21 - 7.35 (m, 4H), 7.08 - 7.20 (m, 3H), 6.95 (s, 1H), 6.79 (d, J = 7.0 Hz, 1H), 6.66 (dd, J = 5.6, 2.3 Hz, 1H), 3.37 (s, 6H), 2.28 (s, 3H) LR MS (ES+): 526 (M+Na⁺)

LR MS (ES-): 502 (M-H) Example 98

2-hydroxyethyl 5-{4-[4-({[(4-chloro-3- (trifluoromethyl)phenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3- carboxylate

Similar procedure as Example 131.

1H NMR (d₆-DMSO,300MHz): 12.12 (br. s., 1 H), 9.19 (s, 1 H), 8.97 (s, 1 H), 8.40 (d, J=5.9 Hz, 1 H), 8.12 (d, J=2.1 Hz, 1 H), 7.53 - 7.70 (m, 4 H), 7.48 (dd, J=3.1, 1.6 Hz, 1 H), 7.35 (d, J=2.1 Hz, 1 H), 7.16 (d, J=9.1 Hz, 2 H), 7.09 (d, J=2.3 Hz, 1 H), 6.68 (dd, J=5.6, 2.3 Hz, 1 H), 4.83 (t, J=5.9 Hz, 1 H), 4.15 (t, J=5.0 Hz, 2 H), 3.59 - 3.69 (m, 2 H)

LR MS (ES+): 583 (M+Na⁺), 585

LR MS (ES-): 559 (M-H), 561 Example 99

N-[dimethyl(oxido)-lambda~4~-sulfanylidene]-5-{4-[4-({[(4-chloro-3- (trifluoromethyl)phenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3- carboxamide

Similar procedure as Example 101.

1H NMR (d₆-DMSO,300MHz) 11.83 (br. s., 1 H), 9.19 (s, 1 H), 8.97 (s, 1 H), 8.37 (d, J=5.9 Hz, 1 H), 8.12 (d, J=2.3 Hz, 1 H), 7.54 - 7.69 (m, 4 H), 7.23 - 7.31 (m, 2 H), 7.12 - 7.19 (m, 2 H), 6.93 - 6.97 (m, 1 H), 6.67 (dd, J=5.9, 2.3 Hz, 1 H), 3.37 (s, 6 H)

LR MS (ES-): 590 (M-H) Example 100

methy 4-(N-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxyl)-S-methylsulfonimidoyl)butanoate

Similar procedure as Example 101.

LR MS (ES+): 630 (M+Na⁺)

LR MS (ES-): 606 (M-H) Example 101

N-[dimethyl(oxido)-lambda~4~-sulfanylidene]-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (60mg, 0.13mmol), HATU (60mg, 0.16mmol),

sulfonimidoyldimethane (24mg, 0.26mmol), N,N-diisopropylethylamine (37mg, 0.29mmol), 200mg of 4Å molecular sieves and 5ml of anhydrous 1,4-dioxane was added to a thick walled reaction vessel and purged with N₂. The reaction vessel was sealed and the mixture stirred at 90°C for 18 hours. The reaction vessel was cooled to room temperature and the mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 3~5% MeOH/CHCl₃ to give N-[dimethyl(oxido)-lambda~4~-sulfanylidene]-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 38mg, 54%.

1H NMR (d₆-DMSO): 11.83 (br. s., 1H), 9.16 (s, 1H), 8.48 (br. s., 1H), 8.37 (d, J = 5.9 Hz, 1H), 7.98 (d, J = 6.7 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.26 (dd, J = 8.6, 1.6 Hz, 2H), 7.05 - 7.19 (m, 3H), 6.96 (s, 1H), 6.75 - 6.85 (m, 1H), 6.66 (dd, J = 5.4, 1.6 Hz, 1H), 3.37 (s, 6H), 2.27 (s, 3H) LR MS (ES+): 544 (M+Na⁺)

LR MS (ES-): 520 (M-H) Example 102

methyl (2S)-1-(2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)pyrrolidine-2-carboxylate

Similar procedure as Example 132.

LR MS (ES+): 623 (M+Na⁺)

LR MS (ES-): 599 (M-H) Example 103

N,N-diethyl-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.97 (br. s., 1H), 9.19 (s, 1H), 8.49 (d, J = 2.6 Hz, 1H), 8.40 (d, J = 6.2 Hz, 1H), 7.98 (dd, J = 7.8, 1.9 Hz, 1H), 7.53 - 7.61 (m, 2H), 7.40 (d, J = 1.5 Hz, 1H), 7.05 - 7.25 (m, 4H), 7.01 (br. s., 1H), 6.76 - 6.86 (m, 1H), 6.67 - 6.76 (m, 1H), 3.26 - 3.64 (m, 4H), 2.27 (s, 3H), 1.13 (t, J = 7.0 Hz, 6H)

LR MS (ES+): 524 (M+Na⁺)

LR MS (ES-): 500 (M-H) Example 104

1-(2-fluoro-5-methylphenyl)-3-{4-[(2-{4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2- yl}pyridin-4-yl)oxy]phenyl}urea

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.87 (br. s., 1H), 9.16 (s, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.98 (dd, J = 8.1, 1.9 Hz, 1H), 7.50 - 7.59 (m, 2H), 7.35 (d, J = 2.3 Hz, 1H), 7.08 - 7.19 (m, 4H), 6.87 - 6.95 (m, 1H), 6.80 (ddd, J = 7.7, 5.1, 2.2 Hz, 1H), 6.63 (dd, J = 5.9, 2.3 Hz, 1H), 3.60 (d, J = 4.1 Hz, 4H), 2.23 - 2.35 (m, 7H), 2.18 (s, 3H)

LR MS (ES+): 551 (M+Na⁺)

LR MS (ES-): 527 (M-H) Example 105

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2- pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.80 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.98 (dd, J = 7.9, 2.1 Hz, 1H), 7.82 (t, J = 5.7 Hz, 1H), 7.50 - 7.63 (m, 2H), 7.35 (dd, J = 2.9, 1.8 Hz, 1H), 7.00 - 7.20 (m, 5H), 6.80 (dt, J = 7.9, 2.2 Hz, 1H), 6.70 (dd, J = 5.9, 2.3 Hz, 1H), 3.21 - 3.35 (m, 2H), 2.37 - 2.57 (m, 6H), 2.27 (s, 3H), 1.65 (dt, J = 6.6, 3.1 Hz, 4H) LR MS (ES+): 565 (M+Na⁺) LR MS (ES-): 541 (M-H) Example 106

1-(4-((2-(4-(4,5-dihydrooxazol-2-yl)-1H-pyrrol-2-yl)pyridin-4-yl)oxy)phenyl)-3-(2-fluoro-5- methylphenyl)urea

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.90 (br. s., 1H), 9.15 (s, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.36 (d, J = 5.9 Hz, 1H), 7.97 (dd, J = 8.2, 2.1 Hz, 1H), 7.50 - 7.58 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.23 (br. s., 1H), 7.04 - 7.17 (m, 3H), 6.97 (br. s., 1H), 6.79 (ddd, J = 7.5, 5.1, 2.3 Hz, 1H), 6.65 (dd, J = 5.7, 2.5 Hz, 1H), 4.17 - 4.31 (m, 2H), 3.82 (t, J = 9.2 Hz, 2H), 2.26 (s, 3H)

LR MS (ES+): 494 (M+Na⁺)

LR MS (ES-): 470 (M-H) Example 107

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.89 (br. s., 1H), 9.21 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.98 (dd, J = 8.1, 1.9 Hz, 1H), 7.53 - 7.62 (m, 2H), 7.43 (br. s., 2H), 7.05 - 7.24 (m, 5H), 6.71 - 6.86 (m, 3H), 2.27 (s, 3H)

LR MS (ES+): 468 (M+Na⁺)

LR MS (ES-): 444 (M-H) Example 108

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-hydroxy- 1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 12.10 (br. s., 1H), 10.66 (br. s., 1H), 9.29 (s, 1H), 8.53 (br. s., 1H), 8.43 (d, J = 6.2 Hz, 1H), 7.93 - 8.03 (m, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.39 - 7.50 (m, 1H), 7.30 (br. s., 1H), 7.05 - 7.26 (m, 4H), 6.75 - 6.91 (m, 2H), 2.27 (s, 3H)

LR MS (ES+): 484 (M+Na⁺)

LR MS (ES-): 460 (M-H) Example 109

1-(4-((2-(4-(5,6-dihydro-4H-1,3-oxazin-2-yl)-1H-pyrrol-2-yl)pyridin-4-yl)oxy)phenyl)-3-(2- fluoro-5-methylphenyl)urea

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.67 (br. s., 1H), 9.16 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 5.6 Hz, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.54 (d, J = 9.1 Hz, 2H), 7.02 - 7.23 (m, 5H), 6.86 (br. s., 1H), 6.74 - 6.83 (m, 1H), 6.64 (dd, J = 5.9, 2.3 Hz, 1H), 4.14 - 4.28 (m, 2H), 3.33 - 3.42 (m, 2H), 2.26 (s, 3H), 1.83 (br. s., 2H)

LR MS (ES+): 486 (M+H)

LR MS (ES-): 484 (M-H) Example 110 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3- hydroxypropyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.78 (br. s., 1H), 9.20 (s, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 7.9, 1.8 Hz, 1H), 7.83 (t, J = 5.7 Hz, 1H), 7.55 (d, J = 9.1 Hz, 2H), 7.32 - 7.36 (m, 1H), 7.02 - 7.17 (m, 5H), 6.78 (td, J = 5.3, 2.6 Hz, 1H), 6.69 (dd, J = 5.6, 2.3 Hz, 1H), 4.42 (t, J = 5.3 Hz, 1 H), 3.41 (q, J = 6.2 Hz, 2H), 3.15 - 3.26 (m, 2H), 2.26 (s, 3H), 1.60 (quin, J = 6.7 Hz, 2H)

LR MS (ES+): 526 (M+Na⁺)

LR MS (ES-): 502 (M-H) Example 111

2-(2-methoxyethoxy)ethyl 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 131.

1H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.15 (s, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 7.97 (dd, J = 8.1, 1.9 Hz, 1H), 7.49 - 7.59 (m, 2H), 7.41 (dd, J = 3.1, 1.6 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.03 - 7.17 (m, 4H), 6.74 - 6.84 (m, 1H), 6.67 (dd, J = 5.7, 2.5 Hz, 1H), 4.20 - 4.28 (m, 2H), 3.62 - 3.70 (m, 2H), 3.51 - 3.59 (m, 2H), 3.39 - 3.46 (m, 2H), 3.18 - 3.24 (m, 3H), 2.26 (s, 3H) LR MS (ES+): 571 (M+Na⁺)

LR MS (ES-): 547 (M-H) Example 112

N-ethyl-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.93 (br. s., 1H), 9.23 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 6.2 Hz, 1H), 7.96 (dd, J = 7.9, 1.8 Hz, 1H), 7.87 (t, J = 5.6 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.42 (br. s., 1H), 7.02 - 7.27 (m, 5H), 6.72 - 6.86 (m, 2H), 3.09 - 3.25 (m, 2H), 2.26 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H)

LR MS (ES+): 496 (M+Na⁺)

LR MS (ES-): 472 (M-H) Example 113

2-methoxyethyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 131.

1H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.15 (s, 1H), 8.46 (br. s., 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.98 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.01 - 7.19 (m, 4H), 6.78 (d, J = 5.9 Hz, 1H), 6.66 (dd, J = 5.9, 2.1 Hz, 1H), 4.17 - 4.32 (m, 2H), 3.51 - 3.65 (m, 2H), 3.29 (s, 3H), 2.26 (s, 3H) LR MS (ES+): 527 (M+Na⁺)

LR MS (ES-): 503 (M-H) Example 114

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2- methoxyethyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.86 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 7.86 - 8.02 (m, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.40 (br. s., 1H), 7.02 - 7.21 (m, 5H), 6.67 - 6.84 (m, 2H), 3.26 - 3.50 (m, 7H), 2.26 (s, 3H)

LR MS (ES+): 526 (M+Na⁺)

LR MS (ES-): 502 (M-H) Example 115

5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3- carboxylic acid

Similar procedure as Example 134.

1H NMR (d₆-DMSO): 12.05 (br. s., 1H), 8.79 (s, 1H), 8.62 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.52 - 7.61 (m, 2H), 7.39 (dd, J = 3.1, 1.6 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.30 (s, 1H), 7.21 - 7.27 (m, 1H), 7.10 - 7.20 (m, 3H), 7.05 (s, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 2.28 (s, 3H)

LR MS (ES-): 427 (M-H) Example 116

methyl 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole- 3-carboxylate

Similar procedure as Example 135.

1H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.02 (br. s., 1H), 8.85 (br. s., 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.50 - 7.59 (m, 2H), 7.41 (d, J = 1.5 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.08 - 7.18 (m, 3H), 7.06 (d, J = 1.5 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.65 (dd, J = 5.6, 2.3 Hz, 1H), 3.69 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 465 (M+Na⁺)

LR MS (ES-): 441 (M-H) Example 117

5-{4-[2-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrole-3-carboxylic acid

Similar procedure as Example 134.

1H NMR (d₆-DMSO): 12.03 (br. s., 1H), 11.86 (br. s., 1H), 9.62 (s, 1H), 8.65 (s, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.94 (dd, J = 7.9, 1.8 Hz, 1H), 7.72 (dd, J = 13.2, 2.3 Hz, 1H), 7.26 - 7.40 (m, 3H), 7.15 - 7.24 (m, 1H), 7.01 - 7.14 (m, 2H), 6.81 (td, J = 5.3, 2.3 Hz, 1H), 6.68 (dd, J = 5.7, 2.2 Hz, 1H), 2.26 (s, 3H)

LR MS (ES+): 487 (M+Na⁺)

LR MS (ES-): 463 (M-H) Example 118

methyl 5-{4-[2-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 135.

1H NMR (d₆-DMSO): 12.13 (br. s., 1H), 9.34 (s, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.94 (dd, J = 7.8, 1.6 Hz, 1H), 7.72 (dd, J = 13.5, 2.3 Hz, 1H), 7.43 (dd, J = 3.2, 1.8 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.26 - 7.36 (m, 1H), 7.18 (dd, J = 8.9, 1.6 Hz, 1H), 7.05 - 7.15 (m, 2H), 6.77 - 6.87 (m, 1H), 6.70 (dd, J = 5.6, 2.3 Hz, 1H), 3.70 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 501 (M+Na⁺)

LR MS (ES-): 477 (M-H) Example 119

5-(4-{4-[({[4-fluoro-3

-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylic acid

Similar procedure as Example 134.

1H NMR (d₆-DMSO): 12.05 (d, 1H), 9.11 (s, 1H), 8.96 (s, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 6.4, 2.3 Hz, 1H), 7.60 - 7.72 (m, 1H), 7.56 (d, J = 9.1 Hz, 2H), 7.27 - 7.49 (m, 3H), 7.14 (d, J = 9.1 Hz, 2H), 7.03 (br. s., 1H), 6.67 (dd, J = 5.7, 2.2 Hz, 1H)

LR MS (ES-): 499 (M-H) Example 120 methyl 5-(4-{4-[({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin- 2-yl)-1H-pyrrole-3-carboxylate

Similar procedure as Example 135.

1H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.04 (s, 1H), 8.91 (s, 1H), 8.37 (d, J = 6.2 Hz, 1H), 7.99 (dd, J = 6.4, 2.6 Hz, 1H), 7.60 - 7.69 (m, 1H), 7.51 - 7.61 (m, 2H), 7.37 - 7.49 (m, 2H), 7.34 (d, J = 2.1 Hz, 1H), 7.09 - 7.18 (m, 2H), 7.01 - 7.09 (m, 1H), 6.66 (dd, J = 5.6, 2.3 Hz, 1H), 3.70 (s, 3H)

LR MS (ES+): 537 (M+Na⁺)

LR MS (ES-): 513 (M-H) Example 121

5-(4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)- 1H-pyrrole-3-carboxylic acid

Similar procedure as Example 134.

1H NMR (d₆-DMSO): 12.08 (br. s., 1H), 9.23 (s, 1H), 9.00 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.10 (s, 1H), 7.48 - 7.72 (m, 4H), 7.27 - 7.47 (m, 2H), 7.00 - 7.23 (m, 3H), 6.69 (br. s., 1H)

LR MS (ES-): 515 (M-H) Example 122

methyl 5-(4-{4-[({[4-chloro-3- (trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylate

Similar procedure as Example 135.

1H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.17 (s, 1H), 8.94 (s, 1H), 8.38 (d, J = 5.9 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.51 - 7.69 (m, 4H), 7.42 (dd, J = 3.2, 1.8 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.10 - 7.18 (m, 2H), 7.03 - 7.09 (m, 1H), 6.66 (dd, J = 5.9, 2.3 Hz, 1H), 3.70 (s, 3H)

LR MS (ES+): 553 (M+Na⁺)

LR MS (ES-): 529 (M-H) Example 123

4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene- 2-carboxylic acid

To a stirred solution of methyl 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylate (550mg, 1.15mmol) in a mixture of solvents - THF/MeOH (20ml/20ml) was added 1ml of 5M NaOH (5mmol) solution. The mixture was heated in a 66°C bath for 2 hours, cooled to room temperature and poured into 200ml of water. 2M HCl was added until pH = 5. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylic acid as off- white solid. Yield: 520mg, 97%.

1H NMR (d₆-DMSO): 9.30 (s, 1H), 8.59 (d, J = 2.6 Hz, 1H), 8.43 (d, J = 5.9 Hz, 1H), 8.35 (br. s., 1H), 8.13 (br. s., 1H), 7.95 (dd, J = 7.8, 1.9 Hz, 1H), 7.51 - 7.59 (m, 2H), 7.45 (s, 1H), 7.03 - 7.18 (m, 3H), 6.75 - 6.83 (m, 1H), 6.72 (dd, J = 5.6, 2.3 Hz, 1H), 2.25 (s, 3H)

LR MS (ES-): 462 (M-H) Example 124

2-hydroxyethyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-2-carboxylate

Similar procedure as Example 131.

1H NMR (DMSO-d₆) δ: 12.11 (br. s., 1H), 9.15 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 7.9, 1.8 Hz, 1H), 7.63 (dd, J = 2.9, 1.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.22 - 7.37 (m, 2H), 7.01 - 7.18 (m, 3H), 6.72 - 6.85 (m, 1H), 6.58 (dd, J = 5.6, 2.3 Hz, 1H), 4.83 (t, J = 5.9 Hz, 1H), 4.19 (t, J = 5.1 Hz, 2H), 3.57 - 3.73 (m, 2H), 2.25 (s, 3H)

LR MS (ES+): 491 (MH), 513 (M+Na⁺)

LR MS (ES-): 489 (M-H) Example 125

{1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]piperidin-4-yl}acetic acid

To a stirred solution of methyl {1-[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]piperidin-4-yl}acetate (50mg, 0.085mmol) in THF/MeOH (5ml/5ml) was added 1M NaOH solution (3ml, 3mmol). The mixture was stirred at room temperature for one hour, and poured into 50ml of water. 2M HCl was added until pH = 4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give {1-[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]piperidin-4-yl}acetic acid as white solid. Yield: 47mg, 96%.

LR MS (ES-): 570 (M-H) Example 126

methyl {1-[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}acetate

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.83 (br. s., 1H), 9.14 (s, 1H), 8.46 (br. s., 1H), 8.35 (d, J = 5.6 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 1.8 Hz, 1H), 7.01 - 7.18 (m, 4H), 6.86 (s, 1H), 6.80 (d, J = 4.4 Hz, 1H), 6.61 (dd, J = 5.9, 2.1 Hz, 1H), 4.26 (br. s., 2H), 3.57 (s, 3H), 2.87 (br. s., 2H), 2.18 - 2.32 (m, 5H), 1.93 (br. s., 1H), 1.65 (br. s., 2H), 1.14 (br. s., 2H) LR MS (ES+): 608 (M+Na⁺)

LR MS (ES-): 584 (M-H) Example 127

N-(2,3-dihydroxypropyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide

Similar procedure as Example 132. ¹H NMR (d₆-DMSO): 11.81 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 7.8, 1.9 Hz, 1H), 7.86 (t, J = 5.7 Hz, 1H), 7.51 - 7.60 (m, 2H), 7.38 (dd, J = 3.1, 1.6 Hz, 1H), 7.10 - 7.19 (m, 3H), 7.07 (td, J = 4.3, 2.5 Hz, 2H), 6.74 - 6.84 (m, 1H), 6.69 (dd, J = 5.6, 2.3 Hz, 1H), 4.78 (d, J = 5.0 Hz, 1H), 4.54 (t, J = 5.9 Hz, 1H), 3.48 - 3.60 (m, 1H), 3.23 - 3.36 (m, 3H), 3.05 - 3.18 (m, 1H), 2.26 (s, 3H)

LR MS (ES+): 542 (M+Na⁺)

LR MS (ES-): 518 (M-H) Example 128

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2- hydroxyethyl)-1H-pyrrole-3-carboxamide

Similar procedure as Example 132.

1H NMR (d₆-DMSO): 11.79 (br. s., 1H), 9.30 (s, 1H), 8.57 (d, J = 1.5 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.95 (dd, J = 7.9, 1.8 Hz, 1H), 7.84 (t, J = 5.6 Hz, 1H), 7.50 - 7.63 (m, 2H), 7.35 (d, J = 1.5 Hz, 1H), 7.00 - 7.21 (m, 5H), 6.79 (td, J = 5.3, 2.5 Hz, 1H), 6.69 (dd, J = 5.6, 2.3 Hz, 1H), 4.66 (t, J = 5.6 Hz, 1 H), 3.38 - 3.51 (m, 2H), 3.22 (q, J = 6.1 Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 512 (M+Na⁺)

LR MS (ES-): 488 (M-H) Example 129

1-(2-fluoro-5-methylphenyl)-3-{4-[(2-{4-[(4-hydroxypiperidin-1-yl)carbonyl]-1H-pyrrol-2- yl}pyridin-4-yl)oxy]phenyl}urea

S_{imilar procedure as Example 132.}

1H NMR (d₆-DMSO): 11.84 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 7.9, 1.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 2.3 Hz, 1H), 7.04 - 7.20 (m, 4H), 6.89 (s, 1H), 6.81 (td, J = 5.3, 2.3 Hz, 1H), 6.63 (dd, J = 5.9, 2.3 Hz, 1H), 4.73 (d, J = 4.1 Hz, 1H), 3.90 - 4.06 (m, 2H), 3.71 (dt, J = 8.4, 4.3 Hz, 1H), 3.25 (d, J = 2.6 Hz, 2H), 2.27 (s, 3H), 1.73 (d, J = 4.1 Hz, 2H), 1.21 - 1.44 (m, 2H)

LR MS (ES+): 552 (M+Na⁺)

LR MS (ES-): 528 (M-H) Example 130

2,3-dihydroxypropyl 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate

Similar procedure as Example 131.

1H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.24 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.98 (dd, J = 7.8, 1.9 Hz, 1H), 7.51 - 7.62 (m, 2H), 7.48 (dd, J = 3.1, 1.6 Hz, 1H), 7.34 - 7.40 (m, 1H), 7.05 - 7.20 (m, 4H), 6.75 - 6.87 (m, 1H), 6.68 (dd, J = 5.9, 2.3 Hz, 1H), 4.92 (d, J = 5.3 Hz, 1H), 4.64 (t, J = 5.7 Hz, 1H), 4.11 - 4.22 (m, 1H), 3.97 - 4.09 (m, 1H), 3.67 - 3.79 (m, 1H), 3.38 - 3.46 (m, 2H), 2.28 (s, 3H)

LR MS (ES+): 543 (M+Na⁺)

LR MS (ES-): 519 (M-H) Example 131

2-hydroxyethyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylate

A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (50mg, 0.11mmol), ethylene glycol (1ml), 1-Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride (EDC• HCl, 25mg, 0.13mmol) and 4- dimethylaminopyridine (DMAP, 5mg, 0.04mmol) in anhydrous THF (10ml) was stirred at 60°C for 16 hours. The mixture was poured into 100ml of water. 2M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography with a gradient of 3~5% MeOH/CHCl₃ to give 2-hydroxyethyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 36mg, 67%.

1H NMR (d₆-DMSO): 12.12 (br. s., 1H), 9.18 (s, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.94 - 8.05 (m, 1H), 7.56 (d, J = 9.1 Hz, 2H), 7.48 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.03 - 7.23 (m, 4H), 6.75 - 6.86 (m, 1H), 6.69 (dd, J = 5.7, 2.2 Hz, 1H), 4.83 (t, J = 5.7 Hz, 1H), 4.15 (t, J = 5.1 Hz, 2H), 3.64 (q, J = 5.4 Hz, 2H), 2.27 (s, 3H)

LR MS (ES+): 513 (M+Na⁺)

LR MS (ES-): 489 (M-H) Example 132

1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H-pyrrol- 2-yl)pyridin-4-yl]oxy}phenyl)urea

A_{mixture of 5-{4-[4-({ [(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-} yl}-1H-pyrrole-3-carboxylic acid (50mg, 0.11mmol), HATU (51mg, 0.13mmol) and N,N- diisopropylethylamine (31mg, 0.24mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of (R)-3-pyrrolidinol (14mg, 0.16mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. 2M HCl was added dropwise until pH = 4~5. The precipitates were filtered, washed with water and dried in vacuo to give 1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H- pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea as white solid. Yield: 40mg, 71%.

1H NMR (d₆-DMSO): 11.90 (br. s., 1H), 9.17 (s, 1H), 8.49 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 7.99 (dd, J = 7.8, 1.9 Hz, 1H), 7.51 - 7.62 (m, 2H), 7.37 (d, J = 2.3 Hz, 1H), 7.25 (br. s., 1H), 7.02 - 7.19 (m, 4H), 6.76 - 6.86 (m, 1H), 6.64 (dd, J = 5.6, 2.3 Hz, 1H), 4.93 (br. s., 1H), 4.22 - 4.38 (m, 1H), 3.69 - 3.87 (m, 1H), 3.43 - 3.59 (m, 2H), 3.35 - 3.42 (m, 1H), 2.27 (s, 3H), 1.90 (br. s., 2H)

LR MS (ES+): 538 (M+Na⁺)

LR MS (ES-): 514 (M-H) Example 133

1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(4-{[(3S)-3-hydroxypyrrolidin-1 -yl]carbonyl}-1H-pyrrol- 2-yl)pyridin-4-yl]oxy}phenyl)urea

Similar procedure as Example 132.

LR MS (ES+): 538 (M+Na⁺) LR MS (ES-): 514 (M-H) Example 134

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxylic acid

To a stirred solution of methyl 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate (1.38g, 3.00mmol) in a mixture of solvents THF/MeOH (20ml/20ml) was added 2ml of 5M NaOH (10mmol) solution. The mixture was heated in a 72°C bath for 5 hours, cooled to room temperature and poured into 200ml of water. 2M HCl was added until pH = 3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 1.28g, 96%.

1H NMR (d₆-DMSO): 12.04 (br. s., 1H), 11.88 (br. s., 1H), 9.18 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.94 - 8.05 (m, 1H), 7.56 (d, J = 9.1 Hz, 2H), 7.31 - 7.42 (m, 2H), 7.01 - 7.21 (m, 4H), 6.81 (td, J = 5.2, 2.2 Hz, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1 H), 2.27 (s, 3H)

LR MS (ES-): 467 (M-H) Example 135

methyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxylate

To a stirred solution of methyl 5-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylate (1.0g, 3.23mmol) in anhydrous THF (10ml) was added 2-fluoro-5-methyl-phenylisocyanate (488mg, 3.23mmol). The mixture was stirred at room temperature for one hour and poured into 200ml of 0.02M HCl solution with vigorous stirring. The resulting precipitates were filtered, washed with water, and dried in vacuo to give methyl 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 1.38g, 93%.

1H NMR (d₆-DMSO): 12.14 (br. s., 1H), 9.17 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.99 (dd, J = 7.9, 1.8 Hz, 1H), 7.53 - 7.59 (m, 2H), 7.44 (dd, J = 3.2, 1.5 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.06 - 7.18 (m, 4H), 6.77 - 6.85 (m, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 3.72 (s, 3H), 2.28 (s, 3H)

LR MS (ES+): 483 (M+Na⁺)

LR MS (ES-): 459 (M-H) Preparation of1-tert-butyl 2-methyl 4-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2- dicarboxylate

Similar procedure as 1-tert-butyl 2-methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2- dicarboxylate.

1H NMR (d₆-DMSO): 8.38 (d, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.67 (dd, J = 5.7, 2.2 Hz, 1H), 6.43 (d, J = 7.9 Hz, 1H), 6.20 - 6.33 (m, 2H), 5.32 (br. s., 2H), 3.72 - 3.85 (m, 3H), 1.53 (s, 9H)

LR MS (ES+): 432 (M+Na⁺) Example 136

methyl 4-{4-[3-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-2-carboxylate

To a stirred solution of 1-tert-butyl 2-methyl 4-[4-(3-aminophenoxy)pyridin-2-yl]-1H-pyrrole- 1,2-dicarboxylate (150 mg, 0.37 mmol) in anhydrous THF (10ml) was added 2-fluoro-5-methyl- phenylisocyanate (67mg, 0.44mmol). The mixture was stirred at room temperature for 3 hours and poured into 100ml of water. The resulting precipitates were filtered, washed with water, and dried in vacuo to give the Boc-protected intermediate as brown solid. This intermediate was dissolved in 5ml of methylene chloride, and 3ml of trifluoroacetic acid was added. Stirring was continued for 20 minutes. The mixture was evaporated to dryness to give the crude product, which was purified by silica gel chromatography eluting with 5% MeOH/CHCl₃ to give methyl 4-{4-[3-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-2-carboxylate as white solid. Yield: 67mg, 39%.

1H NMR (d₆-DMSO): 12.18 (br. s., 1H), 9.23 (s, 1H), 8.47 (br. s., 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.63 (br. s., 1H), 7.25 - 7.47 (m, 4H), 7.16 (d, J = 7.9 Hz, 1H), 7.07 (dd, J = 11.4, 8.5 Hz, 1H), 6.72 - 6.85 (m, 2H), 6.65 (dd, J = 5.6, 2.1 Hz, 1H), 3.76 (s, 3H), 2.22 (s, 3H)

LR MS (ES+): 483 (M+Na⁺)

LR MS (ES-): 459 (M-H) Example 137

N-[dimethyl(oxido)-lambda~4~-sulfanylidene]-4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxamide

Similar procedure as Example 101.

LR MS (ES+): 544 (M+Na⁺) LR MS (ES-): 520 (M-H) Example 138

4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N,N- dimethyl-1H-pyrrole-2-carboxamide

The title compound was isolated as a side product in the synthesis of Example 137.

LR MS (ES+): 474 (M+H)

LR MS (ES-): 472 (M-H Example 139

4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-methyl- 1H-pyrrole-2-carboxamide

A mixture of 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-2-carboxylic acid (50mg, 0.11mmol), HATU (50mg, 0.13mmol), 2M methylamine/ THF solution (0.1ml, 0.2mmol) and N,N-diisopropylethylamine (31mg,

0.24mmol) in anhydrous DMF (8ml) was stirred at room temperature for 10 minutes. The mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography with 3~5%

MeOH/CHCl₃ to give 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-methyl-1H-pyrrole-2- carboxamide as white solid. Yield: 21mg, 41%. ¹H NMR (d₆-DMSO): 11.69 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H), 8.01 - 8.12 (m, 1H), 7.96 (dd, J = 7.8, 1.9 Hz, 1H), 7.48 - 7.61 (m, 2H), 7.43 (dd, J = 2.9, 1.5 Hz, 1H), 7.03 - 7.23 (m, 5H), 6.79 (dt, J = 8.1, 2.3 Hz, 1H), 6.61 (dd, J = 5.6, 2.3 Hz, 1H), 2.71 (d, J = 4.7 Hz, 3H), 2.26 (s, 3H)

LR MS (ES+): 482 (M+Na⁺)

LR MS (ES-): 458 (M-H) Preparation of 4-(4-aminophenoxy)-6-chloropyridin-2-amine

A stirred solution of 4-aminophenol (335mg, 3.1mmol) in anhydrous DMSO (8ml) was flushed with nitrogen and treated with 1M KOBu^t / THF solution (3.1ml, 3.1mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. 4,6-dichloropyridin-2-ylamine (500mg, 3.1mmol) was added and the mixture was heated at 88ºC for 16 hours, cooled to room temperature and poured into 100ml of water. The resulting precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography with 2~5% MeOH/CHCl₃ to give 4-(4-aminophenoxy)-6-chloropyridin-2-amine as light brown solid. Yield: 350mg, 49%. Example 140

1-tert-butyl 2-methyl 4-{6-amino-4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-1,2-dicarboxylate

Similar procedure as Example 148.

LR MS (ES+): 598 (M+Na⁺) Example 141

1-(4-{[2-amino-6-(1 H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-3-(2-fluoro-5-methylphenyl)urea

Similar procedure as Example 148.

1H NMR (d₆-DMSO): 11.02 (br. s., 1H), 9.11 (s, 1H), 8.44 (br. s., 1H), 7.97 (d, 1H), 7.50 (d, J = 8.8 Hz, 2H), 6.98 - 7.17 (m, 3H), 6.78 (br. s., 2H), 6.53 (br. s., 2H), 6.05 (br. s., 1H), 5.74 (br. s., 2H), 5.61 (s, 1H), 2.25 (s, 3H)

LR MS (ES+): 418 (M+H)

LR MS (ES-): 416 (M-H) Example 142

4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-2-carboxylic acid

To a stirred solution of methyl 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylate (220mg, 0.48mmol) in THF/MeOH (3ml/10ml) was added 1M NaOH (4.0ml, 4.0mmol). The mixture was heated at 70°C for 2 hours, cooled to room temperature and poured into 100ml of water. 1M HCl was added until pH = 4 and the resulting precipitates were filtered, washed with water and dried in vacuo to give 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylic acid. Yield: 200mg, 94%.

1H NMR (d₆-DMSO): 12.38 (br. s., 1H), 12.04 (br. s., 1H), 9.14 - 9.23 (m, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 7.9, 2.1 Hz, 1H), 7.60 (br. s., 1H), 7.50 - 7.58 (m, 2H), 7.30 (d, J = 2.1 Hz, 1H), 7.22 (s, 1H), 7.03 - 7.18 (m, 3H), 6.73 - 6.84 (m, 1H), 6.60 (dd, J = 5.6, 2.3 Hz, 1H), 2.25 (s, 3H)

LR MS (ES-): 445 (M-H) Preparation of 1-tert-butyl 2-methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2- dicarboxylate

A 100ml flask was charged with 4-((2-chloropyridin-4-yl)oxy)aniline (150mg, 0.68mmol), 1- tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2- dicarboxylate (260mg, 0.81mmol), 2M Na₂CO₃ solution (0.5ml, 1.0mmol), PdCl₂(PPh₃)₂ (5mg, 0.007mmol), 10ml of 1,4-dioxane and 3ml of water. The mixture was flushed with nitrogen and heated at 70ºC for 30 minutes. The mixture was cooled to room temperature and poured into 100ml of water. The precipitates were filtered and dried to give the crude, which was further purified by silica gel chromatography eluting with 2-3% MeOH/CHCl₃ to give 1-tert-butyl 2- methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate as light brown oil. Yield: 240mg, 86%. Example 143

Methyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-2-carboxylate

To a stirred solution of 1-tert-butyl 2-methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole- 1,2-dicarboxylate (240 mg, 0.59 mmol) in anhydrous THF (10ml) was added 2-fluoro-5-methyl- phenylisocyanate (107mg, 0.71mmol). The mixture was stirred at room temperature for 30 minutes and poured into 100ml of water. The resulting precipitates were filtered, washed with water and dried to give a brown oil. Purification by silica gel chromatography eluting with 2-3% MeOH/CHCl₃ gave the Boc-protected intermediate as light green oil, which was dissolved in 5ml of methylene chloride, followed by addition of 3ml of trifluoroacetic acid. The mixture was stirred at room temperature for 10 minutes, evaporated to dryness, and purified by silica gel chromatography eluting with 2-5% MeOH/CHCl₃ to give methyl 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxylate as white solid. Yield: 135mg, 50%.

1H NMR (d₆-DMSO): 12.17 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 5.9 Hz, 1H), 7.91 - 8.04 (m, 1H), 7.61 (dd, J = 3.1, 1.6 Hz, 1H), 7.53 (d, J = 9.1 Hz, 2H), 7.22 - 7.31 (m, 2H), 7.02 - 7.17 (m, 3H), 6.73 - 6.85 (m, 1H), 6.58 (dd, J = 5.7, 2.5 Hz, 1H), 3.76 (s, 3H), 2.26 (s, 3H)

LR MS (ES+): 483 (M+Na⁺)

LR MS (ES-): 459 (M-H) Preparation of tert-butyl 2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate

To a stirred mixture of N-Boc-pyrrole-2-boronic acid (114mg, 0.54mmol) and 4-((2- chloropyridin-4-yl)oxy)aniline (100mg, 0.45mmol) in 8ml of 1,4-dioxane, was added

PdCl₂(PPh₃)₂ (10mg, 0.014mmol) and 1M Na₂CO₃ aqueous solution (0.5ml, 1.0mmol). The mixture was heated at 72 °C under N₂ for one hour, cooled to room temperature and poured into 100ml of water. The resulting mixture was extracted with EtOAc (2x50ml). The organic layers were combined, washed with brine (50ml), dried over Na₂SO₄, and evaporated to give a brown oil, which was purified by silica gel chromatography with a gradient of 20~50% EtOAc/hexanes to give tert-butyl 2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate as colorless oil. Yield: 110mg, 70%. Example 144

1-(2-fluoro-5-methylphenyl)-3-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea

To a stirred solution of tert-butyl 2-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1-carboxylate (100 mg, 0.28 mmol) in anhydrous THF (10ml) was added 2-fluoro-5-methyl-phenylisocyanate (51mg, 0.34mmol). The mixture was stirred at room temperature for one hour and poured into 100ml of water. The resulting mixture was extracted with EtOAc (2x50ml). The organic layers were combined, washed with brine (50ml), dried over Na₂SO₄, and evaporated to give a brown oil, which was purified by silica gel chromatography with 2-5% MeOH/CHCl₃ to give the Boc- protected intermediate as light green oil. The oil was dissolved in 5ml of methylene chloride, and 3ml of trifluoroacetic acid was added. Stirring was continued for 10 hours, and the mixture was evaporated to dryness. The brown residue was dissolved in methanol (5ml). This methanol solution was then added dropwise into 100ml of 1M NaHCO₃ solution with stirring. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 1-(2-fluoro-5- methylphenyl)-3-(4-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)urea as light grey solid.

1H NMR (d₆-DMSO): 11.43 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.32 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 7.9, 1.8 Hz, 1H), 7.48 - 7.58 (m, 2H), 7.20 (d, J = 2.1 Hz, 1H), 7.04 - 7.16 (m, 3H), 6.75 - 6.86 (m, 2H), 6.67 (dt, J = 3.8, 1.9 Hz, 1H), 6.57 (dd, J = 5.9, 2.3 Hz, 1H), 6.05 - 6.13 (m, 1H), 2.25 (s, 3H) Example 145

1-phenyl-3-{4-[6-(1H-pyrrol-2-yl)pyridin-3-yl]phenyl}urea

Similar procedure as Example 148.

1H NMR (DMSO-d₆): 11.46 (br. s., 1H), 8.79 (s, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.67 (s, 1H), 7.98 (dd, J = 8.4, 2.5 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.27 (t, J = 7.9 Hz, 2H), 6.96 (t, J = 7.3 Hz, 1H), 6.84 - 6.88 (m, 1H), 6.77 (t, J = 3.8 Hz, 1H), 6.11 - 6.16 (m, 1H) Example 146

1-(2-fluoro-5-methylphenyl)-3-{3-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea

Similar procedure as Example 148

LR MS (ES+): 387 (M+H⁺) Example 147

1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-3-yl)pyridin-4-yl]phenyl}urea

Similar procedure as Example 148.

1H NMR (d₆-DMSO): 11.72 (br. s., 1H), 9.49 (br. s., 1H), 8.63 (s, 1H), 8.53 (d, J = 6.4 Hz, 1H), 8.38 (br. s., 1H), 8.07 (d, J = 8.5 Hz, 2H), 8.00 - 8.04 (m, 1H), 7.97 (dd, J = 7.9, 1.8 Hz, 1H), 7.81 - 7.90 (m, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.13 (dd, J = 11.3, 8.4 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.98 (br. s., 1H), 6.84 (ddd, J = 7.8, 5.3, 2.1 Hz, 1H), 2.21 - 2.36 (m, 3H)

LR MS (ES+): 387 (M+H) tert-butyl (4-(2-chloropyridin-4-yl)phenyl)carbamate

To a mixture of (4-boc-aminophenyl)boronic acid (200mg, 0.84mmol) and 2-chloro-4- bromopyridine (162mg, 0.84mmol) in 10ml of 1,4-dioxane, was added PdCl₂(PPh₃)₂ (10mg, 0.014mmol) and 1M Na₂CO₃ aqueous solution (0.5ml, 1.0mmol). The mixture was heated at 70 °C under N₂ for 2 hours, cooled to room temperature and poured into 100ml of water. The brown precipitates were filtered, washed with water and dried to give tert-butyl (4-(2- chloropyridin-4-yl)phenyl)carbamate as the crude product. 4-(2-(1H-pyrrol-2-yl)pyridin-4-yl)aniline

To a mixture of N-Boc-pyrrole-2-boronic acid (210mg, 1.0mmol) and tert-butyl (4-(2- chloropyridin-4-yl)phenyl)carbamate (250mg, 0.82mmol) in 10ml of 1,4-dioxane, was added PdCl₂(PPh₃)₂ (10mg, 0.014mmol) and 1M Na₂CO₃ aqueous solution (0.75ml, 1.5mmol). The mixture was heated at 60 °C under N₂ for 3 hours, cooled to room temperature and poured into 100ml of water. The precipitates were filtered, dried and purified by silica gel chromatography with 1-5% MeOH/CHCl₃ to give the intermediate as light yellow oil. This intermediate was dissolved in 10ml of methylene chloride and 3ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 16 hours and evaporated to dryness to give 4-(2-(1H-pyrrol- 2-yl)pyridin-4-yl)aniline TFA salt as light brown solid. Yield: 290mg, 100%. Example 148

1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea

To a stirred suspension of 4-(2-(1H-pyrrol-2-yl)pyridin-4-yl)aniline TFA salt (60 mg, 0.17 mmol) in anhydrous THF (10ml) was added 2-fluoro-5-methyl-phenylisocyanate (48mg, 0.32mmol) and N,N-diisopropylethylamine (40 mg, 0.31 mmol). After 1 hour, the reaction mixture was evaporated and purified by silica gel chromatography with 2-3% MeOH/CHCl₃ to give 1-(2-fluoro-5-methylphenyl)-3-{4-[2-(1 H-pyrrol-2-yl)pyridin-4-yl]phenyl}urea as off-white solid. Yield: 28mg.

1H NMR (d₆-DMSO): 11.49 (br. s., 1H), 9.29 (br. s., 1H), 8.52 - 8.60 (m, 1H), 8.48 (d, J = 5.3 Hz, 1H), 7.94 - 8.04 (m, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.42 (dd, J = 5.3, 1.5 Hz, 1H), 7.12 (dd, J = 11.4, 8.2 Hz, 1H), 6.89 (s, 2H), 6.82 (dt, J = 5.4, 2.6 Hz, 1H), 6.16 (t, J = 2.9 Hz, 1H), 2.29 (s, 3H)

LR MS (ES+): 409 (M+Na⁺)

LR MS (ES-): 385 (M-H) Synthesis and characteriziation of additional compounds are listed below.

Example 149

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[3-(2H- tetrazol-5-yl)propyl]-1H-pyrrole-3-carboxamide To a stirred solution of 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100mg, 0.22mmol) in 10ml of anhydrous DMF were added HATU (91mg, 0.24mmol) and N,N- diisopropylethylamine (85mg, 0.66mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3-(1H-tetrazol-5-yl)propan-1-amine hydrochloride (54mg, 0.33mmol). The mixture was stirred at room temperature for another 60 minutes and poured into 100ml of water with vigorous stirring. 1M HCl was added dropwise until pH = 5. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[3-(2H-tetrazol-5-yl)propyl]- 1H-pyrrole-3-carboxamide as light brown solid. Yield: 105mg, 85%. ¹H NMR (DMSO-d₆): 11.83 (t, J = 2.9 Hz, 1H), 9.17 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 7.98 - 8.00 (m, 2H), 7.55 - 7.58 (m, 2H), 7.37 (dd, J = 3.2, 1.8 Hz, 1H), 7.14 - 7.17 (m, 3H), 7.11 (dd, J = 11.4, 8.2 Hz, 1H), 7.06 - 7.07 (m, 1H), 6.80 - 6.82 (m, 1H), 6.71 (dd, J = 5.6, 2.3 Hz, 1H), 3.24 - 3.27 (m, 2H), 2.90 (t, J = 7.8 Hz, 2H), 2.28 (s, 3H), 1.91 (quin, J = 7.3 Hz, 2H)

LR MS (ES-): 554 (M-H) The following Example 150 was prepared using the experiment procedure described in Example 149, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 150

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[2-(2H- tetrazol-5-yl)ethyl]-1H-pyrrole-3-carboxamide ¹H NMR (DMSO-d₆): 11.92 (br. s., 1H), 9.22 (s, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.40 (d, J = 5.9 Hz, 1H), 8.10 (t, J = 5.7 Hz, 1H), 7.98 (dd, J = 8.4, 1.9 Hz, 1H), 7.56 - 7.59 (m, 2H), 7.40 (br. s., 1H), 7.20 (br. s., 1H), 7.16 - 7.19 (m, 2H), 7.11 (dd, J = 11.3, 8.4 Hz, 1 H), 7.09 (br. s., 1H), 6.80 - 6.83 (m, 1H), 6.77 (br. s., 1H), 3.54 - 3.57 (m, 2H), 3.10 (t, J = 7.0 Hz, 2H), 2.28 (s, 3H) LR MS (ES+): 542 (MH+)

LR MS (ES-): 540 (M-H) Example 151

N-(3,3-diethoxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxamide To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (Example 115) (700mg, 1.64mmol) in 10ml of anhydrous DMF were added HATU (684mg, 1.84mmol) and N,N-diisopropylethylamine (426mg, 3.3mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (294mg, 2.0mmol). The mixture was stirred at room temperature for another 10 minutes and poured into 150ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-{4-[4- ({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 910mg, 100%. ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 8.77 (s, 1H), 8.60 (s, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.82 (t, J = 5.7 Hz, 1H), 7.53 - 7.60 (m, 2H), 7.35 (dd, J = 3.1, 1.6 Hz, 1H), 7.30 (s, 1H), 7.12 - 7.26 (m, 5H), 7.03 (t, J = 2.2 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 6.70 (dd, J = 5.9, 2.3 Hz, 1H), 4.53 (t, J = 5.4 Hz, 1H), 3.51 - 3.63 (m, 2H), 3.43 (dq, J = 9.7, 7.0 Hz, 2H), 3.16 - 3.24 (m, 2H), 2.28 (s, 3H), 1.68 - 1.78 (m, 2H), 1.11 (t, J = 7.0 Hz, 6H) LR MS (ES-): 556 (M-H) Example 152

N-(2-aminoethyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide To a stirred suspension of tert-butyl (2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)carbamate (355mg, 0.60mmol) in 10ml of methylene chloride was added 5ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5ml) and poured into 100ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH = 8~9. The precipitates were filtered, washed with water and dried in vacuo to give N- (2-aminoethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxamide as brown solid. Yield: 260mg, 88%. LR MS (ES+): 489 (MH+) Example 153

tert-butyl (2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (300mg, 0.67mmol), HATU (280mg, 0.74mmol) and N,N- diisopropylethylamine (190mg, 1.47mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (128mg, 0.80mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (2-{[(5- {4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)carbamate as white solid. Yield: 355mg, 90%. ¹H NMR (DMSO-d₆): 11.84 (br. s., 1H), 9.18 (s, 1H), 8.49 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 7.8, 2.2 Hz, 1H), 7.89 (t, J = 5.4 Hz, 1H), 7.54 - 7.60 (m, 2H), 7.35 - 7.38 (m, 1H), 7.08 - 7.19 (m, 4H), 7.05 (s, 1H), 6.78 - 6.87 (m, 2H), 6.73 (dd, J = 5.9, 2.3 Hz, 1H), 3.17 - 3.24 (m, 2H), 3.00 - 3.08 (m, 2H), 2.27 (s, 3H), 1.36 (s, 9H) LR MS (ES+): 611 (M+Na⁺)

LR MS (ES-): 587 (M-H) Example 154

methyl [(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)amino]acetate To a stirred solution of N-(3-aminopropyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (260mg, 0.52mmol) and N,N-diisopropylethylamine (134mg, 1.04mmol) in 10ml of anhydrous DMF was added methyl bromoacetate (80mg, 0.52mmol). The mixture was stirred at room temperature for 40 minutes and poured into 100ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3~10% MeOH/CHCl3 to afford methyl [(3-{[(5-{4- [4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)amino]acetate as white solid. Yield: 100mg, 34%. ¹H NMR (DMSO-d₆): 11.80 (br. s., 1H), 9.19 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 7.9, 2.1 Hz, 1H), 7.88 (t, J = 5.7 Hz, 1H), 7.55 - 7.58 (m, 2H), 7.35 (dd, J = 3.2, 1.8 Hz, 1H), 7.14 - 7.18 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.05 (dd, J = 2.5, 1.9 Hz, 1H), 6.79 - 6.82 (m, 1H), 6.70 (dd, J = 5.6, 2.3 Hz, 1H), 3.61 (s, 3H), 3.32 (br. s., 2H), 3.19 - 3.23 (m, 2H), 2.53 (t, J = 6.9 Hz, 2H), 2.27 (s, 3H), 1.59 (quin, J = 6.9 Hz, 2H) LR MS (ES+): 575 (MH+)

LR MS (ES-): 573 (M-H)

Example 155

methyl [(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)amino]acetate To a stirred solution of N-(2-aminoethyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (200mg, 0.41mmol) in 10ml of anhydrous DMF, were added N,N-diisopropylethylamine (137mg, 1.06mmol) and methyl bromoacetate (82mg, 0.54mmol). The mixture was stirred at room temperature for 1 hour and poured into 100ml of water. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3~8% of methanol in chloroform to give methyl [(2- {[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}ethyl)amino]acetate as white solid. Yield: 100mg, 43%. ¹H NMR (DMSO-d₆): 11.82 (br. s., 1H), 9.20 (s, 1H), 8.50 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 7.99 (dd, J = 7.9, 2.3 Hz, 1H), 7.85 (t, J = 5.7 Hz, 1H), 7.56 - 7.59 (m, 2H), 7.37 (dd, J = 3.1, 1.6 Hz, 1H), 7.15 - 7.17 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.05 - 7.06 (m, 1H), 6.79 - 6.82 (m, 1H), 6.71 (dd, J = 5.6, 2.3 Hz, 1H), 3.61 (s, 3H), 3.36 (s, 2H), 3.25 (q, J = 6.3 Hz, 2H), 2.64 (t, J = 6.5 Hz, 2H), 2.27 (s, 3H) LR MS (ES+): 561 (MH+)

LR MS (ES-): 559 (M-H) Example 156

dimethyl 2,2'-[(2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)imino]diacetate Example 156 was isolated from the preparation of Example 155. ¹H NMR (DMSO-d₆): 11.82 (t, J = 2.9 Hz, 1H), 9.18 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 8.4, 1.9 Hz, 1H), 7.77 (t, J = 5.4 Hz, 1H), 7.55 - 7.58 (m, 2H), 7.34 (dd, J = 2.9, 1.8 Hz, 1H), 7.14 - 7.18 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.04 (dd, J = 2.3, 1.8 Hz, 1H), 6.79 - 6.82 (m, 1H), 6.71 (dd, J = 5.6, 2.3 Hz, 1H), 3.59 (s, 6H), 3.56 (s, 4H), 3.22 - 3.27 (m, 2H), 2.78 (t, J = 6.7 Hz, 2H), 2.27 (s, 3H) LR MS (ES+): 633 (MH+)

LR MS (ES-): 631 (M-H) Example 157

ethyl [4-(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)piperazin-1-yl]acetate To a stirred solution of 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3- carboxamide (200mg, 0.41mmol) and ethyl piperazinoacetate (141mg, 0.82mmol) in anhydrous DMF (10ml) was added acetic acid (10mg, 0.17mmol). The mixture was stirred under nitrogen for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.8ml, 0.8mmol). The reaction mixture was stirred for another hour, and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 8~12% methanol/chloroform solution to give ethyl [4-(2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)piperazin-1-yl]acetate as white solid. Yield: 90mg, 34%. ¹H NMR (DMSO-d₆): 11.81 (t, J = 2.9 Hz, 1H), 9.20 (s, 1H), 8.50 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 7.99 (dd, J = 7.3, 2.1 Hz, 1H), 7.81 (t, J = 5.7 Hz, 1H), 7.56 - 7.58 (m, 2H), 7.35 (dd, J = 3.2, 1.8 Hz, 1H), 7.14 - 7.17 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.05 (dd, J = 2.5, 1.9 Hz, 1H), 6.79 - 6.82 (m, 1H), 6.70 - 6.71 (m, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.26 - 3.30 (m, 2H), 3.17 (s, 2H), 2.38 - 2.53 (m, 10H), 2.27 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H) LR MS (ES+): 644 (MH+)

LR MS (ES-): 642 (M-H) The following Example 158 through 159 were prepared using the experiment procedure described in Example 160, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation. Example 158

ethyl [4-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)piperazin-1-yl]acetate ¹H NMR (DMSO-d₆): 11.81 (t, J = 3.1 Hz, 1H), 9.19 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 7.9, 2.6 Hz, 1H), 7.88 (t, J = 5.6 Hz, 1H), 7.55 - 7.58 (m, 2H), 7.35 (dd, J = 3.2, 1.8 Hz, 1H), 7.14 - 7.17 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.05 (dd, J = 2.5, 1.9 Hz, 1H), 6.79 - 6.82 (m, 1H), 6.71 (dd, J = 5.6, 2.3 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.18 - 3.21 (m, 2H), 3.17 (s, 2H), 2.30 - 2.54 (m, 10H), 2.27 (s, 3H), 1.62 (quin, J = 7.0 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H)

LR MS (ES+): 658 (MH+)

LR MS (ES-): 656 (M-H) Example 159

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-{3-[2- (hydroxymethyl)morpholin-4-yl]propyl}-1H-pyrrole-3-carboxamide LR MS (ES+): 603 (MH+) Example 160

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-{3-[3- (hydroxymethyl)piperidin-1-yl]propyl}-1H-pyrrole-3-carboxamide To a stirred solution of 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3- carboxamide (120mg, 0.24mmol) and 3-piperidinemethanol (56mg, 0.49mmol) in anhydrous DMF (10ml) was added acetic acid (10mg, 0.17mmol). The mixture was stirred under nitrogen for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.5ml, 0.5mmol). The reaction mixture was stirred for another hour, and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 10~20% methanol/chloroform solution to give 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-{3-[3- (hydroxymethyl)piperidin-1-yl]propyl}-1H-pyrrole-3-carboxamide as white solid. Yield: 58mg, 40%. LR MS (ES+): 601 (MH+)

LR MS (ES-): 599 (M-H) The following Example 161 was prepared using the experiment procedure described in Example 157, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 161

methyl rel-(2R,4S)-1-(2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)-4-hydroxypyrrolidine-2-carboxylate ¹H NMR (DMSO-d₆): 11.81 (t, J = 2.9 Hz, 1H), 9.17 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 8.4, 1.9 Hz, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.55 - 7.58 (m, 2H), 7.34 (dd, J = 3.2, 1.8 Hz, 1H), 7.14 - 7.18 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.04 (dd, J = 2.5, 1.9 Hz, 1H), 6.79 - 6.82 (m, 1H), 6.70 - 6.72 (m, 1H), 4.88 (d, J = 4.4 Hz, 1H), 4.19 - 4.24 (m, 1H), 3.59 (s, 3H), 3.46 (t, J = 7.6 Hz, 1H), 3.26 - 3.31 (m, 2H), 3.15 - 3.21 (m, 1H), 2.75 (dt, J = 11.8, 7.4 Hz, 1H), 2.53 - 2.57 (m, 1H), 2.34 (dd, J = 9.7, 4.1 Hz, 1H), 2.28 (s, 3H), 1.95 (dt, J = 12.8, 7.3 Hz, 1H), 1.84 - 1.89 (m, 1H) LR MS (ES+): 617 (MH+)

LR MS (ES-): 615 (M-H) Example 162

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2- oxoethyl)-1H-pyrrole-3-carboxamide To a stirred solution of N-(2,2-diethoxyethyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (580mg, 1.03mmol) in 10ml of THF was added 1ml of 2M HCl. The mixture was heated under nitrogen at 60C for 2 hours, cooled to room temperature, and poured into 100ml of water.

Saturated NaHCO3 solution was added until pH = 8. The precipitates were filtered, washed with water, and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3- carboxamide as light brown solid. Yield: 450mg, 90%. LR MS (ES+): 488 (MH+)

LR MS (ES-): 486 (M-H) Example 163

N-(2,2-diethoxyethyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (500mg, 1.12mmol), HATU (467mg, 1.23mmol) and N,N- diisopropylethylamine (322mg, 2.5mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of aminoacetaldehyde diethyl acetal (194mg, 1.46mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2,2- diethoxyethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 580mg, 92%. ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 9.18 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 7.9, 2.3 Hz, 1H), 7.94 (t, J = 6.0 Hz, 1H), 7.54 - 7.60 (m, 2H), 7.40 (dd, J = 3.1, 1.6 Hz, 1H), 7.10 - 7.19 (m, 4H), 7.08 (t, J = 2.2 Hz, 1H), 6.78 - 6.84 (m, 1H), 6.71 (dd, J = 5.6, 2.3 Hz, 1H), 4.56 (t, J = 5.6 Hz, 1H), 3.62 (dq, J = 9.7, 7.0 Hz, 2H), 3.47 (dq, J = 9.7, 7.0 Hz, 2H), 3.24 (t, J = 5.7 Hz, 2H), 2.28 (s, 3H), 1.11 (t, J = 7.0 Hz, 6H) LR MS (ES+): 562 (MH+)

LR MS (ES-): 560 (M-H) The following Example 164 was prepared using the experiment procedure described in Example 160, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 164

methyl rel-(2R,4S)-1-(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)-4-hydroxypyrrolidine-2-carboxylate ¹H NMR (DMSO-d₆): 11.80 (t, J = 3.1 Hz, 1H), 9.17 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 7.99 (dd, J = 7.9, 2.3 Hz, 1H), 7.85 (t, J = 5.7 Hz, 1H), 7.55 - 7.58 (m, 2H), 7.34 (dd, J = 3.2, 1.8 Hz, 1H), 7.14 - 7.17 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.04 (dd, J = 2.5, 1.9 Hz, 1H), 6.79 - 6.82 (m, 1H), 6.71 (dd, J = 5.7, 2.5 Hz, 1H), 4.87 (d, J = 4.4 Hz, 1H), 4.18 - 4.23 (m, 1H), 3.59 (s, 3H), 3.36 (t, J = 7.8 Hz, 1H), 3.17 - 3.25 (m, 3H), 2.64 (dt, J = 12.1, 7.9 Hz, 1H), 2.39 - 2.44 (m, 1H), 2.28 (s, 3H), 2.23 (dd, J = 9.5, 4.5 Hz, 1H), 1.96 (dt, J = 12.8, 7.2 Hz, 1H), 1.83 - 1.89 (m, 1H), 1.54 - 1.60 (m, 2H)

LR MS (ES+): 653 (M+Na⁺)

LR MS (ES-): 629 (M-H) Example 165

4-methoxy-4-oxobutyl 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate To a stirred solution of 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150mg, 0.34mmol) in 10ml of anhydrous DMF were added methyl 4-bromobutanoate (123mg, 0.68mmol) and potassium carbonate (94mg, 0.68mmol). The mixture was heated at 60C for 2 hours, cooled to room temperature, and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2~3% of methanol in chloroform to give 4- methoxy-4-oxobutyl 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as off- white solid. Yield: 130mg, 71%. ¹H NMR (DMSO-d₆): 12.13 (br. s., 1H), 9.17 (s, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.99 (dd, J = 7.9, 2.3 Hz, 1H), 7.54 - 7.57 (m, 2H), 7.43 (dd, J = 3.2, 1.8 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.13 - 7.16 (m, 2H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.08 (dd, J = 2.5, 1.9 Hz, 1H), 6.79 - 6.82 (m, 1H), 6.68 (dd, J = 5.7, 2.5 Hz, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.58 (s, 3H), 2.45 (t, J = 7.3 Hz, 2H), 2.27 (s, 3H), 1.92 (quin, J = 6.8 Hz, 2H) LR MS (ES+): 547 (MH+)

LR MS (ES-): 545 (M-H) Example 166

5-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}pentanoic acid To a stirred solution of ethyl 5-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanoate (150mg, 0.26mmol) in 10ml of THF was added 2ml of 1M NaOH solution. The mixture was heated at 55C for 3 hours, cooled to room temperature and poured into 100mlof water. 2M HCl was added dropwise with vigorous stirring until pH = 4. The precipitates were filtered, washed with water, and dried in vacuo to give 5-{[(5-{4-[4-({[(2- fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanoic acid as white solid. Yield: 130mg, 91%. ¹H NMR (DMSO-d₆): 11.96 (br. s., 1H), 11.82 (br. s., 1H), 9.18 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 7.9, 2.3 Hz, 1H), 7.85 (t, J = 5.7 Hz, 1H), 7.56 - 7.58 (m, 2H), 7.37 (br. s., 1H), 7.15 - 7.18 (m, 3H), 7.11 (dd, J = 11.4, 8.2 Hz, 1 H), 7.07 (br. s., 1H), 6.79 - 6.83 (m, 1H), 6.72 (dd, J = 5.6, 2.3 Hz, 1H), 3.17 (q, J = 6.5 Hz, 2H), 2.28 (s, 3H), 2.23 (t, J = 7.2 Hz, 2H), 1.44 - 1.55 (m, 4H) LR MS (ES+): 546 (MH+)

LR MS (ES-): 544 (M-H) Example 167

ethyl 5-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]amino}pentanoate A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (300mg, 0.67mmol), HATU (281mg, 0.74mmol) and N,N- diisopropylethylamine (258mg, 2.0mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of ethyl 5-aminovalerate hydrochloride (145mg, 0.80mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. 2M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3~5% of methanol in chloroform to give ethyl 5-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanoate as white solid. Yield: 288mg, 75%. ¹H NMR (DMSO-d₆): 11.79 (t, J = 3.1 Hz, 1H), 9.17 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.98 (dd, J = 8.1, 2.2 Hz, 1H), 7.84 (t, J = 5.9 Hz, 1H), 7.55 - 7.58 (m, 2H), 7.35 (dd, J = 3.2, 1.8 Hz, 1H), 7.14 - 7.17 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.05 (dd, J = 2.6, 1.8 Hz, 1H), 6.79 - 6.82 (m, 1H), 6.70 - 6.72 (m, 1H), 4.03 (q, J = 7.2 Hz, 2H), 3.15 - 3.18 (m, 2H), 2.30 (t, J = 7.3 Hz, 2H), 2.27 (s, 3H), 1.51 - 1.56 (m, 2H), 1.44 - 1.50 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H) LR MS (ES+): 574 (MH+)

LR MS (ES-): 572 (M-H) Example 168

ethyl 4-(2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)piperazine-1-carboxylate To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3- carboxamide (200mg, 0.40mmol) and 1-ethoxycarbonylpiperazine (158mg, 1.0mmol) in anhydrous DMF (10ml) was added acetic acid (10mg, 0.17mmol). The mixture was stirred under nitrogen for 60 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (1.0ml, 1.0mmol). The reaction mixture was stirred for another hour, and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 5% methanol/chloroform solution to give ethyl 4-(2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)piperazine-1-carboxylate as white solid. Yield: 77mg, 30%. ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 9.08 (d, J = 2.6 Hz, 1H), 8.97 (d, J = 2.6 Hz, 1H), 8.40 (d, J = 5.6 Hz, 1H), 8.26 (t, J = 9.1 Hz, 1H), 8.01 (dd, J = 7.9, 2.6 Hz, 1 H), 7.82 (t, J = 5.9 Hz, 1H), 7.37 (dd, J = 3.2, 1.8 Hz, 1H), 7.29 (dd, J = 11.9, 2.8 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 10.7, 7.8 Hz, 1H), 7.08 - 7.10 (m, 1H), 7.02 - 7.07 (m, 1H), 6.79 - 6.85 (m, 1H), 6.76 (dd, J = 5.7, 2.5 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 3.26 - 3.39 (m, 6H), 2.44 (t, J = 6.9 Hz, 2H), 2.33 - 2.41 (m, 4H), 2.28 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H) LR MS (ES+): 648 (MH+)

LR MS (ES-): 646 (M-H) Example 169

5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- (2-oxoethyl)-1H-pyrrole-3-carboxamide To a stirred solution of N-(2,2-diethoxyethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (550mg, 0.95mmol) in 10ml of THF was added 2 ml of 2M HCl. The mixture was stirred at room temperature under nitrogen for overnight, and poured into 100ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH = 8. The precipitates were filtered, washed with water, and dried to give 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3- carboxamide as off-white solid. Yield: 475mg, 99%. LR MS (ES+): 506 (MH+)

LR MS (ES-): 504 (M-H) Example 170

N-(2,2-diethoxyethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (500mg, 1.08mmol), HATU (456mg, 1.20mmol) and N,N-diisopropylethylamine (278mg, 2.16mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of aminoacetaldehyde diethyl acetal (173mg, 1.30mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2,2-diethoxyethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 550mg, 88%. ¹H NMR (DMSO-d₆): 11.85 (br. s., 1H), 9.08 (d, J = 2.3 Hz, 1H), 8.97 (d, J = 2.6 Hz, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.26 (t, J = 9.1 Hz, 1H), 8.01 (dd, J = 7.9, 2.3 Hz, 1 H), 7.94 (t, J = 6.0 Hz, 1H), 7.41 (dd, J = 3.1, 1.6 Hz, 1H), 7.29 (dd, J = 11.7, 2.6 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.08 - 7.16 (m, 2H), 7.05 (ddd, J = 9.1, 2.8, 1.3 Hz, 1H), 6.79 - 6.85 (m, 1H), 6.77 (dd, J = 5.7, 2.5 Hz, 1H), 4.54 - 4.59 (m, 1H), 3.57 - 3.68 (m, 2H), 3.47 (dq, J = 9.7, 7.0 Hz, 2H), 3.24 (t, J = 5.7 Hz, 2H), 2.28 (s, 3H), 1.11 (t, J = 7.0 Hz, 6H) LR MS (ES+): 580 (MH+)

LR MS (ES-): 578 (M-H) The following Example 171 was prepared using the experiment procedure described in Example 184, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 171

ethyl 4-{3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}piperazine-1-carboxylate ¹H NMR (DMSO-d₆): 11.84 (br. s., 1H), 10.15 (s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 7.98 - 8.04 (m, 2H), 7.86 (t, J = 5.6 Hz, 1H), 7.66 (t, J = 9.7 Hz, 1H), 7.35 - 7.40 (m, 2H), 7.28 (d, J = 2.3 Hz, 1H), 7.13 - 7.20 (m, 2H), 7.04 - 7.10 (m, 1H), 6.83 (dd, J = 5.9, 2.3 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 3.31 - 3.38 (m, 4H), 3.16 - 3.24 (m, 2H), 2.29 (s, 3H), 2.28 - 2.35 (m, 6H), 1.63 (quin, J = 7.2 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H) LR MS (ES+): 647 (MH+)

LR MS (ES-): 645 (M-H) The following Example 172 was prepared using the experiment procedure described in Example 212, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 172

ethyl 4-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)piperazine-1-carboxylate ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 9.08 (d, J = 2.6 Hz, 1H), 8.97 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 5.9 Hz, 1H), 8.25 (t, J = 9.2 Hz, 1H), 7.99 - 8.03 (m, 1H), 7.86 (t, J = 5.6 Hz, 1H), 7.36 (dd, J = 2.9, 1.8 Hz, 1H), 7.29 (dd, J = 11.7, 2.6 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.08 - 7.15 (m, 2H), 7.04 (ddd, J = 9.1, 2.8, 1.3 Hz, 1H), 6.79 - 6.85 (m, 1H), 6.76 (dd, J = 5.6, 2.3 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 3.34 (dd, J = 5.6, 4.4 Hz, 4H), 3.16 - 3.24 (m, 2H), 2.29 - 2.34 (m, 6H), 2.28 (s, 3H), 1.63 (quin, J = 7.1 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H) LR MS (ES+): 662 (MH+)

LR MS (ES-): 660 (M-H) Example 173

ethyl 3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2- thienyl)carbonyl]amino}propanoate Example 174

methyl 3-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate A mixture of 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid ( Example 75) (1.50g, 3.36mmol), HATU (1.41g, 3.70mmol) and N,N-diisopropylethylamine (1.29g, 10mmol) in anhydrous DMF (15ml) was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (558mg, 4.0mmol). The mixture was stirred for another 10 minutes and poured into 200ml of water with vigorous stirring. 2M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3% of methanol in chloroform to give methyl 3-{[(5-{4-[3-fluoro- 4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propanoate as off-white solid. Yield: 1.18g, 66%. ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 8.99 (s, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 5.9 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 7.96 (t, J = 5.7 Hz, 1H), 7.37 (dd, J = 3.2, 1.8 Hz, 1H), 7.30 (s, 1H), 7.28 (dd, J = 11.7, 2.6 Hz, 1H), 7.23 - 7.25 (m, 1H), 7.20 (d, J = 2.6 Hz, 1H), 7.16 - 7.19 (m, 1H), 7.09 (t, J = 2.3 Hz, 1H), 7.04 (dd, J = 9.0, 3.1 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 5.7, 2.5 Hz, 1H), 3.60 (s, 3H), 3.39 - 3.42 (m, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.29 (s, 3H) LR MS (ES+): 532 (MH+)

LR MS (ES-): 530 (M-H) Example 175

methyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propanoate A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid(Example 96) (200mg, 0.43mmol), HATU (179mg, 0.47mmol) and N,N- diisopropylethylamine (166mg, 1.29mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (91mg, 0.65mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water with vigorous stirring. 2M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propanoate as brown solid. Yield: 180mg, 76%. ¹H NMR (DMSO-d₆): 11.89 (br. s., 1H), 9.09 (d, J = 1.8 Hz, 1H), 8.97 (d, J = 2.6 Hz, 1H), 8.41 (d, J = 5.9 Hz, 1H), 8.26 (t, J = 9.1 Hz, 1H), 8.01 (dd, J = 7.5, 2.2 Hz, 1 H), 7.98 (t, J = 5.7 Hz, 1H), 7.40 (br. s., 1H), 7.30 (dd, J = 11.9, 2.8 Hz, 1H), 7.23 (br. s., 1H), 7.10 - 7.14 (m, 2H), 7.04 - 7.07 (m, 1H), 6.79 - 6.83 (m, 2H), 3.59 (s, 3H), 3.39 - 3.42 (m, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.27 (s, 3H) LR MS (ES+): 550 (MH+)

LR MS (ES-): 548 (M-H) Example 176

methyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate To a stirred solution of 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid(Example 115) (200mg, 0.45mmol) in 10ml of anhydrous DMF were added HATU (190mg, 0.50mmol) and N,N-diisopropylethylamine (174mg, 1.35mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of methyl 4-aminobutyrate hydrochloride (104mg, 0.68mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water with vigorous stirring. 1M HCl was added slowly until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 4-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoate as white solid. Yield: 220mg, 90%. ¹H NMR (DMSO-d₆): 11.84 (br. s., 1H), 9.18 (s, 1H), 8.49 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 7.6, 2.3 Hz, 1H), 7.89 (t, J = 5.6 Hz, 1H), 7.56 - 7.59 (m, 2H), 7.38 (br. s., 1H), 7.15 - 7.18 (m, 3H), 7.11 (dd, J = 11.3, 8.4 Hz, 1H), 7.08 (br. s., 1H), 6.80 - 6.83 (m, 1H), 6.72 - 6.74 (m, 1H), 3.58 (s, 3H), 3.17 - 3.21 (m, 2H), 2.34 (t, J = 7.3 Hz, 2H), 2.28 (s, 3H), 1.73 (quin, J = 7.2 Hz, 2H) LR MS (ES+): 546 (MH+)

LR MS (ES-): 544 (M-H) Example 177

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(4- hydrazino-4-oxobutyl)-1H-pyrrole-3-carboxamide A mixture of 4-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoic acid (Example 78) (120mg, 0.23mmol), HATU (95mg, 0.25mmol) and N,N-diisopropylethylamine (59mg, 0.46mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of hydrazine monohydrate (0.125ml, 2.6mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 10~12% of methanol in chloroform to give 5- {4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(4- hydrazino-4-oxobutyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 60mg, 49%. ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 9.17 (s, 1H), 8.95 (br. s., 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 7.99 (dd, J = 7.9, 2.3 Hz, 1H), 7.88 (t, J = 5.9 Hz, 1H), 7.55 - 7.58 (m, 2H), 7.36 - 7.37 (m, 1H), 7.14 - 7.17 (m, 3H), 7.11 (dd, J = 11.4, 8.2 Hz, 1H), 7.06 (t, J = 2.3 Hz, 1H), 6.79 - 6.83 (m, 1H), 6.71 (dd, J = 5.7, 2.5 Hz, 1H), 4.13 - 4.15 (m, 2H), 3.16 (q, J = 6.7 Hz, 2H), 2.28 (s, 3H), 2.04 (t, J = 7.5 Hz, 2H), 1.69 (quin, J = 7.3 Hz, 2H) LR MS (ES+): 546 (MH+)

LR MS (ES-): 544 (M-H) Example 178

dimethyl 2,2’-({3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propyl}imino)diacetate To a stirred solution of N-(3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (85mg, 0.17mmol) and N,N-diisopropylethylamine (100mg, 0.78mmol) in 10ml of anhydrous DMF was added methyl bromoacetate (100mg, 0.65mmol). The mixture was heated at 55°C for 30 minutes and poured into 100ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3~5% of MeOH in CHCl₃ to afford dimethyl 2,2’-({3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propyl}imino)diacetate as white solid. Yield: 70mg, 64%. ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 10.13 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.96 - 7.99 (m, 1H), 7.80 (t, J = 5.7 Hz, 1H), 7.63 (t, J = 9.5 Hz, 1H), 7.33 - 7.37 (m, 2H), 7.26 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 10.4, 8.1 Hz, 1H), 7.10 - 7.12 (m, 1H), 7.02 - 7.06 (m, 1H), 6.79 (dd, J = 5.7, 2.5 Hz, 1H), 3.57 (s, 6H), 3.49 (s, 4H), 3.17 (q, J = 6.7 Hz, 2H), 2.63 (t, J = 6.9 Hz, 2H), 2.26 (s, 3H), 1.55 (quin, J = 6.9 Hz, 2H) LR MS (ES+): 650 (MH+)

LR MS (ES-): 648 (M-H) Example 179

dimethyl 2,2’-({2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]ethyl}imino)diacetate To a stirred solution of N-(2-aminoethyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (100mg, 0.20mmol) and N,N-diisopropylethylamine (129mg, 1.0mmol) in 10ml of anhydrous DMF was added methyl bromoacetate (77mg, 0.50mmol). The mixture was heated at 55°C for 30 minutes and poured into 100ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2~3% of MeOH in CHCl₃ to afford dimethyl 2,2’-({2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]ethyl}imino)diacetate as off-white solid. Yield: 80mg, 62%. ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 10.12 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 7.95 - 8.01 (m, 2H), 7.73 (t, J = 5.6 Hz, 1H), 7.60 - 7.65 (m, 1H), 7.32 - 7.37 (m, 2H), 7.25 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 10.4, 8.4 Hz, 1H), 7.09 (t, J = 2.2 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 3.57 (s, 6H), 3.54 (s, 4H), 3.21 (q, J = 6.5 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H), 2.26 (s, 3H) LR MS (ES+): 636 (MH+)

LR MS (ES-): 634 (M-H) Example 180

methyl ({3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}amino)acetate To a stirred solution of N-(3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (100mg, 0.20mmol) and N,N-diisopropylethylamine (52mg, 0.40mmol) in 10ml of anhydrous DMF was added methyl bromoacetate (30mg, 0.20mmol). The mixture was stirred at room temperature for 50 minutes and poured into 100ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2~3% of MeOH in CHCl₃ to afford methyl ({3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propyl}amino)acetate as white solid. Yield: 40mg, 35%. LR MS (ES+): 578 (MH+)

LR MS (ES-): 576 (M-H) Example 181

methyl ({2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}amino)acetate To a stirred solution of N-(2-aminoethyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (80mg, 0.16mmol) in 10ml of anhydrous DMF, were added N,N-diisopropylethylamine (60mg, 0.47mmol) and methyl bromoacetate (30mg, 0.20mmol). The mixture was stirred at room temperature for 1 hour and poured into 100ml of water. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel

chromatography eluting with a gradient of 3~5% of methanol in chloroform to give methyl ({2- [({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]ethyl}amino)acetate as white solid. Yield: 38mg, 41%. ¹H NMR (DMSO-d₆): 11.82 (br. s., 1H), 10.13 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 7.96 - 8.02 (m, 2H), 7.81 (t, J = 5.7 Hz, 1H), 7.63 (t, J = 9.7 Hz, 1H), 7.33 - 7.39 (m, 2H), 7.26 (d, J = 1.8 Hz, 1H), 7.10 - 7.16 (m, 2H), 7.01 - 7.06 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 3.58 (s, 3H), 3.34 (s, 2H), 3.22 (q, J = 6.5 Hz, 2H), 2.61 (t, J = 6.5 Hz, 2H), 2.26 (s, 3H) LR MS (ES+): 564 (MH+)

LR MS (ES-): 562 (M-H)

Example 182

N-(2-aminoethyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide To a stirred suspension of tert-butyl {2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]ethyl}carbamate (360mg, 0.61mmol) in 5ml of methylene chloride was added 3ml of trifluoroacetic acid. The mixture was stirred at room temperature for 20 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5ml) and poured into 100ml of water with vigorous stirring. Saturated NaHCO₃ solution was added until pH = 8~9. The precipitates were filtered, washed with water and dried in vacuo to give N- (2-aminoethyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin- 2-yl]-1H-pyrrole-3-carboxamide as beige solid. Yield: 280mg, 94%. LR MS (ES+): 492 (MH+)

LR MS (ES-): 490 (M-H) Example 183

tert-butyl {2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin- 2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}carbamate A mixture of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrole-3-carboxylic acid (Example 13) (300mg, 0.67mmol), HATU (281mg, 0.74mmol) and N,N-diisopropylethylamine (190mg, 1.47mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (160mg, 1.0mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl {2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]ethyl}carbamate as white solid. Yield: 395mg, 100%. ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 10.12 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.95 - 8.01 (m, 2H), 7.85 (t, J = 5.7 Hz, 1H), 7.60 - 7.66 (m, 1H), 7.36 (dd, J = 2.9, 1.8 Hz, 1H), 7.34 (dd, J = 7.3, 2.3 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 10.6, 8.2 Hz, 1 H), 7.10 (t, J = 2.2 Hz, 1H), 7.02 - 7.06 (m, 1H), 6.82 - 6.85 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 3.18 (q, J = 6.5 Hz, 2H), 3.02 (q, J = 6.4 Hz, 2H), 2.26 (s, 3H), 1.34 (s, 9H) LR MS (ES+): 592 (MH+)

LR MS (ES-): 590 (M-H) Example 184

5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-[3-(4- hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-oxopropyl)-1H-pyrrole-3- carboxamide (205mg, 0.41mmol) in 10ml of anhydrous DMF were added 4-hydroxypiperidine (83mg, 0.82mmol) and acetic acid (10mg, 0.17mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.80ml, 0.80mmol) and stirring was continued for one more hour. The mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 20% of MeOH in CHCl₃ to give 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-N-[3-(4-hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide as white solid. Yield: 85mg, 35%. ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 10.12 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 7.96 - 8.01 (m, 2H), 7.84 (br. s., 1H), 7.63 (t, J = 9.5 Hz, 1H), 7.32 - 7.37 (m, 2H), 7.25 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 10.3, 8.5 Hz, 1H), 7.10 (s, 1H), 7.02 - 7.07 (m, 1H), 6.80 (dd, J = 5.6, 2.1 Hz, 1H), 4.47 (br. s., 1H), 3.39 (br. s., 1H), 3.16 (br. s., 2H), 2.65 (br. s., 2H), 2.26 (s, 3H), 2.23 (br. s., 2H), 1.92 (br. s., 2H), 1.66 (br. s., 2H), 1.58 (br. s., 2H), 1.34 (br. s., 2H) LR MS (ES+): 590 (MH+)

Example 185

1-[4-({2-[4-(azetidin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(2-fluoro-5- methylphenyl)urea A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (100mg, 0.22mmol), HATU (99mg, 0.26mmol) and N,N- diisopropylethylamine (62mg, 0.48mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of azetidine (20mg, 0.35mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water. 2M HCl was added dropwise until pH = 4~5. The precipitates were filtered, washed with water and dried in vacuo to give 1- [4-({2-[4-(azetidin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(2-fluoro-5- methylphenyl)urea as light brown solid. Yield: 95mg, 87%. 1H NMR (DMSO-d6): 12.18 (br. s., 1H), 9.28 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.43 (d, J = 5.9 Hz, 1H), 7.96 - 8.01 (m, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.48 (br. s., 1H), 7.34 (br. s., 1H), 7.08 - 7.22 (m, 4H), 6.81 (td, J = 5.3, 2.6 Hz, 2H), 4.39 (br. s., 2H), 3.97 (br. s., 2H), 2.22 - 2.31 (m, 5H) LR MS (ES+): 508 (M+Na+)

LR MS (ES-): 484 (M-H) The following Example 186 was prepared using the experiment procedure described in Example 187, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 186

5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-[3-(4- methylpiperazin-1-yl)propyl]-1H-pyrrole-3-carboxamide ¹H NMR (DMSO-d₆): 11.82 (br. s., 1H), 10.12 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 7.94 - 8.03 (m, 2H), 7.84 (t, J = 5.4 Hz, 1H), 7.63 (t, J = 9.5 Hz, 1H), 7.32 - 7.39 (m, 2H), 7.25 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 10.3, 8.5 Hz, 1H), 7.08 - 7.11 (m, 1H), 7.04 (dt, J = 8.2, 2.3 Hz, 1H), 6.80 (dd, J = 5.6, 2.3 Hz, 1H), 3.17 (q, J = 6.7 Hz, 2H), 2.20 - 2.45 (br. s., 10H), 2.26 (s, 3H), 2.12 (s, 3H), 1.55 - 1.62 (m, 2H) LR MS (ES+): 589 (MH+)

LR MS (ES-): 587 (M-H) Example 187

5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3- pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (150mg, 0.33mmol) in 10ml of anhydrous DMF were added HATU (152mg, 0.40mmol) and N,N- diisopropylethylamine (94mg, 0.73mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)pyrrolidine (85mg, 0.66mmol), and stirring was continued for another 10 minutes. The mixture was poured into 50ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5- [4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3- pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 160mg, 86%. ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 10.12 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.97 (br. s., 1H), 7.89 (t, J = 5.6 Hz, 1H), 7.63 (t, J = 9.5 Hz, 1H), 7.32 - 7.38 (m, 2H), 7.24 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 10.3, 8.5 Hz, 1H), 7.08 (s, 1H), 7.01 - 7.07 (m, 1H), 6.80 (dd, J = 5.6, 2.3 Hz, 1H), 3.19 (q, J = 6.7 Hz, 2H), 2.40 (br. s., 6H), 2.26 (s, 3H), 1.64 (br. s., 4H), 1.58 - 1.63 (m, 2H) LR MS (ES+): 560 (MH+)

LR MS (ES-): 558 (M-H)

Example 188

methyl 1-[3-({[5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)propyl]pyrrolidine-2-carboxylate To a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N- (3-oxopropyl)-1H-pyrrole-3-carboxamide (140mg, 0.29mmol) in 10ml of anhydrous DMF were added L-proline methyl ester hydrochloride (96mg, 0.58mmol) and triethylamine (58mg, 0.58mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.60ml, 0.60mmol) and stirring was continued for another 30 minutes. The mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 5% of MeOH in CHCl₃ to give methyl 1-[3-({[5-(4- {4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)propyl]pyrrolidine-2-carboxylate as light beige solid. Yield: 70mg, 40%. LR MS (ES+): 590 (MH+)

LR MS (ES-): 588 (M-H) The following Example 189 was prepared using the experiment procedure described in Example 188, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation.

Example 189

5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-[3-(4-hydroxypiperidin- 1-yl)propyl]-1H-pyrrole-3-carboxamide LR MS (ES+): 562 (MH+)

LR MS (ES-): 560 (M-H) Example 190

5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-oxopropyl)-1H- pyrrole-3-carboxamide To a stirred solution of N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide (380mg, 0.69mmol) in 15ml of tetrahydrofuran was added 1ml of 2M HCl (2.0mmol). The mixture was stirred at room temperature for 90 minutes and poured into 100ml of water. 1M NaOH solution was added slowly until pH = 7~8. The precipitates were filtered, washed with water and dried in vacuo to give 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-oxopropyl)-1H- pyrrole-3-carboxamide as white solid. Yield: 270mg, 82%. ¹H NMR (CHLOROFORM-d): 10.50 (br. s., 1H), 9.84 (s, 1H), 8.36 - 8.44 (m, 2H), 8.30 (d, J = 6.2 Hz, 1H), 7.43 (s, 1H), 7.40 (br. s., 1H), 7.22 (t, J = 9.5 Hz, 1H), 7.06 (br. s., 1H), 6.80 - 6.88 (m, 2H), 6.73 - 6.79 (m, 1H), 6.42 (s, 1H), 6.23 (t, J = 5.7 Hz, 1H), 3.69 (q, J = 5.8 Hz, 2H), 2.84 (t, J = 5.7 Hz, 2H), 2.42 (s, 3H) LR MS (ES+): 477 (MH+)

LR MS (ES-): 475 (M-H)

Example 191

5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-piperidin-1-ylpropyl)- 1H-pyrrole-3-carboxamide ¹H NMR (DMSO-d₆): 11.79 (br. s., 1H), 9.71 (s, 1H), 8.39 (d, 1H), 7.85 (br. s., 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.58 (dd, J = 6.5, 2.9 Hz, 1H), 7.39 (t, J = 9.5 Hz, 1H), 7.34 (br. s., 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.06 - 7.09 (m, 1H), 7.04 - 7.06 (m, 1H), 6.72 (dd, J = 5.6, 2.3 Hz, 1H), 6.57 (d, 1H), 3.16 (q, J = 6.1 Hz, 2H), 2.28 (s, 3H), 2.21 - 2.30 (m, 6H), 1.59 (br. s., 2H), 1.45 (br. s., 4H), 1.33 (br. s., 2H) LR MS (ES+): 546 (MH+)

LR MS (ES-): 544 (M-H)

Example 192

5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-pyrrolidin-1-ylpropyl)- 1H-pyrrole-3-carboxamide ¹H NMR (DMSO-d₆): 11.79 (br. s., 1H), 9.71 (s, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.89 (t, J = 5.4 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.58 (dd, J = 6.2, 2.9 Hz, 1H), 7.39 (t, J = 9.5 Hz, 1H), 7.33 (dd, J = 2.9, 1.8 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.07 (dt, J = 8.9, 3.5 Hz, 1H), 7.01 - 7.05 (m, 1H), 6.72 (dd, J = 5.6, 2.3 Hz, 1H), 6.57 (d, J = 1.2 Hz, 1H), 3.19 (q, J = 6.7 Hz, 2H), 2.42 (br. s., 6H), 2.28 (s, 3H), 1.58 - 1.69 (m, 6H) LR MS (ES+): 532 (MH+)

LR MS (ES-): 530 (M-H) Example 193

5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-[3-(4-methylpiperazin-1- yl)propyl]-1H-pyrrole-3-carboxamide 1H NMR (DMSO-d₆): 11.80 (br. s., 1H), 9.71 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.85 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.57 (dd, J = 6.5, 2.9 Hz, 1H), 7.39 (t, J = 9.5 Hz, 1H), 7.34 (br. s., 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.06 - 7.09 (m, 1H), 7.05 - 7.06 (m, 1H), 6.72 (dd, J = 5.7, 2.2 Hz, 1H), 6.57 (s, 1H), 3.16 (q, J = 6.5 Hz, 2H), 2.31 (br. s., 10H), 2.28 (s, 3H), 2.13 (s, 3H), 1.59 (quin, J = 7.0 Hz, 2H) LR MS (ES+): 561 (MH+)

LR MS (ES-): 559 (M-H) Example 194

₁₅

5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-morpholin-4- ylpropyl)-1H-pyrrole-3-carboxamide To a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxylic acid (Example 28) (150mg, 0.36mmol) in 10ml of anhydrous DMF were added HATU (163mg, 0.43mmol) and N,N-diisopropylethylamine (102mg, 0.79mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3- morpholinopropylamine (104mg, 0.72mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 10% methanol in chloroform to give 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2- yl)-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 110mg, 56%. ¹H NMR (DMSO-d₆): 11.79 (br. s., 1H), 9.71 (s, 1H), 8.39 (d, J = 5.9 Hz, 1H), 7.84 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.58 (dd, J = 6.5, 2.9 Hz, 1H), 7.39 (t, J = 9.5 Hz, 1H), 7.33 - 7.36 (m, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.07 - 7.09 (m, 1H), 7.05 - 7.07 (m, 1H), 6.72 (dd, J = 5.7, 2.2 Hz, 1H), 6.57 (d, J = 1.5 Hz, 1H), 3.53 (t, J = 4.5 Hz, 4H), 3.17 (q, J = 6.7 Hz, 2H), 2.30 (br. s., 4H), 2.28 (s, 3H), 2.26 (t, J = 7.3 Hz, 2H), 1.60 (quin, J = 7.0 Hz, 2H)

LR MS (ES+): 548 (MH+)

LR MS (ES-): 546 (M-H) The following Examples 195 and 196 were prepared using the experiment procedure described in Example 212, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation. Example 195

N-{3-[(2,3-dihydroxypropyl)(methyl)amino]propyl}-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide LR MS (ES+): 609 (MH+) LR MS (ES-): 607 (M-H) Example 196

methyl [(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)amino]acetate ¹H NMR (DMSO-d₆): 11.80 (br. s., 1H), 9.12 (d, J = 2.3 Hz, 1H), 9.01 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 5.9 Hz, 1H), 8.22 (t, J = 9.1 Hz, 1H), 7.97 (dd, J = 7.0, 1.8 Hz, 1 H), 7.88 (t, J = 5.7 Hz, 1H), 7.34 (dd, J = 3.1, 1.9 Hz, 1H), 7.25 (dd, J = 11.7, 2.9 Hz, 1H), 7.17 - 7.20 (m, 1H), 7.05 - 7.11 (m, 2H), 7.01 (dt, J = 9.3, 1.5 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.73 (dd, J = 5.6, 2.3 Hz, 1H), 3.59 (s, 3H), 3.36 (s, 2H), 3.19 (q, J = 6.7 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H), 1.58 (quin, J = 7.0 Hz, 2H) LR MS (ES+): 593 (MH+)

LR MS (ES-): 591 (M-H) Example 197

3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-2-thienyl)carbonyl]amino}propanoic acid

1H NMR (DMSO-d₆): 9.14 (d, J=2.34 Hz, 1 H) 9.01 (d, J=2.34 Hz, 1 H) 8.72 (t, J=5.42 Hz, 1 H) 8.54 (d, J=6.15 Hz, 1 H) 8.47 (s, 1 H) 8.41 (d, J=1.17 Hz, 1 H) 8.27 (t, J=9.08 Hz, 1 H) 8.00 (dd, J=7.62, 1.76 Hz, 1 H) 7.54 (d, J=2.34 Hz, 1 H) 7.33 (dd, J=11.87, 2.78 Hz, 1 H) 7.05 - 7.16 (m, 2 H) 6.95 (dd, J=5.86, 2.34 Hz, 1 H) 6.79 - 6.85 (m, 1 H) 3.40 - 3.49 (m, 2 H) 2.50 - 2.55 (m, 2 H) 2.28 (s, 3 H)

LR MS (ES-): 551 (M-H) Example 198

methyl 3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2- thienyl)carbonyl]amino}propanoate

1H NMR (DMSO-d₆): 9.08 (d, J=2.05 Hz, 1 H) 8.97 (d, J=2.64 Hz, 1 H) 8.72 (t, J=5.57 Hz, 1 H) 8.49 (d, J=5.86 Hz, 1 H) 8.39 (br. s, 2 H) 8.25 (t, J=9.08 Hz, 1 H) 8.01 (dd, J=7.76, 1.90 Hz, 1 H) 7.46 (d, J=2.34 Hz, 1 H) 7.30 (dd, J=11.87, 2.78 Hz, 1 H) 7.12 (dd, J=11.43, 8.20 Hz, 1 H) 7.05 (ddd, J=9.01, 2.71, 1.17 Hz, 1 H) 6.85 (dd, J=5.86, 2.34 Hz, 1 H) 6.81 (m, 1 H) 3.61 (s, 3 H) 3.43 - 3.52 (m, 2 H) 2.60 (t, J=6.89 Hz, 2 H) 2.28 (s, 3 H)

LR MS (ES+): 589 (M+Na⁺)

LR MS (ES-): 565 (M-H) Example 199

3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-2-yl)carbonyl]amino}propanoic acid

1H NMR (DMSO-d₆): 11.93 (br. s., 1 H) 9.13 (d, J=1.47 Hz, 1 H) 9.01 (d, J=1.76 Hz, 1 H) 8.42 (d, J=5.86 Hz, 1 H) 8.21 - 8.31 (m, 2 H) 8.01 (dd, J=7.76, 1.61 Hz, 1 H) 7.65 (br. s., 1 H) 7.29 - 7.35 (m, 2 H) 7.24 (d, J=1.76 Hz, 1 H) 7.05 - 7.17 (m, 2 H) 6.79 - 6.86 (m, 2 H) 3.38 - 3.47 (m, 2 H) 2.47 - 2.51 (m, 2 H) 2.29 (s, 3 H)

LR MS (ES-): 534 (M-H)

Example 200

methyl 3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-2- yl)carbonyl]amino}propanoate

1H NMR (DMSO-d₆): 11.74 (br. s., 1 H) 9.06 (d, J=2.05 Hz, 1 H) 8.96 (d, J=2.64 Hz, 1 H) 8.36 (d, J=5.86 Hz, 1 H) 8.18 - 8.27 (m, 2 H) 8.01 (dd, J=7.62, 2.05 Hz, 1 H) 7.50 (dd, J=3.08, 1.61 Hz, 1 H) 7.23 - 7.29 (m, 2 H) 7.08 - 7.16 (m, 2 H) 7.02 (ddd, J=9.01, 2.56, 1.32 Hz, 1 H) 6.82 (m, 1 H) 6.69 (dd, J=5.71, 2.49 Hz, 1 H) 3.60 (s, 3 H) 3.40 - 3.49 (m, 2 H) 2.57 (t, J=7.03 Hz, 2 H) 2.28 (s, 3 H)

LR MS (ES+): 572 (M+Na⁺)

LR MS (ES-): 548 (M-H) Example 201

N-(3,3-diethoxypropyl)-4-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxamide

1H NMR (DMSO-d₆): 9.08 (d, J=2.05 Hz, 1 H) 8.97 (d, J=2.34 Hz, 1 H) 8.59 (t, J=5.42 Hz, 1 H) 8.49 (d, J=5.57 Hz, 1 H) 8.37 - 8.39 (m, 2 H) 8.25 (t, J=9.08 Hz, 1 H) 8.01 (dd, J=7.91, 1.76 Hz, 1 H) 7.46 (d, J=2.34 Hz, 1 H) 7.30 (dd, J=11.72, 2.64 Hz, 1 H) 7.12 (dd, J=11.43, 8.50 Hz, 1 H) 7.05 (ddd, J=9.01, 2.71, 1.17 Hz, 1 H) 6.85 (dd, J=5.71, 2.49 Hz, 1 H) 6.79 - 6.83 (m, 1 H) 4.56 (t, J=5.57 Hz, 1 H) 3.52 - 3.64 (m, 2 H) 3.45 (dq, J=9.67, 7.13 Hz, 2 H) 3.24 - 3.31 (m, 2 H) 2.28 (s, 3 H) 1.74 - 1.83 (m, 2 H) 1.11 (t, J=7.03 Hz, 6 H)

LR MS (ES+): 633 (M+Na⁺)

LR MS (ES-): 609 (M-H) Example 202

N-(3,3-diethoxypropyl)-4-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxamide ¹H NMR (DMSO-d₆): 11.75 (br. s., 1 H) 9.07 (d, J=1.76 Hz, 1 H) 8.96 (d, J=2.34 Hz, 1 H) 8.38 (d, J=5.86 Hz, 1 H) 8.24 (t, J=9.08 Hz, 1 H) 8.08 (t, J=5.57 Hz, 1 H) 8.01 (dd, J=7.76, 1.90 Hz, 1 H) 7.49 - 7.55 (m, 1 H) 7.27 (m, 2 H) 7.08 - 7.18 (m, 2 H) 7.03 (m, 1 H) 6.82 (m, 1 H) 6.69 - 6.73 (m, 1 H) 4.55 (t, J=5.57 Hz, 1 H) 3.58 (dq, J=9.38, 7.03 Hz, 2 H) 3.44 (dq, J=9.67, 7.03 Hz, 2 H) 3.19 - 3.29 (m, 2 H) 2.27 (s, 3 H) 1.75 (q, J=6.45 Hz, 2 H) 1.11 (t, J=7.03 Hz, 6 H) LR MS (ES+): 616 (M+Na⁺)

LR MS (ES-): 592 (M-H) Example 203

N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxamide To a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrole-3-carboxylic acid (300mg, 0.71mmol) in 10ml of anhydrous DMF were added HATU (324mg, 0.85mmol) and N,N-diisopropylethylamine (200mg, 1.55mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3- diethoxypropane (157mg, 1.06mmol), and stirring was continued for another 10 minutes. The mixture was poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3- methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide as white solid. Yield: 380mg, 97%. ¹H NMR (DMSO-d₆): 11.79 (br. s., 1H), 9.71 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.79 (t, J = 5.6 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.57 (dd, J = 6.3, 3.1 Hz, 1H), 7.39 (t, J = 9.4 Hz, 1H), 7.34 (dd, J = 2.8, 1.6 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.06 - 7.09 (m, 1H), 7.04 - 7.06 (m, 1H), 6.72 (dd, J = 5.6, 2.3 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 4.51 (t, J = 5.6 Hz, 1H), 3.54 (dq, J = 9.5, 7.1 Hz, 2H), 3.41 (dq, J = 9.4, 7.1 Hz, 2H), 3.18 (q, J = 7.0 Hz, 2H), 2.28 (s, 3H), 1.71 (q, J = 6.5 Hz, 2H), 1.08 (t, J = 7.0 Hz, 6H) LR MS (ES+): 551 (MH+)

LR MS (ES-): 549 (M-H) Example 204

N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (200mg, 0.45mmol) in 10ml of anhydrous DMF were added HATU (205mg, 0.54mmol) and N,N- diisopropylethylamine (128mg, 0.99mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (100mg, 0.68mmol), and stirring was continued for another 10 minutes. The mixture was poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide as white solid. Yield: 250mg, 97%. ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 10.12 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.96 - 7.98 (m, 1H), 7.79 (t, J = 5.6 Hz, 1H), 7.63 (t, J = 9.5 Hz, 1H), 7.36 (dd, J = 2.8, 1.9 Hz, 1H), 7.33 - 7.35 (m, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 10.3, 8.5 Hz, 1H), 7.10 (s, 1H), 7.01 - 7.07 (m, 1H), 6.80 (dd, J = 5.9, 2.3 Hz, 1H), 4.51 (t, J = 5.4 Hz, 1H), 3.54 (dq, J = 9.4, 7.0 Hz, 2H), 3.41 (dq, J = 9.4, 7.1 Hz, 2H), 3.15 - 3.21 (m, 2H), 2.26 (s, 3H), 1.65 - 1.76 (m, 2H), 1.08 (t, J = 7.0 Hz, 6H) LR MS (ES-): 577 (M-H) The following Examples 205 and 206 were prepared using the experiment procedure described in Example 207, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation. Example 205

5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- {3-[3-(hydroxymethyl)piperidin-1-yl]propyl}-1H-pyrrole-3-carboxamide LR MS (ES+): 619 (MH+)

LR MS (ES-): 617 (M-H)

Example 206

5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- {3-[2-(hydroxymethyl)morpholin-4-yl]propyl}-1H-pyrrole-3-carboxamide LR MS (ES+): 621 (MH+) LR MS (ES-): 619 (M-H) Example 207

5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- [3-(4-hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3- carboxamide (150mg, 0.29mmol) in 10ml of anhydrous DMF were added 4-hydroxypiperidine (59mg, 0.58mmol) and acetic acid (10mg, 0.17mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.60ml, 0.60mmol) and stirring was continued for another 60 minutes. The mixture was poured into 50ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 20% of MeOH in CHCl₃ to give 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[3-(4-hydroxypiperidin-1- yl)propyl]-1H-pyrrole-3-carboxamide as white solid. Yield: 110mg, 63%. LR MS (ES+): 605 (MH+)

LR MS (ES-): 603 (M-H) The following Example 208 was prepared using the experiment procedure described in Example 163, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 208

N-(3,3-diethoxypropyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide The following Example 209 was prepared using the experiment procedure described in Example 170, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 209

N-(3,3-diethoxypropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide Example 210

{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}acetic acid To a stirred solution of methyl {[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}acetate (100mg, 0.19mmol) in 10ml of MeOH was added 1M NaOH solution (1ml, 1mmol). The mixture was stirred at room temperature for one hour and poured into 100ml of water. 1M HCl was added dropwise with vigorous stirring until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give {[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}acetic acid as white solid. Yield: 95mg, 98%. ¹H NMR (DMSO-d₆): 12.41 (br. s., 1H), 11.86 (br. s., 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 8.20 (t, J = 6.0 Hz, 1H), 7.98 (dd, J = 7.6, 2.1 Hz, 1H), 7.40 (dd, J = 3.1, 1.6 Hz, 1H), 7.27 (dd, J = 11.9, 2.8 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.11 (s, 1H), 7.07 - 7.12 (m, 1H), 7.03 (dd, J = 9.1, 1.8 Hz, 1H), 6.77 - 6.82 (m, 1H), 6.75 (dd, J = 5.6, 2.3 Hz, 1H), 3.81 (d, J = 5.9 Hz, 2H), 2.25 (s, 3H) LR MS (ES-): 520 (M-H) The following Examples 211 was prepared using the experiment procedure described in

Example 175, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue experimentation. Example 211

methyl {[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}acetate ¹H NMR (DMSO-d₆): 11.87 (t, J = 2.9 Hz, 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.32 (t, J = 5.9 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.9, 2.3 Hz, 1H), 7.39 (dd, J = 3.2, 1.8 Hz, 1H), 7.27 (dd, J = 11.9, 2.8 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.06 - 7.12 (m, 2H), 7.02 (ddd, J = 9.0, 2.9, 1.0 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.74 (dd, J = 5.6, 2.3 Hz, 1H), 3.90 (d, J = 5.9 Hz, 2H), 3.61 (s, 3H), 2.25 (s, 3H) LR MS (ES+): 558 (M+Na+)

LR MS (ES-): 534 (M-H)

Example 212

tert-butyl (3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)carbamate A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (400mg, 0.86mmol), HATU (380mg, 1.0mmol) and N,N-diisopropylethylamine (244mg, 1.9mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of N-Boc-1,3-propanediamine (174mg, 1.0mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)carbamate as white solid. Yield: 500mg, 94%. ¹H NMR (DMSO-d₆): 11.86 (br. s., 1H), 9.07 (d, J = 2.1 Hz, 1H), 8.95 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 8.24 (t, J = 9.2 Hz, 1H), 7.98 (dd, J = 7.6, 2.3 Hz, 1 H), 7.82 (t, J = 5.7 Hz, 1H), 7.37 (br. s., 1H), 7.28 (dd, J = 11.7, 2.6 Hz, 1H), 7.20 (br. s., 1H), 7.11 (br. s., 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.03 (dd, J = 9.1, 1.8 Hz, 1H), 6.77 - 6.81 (m, 2H), 6.75 (t, J = 5.6 Hz, 1H), 3.14 (q, J = 6.7 Hz, 2H), 2.91 (q, J = 6.9 Hz, 2H), 2.25 (s, 3H), 1.54 (quin, J = 7.0 Hz, 2H), 1.34 (s, 9H) LR MS (ES+): 643 (M+Na+)

LR MS (ES-): 619 (M-H) Example 213

dimethyl 2,2’-[(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)imino]diacetate To a stirred suspension of N-(3-aminopropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (240mg, 0.46mmol) in 10ml of anhydrous THF were added N,N-diisopropylethylamine (1ml, 5.6mmol) and methyl bromoacetate (300mg, 2.0mmol). The mixture was heated at 55°C for 3 hours and poured into 100ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3~4% of MeOH in CHCl₃ to afford dimethyl 2,2’-[(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)imino]diacetate as white solid. Yield: 160mg, 52%. ¹H NMR (DMSO-d₆): 11.79 (br. s., 1H), 9.05 (d, J = 2.6 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.23 (t, J = 9.2 Hz, 1H), 7.98 (dd, J = 7.9, 2.3 Hz, 1 H), 7.79 (t, J = 5.7 Hz, 1H), 7.33 (dd, J = 3.2, 1.8 Hz, 1H), 7.26 (dd, J = 11.7, 2.6 Hz, 1H), 7.18 (d, J = 2.6 Hz, 1H), 7.08 - 7.12 (m, 1H), 7.07 (dd, J = 2.5, 1.9 Hz, 1H), 7.01 (ddd, J = 9.0, 2.9, 1.0 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.73 (dd, J = 5.9, 2.3 Hz, 1H), 3.56 (s, 6H), 3.49 (s, 4H), 3.12 - 3.21 (m, 2H), 2.63 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H), 1.49 - 1.60 (m, 2H) LR MS (ES+): 687 (M+Na+)

LR MS (ES-): 663 (M-H) Example 214

2,2’-[(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}- 1H-pyrrol-3-yl)carbonyl]amino}propyl)imino]diacetic acid To a stirred solution of dimethyl 2,2’-[(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)imino]diacetate (100mg, 0.15mmol) in a mixture of THF/MeOH (5ml/5ml) was added 1M NaOH solution (1ml, 1mmol). The mixture was stirred at room temperature for 4 hours and poured into 50ml of water. 1M HCl was added dropwise with vigorous stirring until pH = 5. The precipitates were filtered, washed with water and dried in vacuo to give 2,2’-[(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)imino]diacetic acid as white solid. Yield: 82mg, 78%. ¹H NMR (DMSO-d₆): 12.23 (br. s., 1H), 11.77 (br. s., 1H), 9.16 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 7.9, 2.6 Hz, 1H), 7.84 (t, J = 5.7 Hz, 1H), 7.54 (d, J = 9.1 Hz, 2H), 7.52 - 7.55 (m, 1H), 7.32 (dd, J = 2.9, 1.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.11 - 7.15 (m, 1H), 7.08 (dd, J = 11.4, 8.2 Hz, 1H), 7.02 (t, J = 2.2 Hz, 1H), 6.76 - 6.80 (m, 1H), 6.67 (dd, J = 5.6, 2.3 Hz, 1H), 3.38 (s, 4H), 3.14 - 3.20 (m, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.25 (s, 3H), 1.56 (quin, J = 7.0 Hz, 2H) LR MS (ES-): 617 (M-H) Example 215

dimethyl 2,2’-[(2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)imino]diacetate To a stirred suspension of N-(2-aminoethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (120mg, 0.24mmol) in 10ml of anhydrous THF were added N,N-diisopropylethylamine (1ml, 5.6mmol) and methyl bromoacetate (300mg, 2.0mmol). The mixture was heated at 55°C for 2 hours and poured into 100ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3~4% of MeOH in CHCl₃ to afford dimethyl 2,2’-[(2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)imino]diacetate as white solid. Yield: 110mg, 71%. ¹H NMR (DMSO-d₆): 11.80 (t, J = 2.9 Hz, 1H), 9.05 (s, 1H), 8.94 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.22 (t, J = 9.1 Hz, 1H), 7.97 - 8.00 (m, 1H), 7.73 (t, J = 5.4 Hz, 1H), 7.32 (dd, J = 3.1, 1.6 Hz, 1H), 7.26 (dd, J = 11.7, 2.9 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 11.4, 8.2 Hz, 1H), 7.04 - 7.06 (m, 1H), 7.02 (dt, J = 9.1, 1.5 Hz, 1H), 6.77 - 6.82 (m, 1H), 6.74 (dd, J = 5.9, 2.3 Hz, 1H), 3.56 (s, 6H), 3.54 (s, 4H), 3.21 (q, J = 6.3 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 673 (M+Na+)

LR MS (ES-): 649 (M-H) Example 216

tert-butyl (2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)carbamate A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300mg, 0.65mmol), HATU (296mg, 0.78mmol) and N,N-diisopropylethylamine (185mg, 1.43mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (125mg, 0.78mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (2- {[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate as white solid. Yield: 350mg, 89%. ¹H NMR (DMSO-d₆): 11.88 (br. s., 1H), 9.07 (d, J = 1.5 Hz, 1H), 8.95 (d, J = 2.6 Hz, 1H), 8.40 (d, J = 5.9 Hz, 1H), 8.25 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.9, 2.3 Hz, 1H), 7.84 - 7.90 (m, 1H), 7.38 (br. s., 1H), 7.26 - 7.30 (m, 1H), 7.20 (br. s., 1H), 7.11 (br. s., 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.03 (dd, J = 8.8, 1.8 Hz, 1H), 6.82 (t, J = 5.7 Hz, 1H), 6.77 - 6.81 (m, 2H), 3.16 - 3.20 (m, 2H), 3.02 (q, J = 6.4 Hz, 2H), 2.25 (s, 3H), 1.34 (s, 9H) LR MS (ES+): 629 (M+Na+)

LR MS (ES-): 605 (M-H) The following Example 217 was prepared using the experiment procedure described in Example 207, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 217

methyl rel-(2R,4S)-1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)-4-hydroxypyrrolidine-2-carboxylate ¹H NMR (DMSO-d₆): 11.78 (br. s., 1H), 9.05 (s, 1H), 8.94 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.22 (t, J = 9.1 Hz, 1H), 7.97 - 8.00 (m, 1H), 7.82 (t, J = 5.7 Hz, 1H), 7.30 - 7.34 (m, 1H), 7.26 (dd, J = 11.7, 2.9 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.05 - 7.07 (m, 1H), 7.01 (dt, J = 9.0, 1.5 Hz, 1H), 6.76 - 6.82 (m, 1H), 6.73 (dd, J = 5.7, 2.5 Hz, 1H), 4.84 (d, J = 4.4 Hz, 1H), 4.14 - 4.21 (m, 1H), 3.57 (s, 3H), 3.33 (t, J = 7.6 Hz, 1H), 3.12 - 3.23 (m, 3H), 2.57 - 2.65 (m, 1H), 2.36 - 2.42 (m, 1H), 2.25 (s, 3H), 2.20 (dd, J = 9.7, 4.4 Hz, 1H), 1.93 (dt, J = 12.8, 7.2 Hz, 1H), 1.79 - 1.88 (m, 1H), 1.49 - 1.59 (m, 2H) LR MS (ES+): 649 (MH+)

LR MS (ES-): 647 (M-H) Example 218

{4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]piperazin-1-yl}acetic acid To a stirred solution of ethyl {4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]piperazin-1-yl}acetate (175mg, 0.28mmol) in MeOH (8ml) was added 1M NaOH solution (1ml, 1mmol). The mixture was stirred at room temperature for 16 hours and poured into 50ml of water. 1M HCl was added dropwise with vigorous stirring until pH = 7. The precipitates were filtered, washed with water and dried in vacuo to give {4-[(5-{4-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]piperazin-1-yl}acetic acid as white solid. Yield: 160mg, 96%. ¹H NMR (DMSO-d₆): 11.87 (br. s., 1H), 9.05 (d, J = 2.1 Hz, 1H), 8.94 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.21 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.8, 1.6 Hz, 1 H), 7.37 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 11.7, 2.6 Hz, 1H), 7.13 (dd, J = 2.9, 1.8 Hz, 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.00 (dd, J = 9.0, 1.6 Hz, 1H), 6.93 (dd, J = 2.5, 1.9 Hz, 1H), 6.76 - 6.82 (m, 1H), 6.68 (dd, J = 5.7, 2.5 Hz, 1H), 3.61 (br. s., 4H), 3.15 (s, 2H), 2.53 (t, J = 4.8 Hz, 4H), 2.25 (s, 3H) LR MS (ES-): 589 (M-H) Example 219

ethyl {4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]piperazin-1-yl}acetate A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300mg, 0.65mmol), HATU (296mg, 0.78mmol) and N,N-diisopropylethylamine (185mg, 1.43mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of ethyl piperazinoacetate (168mg, 0.98mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give to the crude, which was purified by silica gel chromatography eluting with 5~8% of methanol in chloroform to afford ethyl {4-[(5-{4-[3- fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol- 3-yl)carbonyl]piperazin-1-yl}acetate as white solid. Yield: 250mg, 63%. ¹H NMR (DMSO-d₆): 11.86 (br. s., 1H), 9.04 (d, J = 2.3 Hz, 1H), 8.93 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.21 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.9, 2.3 Hz, 1 H), 7.37 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 11.7, 2.6 Hz, 1H), 7.12 (dd, J = 3.2, 1.8 Hz, 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.00 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 6.92 (dd, J = 2.5, 1.9 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.60 (br. s., 4H), 3.23 (s, 2H), 2.48 - 2.52 (m, 4H), 2.25 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H) LR MS (ES+): 641 (M+Na+) LR MS (ES-): 617 (M-H) Example 220

1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylic acid To a stirred suspension of methyl 1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylate (100mg, 0.16mmol) in 1ml of MeOH was added 0.2N NaOH solution (2ml, 0.4mmol). The mixture was heated at 50°C for 16 hours and cooled to room temperature. 1M HCl was added dropwise with vigorous stirring until pH = 7. The precipitates were filtered, washed with water and dried in vacuo to give 1-(3-{[(5-{4-[3- fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol- 3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylic acid as white solid. Yield: 72mg, 73%. ¹H NMR (DMSO-d₆): 11.83 (t, J = 2.9 Hz, 1H), 9.14 (d, J = 1.8 Hz, 1H), 9.02 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.21 (t, J = 9.1 Hz, 1H), 7.93 - 8.00 (m, 2H), 7.35 (dd, J = 3.1, 1.6 Hz, 1H), 7.26 (dd, J = 11.7, 2.6 Hz, 1H), 7.16 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 11.2, 8.2 Hz, 1H), 7.05 - 7.07 (m, 1H), 7.01 (dd, J = 9.0, 1.9 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.74 (dd, J = 5.7, 2.5 Hz, 1H), 3.46 - 3.52 (m, 2H), 3.25 (td, J = 13.3, 6.6 Hz, 1H), 3.15 - 3.22 (m, 1H), 3.04 (ddd, J = 12.4, 9.0, 6.5 Hz, 1H), 2.89 (ddd, J = 12.5, 9.1, 6.6 Hz, 1H), 2.79 (td, J = 10.3, 7.0 Hz, 1H), 2.25 (s, 3H), 2.07 - 2.17 (m, 1H), 1.87 - 1.94 (m, 1H), 1.79 - 1.87 (m, 1 H), 1.70 - 1.79 (m, 2H), 1.58 - 1.69 (m, 1H) LR MS (ES+): 619 (MH+)

LR MS (ES-): 617 (M-H) Example 221

1-(2-fluoro-5-methylphenyl)-3-[2-fluoro-4-({2-[4-(piperazin-1-ylcarbonyl)-1H-pyrrol-2- yl]pyridin-4-yl}oxy)phenyl]urea To a stirred solution of tert-butyl 4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]piperazine-1-carboxylate (200mg, 0.32mmol) in 10ml of methylene chloride was added 3ml of TFA. The mixture was stirred at room temperature for 30 minutes, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5ml of methanol and poured into 100ml of water with vigorous stirring. Saturated NaHCO₃ solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 12% methanol in chloroform to give 1- (2-fluoro-5-methylphenyl)-3-[2-fluoro-4-({2-[4-(piperazin-1-ylcarbonyl)-1H-pyrrol-2- yl]pyridin-4-yl}oxy)phenyl]urea as white solid. Yield: 145mg, 86% ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 9.05 (s, 1H), 8.94 (s, 1H), 8.37 (d, J = 5.9 Hz, 1H), 8.21 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.9, 2.3 Hz, 1H), 7.36 (d, 1H), 7.23 (dd, J = 11.7, 2.9 Hz, 1H), 7.10 (s, 1H), 7.06 - 7.10 (m, 1H), 6.99 (dd, J = 8.7, 1.6 Hz, 1H), 6.90 (t, J = 2.2 Hz, 1H), 6.79 (dt, J = 5.5, 2.7 Hz, 1H), 6.68 (dd, J = 5.7, 2.5 Hz, 1H), 3.42 - 3.56 (m, 4H), 2.61 - 2.70 (m, 4H), 2.25 (s, 3H) Example 222

N-(2-aminoethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide To a stirred suspension of tert-butyl (2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)carbamate (300mg, 0.49mmol) in 10ml of methylene chloride was added 3ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5ml) and poured into 100ml of water with vigorous stirring. Saturated NaHCO₃ solution was added until pH = 8~9. The precipitates were filtered, washed with water and dried in vacuo to give N- (2-aminoethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as beige solid. Yield: 200mg, 80%. LR MS (ES+): 507 (M+Na+)

LR MS (ES-): 505 (M-H) Example 223

N-(3-aminopropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide To a stirred suspension of tert-butyl (3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)carbamate (450mg, 0.72mmol) in 10ml of methylene chloride was added 5ml of trifluoroacetic acid. The mixture was stirred at room temperature for 20 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5ml) and poured into 100ml of water with vigorous stirring. Saturated NaHCO₃ solution was added until pH = 8~9. The precipitates were filtered, washed with water and dried in vacuo to give N- (3-aminopropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as grey solid. Yield: 320mg, 85%. LR MS (ES+): 521 (MH+) Example 224

tert-butyl 4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]piperazine-1-carboxylate To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300mg, 0.65mmol) in 10ml of anhydrous DMF were added HATU (296mg, 0.78mmol) and N,N-diisopropylethylamine (185mg, 1.43mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of tert-butyl 1-piperazinecarboxylate (182mg, 0.98mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. 1M HCl was added slowly until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl 4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]piperazine-1-carboxylate as white solid. Yield: 290mg, 84%. ¹H NMR (acetone): 11.10 (br. s., 1H), 8.52 (d, J = 3.2 Hz, 1H), 8.38 - 8.44 (m, 3H), 8.15 (dd, J = 7.9, 2.3 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 3.2, 1.8 Hz, 1H), 7.12 (dd, J = 11.7, 2.9 Hz, 1H), 6.99 - 7.06 (m, 3H), 6.81 - 6.85 (m, 1H), 6.79 (dd, J = 5.9, 2.6 Hz, 1H), 3.64 - 3.71 (m, 4H), 3.41 - 3.47 (m, 4H), 2.31 (s, 3H), 1.44 (s, 9H) LR MS (ES+): 655 (M+Na+)

LR MS (ES-): 631 (M-H) Example 225

5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- (3-oxopropyl)-1H-pyrrole-3-carboxamide To a stirred solution of N-(3,3-diethoxypropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (240mg, 0.40mmol) in 10ml of THF, was added 2M HCl (1ml, 2mmol). The mixture was stirred at room temperature for 1 hour, and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)- 1H-pyrrole-3-carboxamide as brown solid. Yield: 186mg, 89%. LR MS (ES+): 542 (M+Na+) LR MS (ES-): 518 (M-H) Example 226

5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- (3-pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide

To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200mg, 0.43mmol) in 10ml of anhydrous DMF were added HATU (198mg, 0.52mmol) and N,N-diisopropylethylamine (166mg, 1.3mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)pyrrolidine (110mg, 0.86mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude which was purified by silica gel chromatography eluting with 10~20% of methanol in chloroform to give 5-{4-[3-fluoro-4-({[(2- fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-pyrrolidin-1- ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 160mg, 65%.

¹H NMR (DMSO-d₆): 11.78 (t, J = 2.9 Hz, 1H), 9.06 (dd, J = 2.1, 0.6 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.6, 2.1 Hz, 1H), 7.89 (t, J = 5.7 Hz, 1H), 7.32 (dd, J = 3.2, 1.8 Hz, 1H), 7.26 (dd, J = 11.9, 2.8 Hz, 1H), 7.16 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 11.4, 8.2 Hz, 1H), 7.03 - 7.05 (m, 1H), 7.02 (ddd, J = 9.0, 2.9, 1.0 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.74 (dd, J = 5.9, 2.3 Hz, 1H), 3.14 - 3.22 (m, 2H), 2.40 (br. s., 6H), 2.25 (s, 3H), 1.58 - 1.67 (m, 6H)

LR MS (ES+): 575 (MH+)

LR MS (ES-): 573 (M-H) The following Example 232 was prepared using the experiment procedure described in Example 234, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 227

2-methoxyethyl 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate ¹H NMR (DMSO-d₆): 12.12 (t, J = 3.1 Hz, 1H), 9.05 (d, J = 2.1 Hz, 1H), 8.94 (d, J = 2.3 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.22 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 8.2, 2.1 Hz, 1H), 7.41 (dd, J = 3.4, 1.6 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 11.7, 2.6 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 12.0, 9.1 Hz, 1H), 7.00 (ddd, J = 9.2, 2.7, 1.0 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.73 (dd, J = 5.7, 2.5 Hz, 1H), 4.23 - 4.26 (m, 2H), 3.55 - 3.59 (m, 2H), 3.27 (s, 3H), 2.25 (s, 3H) LR MS (ES+): 545 (M+Na+)

LR MS (ES-): 521 (M-H) The following Example 228 was prepared using the experiment procedure described in Example 207, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 228

methyl 1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylate ¹H NMR (DMSO-d₆): 11.78 (t, J = 3.1 Hz, 1H), 9.05 (d, J = 2.6 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.9 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.9, 2.6 Hz, 1H), 7.84 (t, J = 5.7 Hz, 1H), 7.32 (dd, J = 2.9, 1.8 Hz, 1H), 7.26 (dd, J = 11.7, 2.9 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.04 - 7.05 (m, 1H), 7.01 (ddd, J = 9.0, 2.8, 1.2 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.74 (dd, J = 5.7, 2.5 Hz, 1H), 3.57 (s, 3H), 3.16 - 3.21 (m, 2H), 3.14 (dd, J = 9.0, 5.4 Hz, 1H), 2.94 - 3.02 (m, 1H), 2.62 (dt, J = 11.7, 7.6 Hz, 1H), 2.37 (dt, J = 12.3, 6.3 Hz, 1H), 2.26 - 2.32 (m, 1H), 2.25 (s, 3H), 1.94 - 2.05 (m, 1H), 1.67 - 1.78 (m, 3H), 1.57 (quin, J = 7.0 Hz, 2H) LR MS (ES+): 633 (MH+)

LR MS (ES-): 631 (M-H) Example 229

3-morpholin-4-ylpropyl 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate To a stirred suspension of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200mg, 0.43mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 124mg, 0.65mmol) in 10ml of anhydrous tetrahydrofuran were added N-(3- hydroxypropyl)morpholine (125mg, 0.86mmol) and 4-dimethylaminopyridine (10mg,

0.08mmol). The mixture was heated at 60°C for 16 hours, cooled to room temperature and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 3~5% of methanol in chloroform to afford 3-morpholin-4-ylpropyl 5-{4-[3-fluoro-4-({[(2- fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 90mg, 35%. ¹H NMR (DMSO-d₆): 12.10 (t, J = 3.1 Hz, 1H), 9.05 (d, J = 2.6 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.9 Hz, 1H), 8.22 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.9, 2.3 Hz, 1H), 7.41 (dd, J = 3.2, 1.5 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 11.7, 2.6 Hz, 1H), 7.07 - 7.11 (m, 2H), 7.00 (dd, J = 8.9, 2.8 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.72 (dd, J = 5.7, 2.5 Hz, 1H), 4.15 (t, J = 6.6 Hz, 2H), 3.53 (t, J = 4.7 Hz, 4H), 2.35 (t, J = 7.2 Hz, 2H), 2.32 (br. s., 4H), 2.25 (s, 3H), 1.78 (quin, J = 6.9 Hz, 2H) LR MS (ES+): 592 (MH+)

LR MS (ES-): 590 (M-H) Example 230

dimethyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate To a stirred solution of 5-{4-[3-fluoro-4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150mg, 0.34mmol) in 10ml of anhydrous DMF were added HATU (156mg, 0.41mmol) and N,N-diisopropylethylamine (175mg, 1.36mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (108mg, 0.51mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3~5% methanol in chloroform to give dimethyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as white solid. Yield: 120mg, 59%. ¹H NMR (DMSO-d₆): 11.87 (t, J = 2.9 Hz, 1H), 8.96 (s, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.20 (t, J = 9.1 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.43 (dd, J = 3.1, 1.9 Hz, 1H), 7.27 (s, 1H), 7.25 (dd, J = 11.7, 2.9 Hz, 1H), 7.19 - 7.23 (m, 2H), 7.12 - 7.17 (m, 2H), 7.01 (dd, J = 8.1, 2.5 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.73 (dd, J = 5.7, 2.5 Hz, 1H), 4.37 (ddd, J = 9.6, 7.6, 5.1 Hz, 1H), 3.59 (s, 3H), 3.55 (s, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.26 (s, 3H), 1.98 - 2.10 (m, 1H), 1.86 - 1.97 (m, 1H) LR MS (ES+): 626 (M+Na+)

LR MS (ES-): 602 (M-H) Example 231

ethyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propanoate To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200mg, 0.43mmol) in 10ml of anhydrous DMF were added HATU (179mg, 0.47mmol) and N,N-diisopropylethylamine (166mg, 1.29mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine ethyl ester hydrochloride (100mg, 0.65mmol). The mixture was stirred for another 10 minutes and poured into 100ml of water with vigorous stirring. 1M HCl was added slowly until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propanoate as white solid. Yield: 200mg, 82%. ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 7.98 (dd, J = 7.9, 2.3 Hz, 1 H), 7.93 (t, J = 5.7 Hz, 1H), 7.35 (br. s., 1H), 7.26 (dd, J = 11.7, 2.9 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.06 - 7.08 (m, 1H), 7.02 (dd, J = 8.7, 2.8 Hz, 1H), 6.77 - 6.81 (m, 1H), 6.74 (dd, J = 5.7, 2.5 Hz, 1H), 4.03 (q, 2H), 3.35 - 3.39 (m, 2H), 2.49 (t, J = 7.04 Hz, 2H), 2.25 (s, 3H), 1.14 (t, J = 7.0 Hz, 3H) LR MS (ES+): 564 (MH+)

LR MS (ES-): 562 (M-H) Example 232

dimethyl 2,2’-[(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)imino]diacetate To a stirred suspension of N-(3-aminopropyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (200mg, 0.40mmol) and N,N-diisopropylethylamine (0.5ml, 2.8mmol) in 10ml of anhydrous THF was added methyl bromoacetate (200mg, 1.30mmol). The mixture was heated at 60°C for 16 hours and poured into 100ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 5% of MeOH in CHCl₃ to afford dimethyl 2,2’-[(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)imino]diacetate as white solid. Yield: 210mg, 82%. ¹H NMR (DMSO-d₆): 11.77 (t, J = 2.9 Hz, 1H), 9.14 (s, 1H), 8.46 (d, J = 2.9 Hz, 1H), 8.35 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 7.9, 2.3 Hz, 1H), 7.79 (t, J = 5.7 Hz, 1H), 7.52 - 7.56 (m, 2H), 7.32 (dd, J = 3.1, 1.6 Hz, 1H), 7.11 - 7.15 (m, 3H), 7.08 (dd, J = 11.4, 8.2 Hz, 1H), 7.02 (dd, J = 2.3, 1.8 Hz, 1H), 6.76 - 6.80 (m, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 3.56 (s, 6H), 3.48 (s, 4H), 3.12 - 3.20 (m, 2H), 2.63 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H), 1.54 (quin, J = 7.0 Hz, 2H) LR MS (ES+): 669 (M+Na+)

LR MS (ES-): 645 (M-H) Example 233

2-methoxyethyl 4-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoate To a stirred solution of 4-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoic acid (300mg, 0.56mmol) in 10ml of anhydrous DMF were added HATU (255mg, 0.67mmol) and N,N-diisopropylethylamine (217mg, 1.68mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 2-methoxyethanol (0.50ml, 6.3mmol). The mixture was heated at 66°C for 1 hour, and poured into 100ml of water with vigorous stirring. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with ethyl acetate to give 2-methoxyethyl 4-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoate as white solid. Yield: 215mg, 65%. ¹H NMR (DMSO-d₆): 11.78 (t, J = 3.1 Hz, 1H), 9.14 (s, 1H), 8.46 (d, J = 2.9 Hz, 1H), 8.35 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 7.9, 2.3 Hz, 1H), 7.85 (t, J = 5.9 Hz, 1H), 7.52 - 7.56 (m, 2H), 7.33 (dd, J = 3.2, 1.8 Hz, 1H), 7.11 - 7.15 (m, 3H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 7.03 (dd, J = 2.5, 1.9 Hz, 1H), 6.76 - 6.80 (m, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 4.07 - 4.10 (m, 2H), 3.45 - 3.49 (m, 2H), 3.21 (s, 3H), 3.13 - 3.19 (m, 2H), 2.32 (t, J = 7.5 Hz, 2H), 2.25 (s, 3H), 1.70 (quin, J = 7.2 Hz, 2H) LR MS (ES+): 612 (M+Na+)

LR MS (ES-): 588 (M-H) The following Example 234 was prepared using the experiment procedure described in Example 233, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 234

3-hydroxy-2,2-bis(hydroxymethyl)propyl 4-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoate ¹H NMR (DMSO-d₆): 11.79 (t, J = 2.9 Hz, 1H), 9.14 (s, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.35 (d, J = 5.9 Hz, 1H), 7.96 (dd, J = 7.6, 2.3 Hz, 1H), 7.88 (t, J = 5.7 Hz, 1H), 7.52 - 7.56 (m, 2H), 7.35 (dd, J = 3.2, 1.8 Hz, 1H), 7.12 - 7.15 (m, 3H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 7.04 (dd, J = 2.5, 1.9 Hz, 1H), 6.76 - 6.80 (m, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 4.33 (t, J = 5.4 Hz, 3H), 3.89 (s, 2H), 3.33 (d, J = 5.3 Hz, 6H), 3.17 (q, J = 6.7 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 2.25 (s, 3H), 1.70 (quin, J = 7.2 Hz, 2H) LR MS (ES+): 672 (M+Na+)

LR MS (ES-): 648 (M-H) Example 235

N-[3-(4-hydroxypiperidin-1-yl)propyl]-5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide (150mg, 0.31mmol) in 10ml of anhydrous DMF were added 4-hydroxypiperidine (59mg, 0.58mmol) and acetic acid (10mg, 0.17mmol). The mixture was stirred at room temperature for 60 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.60ml, 0.60mmol). Stirring was continued for another 60 minutes and the mixture was poured into 50ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 20% of MeOH in CHCl₃ to give N-[3-(4-hydroxypiperidin-1-yl)propyl]-5-{4-[4- ({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as off-white solid. Yield: 102mg, 58%. LR MS (ES+): 569 (MH+)

LR MS (ES-): 567 (M-H) Example 236

5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)- 1H-pyrrole-3-carboxamide To a stirred solution of N-(3-hydroxypropyl)-5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (1.0g, 2.06mmol) in 20ml of anhydrous DMF was added Dess-Martin periodinane (1.22g, 2.88mmol). The mixture was stirred at room temperature under nitrogen for 80 minutes and poured into 100ml of water with vigorous stirring. Saturated NaHCO₃ solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude 5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3- carboxamide as light brown solid, which was used in the next step without further purification. Yield: 1.0g, 100%. LR MS (ES+): 484 (MH+)

LR MS (ES-): 482 (M-H) Example 237

N-(3-hydroxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxamide

To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (1.00g, 2.34mmol) in 20ml of anhydrous DMF were added HATU (1.07g, 2.80mmol) and N,N-diisopropylethylamine (604mg, 4.68mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3-amino-1-propanol (263mg, 3.51mmol). The mixture was stirred for another 5 minutes and poured into 200ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-hydroxypropyl)-5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 1.10g, 97%. ¹H NMR (DMSO-d₆): 12.02 (br. s., 1H), 8.82 (s, 1H), 8.62 (s, 1H), 8.41 (d, J = 6.2 Hz, 1H), 7.85 - 7.95 (m, 1H), 7.53 - 7.61 (m, 2H), 7.45 - 7.51 (m, 1H), 7.25 - 7.31 (m, 2H), 7.19 - 7.25 (m, 2H), 7.09 - 7.19 (m, 3H), 6.81 - 6.88 (m, 1H), 6.78 (d, J = 7.3 Hz, 1H), 3.42 (t, J = 6.3 Hz, 2H), 3.22 (q, J = 6.5 Hz, 2H), 2.26 (s, 3H), 1.61 (quin, J = 6.7 Hz, 2H) LR MS (ES+): 486 (M+Na+)

LR MS (ES-): 484 (M-H) Example 238

1-[4-({2-[4-(hydrazinocarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(3- methylphenyl)urea To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (100mg, 0.23mmol) in 10ml of anhydrous DMF were added HATU (105mg, 0.28mmol) and N,N-diisopropylethylamine (89mg, 0.69mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of hydrazine monohydrate (0.25ml, 5.2mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 1-[4-({2-[4- (hydrazinocarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(3-methylphenyl)urea as white solid. Yield: 98mg, 95%. ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 9.22 - 9.36 (m, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.35 (d, J = 5.6 Hz, 1H), 7.51 - 7.56 (m, 2H), 7.36 (br. s., 1H), 7.27 (s, 1H), 7.19 - 7.23 (m, 1H), 7.09 - 7.15 (m, 4H), 7.02 - 7.06 (m, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.67 (dd, J = 5.9, 2.3 Hz, 1H), 2.25 (s, 3H)

LR MS (ES+): 465 (M+Na+)

LR MS (ES-): 441 (M-H) Example 239

5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-morpholin-4- ylpropyl)-1H-pyrrole-3-carboxamide To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxylic acid (100mg, 0.23mmol) in 10ml of anhydrous DMF were added HATU (106mg, 0.28mmol) and N,N-diisopropylethylamine (90mg, 0.70mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3- aminopropyl)morpholine (68mg, 0.47mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3- morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 110mg, 85%. 1H NMR (DMSO-d₆): 11.77 (t, J = 2.9 Hz, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.35 (d, J = 5.9 Hz, 1H), 7.83 (t, J = 5.7 Hz, 1H), 7.51 - 7.55 (m, 2H), 7.32 (dd, J = 3.1, 1.6 Hz, 1H), 7.27 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.10 - 7.15 (m, 4H), 7.01 (dd, J = 2.5, 1.9 Hz, 1H), 6.77 (d, J = 7.3 Hz, 1H), 6.67 (dd, J = 5.6, 2.3 Hz, 1H), 3.53 (t, J = 4.7 Hz, 4H), 3.14 - 3.19 (m, 2H), 2.26 - 2.33 (m, 6H), 2.25 (s, 3H), 1.60 (quin, J = 7.1 Hz, 2H) LR MS (ES+): 555 (MH+)

LR MS (ES-): 553 (M-H) Example 240

3-hydroxy-2,2-bis(hydroxymethyl)propyl 5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate To a stirred suspension of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrole-3-carboxylic acid (150mg, 0.35mmol) and N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide hydrochloride (EDC, 102mg, 0.53mmol) in 10ml of anhydrous

tetrahydrofuran were added pentaerythritol (143mg, 1.05mmol) and 4-dimethylaminopyridine (10mg, 0.08mmol). The mixture was heated at 60°C for 16 hours, cooled to room temperature and evaporated to dryness. The residue was purified by C-18 reverse phase chromatography eluting with a gradient of 10~50% of acetonitrile in water to afford 3-hydroxy-2,2- bis(hydroxymethyl)propyl 5-{4-[4-({[(3- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 46mg, 24%. ¹H NMR (DMSO-d₆): 12.08 (t, J = 2.9 Hz, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.50 - 7.56 (m, 2H), 7.40 (dd, J = 3.2, 1.8 Hz, 1H), 7.38 (d, J = 2.3 Hz, 1H), 7.27 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1 H), 7.11 (d, J = 9.1 Hz, 2H), 7.07 - 7.09 (m, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.62 (dd, J = 5.9, 2.3 Hz, 1H), 4.34 (t, J = 5.3 Hz, 3H), 4.03 (s, 2H), 3.42 (d, J = 5.3 Hz, 6H), 2.25 (s, 3H) LR MS (ES+): 547 (MH+)

LR MS (ES-): 545 (M-H) The following Example 241 was prepared using the experiment procedure described in Example 238, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 241

1-(2-fluoro-5-methylphenyl)-3-[4-({2-[4-(hydrazinocarbonyl)-1H-pyrrol-2-yl]pyridin-4- yl}oxy)phenyl]urea ¹H NMR (DMSO-d₆): 11.79 (t, J = 3.1 Hz, 1H), 9.16 (s, 1H), 9.11 (t, J = 4.0 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.35 (d, J = 5.9 Hz, 1H), 7.96 (dd, J = 7.9, 2.3 Hz, 1H), 7.52 - 7.56 (m, 2H), 7.34 (dd, J = 2.9, 1.8 Hz, 1H), 7.11 - 7.15 (m, 3H), 7.08 (dd, J = 11.4, 8.2 Hz, 1H), 7.03 (dd, J = 2.5, 1.9 Hz, 1H), 6.75 - 6.81 (m, 1H), 6.67 (dd, J = 5.6, 2.3 Hz, 1H), 4.21 (d, J = 3.8 Hz, 2H), 2.25 (s, 3H)

LR MS (ES+): 483 (M+Na+)

LR MS (ES-): 459 (M-H) Example 242

5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3- oxopropyl)-1H-pyrrole-3-carboxamide To a stirred solution of N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (250mg, 0.43mmol) in 10ml of tetrahydrofuran was added 1ml of 1M HCl (1.0mmol). The mixture was stirred at room temperature for 60 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-oxopropyl)-1H-pyrrole-3- carboxamide as white solid. Yield: 205mg, 94%. ¹H NMR (DMSO-d₆): 11.83 (t, J = 3.1 Hz, 1H), 10.12 (s, 1H), 9.65 (t, J = 1.9 Hz, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.97 - 8.01 (m, 2H), 7.95 (t, J = 5.7 Hz, 1H), 7.61 - 7.66 (m, 1H), 7.32 - 7.37 (m, 2H), 7.25 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 10.6, 8.2 Hz, 1H), 7.09 - 7.10 (m, 1H), 7.02 - 7.06 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 3.40 - 3.48 (m, 2H), 2.59 (td, J = 6.6, 2.1 Hz, 2H), 2.27 (s, 3H) LR MS (ES-): 503 (M-H) The following Example 248 was prepared using the experiment procedure described in Example 184, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 243

methyl (2S)-1-{3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate ¹H NMR (DMSO-d₆): 11.82 (br. s., 1H), 10.13 (s, 1H), 8.42 (d, J = 5.9 Hz, 1H), 7.94 - 8.04 (m, 2H), 7.86 (t, J = 5.7 Hz, 1H), 7.58 - 7.69 (m, 1H), 7.32 - 7.38 (m, 2H), 7.25 (d, J = 2.3 Hz, 1H), 7.11 - 7.19 (m, 1H), 7.08 - 7.11 (m, 1H), 7.01 - 7.09 (m, 1H), 6.81 (dd, J = 5.7, 2.5 Hz, 1H), 3.58 (s, 3H), 3.11 - 3.24 (m, 3H), 2.93 - 3.05 (m, 1 H), 2.56 - 2.70 (m, 1H), 2.37 - 2.45 (m, 1H), 2.30 - 2.37 (m, 1H), 2.27 (s, 3H), 1.93 - 2.09 (m, 1H), 1.65 - 1.81 (m, 3H), 1.52 - 1.65 (m, 2H) LR MS (ES+): 618 (MH+)

LR MS (ES-): 616 (M-H) The following Example 249 was prepared using the experiment procedure described in Example 264, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 244

5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3- hydroxypropyl)-1H-pyrrole-3-carboxamide ¹H NMR (DMSO-d₆): 11.82 (br. s., 1H), 10.13 (s, 1H), 8.42 (d, J = 5.9 Hz, 1H), 7.95 - 8.04 (m, 2H), 7.83 (t, J = 5.7 Hz, 1H), 7.59 - 7.70 (m, 1H), 7.32 - 7.40 (m, 2H), 7.26 (d, J = 2.3 Hz, 1H), 7.12 - 7.13 (m, 1H), 7.11 - 7.19 (m, 1H), 7.01 - 7.09 (m, 1H), 6.81 (dd, J = 5.6, 2.3 Hz, 1H), 4.43 (t, J = 5.3 Hz, 1H), 3.41 (q, J = 6.2 Hz, 2H), 3.15 - 3.26 (m, 2H), 2.27 (s, 3H), 1.60 (quin, J = 6.7 Hz, 2H) LR MS (ES+): 507 (MH+)

LR MS (ES-): 505 (M-H) Example 245

ethyl 4-{N-[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]-S-methylsulfonimidoyl}butanoate

Example 246

N,N’-diethyl-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]pentanediamide To a stirred solution of 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]pentanedioic acid (100mg, 0.17mmol) and N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide hydrochloride (EDC, 83mg, 0.43mmol) in 10ml of anhydrous DMF was added 2M ethylamine solution in THF (0.43ml, 0.86mmol). The mixture was stirred at room temperature for overnight and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 5~8% of methanol in chloroform to afford N,N’-diethyl-2-[({5-[4- (2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]pentanediamide as white solid. Yield: 76mg, 69%. ¹H NMR (DMSO-d₆): 11.86 (t, J = 3.1 Hz, 1H), 10.12 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.96 - 8.01 (m, 2H), 7.79 - 7.83 (m, 2H), 7.75 (t, J = 5.6 Hz, 1H), 7.63 (dd, J = 10.4, 9.0 Hz, 1H), 7.46 (dd, J = 3.2, 1.8 Hz, 1H), 7.34 (dd, J = 7.2, 2.2 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.19 (dd, J = 2.5, 1.9 Hz, 1H), 7.14 (dd, J = 10.6, 8.5 Hz, 1 H), 7.02 - 7.07 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 4.20 - 4.32 (m, 1H), 3.02 - 3.08 (m, 2H), 2.97 - 3.03 (m, 2H), 2.26 (s, 3H), 2.00 - 2.15 (m, 2H), 1.86 - 1.97 (m, 1H), 1.73 - 1.85 (m, 1H), 0.98 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H) LR MS (ES+): 633 (MH+)

LR MS (ES-): 631 (M-H) Example 247

1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylic acid To a stirred solution of methyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylate (Example 50) (68mg, 0.11mmol) in a mixture of THF/MeOH (5ml/5ml) was added 1M NaOH solution (1ml, 1mmol). The mixture was stirred at room temperature for 16 hours and poured into 30ml of water. 1M HCl was added dropwise with vigorous stirring until pH = 7. The precipitates were filtered, washed with water and dried in vacuo to give 1-(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylic acid as light reddish solid. Yield: 60mg, 91%. LR MS (ES+): 601 (MH+)

LR MS (ES-): 599 (M-H) Example 248

2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]pentanedioic acid To a stirred solution of dimethyl 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]pentanedioate (320mg, 0.53mmol) in MeOH (20ml) was added 1M NaOH solution (2ml, 2mmol). The mixture was stirred at room temperature for 16 hours and poured into 100ml of water. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]pentanedioic acid as white solid. Yield: 305mg, 100%. ¹H NMR (DMSO-d₆): 12.47 (br. s., 1H), 12.09 (br. s., 1H), 11.88 (t, J = 2.9 Hz, 1H), 10.12 (s, 1H), 8.42 (d, J = 5.9 Hz, 1H), 7.94 - 8.02 (m, 3H), 7.63 (dd, J = 10.4, 8.4 Hz, 1H), 7.46 (dd, J = 3.2, 1.8 Hz, 1H), 7.35 (dd, J = 7.3, 2.6 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.18 - 7.21 (m, 1H), 7.14 (dd, J = 10.6, 8.5 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 4.32 (ddd, J = 9.8, 7.7, 4.8 Hz, 1H), 2.30 (t, J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.97 - 2.07 (m, 1H), 1.80 - 1.91 (m, 1H)

LR MS (ES+): 579 (MH+)

LR MS (ES-): 577 (M-H) The following Example 249 was prepared using the experiment procedure described in Example 259, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 249

dimethyl 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanedioate ¹H NMR (DMSO-d₆): 11.94 (br. s., 1H), 10.13 (s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.95 - 8.05 (m, 2H), 7.60 - 7.69 (m, 1H), 7.49 (dd, J = 3.1, 1.6 Hz, 1H), 7.35 (dd, J = 7.5, 2.5 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.21 (t, J = 2.2 Hz, 1H), 7.10 - 7.19 (m, 1H), 7.01 - 7.09 (m, 1H), 6.84 (dd, J = 5.9, 2.3 Hz, 1H), 4.30 - 4.46 (m, 1H), 3.61 (s, 3H), 3.56 (s, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.27 (s, 3H), 1.99 - 2.13 (m, 1H), 1.84 - 1.99 (m, 1H) LR MS (ES+): 607 (MH+)

LR MS (ES-): 605 (M-H) Example 250

N-(3-aminopropyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide To a stirred suspension of tert-butyl (3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)carbamate (70mg, 0.12mmol) in 10ml of methylene chloride was added 1ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5ml) and poured into 100ml of water with vigorous stirring. Saturated NaHCO₃ solution was added until pH = 8~9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3- aminopropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrole-3-carboxamide as yellow solid. Yield: 40mg, 63%. LR MS (ES+): 503 (MH+)

LR MS (ES-): 501 (M-H) Example 251

tert-butyl (3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate To a stirred solution of 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100mg, 0.22mmol) in 10ml of anhydrous DMF were added HATU (100mg, 0.26mmol) and N,N-diisopropylethylamine (85mg, 0.66mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-Boc-1 ,3-propanediamine (57mg, 0.33mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water with vigorous stirring. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)carbamate as white solid. Yield: 120mg, 89%. ¹H NMR (DMSO-d₆): 11.79 (br. s., 1H), 9.16 (s, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.35 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 7.5, 2.2 Hz, 1H), 7.81 (t, J = 5.9 Hz, 1H), 7.51 - 7.56 (m, 2H), 7.32 (dd, J = 3.2, 1.8 Hz, 1H), 7.12 - 7.15 (m, 2H), 7.11 - 7.13 (m, 1H), 7.08 (dd, J = 11.4, 8.2 Hz, 1H), 7.01 - 7.02 (m, 1H), 6.76 - 6.80 (m, 1H), 6.75 (t, J = 6.3 Hz, 1H), 6.69 (dd, J = 5.9, 2.3 Hz, 1H), 3.14 (q, J = 6.7 Hz, 2H), 2.91 (q, J = 6.7 Hz, 2H), 2.25 (s, 3H), 1.53 (quin, J = 7.0 Hz, 2H), 1.33 (s, 9H) LR MS (ES+): 625 (M+Na+)

LR MS (ES-): 601 (M-H) Example 252

N-(3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide To a stirred suspension of tert-butyl {3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propyl}carbamate (100mg, 0.165mmol) in 10ml of methylene chloride was added 1ml of trifluoroacetic acid. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5ml) and poured into 100ml of water with vigorous stirring. Saturated NaHCO₃ solution was added until pH = 8~9. The precipitates were filtered, washed with water and dried in vacuo to give N- (3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide as grey solid. Yield: 70mg, 84%. LR MS (ES+): 506 (MH+)

LR MS (ES-): 504 (M-H) The following Example 253 was prepared using the experiment procedure described in Example 254, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 253

tert-butyl {3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin- 2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}carbamate ¹H NMR (DMSO-d₆): 11.82 (t, J = 2.9 Hz, 1H), 10.12 (s, 1H), 8.41 (d, J = 5.9 Hz, 1H), 7.96 - 8.01 (m, 2H), 7.81 (t, J = 5.9 Hz, 1H), 7.60 - 7.66 (m, 1H), 7.36 (dd, J = 3.2, 1.8 Hz, 1H), 7.34 (dd, J = 7.2, 2.2 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 10.6, 8.5 Hz, 1H), 7.11 (dd, J = 2.6, 1.8 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 6.75 (t, J = 6.0 Hz, 1H), 3.12 - 3.18 (m, 2H), 2.87 - 2.96 (m, 2H), 2.26 (s, 3H), 1.54 (quin, J = 7.0 Hz, 2H), 1.34 (s, 9H) LR MS (ES+): 606 (MH+)

LR MS (ES-): 604 (M-H) Example 254

5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3- morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (100mg, 0.22mmol) in 10ml of anhydrous DMF were added HATU (100mg, 0.26mmol) and N,N- diisopropylethylamine (85mg, 0.66mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)morpholine (48mg, 0.33mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-morpholin-4-ylpropyl)-1H-pyrrole- 3-carboxamide as white solid. Yield: 122mg, 95%. ¹H NMR (DMSO-d₆): 11.81 (br. s., 1H), 10.12 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.96 - 8.01 (m, 2H), 7.84 (br. s., 1H), 7.61 - 7.65 (m, 1H), 7.36 (dd, 1H), 7.34 (dd, J = 7.3, 2.3 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 10.4, 8.4 Hz, 1H), 7.11 (dd, J = 2.3, 1.8 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 3.54 (br. s., 4H), 3.18 (q, J = 6.6 Hz, 2H), 2.31 (br. s., 6H), 2.27 (s, 3H), 1.61 (br. s., 2H) LR MS (ES+): 576 (MH+)

LR MS (ES-): 574 (M-H) Example 255

5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoic acid To a stirred solution of tert-butyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoate (75mg, 0.11mmol) in 5ml of methylene chloride was added 1ml of TFA. The mixture was stirred at room temperature for 90 minutes, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5ml of methanol and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoic acid as white solid. Yield: 60mg, 87%. ¹H NMR (DMSO-d₆): 12.05 (br. s., 1H), 11.90 (br. s., 1H), 10.13 (s, 1 H), 8.43 (d, J = 5.9 Hz, 1H), 7.97 - 8.02 (m, 2H), 7.83 (t, J = 5.6 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 9.7, 8.8 Hz, 1H), 7.50 (br. s., 1H), 7.34 (dd, J = 7.5, 1.9 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.23 (br. s., 1H), 7.14 (dd, J = 10.3, 8.5 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.83 (d, J = 5.3 Hz, 1H), 4.32 (td, J = 8.7, 5.3 Hz, 1H), 3.00 - 3.09 (m, 2H), 2.27 (s, 3H), 2.18 - 2.25 (m, 2H), 1.88 - 1.99 (m, 1H), 1.74 - 1.86 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H) LR MS (ES+): 606 (MH+)

LR MS (ES-): 604 (M-H) Example 256

tert-butyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoate To a stirred suspension of 5-tert-butoxy-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoic acid (150mg, 0.24mmol) in 10ml of anhydrous tetrahydrofuran were added HATU (109mg, 0.29mmol) and N,N-diisopropylethylamine (93mg, 0.72mmol). The mixture was heated at 60°C for 15 minutes and cooled to room temperature, followed by addition of 2M ethylamine solution in THF (0.18ml, 0.36mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water with vigorous stirring. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3~5% methanol in chloroform to give tert-butyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoate as white solid. Yield: 100mg, 64%. ¹H NMR (DMSO-d₆): 11.86 (br. s., 1H), 10.12 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.96 - 8.01 (m, 2H), 7.82 (t, J = 5.7 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 10.1, 8.7 Hz, 1H), 7.48 (dd, J = 2.9, 1.8 Hz, 1H), 7.34 (dd, J = 7.3, 1.8 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.19 - 7.22 (m, 1H), 7.14 (dd, J = 10.4, 8.4 Hz, 1H), 7.02 - 7.06 (m, 1H), 6.80 (dd, J = 5.6, 2.3 Hz, 1H), 4.31 (td, J = 8.7, 5.3 Hz, 1H), 2.99 - 3.10 (m, 2H), 2.26 (s, 3H), 2.17 - 2.24 (m, 2H), 1.86 - 1.96 (m, 1H), 1.72 - 1.83 (m, 1H), 1.35 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H) LR MS (ES+): 662 (MH+)

LR MS (ES-): 660 (M-H) Example 257

5-tert-butoxy-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoic acid To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (150mg, 0.33mmol) in 10ml of anhydrous DMF were added HATU (150mg, 0.39mmol) and N,N- diisopropylethylamine (128mg, 0.99mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert-butyl ester (102mg, 0.50mmol). The mixture was heated at 60°C for 30 minutes, cooled to room temperature, and poured into 100ml of water. 2M HCl was added dropwise with vigorous stirring until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert-butoxy-2-[({5-[4-(2-fluoro-5- {[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]-5-oxopentanoic acid as white solid. Yield: 185mg, 87%. ¹H NMR (DMSO-d₆): 12.49 (br. s., 1H), 11.88 (br. s., 1H), 10.12 (s, 1 H), 8.42 (d, J = 5.9 Hz, 1H), 7.96 - 8.02 (m, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.63 (dd, J = 10.1, 8.7 Hz, 1H), 7.46 (dd, J = 3.1, 1.6 Hz, 1H), 7.34 (dd, J = 7.3, 1.8 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.19 (dd, J = 2.6, 1.8 Hz, 1H), 7.14 (dd, J = 10.4, 8.4 Hz, 1H), 7.02 - 7.06 (m, 1H), 6.80 (dd, J = 5.6, 2.3 Hz, 1H), 4.32 (ddd, 1H), 2.28 (t, J = 7.9 Hz, 2H), 2.26 (s, 3H), 1.94 - 2.04 (m, 1H), 1.80 - 1.89 (m, 1H), 1.36 (s, 9H) LR MS (ES-): 633 (M-H) Example 258

3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]propanoic acid To a stirred solution of methyl 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propanoate (82mg, 0.15mmol) in a mixture of THF/MeOH (10ml/10ml) was added 1M NaOH solution (1ml, 1mmol). The mixture was stirred at room temperature for 2 hours and poured into 100ml of water. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give 3-[({5-[4-(2-fluoro-5- {[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propanoic acid as white solid. Yield: 70mg, 88%. ¹H NMR (DMSO-d₆): 12.15 (br. s., 1H), 11.85 (br. s., 1H), 10.13 (s, 1 H), 8.42 (d, J = 5.6 Hz, 1H), 8.00 (d, J = 5.9 Hz, 1H), 7.97 - 7.99 (m, 1H), 7.91 (t, J = 5.6 Hz, 1H), 7.61 - 7.66 (m, 1H), 7.38 (br. s., 1H), 7.35 (dd, J = 7.6, 2.1 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.11 - 7.16 (m, 2H), 7.02 - 7.07 (m, 1H), 6.82 (dd, J = 5.6, 2.1 Hz, 1H), 3.32 - 3.38 (m, 2H), 2.43 (t, J = 7.0 Hz, 2H), 2.27 (s, 3H)

LR MS (ES-): 519 (M-H) Example 259

methyl 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (100mg, 0.22mmol) in 10ml of anhydrous DMF were added HATU (100mg, 0.26mmol) and N,N- diisopropylethylamine (85mg, 0.66mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46mg, 0.33mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water. 2M HCl was added dropwise with vigorous stirring until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propanoate as white solid. Yield: 110mg, 92%. ¹H NMR (DMSO-d₆): 11.83 (br. s., 1H), 10.12 (s, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.96 - 8.02 (m, 2H), 7.94 (t, J = 5.7 Hz, 1H), 7.63 (dd, J = 10.1, 9.0 Hz, 1H), 7.37 (dd, J = 2.9, 1.8 Hz, 1H), 7.34 (dd, J = 7.5, 1.9 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 10.4, 8.4 Hz, 1H), 7.10 (dd, J = 2.3, 1.8 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.80 (dd, J = 5.7, 2.5 Hz, 1H), 3.57 (s, 3H), 3.36 - 3.41 (m, 2H), 2.52 (t, J = 6.9 Hz, 2H), 2.27 (s, 3H) LR MS (ES+): 557 (M+Na+)

LR MS (ES-): 533 (M-H) Example 260

ethyl 4-{N-[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]-S- methylsulfonimidoyl}butanoate Example 261

methyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoate To a stirred suspension of 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- methoxy-5-oxopentanoic acid (260mg, 0.44mmol) in 20ml of anhydrous tetrahydrofuran were added HATU (200mg, 0.53mmol) and N,N-diisopropylethylamine (170mg, 1.32mmol). The mixture was heated at 60°C for 15 minutes and cooled to room temperature, followed by addition of 2M ethylamine solution in THF (0.44ml, 0.88mmol). The mixture was stirred for another 5 minutes, and poured into 100ml of water with vigorous stirring. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2~5% methanol in chloroform to give methyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoate as white solid. Yield: 127mg, 47%. ¹H NMR (DMSO-d₆): 11.87 (br. s., 1H), 10.12 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.95 - 8.01 (m, 2H), 7.85 (t, J = 5.6 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 10.1, 8.7 Hz, 1H), 7.48 (dd, J = 3.1, 1.6 Hz, 1H), 7.34 (dd, J = 7.5, 1.9 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.20 (dd, J = 2.5, 1.6 Hz, 1H), 7.14 (dd, J = 10.4, 8.4 Hz, 1H), 7.02 - 7.07 (m, 1H), 6.80 (dd, J = 5.9, 2.3 Hz, 1H), 4.32 (td, J = 8.7, 5.6 Hz, 1H), 3.54 (s, 3H), 2.97 - 3.10 (m, 2H), 2.29 - 2.33 (m, 2H), 2.26 (s, 3H), 1.91 - 2.01 (m, 1H), 1.78 - 1.89 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H) LR MS (ES+): 642 (M+Na+)

LR MS (ES-): 618 (M-H) Example 262

2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]-5-methoxy-5-oxopentanoic acid To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (60mg, 0.13mmol) in 10ml of anhydrous DMF were added HATU (61mg, 0.16mmol) and N,N- diisopropylethylamine (52mg, 0.40mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 5-methyl L-glutamate (32mg, 0.20mmol). The mixture was heated at 60°C for 1 hour, cooled to room temperature and poured into 100ml of water with vigorous stirring. 2M HCl was added slowly until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- methoxy-5-oxopentanoic acid as white solid. Yield: 30mg, 38%. ¹H NMR (DMSO-d₆): 12.53 (br. s., 1H), 11.89 (br. s., 1H), 10.12 (s, 1 H), 8.43 (d, J = 5.9 Hz, 1H), 7.96 - 8.01 (m, 3H), 7.63 (dd, J = 10.3, 8.5 Hz, 1H), 7.47 (dd, J = 3.1, 1.6 Hz, 1H), 7.34 (dd, J = 7.3, 2.1 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.18 - 7.20 (m, 1H), 7.14 (dd, J = 10.4, 8.4 Hz, 1H), 7.01 - 7.07 (m, 1H), 6.81 (dd, J = 5.6, 2.3 Hz, 1H), 4.32 (ddd, J = 9.5, 8.0, 5.1 Hz, 1H), 3.55 (s, 3H), 2.37 - 2.41 (m, 2H), 2.26 (s, 3H), 1.99 - 2.10 (m, 1H), 1.83 - 1.95 (m, 1H) LR MS (ES-): 591 (M-H)

Example 263

N,N’-diethyl-2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanediamide To a stirred solution of 2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioic acid(Example 63) (100mg, 0.17mmol) in 10ml of anhydrous DMF was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 84mg, 0.44mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 2M ethylamine solution in THF (0.45ml, 0.90mmol). The mixture was stirred for another 16 hours, and poured into 100ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 3~5% of methanol in chloroform to afford N,N’-diethyl-2-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanediamide as white solid. Yield: 60mg, 55%. ¹H NMR (DMSO-d₆): 11.82 (br. s., 1H), 9.14 (s, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 7.9, 2.1 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 5.6 Hz, 1H), 7.75 (t, J = 5.3 Hz, 1H), 7.51 - 7.56 (m, 2H), 7.42 (dd, J = 3.1, 1.6 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.12 - 7.15 (m, 2H), 7.11 (dd, J = 2.6, 1.8 Hz, 1H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.75 - 6.80 (m, 1H), 6.68 (dd, J = 5.9, 2.3 Hz, 1H), 4.25 (td, J = 8.6, 5.1 Hz, 1H), 3.02 - 3.07 (m, 2H), 2.97 - 3.02 (m, 2H), 2.25 (s, 3H), 2.00 - 2.14 (m, 2H), 1.86 - 1.95 (m, 1H), 1.74 - 1.83 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.3 Hz, 3H) LR MS (ES+): 652 (M+Na+)

LR MS (ES-): 628 (M-H)

Example 264

5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)-5-oxopentanoic acid To a stirred solution of tert-butyl 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoate (34mg, 0.055mmol) in 5ml of methylene chloride was added 2ml of TFA. The mixture was stirred at room temperature for 1 hour, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5ml of methanol and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-(ethylamino)-4- ({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)- 5-oxopentanoic acid as white solid. Yield: 26mg, 84%. ¹H NMR (DMSO-d₆): 12.04 (br. s., 1H), 11.85 (br. s., 1H), 10.19 (s, 1 H), 8.39 (d, J = 5.6 Hz, 1H), 7.82 (t, J = 5.7 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.68 - 7.70 (m, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.45 (dd, J = 3.1, 1.6 Hz, 1H), 7.38 - 7.43 (m, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 2.3, 1.8 Hz, 1H), 6.88 - 6.91 (m, 1H), 6.74 (dd, J = 5.6, 2.3 Hz, 1H), 6.56 (d, J = 1.5 Hz, 1H), 4.31 (td, J = 8.7, 5.3 Hz, 1H), 2.98 - 3.10 (m, 2H), 2.29 (s, 3H), 2.17 - 2.26 (m, 2H), 1.89 - 1.98 (m, 1H), 1.75 - 1.84 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H) LR MS (ES-): 558 (M-H) Example 265

tert-butyl 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H- pyrrol-3-yl]carbonyl}amino)-5-oxopentanoate To a stirred suspension of 5-tert-butoxy-2-({[5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid (100mg, 0.17mmol) in 10ml of anhydrous tetrahydrofuran were added HATU (76mg,

0.20mmol) and N,N-diisopropylethylamine (66mg, 0.51mmol). The mixture was heated at 60°C for 15 minutes and cooled to room temperature, followed by addition of 2M ethylamine solution in THF (0.25ml, 0.50mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water with vigorous stirring. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3~5% methanol in chloroform to give tert- butyl 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol- 3-yl]carbonyl}amino)-5-oxopentanoate as white solid. Yield: 82mg, 78%. ¹H NMR (DMSO-d₆): 11.84 (br. s., 1H), 10.19 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.80 (t, J = 5.6 Hz, 1H), 7.75 - 7.79 (m, 2H), 7.68 - 7.70 (m, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.45 (dd, J = 3.1, 1.6 Hz, 1H), 7.38 - 7.43 (m, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 2.6, 1.8 Hz, 1H), 6.88 - 6.91 (m, 1H), 6.74 (dd, J = 5.9, 2.3 Hz, 1H), 6.56 (d, J = 1.8 Hz, 1H), 4.30 (td, J = 8.7, 5.4 Hz, 1H), 2.99 - 3.09 (m, 2H), 2.29 (s, 3H), 2.13 - 2.25 (m, 2H), 1.86 - 1.96 (m, 1 H), 1.75 - 1.81 (m, 1H), 1.34 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H) LR MS (ES+): 638 (M+Na+)

LR MS (ES-): 614 (M-H) Example 266

5-tert-butoxy-2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)-5-oxopentanoic acid To a stirred solution of 5-tert-butyl 1-methyl 2-({[5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)pentanedioate (170mg, 0.28mmol) in a mixture of THF/MeOH (10ml/10ml) was added 1M NaOH solution (2ml, 2mmol). The mixture was stirred at room temperature for 2 hours and poured into 100ml of water. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert-butoxy-2-({[5-(4-{3-[(3-methyl-2- furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid as white solid. Yield: 145mg, 87%. ¹H NMR (DMSO-d₆): 12.48 (br. s., 1H), 11.88 (br. s., 1H), 10.20 (s, 1 H), 8.40 (d, J = 5.9 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.67 - 7.71 (m, 2H), 7.45 (br. s., 1H), 7.41 (t, J = 8.2 Hz, 1 H), 7.26 (d, J = 1.5 Hz, 1H), 7.16 (br. s., 1H), 6.90 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 6.76 (d, J = 3.8 Hz, 1H), 6.56 (dd, J = 1.8, 0.6 Hz, 1H), 4.31 (ddd, J = 9.8, 7.9, 4.8 Hz, 1H), 2.29 (s, 3H), 2.25 - 2.29 (m, 2H), 1.94 - 2.05 (m, 1H), 1.79 - 1.89 (m, 1H), 1.35 (s, 9H) LR MS (ES-): 587 (M-H)

Example 267

5-tert-butyl 1-methyl 2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol- 3-yl]carbonyl}amino)pentanedioate To a stirred solution of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3- carboxylic acid (Example 32)(140mg, 0.35mmol) in 10ml of anhydrous DMF were added HATU (160mg, 0.42mmol) and N,N-diisopropylethylamine (135mg, 1.05mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert- butyl 1-methyl ester hydrochloride (135mg, 0.53mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water. 2M HCl was added dropwise with vigorous stirring until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert- butyl 1-methyl 2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3- yl]carbonyl}amino)pentanedioate as white solid. Yield: 170mg, 81%. ¹H NMR (DMSO-d₆): 11.96 (br. s., 1H), 10.21 (s, 1H), 8.42 (d, J = 5.9 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.68 - 7.72 (m, 2H), 7.48 (br. s., 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.29 (br. s., 1H), 7.19 (br. s., 1H), 6.91 (dd, J = 7.6, 1.8 Hz, 1H), 6.80 (br. s., 1H), 6.56 (d, J = 1.2 Hz, 1H), 4.37 (ddd, J = 9.5, 7.5, 5.3 Hz, 1H), 3.60 (s, 3H), 2.29 (s, 3H), 2.28 (t, J = 7.6 Hz, 2H), 1.94 - 2.02 (m, 1H), 1.82 - 1.91 (m, 1H), 1.35 (s, 9H) LR MS (ES+): 625 (M+Na+)

LR MS (ES-): 601 (M-H)

Example 268

1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylic acid To a stirred solution of tert-butyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylate (22mg, 0.033mmol) in 2ml of methylene chloride was added 1ml of TFA. The mixture was stirred at room temperature for 16 hours, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 2ml of methanol and poured into 10ml of water with vigorous stirring. Saturated NaHCO₃ solution was added dropwise until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylic acid as light reddish solid. Yield: 18mg, 90%. The following Example 269 was prepared using the experiment procedure described in Example 271, but with the appropriate reagent, reaction conditions and reactant substitutions that will be readily realized by those of ordinary skill in this art without the exercise of undue

experimentation. Example 269

tert-butyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylate LR MS (ES+): 657 (MH+)

LR MS (ES-): 655 (M-H)

Example 270

dimethyl 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (120mg, 0.26mmol), HATU (110mg, 0.29mmol) and N,N-diisopropylethylamine (100mg, 0.78mmol) in anhydrous DMF (10ml) was stirred at room temperature for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (66mg, 0.31mmol). The mixture was heated at 50°C for 15 minutes, cooled to room temperature and poured into 100ml of water with vigorous stirring. 2M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give dimethyl 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate as white solid. Yield: 130mg, 81%. ¹H NMR (DMSO-d₆): 11.91 (br. s., 1H), 9.08 (d, J = 2.3 Hz, 1H), 8.97 (d, J = 2.6 Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.25 (t, J = 9.1 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 8.01 (dd, J = 7.9, 2.3 Hz, 1H), 7.47 (dd, J = 3.1, 1.6 Hz, 1H), 7.30 (dd, J = 11.7, 2.6 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 7.17 - 7.18 (m, 1H), 7.12 (dd, J = 11.4, 8.2 Hz, 1H), 7.05 (ddd, J = 9.0, 2.8, 1.2 Hz, 1H), 6.81 - 6.83 (m, 1H), 6.77 (dd, J = 5.7, 2.5 Hz, 1H), 4.38 - 4.42 (m, 1H), 3.62 (s, 3H), 3.58 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.28 (s, 3H), 2.07 (dtd, J = 13.6, 7.9, 5.4 Hz, 1H), 1.91 - 1.98 (m, 1H)

LR MS (ES+): 644 (M+Na⁺)

LR MS (ES-): 620 (M-H) Example 271

2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioic acid

To a stirred solution of dimethyl 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioate (75mg, 0.12mmol) in 10ml of MeOH was added 2ml of 1M NaOH. The mixture was heated at 60°C for one hour, cooled to room temperature and poured into 100ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 2-{[(5-{4-[3-fluoro-4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}pentanedioic acid as off-white solid. Yield: 72mg, 100%.

1H NMR (DMSO-d₆) : 12.48 (br. s., 1H), 12.10 (br. s., 1H), 11.88 (br. s., 1H), 9.06 (d, J = 1.5 Hz, 1H), 8.94 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 7.93 - 8.02 (m, 2H), 7.45 (br. s., 1H), 7.27 (dd, J = 11.7, 2.6 Hz, 1H), 7.23 (s, 1H), 7.17 (br. s., 1H), 7.09 (dd, J = 11.3, 8.4 Hz, 1H), 7.02 (dd, J = 9.1, 1.5 Hz, 1H), 6.79 (td, J = 5.2, 2.5 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 4.32 (ddd, J = 9.5, 7.8, 5.0 Hz, 1H), 2.30 (t, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.95 - 2.08 (m, 1H), 1.79 - 1.92 (m, 1H)

LR MS (ES-): 592 (M-H)

Example 272

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[3-(4- hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide To a stirred solution of 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3- carboxamide (100mg, 0.20mmol) in 10ml of anhydrous DMF were added 4-hydroxypiperidine (30mg, 0.30mmol) and acetic acid (10mg, 0.17mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.30ml, 0.30mmol) and stirring was continued for one more hour. The mixture was poured into 100ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 20% of MeOH in CHCl₃ to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-N-[3-(4-hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide as white solid. Yield: 55mg, 47%. LR MS (ES+): 587 (MH+)

LR MS (ES-): 585 (M-H) Example 273

5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3- oxopropyl)-1H-pyrrole-3-carboxamide To a stirred solution of N-(3,3-diethoxypropyl)-5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (800mg, 1.39mmol) in 10ml of THF was added 2M HCl (1ml, 1mmol). The mixture was stirred at room temperature under nitrogen for 1.5 hours, and poured into 100ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give 5-{4-[4- ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)- 1H-pyrrole-3-carboxamide as off-white solid. Yield: 680mg, 98%. LR MS (ES+): 524 (M+Na+)

LR MS (ES-): 500 (M-H) Example 274

3-morpholin-4-ylpropyl 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate To a stirred suspension of 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100mg, 0.22mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 63mg, 0.33mmol) in 10ml of anhydrous tetrahydrofuran were added N-(3- hydroxypropyl)morpholine (64mg, 0.44mmol) and 4-dimethylaminopyridine (10mg, 0.08mmol). The mixture was heated at 60°C for 3 hours, cooled to room temperature and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 3~5% of methanol in chloroform to afford 3-morpholin-4-ylpropyl 5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 72mg, 56%. LR MS (ES+): 574 (MH+)

LR MS (ES-): 572 (M-H) Example 275

3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propanoic acid To a stirred solution of methyl 3-[({5-[4-(2-fluoro-5-{[(3- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propanoate (80mg, 0.16mmol) in a mixture of THF/MeOH (5ml/5ml) was added 1M NaOH solution (1ml, 1mmol). The mixture was stirred at room temperature for 3 hours and poured into 50ml of water. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give 3-[({5-[4-(2-fluoro-5- {[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3- yl}carbonyl)amino]propanoic acid as white solid. Yield: 70mg, 90%. ¹H NMR (DMSO-d₆): 12.15 (br. s., 1H), 11.85 (br. s., 1H), 10.18 (s, 1 H), 8.42 (d, J = 5.6 Hz, 1H), 8.02 (dd, J = 7.6, 2.3 Hz, 1H), 7.97 - 8.00 (m, 1H), 7.91 (t, J = 5.6 Hz, 1H), 7.63 (dd, J = 10.3, 8.8 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.38 (br. s., 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.12 (br. s., 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.81 (dd, J = 5.7, 2.5 Hz, 1H), 3.32 - 3.37 (m, 2H), 2.43 (t, J = 7.0 Hz, 2H), 2.27 (s, 3H) LR MS (ES-): 501 (M-H) Example 276

5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3- carboxylic acid

Example 277

methyl 3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]propanoate To a stirred solution of 5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrole-3-carboxylic acid (Example 275) (100mg, 0.23mmol) in 10ml of anhydrous DMF were added HATU (100mg, 0.26mmol) and N,N-diisopropylethylamine (85mg,

0.66mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46mg, 0.33mmol). The mixture was stirred for another 5 minutes and poured into 100ml of water. 2M HCl was added dropwise with vigorous stirring until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H- pyrrol-3-yl}carbonyl)amino]propanoate as white solid. Yield: 110mg, 92%. ¹H NMR (DMSO-d₆): 11.95 (br. s., 1H), 10.19 (s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 8.03 (dd, J = 7.6, 2.3 Hz, 1H), 8.00 (ddd, J = 8.7, 4.5, 2.3 Hz, 1H), 7.97 (t, J = 5.7 Hz, 1H), 7.64 (dd, J = 10.3, 8.5 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.43 (br. s., 1H), 7.31 (br. s., 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.18 (br. s., 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.88 (br. s., 1H), 3.57 (s, 3H), 3.35 - 3.42 (m, 2H), 2.52 (t, J = 6.9 Hz, 2H), 2.27 (s, 3H) LR MS (ES+): 539 (M+Na+)

LR MS (ES-): 515 (M-H) Example 278

3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2- thienyl)carbonyl]amino}propanoic acid To a stirred solution of methyl 3-{[(4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2- thienyl)carbonyl]amino}propanoate (85mg, 0.16mmol) in a mixture of THF/MeOH (5ml/5ml) was added 1M NaOH solution (2ml, 2mmol). The mixture was heated at 50°C for one hour and poured into 100ml of water. 1M HCl was added dropwise with vigorous stirring until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give 3-{[(4-{4-[4-({[(2- fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2- thienyl)carbonyl]amino}propanoic acid as white solid. Yield: 80mg, 96%. ¹H NMR (DMSO-d₆): 12.17 (br. s., 1H), 9.15 (s, 1H), 8.68 (t, J = 5.6 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 1.2 Hz, 1H), 8.33 (d, J = 1.2 Hz, 1H), 7.95 (dd, J = 7.9, 2.3 Hz, 1H), 7.51 - 7.56 (m, 2H), 7.41 (d, J = 2.3 Hz, 1H), 7.12 - 7.17 (m, 2H), 7.08 (dd, J = 11.4, 8.2 Hz, 1H), 6.77 - 6.80 (m, 1H), 6.76 (dd, J = 5.9, 2.3 Hz, 1H), 3.38 - 3.44 (m, 2H), 2.49 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H) LR MS (ES-): 533 (M-H) Example 279

methyl 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2- yl}-2-thienyl)carbonyl]amino}propanoate To a stirred solution of 4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylic

acid(Example 123) (100mg, 0.22mmol) in 10ml of anhydrous DMF were added HATU (100mg, 0.26mmol) and N,N-diisopropylethylamine (85mg, 0.66mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46mg, 0.33mmol). The mixture was stirred for another 10 minutes, and poured into 100ml of water with vigorous stirring. 1M HCl was added dropwise until pH = 4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-{[(4-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-2- thienyl)carbonyl]amino}propanoate as off-white solid. Yield: 115mg, 97%. ¹H NMR (DMSO-d₆): 9.21 (s, 1H), 8.70 (t, J = 5.6 Hz, 1H), 8.45 - 8.50 (m, 2H), 8.36 (d, J = 18.2 Hz, 2H), 7.93 - 7.97 (m, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.45 (br. s., 1H), 7.16 (d, J = 9.1 Hz, 2H), 7.08 (dd, J = 11.3, 8.4 Hz, 1H), 6.72 - 6.88 (m, 2H), 3.58 (s, 3H), 3.39 - 3.50 (m, 2H), 2.57 (t, J = 6.9 Hz, 2H), 2.25 (s, 3H) LR MS (ES+): 571 (M+Na+)

LR MS (ES-): 547 (M-H)

3.2 Biological Testing Biological data for the compounds of the present invention was generated by the use of one or more of the following assays. VEGF Stimulated Ca.sup.++ Signal in Vitro Automated FLIPR (Fluorometric Imaging Plate Reader) technology was used to screen for inhibitors of VEGF induced increases in intracellular calcium levels in fluorescent dye loaded endothelial cells. HUVEC (human umbilical vein endothelial cells) (Clonetics) were seeded in 96-well fibronectin coated black-walled plates overnight at 37.degree. C./5%

CO.sub.2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37.degree. C. Cells were washed 4 times (Original Cell Wash, Labsystems) to remove extracellular dye. Test compounds were reconstituted in 100% DMSO and added to the cells to give a final DMSO concentration of 0.1%. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10.mu.M) or at concentrations ranging from 0.01 to 10.0.mu.M followed by VEGF stimulation (5 ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 96 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC.sub.50 values for test compounds were calculated from % inhibition of VEGF stimulated responses in the absence of inhibitor. VEGFR2 Kinase Assay The cytoplasmic domain of the human VEGF receptor (VEGFR-2) was expressed as a Histidine-tagged fusion protein following infection of insect cells using an His engineered baculovirus. His-VEGFR-2 was purified to homogeneity, as determined by SDS-PAGE, using nickel resin chromatography. Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30.mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120.mu.L reaction volumes containing 3.6 .mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree. C., the reactions were washed four times with PBS containing 0.05% Tween-20. 100 .mu.l of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes. Following four washes with PBS- Tween-20, 100.mu.l of O-phenylenediamine Dihydrochloride in Phosphate-citrate buffer, containing urea hydrogen peroxide, was added to the wells for 7 minutes as a colorimetric substrate for the peroxidase. The reaction was terminated by the addition of 100.mu.l of 2.5N H.sub.2 SO.sub.4 to each well and read using a microplate ELISA reader set at 492 nm.

IC.sub.50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.

Compounds of the current invention have the IC50 value in the range of 0.01 to 500 nM. VEGF-induced Dermal Extravasation in Guinea Pig (Miles Assay) Male Hartley guinea pigs (300-600 g) were anesthetized with isofluorane, sheared, and given a single dose of drug or the respective vehicle. The guinea pigs were dosed orally unless indicated otherwise in Table 3. Ten minutes prior to the end of drug treatment, guinea pigs were anesthetized with isofluorane, and 0.5% Evans blue dye (EBD) in PBS (13-15 mg/kg dose of EBD) was injected intravenously. After 5 minutes, triplicate intradermal injections of 100 ng rhVEGF.sub.165 in 100.mu.l PBS and of 100.mu.l PBS alone were administered on the flank. After 20 minutes, each animal was cuthanized with Pentosol, and the skin containing the intradermal injection sites was removed for image analysis. Using an analog video camera coupled to a PC, an image of each trans-illuminated skin sample was captured, and the integrated optical density of each injection site was measured using ImagePro 4. For each skin sample, the difference between the mean optical density of the VEGF sites and mean optical density of the PBS sites is the measure of VEGF-induced EBD extravasation in that animal. These measured values were averaged per study group to determine the mean VEGF-induced EBD extravasation for each experimental condition, and the group means were then compared to assess inhibition of VEGF-induced EBD extravasation in the drug-treated groups relative to the vehicle-treated controls. To determine the dose required for 50% inhibition (ID.sub.50), the percent inhibition data was plotted as a function of oral dose, using the `best-fit` analysis within MicroSoft Excel software. The ID.sub.50 value was verified visually by using the plotted data (horizontal line from 50% y value, at intersection with best-fit line drop vertical line to x axis (dose). Laser-induced Choroidal Neovascularization (CNV) in Rat (CNV Assay). CNV was induced and quantified in this model as previously described (Edelman and Castro. Exp. Eye Res. 2000; 71:523-533). On day 0, male Brown Norway rats (200-300 g) were anesthetized with 100 mg/kg Ketamine and 10 mg/kg Xylazine, and pupils were dilated with 1% Tropicamide. Using the blue-green setting of a Coherent Novus Argon Laser, 3 laser bums (90 mW for 0.1 s; 100 .mu.m diameter) were given to each eye between the retinal vessels around the optic nerve head. Rats were dosed with test compounds in their indicated vehicles orally once daily. On day 10, rats were sacrificed with 100% CO.sub.2, and blood vessels were labeled by vascular perfusion with 10 mg/ml FITC-dextran (MW 2.times.10.sup.6). Using an

epifluorescence microscope (20.times.) coupled to a spot digital camera and a PC, images were obtained from the flat mounts of the RPE-choroid-sclera from each eye, and the area occupied by hyperfluorescent neovessels within each laser lesion was measured using ImagePro 4 software. To determine the dose required for 50% inhibition (ID.sub.50), the percent inhibition data was plotted as a function of oral dose, using the `best-fit` analysis within MicroSoft Excel software. The ID.sub.50 value was verified visually by using the plotted data (horizontal line from 50% y value, at intersection with best-fit line drop vertical line to x axis (dose). The foregoing description can be employed to practice the present invention, and represents the best mode contemplated. It should not be construed as limiting the overall scope hereof. Rabbit Eye VEGF Permeability Model

Assay used was detailed by Jeffrey Edelman, etc in Exp. Eye. Res. 80(2005), Pg 249- 258. PDGF Stimulated Ca²⁺ Signal in Vitro

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was used to screen for inhibitors of PDGF induced increases in intracellular calcium levels in fluorescent dye loaded endothelial cells. NHDF-Ad (Normal human dermal fibroblasts) (Lonza) were seeded in 384-well fibronectin coated black-walled plates overnight at 37° C/5% CO₂ . Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cells were washed 4 times (ELx405- CW, Bio-Tek) to remove extracellular dye. Test compounds were reconstituted in 100% DMSO and added to the cells to give a final DMSO concentration of 0.1%. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 µM) or at concentrations ranging from 0.001nM to 10 µM followed by PDGF stimulation (10 ng/mL). Changes in fluorescence at 515nm were measured simultaneously in all 384 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for

unstimulated, stimulated, and drug treated samples. IC₅₀ values for test compounds were calculated from % inhibition of PDGF stimulated responses in the absence of inhibitor. Table II and III present the biodata of some of the compounds of the present invention.

Table II: Biodata of Compounds of the Present Invention with Amide Linker

Table III: Biodata of Compounds of the Present Invention with Urea Linker

Urea Linker

Claims

What is claimed is: 1. A compound selected from the group consisting of :

(1’) 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-[3-(2H-tetrazol-5-yl)propyl]-1H-pyrrole-3-carboxamide; (2’) 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-[2-(2H-tetrazol-5-yl)ethyl]-1H-pyrrole-3-carboxamide; (3’) N-(3,3-diethoxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (4’) N-(2-aminoethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (5’) tert-butyl (2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate; (6’) methyl [(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)amino]acetate; (7’) methyl [(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}

amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)amino]acetate; (8’) dimethyl 2,2'-[(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}

amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}ethyl)imino]diacetate; (9’) ethyl [4-(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)piperazin-1- yl]acetate; (10’) ethyl [4-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)piperazin-1- yl]acetate (11’) 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}-1H-pyrrole-3- carboxamide; (12’) 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}-1H-pyrrole-3-carboxamide (13’) methyl rel-(2R,4S)-1-(2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]

carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)-4- hydroxypyrrolidine-2-carboxylate; (14’) 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-(2-oxoethyl)-1H-pyrrole-3-carboxamide; (15’) N-(2,2-diethoxyethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (16’) methyl rel-(2R,4S)-1-(3-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}propyl)-4-hydroxypyrrolidine-2-carboxylate; (17’) 4-methoxy-4-oxobutyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate; (18’) 5-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanoic acid; (19’) ethyl 5-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)

phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanoate; (20’) ethyl 4-(2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)piperazine- 1-carboxylate; (21’) 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)

phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3-carboxamide; (22’) N-(2,2-diethoxyethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (23’) ethyl 4-{3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}piperazine-1- carboxylate; (24’) ethyl 4-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)piperazine- 1-carboxylate; (25’) ethyl 3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoate; (26’) methyl 3-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate; (27’) methyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate; (28’) methyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}

amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate; (29’) 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-(4-hydrazino-4-oxobutyl)-1H-pyrrole-3-carboxamide; (30’) dimethyl 2,2’-({3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl) amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)

amino]propyl}imino)diacetate (31’) dimethyl 2,2’-({2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino] carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}imino) diacetate (32’) methyl ({3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}amino)acetate; (33’) methyl ({2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}amino)acetate; (34’) N-(2-aminoethyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]

carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (35’) tert-butyl {2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}carbamate; (36’) 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-[3-(4-hydroxypiperidin- 1-yl)propyl]-1H-pyrrole-3-carboxamide; (37’) 1-[4-({2-[4-(azetidin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3- (2-fluoro-5-methylphenyl)urea; (38’) 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin- 2-yl]-N-[3-(4-methylpiperazin-1-yl)propyl]-1H-pyrrole-3-carboxamide;

(39’) 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin- 2-yl]-N-(3-pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide; (40’) methyl 1-[3-({[5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2- yl)-1H-pyrrol-3-yl]carbonyl}amino)propyl]pyrrolidine-2-carboxylate; (41’) 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-[3-(4- hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide;

(42’) 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3- oxopropyl)-1H-pyrrole-3-carboxamide; (43’) 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3- piperidin-1-ylpropyl)-1H-pyrrole-3-carboxamide; (44’) 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3- pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide; (45’) 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-[3-(4- methylpiperazin-1-yl)propyl]-1H-pyrrole-3-carboxamide; (46’) 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3- morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide; (47’) N-{3-[(2,3-dihydroxypropyl)(methyl)amino]propyl}-5-{4-[3-fluoro-4-({[(2- fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H- pyrrole-3-carboxamide; (48’) methyl [(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)amino] acetate; (49’) 3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoic acid; (50’) methyl 3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoate; (51’) 3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-2-yl)carbonyl]amino}propanoic acid; (52’) methyl 3-{[(4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-2-yl)carbonyl]amino}propanoate; (53’) N-(3,3-diethoxypropyl)-4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxamide;

(54’) N-(3,3-diethoxypropyl)-4-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-2-carboxamide; (55’) N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy} pyridin-2-yl)-1H-pyrrole-3-carboxamide; (56’) N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino] carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide; (57’) 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}-1H-pyrrole-3- carboxamide; (58’) 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}-1H-pyrrole-3- carboxamide; (59’) 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-N-[3-(4-hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide; (60’) N-(3,3-diethoxypropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (61’) N-(3,3-diethoxypropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (62’) {[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)

phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetic acid; (63’) methyl {[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}acetate; (64’) tert-butyl (3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate; (65’) dimethyl 2,2’-[(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]

carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino} propyl)imino]diacetate; (66’) 2,2’-[(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)

phenoxy]pyridine-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)imino]diacetic acid; (67’) dimethyl 2,2’-[(2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]

carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl) imino]diacetate;

(68’) tert-butyl (2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate; (69’) methyl rel-(2R,4S)-1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino} propyl)-4-hydroxypyrrolidine-2-carboxylate; (71’) {4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazin-1-yl}acetic acid; (72’) ethyl {4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}

amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazin-1-yl}acetate; (73’) 1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2- carboxylic acid; (74’) 1-(2-fluoro-5-methylphenyl)-3-[2-fluoro-4-({2-[4-(piperazin-1-ylcarbonyl)-1H- pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]urea; (75’) N-(2-aminoethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]

carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (76’) N-(3-aminopropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]

carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (77’) tert-butyl 4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazine-1-carboxylate; (78’) 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide; (79’) 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-N-(3-pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide; (80’) 2-methoxyethyl 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate;

(81’) methyl 1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl) pyrrolidine-2-carboxylate; (82’) 3-morpholin-4-ylpropyl 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)

amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate; (83’) dimethyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate; (84’) ethyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate; (85’) dimethyl 2,2’-[(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)imino] diacetate; (86’) 2-methoxyethyl 4-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}butanoate; (87’) 3-hydroxy-2,2-bis(hydroxymethyl)propyl 4-{[(5-{4-[4-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3- yl)carbonyl]amino}butanoate; (88’) N-[3-(4-hydroxypiperidin-1-yl)propyl]-5-{4-[4-({[(3-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (89’) 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- (3-oxopropyl)-1H-pyrrole-3-carboxamide; (90’) N-(3-hydroxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (91’) 1-[4-({2-[4-(hydrazinocarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(3- methylphenyl)urea; (92’) 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N- (3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide; (93’) 3-hydroxy-2,2-bis(hydroxymethyl)propyl 5-{4-[4-({[(3-methylphenyl)amino] carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate; (94’) 1-(2-fluoro-5-methylphenyl)-3-[4-({2-[4-(hydrazinocarbonyl)-1H-pyrrol-2- yl]pyridin-4-yl}oxy)phenyl]urea; (95’) 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin- 2-yl]-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide; (96’) methyl (2S)-1-{3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]

carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl} pyrrolidine-2-carboxylate; (97’) 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin- 2-yl]-N-(3-hydroxypropyl)-1H-pyrrole-3-carboxamide; (98’) ethyl 4-{N-[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]-S-methylsulfonimidoyl} butanoate; (99’) N,N’-diethyl-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanediamide; (101’) 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylic acid; (102’) 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanedioic acid; (103’) dimethyl 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]pentanedioate; (104’) N-(3-aminopropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide; (105’) tert-butyl (3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate; (106’) N-(3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]

carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide; (107’) tert-butyl {3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}carbamate; (108’) 5-[4-(2-fluoro-5-{[(2-fluoro-5- methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-N-(3-morpholin-4- ylpropyl)-1H-pyrrole-3-carboxamide; (109’) 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino] carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoic acid; (110’) tert-butyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl) amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoate; (111’) 5-tert-butoxy-2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino] carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoic acid; (112’) 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoic acid; (113’) methyl 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl} phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate; (114’) ethyl 4-{N-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]-S-methylsulfonimidoyl} butanoate; (115’) methyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl) amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5- oxopentanoate; (116’) 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-methoxy-5-oxopentanoic acid; (117’) N,N’-diethyl-2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanediamide; (118’) 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2- yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid; (119’) tert-butyl 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy} pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoate; (120’) 5-tert-butoxy-2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)- 1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid; (121’) 5-tert-butyl 1-methyl 2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy} pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)pentanedioate; (122’) 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylic acid; (123’) tert-butyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3- carboxylate; (124’) dimethyl 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate; (125’) 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioic acid; (126’) 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-[3-(4-hydroxypiperidin-1-yl)propyl]-1H-pyrrole-3-carboxamide; (127’) 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin- 2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide; (128’) 3-morpholin-4-ylpropyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl} amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate; (129’) 3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2- yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoic acid; (130’) 5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]- 1H-pyrrole-3-carboxylic acid; (131’) methyl 3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy) pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate; (132’) 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy] pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoic acid; and (133’) methyl 3-{[(4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino) phenoxy]pyridin-2-yl}-2-thienyl)carbonyl]amino}propanoate, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a therapeutic effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, wherein the composition comprises tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, eye ointments, eye sprays, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts and depots.

4. A method for the treatment of a disease or condition selected from the group consisting of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization,

neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders in the human being, comprising administering to a mammal in need of such treatment at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, where said disease or condition is selected from the group consisting of: diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, and neovascularization associated with keratoplasty.