CA2517256C - Aminoheteroaryl compounds as protein kinase inhibitors - Google Patents

Aminoheteroaryl compounds as protein kinase inhibitors Download PDF

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CA2517256C
CA2517256C CA2517256A CA2517256A CA2517256C CA 2517256 C CA2517256 C CA 2517256C CA 2517256 A CA2517256 A CA 2517256A CA 2517256 A CA2517256 A CA 2517256A CA 2517256 C CA2517256 C CA 2517256C
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phenyl
amino
pyridin
dichloro
benzyloxy
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CA2517256A1 (en
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Jingrong Cui
Dilip Bhumralkar
Iriny Botrous
Ji Yu Chu
Lee A. Funk
Cathleen Elizabeth Hanau
G. Davis Harris
Lei Jia
Joanne Johnson
Stephen A. Kolodziej
Pei-Pei Kung
Xiaoyuan(Sharon) Li
Jason(Qishen) Lin
Jerry Jialun Meng
Mitchell David Nambu
Christopher G. Nelson
Mason Alan Pairish
Hong Shen
Michelle Tran-Dube
Allison Walter
Fang-Jie Zhang
Jennifer Zhang
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Sugen LLC
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Abstract

Aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use are provided. Preferred compounds of formula 1 have activity as protein kinase inhibitors, including as inhibitors of c-MET.

Description

DEMANDES OU BREVETS VOLUMINEUX

LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional volumes please contact the Canadian Patent Office.

AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS

FIELD OF THE INVENTION
The present invention relates generally to novel chemical compounds and methods. More particularly, the invention provides novel aminoheteroaryl compounds, particularly aminopyridines and aminopyrazines, having protein tyrosine kinase activity, and methods of synthesizing and using such compounds.
BACKGROUND
Protein kinases ("PKs") are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
The PKs can be conveniently broken doyvn into two classes, the. protein tyrosine kinases (PTKs) and the serine-threonine kinases (STIKs).
One of the prime aspects of PT': activity is their involvement with orowih factor receptors.
Growth factor receptors are cell-surface proteins. When bound by a growth factor lioand, growth factor receptors are converted to an active form which interacts with proteins on the inner surface of a cell membrane. This leads to phosphorylation on tyrosine residues of the receptor and other proteins and to the formation inside the cell of complexes with a variety of cytoplasmic signaling molecules that, in turn, effect numerous cellular responses such as cell division (proliferation), cell differentiation, cell growth, expression of metabolic effects to the extracellular mlcroenvironment, etc.
For a more complete discussion, see Schiessinger and Ulirich, Neuron 9:303-391 (1992), Growth factor receptors with PTK activity are known as receptor tyrosine kinases ("RTKs").
They comprise a large family of transmembrane receptors with diverse biological activity. At present, at least nineteen (19) distinct subfamilies of RTKs have been identified. An example of these is the subfamily designated the "HER" RTKs, which include EGFR (epithelial Growth factor receptor), HER2, HER3 and HER4. These RTKs consist of an extracellular glycosylated ligand binding domain,. a transmembrane domain and an intracellular cytoplasmic catalytic domain that can phosphorylate tyrosine residues on proteins.
Another RTK subfamily consists of insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor related receptor (IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-II to form a heterotetramer of two entirely extracellular glycosylated a subunits and two 13 subunits which . cross the cell membrane and which contain the tyrosine kinase domain.
A third RTK subfamily is referred to as the platelet derived growth factor receptor ("PDGFR") group, which includes PDGFRa, PDGFRj3, CSFIR, c-kit and c-fms. These receptors consist of glycosylated extracellular domains composed of variable numbers of immunoglobin-like loops and an =
intracellular domain wherein the tyrosine kinase domain is interrupted by unrelated amino acid sequences.
Another group which, because of its similarity to the POGFR subfamily, is sometimes subsumed into the later group is the fetus liver kinase (ilk") receptor subfamily. This group is believed to be made up of kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), flk-4 and fms-like tyrosine kinase 1 (fit-1).
A further member of the tyrosine kinase growth factor receptor family is the fibroblast growth factor ("FOE") receptor subgroup. This group consists of four receptors, FGFR1-4, and 'seven ligands, FGF1-7. While not yet well defined, it appears that the receptors consist of a g-lycosylated extracellular domain containing a variable number of immunoglobin-like loops and an intracellular domain in which the tyrosine kinase sequence is interrupted by regions of unrelated amino acid sequences.
Still another member of the tyrosine kinase growth factor receptor family is the vascular endothelial growth factor ("VEGF") receptor subgroup. VEGF is a dimeric glycoprotein similar to PDGF
but has different biological functions and target cell specificity in vivo. In particular, VEGF is presently thought to play an essential role is vasculogenesis and anaiogenesis.
Still another member of the tyrosine kinase growth factor receptor family is MET, often referred to as c-Met, also known as human hepatocyte growth factor receptor tyrosine kinase (hHGFR). c-Met is thought to play 2 role in primary tumor growth and metastasis.
A more complete listing of the known RTK subfamilies is described in Plowman et al., OW, 7(6):334-339 (1994), In addition to the RIKs, there also exists a family of entirely intracellular PTKs called "non-receptor tyrosine kinases" or "cellular tyrosine kinases." This latter designation, abbreviated "CTK," will be used herein. CTKs do not contain extracellular and transmembrane domains.
At present, over 24 CTKs In 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack) have been Identified. The Src subfamily appear so far to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2 and Yrk. For a more detailed discussion of CTKs, see Bolen, Oncogene, 8:2025-2031 (1993,) The serine/threonine kinases, STKs, like the CTKs, are predominantly intracellular although there are a few receptor kinases of the STK type. STKs are the most common of the cytosolic kinases;
i.e., kinases that perform their function in that part of the cytoplasm other than the cytoplasmic organelles and cytoskelton. The cytosol is the region within the cell where much of the cell's intermediary metabolic and biosynthetic activity occurs; e.g., it is in the cytosol that proteins are synthesized on ribosomes. The STKs include CDk2, Raf, the ZC family of kinases, the NEK family of kinases, and BUB1.RTKs, CTKs and STKs have all been implicated in a host of pathogenic conditions including, significantly, cancer. Other pathogenic conditions which have been associated with PTKs include, without limitation, psoriasis, hepatic cirrhosis, diabetes, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis and other inflammatory disorders, immunological disorders such as autoimmune disease, cardiovascular disease such as atherosclerosis and a variety of renal disorders.
With regard to cancer, two of the major hypotheses advanced to explain the excessive cellular proliferation that drives tumor development relate to functions known to be PK
regulated. That is, it has been suggested that malignant cell growth results from a breakdown in the mechanisms that control cell division and/or differentiation. It has been shown that the protein products of a number of proto-oncogenes are involved in the signal transduction pathways that regulate cell growth and differentiation.
These protein products of proto-oncogenes include the extracellular growth factors, transmembrane growth factor PTK receptors (RTKs), cytoplasmic PTKs (CTKs) and cytosolic STKs, discussed above.
In view of the apparent link between PK-related cellular activities and wide variety of human disorders, it is no surprise that a great deal of effort is being expended in an attempt to identify ways to modulate PK activity. Some of these have involved biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (U.S. Application Serial No. 4,966,849); soluble receptors and antibodies (Application No. WO 94/10202, Kendall and Thomas, Proc. Nat'l Acad. Sc,, 90:10705-10709 (1994), Kim, et al., Nature, 362:841-844 (1993)); RNA ligands (Jelinek, etal., Biochemistry, 33:10450-56); Taken , at at., Mol. Bio, Cell, 4:358A (1993); Kinsella, et aL, Exp. Cell Res., 199:56-62 (1992); Wright, at al., J. Cellular Phys., 152:448-57) and tyrosine kinase inhibitors ONO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Patent No. 5,330,992;
Mariani, etal., Proc. Am. Assoc. Cancer Res., 35:2268 (1994)).
In addition to the above, attempts have been made to identify small molecules which act as PK
inhibitors. For example, bis-monocylic, bicyclic and heterocyclic aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808) and 1-cyclopropy1-4-pyridylquinolones (U.S. Patent No. 5,330,992) have been described as tyrosine kinase inhibitors. Styryl compounds (U.S. Patent No.
5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,302,606), quinazoline derivatives (EP Application No. 0 566 266 Al), selenaindoles and selenides (PCT WO
94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO
91/15495) have all been described as PTK inhibitors useful in the treatment of cancer.
SUMMARY
In one embodiment, the invention provides a compound of formula 1 Y

A

wherein:
Y is N or CR12;

R1 is selected from C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl, 3-12 membered heteroalicyclic, -0(CR6R7)õR4, -C(0)R4, -C(0)0R4, -CN, -NO2, -S(0)mR4, -S02NR4R5, -C(0)NR4R5, -NR4C(0)R5, -C(=NR6)NR4R5, C1.8 alkyl, C2-8 alkenyl, and C2-8 alkynyl; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R2 is hydrogen, halogen, C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C3-12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)r,,R4, -SO2NR4R5, -S(0)20R4, -NO2, -NR4R5, -(CR6R7)OR4, -ON, -C(0)R4, -0C(0)R4, -0(CR6R7)nR4, -NR4C(0)W, -(CR6R7)nC(0)0R4, -(CR6R7)nNCR4R6, -C(=NR6)NR4R5, -NR4C(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5, and each hydrogen in R2 is optionally substituted by one or more R8 groups;
R3 is halogen, C1_12 alkyl, C2.12 alkenyl, C2.12 alkynyl, C3_12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -SO2NR4R5, -S(0)20R4, -NO2, -NR4R6, -(CR6R7)n0R4, -ON, -C(0)R4, -0C(0)R4, -0(CR6R7)nR4, -NR4C(0)R6, -(CR6R7),C(0)0R4, -(CR6R7)õNCR4R6, -C(=NR6)NR4R5, -NR4C(0)NR8R6, -NR4S(0)pR6 or -C(0)NR4R5, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a CG-12 aryl, 5-12 membered heteroaryl, 03_12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, RG, R6 and R7 is independently hydrogen, halogen, 01_12 alkyl, C2_12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, 0, and S;
or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, RG, RG and R7 is optionally substituted by one or more R8 groups;
each R8 is independently halogen, C1_12 alkyl, C2-12 alkenyl, C2.12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -ON, -0-C112 alkyl, -0-(CH2)nC3-12 cycloalkyl, -0-(CH2)nC6_12 aryl, -0-(CH2)(3-12 membered heteroalicyclic) or -0-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
A1 is -(CR9R19)n-A2 except that:
(i) when Y is N and R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, A1 is -(CR9K ) A2 and n is not zero; and (ii) when Y is N and R2 is H and A1 is m-chlorobenzyl, al is not unsubstituted piperazine;
each R9 and R19 is independently hydrogen, halogen, 01_12 alkyl, 03-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0),,R4, -SO2NR4R5, -S(0)20R4, -NO2, -NR4R6, -(CR6R7)n0R4, -ON, -C(0)R4, -0C(0)R4, -NR4C(0)R5, -(CR6R7)nC(0)0R4, -(CR6R7)nNCR4R5, -NR4C(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5; R9 and R1 may combine to form a C3-12 cycloalkyl, 3-12 membered heteroalicyclic, 06-12 aryl or 5-12 membered heteroaryl ring; and each hydrogen in R9 and R1 is optionally substituted by one or more R3 groups;

A2 is C6-12 aryl, 6-12 membered heteroaryl, 0342 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups;
each R11 is independently halogen, C1..12 alkyl, C1..12 alkoxy, C3-12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-0142 alkyl, -0-(CH2)1103.12 cycloalkyl, -0-(CH2)õCs.12 aryl, -0-(CH2)õ(3-12 membered heteroalicyclic), -0-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -01.12 alkyl which may be partially or fully halogenated; -0-C1.12 alkyl which may be partially or fully halogenated, -CO, -SO and -SO2;
R12 is hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, 0242 alkYnyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -SO2NR4R5, -S(0)20114, -NO2, ¨NR4R5, -(CR6R7)OR4, -CN. -q(0)R4, -0C(0)R4, -0(CR6R7)R4, -NR4C(0)R5, -(CR6R7)0C(0)0R4, -(CR8R7)õNCR4R5, -C(=NR8)NR4R5, -NR4C(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5, and each hydrogen In R12 is optionally substituted by one or more R3 groups;
R1 and R2 or R1 and R12 may be combined together to form a C6.12 aryl, 5-12 membered 16 heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
m is 0, jar 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In one aspect of this embodiment, R2 and R12 are each hydrogen.
In a particular aspect of this embodiment, Y is N. In a preferred aspect, R1 is not piperazine. In another preferred aspect, R1 Is not heteroalicyclic.
In another particular aspect of this embodiment, Y is CR12.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, the compound has formula la R'n Rlo y R2 1a A2>4¨o NH2 wherein A2 is C6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, R1 is selected from C6.12 aryl and 5-12 membered heteroaryl, and each hydrogen in R1 is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is selected from Ca.12 cycloalkyl, 3-12 membered heteroalicyclic, -0(CR8R7),,R4, -C(0)R4, -C(0)0R4, -CN, -NO2, -SO2NR4R5 , =
-C(0)NR4R5, -NR4C(0)R5, ^C(=NR6)NR4R5, C1-8 alkyl, C2..8 alkenyl, and C2.8 alkynyl; and each hydrogen in RI is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, A2 is substituted by at least one halogen atom.
6 In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, R2 is .hydrogen, R9 and R19 are independently C14 alkyl, and A2 is phenyl substituted by at least one halogen atom.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of Ri, Ri is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxoiane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazolin.e, pyrazolidine, isoxazole, isothlazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazIne, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups.
in particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, 1141 is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thlomorpholine, pyridazine, pyrimidine, pyrazine, triazine, trithiane or phenyl group, and each hydrogen in 111 is optionally substituted by one or more R3 groups.
In a more particular aspect, R1 is not heteroalicyclic.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of Ri, Ri is a fused ring heteroaryi group, and each hydrogen in Ri is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of Ri, Ri is a -SO2NR4R9 group.
In another embodiment, the invention provides a compound of formula 2 wherein:
R1 is selected from C6.12 aryl, 5-12 membered heteroaryl, C3.12 cycloalkyl, 3-12 membered heteroalicyclic, -0(CR6R7)nR4, -C(0)R4, -C(0)0R4, -CN, -NO2, -S(0)õ,R4, -S02NR4R6, -C(0)NR4R6, -NR4C(o)R5, -c(=NR)NR4R5, C143 alkyl, C2.8 alkenyl, and C2.8 alkynyl; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R2 is hydrogen, halogen, C1-12 alkyl, C2_12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -SO2NR4R5, -S(0)20R4, -NO2, -NR4R5, -(CR6R7)n0R4, -CN, -C(0)R4, -0C(0)R4, -0(CR6R7)nR4, -NR4C(0)R5, -(CR6R7)nC(0)0R4, -(CR6R7)NCR4R5, -C(=NR6)NR4R5, -NR4C(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5, and each hydrogen in R2 is optionally substituted by one or more R8 groups;
R3 is halogen, 01-12 alkyl, C2_12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0),,R4, -S02NR4R5, -S(0)20R4, -NO2, -NR4R5, -(CR6R7)n0R4, -CN, -C(0)R4, -0C(0)R4, -0(CR6R7)nR4, -NR4C(0)R5, -(CR6R7)nC(0)0R4, -(CR6R7)NCR4R5, -C(=NR6)NR4R5, -NR4C(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, 01-12 alkyl, 02_12 alkenyl, 02.12 alkynyl, 03_12 cycloalkyl, 06.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, 0, and S;
or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally substituted by one or more R8 groups;
each R3 is independently halogen, C1_12 alkyl, 02-12 alkenyl, C2_12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -0-C1_12 alkyl, -0-(CH2)nC3-12 cycloalkyl, -0-(CH2)nC6.12 aryl, -0-(CI-12)n(3-12 membered heteroalicyclic) or -0-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
A1 is -(CR9R16)n-A2;
each R9 and R1 is independently hydrogen, halogen, C112 alkyl, 03_12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -SO2NR4R5, -S(0)20R4, -NO2, -NR4R5, -(CR6R7)OR4, -CN, -C(0)R4, -0C(0)R4, -NR4C(0)R5, -(CR6R7)nC(0)0R4, -(CR6R7)NCR4R5, -NR4C(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5; R9 and R1 may combine to form a C3-12 cycloalkyl, 3-12 membered heteroalicyclic, 06-12 aryl or 5-12 membered heteroaryl ring; and each hydrogen in R9 and R1 is optionally substituted by one or more R3 groups;
A2 is 06-12 aryl, 5-12 membered heteroaryl, 03.12 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups;
each R11 is independently halogen, C1_12 alkyl, C1_12 alkoxy, C3_12 cycloalkyl, 06-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C1_12 alkyl, -0-(CH2)nC3_12 cycloalkyl, -0-(CH2)C6_12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), -0-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -0-C1_12 alkyl which may be partially or fully halogenated, -CO, -SO and -S02;
R12 Is hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3.12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -S02NR4R6, -S(0)20R4, -NO2, ¨NR4R6, -(CR6R7)õ0R4, -CN, -C(0)R4, -0C(0)R4, -0(CR6R7)õR4, -NR4C(0)R5, -(CR6R7)0C(0)0R4, = -(CR6R7)õNCR4R6, -C(=NR6)NR4R6, -NR4C(0)NR6116, -NR4S(0)ple or -C(0)NR4R6, and each hydrogen in R12 is optionally substituted by one or more R3 groups;
R1 and R2 or R1 and R12 may be combined together to form a C6.12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In one aspect of this embodiment, R2 and R12 areeach hydrogen.
In a particular aspect of this embodiment, the compound has formula 2a Re R10 1 2a wherein A2 is Ce.12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, R1 is selected from C6-12 aryl and 5-12 membered heteroaryl, and each hydrogen in R1 Is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is selected from C3-12 cycloalkyl, 3-12 membered heteroalicyclic, -0(CR6R7)nR4, -C(0)R4, -C(0)0R4, -CN, -NO2, -SO2NR4R5, -C(0)NR4R5, -NR4C(0)R5, -C(=NR)NR4R6, Ci.8 alkyl, C2..8 alkenyl, and C2-8 alkynyl; and each hydrogen 26 in Ri is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, A2 is substituted by at least one halogen atom.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, R2 is hydrogen, R9 and RID are Independently C1.4 alkyl, and A2 is phenyl substituted by at least one halogen atom.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is a fused ring heteroaryl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is a -SO2NR4R5 group.
In another embodiment, the invention provides a compound of formula 3 A 1 ii N

wherein: NH2 R1 is selected from C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl, 3-12 membered heteroalicyclic, -0(CR6R7)r,R4, -C(0)R4, -C(0)0R4, -CN, -NO2, -S(0)mR4, -S02NR4R5, -C(0)NR4R5, -NR4C(0)R5, -C(=NR6)NR4R5, Ci_3 alkyl, C2_3 alkenyl, and C2_8 alkynyl; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R2 is hydrogen, halogen, C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C3_12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0),R4, -S02NR4R5, -S(0)20R4, -NO2, -NR4R5, -(CR6R7)õ0R4, -CN, -C(0)R4, -0C(0)R4, -o(cR6R7)R4, _NR4C(0)R5, -(CR6R7)nC(0)0R4, -(CR6R)riNCR4R6, -C(=NR6)NR4R6, -NR4C(0)NR6R6, -NR4S(0)pR5 or -C(0)NR4R5, and each hydrogen in R2 is optionally substituted by one or more R8 groups;
R3 is halogen, C1_12 alkyl, C2.12 alkenyl, C2.12 alkynyl, C3_12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -S02NR4R5, -S(0)20R4, -NO2, -NR4R5, -(CR6R7),-OR4, -CN, -C(0)R4, -0C(0)R4, -0(CR6R7)nR4, -NR4C(0)R5, -(CR6R7)C(0)0R4, -(CR6R7),NCR4R5, -C(=NR6)NR4R5, -NR4C(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3_12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, C1_12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, 0, and S;
or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3.12 cycloalkyl, C6-12 aryl, 3-12 =
membered heteroalicyclic or 6-12 membered heteroaryl group; and each hydrogen in R4, R5, R8 and R7 is optionally substituted by one or more R8 groups;
each R8 is independently halogen, C1-12 alkyl, C2..12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C8.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -0-C1_12 alkyl, -0-(CH2)nC3-12 cycloalkyl, -0-(CH2)nCs-12 aryl, -0-(CNOrt(3-12 membered heteroalicyclic) or -0-(CH2)n(5-12 membered heteroaryl); and each hydrogen In R8 is optionally substituted by one or more R11 groups;
A1 is ¨(CR9R19),rA2 except that:
(i) when R1 Is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, Al Is ¨(CR9R19)n-A2 and n Is not zero; and (ii) when R2 is H and A1 is m-chlorobenzyl, R1 Is not unsubstituted piperazine;
each R9 and R19 Is Independently hydrogen, halogen, Cm2 alkyl, C3.12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclic, 6-12 membered heteroaryl, -S(0)õ,R4, -S02NR4R5, -S(0)20R4, -NO2, ¨NR4R5, -(CR8R7)õOR4, -CN, -C(0)R4, -0C(0)R4, -NR4C(0)R5, -(CR8R7)õC(0)0R4, -(CR8R7)nNCR4R5, -NR4C(0)NR5R8, -NR4S(0)pR8 or -C(0)NR4R5; R9 and R19 may combine to form a C3.12 cycloalkyl, 3-12 membered heteroalicyclic, C6-12 aryl or 6-12 membered heteroaryl ring; and each hydrogen In R9 and R19 is optionally substituted by one or more 113 groups;
A2 is C6.12 aryl, 6-12 membered heteroaryl, C342 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups;
each R11 is independently halogen, C1.-12 alkyl, C1-12 alkoxy, C3_12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C1_12 alkyl, -0-(CH2)õC3_i2 cycloalkyl, -0-(CH2)õC6.12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic), -0-(CH2)õ(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -Ci_12 alkyl which may be partially or fully halogenated, -0-C1.12 alkyl which may be partially or fully halogenated, -CO, -SO and -SO2;
26 R1 and R2 may be combined together to form a C6-12 aryl, 5-12 membered heteroaryl, C3_12 cycloalkyl or 3-12 membered heteroalicyclIc group;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In one aspect of this embodiment, R2 and R12 are each hydrogen.

In a particular aspect of this embodiment, the compound has formula 3a 3a 9 Rl N

wherein A2 is C6.12 aryl or 5-12 membered heteroaryl optionally substituted by one or more fe groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, R1 is selected from C6.12 aryl and 5-12 membered heteroaryl, and each hydrogen in R1 is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is selected from C3_12 cycloalkyl, 3-12 membered heteroalicyclic, -0(CR6R7)nR4, -C(0)R4, -C(0)0R4, -CN, -NO2, -S(0)mR4,- -S02NR4R5, -C(0)NR4R5, -NR4C(0)R5, -C(=NR)NR4R5, C143 alkyl, C24 alkenyl, and C243 alkynyl; and each hydrogen in R1 is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, A2 lisubstituted by at least one halogen atom.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment, R2 is hydrogen, R9 and R19 are independently C14 alkyl, and A2 is phenyl substituted by at least one halogen atom.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazollne, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dloxane, morphollne, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is a furan, thlopene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, triazine, trithiane or phenyl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups.
In still more particular aspects, R1 is not heteroalicyc,lic.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is a fused ring heteroaryl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups.
In particular aspects of this embodiment, and in combination with any other particular aspects of this embodiment not inconsistent with the following definition of R1, R1 is a -302NR4R5 group.
In another embodiment, the invention provides a compound of formula 4 Rio 4 wherein:
R1 is selected from C6.12 aryl, 5-12 membered heteroaryl, 03_12 cycloalkyl, 3-12 membered heteroalicyclic, -0(CR8R7)nR4, -C(0)R4, -C(0)0R4, -CN, -NO2, -S(0)mR4, -S02NR4R8, -C(0)NR4R8, -NR4C(0)R8, -C(=NR8)NR4R8, C1.8 alkyl, 02.8 alkenyl, and C2.8 alkynyl; and each hydrogen in R1 is optionally substituted by one or more 1:23 groups;
R3 is halogen, C1-12 alkyl, C2_12 alkenyl, 02_12 alkynyl, C3_12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -S02NR4R8, -S(0)20R4, -NO2, -NR4R5, -(CR6R7)n0R4, -ON, -0(0)R4, -00(0)R4, -0(CR6R7)nR4, -NR4C(0)R5, -(0R6R7)nC(0)0R4, -(CR6R7)nNCR4R5, -0(=NR6)NR4R5, -NR40(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a C6_12 aryl, 5-12 membered heteroaryl, 03.12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, 02-12 alkenyl, 02-12 alkynyl, C3_12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, 0, and S;
or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a 03_12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally substituted by one or more R8 groups;
each R8 is independently halogen, 01.12 alkyl, C2_12 alkenyl, 02_12 alkynyl, C3-12 cycloalkyl, 03.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -ON, -0-01.12 alkyl, -0-(CH2)nC3-e2 cycloalkyl, -0-(CH2)nC6.12 aryl, -0-(CH2)n(3-12 membered heteroalicyclic) or -0-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
each R9 and R1 is independently hydrogen, halogen, 01-12 alkyl, 03_12 cycloalkyl, 06_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -S02NR4R8, -S(0)20R4, -NO2, -NW/R.8, -(CR8R7)n0R4, -ON, -C(0)R4, -0C(0)R4, -NR4C(0)R8, -(CR8R7)C(0)0R4, -(CR8R7)nNCR4R8, -NR4C(0)NR8R6, -NR4S(0)pR8 or -C(0)NR4R8; R9 and R1 may combine to form a 03_12 cycloalkyl, 3-12 membered heteroalicyclic, 06.12 aryl or 5-12 membered heteroaryl ring; and each hydrogen in R9 and R1 is optionally substituted by one or more R3 groups;
A2 is 06.12 aryl, 5-12 membered heteroaryl, 03_12 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups;
each R" is independently halogen, C1_12 alkyl, C1_12 alkoxy, C3-12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C1_12 alkyl, -0-(CH2)C3_12 cycloalkyl, -0-(CH2)nC6.12 aryl, -0-(CH2)(3-12 membered heteroalicyclic), -0-(CH2)n(5-12 membered heteroaryl) or -ON, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -ON, -C1-12 alkyl which may be partially or fully halogenated, -0-C1_12 alkyl which may be partially or fully halogenated, -CO, -SO and -802;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In a particular aspect of this embodiment, A2 is C6_12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups.
In other particular aspects of this embodiment, preferred substituents and groups of substituents include those defined in particular aspects of the previous embodiments.
In another embodiment, the invention provides a compound of formula 5 wherein:
R1 is selected from C6_12 aryl, 5-12 membered heteroaryl, C3_12 cycloalkyl, 3-12 membered heteroalicyclic, -0(CR6R7)R4, C(0) R4, -C(0)0R4, -ON, -NO2, -S(0)mR4, -S02NR4R5, -C(0)NR4R5, -NR4C(0)R5, -C(=NR6)NR4R5, C1.8 alkyl, C2-8 alkenyl, and 02_8 alkynyl; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R3 is halogen, C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C3_12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -SO2NR4R5, -5(0)20R4, -NO2, -NR4R5, -(CR6R7)0R4, -CN, -0(0)R4, -0C(0)R4, -0(CR6R7),R4, -NR4C(0)R5, -(CR6R7)C(0)0R4, -(CR6R7)NCR4R5, -C(=NR6)NR4R5, -NR4C(0)NR5R6, -NR4S(0)pR5 or -C(0)NR4R5, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, 03.12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, 0, and S;
or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R8, R6 and R7 is optionally substituted by one or more R8 groups;
each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3_12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -0-C1.12 alkyl, -0-(CH2)nC3-12 cycloalkyl, -0-(C1-12)nC6-12 aryl, -0-(CH2)(3-12 membered heteroalicyclic) or -0-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
each R9 and R19 is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0),,R4, -S02NR4R6, -S(0)20R4, -NO2, ¨NR4R8, -(CR6R7)OR4, -CN, -C(0)R4, -0C(0)R4, -NR4C(0)R6, -(CR6R7)nC(0)0R4, -(CR6R7)nNCR4R6, -NR4C(0)NR8R6, -NR4S(0)pR8 or -C(0)NR4R8; R9 and R19 may combine to form a C3_12 cycloalkyl, 3-12 membered heteroalicyclic, 06.12 aryl or 5-12 membered heteroaryl ring; and each hydrogen in R9 and R19 is optionally substituted by one or more R3 groups;
A2 is C6.12 aryl, 5-12 membered heteroaryl, C3_12 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups; except that when R2, R9 and R19 are all H and A2 is m-chlorophenyl, R1 is not unsubstituted piperazine;
each R11 is independently halogen, 01.12 alkyl, C1_12 alkoxy, C3_12 cycloalkyl, C6_12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -0-C1-12 alkyl, -0-(CH2)nC3-12 cycloalkyl, -0-(CH2)C6..12 aryl, -0-(01-12)(3-12 membered heteroalicyclic), -0-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -01.12 alkyl which may be partially or fully halogenated, -0-Ci_12 alkyl which may be partially or fully halogenated, -CO, -SO and -SO2, m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In a particular aspect of this embodiment, A2 is C5.12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups.
In other particular aspects of this embodiment, preferred substituents and groups of substituents include those defined in particular aspects of the previous embodiments.
In another embodiment, the invention provides a compound selected from the group consisting of: 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yll-phenol; 3-(2,6-dichloro-benzyloxy)-544-(2-morpholin-4-yl-ethoxy)-pheny1]-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-543-(2-morpholin-4-yl-ethoxy)-pheny1]-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(1H-indo1-4-y1)-pyridin-2-ylamine; 342-chloro-6-(1H-indo1-4-y1)-benzyloxy]-5-(1H-indol-4-y1)-pyridin-2-ylamine; 2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pyrrole-1-carboxylic acid tert-butyl ester; 3-(2,6-dichloro-benzyloxy)-5-(1H-pyrrol-2-y1)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(4-fluoro-pheny1)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(2-fluoro-PhenyI)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-fluoro-pheny1)-pyridin-2-ylamine; 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; N-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pheny1}-methanesulfonamide; N-{446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-acetamide; 3-[6-amino-5-(216-dichloro-benzyloxy)-pyridin-3-yl]-phenol; 3-(2,6-dichloro-benzyloxy)-5-(4-methoxy-phenyI)-pyridin-2-ylamine; 5-(3-amino-phenyI)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-trifluoromethoxy-phenyl)-pyridin-2-ylamine; 2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yI]-phenol; 3-(2,6-dichloro-benzyloxy)-5-(2-phenoxy-phenyI)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3,4-difluoro-pheny1)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-isopropyl-phenyI)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(2-trifluoromethyl-phenyI)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(2-methoxy-pheny1)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine; N-{246-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-methanesulfonamide; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-methanol; 5-benzo[1,3]dioxo1-5-y1-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(2-trifluoromethoxy-pheny1)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-6-(4-methyl-thiophen-2-yI)-pyridin-2-ylamine; 5-(2-benzyloxy-phenyI)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-methoxy-phenyI)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(1H-indo1-2-y1)-pyridin-2-ylamine; 5-(4-benzyloxy-3-fluoro-phenyI)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-benzoic acid; 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yli-N-(2-diethylamino-ethyl)-benzamide; 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-N-(3-diethylamino-propy1)-benzannide; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-(4-methyl-piperazin-1-y1)-methanone; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yll-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yll-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-melhanone; {4-[6-arnino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-(41-pyrrolidin-1-yl-piperidin-1-y1)-methanone; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-pheny1}44-(2-hydroxy-ethyl)-piperidin-1-y1]-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-yll-methanone; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yll-pheny1}-[(3R)-3-dimethylamino-pyrrolidin-1-y1]-methanone; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yll-pheny1}-[(3S)-3-cyclopropylaminonnethyl-piperidin-1-y1]-methanone; 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-N-(2-hydroxy-3-pyrrolidin-1-yl-propy1)-benzamide; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yll-pheny1}-[(2S)-2-(3-fluoro-piperidin-1-ylmethyl)-pyrrolidin-1-yll-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pheny1}-(4-cyclopropyl-piperazin-1-y1)-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-{(2R)-2-[(cyclopropylmethyl-amino)-methyl]-pyrrolidin-1-y1}-methanone; 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yI]-N-cyclopropylmethyl-N-(2R)-pyrrolidin-2-ylmethyl-benzamide; 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-N-(2-hydroxy-3-pyrrolidin-1-yl-propy1)-N-methyl-benzamide; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-{(2S)-2-[(3R)-3-hydroxy-pyrrolidin-1-ylmethyl]-pyrrolidin-1-y1}-methanone; 346-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-benzoic acid; {3-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-nnethanone; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-phenoxy}-acetic acid; 2-{446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yll-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-ethanone;
2-{4-16-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-111]-ethanone; 3-(2,6-dichloro-benzyloxy)-5-(1H-indo1-5-y1)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methy1-1,2,3,6-tetrahydro-pyridin-4-y1)-1H-indo1-5-y1]-pyridin-2-ylamine; 3-(2,6-dich(oro-benzyloxy)-543-(1-methyl-piperidin-4-y1)-1H-indo1-5-y1]-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-morpholin-4-ylmethy1-1H-indo1-5-y1)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-piperidin-1-ylmethy1-1H-indo1-5-y1)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-pyrrolidin-1-ylmethy1-1H-indo1-5-0)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-diethylaminomethy1-1H-indo1-5-y1)-pyridin-2-ylamine; (1-{546-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-1H-indo1-3-ylmethyl}-(3R)-pyrrolidin-3-y1)-carbamic acid tert-butyl ester; 3-(2,6-dichloro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-0]-pyridin-2-ylamine; N-(1-{546-amino-5-(2,6-dich loro-benzyloxy)-pyridin-3-y1]-1H-indo1-3-ylmethy1}-(3R)-pyrrolidin-3-y1)-acetamide; 1-(4-{546-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-1H-indo1-3-ylmethyl}-piperazin-1-y1)-ethanone; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(1H-indo1-5-y1)-pyridin-2-ylamine; 1-(4-{546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y11-1H-indo1-3-ylmethyl}-piperazin-1-y1)-ethanone; 3-(2-chloro-316-difluoro-benzyloxy)-543-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indo1-5-y11-pyridin-2-ylamine; N-(1-{546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-1 H-Ind ol-3-ylmeth y1}-(3 ,S)-pyrrol id i n-3-y1)-a cetamid e; 3-(2-chl oro-3,6-d ifl uoro-benzyl oxy)-5-(3-pi perid in-1-ylmethy1-1H-indo1-511)-pyridin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indo1-5-y1)-pyridin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-ylmethy1-1H-indol-5-y1)-pyridin-2-ylamine; 546-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-1H-indole-2-carboxylic acid ethyl ester; 546-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-1H-indole-2-carboxylic acid; (546-amino-5-(2,6-dich loro-benzylo4)-pyridin-3-y11-1H-indo1-2-y1)-(4-methyl-piperazin-1-y1)-methanone; (5-[6-amino-5-(2,6-dichloro-benayloxy)-pyridin-3-y1]-1 H-indo1-2-y1}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone;
{5-16-amino-5-(2,6-dichl oro-benzyloxy)-pyri di n-3-y11-1H-in d o1-2-y1}-[(2 R)-2-pyrrol id in-1-ylmethyl-pyrrolidin-1-yll-methanone; 546-amino-5-(216-dichloro-benzyloxy)-pyridin-3-y1]-IH-indole-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide; 546-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-1H-indole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; (1-{546-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-0]-1H-indole-2-carbonyll--(3S)-pyrrolidin-3-y1)-carbamic acid tert-butyl ester;
{546-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-1H-indo1-2-y1}-[(3S)-3-amino-pyrrolidin-1-yll-methanone; 546-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-01-1H-indole-2-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propy1)-amide;
4-(6-amino-5-benzyloxy-pyridin-3-y1)-phenol; 3-benzyloxy-5-phenyl-pyridin-2-ylamine; 3-(3-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-4-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2,5-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-5-trifluoromethyl-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2,4-dichloro-5-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-3-trifluoromethyl-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(3,4-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 2-(2-amino-5-phenyl-pyridin-3-yloxymethyl)-benzonitrile;
3-(2-chloro-6-fluoro-3-methyl-benzyloxy)-5-phenyl-pyridin-2-ylamine; 5-Phenyl-3-(2,3,6-trifluoro-benzyloxy)-pyridin-2-ylamine; 3-(2,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2,6-difluoro-3-methyl-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(3-chloro-2,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-6-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(3-Fluoro-4-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine; N-[3-(2-amino-5-phenyl-pyridin-3-yloxymethyl)-pheny1]-methanesulfonamide; 544-(2-morpholin-4-yl-ethoxy)-pheny1]-3-(3-nitro-benzyloxy)-pyridin-2-ylamine; 5-[4-(2-morpholin-4-yl-ethoxy)-pheny1]-3-(naphthalen-1-ylmethoxy)-pyridin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-544-(2-morpholin-4-yl-ethoxy)-pheny1]-pyridin-2-ylamine; 2-{2-amino-5-[4-(2-morpholin-4-yl-ethoxy)-pheny1]-pyridin-3-yloxy}-N-(4-isopropyl-pheny1)-2-phenyl-acetannide; 3-(5-chloro-benzo[b]thiophen-3-ylmethoxy)-544-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; {446-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y0-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; {4-[6-amino-5-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-3-yll-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; {4-[6-amino-5-(5-fluoro-2-trifl uorometh yl- benzyloxy)-pyridin-3-yll- ph eny1}-[(2R)-2-pyrrolid in-1-ylmeth yl-pyrrolid in-1-y1]-etha none; (4-{6-amino-541-(2-trifluoromethyl-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y11-methanone; {446-amino-5-(2-bromo-benzyloxy)-pyridin-3-yll-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {446-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y1]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; 4-[6-amino-5-(216-difluoro-benzyloxy)-pyridin-3-y1]-phenol; 3-(2,6-difluoro-benzyloxy)-5-(1H-indo1-4-y1)-pyridin-2-ylamine; 3-(2,6-difluoro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 4-[6-amino-5-(216-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid; {446-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; {4-[6-amino-5-(216-difluoro-benzyloxy)-pyridin-3-yl]-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yll-methanone; {446-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yll-phenoxy}-acetic acid ethyl ester; {446-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yli-phenoxy)-acetic acid; 2-{4-[6-amino-5-(2,6-difluoro-ben2.yloxy)-pyridin-3-yl]-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-ethanone; 2-{446-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-y1]-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-ethanone; 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1]-phenol; 446-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-y1]-phenol; 4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenol; 242-amino-5-(4-hydroxy-pheny1)-pyridin-3-yloxymethyll-benzonitrile; 446-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yll-phenol; 446-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1]-phenol; 446-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-y11-phenol; N-{446-amino-5-(2-cyano-benzyloxy)-pyridin-311]-pheny1}-methanesulfonamide; 2-[2-amino-5-(4-methanesulfonylamino-pheny1)-pyridin-3-yloxymethy1]-benzamide;
2-[2-amino-5-(4-methanesu Ifonyla m ino- pheny1)-pyridin-3-yloxymethyI]- benzoic acid; N-(4-{6-amin o-542-(4-methyl-pipe razine-1-ca rbony1)-b enzyloxyl-pyridin-3-yll-p heny1)-metha nesu Ifonam ide; 2-[2-amino-5-(4-rnethanesulfonylamino-pheny1)-pyridin-3-yloxymethyl]-N-(2-hydroxy-ethyl)-benzamide; 242-arnino-5-(4-methanesulfonylamino-pheny1)-pyridin-3-yloxymethyli-N-isobutyl-benzamide; 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1]-benzoic acid; {4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; {446-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; {446-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-y1]-methanone; {4-[6-a m ino-5-(2-chloro-6-fluoro-benzyloxy)-pyridi n-3-y11-p hen y1}-[(3S)-3-a m ino-pyrrolid in-1-y1]-meth anon e;
(446-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1Fpheny1}-(4-methyl-piperazin-l-y1)-methanone;

1-(4-{446-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1}-benzoy1}-piperazin-1-y1)-ethanone; 446-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1]-N-(2-morpholin-4-yl-ethyl)-benzamide; 446-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1]-N-(3-morpholin-4-yl-propy1)-benzamide; 446-amino-5-(2-chloro-benzyloxy)-pyridin-3-yll-benzoic acid; (446-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1}-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1}-methanone; (446-amino-5-(2-chloro-benzyloxy)-pyridin-3-y11-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yli-methanone; (4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1]-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-y1]-rnethanone;
(4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1]-pheny1}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone;
(446-amino-5-(2-chloro-benzyloxy)-pyridin-3-A-phenyl}-(4-pyrrolidin-1-yl-piperidin-111)-methanone;
(446-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1}-pheny1}-(4-methyl-piperazin-1-y1)-methanone; 1-(4-(446-amino-5-(2-ch(oro-benzyloxy)-pyridin-3-y11-benzoy1}-piperazin-1-y1)-ethanone; 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1]-N-(2-morpholin-4-yl-ethyl)-benzamide; 446-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1]-N-(3-morpholin-4-yl-propyI)-benzamide; 446-amino-5-(2-cyano-benzyloxy)-pyridin-3-yli-benzoic acid; 242-amino-5444(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbony1)-pheny9-pyridin-3-yloxymethy1}-benzonitrile; 2-(2-amino-544-((2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbony1)-phenyl]-pyridin-3-yloxymethy1}-benzonitrile; 2-{2-amino-544-((3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-phenyllpyridin-3-yloxymethyl}-benzonitrile; 2-(2-amino-544-((3S)-3-amino-pyrrolidine-1-carbonyl)-phenyll-pyridin-3-yloxymethyl}-benzonitrile; 2-(2-amino-544-(4-pyrrolidin-1-yl-piperidine-1-carbony1)-phenyll-pyridin-3-yloxymethyI}-benzonitrile; 2-(2-amino-544-(4-methyl-piperazine-1-carbony1)-phenyl]-pyridin-3-yloy,ymethyI}-benzonitrile; 2-044-(4-acetyl-piperazine-1-carbonyl)-phenyl]-2-amino-pyridin-3-yloxymethylybenzonitrile; 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-0]-N-(1-methyl-piperidin-4-y1)-benzamide; 446-amino-5-(2-cyano-benzyloxy)-pyridin-3-y1]-N-(2-morpholin-4-yl-ethyl)-benzamide; 446-amino-5-(2-cyano-benzyloxy)-pyridin-3-yli-N-(3-morpholin-4-yl-propy1)-benzamide; 4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-y1]-benzoic acid; {446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yll-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; {446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-y1j-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y11-methanone; {4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-A-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-y1]-methanone; {446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yli-pheny1}-[(3S)-3-amino-pyrrolidin-1-y1]-methanone; (446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-M-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; {446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yli-pheny1}-(4-methyl-piperazin-1-y1)-methanone; 1-(4-(446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-y1]-benzoy1}-piperazin-1-y1)-ethanone; 446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-y1]-N-(1-methyl-piperidin-4-y1)-benzamide; 446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-y1]-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-y1]-N-(3-morpholin-4-yl-propyI)-benzamide; 446-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-y1]-benzoic acid; (446-amino-5-(2-trifluoromethyl-benzylm)-pyridin-3-yll-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-, pyrrolidin-1-y11-methanone; (4-(6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yli-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (446-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yli-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-yll-methanone; [(3S)-3-amino-pyrrolidin-1-y1}-{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yll-pheny1}-methanone; {4-[6-amino-5-(2-trifl uoromethyl-benzyloxy)-pyridin-3-y1]-pheny1)-(4-pyrro lid in-1-yl-piperidin-111)-methanone; {4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-A-pheny1)-(4-methyl-piperazin-1-y1)-methanone; 1-(4-{446-amino-5-(2-trifluoromethyl-benzylm)-pyridin-3-y1]-benzoy1}-piperazin-1-y1)-ethanone;
4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yll-N-(1-methyl-piperidin-411)-benzamide;
4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;
4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propy1)-benzamide; 446-amino-5-(4-#tert!-butyl-benzyloxy)-pyridin-3-y1]-benzoic acid; {4-[6-amino-5-(4-tett-butyl-benzyloxy)-pyridin-3-y1]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; {4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-pheny1H(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yli-methanone;
{4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-311]-pheny1}-[(3R)-3-dimethylamino-pyrrolidin-1-y1]-methanone; {4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-y1]-pheny1}-(4-methyl-piperazin-1-y1)-methanone; 1-(4-{446-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-y1]-benzoy1}-piperazin-1-y1)-ethanone; 4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-y1]-N-(1-methyl-piperidin-4-y1)-benzamide; 4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yI]-N-(2-morpholin-4-yl-ethyl)-benzamide; 446-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-A-N-(3-morpholin-4-yl-propy1)-benzamide; 446-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-311]-benzoic acid; {4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-i-y1]-methanone; {446-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-y11-pheny1}-[(2s)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yI]-methanone; {4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-yll-methanone; {446-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yI]-pheny1}-[(3S)-3-amino-pyrrolidin-1-ylj-methanone; {446-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yll-pheny1}-(4-methyl-piperazin-1-y1)-methanone; 1-(4-046-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-311]-benzoy1}-piperazin-1-y1)-ethanone; 446-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-M-N-(2-morpholin-4-yl-ethyl)-benzamide; 446-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-y1]-A1-(3-morpholin-4-yl-propy1)-benzamide; 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yli-benzoic acid; {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-311]-phenyl}-(4-methyl-piperazin-1-y1)-methanone; {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yli-phenyll-(4-pyrrolidin-l-yl-piperidin-1-y1)-methanone; {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-(4-amino-piperidin-1-yI)-methanone; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-(3,5-dimethyl-piperazin-1-yI)-methanone; {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yli-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(3R)-3-amino-pyrrolidin-1-y1]-methanone; {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(3S)-3-amino-pyrrolidin-1-y1]-methanone;
446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-N-(1-methyl-piperidin-4-y1)-benzamide; 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-pyrrolidin-1-yl-propy1)-benzamide; 446-amino-5-(2-chloro-316-difluoro-benzyloxy)-pyridin-3-y1]-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-N-(3-morpholin-4-yl-propy1)-benzamide; 346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-benzoic acid; {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1}-pheny1}-(4-methyl-piperazin-1-y1)-methanone;
{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yI]-pheny1}-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-311]-pheny1}-(4-amino-piperidin-1-y1)-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-pheny1}-(315-dimethyl-piperazin-1-y1)-methanone; {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1}-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1}-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-311]-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-y1]-methanone; {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1}-pheny1}-[(3R)-3-amino-pyrrolidin-1-y1]-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-[(3S)-amino-pyrrolidin-1-y1]-methanone; 3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-N-(1-methyl-piperidin-4-y1)-benzamide; 346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-N-(3-pyrrolidin-1-yl-propy1)-benzamide; 346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-N-(2-morpholin-4-yl-ethyl)-benzamide; 3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-A-N-(3-morpholin-4-yl-propy1)-benzamide; N42-(4-acetyl-piperazin-1-y1)-ethy11-3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-benzamide;
3-(2-chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-16-isothiazolidin-2-y1)-pheny1]-pyridin-2-ylamine;
3-(2,6-dichloro-benzyloxy)-544-(1,1-dioxo-126-isothiazolidin-2-y1)-phenyll-pyridin-2-ylamine; 5-[4-(1,1-dioxo-1k6-isothiazolidin-2-y1)-pheny1]-3-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-2-ylamine; 2-diethylamino-ethanesulfonic acid {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-A-phenylyamide;
2-cyclopropylamino-ethanesulfonic acid {446-amino-542-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y11-phenylyamide; 2-Pyrrolidin-1-yl-ethanesulfonic acid {446-amino-5-(2-chloro-3,6-difluoro-benzyloq)-pyridin-3-y1j-pheny1}-amide; 2-(4-hydroxy-piperidin-i-yI)-ethanesulfonic acid {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y11-phenylyamide; 2-morpholin-4-yl-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-phenyl}-amide; 2-Piperidin-1-yl-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1}-phenylyamide; 2-dimethylamino-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-phenylyamide; 2-(4-acetyl-piperazin-1-yI)-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-phenyl}-amide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yli-phenylyamide;
2-[(3R)-3-hydroxy-pyrrolidin-1-yI]-ethanesulfonic acid {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-A-phenylyamide; 2-[(2S)-2-hydroxymethyl-pyrrolidin-1-A-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-phenylyamide; 2-[4-(2-hydroxy-acety1)-piperazin-1-y1]-ethanesulfonic acid {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1}-phenylyamide; 2-(4-acetyl-piperazin-1-y1)-ethanesulfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-phenyl}-amide; 2-Pyrrolidin-1-yl-ethanesulfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-amide; 2-morpholin-4-yl-ethanesulfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-pheny1}-amide; 2-diethylamino-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-A-pheny1}-amide; 2-dimethylamino-ethanesulfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-amide; 2-Piperidin-1-yl-ethanesulfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y11-phenyl}-amide; 2-[(3R)-3-hydroxymethyl-pyrrolidin-1-y1Fethanesulfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-pheny1}-amide; 2-(4-hydroxy-piperidin-1-yI)-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-pheny1}-amide; 2-[4-(2-hydroxy-acetyl)-piperazin-1-y1]-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yli-phenyl}amide; 2-[(3R)-3-hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid {3-(6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-311]-pheny1}-amide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-pheny1}-amide; 2-cyclopropylamino-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-pheny1}-amide; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(2-dimethylaminomethyl-phenyI)-pyridin-2-ylamine; compound with trifluoro-acetic acid; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-yl-pheny1)-pyridin-2-ylamine; compound with trifluoro-acetic acid; N-{446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-phenylymethanesulfonamide; compound with trifluoro-acetic acid;
546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y11-thiophene-2-carboxylic acid; {546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yli-thiophen-2-y1}-(4-methyl-piperazin-1-y1)-methanone; {5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-thiophen-2-y1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y11-methanone; 546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-ylphiophene-2-carboxylic acid (1-methyl-piperidin-4-yI)-amide; {546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y11-thiophen-2-y1)-(3,5-dimethyl-piperazin-1-0)-methanone; 546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-thiophene-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide; {546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-thiophen-2-y1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y1}-benzoic acid;
{446-aminc-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y1]-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y1]-N-(1-methyl-piperidin-4-y1)-benzamide; {446-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yll-pheny1}-(3,5-dimethyl-piperazin-l-y1)-methanone;
{4-(6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y11-pheny1)-(3-dimethylamino-pyrrolidin-1-y1)-methanone; {4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-pheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone; 446-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y11-#N1-(2-morpholin-4-yl-ethyl)-benzamide; {446-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yli-pheny1)-(4-methyl-piperazin-1-y1)-methanone; N42-(4-acetyl-piperazin-111)-ethy1]-4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y1]-benzamide; 2-Piperidin-1-yl-ethanesulfonic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-phenylyamide;
2-(4-hydroxy-piperidin-1y)-ethanesulfonic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-amide; 2-dimethylamino-ethanesulfonic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-amide; 2-cyclopropylamino-ethanesulfonic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-amide; 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-benzoic acid; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrro(idin-1-y1)-methanone; 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-N-(1-methyl-piperidin-4-y1)-benzamide; (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-phenyl)-[(3R)-3-amino-pyrrolidin-1-y1)]-methanone;
(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-yI)-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-(4-methyl-piperazin-1-y1)-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-(3,5-dimethyl-piperazin-1-y1)-methanone; 2-cyclopropylamino-ethanesulfonic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-amide; 2-dimethylamino-ethanesulfonic acid (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-amide;
2-[(3R)-3-hydroxy-pyrrolidin-1-y1)]-ethanesulfonic acid (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-amide; and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another embodiment, the invention provides a compound selected from the group consisting of: 4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenol; 3-(2,6-dichloro-benzyloxy)-5-[4-(1,1-dioxo-126-isothiazolidin-2-y1)-phenyll-pyrazin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-543-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-544-(2-morpholin-4-yl-ethoxy)-pheny1]-pyrazin-2-ylamine; 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine; 445-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yll-benzoic acid; {445-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yli-phenyI}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-y1]-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 2-morpholin-4-yl-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-amide;
2-piperidin-1-yl-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-amide; 2-(4-Hydroxy-piperidin-1-y1)-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y11-phenyl}-amide; 2-pyrrolidin-1-yl-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-phenylyamide; 2-[(3R)-3-Hydroxy-pyrrolidin-1-yll-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylypheny1}-amide; 2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yli-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-amide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-dimethylamino-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yI]-phenyll-amide; 2-diethylamino-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-phenylyamide; 2-(4-acetyl-piperazin-1-yI)-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-amide;
2-[4-(2-Hydroxy-acety1)-piperazin-1-y1]-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-amide; 2-cyclopropylamino-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyll-amide; 2-[(3R)-3-Hydroxymethyl-pyrrolidin-1-yll-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-phenylyamide; 2-(4-Hydroxy-piperidin-1-yI)-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y11-phenylyamide; 2-(4-acetyl-piperazin-1-y1)-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-A-pheny1}-amide; 2-piperidin-1-yl-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-pheny1}-amide; 2-diethylamino-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-phenylyamide; 2-morpholin-4-yl-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-amide; 2-pyrrolidin-1-yl-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yli-phenylyamide; 2-dimethylamino-ethanesulfonic acid {3-[5-amino-6-(2-chloro-- 23 -3,6-difluoro-benzyloxy)-pyrazin-2-A-phenylyamide;
2-[4-(2-Hydroxy-acetyI)-piperazin-1-y1]-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-phenylyamide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yli-phenyll-amide; 2-[(3R)-3-Hydroxy-pyrrolidin-1-0]-ethanesulfonic acid {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide; 2-cyclopropylamino-ethanesulfonic acid {345-amino-6-(2-chloro-316-difluoro-benzyloxy)-pyrazin-2-A-phenyll-amide;
445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yli-benzoic acid; {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone;
445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;
(445-a mino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2111-pheny1}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone; N-[2-(4-acetyl-piperazin-1-y1)-ethyl]-445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yli-benzamide; 4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-propy1)-benzamide; {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y11-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-y1]-methanone;
{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-[(3R)-3-dimethylamino-pyrrolidin-1-ylj-methanone; {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1)-(3,5-dimethyl-piperazin-1-yI)-methanone; {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-0)-methanone; 445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-N-(3-morpholin-4-yl-propy1)-benzamide; 4-[5-amino-5-(2-chloro-316-difluoro-benzyloxy)-pyrazin-2-A-N-(1-methyl-piperidin-4-y1)-benzamide; 445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-03-N-(2-morpholin-411-ethyl)-benzamide; {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yli-pheny1}-(4-methyl-piperazin-1-y1)-methanone; 345-amino-6-(2-chloro-3,6-difluoro-benzyloyq)-pyrazin-2-y11-benzoic acid; {345-amino-6-(2-chloro-3,6-difluoro-bem-yloxy)-pyrazin-2-yli-pheny1}-0-meihyl-piperazin-1-y1)-methanone; {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yli-phany1}-[(3R)-3-amino-pyrrolidin-1-y11-methanone; (345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone; {345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-(3,5-dimethyl-piperazin-1-y1)-methanone; 3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-N-(3-morpholin-4-yl-propy1)-benzamide; {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-pheny1}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;
3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-211]-N-(1-methyl-piperidin-4-y1)-benzamide;
(345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y11-pheny1}-[(2S)-pyrrolidin-1-ylmethyl-Pyrrolidin-111]-methanone; 345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-A-N-(2-morpholin-4-yl-ethyl)-benzamide; N-[2-(4-acetyl-piperazin-1-y1)-ethy1]-345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1)-benzamide; 3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-N-(3-pyrrolidin-111-propy1)-benzamide; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(1H-indo1-5-y1)-pyrazin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-ylmethy1-1H-indo1-5-y1)-pyrazin-2-ylamine;
3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-diethylaminomethy1-1H-indo1-5-y1)-pyrazin-2-ylarnine;
1-(4-{545-amino-6-(2-chloro-3,6-dif(uoro-benzyloxy)-pyrazin-2-y1]-1H-indo1-3-ylmethy1}-piperazin-1-y1)-ethanone;
3-(2-chloro-3,6-difluoro-benzyloxy)-543-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indo1-511]-pyrazin-2-ylamine; N-(1-{545-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-1H-indo1-3-ylmethy1}-(3S)-pyrrolidin-3-y1)-acetamide; 3-(2-chloro-3,6-difluoro-benzyloxy)-543-piperidin-1-yimethyl-1H-indol-5-y1)-pyrazin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-543-morpholin-4-ylmethy1-1H-indo1-5-y1)-pyrazin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-pheny1)-2-methyl-propoxy]-544-(2-morpholin-4-yl-ethoxy)-phenyn-pyrazin-2-ylamine; 341-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-544-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine; compound with trifluoro-acetic acid; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-544-(2-morpholin-4-yl-ethoxy)-phenylFpyrazin-2-ylamine; compound with trifluoro-acetic acid; N-(4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-methanesulfonamide; 2-pyrrolidin-1-yl-ethanesulfonic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-pheny1)-amide; 2-(4-Hydroxy-piperidin-1-y1)-ethanesulfonic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-phenylyamide; 2-piperidin-1-yl-ethanesulfordc acid (4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxylpyrazin-2-y1}-pheny1)-amide; 2-(cycloPropylmethyl-amino)-ethanesulfonic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-pheny1)-amide;
2-[(3R)-3-Hydroxy-pyrrolidin-1-y1]-ethanesulfonic acid (445-amino-641-(2-chloro-316-difluoro-pheny1)-ethoxy]-pyrazin-2-y1)-pheny1)-amide;
2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-y1]-ethanesulfonic acid (4-{5-amino-611-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-pheny0-amide; 2-dimethylamino-ethanesulfonic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-amide; 2-morpholin-4-yl-ethanesulfonic acid (4-{5-amino-641 -(2-chloro-3,6-difluoro-pheny1)-ethoxylpyrazin-2-y1}-pheny1)-amide; 2-diethylamino-ethanesulfonic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-amide;
2-cyclopropylamino-ethanesulfanic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-amide; 3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid;
(3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-phenyl)-[(3S)-3-amino-pyrrolidin-1-yI)-m-ethanone; (3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-phenyl)-[(3R)-3-amino-pyrrolidin-1-yI)-m-ethanone; (3-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; N42-(4-acetyl-piperazin-1-y1)-ethy1]-3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-benzamide;
(3-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-y1}-pheny1)-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-l-y1)-methanone; 3-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-benzoic acid; 3-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-y1}-N-(1-methyl-piperidin-4-y1)-benzamide; 3-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-y1}-N-(3-pyrrolidin-1-yl-propy1)-benzamide;
(3-{5-amino-6-[I-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yI)-methanone; 445-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yli-benzoic acid; 445-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-y1]-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-A-N-(1-methyl-piperidin-4-y1)-benzamide; and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another embodiment, the invention provides a compound selected from the group consisting of: (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-(4-methyl-piperazin-1-y1)-methanone; N42-(4-acetyl-piperazin-l-y1)-ethyl]-4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-yll-benzamide; 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy}-pyridin-3-y1}-N-(3-pyrrolidin-1-yl-propyI)-benzamide; 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy}-pyridin-3-y1}-pheny1)-((S)-3-amino-pyrrolidin-1-y1)-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyy pyridin-3-y1}-phenyl)-((R)-3-amino-pyrrolidin-1-y1)-methanone;
(4-{6-amino-5-[1 -(2 ,6-dichloro-3-fluoro-pheny1)-ethoxy}-pyridin-3-y1}-pheny1)-(4-amino-piperidi n-1-yI)-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-((S)-3-hydroxy-pyrrolidin-111)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-phenyl)-((R)-3-hydroxy-pyrrolidin-1-y1)-methanone;
(4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-((R)-2-hydroxymethyl-pyrrolidin-1-yI)-methanone; 4-{6-amino-541-(2 , 6-d ichloro-3-fluoro-phenyl)-ethoxy}-pyrid in-3-yI}-N-(2-diethyla mi no-ethyl)- benza mide ; 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;
3-{6-amino-5-0-(2,6-dichloro-3-fluoro-phenyl)-ethoxylpyridin-3-y1}-benzoic acid; (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-(4-methyl-piperazin-1-y1)-methanone; 3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-N-(1-methyl-piperidin-4-yI)-benzamide; (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; N-[2-(4-acetyl-piperazin-1-y1)-ethy1]-3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-benzamide;

(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-Oridin-3-y1}-pheny1)-((S)-3-amino-pyrrolidin-1-y1)-methanone;
3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-N-(3-morpholin-4-yl-propy1)-benzamide;
(3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy}-pyridin-3-y1}-Pheny1)-((R)-2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; 3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-{6-amino-541-(2,6-dichloro-3-1iuoro-phenyl)-ethoxy]-pyridin-3-y1}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide; (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 2-diethylamino-ethanesulfonic acid (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-Phenylyamide;

2-(4-Hydroxy-piperidin-1-yI)-ethanesulfonic acid (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-amide;
2-piperidin-1-yl-ethanesulfonic acid (4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-pheny1)-amide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid (4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy}-pyridin-3-y1}-phenyl)-amide; 2-((R)-3-Hydroxy-pyrrolidin-1-yI)-ethanesulfonic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-y1}-pheny1)-amide;

2-cyclopropylamino-ethanesulfonic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-amide;
2-diethylamino-ethanesulfonic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-phenylyamide; 4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-Pyridin-311}-benzoic acid; 4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-N-(2-morPholin-411-ethyl)-benzamide; 4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxylpyridin-3-y1}-N-(1-methyl-PiPeridin-411)-benzamide;
(4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-y1}-pheny1)-((R)-2-pyrrolidin-1-ylmethyl-= pyrrolidin-1-y1)-methanone; (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenylyethoxy]-pyridin-3-y1}-pheny1)-((R)-3-amino-pyrrolidin-1-y1)-methanone; (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy}-pyridin-- 26 -3-y1}-pheny1)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone;
4-{6-amino-5-0 -(2-chloro-3,6-difluoro-pheny1)-ethoxyi-pyridin-3-y1}-N-(3-pyrrolidin-1-yl-propy1)-benzamide; (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-(4-methyl-piperazin-1-y1)-methanone; (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy}-pyridin-3-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; (4-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-((S)-3-amino-pyrrolidin-1-y1)-methanone; 3-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-benzoic acid; (3-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-((3R,5S)-3,5-dimethyl-piperazin-1-yI)-methanone; (3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyI)-ethoxy]-pyridin-3-y1}-pheny1)-((R)-3-amino-pyrrolidin-1-y1)-methanone; 3-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-N-(1-methyl-piperidin-4-y1)-benzamide;
(3-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-(4-methyl-piperazin-1-y1)-methanone; 3-{6-amino-5-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-3-y1}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; (3-{6-amino--(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-((S)-3-amino-pyrrolidin-1-y1)-methanone;
3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-N-(2-morpholin-4-yl-ethyl)-benzarnide; (3-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyI)-ethoxy]-pyridin-3-y1}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone;
341-(2-chloro-3,6-difluoro-pheny1)-ethoxy1-544-(2-morpholin-4-yl-ethoxy)-phenyll-pyridin-2-ylamine;
-(2-chloro-3,6-difluoro-phenyl)-ethoxy1-543-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;
341-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-544-(2-pyrrolidin-1 -yl-ethoxy)-phenyl]-pyridin-2-ylamine;
341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-{442-(1-methyl-pyrrolidin-2-y1)-ethoxy]-pheny1}-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-544-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-543-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenoxy)-3-morpholin-4-yl-propan-2-ol; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-544-(2-diethylamino-ethoxy)-pheny1]-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-544-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-544-(2-diisopropylamino-ethoxy)-pheny1]-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-544-(1-methyl-piperidin-4-yloxy)-pheny1]-pyridin-2-ylamine; N-(4-{6-amino-5-[1 -(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-methanesulfonamide; 341-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-544-(1,1-dioxo-llambda*6*-isothiazolidin-2-y1)-pheny1]-pyridin-2-ylamine; N-(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-phenyly methanesulfonamide; -(2,6-dichloro-3-fluoro-phenyI)-ethoxy]-5-phenyl-pyridin-2-ylamine; N-(4-{6-amino-5-[(R)-1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-y1}-pheny1)-methanesulfonamide; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-thiophen-3-yl-pyridin-2-ylamine; 5-benzo[b]thiophen-2-y1-341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 4-methyl-piperazine-1 -carboxylic acid (4-{6-amino-5-[l -(2,6-dichloro-3-fluoro-pheny1)-ethoxy}-pyridin-3-y1}-phenylyamide;
1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 1-(4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-3-(2-hydroxy-ethyl)-urea; 1-(4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea; (R)-3-amino-pyrrolidine-1-carboxylic acid (4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-amide; (S)-3-amino-pyrrolidine-1-carboxylic acid (4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-amide; 1-(4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylyphenyl)-3-(1-methyl-piperidin-4-y1)-urea; 1-(4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yll-phenyl)-3-(1-methyl-piperidin-4-y1)-urea; (R)-3-amino-pyrrolidine-1-carboxylic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxylpyridin-3-y1}-phenylyamide;
(S)-3-amino-pyrrolidine-1-carboxylic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-amide; 1-(4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-3-(2-hydroxy-ethyl)-urea; 4-methyl-piperazine-1-carboxylic acid (4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-y1}-phenyl)-amide; 1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1)-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (4-{6-amino-5-0-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-y1}-pheny1)-amide; 3-{6-amino-541-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-benzoic acid; (3-{6-amino-541-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone; (3-{6-amino-541-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-y1}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone;
-(2,6-dichioro-3-{6-amino-5-[1-(2,6-dichloro-phany1)-ethoxy]-pyridin-3-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide; (3-{6-amino-5-[1-(2,6-dichloro-pheny1)-ethoxA-pyridin-3-y1}-phany1)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; 3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-N-(3-pyrrolidin-1-yl-propy1)-benzamide; N42-(4-acetyl-piperazin-1-y1)-ethyl]-3-{6-amino-541-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-benzamide; 3-{6-amino-541-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-y1)-N-(1-methyl-piperidin-4-y1)-benzamide; (3-{6-amino-541-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-(4-methyl-piperazin-1-y1)-methanone; (3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (3-{6-amino-541-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-((S)-3-amino-pyrrolidin-1-y1)-methanone; (3-{6-amino-541-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-y1}-phenyl)-((R)-3-amino-pyrrolidin-1-yI)-methanone; 4-{6-amino-5-0-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-y1}-benzoic acid; 4-{6-amino-5-0 -(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-y1}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 4-{6-amino-5-0-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide; (4-{6-amino-541-(2,6-dichloro-pheny1)-ethoxy]-pyridin-3-y1}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; 4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-N-(1-methyl-piperidin-4-y1)-benzamide; (4-{6-amino-541-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone; N42-(4-acetyl-piperazin-1-y1)-ethyl]-4-{6-amino-541-(2,6-dichloro-pheny1)-ethoxy]-pyridin-3-y1}-benzamide; 4-{6-amino-541-(2,6-dichloro-pheny1)-ethoxyl-pyridin-3-yll-N-(3-pyrrolidin-1-yl-propyI)-benzannide; (4-{6-amino-5-[I-(2,6-dichloro-pheny1)-ethoxy]-pyridin-3-y1}-phenyl)-((S)-3-aminopyrrolidin-1-y1)-methanone; (4-{6-amino-541-(2,6-dichloro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1X(R)-3-amino-pyrrolidin-1-y1)-methanone; (4-{6-amino-541-(2,6-dichloro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone;
(4-{6-amino-541-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-111)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-(4-methyl-piperazin-111)-methanone; (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-prop-2-yny1)-amide; 4-methyl-piperazine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-prop-2-yny1)-amide; 4-pyrrolidin-1-yl-piperidine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-prop-2-ynylyamide; (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-prop-2-ynyI)-amide; 1-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-prop-2-yny1)-3-(1-methyl-piperidin-4-y1)-urea; 1-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-proP-2-yny1)-3-(3-pyrrolidin-1-yl-propyl)-urea; 1-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyi-pyridin-3-yll-prop-2-yny1)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 1-(3-{6-a m in o-541 -(2 ,6-dichloro-3-fluoro-phenyl)-ethoxy}-pyridin-3-y1}-prop-2-yny1)-3-(2-morpholin-4-yl-ethyl)-urea;
1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy}-pyridin-3-y1}-prop-2-yny1)-3-(3-morPholin-411-Propyl)-urea; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyi-pyridin-3-y1}-prop-2-yny1)-amide; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-dimethylamino-prop-1-yny1)-pyridin-2-ylamine; (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-Prop-2-ynylyurea; N-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-311}-prop-2-m1)-2-piperidin-1-yl-acetamide; N-(3-{6-amino-5-0-(2,6-dichloro-3-fluoro-phenylyethoxy]-pyridin-3-y1}-proP-2-yny1)-2-morpholin-4-yl-acetamide; N-(3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-311}-prop-2-yny1)-2-pyrrolidin-1-yl-acetamide; N-(3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy}-pyridin-3-y1}-prop-2-yny1)-2-((R)-3-hydroxy-pyrrolidin-1-y1)-acetamide; N-(3-{6-amino-541-(2,6-dichloro-3-5-[1 fluoro-phenyl)-ethoxylpyridin-3-y1}-prop-2-yny1)-2-(4-hydroxy-PiPeridin-111)-acetamide; N-(3-{6-amino- N-(3-{6-amino-5-[1 2-(4-acetyl-piperazi n-1-y1)-N-(3-{6-a min o-5-[1-(2 ,6-dichloro-3-fluoro-ph enyl)-ethoxylpyridin-3-y1}-prop-2-yn y1)-acetamide; 4-methyl-piperazine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-1,1-dimethyl-prop-2-ynyl)-amide; (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy)-pyridin-311}-1,1-dimethyl-ProP-2-ynylyamide;
(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-1,1-dimethyl-prop-2-ynylyamide; (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-311}-1,1-dimethyl-prop-2-yny1)-amide; 1-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-311}-1,1-dimethyl-Prop-2-yny1)-3-(2-morpholin-4-yl-ethyl)-urea; 1-(3-{6-amino-5-0-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-1,1-dimethyl-prop-2-yny1)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 4-pyrrolidin-1-yl-piperidine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-1,1-dimethyl-Prop-2-yny1)-amide; 3-{6-amino-5-0 -(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-311}-proPynoic acid cyclohexylamide; 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-Phenyl)ethoxy]-pyridin-3-y1}-Prommoic acid isopropylamide; 4-(3-amino-3-methyl-but-1-yny1)-241-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-phenylamine; (4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-(4-methyl-piperazin-1-y1)-methanone; (4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-pheny1)-ethoxy]-pyridin-3111-pheny1)-(4-pyrrolidin-1-yl-piperidin-1yI)-methanone; (4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-y1}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yI)-methanone; (4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (4-{6-amino-541-(3-fl uoro-2-trifl uoromethyl-phenyl)-ethoxyl-pyrid in-3-yI}-ph enylX(R)-2-pyrrol idi n-1-y1 m ethyl-pyrrol id i n-1-yI)-methanone; 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-y1}-N-(1-methyl-piperidin-4-yI)-benzamide; 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-pheny1)-ethoxyl-pyridin-3-y1}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-yll-N-(3-pyrrolidin-1-yl-propyI)-benzamide; 4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-pheny1)-ethoxy]-pyridin-3-y1}-N-(3-morpholin-4-yl-propy1)-benzamide; 6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile; 6-amino-541-(2,6-dichloro-3-cyano-phenyl)-ethoxy]-nicotinonitrile; 5-aminomethy1-341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid {6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethy1}-amide; N-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-ylmethylymethanesulfonamide;
N-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethy1}-acetamide; N-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-ylmethy1}-4-methyl-benzenesulfonamide; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine; (S)-1-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-ethane-1,2-diol; (R)-1-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-ethane-i ,2-diol; 341-(2,6-diohloro-3-fluoro-pheny1)-ethoxy]-5-(1 Fl-pyrazol-4-y1)-pyridin-2-yla mine; 341-(2,6-dichloro-3-iluoro-phenyl)-ethoxy]-541-(2-pyrrolidin-1 -yl-ethyl)-1H-pyrazol-4-y11-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-541-(2-diisopropylamino-ethyl)-1H-pyrazol-4-y1]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-541-(2-morpholin-411-ethyl)-1H-pyrazol-4-y1]-pyridin-2-ylamine; 5-bromo-3-(3-fluoro-2-methoxy-benzyloxy)-pyridin-2-ylamine; 5-bromo-341-(3-fluoro-2-methoxy-pheny1)-ethoxyl-pyridin-2-ylamine; {4-[6-amino-5-(3-fluoro-2-methoxy-benzyloxy)-pyridin-3-yl]-pheny1H(3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone; (4-{6-amino-541-(3-fluoro-2-methoxy-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-((3R,5S)-3,5-dimethyl-piPerazin-1-y1)-methanone; 5-bromo-3-(3-fluoro-2-isopropoxy-benzyloxy)-pyridin-2-ylamine; {446-amino-5-(3-fluoro-2-isopropoxy-benzyloxy)-pyridin-3-yn-phenylH(3R,5S)-3,5-dimethyl-piperazin-111)-methanone;
5-(4-amino-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-phenoxy)-acetic acid methyl ester; (446-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-phenoxy)-acetic acid; 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyI)-ethoxy]-pyridin-3-y1}-phenoxy)-1-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-ethanone; 2-(4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-phenoxy)-1-((R)-3-hydroxy-pyrrolidin-1-y1)-ethanone;
4-[2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenoxy)-acetyli-piperazine-1-carboxylic acid tert-butyl ester; 2-(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethonl-Pyridin-3-y1}-phenoxy)-1-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-ethanone; 5-bromo-3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-2-ylamine; {446-amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-y11-pheny1H(3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone; 3-(3-fluoro-6,7, 8, 9-tetra hyd ro-5 H-benzocyclohepten-5-yloxy)-5-[4-(2-pyrrolidi n-l-yl-ethoxy)-phenyl]-pyridin-2-ylamine; N-{4-[6-amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-p henyI}-methan esu Ifonam ide; 3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-(1H-pyrazol-4-y1)-pyridin-2-ylamine; 5-bromo-341-(2-chloro-3-fluoro-pheny1)-ethoxy]-pyridin-2-ylamine; 341-(2-chloro-3-fluoro-phenyl)-ethoxy]-544-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 5'-benzyloxy-[2,31]bipyridiny1-6'-ylamine; 5-benzyloxy-[3,31bipyridiny1-6-ylamine; 3-benzyloxy-5-pyrimidin-5-yl-pyridin-2-ylamine; 5-benzyloxy-[3,31bipyridiny1-6,6'-diamine; 5'-(2-chloro-benzyloxy)-[2,31bipyridinyl-6'-ylamine;
5-(2-chloro-benzyloxy)43,31bipyridiny1-6-ylamine; 3-(2-chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine; 5-(2-chloro-benzyloxy)43,31]bipyridinyl-6,6'-diamine; 5'-(4-chloro-benzyloxy)42,31bipyridinyl-6'-ylamine; 5-(4-chloro-benzyloxy)-[3,31bipyridiny1-6-ylamine; 3-(4-chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine; 5-(4-chloro-benzyloxy)43,3pipyridiny1-6,6'-diamine;
5'-(2-chloro-3,6-difluoro-benzyloxy)42,31bipyridiny1-6'-ylamine; 5-(2-chloro-3,6-difluoro-benzyloxy)-13,31bipyridiny1-6-ylamine; 5-(2-chloro-3,6-difluoro-benzyloxy)43,41bipyridiny1-6-ylamine; 3-(2-chloro3,6-difluoro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine; 5-(2-chloro-3,6-difluoro-benzyloxy)43,31bipyridiny1-6,6'-diamine; 5'-(2,6-dichloro-benzyloxy)42,3]bipyridiny1-6'-ylamine; 5-(2,6-dichloro-benzyloxy)43,311bipyridinyl-6-ylamine; 5-(2,6-dichloro-benzyloxy)-(3,41bipyridiny1-6-ylamine; 3-(2,6-dichloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine; 5-(2,6-dichloro-benzyloxy)43,31bipyridiny1-6,6'-diamine; 541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-[3,3lbipyridiny1-6,6'-diamine; {6'-amino-5'41-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-[2,31bipyridiny1-4-y11-(4-methyl-piperazin-1-y1)-methanone; {6'-amino-5'41-(2,6-dichloro-3-fluoro-pheny1)-ethaxyH2,31bipyridinyl-6-y1}-(4-methyl-piperazin-1-y1)-methanone; {6'-arnino-5'41-(2,6-dichloro-3-fluoro-pheny1)-ethoxyH3,31bipyridinyl-5-y1}-(4-methyl-piperazin-1-y1)-methanone; {6'-amino-5'41-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-[3,31bipyridiny1-6-y1}-(4-methyl-piperazin-1-y1)-methanone; {6-amino-511-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-[3,41bipyridinyl-2'-y1}-(4-methyl-piperazin-1-y1)-methanone; 541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-[3,31]bipyridiny1-6,6'-diamine; {6'-amino-5'41-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-[2,3pipyridinyl-5-y1}-(4-methyl-piperazin-1-y1)-methanone; {6'-amino-5'41-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-(2,31bipyridiny1-4-y1}-(4-methyl-piperazin-1-y1)-methanone; {6'-amino-5'41-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-(2,31bipyridinyl-6-y1)-(4-methyl-piperazin-1-y1)-methanone; (6'-amino-5'41-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-[3,31bipyridinyl-5-y1}-(4-methyl-piperazin-l-y1)-methanone;
{6'-amino-5'41-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-[3,31]bipyridiny1-6-y1}-(4-methyl-piperazin-1-y1)-methanone; {6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-[3,41]bipyridiny1-2'-y1}-(4-methyl-piperazin-1-yI)-methanone; 5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,31bipyridiny1-6'-ylamine; 5'41-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-12,31bipyridiny1-6'-ylamine; 5-[1-(2-chloro-3,6-difluoro-phenyI)-ethoxy]-[3,31bipyridiny1-6-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyI)-ethoxy]-5-pyrimidin-5-yl-pyridin-2-ylamine; {6'-amino-5'41-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,31bipyridiny1-5-y1}-(4-methyl-piperazin-1-y1)-methanone; 5-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-(3,41bipyridinyl-6-ylamine; 5-benzyloxy-3-[1-(2-chloro-3,6-difluoro-phenyI)-ethoxy]-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyI)-ethoxy]-5-(2-ethyl-butoxy)-pyridin-2-ylamine; 3-0-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-5-(3-methyl-butoxy)-pyridin-2-ylamine; 3-0-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-butoxy-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-propoxy-pyridin-2-ylamine; 341-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-5-cyclohexylmethoxy-pyridin-2-ylamine; 6-amino-5-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-ol; 3-[1-(2-chloro-3,6-difluoro-phenyI)-ethoxy]-5-(2-cyclohexyl-ethoxy)-pyridin-2-ylamine; 341-(2-chloro-3,6-difluoro-phenyI)-ethoxy]-5-isobutoxy-pyridin-2-ylamine; 3-0-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-5-phenethyloxy-pyridin-2-ylamine; 341-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-5-(pyridin-2-ylmethoxy)-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(pyridin-4-ylmethoxy)-pyridin-2-ylamine;
(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-l-yI)-methanone; (4-{6-amino-5-[l-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-((3R,5S)-3,5-dimethyl-piperazin-l-y1)-methanone; 5-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-2-fluoro-benzonitrile; 4-(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-phenylypiperidin-4-ol; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-phenyly piperidin-l-yl-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-pyrrolidin-1-yl-methanone; 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-3-methyl-benzoic acid methyl ester; 3-fl -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-544-(dimethyl-piperazin-1-ylmethyl)-pheny1]-pyridin-2-ylamine; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-3,5-dimethoxy-phenyl)-(dimethyl-piperazin-1-y1)-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-2-fluoro-pheny1)-(dimethyl-piperazin-l-y1)-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-3-fluoro-pheny1)-(dimethyl-piperazin-1-y1)-methanone;
(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-3-methyl-pheny1)-(dimethyl-piperazin-1-yI)-melhanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylypheny1)-(4-methyl-ri Adizzeran-1-y1)-methanone; (4-16-smino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1)-pheny1)41,4]diazepan-1-yl-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-piperazin-1-yl-methanone; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-vinyl-pyridin-2-ylamine; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-((3R,4S)-3,4-dihydroxy-pyrrolidin-1-y1)-methanone; 5-[(1-benzyl-pyrrolidin-3-ylamino)-methy1]-341-(216-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-2-ylamine; 4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-N-azetidin-3-yl-benzamide; 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-N,N-dinnethyl-benzenesulfonamide; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1H-benzoimidazol-2-y1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(6-methoxy-1-methy1-1H-benzoimidazol-2-y1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-544-(4-methyl-[1,4]diazepane-1-sulfony1)-phenyll-pyridin-2-ylamine; 6-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-1-methyl-1H-indazole-3-carboxylic acid amide; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(1-methy1-1H-pyrazol-4-y1)-pyridin-2-ylamine; 5-(3-chloro-pheny1)-341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-6-(4-fluoro-3-methyl-pheny1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3-trifluoromethyl-phenyI)-pyridin-2-ylamine; 3-[l-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3-fluoro-pheny1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3-trifluoromethoxy-pheny1)-pyridin-2-ylamine; 5-benzo[1,3]dioxo1-5-y1-341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-2-ylamine; 3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenol; (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-methanol; 3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-benzonitrile; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3-methoxy-pheny1)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dichloro-pheny1)-pyridin-2-ylamine;
341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2,5-dimethyl-pheny1)-pyridin-2-ylamine; 5-(5-chloro-2-methoxy-pheny1)-341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-2-ylamine;
5-(3-chloro-4-fluoro-pheny1)-341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(5-fluoro-2-methoxy-pheny1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3-isopropyl-pheny1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(314-dichloro-phenyI)-pyridin-2-ylamine; 4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-benzonitrile; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3,4-difluoro-phenyl)-pyridin-2-ylamine; (4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-pheny1)-((2R,6S)-2,6-dimethyl-morpholin-4-yI)-methanone; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2-ethoxy-pheny1)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2,5-dinnethoxy-pheny1)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2,4-dimethoxy-phenyl)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2,6-dimethoxy-pheny1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy1-5-(2-trifluoromethyl-pheny1)-pyridin-2-ylamine; 5-(2-chloro-pheny1)-341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-2-ylamine; 341-(2,6-dichlora-3-fluoro-pheny1)-ethoxy]-5-(2-trifluoromethoxy-pheny1)-pyridin-2-ylamine; 1-(2-{6-amino-5-[1 -(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-phenylyethanone; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2-fluoro-pheny1)-pyridin-2-ylamine;
(2-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-methanol; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-o-tolyl-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2-methoxy-pheny1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2,6-dimethyl-pheny1)-pyridin-2-ylamine;
(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-morpholin-4-yl-meihanone;
(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-Pyridin-311}-2-chloro-pheny1)-((3R,5S)-dimethyl-piperazin-l-y1)-methanone; 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-2-methyl-pheny1)-((3R,5S)-dimethyl-piperazin-l-y1)-methanone; 341 -(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-544-((2R,6S)-2,6-dimethyl-morpholin-4-ylmethyl)-pheny1]-Pyridin-2-ylamine;
341-(2,6-dichloro-3-fluoro-phenyI)-ethoxy]-5-(4-morpholin-4-ylmethyl-Pheny1)-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dimethyl-phenyl)-pyridin-2-ylamine; 3-0-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-m-tolyl-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3,4-dimethoxy-pheny1)-pyridin-2-ylamine; 5-bipheny1-3-y1-341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-Pyridin-2-ylamine; 5-(3,5-bis-trifluoromethyl-pheny1)-341 -(2,6-dichloro-3-fluoro-phenyl)-ethoM-pyridin-2-ylamine; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dichloro-pheny1)-pyridin-2-ylamine; 1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-ethanone; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3,5-difluoro-pheny1)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(2,5-dichloro-pheny1)-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-4-trifluoromethyl-pheny1)-ethoxy]-Pyridin-3-y1}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(3-ethoxy-pheny1)-pyridin-2-ylamine; (4-{6-amino-541-(2-trifluoromethyl-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-(3,5-dimethyl-piperazin-1-y1)-methanone; (4-{6-amino-541-(3-trifluoromethyl-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-(3,5-dimethyl-piperazin-1-y1)-methanone; 7-[4-(3,5-dimethyl-piperazine-1-carbony1)-pheny11-2-pheny1-4H-pyrido[3,2-141,4]oxazin-3-one; {4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-pheny1}-(3,5-dimethyl-piperazin-1-y1)-methanone; {4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)-(3,5-dimethyl-piperazin-1-y1)-methanone; [4-(6-amino-5-benzyloxy-pyridin-3-y1)-pheny1]-(3,5-dimethyl-piperazin-1-y1)-methanone; (4-{6-amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-(4-ethyl-piperazin-1-y1)-methanone;
[4-(6-amino-5-benzyloxy-pyridin-3-y1)-pheny1]-(4-ethyl-piperazin-1-y1)-methanone; {4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-y11-pheny1)-(3,5-dimethyl-piperazin-1-y1)-methanone; 3-{2-amino-544-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzoic acid methyl ester; 3-{2-amino-544-(3,5-dimethyl-piperazine-1-carbony1)-phenyll-pyridin-3-yloxymethylybenzoic acid methyl ester; {4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-A-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; [4-(6-amino-5-cyclohexylmethoxy-pyridin-3-y1)-pheny1]-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbony1)-phenyl]-pyridin-3-yloxyyethyl)42-(3-hydroxy-pheny1)-ethyl]-benzamide; 4-(1-{2-amino-544-(4-pyrrolidin-1-yl-piperidine-1-carbony1)-phenyll-pyridin-3-yloxyyethyl)42-(2,6-dichloro-pheny1)-ethylFbenzamide; 4-(1-{2-amino-544-(4-pyrrolidin-1-yl-piperidine-1-carbony1)-phenyl]-pyridin-3-yloxy}-ethyl)-(1-benzyl-piperidin-4-y1)-benzamide; 4-(1-{2-amino-544-(4-pyrrolidin-1-yl-piperidine-1-carbony1)-pheny1]-pyridin-3-yloxy}-ethy1)43-(2-oxo-pyrrolidin-1-y1)-proPyli-benzamide; (4-{6-amino-5-0-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-yll-pheny1)-(4-ethyl-PiPerazin-1-yly methanone; {446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-phenyl}-(3,5-dimethyl-piperazin-1-y1)-methanone; (6-amino-3-aza-bicyclo[3.1.0]hex-3-y1)-(4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-ylypheny1)-methanone; 5-0-(2,6-dichloro-3-fluoro-pheny1)-eihoxy1-6'-(2-morpholin-4-yl-ethoxy)43,31bipyridinyl-6-ylamine; 8'-8lmino-5'41-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H43,3']bipyridiny1-6-one; 541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-6'-(2-pyrrolidin-1-yl-ethoxy)43,3']bipyridinyl-6-ylamine; 6'-amino-5'41-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-142-(1-methyl-pyrrolidin-2-y1)-ethyl]-1H43,31]bipyridinyl-6-one; (4-{6-amino-541-(2,4,6-trimethyl-pheny1)-ethoxy]-pyridin-3-y1}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; (4-{6-amino-541-(2-chloro-6-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone;
341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(4-fluoro-phenyl)-pyridin-2-ylamine; 6'-amino-5'41-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-1H43,31bipyridiny1-6-one; 5'-bromo-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-(3,31bipyridiny1-6-ylamine; 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(4-dimethylamino-pheny1)-Pyridin-2-ylamine; 5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-2'-methoxy-[3,31bipyridinyl-6-ylamine;
341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(1H-indo1-5-y1)-pyridin-2-ylamine; (4-{6-amino-541-(2,6-dichloro-pheny1)-propoxyl-pyridin-3-y1}-pheny1)-(3,5-dimethyl-piperazin-1-y1)-methanone; [4-(6-amino-5-benzyloxy-pyridin-3-yI)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 3-(2,6-dichloro-3-fluoro-benzyloxy)-5-thiazol-2-yl-pyridin-2-ylamine; (4-{6-amino-541-(2-fluoro-6-trifluoromethyl-pheny1)-ethoxyypyridin-311)-Pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 3-(2,6-dichloro-3-fluoro-benzyloxy)-5-(1-methy1-1H-imidazol-2-y1)-pyridin-2-ylamine; {446-amino-5-(2,4,6-trimethyl-benzyloxy)-pyridin-3-y1]-pheny1H4-pyrrolidin-l-yl-piperidin-l-y1)-methanone; {4-[6-amino-5-(2,3,5,6-tetramethyl-benzyloxy)-pyridin-3-yl]-pheny1}-(4-pyrrolidin-l-yl-piperidin-1-y1)-methanone; (446-amino-5-(2,4,6-trifluoro-benzyloxy)-pyridin-319-pheny1)-(4-pyrrolidin-l-yl-piperidin-l-y1)-methanone; (4-(6-amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-l-y1)-methanone; 6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-N-methyl-nicotinamidine; 6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-N-(2-morpholin-4-yl-ethyl)-nicotinamidine; (4-(6-amino-5-[1-(2,4,5-trifluoro-pheny1)-propoxy]-pyridin-3-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; (4-(6-amino-541-(6-chloro-2-fluoro-3-methyl-pheny1)-ethoxylpyridin-3-y1}-pheny1)-(4-pyrrolidin-l-yl-piperidin-1-y1)-methanone; 3-(1-{2-amino-544-(4-pyrrolidin-1-yl-piperidine-1-carbony1)-phenyl]-pyridin-3-yloxy}-ethyl)-benzoic acid; and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another embodiment, the invention provides a compound selected from the group consisting of: 3-(5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1)-N-(3-pyrrolidin-1-yl-propy1)-benzamide; 3-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-N-(1-methyl-piperidin-4-y1)-benzamide; 3-(5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1)-N-(2-morpholin-4-yl-ethyl)-benzamide; N-[2-(4-acetyl-piperazin-1-y1)-ethy1]-3-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-benzamide; (3-(5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-(4-methyl-piperazin-l-y1)-methanone; (3-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; (3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenylyethoxy]-pyrazin-2-y1}-pheny1)-((3R,55)-3,5-dimethyl-piperazin-1-y1)-methanone; (3-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-ylypheny1)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yI)-methanone; (3-(5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-pheny1)-((R)-3-amino-pyrrolidin-1-y1)-methanone; (3-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-pheny1)-((S)-3-amino-pyrrolidin-1-y1)-methanone;
4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-benzoic acid; 4-(5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-(3-pyrrolidin-1-yl-propy1)-benzamide; (4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-y1}-pheny1)-(4-methyl-piperazin-l-y1)-methanone; (4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-phenyl)-(4-pyrrolidin-1-yl-piperidin-l-y1)-methanone; 4-(5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy1-pyrazin-2-y1}-pheny1)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone; (4-(5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (4-(5-amino-6-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-((R)-2-pyrrolidin-l-ylmethyl-pyrrolidin-l-y1)-methanone; (4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-pheny1)-((R)-3-amino-Pyrrolidin-111)-methanone; 4-{5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-(1-methyl-piperidin-4-y1)-benzamide;
4-(5-amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy1-pyrazin-2-y1}-N-(2-Pyrrolidin-l-yl-ethyl)-benzamide; 4-{5-amino-6-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide; N42-(4-acetyl-piperazin-l-y1)-ethyl]-4-(5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-benzamide; 244-(2-Hydroxy-acety1)-piperazin-1-y11-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-amide;
3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-y1]-benzoic acid; {3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-pheny1}-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone;
3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-A-N-{2-[ethyl-(2-methoxy-ethyl)-amino]-ethylybenzamide; {345-ami no-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylyp heny1}-(4-methyl-piperazin-1-y1)-methanone; 3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-A-N-(3-pyrrolidin-1-yl-propy1)-benzamide; N42-(4-acetyl-piperazin-1-y1)-ethy1]-345-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylybenzamide; {4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-pheny1}-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; {445-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-y1]-pheny1)-(4-methyl-piperazin-1-y1)-methanone; {445-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylypheny1}-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone;
(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-(4-methyl-piperazin-1-y1)-methanone; (3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyrazin-2-y1}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone; 3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1)-N-(1-methyl-piperidin-4-y1)-benzamide; 345-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyrazin-2-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide; 3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1)-N-(3-morpholin-4-yl-propy1)-benzamide; (3-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxyypyrazin-2-y1}-pheny1)-(4-cyclopropylamino-piperidin-1-y1)-methanone; 3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1)-N-((S)-2-hydroxy-3-morpholin-4-yl-propy1)-benzamide; 3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propy1)-benzamide; (3-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyridin-311)-pheny1)-(4-pyrrolidin-1-0-piperidin-1-y1)-methanone; 2-diethylamino-ethanesulfonic acid (4-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-ylypheny1)-amide; 2-(4-Hydroxy-piperidin-1-yI)-ethanesulfonic acid (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-phenyl)-amide;
2-dimethylamino-ethanesulfonic acid (4-{5-amino-641-(2,6-dichioro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-y1}-pheny1)-amide;
2-((R)-3-Hydroxy-pyrrolidin-1-yI)-ethanesulfonic acid (4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyrazin-2-y1}-phenyl)-amide; 2-pyrrolidin-1-ylethanesulfonic acid (4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyrazin-2-y1}-phenylyamide; 4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyrazin-2-y1}-benzoic acid; 4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyrazin-2-y1}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyI)-benzamide; (4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyrazin-2-y1}-phenyl)-(4-cyclopropylamino-piperidin-1-y1)-methanone;
4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-((S)-2-hydroxy-3-pyrrolidin-1-yl-propy1)-benzamide; 4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-211}-N-((R)-2-hydroxy-3-morpholin-4-yl-propyI)-benzamide; 4-{5-amino-6-0-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyrazin-2-y1)-N-(1-methyl-piperidin-4-yI)-benzamide; (4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyrazin-2-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide;
(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-yll-pheny1)-(4-methyl-piperazin-1-y1)-methanone; (4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-((3R,5S)-3,5-dimethyl-piperazin-1-yI)-methanone; 4-{5-amino-641-(2,6-dichloro-pheny1)-ethoxyl-pyrazin-2-ylybenzoic acid; (4-{5-amino-641-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-y1}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; 4-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1)-N-(2-morpholin-4-yl-ethyl)-benzamide; (4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone; 4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1)-N-(1-methyl-piperidin-4-y1)-benzamide; (4-{5-amino-641-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-y1}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethon]-pyrazin-2-yly phenylX(S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone; (4-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-(4-methyl-piperazin-1-y1)-methanone; (4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-((R)-3-aminopyrrolidin-1-y1)-methanone;
(4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-((S)-3-aminopyrrolidin-1-y1)-methanone hydrogen chloride; 4-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-N-(3-pyrrolidin-1-yl-propy1)-benzamide; 3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-benzoic acid; 3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-y1}-N-(1-methyl-piperidin-4-y1)-benzamide; 3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;
(3-{5-amino-6-[1-(2,6-d oro-ph enyl)-ethoxy]-pyrazi n-2-y1)-pheny1)-((3 R, 5S)-3,5-d methyl-p iperazi n-1-yI)-methan one; 3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1)-N-(2-morpholin-4-yl-ethyl)-benzamide; (3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-l-y1)-methanone; (3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-y1)-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; KI-[2-(4-acetyl-piperazin-1-y1)-ethyl]-4-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-benzamide; N42-(4-acetyl-piperazin-1-y1)-ethy11-3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-ylybenzamide; (3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yly phenyl)(R)-2-pyrrolidin-I-ylmethyl-pyrrolidin-1-y1)-methanone; 3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1)-N-(3-pyrrolidin-1-yl-propy1)-benzamide; (3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-pheny1)-((S)-3-amino-pyrrolidin-1-y1)-methanone; (3-{5-amino-641-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-((R)-3-amino-pyrrolidin-1-y1)-methanone hydrochloride salt; (3-{5-amino-6-0-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-y1}-phenyl)-(4-methyl-piperazin-1-y1)-methanone; 1-(4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-amide; 1-(4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 4-methyl-piperazine-1-carboxylic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-amide; 1-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-pheny1)-3-(2-hydroxy-ethyl)-urea;
(S)-3-amino-pyrrolidine-1-carboxylic acid (4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-amide; 1-(4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-y1}-phenyl)-3-(1-methyl-piperidin-4-y1)-urea; 4-methyl-piperazine-1-carboxylic acid (4-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-y1}-phenyl)-amide; 1-(4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pheny1)-3-(2-hydroxy-ethyl)-urea; (S)-3-amino-pyrrolidine-1-carboxylic acid (4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-phenyl)-amide; 1-(4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-phenyl)-3-(1-methyl-piperidin-4-y1)-urea;
5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-thiophene-2-carboxylic acid; {545-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-thiophen-2-y1)-(4-methyl-piperazin-1-y1)-methanone;
{5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-thiophen-2-y1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone; {545-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-thiophen-2-y1)-((3R,5S)-3,5-dimethyl-piperazin-1-yI)-methanone; {545-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-A-thiophen-2-y1H(R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yI)-methanone; 5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yI]-thiophene-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yllpyrazin-2-amine trifluoroacetate;
341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-pyridin-4-yl-pyrazin-2-ylamine;
341-(2,6-dichloro-3-fluoro-phenyI)-ethoxy]-5-(1H-pyrrol-2-y1)-pyrazin-2-ylamine; (6-{5-amino-641-(2,6-d ichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-yI)-pyrid in-3-y1)-(4-methyl-piperazin-1-y1)-methanone; (2-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pyridin-4-y1)-(4-methyl-piperazin-1-y1)-methanone; (6-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyrazin-2-y1}-pyridin-2-y1)-(4-methyl-piperazin-1-y1)-methanone; (5-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyrazin-2-y1}-pyridin-3-y1)-(4-methyl-piperazin-1-y1)-methanone; (4-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pyridin-2-y1)-(4-methyl-piperazin-1-y1)-methanone; 6-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-y1)-N-(2-morpholin-4-yl-ethyl)-nicotinamide; 5-{5-amino-6-[I-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1)-N-(2-morpholin-4-yl-ethyl)-nicotinamide; 6-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1)-N-(3-morpholin-4-yl-propy1)-nicotinamide; 5-{5-amino-6-11-(2,6-dichloro-3-fluoro-phenyl)-ethoxy}pyrazin-2-y1}-N-(3-morpholin-4-yl-propyl)-nicotinamide; (6-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-pyridin-3-y1)-(4-isopropyl-piperazin-1-y1)-methanone;
and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 1 and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 2 and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another aspect, the invention provides a compound selected from the group consisting of the , compounds shown in Table 3 and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 4 and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 5 and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 6 and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 7 and pharmaceutically acceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from the group consisting of the compounds shown in Table 8 and pharmaceutically acceptable salts, hydrates and solvates thereof.
In another embodiment, the invention provides compounds having the following chemical structure (Formula ):

R2,1 R22 I
Aryl 0 wherein, Z is CH or N;
Aryl is an optionally fused aryl or an optionally fused heteroaryl group which is optionally substituted by one or more substituents selected from the group consisting of a halogen, -0R24, -00R24, -000R24, -00NR24R25, -ON, -NO2, -S(0),,R24, -S02NR24R25, perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, aryl, _NR 25 and ¨N R24 S (0)p R25 ;
R21 and R22 are independently selected from the group consisting of hydrogen, halogen, -C0R24, -000R24, -00NR24R25, -ON, perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, and aryl;
15R23 is selected from the group consisting of:
an optionally fused aryl, heteroaryl, alicyclic or heterocyclic group, optionally substituted by one or more substituents selected from the group consisting of a halogen, -(CH2)n-OR24, -COR24, -000R24, -0ONR24R25, -ON, -NO2, -S(0),õR24, -S02NR24R25, perfluoroalkyl, -0-perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, heteroaryl, alkenyl, alkynyl, aryl, -(CH2)-NR24R25, -NR240(0)R25 and ¨NR24S(0)pR25, wherein said heterocycle, heteroaryl and aryl substituents may be optionally substituted by a group selected from the group consisting of lower alkyl, halogen, -C(0)NR24R25, NR24R25, New- )R -25 and NR24S(0)pR25;
-0R24, -00R24, -000R24, -ON, -NO2, -S02NR24R25, perfluoroalkyl, cycloalkyl, heterocycle, alkenyl, and alkynyl;
R24 and R25 are independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aminoalkyl, alkylaminoalkyl, alkylaminocycloalkyl, dialkylaminoalkyl and ¨(CH2)-heterocycle, wherein said ¨(CH2)õ-heterocycle may be further substituted by one or more of lower alkyl, -(OH2)-hydroxy, heterocycle and -C(0)R26, or R24 and R25 can combine to form a 5- to 6-membered heterocyclic ring having one or more heteroatoms selected from the group consisting of N, 0, S, S(0) and 802, said 5- to 6-membered heterocyclic ring may be optionally substituted by lower alkyl, ¨(CH2)n-heterocycle, cycloalkyl, halo, -(CH2)n-NR26R27, amino, -C(0)R26, -N-26. C(0)0R27 and -NR26-C(0)R27;
wherein R26 and R27 are independently selected from the group consisting of hydrogen, lower alkyl, ¨(CH2)n-cycloalkyl and -C(0)-(CH2)n-OH;
except that when Z is N and R21 and R22 are H and Aryl is m-chlorophenyl, R23 is not piperazine;
m is 0, 1 or 2;
n is 0, 1, 2 or 3;
p is 1 or 2;
or a pharmaceutically acceptable salt thereof.
In preferred aspect of this embodiment, in the compound of Formula (6), R23 is aryl or heteroaryl.
In another preferred aspect of this embodiment, when Z is N, R23 is not heteroalicyclic.
In another embodiment, the invention provides a pharmaceutical composition comprising any of the inventive compounds described herein. In particular aspects of this embodiment, the pharmaceutical composition comprises a compound of formula 1, a compound of formula 2, a compound of formula 3, a compound of formula 4, a compound of formula 5, a compound of formula 6, or a pharmaceutically acceptable salt, hydrate or solvate thereof, including particular aspects thereof as described above. In other particular aspects of this embodiment, the pharmaceutical composition comprises a compound selected from the compounds shown in Table 1, a compound selected from the compounds shown in Table 2, a compound selected from the compounds shown in Table 3, a compound selected from the compounds shown in Table 4, a compound selected from the compounds shown in Table 5, a compound selected from the compounds shown in Table 6, a compound selected from the compounds shown in Table 7, a compound selected from the compounds shown in Table 8, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
Preferred compounds of the invention include those having c-MET inhibitory activity as defined by any one or more of IC50, Ki, or percent inhibition. One skilled in the art can readily determine if a compound has such activity by carrying out the appropriate assay. In one embodiment, particularly preferred compounds have a c-MET IC50 of less than 5 pM, or less than 2 pM, or less than 1 pM, or less than 500 nM, or less than 400 nM, or less than 300 nM, or less than 200 nM, or less than 100 nM, or less than 50 nM. In another embodiment, particularly preferred compounds have a c-MET Ki of less than 5 pM or less than 2 pM, or less than 1 pM, or less than 500 nM, or less than 400 nM, or less than 300 nM, or less than 200 nM, or less than 100 nM, or less than 50 nM. In another embodiment, particularly preferred compounds have a c-MET inhibition at 1 pM of at least 10% or at least 20% or at least 30% or at least 40% or at least 50% or at least 60% or at least 70% or at least 80% or at least 90%.
In another embodiment, the invention provides a process of preparing the compound of Formula (6), comprising (i) brominating a compound of the formula (a):

R21 R22 -µr=/..%, (a) to give a compound of formula (b):
and Br R21 R22 y s......./H

X )yN (b) Aryl 0 ii. reacting (b) with a boronic acid or ester derivative of the formula R23B(OR)2 in the presence of a palladium catalyst;
wherein R is hydrogen or an alcohol protecting group and Aryl, R21, R22, and R23 are as defined defined above.
In another embodiment, R23 is aryl or heteroaryl.
In another embodiment the invention provides a method of treating a subject suffering from a condition for which inhibition of Met receptor tyrosine kinase is indicated, comprising administering to the subject a therapeutically effective amount of any of the inventive compounds described herein.
The chemical formulae referred to herein may exhibit the phenomena of tautomerism and structural isomerism. This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate RTK, CTK and/or STK
activity and is not limited to any one tautomeric or structural isomeric form.
In addition, the formulae referred to herein may also exhibit stereoisomerism, in which such compounds may adopt an R or S configuration at chiral centers. Thus, this invention also encompasses any stereoisomeric form, their corresponding enantiomers (d- and l- or (+) and (-) isomers) and diastereomers thereof, and mixtures thereof, which possess the ability to modulate RTK, CTK and/or STK activity and is not limited to any one stereoisomeric form.
In particular embodiments, the compound is chosen from the compounds in Tables 1-8.
Another embodiment of the invention relates to a method of treating a subject suffering from a condition for which inhibition of protein kinase is indicated, comprising administering to the subject a therapeutically effective amount of any of the inventive compounds described herein.

Another aspect of this invention relates to a method for the modulation of the catalytic activity of a PK by contacting a PK with a compound of this invention or a physiologically acceptable salt thereof.
A further aspect of this invention is that the modulation of the catalytic activity of PKs using a compound of this invention may be carried out in vitro or in vivo.
A still further aspect of this invention is that the protein kinase whose catalytic activity is being modulated by a compound of this invention is selected from the group consisting of receptor protein tyrosine kinases, cellular tyrosine kinases and serine-threonine kinases.
It is an aspect of this invention that the receptor tyrosine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRa, PDGFRI3, CSFIR, C-Kit, C-fms, Flk-1R, F1k4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, MET, DDR-1 and DDR-2.
In addition, it is an aspect of this invention that the cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
Another aspect of this invention is that the serine-threonine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2, Raf, NEK and Kai .
Another aspect of this invention relates to a method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of any of the inventive compounds described herein to an organism, such as a mammal, particularly a human.
It is an aspect of this invention that the above-referenced protein kinase related disorder is selected from the group consisting of a receptor protein tyrosine kinase related disorder, a cellular tyrosine kinase disorder and a serine-threonine kinase related disorder.
In yet another aspect of this invention, the above referenced protein kinase related disorder is selected from the group consisting of a Met related disorder, an AUR2 related disorder, a ZC1 related disorder, a PDGFR related disorder, an IGFR related disorder and a fik related disorder.
The above referenced protein kinase related disorders include by way of example and not limitation, cancers such as lung cancer, NSCLC (non small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endonnetrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lynphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), pediatric malignancy, neoplasms of the central nervous system (e.g., primary CNS
lymphoma, spinal axis tumors, brain stem glioma or pituitary adenomas), cancers of the bloodsuch as acute myeloid leukemia, chronic mueloid leukemia, etc, Barrett's esophagus (pre-malignant syndrome), neoplastic cutaneous disease, psoriasis, mycoses fungoides and benign prostatic hypertrophy, diabetes related diseases such as diabetic retinopathy, retinal ischemia and retinal neovascularization, hepatic cirrhosis, cardiovascular disease such as atherosclerosis, immunological disease such as autoimmune disease and renal disease. Preferably, the disease is cancer such as acute myeloid leukemia and colorectal cancer.
The above referenced protein kinase related disorder also includes disorders selected from the group consisting of diabetes, a hyper-proliferation disorder, hyperproliferative disorders of the kidney, von Hippel-Lindau disease, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.
Additional disorders which may be treated or prevented using the compounds of this invention are immunological disorders such as autoimmune diseases (e.g., AIDS, lupus, etc.) and cardiovascular disorders such as atherosclerosis.
It is an aspect of this invention that the protein kinase related disorder being treated or prevented by administration of a compound of this invention is a met kinase related disorder.
The organism in which the protein kinase related disorder is being treated or prevented is a human being in yet another aspect of this invention.
It is also an aspect of this invention that a compound described herein, or its salt, might be combined with other chemotherapeutic agents for the treatment of the diseases and disorders discussed above. For instance, a compound or salt of this invention might be combined with alkylating agents such as fluorouracil (5-FU) alone or in further combination with leukovorin;
or other alkylating agents such as, without limitation, other pyrimidine analogs such as UFT, capecitabine, gemcitabine and cytarabine, the alkyl sulfonates, e.g., busulfan (used in the treatment of chronic granulocytic leukemia), improsulfan and piposulfan; aziridines, e.g., benzodepa, carboquone, meturedepa and uredepa;
ethyleneimines and methylmelamines, e.g., altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; and the nitrogen mustards, e.g., chlorambucil (used in the treatment of chronic lymphocytic leukemia, primary macroglobulinemia and non-Hodgkin's lymphoma), cyclophosphamide (used in the treatment of Hodgkin's disease, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilm's tumor and rhabdomyosarcoma), estramustine, ifosfamide, novembrichin, prednimustine and uracil mustard (used in the treatment of primary thrombocytosis, non-Hodgkin's lymphoma, Hodgkin's disease and ovarian cancer); and triazines, e.g., dacarbazine (used in the treatment of soft tissue sarcoma).
Likewise a compound or salt of this invention might be expected to have a beneficial effect in combination with other antimetabolite chemotherapeutic agents such as, without limitation, folic acid analogs, e.g. methotrexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancer and osteogenic sarcoma) and pteropterin; and the purine analogs such as mercaptopurine and thioguanine which find use in the treatment of acute granulocytic, acute lymphocytic and chronic granulocytic leukemias.

A compound or salt of this invention might also be expected to prove efficacious in combination with natural product based chemotherapeutic agents such as, without limitation, the vinca alkaloids, e.g., vinblastin (used in the treatment of breast and testicular cancer), vincristine and vindesine; the epipodophylotoxins, e.g., etoposide and= teniposide, both of which are useful in the treatment of testicular cancer and Kaposi's sarcoma; the antibiotic chemotherapeutic agents, e.g., daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat stomach, cervix, colon, breast, bladder and pancreatic cancer), dactinomycin, temozolomide, plicamycin, bleomycin (used in the treatment of skin, esophagus and genitourinary tract cancer); and the enzymatic chemotherapeutic agents such as L-asparaginase.
In addition to the above, a compound or salt of this invention might be expected to have a beneficial effect used in combination with the platinum coordination complexes (cisplatin, etc.);
substituted ureas such as hydroxyurea; rnethylhydrazine derivatives, e.g., procarbazine; adrenocortical suppressants, e.g., mitotane, aminoglutethimide; and hormone and hormone antagonists such as the adrenocorticosteriods (e.g., prednisone), prooestins (e.g., hydroxyprogesterone caproate); estrogens (e.g., diethylstilbesterol); antiestrogens such as tamoxifen; androgens, e.g., testosterone propionate;
and aromatase inhibitors (such as anastrozole.
Finally, the combination of a compound of this invention might be expected to be particularly effective in combination with mitoxantrone or paclitaxel for the treatment of solid tumor cancers or leukemias such as, without limitation, acute myelogenous (non-lymphocytic) leukemia.
The above method can be carried out in combination with a chemotherapeutic agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, antiangiogenic agents such as MMP-2, MMP-9 and COX-2 inhibitors, and anti-androgens.

Examples of useful COX-II inhibitors include VIOXX7m, CELEBREXTM (alecoxib), valdecoxib, paracoxib, rofecoxib, and Cox 189. Examples of useful matrix metalloproteinase inhibitors are =

described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), (published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European Patent Publication 606,046 (published Jul. 13, 1994), European Patent Publication 931,788 (published Jul.
28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21, 1999), (published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), U.S. Pat.
No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent Publication 780,386 (published Jun. 25, 1997). Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MM P-1. More preferred, are those that selectively inhibit MMP-2 =
=

and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in the following list:
3-114-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cycloPenty1)-amino]-propionic acid; 3-exo-344-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.
1]octane-3-carboxylic acid hydroxyamide; (2R, 3R) 144-(2-chloro-4-fluoro-benzyloxy)-benzenesulfony1]-3-hydroxy-3-methyl-pip eridine-2-carboxylic acid hydroxyamide; 444-(4-fluoro-phenoxy)-benzenesulfonylaminoHetrahydro-pyran-4-carboxylic acid hydroxyamide; 34[4-(4-fluoro-phenoxy)-benzenesulfony1]-(1-hydroxycarbamoyl-cyclobutyI)-a mino]-propionic acid; 4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide; (R) 3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxyli c acid hydroxyamide; (2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyI]-3-hydroxy-3-methyl-pip eridine-2-carboxylic acid hydroxyamide; 3-[[(4-(4-fluoro-phenoxy)-benzenesulfony1]-(1-hydroxycarbamoy1-1-methyl-ethyp-amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy)-benzenesulfony1]-(4-hydroxycarbamoyl-tetrahydro-py ran-4-yI)-amino]-propionic acid; 3-exo-344-(4-chloro-phenoxy)-benzenesulfonylamino1-8-oxa-bicyclo[3.2. floctane-3-carboxylic acid hydroxyamide; 3-endo-344-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2. l]octane-3-carboxylic acid hydroxyamide;
and (R) 344-(4-fluoro-phenoxy)-benzenesulfonylaminoHetrahydro-furan-3-carboxyli c acid hydroxyamide; and pharmaceutically acceptable salts and solvates of said compounds.
Other anti-angiogenesis agents, including other COX-II inhibitors and other MMP inhibitors, can also be used in the present invention.
A compound of the invention can also be used with signal transduction inhibitors, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPT1N8 (Genentech, Inc. of South San Francisco, Calif., USA). EGFR
inhibitors are described in, for example in WO 95/19970 (published Jul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434 (published Jan. 22, 1998), and U.S. Pat.
No. 5,747,498 (issued May 5, 1998), and such substances can be used in the present invention as described herein.
EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and anti-EGFR 22Mab (lmClone Systems Incorporated of New York, N.Y., USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Inge!helm), MDX-447 (Medarex Inc. of Annandale, N.J., USA), and OLX-103 (Merck & Co. of Whitehouse Station, N.J., USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Mass.).
These and other EGFR-inhibiting agents can be used in the present invention.
VEGF inhibitors, for example 3-(2,4-Dimethylpyrrol-5-yl)methylene-2-indolinone, 5-(5-Fluoro-2-oxo-1,2-dihydro-indo1-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide, 3-[2,4-dimethy1-5-oxo-1,2-dihydroindole-3-ylidenemethyl)-1H-pyrrol-3-yl-propionic acid (Sugen Inc. of South San Francisco, Calif., USA), can also be combined with an inventive compound described herein. VEGF inhibitors are described in, for example in WO 99/24440, in WO 95/21613, WO 99/61422 (published Dec. 2,1999), U.S. Pat.
No. 5,834,504 (issued Nov. 10, 1998), WO 01/60814,WO 02104407, WO 98/50356, U.S. Pat. No.
5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat. No.
5,792,783 (issued Aug. 11, 1998), WO 99110349 (published Mar. 4, 1999), WO
97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun.26, 1997), WO 98/54093 (published Dec. 3, 1998); WO
98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and (published Jan. 22, 1998), Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Wash., USA); anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryviile, Calif.). These and other VEGF Inhibitors can be used In the present invention as described herein.
ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), can furthermore be combined with a compound any of the inventive compounds described herein, for example those indicated in WO 98/02434 (published Jan. 22, 1998), WO
99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat.
No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar.
2, 1999). =
The erbB2 receptor inhibitor compounds and substance described in the aforementioned PCT applications, U.S. patents, and.
U.S. provisional applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with the inventive compounds described herein.
The inventive compounds described herein can also be used with other agents useful in treating cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lyMphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferaSe inhibitors described In the references cited in the "Background" section, of US Patent No, 6,258,824 131.

The above method can be also be carried out in combination with radiation therapy, wherein the amount of the inventive compound in combination with the radiation therapy is.
effective in treating the above diseases. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.

Another aspect of the invention is directed to the use of any of the inventive compounds described herein in the preparation of a medicament, which is useful in the treatment of a disease mediated by abnormal Met kinase activity, such as cancer.
In a further embodiment, the invention provides a pharmaceutical composition comprising any of the inventive compounds described herein and a pharmaceutically acceptable carrier.
In yet a further embodiment, the invention is directed to a pharmaceutical composition for use in the treatment of abnormal cell growth in a mammal, the pharmaceutical composition comprising any of the inventive compounds described herein and a pharmaceutically acceptable carrier.
In yet a further embodiment, the invention is directed to the use of any of the inventive compounds described herein for the treatment of abnormal cell growth in a mammal.

50054-101 =

- 46a -DETAILED DESCRIPTION

5 Definitions The terms pyridine and pyrazine refer to the following structures respectively:

N N

"Pharmaceutically acceptable salt" or 'pharmaceutically acceptable salt thereof refer to those salts which retain the biological effectiveness and properties of the free bases and which are obtained 10 by reaction with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesullonic acid, salicylic acid, acetic acid, benzene.sulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and the like.

15 A "pharmaceutical composition" refers to a mixture of one or more of the compounds described = herein, or physiologically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition Is to facilitate administration of a compound to an organism.

As used herein, a "physiologically acceptable carrier' refers to a carder or diluent that does not 20 cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

An "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various supers and types of starch, cellulose derivatives (including 25 microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or arrangements of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not 30 mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for = example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be = characterized by the absolute configuration of its asymmetric center and is described by the R- and S-.

= sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of 35 polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).

A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
The compounds of this invention may possess one or more asymmetric centers;
such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).
The inventive compounds herein may exhibit the phenomena of tautomerism and structural isomerism. This invention encompasses any tautomeric or structural isomeric form and mixtures thereof which possess the ability to modulate RTK, CTK and/or STK activity and is not limited to any one tautomeric or structural isomeric form.
It is contemplated that an inventive compound as described herein would be metabolized by enzymes in the body of the organism such as human being to generate a metabolite that can modulate the activity of the protein kinases. Such metabolites are within the scope of the present invention.
As used herein, "PK" refers to receptor protein tyrosine kinase (RTKs), non-receptor or "cellular"
tyrosine kinase (CTKs) and serine-threonine kinases (STKs).
The term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by, practitioners of the chemical, pharmaceutical, biological, biochemical and medical arts.
As used herein, the term "modulation" or "modulating" refers to the alteration of the catalytic activity of RTKs, CTKs and STKs. In particular, modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK or STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
The term "catalytic activity" as used herein refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.
The term "contacting" as used herein refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itself, or indirectly, L e., by interacting with another molecule on which the catalytic activity of the kinase is dependent. Such "contacting"
can be accomplished in vitro, i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder, i.e., the IC50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
"In vitro" refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium. The skilled artisan will understand that, for example, an isolated PK may be contacted with a modulator in an in vitro environment.
Alternatively, an isolated cell may be contacted with a modulator in an in vitro environment.
As used herein, "in vivo" refers to procedures performed within a living organism such as, without limitation, a mouse, rat, rabbit, ungulate, bovine, equine, porcine, canine, feline, primate, or human.
As used herein, "PK related disorder," "PK driven disorder," and "abnormal PK
activity" all refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs, (2) increased PK
expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK
expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. Over-activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases.
As used herein, the terms "prevent", "preventing" and "prevention" refer to a method for barring an organism from acquiring a PK related disorder in the first place.
As used herein, the terms "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a PK mediated cellular disorder and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
The term "organism" refers to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukaryotic cell or as complex as a mammal. In a preferred aspect, the organism is a mammal. In a particularly preferred aspect, the mammal is a human being.
The term "therapeutically effective amount" as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and/or, (4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
By "monitoring" is meant observing or detecting the effect of contacting a compound with a cell expressing a particular PK. The observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner.
Techniques for observing or detecting such effects are well-known in the art.
For example, the catalytic activity of a PK may be observed by determining the rate or amount of phosphorylation of a target molecule.
Reference to compounds of the invention includes pharmaceutically acceptable salts, solvates and hydrates thereof.
"Cell phenotype" refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known in the art.
A "natural binding partner" refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in propagating a signal in a PK-mediated signal transduction process. A
change in the interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction.
As used herein, "administer" or "administration" refers to the delivery of a compound or salt of the present invention or of a pharmaceutical composition containing a compound or salt of this invention to an organism for the purpose of prevention or treatment a a PIK-related disorder.
A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
"Pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
"Pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) acid addition salt which is obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like, preferably hydrochloric acid or (L)-malic acid; and (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

The inventive compounds described herein may also act as a prodrug. A
"prodrug" refers to an agent, which is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.

Indications The PKs whose catalytic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs), and serine-threonine kinases (STKs). RTK mediated signal transduction, is initiated by extracellular interaction with a specific growth factor (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 effects on the extracellular microenvironment, etc.). See, Schlessinger and Ullrich, Neuron, 9:303-391 (1992).
It has been shown that tyrosine phosphorylation sites on growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Fantl at al., Cell, 69:413-423 (1992), Songyang et aL, MoL Cell. Biol., 14:2777-2785 (1994), Songyang at aL, Cell, 72:767-778 (1993), and Koch et aL, Science, 252:668-678 (1991). Several intracellular substrate proteins that associate with RTKs have been identified. They may be divided into two principal groups:
(1) substrates that have a catalytic domain, and (2) substrates which lack such domain but which serve as adapters and associate with catalytically active molecules. Songyang at aL, Cell, 72:767-778 (1993).
The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the 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. Songyang at aL, Cell, 72:767-778 (1993).
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.
STKs, being primarily cytosolic, affect the internal biochemistry of the cell, often as a down-line response to a PTK event. STKs have been implicated in the signaling process which initiates DNA
synthesis and subsequent mitosis leading to cell proliferation.
Thus, PK signal transduction results in, among other responses, cell proliferation, differentiation, growth and metabolism. Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, glioblastoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and/or vasculogenesis.

A precise understanding of the mechanism by which the compounds of the invention, in particular, the compounds generated in vivo from the compounds of the invention, inhibit PKs is not required in order to practice the present invention. However, while not hereby being bound to any particular mechanism or theory, it is believed that the compounds interact with the amino acids in the catalytic region of PKs. PKs typically possess a bi-lobate structure wherein ATP appears to bind in the cleft between the two lobes in a region where the amino acids are conserved among PKs. Inhibitors of PKs are believed to bind by non-covalent interactions such as hydrogen bonding, van der Weals forces and ionic interactions in the same general region where the aforesaid ATP
binds to the PKs. More specifically, it is thought that the compounds of this invention binds in the general space normally occupied by the adenine ring of ATP.

In another aspect, the protein kinase, the catalytic activity of which is modulated by contact with a compound of this invention, is a protein tyrosine kinase, more particularly, a receptor protein tyrosine kinase. Among the receptor protein tyrosine kinases whose catalytic activity can be modulated with a compound of this invention, or salt thereof, are, without limitation, selected from the group consisting of Met, Flk, FGFR, PDGFR, HER, IR, IGF, IRR, CSFIR, C-Kit, C-fms, flt. In a preferred aspect, the receptor protein tyrosine kinase whose catalytic activity can be modulated with a compound of this invention, or salt thereof.
The protein tyrosine kinase whose catalytic activity is modulated by contact with a compound of this invention, or a salt thereof, can also be a non-receptor or cellular protein tyrosine kinase (CTK).

Thus, the catalytic activity of CTKe such as, without limitation, Src, Fric, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, Aur2 and Yrk may be modulated by contact with a compound or salt of this invention.

Still another group of PKs which may have their catalytic activity modulated by contact with a compound of this invention are the serine-threonine protein kinases such as, without limitation, CDK2, Raf, NEK (including NEK 4a, NEK 4b, NEK 5 and NEK 6) and BUB1.

In another aspect, this invention relates to a method for treating or preventing a PK related disorder by administering a therapeutically effective amount of a compound of this invention, or a salt thereof, to an organism.

It is also an aspect of this invention that a pharmaceutical composition containing a compound of this invention, or a salt thereof, is administered to an organism for the purpose of preventing or treating a PK related disorder.
This invention is therefore directed to compounds that modulate PK signal transduction by affecting the enzymatic activity of RTKs, CTKs and/or STKs, thereby interfering with the signals transduced by such proteins. More particularly, the present invention is directed to compounds which modulate RTK, CTK and/or STK mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including but not limited to carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma.

cancers such as lung cancer, NSCLC (non small cell ling cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lynphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), pediatric malignancy, neoplasms of the central nervous system (e.g., primary CNS
lymphoma, spinal axis tumors, brain stem glioma or pituitary adenomas), cancers of the bloodsuch as acute myeloid leukemia, chronic mueloid leukemia, etc, Barrett's esophagus (pre-malignant syndrome), neoplastic cutaneous disease, psoriasis, mycoses fungoides and benign prostatic hypertrophy, diabetes related diseases such as diabetic retinopathy, retinal ischemia and retinal neovascularization, hepatic cirrhosis, cardiovascular disease such as atherosclerosis, immunological disease such as autoimmune disease and renal disease. Preferably, the disease is cancer such as acute myeloid leukemia and colorectal cancer.
Further examples, without limitation, of the types of disorders related to inappropriate PK activity that the compounds described herein may be useful in preventing, treating and studying, are cell proliferative disorders, fibrotic disorders, metabolic disorders and infectious diseases.
Cell proliferative disorders, which may be prevented, treated or further studied by the present invention include cancer, blood vessel proliferative disorders and mesangial cell proliferative disorders.
Blood vessel proliferative disorders refer to disorders related to abnormal vasculogenesis (blood vessel formation) and angiogenesis (spreading of blood vessels). While vasculogenesis and angiogenesis play important roles in a variety of normal physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration, they also play a pivotal role in cancer development where they result in the formation of new capillaries needed to keep a tumor alive. Other examples of blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and ocular diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness.
Normal vasculogenesis and angiogenesis play important roles in a variety of physiological processes such as embryonic development, wound healing, organ regeneration and female reproductive processes such as follicle development in the corpus luteum during ovulation and placental growth after pregnancy. Folkman & Shing, J. Biological Chem., 267(16):10931-10934 (1992).
Uncontrolled vasculogenesis and/or angiogenesis has been associated with diseases such as diabetes as well as with malignant solid tumors that rely on vascularization for growth. Klagsburn & Soker, Current Biology, 3(10):699-702 (1993); Folkham, J. Natl. Cancer Inst., 82:4-6 (1991); Weidner, et aL, New EngL J. Med., 324:1-5 (1991).

As presently understood, the role of VEGF in endothelial cell proliferation and migration during angiogenesis and vasculogenesis indicates an important role for the KDR/FLK-1 receptor in these processes. Diseases such as diabetes mellitus (Folkman, 198, in Xlth Congress of Thrombosis and Haemostasis (Verstraeta, et al., eds.), pp. 583-596, Leuven University Press, Leuven) and arthritis, as well as malignant tumor growth may result from uncontrolled angiogenesis. See e.g., Folkman, N. EngL
J. Med., 285:1182-1186 (1971). The receptors to which VEGF specifically binds are an important and powerful therapeutic target for the regulation and modulation of vasculogenesis and/or angiogenesis and a variety of severe diseases which involve abnormal cellular growth caused by such processes.
Plowman, et aL, DN&P, 7(6):334-339 (1994). More particularly, the KDR/FLK-1 receptor's highly specific role in neovascularization make it a choice target for therapeutic approaches to the treatment of cancer and other diseases which involve the uncontrolled formation of blood vessels.
Thus, one aspect of the present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction including KDR/FLK-1 receptor signal transduction in order to inhibit or promote angiogenesis and/or vasculogenesis, that is, compounds that inhibit, prevent, or interfere with the signal transduced by KDR/FLK-1 when activated by ligands such as VEGF.
Although it is believed that the compounds of the present invention act on a receptor or other component along the tyrosine kinase signal transduction pathway, they may also act directly on the tumor cells that result from uncontrolled angiogenesis.
Thus, in one aspect, this invention is directed to compounds that regulate, modulate and/or inhibit vasculogenesis and/or angiogenesis by affecting the enzymatic activity of the KDR/FLK-1 receptor and interfering with the signal transduced by KDR/FLK-1. In another aspect, the present invention is directed to compounds which regulate, modulate and/or inhibit the KDR/FLK-1 mediated signal transduction pathway as a therapeutic approach to the treatment of many kinds of solid tumors including, but not limited to, glioblastoma, melanoma and Kaposi's sarcoma, and ovarian, lung, mammary, prostate, pancreatic, colon and epidermoid carcinoma. In addition, data suggest the administration of compounds which inhibit the KDR/Flk-1 mediated signal transduction pathway may also be used in the treatment of hemangioma, restenois and diabetic retinopathy.
A further aspect of this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the fit-I
receptor.
Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and autophosphorylation. Binding sites are thereby created for intracellular signal transduction molecules which leads to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response, e.g., cell division and metabolic effects to the extracellular nnicroenvironment. See, Schlessinger and Ul!rich, Neuron, 9:1-20 (1992).
The close homology of the intracellular regions of KDR/FLK-1 with that of the PDGF-3 receptor (50.3% homology) and/or the related flt-I receptor indicates the induction of overlapping signal transduction pathways. For example, for the PDGF-3 receptor, members of the src family (Twamley et al., Proc. Natl. Acad. ScL USA, 90:7696-7700 (1993)), phosphatidylinosito1-3'-kinase (Hu et aL, MoL
Cell. Biol., 12:981-990 (1992), phospholipase cy (Kashishian & Cooper, Mol Cell. Biol., 4:49-51 (1993)), ras-GTPase-activating protein, (Kashishian et al., EMBO J., 11:1373-1382 (1992), PTP-ID/syp (Kazlauskas et al., Proc. Natl. Acad. Sc!. USA, 90:6939-6943 (1993)), Grb2 (Arvidsson etal., MoL CelL
BioL, 14:6715-6726 (1994)), and the adapter molecules Shc and Nck (Nishimura et al., MoL CelL BioL, 13:6889-6896 (1993)), have been shown to bind to regions involving different autophosphorylation sites.
See generally, Claesson-Welsh, Prog. Growth Factor Res., 5:37-54 (1994). Thus, it is likely that signal transduction pathways activated by KDR/FLK-1 include the ras pathway (Rozakis et aL, Nature, 360:689-692 (1992)), the PI-3'-kinase, the src-mediated and the plcy-mediated pathways. Each of these pathways may play a critical role in the angiogenic and/or vasculogenic effect of KDR/FLK-1 in endothelial cells. Consequently, a still further aspect of this invention relates to the use of the organic compounds described herein to modulate angiogenesis and vasculogenesis as such processes are controlled by these pathways.
Conversely, disorders related to the shrinkage, contraction or closing of blood vessels, such as restenosis, are also implicated and may be treated or prevented by the methods of this invention.
Fibrotic disorders refer to the abnormal formation of extracellular matrices.
Examples of fibrotic disorders include hepatic cirrhosis and mesangial cell proliferative disorders. Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. An increased extracellular matrix resulting in a hepatic scar can also be caused by a viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.
Other fibrotic disorders implicated include atherosclerosis.
Mesangial cell proliferative disorders refer to disorders brought about by abnormal proliferation of mesangial cells. Mesangial proliferative disorders include various human renal diseases such as glomerulonephritis, diabetic nephropathy and malignant nephrosclerosis as well as such disorders as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies. The RTK PDGFR
has been implicated in the maintenance of mesangial cell proliferation. Floege et al., Kidney International, 43:47S-54S (1993).
Many cancers are cell proliferative disorders and, as noted previously, PKs have been associated with cell proliferative disorders. Thus, it is not surprising that PKs such as, for example, members of the RTK family have been associated with the development of cancer.
Some of these receptors, like EGFR (Tuzi et al, Br. J. Cancer, 63:227-233 (1991), Torp et al., APM1S, 100:713-719 (1992)) HER2/neu (Slamon et aL, Science, 244:707-712 (1989)) and PDGF-R
(Kumabe et al., Onco gene, 7:627-633 (1992)) are over-expressed in many tumors and/or persistently activated by autocrine loops. In fact, in the most common and severe cancers these receptor over-expressions (Akbasak and Suner-Akbasak et al., J. NeuroL Sc!., 111:119-133 (1992), Dickson et al., Cancer Treatment Res., 61:249-273 (1992), Korc et al., J. Clin. Invest., 90:1352-1360 (1992)) and autocrine loops (Lee and Donoghue, J. Cell. BioL, 118:1057-1070 (1992), Korc etal., supra, Akbasak and Suner-Akbasak et aL, supra) have been demonstrated. For example, EGFR has been associated with squamous cell carcinoma, astrocytoma, glioblastoma,, head and neck cancer, lung cancer and bladder cancer. HER2 has been associated with breast, ovarian, gastric, lung, pancreas and bladder cancer.
PDGFR has been associated with glioblastoma and melanoma as well as lung, ovarian and prostate cancer. The RTK c-met has also been associated with malignant tumor formation.
For example, c-met has been associated with, among other cancers, colorectal, thyroid, pancreatic, gastric and hepatocellular carcinomas and lymphomas. Additionally c-met has been linked to leukemia. Over-expression of the c-met gene has also been detected in patients with Hodgkins disease and Burkitts disease.
IGF-IR, in addition to being implicated in nutritional support and in type-II
diabetes, has also been associated with several types of cancers. For example, IGF-I has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteaga et al., J.
Clin. Invest., 84:1418-1423 (1989)) and small lung tumor cells (Macauley et aL, Cancer Res., 50:2511-2517 (1990)). In addition, IGF-I, while integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas.
Sandberg-Nordqvist at al., Cancer Res., 53:2475-2478 (1993). The importance of IGF-IR and its ligands in cell proliferation is further supported by the fact that many cell types in culture (fibroblasts, epithelial cells, smooth muscle cells, T-Iymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)) are stimulated to grow by IGF-I. Goldring and Goldring, Eukaryotic Gene Expression, 1:301-326 (1991).
In a series of recent publications, Baserga suggests that IGF-IR plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, Cancer Res., 55:249-252 (1995), Baserga, Cell, 79:927-930 (1994), Coppola etal., CelL Biol., 14:4588-4595 (1994).
STIKs have been implicated in many types of cancer including, notably, breast cancer (Cance, at al., Int. J. Cancer, 54:571-77 (1993)).
The association between abnormal PK activity and disease is not restricted to cancer. For example, RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, von Hippel-Lindau disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas. For example, EGFR has been indicated in corneal and dermal wound healing. Defects in Insulin-R and IGF-1R are indicated in type-II diabetes mellitus. A more complete correlation between specific RTKs and their therapeutic indications is set forth in Plowman etal., DN&P, 7:334-339 (1994).
As noted previously, not only RTKs but CTKs including, but not limited to, src, abl, fps, yes, fyn, lyn, lck, blk, hck, fgr, AUR1, AUR2 and yrk (reviewed by Bolen at aL, FASEB
J., 6:3403-3409 (1992)) are involved in the proliferative and metabolic signal transduction pathway and thus could be expected, and have been shown, to be involved in many PTK-mediated disorders to which the present invention is directed. For example, mutated src (v-src) has been shown to be an oncoprotein (pp60v-') in chicken.
Moreover, its cellular homolog, the proto-oncogene pp60c-src transmits oncogenic signals of many receptors. Over-expression of EGFR or HER2/neu in tumors leads to the constitutive activation of pp6Oc sre, which is characteristic of malignant cells but absent in normal cells. On the other hand, mice deficient in the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src in osteoclast function and a possible involvement in related disorders.
Similarly, Zap70 has been implicated in T-cell signaling which may relate to autoimmune disorders.
STKs have been associated with inflammation, autoimmune disease, immunoresponses, and hyperproliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.
PKs have also been implicated in embryo implantation. Thus, the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents.
In yet another aspect, the compounds of the instant invention can also be used as anti-infective agents.
Finally, both RTKs and CTKs are currently suspected as being involved in hyperimmune disorders.
Pharmaceutical Compositions and Use A compound of the present invention or a physiologically acceptable salt thereof, can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the foregoing materials are mixed with suitable carriers or excipient(s). Techniques for formulation and administration of drugs may be found in "Remington's Pharmacological Sciences," Mack Publishing Co., Easton, PA, latest edition.
Routes of Administration Suitable routes of administration may include, without limitation, oral, intraoral, rectal, transmucosal or intestinal administration or intramuscular, epicutaneous, parenteral, subcutaneous, transdermal, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, intramuscular, intradural, intrarespiratory, nasal inhalation or intraocular injections. The preferred routes of administration are oral and parenteral.
Alternatively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a solid tumor, often in a depot or sustained release formulation.Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with tumor-specific antibody. The liposomes will be targeted to and taken up selectively by the tumor.
Composition/Formulation Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
Pharmaceutical compositions for use in the methods of the present invention may be prepared by any methods of pharmacy, but all methods include the step of bringing in association the active ingredient with the carrier which constitutes one or more necessary ingredients. In particular, pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, syrups, elixirs, gels, powders, magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal or oral sprays, aerosols and the like.
For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such buffers with or without a low concentration of surfactant or cosolvent, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries if desired, to obtain tablets or dragee cores.
Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, for example, maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinyl- pyrrolidone (PVP).
If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid. A salt such as sodium alginate may also be used.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers.
In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono- di- or triglycerides. Stabilizers may be added in these formulations, also.
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insuffiator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may also be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound.
Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. A compound of this invention may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. In addition, certain organic solvents such as dimethylsulfoxide also may be employed, although often at the cost of greater toxicity.
Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art.
Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

The pharmaceutical compositions herein also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Many of the PK modulating compounds of the invention may be provided as physiologically acceptable salts wherein the claimed compound may form the negatively or the positively charged species. Examples of salts in which the compound forms the positively charged moiety include, without limitation, quaternary ammonium (defined elsewhere herein), salts such as the hydrochloride, sulfate, malate, carbonate, lactate, tartrate, maleate, succinate wherein the nitrogen atom of the quaternary ammonium group is a nitrogen of the selected compound of this invention which has reacted with the appropriate acid. Salts in which a compound of this invention forms the negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group in the compound with an appropriate base (e.g.
sodium hydroxide (NaOH), potassium hydroxide (KOH), Calcium hydroxide (Ca(OH)2), etc.).
Dosage Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., the modulation of PK activity or the treatment or prevention of a PK-related disorder.
More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
For any compound used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from cell culture assays. Then, the dosage can be formulated for use in animal models so as to achieve a circulating concentration range that includes the 1050 as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal inhibition of the PK activity). Such information can then be used to more accurately determine useful doses in humans.
Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the 1050 and the LD50 (both of which are discussed elsewhere herein) for a subject compound. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et aL, 1975, in The Pharmacological Basis of Therapeutics", Ch. 1 p.1).
Dosage amount and interval may be adjusted individually to provide plasma levels of the active species which are sufficient to maintain the kinase modulating effects. These plasma levels are referred to as minimal effective concentrations (MECs). The MEC will vary for each compound but can be estimated from in vitro data, e.g., the concentration necessary to achieve 50-90% inhibition of a kinase may be ascertained using the assays described herein. Dosages necessary to achieve the MEG will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. At present, the therapeutically effective amounts of the inventive compounds described herein may range from approximately 25 mg/m2 to 1000- mg/m2 perday. Even more preferably 25 mg/m2 to 150 mg/m2.
In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration and other procedures known in the art may be employed to determine the correct dosage amount and interval.
The amount of a composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
Packaging The compositions may, if desired, be presented in a pack or dispenser device, such as an FDA
approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack.
The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or of human or veterinary administration. Such notice, for example, may be of the labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of a tumor, inhibition of angiogenesis, treatment of fibrosis, diabetes, and the like.EXAMPLES
The following examples are given to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples.
The numbering in the examples corresponds to the numbering in the Tables herein. Reaction schemes and example numbers beginning with a letter (I) relate to pyridine compounds, whereas those beginning with a letter (II) relate to pyrazine compounds. Example numbers beginning with L are library syntheses. Example numbers having a letter notation (a, b, c, etc.) illustrate the synthesis of reagents subsequently used in the synthesis of the inventive compounds, which have a number notation (1, 2, 3, etc.). Reagents can be synthesized as shown herein, or are available from commercial sources (e.g., Aldrich, Milwaukee, WI; Acros, Morris Plains, NJ; Biosynth International, Naperville, IL; Frontier Scientific, Logan, UT; TCI America, Portland, OR; Combi-Blocks, San Diego, CA;
Matrix Scientific, Columbia, SC; Acros, Morris Plains, NJ; Alfa Aesar, Ward Hill, MA; Apollo Scientific, UK; etc.) or can be synthesized by procedures known in the art. When a general or exemplary synthetic procedure is referred to, one skilled in the art can readily determine the appropriate reagents, if not indicated, extrapolating from the general or exemplary procedures.

In the general procedures 1-43 described herein, although some of the procedures are generalized and exemplary, past tense is used to indicate that these general procedures were the procedures used to synthesize the compounds. Some of the general procedures are given as examples for preparing specific compounds. One skilled in the art can readily adapt such procedures to the synthesis of other compounds. It should be understood that R groups shown in the general procedures are meant to be generic and non-limiting, and do not correspond to definitions of R groups elsewhere in this document. Each such R group represents one or multiple chemical moieties that can be the same or different from other chemical moieties also represented by the same R
symbol. Moreover, representation of an unsubstituted position in structures shown or referred to in the general procedures is for convenience and does not preclude substitution as described elsewhere herein. For specific groups that can be present, either as R groups in the general procedures or as optional substitutents not shown, refer to the descriptions in the remainder of this document, including the claims, summary and detailed description. It should be further understood that compound numbers shown in the general schemes and general procedures in the Examples are for convenient reference only, and do not correspond to the numbers used elsewhere throughout this document. For example, the nitropyridine compound (1) in general scheme 1 is different from the compound of formula 1 described herein.

General Scheme 1 for the Synthesis of 5-Aryl-3-(Substituted-Benzyloxy)-Pyridin-2-ylamine (6):

General Scheme 11 for the Synthesis of 5-Aryl-3-(Substituted-Benzyloxy)-Pyrazin-2-ylamine Br cs2co3 0 crµi Fe 0.cv _ HCYcNH2 NO2 DMF
NO2 AcOH/Me0H

Pd(PPh3)2ci2 Aryl DME/Na2CO3/H20 *I 0 CH30N NH2 Aryl Boronic acid 0 NH2 = g r Pd(PPh3)2Cl2 Ai r N DME/Na2CO3/H20 riLrN N11). R
Reflux is OH NaH/THF R 10 /
0)Lr N 800C

NH2 ArB(OH)2 NH, General Procedure 1 for the Synthesis of 5-Bromo-3-(Substituted-Benzyloxy)-Pyridin-2-ylamine (5):

1. Preparation of 3-(substituted-benzyloxy)-2-nitro-pyridine (3): To a stirred solution of Cs2CO3 (1.0 molar equivalent)) in DMF (0.2 M) under a N2 atmosphere containing 3-hydroxy-4-nitro-pyridine (Aldrich, 1.0 molar equilvalent) was added substituted benzyl bromide (1.0 molar equivalent). The mixture was stirred for 6 h at ambient temperature. The reaction was then diluted with Et0Ac , and partitioned with H20. The aqueous layer was extracted with Et0Ac twice. The organic layers were then combined, washed with H20 and brine, dried over Na2SO4, filtered, and concentrated to dryness under vacuum to yield 3-(substituted-benzyloxy)-2-nitro-pyridine (3) as a solid.

2. Preparation of 3-(substituted-benzyloxy)-pyridin-2-ylamine (4): To a stirred mixture of AcOH

and Et0H (1.3:1) was suspended 3-(substituted-benzyloxy-2-nitro-pyridine (1.0 molar equivalent, 1 M) and iron chips (1.0 molar equivalent). The reaction was heated slowly to reflux and allowed to stir for 1 hr. The reaction was cooled to room temperature then filtered through a pad of celite. The resulting filtrate was neutralized with conc. NH4OH, and then extracted with Et0Ac for three times. The combined organic extracts were washed with saturated NaHCO3, H20, and brine, dried over Na2SO4, filtered and concentrated to dryness under vacuum to yield 3-(substituted-benzyloxy)-pyridin-2-ylamine (4) as a solid.

3. Preparation of 5-bromo-3-(substituted benzyloxy)-pyridin-2-ylamine (5): A
stirring solution of 3-(substituted-benzyloxy)-pyridin-2-ylamine (4) (1.0 molar equivalent) in acetonitrile was cooled to 0 C

using an ice bath. To this solution was added N-bromosuccinimide (Aldrich, 1.0 molar equivalent) portionwise. The reaction was stirred at 0 C for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in Et0Ac and partitioned with H20. The organic was then washed with saturated NaHCO3 twice and brine once. Activated charcoal was added to the organic layer and warmed to reflux. The solution was then cooled to room temperature and filtered through a pad of celite. The organic was then concentrated to dryness under vacuum to one third the original volume. The solids were then filtered off to yield 5-bromo-3-(substituted benzyloxy)-pyridin-2-ylamine (5) as a solid.

General Procedure 2 for the Synthesis of 5-Bromo-3-(Substituted-Benzyloxy)-Pyrazin-2-ylamine.

Br Br Br)Lr N +R Nrsi".*'1NaH/THF

OrN NH2 Reflux To an ice cooled solution of substituted benzyl alcohol (1.0 molar equivalent) and anhydrous tetrahydrofuran (0.14 M) was added sodium hydride (1.0 molar equivalent) slowly under nitrogen atmosphere. After stirring for 30 minutes, 3,5-dibromopyrazin-2-ylamine (1.0 molar equivalent) in tetrahydrofuran (0.56 M) was added via an addition funnel at a fast dropwise rate. Once the addition was complete the ice bath was removed and the reaction was refluxed under nitrogen and monitored by reversed phase HPLC. After 18 hr HPLC showed that the majority of the starting 3,5-dibromopyrazin-2-ylamine had been consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with brine.
The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuum. The crude product was purified using a silica gel eluting with 1:1 ethyl acetate/dichloromethane to yield the 5-bromo-3-(substituted-benzyloxy)-pyrazin-2-ylamine as a white solid in 60-90% yield.

General Procedure 3 for the Synthesis of 5-Aryl-3-(Substituted-Benzyloxy)-Pyridin-2-ylamine and 5-Aryl-3-(Substituted-Benzyloxy)-Pyrazin-2-ylamine.

111. Pd(PPh3)2Cl2 Aryl DME/Na2003/H20 1.1 0 NH2 Aryl Boronic acid .= 0 Y: CH or N

A mixture of 5-bromo-3-(substituted-benzyloxy)-pyridin-2-ylamine or 5-bromo-3-(substituted-benzyloxy)-pyrazin-2-ylamine (1 molar equivalent), aryl boronic acid or ester (1.2 molar equivalent), bis(triphenylphosphine) palladium II chloride (0.03 molar equivalent) and sodium carbonate (3.0 molar equivalent.) in ethylene glycol dimethyl ether and water (10:0.5, 0.03 M) was de-gassed and charged with nitrogen for three times, and then heated to reflux under nitrogen for overnight. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The mixture was washed with water, brine, dried over Na2SO4, and purified on a silica gel column to afford 5-aryl-3-(substituted-benzyloxy)-pyridin-2-ylamine, or 5-aryl-3-(substituted-benzyloxy)-pyrazin-2-ylamine.

General Procedure 4 for Amidation Reaction of 6-amino-5-(substituted-benzyloxy)-pyridin-3-yI]-benzoic acid:

=
=

OH
NR'R"
HOBt/EDC
+ HNR'R"
DMF

R

To a solution of 6-amino-5-(substituted-benzyloxy)-pyridin-3-yI]-benzoic acid (1 molar equivalent), 1-hydroxybenzotriazole hydrate (HOBT, 1.2 molar equivalent), and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride (EDC, 1.2 molar equivalent) in DMF (0.2 M) was added amine (1.2 molar equivalent). The reaction solution was stirred at room temperature for overnight, then diluted with Et0Ac, and partitioned with H20. The organic was separated and the aqueous was extracted with Et0Ac. The organic layers were combined, washed with saturated NaHCO3, and concentrated to dryness under vacuum. The material was purified using column chromatography (silica gel, 99:1 to 95:5 CH2C12/Me0H). The fractions containing product were concentrated under vacuum to yield the amide product.
General procedure 5 for the preparation of 3-(substituted-benzyloxy)-5-(3-dialkylaminomethyl-1H-indo1-5-y1)-pyridin-2-ylamine:
H \

io Nil + R'R"NH Formaldehyde 1101 l'12N 10 CH2012 Fs I
R" R.1 NHN2 R' HN R"

= 0 To a solution of benzotriazole (1.0 molar equivalent) in dichloromethane (0.2 M) was added amine (1.0 molar equilvalent). The reaction was stirred for 5 minutes at room temperature after which formaldehyde (37 % by wt, 1.0 molar equivalent) was added and the reaction was capped and stirred at room temperature for 3 hr. Once TLC (10 % ethyl acetate: dichloromethane) showed the consumption of starting benzotriaziole the reaction was dried with anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo. The crude product was purified with a silica gel column eluting with 1:1 ethyl acetate: dichloromethane to yield the desired product as a white solid.
To a solution of the aminomethylbenzotriazole intermediate (1.0 molar equivalent) in dichloromethane (0.43 M) was added aluminum chloride (2.0 molar equivalent), and then followed by 3-(2,6-Dichloro-benzyloxy)-5-(1H-indo1-5-y1)- pyridine-2-ylamin (1.1 molar equivalent). The reaction was capped and heated with stirring to 40 C for 3-4 hr. The reaction was then removed from the heat and allowed to cool to room temperature. The reaction mixture was diluted with sodium hydroxide (0.2 M) and chloroform, recapped and vigorously stirred at room temperature to dissolve the residue in the vial.
The chloroform was extracted away from the aqueous, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified with a silica gel column, first eluting with 1:1, ethyl acetate: dichloromethane, to elute the less polar impurities and then eluting the product with 90:9:1, chloroform:methanol:ammonium hydroxide. (Yields 10-67%.) General Procedure 6 for the synthesis of 3-(Substitited-benzyloxy)-5-phenyl-pyridin-2-ylamine using example 1-88:

- 65 _ H2 NaH/Chlorotrityl , --o 1 Pd(OH)2 Br I
0 2 Methanol HO HO
= NH NH2 HN 0111 p.

C s2C 0 3/ D M F
I 20% TFA/DCM

HN I

*

To a solution of 3-benzyloxy-5-phenyl-pyridin-2-ylamine (Example 1-87, 3.27g, 11.8mmol) in methanol (30mL) was added Pd(OH)2 (2.5g, 2.37mmol). The mixture was degassed and charged with hydrogen three times, and then stirred under hydrogen balloon for 5 hr. The reaction was filtered through a celite pad, washed with methanol, and condensed. After high vacuum dry, 2-amino-5-phenyl-pyridin-3-ol was obtained (2.04g, 93% yield). MS ink 187 [M+1].

To a solution of 2-amino-5-phenyl-pyridin-3-ol (2.04 g, 10.95 mmol) in THF
(anhydrous, 30 mL) was added NaH (1.31 g, 32.85 mmol) slowly. The mixture was stirred under nitrogen for 20 minutes, and then trityl chloride (3.66 g, 13.14 mmol) was added. The reaction was stirred at room temperature for over night under nitrogen. The solvent was evaporated, and the residue was dissolved in dichloromethane, washed with water, and dried over Na2SO4. After filtration and condensation, the crude product was purified on a silica gel column eluting with Et0Ac-Hexane (1:10) to provide 5-phenyl-2-(trityl-amino)-pyridin-3-ol (1.09 g, 23% yield). MS miz 427 [M+1].

To a solution of 5-phenyl-2-(trityl-amino)-pyridin-3-ol (100 mg, 0.24 mmol) in THE (3 mL) was added Cs2CO3 (79 mg, 0.24 mmol). The mixture was stirred at room temperature for 20 minutes, and then 3-methoxybenzylbromide (0.037 mL, 0.26 mmol) was added. The reaction was stirred at room temperature overnight, diluted with dichloromethane (5 mL), and filtered to remove the salts. The solvents were evaporated, and the residue was dissolved in 10% trifluoroacetic acid in dichloromethane (2 mL). The reaction was stirred for 2 hr, and evaporated. The residue was dissolved in dichloromethane, washed by sat. NaHCO3, and dried over Na2SO4. After filtration and concentration, the crude product Was purified on a silica gel column eluting with methanol-dichloromethane (from 3% to 15% gradient) to provide 3-(3-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine as a white solid (43.5 mg, 60% yield).

General Procedure 7 for the Synthesis of 3-(Substituted-benzyloxy)-5-Aryl-pyridin-2-ylamine using Example 1-106:

rtvi ofNr.:, o) *

+ * Br NaH/DMF
I .,.
.N 0 ,N

To a solution of 2-amino-544-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-ol (prepared according to the procedures for 2-amino-5-phenyl-pyridin-3-ol in Example 1-88) (45.5 mg, 0.14 mmol) in DMF (3 mL) at 0 C was added NaH (60% in oil) (5.6 mg, 0.14 mmol) and the mixture was stirred at 0 C for 20 min. Then 1-Bromomethy1-3-nitro-benzene was added and the mixture was stirred at 0 C for 1 hr and at room temperature for 2hr. Cold 1 N aqueous HCI (0.1 mL) was added and the solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (CH2C12:MeOH:NH4OH = 100:3:0.3) to give 5-[4-(2-morpholin-4-yl-ethoxy)-pheny1]-3-(3-nitro-benzyloxy)-pyridin-2-ylamine as yellow solid (44 mg, 68%).

General Procedure 8 for the Synthesis of {446-Amino-5-(substituted-benzyloxy)-pyridin-3-y11-pheny1)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-l-yl]-methanone using Example 1-111:

CDN

r 0 OH

HOBVEDC
io 04Hq + I IP . o 1 ,,N
+ DMF
2 7t*.B., HN
NH2 io 0 2 I.,N
NH

0 ?

H2/ 10%Pd/Cu 0 N
+ so Br NaH/DMF 0 )\-3 Methanol F CF, , ..

HO rµI di 0 NH, F CF, NH2 =

I. 6-Amino-5-benzyloxy-nicotinic acid was prepared according to procedure 3 from 3-benzyloxy-5-bromo-pyridin-2-ylamine and 4-(4,4,5,5-tetramethyl-[1,3,2)dioxaborolan-2-y1)-benzoic acid.

MS m/z 321 (M+1).

2. [4-(6-amino-5-benzyloxy-pyridin-3-y1)-pheny1]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone was prepared following procedure 4 using 6-amino-5-benzyloxy-nicotinic acid and (2R)-pyrrolidin-1-ylmethyl-pyrrolidine (prepared in Example 1-39). MS m/z 457 (M+1).

3. To a solution of [4-(6-amino-5-benzyloxy-pyridin-3-y1)-pheny1]-[(2R)-pyrrolidin-1-ylmethyl-pyrrolidin-1-y11-methanone (2.28 g, 5.00 mmol) in methanol (25 mL) was added 10% Pd/C (100 mg).

The mixture was degassed and charged with hydrogen for three times, and then stirred under hydrogen balloon overnight. The reaction was filtered through a celite pad, washed with methanol, and condensed. After high vacuum dry, [4-(6-amino-5-hydroxy-pyridin-3-y1)-pheny1]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1)-methanone was obtained (1.74 g, 95% yield). 1H
NMR(400 MHz, DMSO-d6) 6 7.79 (s, 1H), 7.54 (m, 3H), 7.46 (m, 2H), 7.14 (s, 1H), 5.68 (s, 2H), 4.22 (m, 1H), 3.45 (m, 2H), 2.66 (m, 1H), 2.52 (m, 4H), 1.96 (m, 2H), 1.84 (m, 3H), 1.64 (m, 4H); MS m/z 367 (M+1).

4. To a stirred solution of [4-(6-amino-5-hydroxy-pyridin-3-y1)-pheny1]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone (100 mg, 0.27mmol) in anhydrous DMF(15 mL) under a N2 atmosphere containing, at 0 C, sodium hydride (60% dispersion in mineral oil, 11 mg, 0.49mmol) was added . The mixture was allowed to stir at 0 C for 30 min. 1-(Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (0.046 mL, 0.27mmol) was added. The mixture was stirred at room temperature for 2hr.The reaction was diluted with Et0Ac, and partitioned with H20. The aqueous layer was extracted with Et0Ac (2 x 25 mL). The organic layers were combined, washed with H20 (1 x 15ml), brine (1 x 15mL), dried over MgSO4, filtered, concentrated, and purified on a silica gel column to yield {446-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y9-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone as off-white crystals.

General Procedure 9 for the Synthesis 2-Dialicylamino-ethanesulfonic acid [6-amino-5-(substituted-benzyloxy)-pyridin-3-yl]-phenyl-amide using Example 1-243.

NH2 HN" .`".' Et2N H

9 10 cH2c12 + 1 Co) HI\I" Nµ

Pd(PPh3)2C12 DME/Na2CO3/H20 1101 + 0 LrN 80 C 31' F 1 1. To a solution of 4-(4,4,5,5-Tetramethy141,3,21dioxaborolan-2-y1)-phenylamine (5 g, 22.8 mmol) in dichloromethane (120 mL ) was added N-methyl morpholine (7.5 mL, 68.4 mmol). This mixture was cooled to 0 C under nitrogen atmosphere. 2-Chloroethanesulfonyl chloride (2.5 mL, 23.9 mmol) in dichloromethane (60 mL) was then added drop wise with stirring. Once the addition was complete the flask was stirred at 0 C for 1 hr and then at room temperature while monitoring by TLC
(1:1 ethyl acetate:hexanes) and staining with ninhydrin. After 4 h stirring some starting boronic ester still remained and an additional 0.2 equivalents (0.5 mL) of 2-chloroethanesulfonyl chloride in dichloromethane (25 mL) was added drop wise at room temperature. After 1 hr the boronic ester had been consumed as shown by TLC and the total reaction volume was reduced by one-half via rotary evaporation. The contents were diluted with ethyl acetate (200 mL), washed with 50% brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified using silica gel (120 g) and eluting with 10% ethyl acetate, dichloromethane to yield ethenesulfonic acid [4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenyTamidea as a white solid (6.2 g, 20.2 mmol, 89%
yield). IH NMR (CDCI3, 300 MHz), 6 7.76 (d, J = 8.4, 2H), 7.12 (d, J = 8.45, 2H) 6.65 (s, 1H), 6.55 (dd, J
= 9.77, 6.7, 1H), 6.31 (d, J = 16.54, 1H), 5.96 (d, J = 9.8, 1H), 1.33 (s, 12H).
2. To a solution of ethenesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenyly amide (0.500 g, 1.6 mmol) in methanol (5 mL) was added diethylamine (0.707 g, 4.0 mmol) in methanol (5 mL), and the reaction was stirred at room temperature and monitored by TLC
(1:1 Ethyl acetate:
hexanes). After 2 hr the reaction was concentrated in vacuum and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate was then washed with 50%
brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum.
Crude product was purified using a 10 g prepacked silica gel column, eluting with 1:1 ethyl acetate:
dichloromethane to provide 2-diethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yI)-phenyll-amide as a white solid (0.346 g, 0.90 mmol, 56%). IH NMR (CDCI3, 300 MHz) 6 7.78 (d, J =
6.65, 2H) 7.15 (d, J =
6.66, 2H), 3.20 (m, 2H), 3.0 (m, 2H), 2.55 (q, J = 7.15, 7.16 4H), 1.34 (s, 12H), 1.05 (t, J = 7.19, 6H).
3. 2-diethylamino-ethanesulfonic acid {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-phenylyamide was prepared following the general Suzuki coupling procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 2-diethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenyTamide prepared in part 2 as a white solid in 60% yield.
General Procedure 10:
1: 4-(4,4,5,5-tetramethyl 1,3,2 dioxaboralan-2-y1) aniline (3 g, 0.013 mol) was dissolved in dichloromethane (350 mL) to which pyridine (1.02 g, 0.013 mol) and 4-nitrophenyl chloroformate was added. The reaction was stirred for 13 hr where TLC analysis showed consumption of all starting materials. The solution was washed with saturated NaHCO3 (3 x 50 mL), water (3 x 50 mL) and brine (3 x 50 mL). The organic layer was dried over Na2SO4 and solvent removed to yield a white crystalline solid [4-(4,4,5,5-Tetrannethyl-[1,3,2]dioxaborolan-2-y1)-pheny9-carbamic acid phenyl ester, 4.45 g, 91%.
IH NMR (CDCI3 300 MHz) 1.4 (s, 12H), 7.1 (brs, 1H), 7.3 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.3 (d, 2H).

0 )0( NH, 0 CI HN 0 PyridineEtõN/CH2C12 + 110 + He CH2Cl2/Reflux R' 0 0 NO2 0 0 HN,I,Nõ R
14, 0 Br ,. CI
HN NR II CI Pd(PPh3)4 N
0-yN NH2 DME/H20 is 0 CI Na2CO, 01 NH2 2: [4-(4,4,5,5-Tetramethy141,3,2]dioxaborolan-2-y1)-phenyli-carbamic acid phenyl ester (500 mg, 1.3 mmol) was dissolved in anhydrous dichloromethane (0.5 mL) and triethylamine (0.187 mL, 1.3 mmol). To this stirred solution was added 1-methyl piperazine (or any other amine) (0.144 mL, 1.3 nnnnol). The solution turned yellow instantly, and tic analysis showed consumption of all starting material. The reaction was washed with water (3 x 500 mL), saturated sodium bicarbonate (2 x 200 mL) and dried prior to removal of solvents in vacuo. The boronic esters were used without purification.

3: To a mixture of 2.1 mL of DME and 2.8 mL of 2N Na2CO3 was added 100 mg of the bromide scaffold, 1 equivalent of the boronic acid, and 5 mai % of Pd(PPh3)4. The reaction was stirred and heated at 80 C overnight in a two dram vial. The crude mixture was filtered through ceolite and extracted with Et0Ac (2 x 100 mL). The combined extracts were washed with NaHCO3 (1 x 100 mL), followed by water (1 x 100 mL), and then saturated brine (lx 100mL). The resulting mixture was concentrated in vacuum. The residue was dissolved in hexane and purified via column chromatography.

General Procedure 11:

r NIS 0 0 21( N
ON NH2 I I Et3NTTHFppho, 110I 0 NH2 NI-12 CH3CN/Ac01-1 CI CI
CI

iro old 1. P Nyridine/CH2Cl2 25%TFA/CH2Cl2 CI

OrN 2. + 101 N
NH2 HRR' 0 1: To a solution of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)ethoxy]-pyridin-2-ylamine (10.0 g, 33.2 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-iodosuccinimide (11.2 g, 49.8 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with Na2S205 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO4.
The crude product was purified on a silica gel column to provide 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (7.1 g, 50% yield).MS miz 427 (M+1]

2: To a solution of 341-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy1-5-iodo-pyridin-2-ylamine (7.1 g, 16.6 mmol) and prop-2-ynyl-carbamic acid tert-butyl ester (3.1 g, 20.0 mmol) in THF (60 mL) and Et3N

(60 mL) was added Cul (63 mg, 0.3 mmol) and Pd(PPh3)4 (384 mg, 0.3 mmol). The mixture was stirred under nitrogen and monitored by TLC until the reaction was complete. The mixture was extracted with Et0Ac and washed by water. The crude product was purified on a silica gel column eluting with 20-40%

Et0Ac in hexanes to provide (3-{6-Amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-prop-2-ynyI)-carbamic acid tert-butyl ester (2.2 g, 29% yield).

3: The solution of (3-(6-Amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-prop-2-yny1)-carbamic acid tert-butyl ester in 25% TFA in dichloromethane was stirred for 2 hr, then washed by 2N NaOH, water twice, brine, dried over Na2SO4. After filtration and evaporation, 5-(3-amino-prop-1-yny1)-341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine was obtained in 93% yield.

4: To a solution of 5-(3-amino-prop-1-yny1)-341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (0.282 mmol, 1 eq) and 4-nitrophenyl chloroformate (1 eq) in anhydrous dichloromethane (10 mL) was added pyridine (1 eq). The reaction was stirred for 4 hr under nitrogen, and then the selected amine (1 eq) and triethylamine (1 eq) were added. The mixture was refluxed for 5 minutes and cooled to room temperature. The reaction mixture was washed with water. The organic layer was evaporated and purified on a silica gel column eluting with 0-20% methanol in dichloromethane on prepacked silica columns. Final yields varied between 24% and 71%.

General Procedure 12:

H

1..1rCI
lly-''NRR' , L \

I1 \ 0 CI , \
NHRR' I
CH2Cl2 i N 1FC1_,ACI
. 0 0...yN

Acetonttrile NH

CI
CI
CI

F
F
F

1: To a solution of 5-(3-amino-prop-1-yny1)-341-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-2-ylamine (prepared in procedure 11) (400 mg, 1.1 mmol) in dichloromethane (17 mL) was added chloroacetyl chloride (153 mg, 1.4 mmol). The reaction was stirred at room temperature with TLC

monitor of the completion of the reaction. After the completion, the solvent was evaporated to get the crude product.

2: To a solution of N-(3-{6-Amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-y1}-prop-2-yny1)-2-chloro-acetamide (1 eq) in acetonitrile (5 eq) was added the individual amine (5 eq). The mixture was refluxing under nitrogen overnight. After evaporation of solvent, the residue was purified on a silica gel column eluting with 1-10% methanol in dichloromethane to provide the product with yields varied between 47% to 97%.

General Procedure 13:

o 0, 0 0, Br 0 0, ,p NBS
Pd(P133)4 H2/Pd/C
(Ro 4:INI + 0 1 -2- --- 1 +
0 !, 0 - NH, ACN
Na2CO3 ', 11 Et0H/H,0 ,,, N

40 NH, - HO
- Hooli DME/H20 ISS
NH

0 OH 0 N.IT
0 0, 0 0,.

DMAP

cH2c6 IP
IP
40 LiOH
HOBt/EDC
SI , 41;3 OH NaH
---3.
.--9,0 I kr -3. DMF
F, 1 Me0Hi 0 , , N F3 F ,,, '. N
F F ,d 4 S.

NH IP

1. To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH3CN (600 mL) at 0 C was added N-bromosuccinimide (37.1 g, 0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with Et0Ac (900 mL) and partitioned with H20 (900 mL).

The organic layer was washed with brine and dried (Na2SO4), filtered and concentrated to dryness =

under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53%). 1H NMR (CDCI3, 300 MHz) 6 4.63-4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).

2. To a stirred mixture of 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol) in a mixture of DME (600 mL) and H20 (600 mL) was added 4-carboxymethylboronic acid (29.9 g, 0.11 mol), Pd(PPh3)4 (6.4 g, 5.55 mmol), and Na2CO3 (82.0 g, 0.78 mol). The reaction was heated slowly to reflux and allowed to stir for 3 hr. The reaction was cooled to room temperature, then diluted with CH2Cl2 (1.5 L) and partitioned with H20 (700 mL). The organic layer was washed with saturated NaHCO3 (700 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by column chromatography (silica gel, 1:1 to 4:1 Et0Ac:hexanes) and the fractions containing product were combined and concentrated in vacuo to yield 4-(6-amino-5-benzyloxy-pyridin-3-yI)-benzoic acid methyl ester (29.4 g, 0.086 mol, 79%). 1H NMR (CDCI3, 300 MHz) 0 3.92 (s, 3H), 4.82-4.94 (brs, 2H), 5.15 (s, 2H), 7.22 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.54 (d, 2H, J, 8.6), 7.98 (d, 1H, J, 1.8 Hz), 8.06(d, 2H, J, 8.6 Hz).
3. To a stirring solution of 4-(6-amino-5-benzyloxy-pyridin-3-yI)-benzoic acid methyl ester (10.0 g, 0.03 mol) in Et0H:H20 (95:5, 600 mL) was added Pd/C (15.9 g, 0.015 mol) (the reaction was de-gassed under vacuum). The solution was allowed to stir under an H2 atmosphere for 22 hr. The solution was filtered through wet celite and the celite washed with Et0H. The filtrate was concentrated under vacuum to yield 4-(6-Amino-5-hydroxy-pyridin-3-yI)-benzoic acid methyl ester (2.3 g, 9.3 mmol, 31%). 1H NMR (Me0D, 300 MHz) 63.90 (s, 3H), 7.21 (d, 1H, J, 1.9 Hz), 7.62 (d, 2H, J, 8.5 Hz), 7.76 (d, 1H, J, 1.9 Hz), 8.04(d, 2H, J, 8.5 Hz).
4. To a stirring solution of 4-(6-amino-5-hydroxy-pyridin-3-yI)-benzoic acid methyl ester (2.3 g, 9.3 mmol) in CH2Cl2 (180 mL) was added N,N-diisopropylethylamine (3.2 mL, 0.019 mol), 4-methyl-benzenesulfonyl chloride (2.66 g, 0.014 mol), and PS-DMAP (catalytic amount).
The reaction was stirred at ambient temperature for 6 hr then filtered to remove the resin. The resin was washed with CH2Cl2 (3 x 20 mL), and the combined fractions were washed with 10% citric acid (100 mL), saturated NaCI (100 mL), dried (Na2SO4) and filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (silica gel, 100% CH2Cl2 to 95:5 CH2C12:Me0H) and the fractions containing the desired product were combined and concentrated in vacua to yield 446-Amino-5-(toluene-4-sulfonyloM-pyridin-3-y9-benzoic acid methyl ester (3.3 g, 8.2 mmol, 88%). 1H NMR
(CDCI3, 300 MHz) 6 2.47 (s, 3H), 3.93 (s, 3H), 4.81-4.88 (brs, 2H), 7.36-7.44 (m, 5H), 7.81 (d, 2H, J, 8.3 Hz), 8.05 (d, 2H, J, 8.4 Hz), 8.19-8.27 (brs, 1H).
5. To a stirred solution of 1-(3-fluoro-2-trifluoromethyl-phenyl)ethanol (2.0 g, 9.6 mmol) in anhydrous DMF (500 mL) at 0 C under a N2 atmosphere was added NaH (0.38 g, 9.6 mmol). The reaction was allowed to stir for 0.5 hr. A solution of 446-Amino-5-(toluene-4-sulfonyloxy)-pyridin-3-y11-benzoic acid methyl ester (3.8 g, 9.6 mmol) in anhydrous DMF (30 mL) was added to the reaction mixture which was allowed to come to ambient temperature slowly and stirred for 21 hr at this temperature. The reaction was diluted with Et0Ac (500 mL) and H20 (100 mL).
The organic layer was separated off and the aqueous was further extracted with Et0Ac (1 x 200 mL).
The organic layers were combined and washed with brine (1 x 100 mL), dried with Na2SO4 and concentrated to dryness under vacuum. The crude mixture was purified by column chromatography (silica gel, 40:60 to 70:30 Et0Ac:hexanes) and the fractions containing product were combined and concentrated in vacuo to yield 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-y1}-benzoic acid methyl ester (1.4 g, 3.2 mmol, 34%). 1H NMR (CDCI3, 300 MHz) 0 1.73 (d, 3H, J, 6.2 Hz), 3.91 (s, 3H), 4.87-4.64 (brs, 2H), 5.81 (q, 1H, J, 6.1, 6.3 Hz), 6.92 (d, 1H, J, 1.8 Hz), 7.38 (d, 2H, J, 8.5 Hz), 7.46-7.66 (m, 3H), 7.93 (d, 1H, J, 1.8 Hz), 8.02 (d, 2H, J, 8.5 Hz).

CT') õ.

27 SE? 2.1104 6. To a stirred solution of 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-pheny1)-ethoxy]-pyridin-3-y1}-benzoic acid methyl ester (1.4 g, 3.2 mmol) in warm IPA (72 mL) was added H20 (38 mL) containing LiOH (0.68 g, 16.2 mmol). The reaction was heated to reflux for 3.5 hr. The reaction was neutralized and diluted with Et0Ac (200 mL) and extracted upon cooling. The organic layer was washed with brine 5 (50 mL), dried over Na2SO4 and concentrated under vacuum to yield 4-{6-Amino-541-(3-fluoro-2-trifluoromethyl-pheny1)-ethoxyypyridin-3-y1}-benzoic acid (1.2 g, 2.8 mmol, 88%). 1H NMR (Me0D, 300 MHz) 5 1.75 (d, 3H, J, 6.2 Hz), 4.88-4.93 (m, 1H), 7.01 (d, 1H, J, 1.8 Hz), 7.39 (d, 2H, J, 8.3 Hz), 7.52-7.67 (m, 3H), 7.80 (d, 1H, J, 1.8 Hz), 7.97 (d, 2H, J, 8.3 Hz).
7. Preparation of amide compounds: A stirring solution of 4-{6-Amino-5-[1-(3-fluoro-2-/---, 10 trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yll-benzoic acid (50 mg, 0.12 mmol), EDC (27.0 mg, 0.13 Au. mmol) and HOBt (18.0 mg, 0.13 mmol) in DMF (2 mL) was added to a two dram vial containing NHR1R2 (0.12 mmol). The reaction was stirred at room temperature for 18 hr. The reaction was then diluted with CH2Cl2 (3 mL) and partitioned with H20. The organic was separated washed with saturated NaCI (1 x 2 mL) and saturated NaHCO3 (1 x 2 mL). The organic was concentrated to dryness under vacuum. The 15 material was purified using column chromatography (silica gel, 99:1 to 95:5 CH2C12/Me0H). The fractions containing product were concentrated under vacuum to yield amide compounds.
General Procedure 14:

? cszcoiomF
Pd(PPh3),C6 SV. Cr-'' _71-4õ F B, 1110 CI NH2 Na,CO3 DMEIH20 io 1: To a mixture of 1-(2-chloroethyl)pyrrolidine hydrochloride (200 mg, 1.18 mmol) 20 and 444-(4,4,5,5-Tetramethy141,3,2]dioxaborolan-2-y1)]-1H-pyrazole (229 mg, 1.19 mmol) in DMF
(6 mL) was added Cs2CO3. The mixture was stirred at room temperature overnight. Water (10 mL) was then added to the mixture. The product was extracted with Et0Ac (3 x 10 mL). The combined extracts were then washed with brine (5 x 10 mL) to remove the DMF, then dried over Na2SO4, and concentrated (142 mg, 41% yield).

25 2: To a mixture of 341-(2,6-Dichloro-3-fluoro-pheny1)-ethoxy]-5-iodo-pyridin-2-ylamine (200 mg, 0.468 mmol), pinacol boronic ester (1.2 eq), Na2CO3 (149 mg, 1.41 mmol) in water (1.25 mL), and dimethyl ethyl glycol (3.75 mL, 0.1M) was added Pd(PPh3)2C12 (16 mg, 0.020 mmol) in a microwave reaction vessel. The system was degassed and charged with nitrogen. The mixture was stirred at 160 C in a microwave apparatus for 15 minutes. The mixture was cooled to room temperature followed 30 by the addition of water (10 mL). The product was extracted with Et0Ac (3 x 20 mL), dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC
with 0.1% TFA in water and acetonitrile.

51111=111.11111.SHEET

General Procedure 15:

r r r NBSNaOH
==
Cs2CO3 R.0 -,' N
--N ---31"
I _.,N + R¨Br -31' O'Y ACN/AcOH ¨ I
HO
--NH
)¨NH

1: To a solution of 3H-oxazolo[4,5-b]pyridin-2-one (13.6 g, 100 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-bromosuccinimide (21.4 g, 120 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with Na2S205 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N
NaOH solution, brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (11.5 g, 55% yield).
2: 6-Bromo-3H-oxazolo[4,5-b]pyridin-2-one (21.5 g, 100 mmol) was supended in NaOH solution (2N, 250 mL, 500 mmol). The mixture was refluxed overnight and a clear solution was obtained. After cooling to room temperature, the reaction solution was neutralized to pH ¨7. A
lot of CO2 was released and also precipitate was observed. The product was filtered, washed with water, and dried under high vacuum to provide 2-amino-5-bromo-pyridin-3-ol as an off-white solid (17.8 g, 98% yield).
3: To a solution of 2-amino-5-bromo-pyridin-3-ol (358 mg, 1.89 mmol) in DMF (8 mL) was added Cs2CO3 (620 mg, 1.89 mmol). The mixture was stirred at room temperature under nitrogen for 1 hr. To the reaction mixture was added bromo-compound (0.9 eq) in DMF (5 mL) slowly. The reaction solution was stirred under nitrogen for five hr, and then partitioned between water and ethyl acetate.
The organic layer was washed with brine for three times, dried over MgSO4. The crude product was purified on a silica gel column eluting with hexane-ethyl acetate (4:1) to provide the product with 70%-80% yield.
General Procedure 16 using Example 1-488:
----.,.r1 r , [10 0 AI
I + 0),Bp pda2oppo0H2a2 0 0 K0Acipms0 ,.
0õ0 -:N

PcdsC21c2(odp3pf).CH2C12 . ,.

I
--N

io 0 2 io 0 NH
Br 1. To a solution of 3-benzyloxy-5-bromo-pyridin-2-ylamine (1 g, 3.58 mmol) in dimethylsulfoxide (7 mL) was added sequentially bis(pinacolato)diborane (1.0 g, 3.94 mmol), potassium acetate (1.05 g, 10.7 mmol) [1,1'-bis(diphenylphosphino)ferrocine]dichloropalladiurn (II), complex with dichloromethane (1:1) (146 mg, 0.18 mmol). The mixture was heated to 80 C for 16 hr and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was washed with water (2X50 mL) and dried over magnesium sulfate. Concentration in vacuo yielded the crude boronate as a brown solid (1.13 g, 97%). 1H NMR (CDCI3) 6 1.32 (s, 12 H), 5.08 (s, 2H), 5.44 (br s, 2H), 7.33-7.42 (m, 6H), 8.03 (s, 1H).

2. An 18 mL reaction vessel was charged with the crude 3-benzyloxy-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yI)-pyridin-2-ylamine (161 mg, 0.49 mmol), dimethoxyethane (3 mL) and 2-bromopyridine (117 mg, 0.74 mmol). To this solution was added [1,1'-bis(diphenylphosphino)ferrocine]dichloropalladium (II), complex with dichloromethane (1:1) (20 mg, 0.05 mmol) and a 2 M solution of cesium carbonate in water (0.75 mL, 1.5 mmol). The reactor was warmed to 80 C for 66 hr under a nitrogen atmosphere, then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (5 mL) and water (5 mL). The organic layer was washed with additional water (5 mL) and diluted with dimethylformamide (5 mL). Polymer-bound sulfonic acid (0.5 g, 2.1 mmol) was added to the organic solution, and the resulting mixture was gently agitated for 2 hr. The resin was filtered and washed with dimethylformamide, methanol and methylene chloride (3X5 mL each solvent). Then the polymer was reacted with 2 M ammonia in methanol for 1 hr.
The resin was filtered and washed with additional 2 M ammonia in methanol (2X5 mL), and the combined filtrates were concentrated in vacuo. Purification of the crude product by flash column chromatography yielded 52.2 mg of product as a tan solid (38% yield).

General Procedure 17:

YA/
YA/ o, ,o oõo /01010j< Na2CO3 F F + RX
a N okN NHBoc Acetone/Waterer NH, 41 NHBoc ,R

1. Cs2CO3/DMF/oxone 1 N

2.4N HCl/Dioxan: F
NH, 1. To the solution of 3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(4,4,5,5-tetramethyl-El ,3,2]dioxaborolan-2-yI)-pyridin-2-ylamine (procedure 16) (10.0 g, 24.3 mmol) in t-butyl alcohol (50 mL) was added boc anhydride (5.83 g, 26.7 mmol) and reaction stirred at room temperature overnight.

Additional boc anhydride (2.25 g, 10.3 mmol) was added and reaction stirred overnight again. Material was concentrated to a viscous black oil and used as-is.

2. The crude boronic ester (24.3 mmol theoretical) in THF (150 mL) was added to a solution of sodium bicarbonate (16.3 g, 194 mmol) in water (150 mL) and acetone (23 mL).
The mixture was cooled to 2 C and oxone (13.5 g, 21.9 mmol) added slowly, keeping temperature below 8 C. Upon completion of addition, reaction was stirred fro 5 minutes then quenched with sodium bisulfite (14.2 g) in water (28 mL). Ethyl acetate was added (200 mL) and layers separated. Aqueous layer was neutralized with 6N HCI and extracted with ethyl acetate (2x200 mL). Combined organics were washed with water (250 mL) and brine (250 mL), dried (Na2S0r) and concentrated to a crude black oil. Silica gel chromatography (ethyl acetate/hexane) gave the product as a light brown foam (4.78 g, 49.0 %). 1H

NMR (CDCI3) 6 1.48 (s, 9H), 1.74 (d, 3H), 5.75 (q, 1H), 6.61 (d, 1H), 76.89 (dt, 1H), 6.94-7.04 (m, 2H), 7.26(d, 1H), 8.19 (bs, 1H). MS m/z 401 (M+H)+.

3. To cesium carbonate in a 2 dram vial was added [3-(2-Chloro-3,6-difluoro-benzyloxy)-5-hydroxy-pyridin-2-y1]-carbamic acid tert-butyl ester (100 mg, 0.25 mmol) in anhydrous DMF (1 mL) followed by benzyl bromide (89.2 pL, 0.75 mmol). The vial was capped and stirred at 90 C overnight.
Reaction was filtered through a 5 mL Chem-Elut tube pre-wetted with water (3.5 mL) and eluted with 1:1 ethyl acetate:methylene chloride. After partial concentration, 4N HCI in dioxane (1-2 mL) was added and solution concentrated. Reverse phase chromatography (water:acetonitrile, 0.05% TFA) followed by lyophilization, gave the desired product as an off white amorphous solid (25.3 mg, 20.0 %) and the bis-addition product as a tan amorphous solid (35.2 mg, 23.7 %).

General Procedure 18:

\*H , HON NO2 A5 Al I NO2 A2 Sodium borohydride (1.5 molar equivalent) was added to solution of ketone (3.89 mmol) in 10 mL of ethanol under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 12 hr. The mixture was then put in an ice bath and quenched with dilute aqueous NCI. The ethanol was evaporated and Et0Ac was added to extract the aqueous solution. The Et0Ac layer was dried over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a oil residue, compound A5. The residue was used without further purification.
3-Hydroxy-2-nitropyridine (1.1 molar equivalent) and triphenylphosphine (1.5 molar equivalent) were added to a solution of compound AS (1.1 mmol) in 10 mL of THF. The reaction mixture was then put in an ice bath and diisopropyl azodicarboxylate (1.5 molar equivalent) was added. The ice bath was removed and the mixture was stirred at room temperature for 12 hr. The solvent was evaporated to give a yellow oil residue. The residue was purified by silica gel chromatography (eluting Et0Ac in hexanes) to give compound Al.

2 M HCI (0.2 mL) was added to solution of compound Al (0.97 mmol) in 2 mL of ethanol. The mixture was then put in an ice bath and Fe powder (365 mg) was added slowly.
The reaction was 26 heated to 85 C for 1 hr and cooled to room temperature. Celite (0.5 g) was added to stir and the resulting mixture was filtered through a bed of celite and rinsed with ethanol. The filtrated was evaporated to give a brown oil residue, compound A2. The residue was used without further purification.

Periodic acid (0.25 molar equivalent), iodine (0.5 molar equivalent), H20 (0.5 mL), and concentrate sulfuric acid (0.03 mL) were added to a solution of compound A2 in 3 mL of acetic acid.

The reaction mixture was heated to 85 C for 5 hr. The reaction mixture was then cooled in an ice bath and basified with sat. aq. Na2CO3 to a pH of 3-4. Ethyl acetate was added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a brown oil residue. The residue was purified by silica gel chromatography (eluting with Et0Ac and hexanes) to give desired product, compound A3.

General Procedure 19:

v A3 0 NH2 N Ryc.

Boronic ester or boronic acid (1.3 molar equivalent) was added to a solution of compound A3 (0.47 mmol) in 5 mL of DME. The mixture was perged with nitrogen several times and then dichlorobis(triphenylphsophino) palladium (11) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent) in 1 mL of H20 was added to the reaction mixture and the resulting solution was heated to 85 C for 12 hr. Water was added to the reaction mixture to quench the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2504. The Na2SO4 was filtered off and the filtrated was evaporated to give a dark brown oil residue. The residue was purified by silica gel chromatography (eluting with CH3OH, CH2Cl2, Et0Ac, and hexanes) to give desired product, compound A4.

General Procedure 20:

0),0 N HATU , A\I

=

Compound A6 was prepared using general procedure 19. 0-(7-azabenzotriazol-1-y1)-N,N,N',N'-tetramethyluronium phosphorus pentafloride (HATU) (1.1 molar equivalent), diisopropylethyl amine (5 molar equivalent) and amine (1.3 molar equivalent) were added to a solution of compound A6 (0.17 mmol) in 3 mL of DMF under a nitrogen atmosphere. The reaction was allowed to stir at room temperature for 12 hr. Saturated NaHCO3 was added to the reaction mixture to quench the reaction.

Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrate was evaporated to give a brown oil residue.
The residue was purified by silica gel chromatography (eluting with Et0Ac and hexanes) to give desired amide product, compound A7, as a yellow oil.

General Procedure 21:

0 N 0 N,R

deprotection step ("%=-"I's0 A\I

Acid (16 molar equivalent or less) was added to compound A7 (0.13 mtnol) at room temperature. The resulting solution was stirred at room temperature or heated to 60 C for 12 hr. The reaction mixture was evaporated and the residue was purified by silica gel chromatography (eluting with CH3OH, Et0Ac and CH2Cl2) to give desired amide product, compound A8, as a yellowish to white solid.

General Procedure 22:

CHO

O

132- R¨ I
R.2¨=, /L NH2 ,N

Boc 'Boc Boc',N'Boc All Compound A9 was prepared using general procedure 19. Di-tert-butyl dicarbonate (3 molar equivalent) and 4-(dimethylarnino)pyridine (0.14 molar equivalent) were added to a solution of compound A9 (3 mmol) in 20 mL of DMF. The reaction mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture to quench the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a brown yellow oil residue. The residue was purified by silica gel chromatography (eluting with 25-30 % Et0Ac in hexanes) to give desired product, compound A10 as a yellowish oil (87.8% yield). Ozone was bubbled through a solution of compound A10 in 50 mL
of CH2Cl2 at -78 C

and dimethyl sulfide was added to quench the reaction. Saturated sodium chloride was added to the reaction mixture and Et0Ac was added to extract the aqueous solution. Combined Et0Ac layer was dried over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a yellow oil residue. The residue was purified by silica gel chromatography (eluting with 35-440 % Et0Ac in hexanes) to give desired product, compound Al 1 as a yellowish oil (58.4%
yield).

General Procedure 23: Reductive Amination CHO N¨R
N¨R

Deprotection N

R2¨
Roc'.N N

'Bac Boc, 'Boo All Al2 Amine hydrochloride salt (1.2 molar equivalent), sodium acetate (2 molar equivalent to the amine hydrochloride salt) were added to a solution of compound All (0.45 mmol) in 4 mL of CH3OH
under a nitrogen atmosphere. Molecular sieve (0.5 g) was added to the reaction mixture and then sodium cyanoborohydride (2 molar equivalent) was added. The resulting mixture was stirred at room temperature for 12 hr under a nitrogen atmosphere. The reaction mixture was filtered through a bed of celite and the filtrate was evaporated and purified by silica gel chromatography (eluting CH3OH, Et0Ac, and CH2C1_2) to give desired product, compound Al2 as an oil (52.6% yield).
Acid (16 molar equivalent or less) was added to compound Al2 (0.17 mmol) at room temperature. The resulting solution was stirred at room temperature or heated to 60 C for 12 hr. The reaction mixture was evaporated and the residue was purified by silica gel chromatography (eluting with CH3OH, Et0Ac and CH2C12) to give desired product, compound A13.
General Procedure 24:

CHO Y¨P1 N Y¨N N

OjON Boc 0J0 Boc 'Boo R NH2N
Al 1 A14 A15 0-phenyldiamines (1.2 molar equivalent) and sodium bisulfite (2.1 molar equivalent) were added to a solution of compound All (0.41 mmol) in 5 mL of DMA. The resulting solution was heated to 110 C for 12 hr. Water was added to the reaction mixture to quench the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a brown yellow oil residue. The residue was purified by silica gel chromatography (eluting with Et0Ac in hexanes) to give desired product, compound A14. Acid (16 molar equivalent or less) was added to compound A14 (0.16 mmol) at room temperature. The resulting solution was stirred at room temperature or heated to 60 C for 12 hr. The reaction mixture was evaporated and the residue was purified by silica gel chromatography (eluting with CH3OH, Et0Ac and CH2Cl2) to give desired amide product, compound A15.
General Procedure 25:

Br Br 0õ0 Re 4N--- -7 A3b NH2 Rj-N Boc,N'Boc 1R.=
Boc,N-Boc ^j().'.(1N

Al 8 Di-tert-butyl dicarbonate (3 molar equivalent), 4-(dimethylamino)pyridine (0.14 molar equivalent) were added to a solution of compound A3b (2 mmol) in 10 mL of DMF. The reaction mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture to quench the reaction. Et0Ac was 'then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4.
The Na2SO4 was filtered off and the filtrated was evaporated to give a brown yellow oil residue (compound a16). The residue was used without further purification.
Bis(pinacolato)diboron (1.2 molar equivalent) and potassium acetate (3.4 molar equivalent) were added to a solution of compound a16 in 4 mL of DMSO. The mixture was perged with nitrogen several times and then dichlorobis(triphenylphsophino) palladium (II) (0.05 molar equivalent) was added.
The resulting solution was heated to 80 C for 12 hr. Water was added to the reaction mixture to quench the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4.
The Na2SO4 was filtered off and the filtrated was evaporated to give a dark brown oil residue. The residue was purified by silica gel chromatography (eluting with 30% Et0Ac in hexanes) to give desired product, compound A17 (76% yield). HCI (5 molar equivalent) was added to a solution of compound A17 (0.43 mmol) in 4 mL of CH2Cl2. The resulting mixture was heated to 50 C
for 12 hr. Saturated NaHCO3 was added to the reaction mixture to neutralize the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give the desired product (compound A18) as a yellow solid (75%
yield).
General Procedure 26:

0,13,0 N
00 -j'j-^).0 4N 0j R

Boc,N'Boc Boc,N'Boo Compound A17 (1.3 molar equivalent) was added to a solution of aryl halide (0.36 mmol) in 3 mL of DME. The mixture was perged with nitrogen several times and then dichlorobis(triphenylphsophino) palladium (II) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent) in 0.8 mL of H20 was added to the reaction mixture and the resulting solution was heated to 85 C for 12 hr. Water was added to the reaction mixture to quench the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a dark brown oil residue. The residue was purified by silica gel chromatography (eluting with Et0Ac in hexanes) to give desired product, compound Al 9 (74.4% yield).

HCI (5 molar equivalent) was added to a solution of compound A19 (0.26 mmol) in 10 mL of isopropyl alcohol. The resulting mixture was heated to 50 C for 12 hr. The solvent was evaporated to give the desired product, compound A20.

General Procedure 27:

( 0õ0 OjO4N )-ROLo It ' NH2 Compound A18 (1.3 molar equivalent) was added to a solution of aryl halide (0.21 mmol) in 3 mL of DME. The mixture was perged with nitrogen several times and then dichlorobis(triphenylphsophino) palladium (II) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent) in 0.6 mL of H20 was added to the reaction mixture and the resulting solution was heated to 85 C for 12 hr. Water was added to the reaction mixture to quench the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a dark brown oil residue. The residue was purified by silica gel chromatography (eluting with CH3OH, CH2Cl2, Et0Ac, and hexanes) to give desired product, compound A21.

General Procedure 28:

N¨R2 111-R2 0õ0 Rç I
I

X= 1, Br, CI

Amine (1.5 molar equivalent) and K2CO3 (1.5 molar equivalent) were added to a solution of 4-halobenzyl halide (1.0 molar equivalent) in 2 mL of toluene. The resulting mixture was microwaved using Smithsynthesizer (150 C, 1 hr). Water was added to the reaction mixture to quench the reaction.

Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give the desired product, compound A23. The residue was used in procedure 11 without further purification to synthesize compound A22.

General Procedure 29:
) 0' Ns,h-R2R1 0 h_R R1 2 0õ0 , I m X = I, Br, CI, Amine (1.2 molar equivalent) and diisopropylamine (5 molar equivalent) were added to a solution of 4-bromobenzenesulfonyl chloride (0.77 mmol) in 5 mL of CHCI3 under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hr.
Water was added to the reaction mixture to quench the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give the desired product, compound A25. The residue was used in procedure 11 without further purification to synthesize compound A24.
General Procedure 30:

I'L) RE:r0 Boronic ester or boronic acid (1.2 molar equivalent) was added to a solution of 1-chloro-4-iodobenzene (0.84 mmol) in 10 mL of ethylene glycol diemthylether (DME) under a nitrogen atmosphere. The mixture was perged with nitrogen several times and then dichlorobis(triphenylphsophino) palladium (II) (0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent) in 1.8 mL of H20 was added to the reaction mixture and the resulting solution was heated to 85 C for 12 hr. Water was added to the reaction mixture to quench the reaction. Et0Ac was then added to extract the aqueous solution. Dry Et0Ac layer over Na2SO4. The Na2SO4 was filtered off and the filtrated was evaporated to give a dark brown oil residue. The residue was purified by silica gel chromatography (eluting with CH3OH, CH2Cl2, Et0Ac, and hexanes) to give desired product, compound A27. Compound A27 was used in procedure 11 to synthesize compound A26.
General Procedure 31 for Chiral Separation of Racemates:

The racemic sample was purified using preparative supercritical fluid chromatoghraphy SFC-MS. The purification conditions were: column- Chiralpak AD-H, 250x21mm, 5 micron, 100A column (Column #:ADHOCJ-C1003); column temperature 35 C; mobile phase 35% methanol (with 0.1%

isopropylamine)-modified CO2; preparative flow rate 52 mUmin; isobaric pressure at 120 bar. The specific chirality of the isomers was not definitively determined.

General Procedure 32: using Example 1-617 o Ana 12o-k (Y-NH

F3C Br NaH TFA

HO N DMF F3C io I -N
F3C 00 0 '- I

in situ To a mixture of 444-(6-Amino-5-hydroxy-pyridin-3-y1)-benzoy11-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-(1-bromo-ethyl)-3-trifluoromethyl-benzene (64 mg, 0.25 mmol) in DMF (2 ml) was added NaH (12 mg, 0.47 mmol) at 0 C. The mixture was stirred overnight. LCIV1S showed that the reaction was completed, DMF and water were removed. TFA (2 mL) was added to the residue and stirred at room temperature for 3 hr. TFA was removed followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-Amino-5-0-(3-trifluoromethyl-pheny1)-ethoxyypyridin-3-y1}-pheny1)-(3,5-dimethyl-piperazin-1-y1)-methanone (30 mg, yield 25.7%).

General Procedure 33: using Example 1-616 o -N1-201e\\--NH

CF3 2 N Cs2CO3 (aci) io TFA
40 Br HO ito 0 to 0 in situ To a mixture of 444-(6-Amino-5-hydroxy-pyridin-3-y1)-benzoy1]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70 C for 8 hr, LCMS
showed that the reaction was completed. The DMF and water were removed. TFA (2 mIL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-541-(2-trifluoromethyl-pheny1)-ethoxylpyridin-3-y1}-pheny1)-(3,5-dimethyl-piperazin-1-y1)-methanone (20 mg, yield 34.2%).

Procedure 34: using Example 1-624 toy-AN 20-k 0 N o N
o 4 N HCl/dioxane 2 N Cs2CO3 (aq) 0 10 Br , HO N N Os 0 -N I
so 0 I-N

in situ To a mixture of (2R,6S)-444-(6-Amino-5-hydroxy-pyridin-3-y1)-benzoy1]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) and 1-bromomethy1-2-methyl-benzene (47 mg, 0.25 mmol) in DMF(2 mL) was added 2 M Cs2003 (0.35 mL, 0.7 mmol) followed by water (0.5 mL). The mixture was stirred at room temperature overnight. LCMS showed the reaction was completed, DMF

was removed, followed by addition of 4 N HCI in dioxane (2 mL) and the reaction was stirred at room temperature for 3 hr. The volatiles were removed followed by addition of methanol. This solution was purified by prep-HPLC to afford {446-Amino-5-(2-methyl-benzyloxy)-pyridin-3-y1]-pheny1)-(3,5-dimethyl-piperazin-1-y1)-methanone (47 mg, yield 46.6%).

Procedure 35: using Example 1-635 1) Pd(dPpf)2Cl2 0 k-if Cs2CO3 atir NH CI -N
0 0 F 4jak 0 Cl NI--12 2) HCl/Dioxane F Cl ci NH2 To a mixture of [3-(4-iodo-benzoy0-3-aza-bicyclo[3.1.01hex-6-yl]-carbamic acid tert-butyl ester (100 mg, 0.234 mmol) and 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pyridin-2-ylamine (100 mg, 0.234 mmol) in DME (2 mL) was added Pd(dIDPO2C12.CH2C12 (10 mg, 0.012mmol) and Cs2CO3 (351 mg, 0.702 mmol). The mixture was bubbled with nitrogen for 10 min then microwaved at 150 C for 30 min. LCMS checked that the reaction was completed. The crude reaction mixture was diluted with ethyl acetate followed by washings with water and brine. The solution was dried over MgSO4. Purification by prep-HPLC
afforded a solid. The solid was stirred with 4 N HCl/dioxane (3 mL) for 3 hr at room temperature. Removal of the volatiles led to a residue that was purified by prep-HPLC to afford (6-amino-3-aza-bicyclo[3.1.0]hex-3-y1)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-methanone (30 mg, yield 26%).

Procedure 36: using Example 1-636 ?1,.) OH

I

ClHO DEAD, I mob N "
la 0 N

CI

To a mixture of 6'-amino-5'41-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-[3,3]bipyridinyl-6-ol (78 mg, 0.20 mmol), triphenyphosphine (63 mg, 0.24 mmol) and 2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) was added DEAD (0.034 mL, 0.22 mmol). After stirring overnight more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After several hours, more alcohol (0.026 mL, 0.22 mmol) was added. After several more hours, more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After stirring overnight, the mixture was partitioned between dichloromethane and half-saturated brine. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2S0.4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol to afford 5-[1-(2,6-Dichloro-3-fluoro-pheny1)-ethoxy]-6'-(2-morpholin-4-yl-ethoxy)-[3,31bipyridiny1-6-ylamine (53 mg, 53%).
Procedure 37: using Example 1-650 Cl BrZn, Cl SyN
o40 ===.. N

3-(2,6-Dichloro-3-fluoro-benzyloxy)-5-thiazol-2-yl-pyridin-2-ylamine: To a microwave tube equipped with a stir bar was added the iodo-pyridyl starting material (300 mg, 0.702 mmol), tetrakis(triphenylphosphine) palladium (0) (40 mg, 5 mol%) and tetrahydrofuran (anhydrous, 6 mL). The vial was capped and purged with nitrogen for 5 minutes. 2-Thiazolylzinc bromide (0.5 M in THF, 1.4 mmol, 2.8 mL) was then added via syringe. The vial was heated to 120 C in the microwave for 10 minutes. TLC (1:1 ethyl actetate:methylene chloride) showed a large amount of starting material remaining. Additional 2-thiazolylzinc bromide (0.5 M in THF, 500 ilL) was added and the vial was heated to 120 C in the microwave for 20 minutes. TLC (1:1 ethyl actetate:methylene chloride) showed a large amount of starting material still remaining. Additional 2-thiazolylzinc bromide (0.5 M in THF, 500 p.L) was added and the vial was heated to 120 C in the microwave for 60 minutes. TLC (1:1 ethyl actetate:methylene chloride) still showed a large amount of starting material still remaining but also had become very messy. The vial contents were poured into a sat. NH4C1 solution (10 mL) and this solution extracted with ethyl acetate (2 x 30 mL). The combined ethyl acetate layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was loaded onto a 10 g prepacked silica gel column and 1:1 ethyl acetate:methylene chloride used to elute the desired product. (40 mg, 15%).
Procedure 38: using Example 1-652 1=\

Cl CI
ci NH, ip 0 0. NH2N

- 86 -341-(2,6-Dichloro-3-fluoro-pheny1)-ethoxy]-5-(1-methy1-1H-imidazol-2-y1)-pyridin-2-ylamine: N-methyl imidazole (92 mg, 1.1 mmol) was dissolved in tetrahydrofuran (anhydrous, 4 mL) in a 50 mL

round bottom flask. The flask was cooled with a dry-ice/acetone bath under nitrogen atmosphere. N-butyl lithium (2.5 M, 562 1.1L, 1.4 mmol) was added via syringe in 100 p.L
portions over 5 minutes. The reaction was stirred at ¨70 C for 30 minutes. Solid zinc chloride (anhydrous, 383 mg, 2.8 mmol) was added and the reaction stirred for 15 minutes. The ice bath was then removed and the reaction allowed to warm to room temperature. Once all of the zinc chloride was in solution and the reaction at room temperature, iodo scaffold (400 mg, 0.936 mmol) was added in tetrahydrofuran (anhydrous, 4 mL), followed by tetrakis(triphenylphosphine) palladium (0) (108 mg, 10 mol%) and the reaction heated to reflux. The reaction was monitored by LC/MS until all of the starting iodo scaffold was consumed. The reaction was allowed to cool and then diluted with a sat. NH4C1 solution (20 mL). This solution was extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was loaded onto a 10 g prepacked silica gel column and 10% methanol:ethyl acetate was used to elute the desired product (25 mg, 7%).

General Procedure 39: using Example 1-657 Cl Cl= MeNH2 Cl CI N HCl/Me0H CI OnAs Me0H CI 0 0- &N-H2N H211 1\1 H2N
Ps1 To 6-Amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-nicotinonitrile (400 mg, 1.23 mmol) in 70 mL dry methanol at 0 C was bubbled HC1 gas for 3 minutes. Stirred overnight at 3 C. Removed volatiles and washed the solids with diethyl ether to yield quanitatively the imidate. To 200 mg of the imidate in 4 mL methanol at 0 C was added 2N methylamine in THF (837 pL). Let stir at 0 C for about 1 hr then let warm to rt overnight. The volatiles were removed and the residue was chromatographed with 10-20% methanol/dichloromethane to yield 70 mg of product.

General Procedure 40:

a CI
HO
Br 0,JL
X-j)L=0 HNO3 OH CI

I H I

H2SO4 02e MDF
CI ...***It 02N N CI
DI PEA

a Fe/HOAc LIOH

Me0H CI C)rfjC * Me0H
-)11 OH

H2N'isK

1. 6-Nitro-5-hydroxynicotinic acid (B2): To a solution of 5-hydroxynicotinic acid (B1) (7.0 g, 50 mmol) in concentrated H2SO4 was added 9 mL of fuming HNO3 (90%) (9 mL). The reaction mixture was stirred at 55-60 C in a sealed tube for four days. The mixture was then poured into ice and the pH was adjusted to 3 with 50% NaOH. MgSO4 was added to saturate the aqueous mixture, which was then extracted with isopropyl alcohol (4x45 mL). After the removal of isopropyl alcohol under reduced pressure, 5.93 g (64% yield) of B2 was obtained as a yellow solid. MS (APCI), (M+H)+ 185. 11-INMR

(DMSO-d6) 5 8.01 (d, 1H, Ar-H), 8.41(d, 1 H, Ar-H).

2. 2,6-Dichlorobenzy1-6-nitro-5-[(2,6-dichlorobenzyl)oxy]nicotinate (B3): 6-nitro-5-hydroxynicotinic acid (B2) (3.4 g, 18.5 mmol), 2,6-dichlorobenzyl bromide (8.88 g, 37 mmol), DIPEA (5.5 g, 42.5 mmol) were dissolved in DMF (25 mL) in a 250 mL round botoomed flask and the reaction was stirred at room temperature for 4.5 hr and then concentrated under reduced pressure. The resulting mixture was poured into ice and the filtered. The solid collected was dried under reduced pressure to give 4.25 g (46% yield) of B3. MS (APCI) (M+H)+ 503. 11-INMR (DMSO-d6) 5 5.47 (s, 2H, ArCH20), 5.71 (s, 2H, ArCH20), 7.24-7.43 (m, 6H, Ar-H), 8.26(d, 1H, Ar-H), 8.66(d, 1H, Ar-H).

3. 2,6-Dichlorobenzy1-6-amino-5-[(2,6-dichlorobenzyl)oxy]nicotinate (B4): A
mixture of 2,6-dichlorobenzy1-6-nitro-5-[(2,6-dichlorobenzypoxy]nicotinate (B3) (5.5 g, 10.96 mmol), iron powder (0.92 g, 16.43 mmol), glacial acetic acid (20 mL) and methanol (17mL) was stirred at 85 C for three hr. The reaction mixture was concentrated to near dryness, and ammonium hydroxide (30%) was added to neutralize the mixture. Minimum amount of DMF was added to dissolve the reaction mixture, which was purified by flash column chromatograph (eluent: Et0Ac-Et0H, 9:1) to give 4.5 g (87%) of B4 as a pale yellow solid. MS (APCI) (M+H)+ 473.

4. 6-Amino-5-[(2,6-dichlorobenzyl)oxy]nicotinic acid (B5): A mixture of 2,6-dichlorobenzy1-6-amino-5-[(2,6-dichlorobenzyl)oxy]nicotinate (B4) (3.5 g, 7.4 mmol), lithium hydroxide (0.41 g, 17 mmol), water (22 mL) and methanol (30 mL) was stirred and reflux at 85 C for 5 hr.
The mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in water, extracted with a mixture of Et20/hexane (1:1, 4x25 mL), neutralized with IN
HCI to form white precipitation, which was filtered and dried under reduced pressure to provide 1.83 grams (79%) of B5 as a white solid. MS (APCI) (M+H)+ 313. 11-INMR (DMSO-d6) 8 5.26 (s, 2H, ArCH20), 6.37 (s, 2H, NH2), 7.43-7.48 (t, 1H, Ar-H), 7.54 (s, 2H, Ar-H), 7.56 (s, 1H, Ar-H), 8.18 (s, 1H, Ar-H).

Nr-D-N17 0 No--N7 Pd black, cyclohexene .N
0 'N HO

COOH CONR'R"

40 HATU, DMF, 40 70 C, 2hr CI R'R"NH Cl , I

Cl CI

To an array of 400 pL of 0.2 M solution of different amines in DMF in a 96-well plate was added 400 pL (0.2 M in DMF) of 446-amino-5-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-3-y1]-benzoic acid, 80 pL of triethylamine (1M in DMF) and 160 pL of HATU (0.5 M in DMF) and the reactions were stirred at 70 C for 2 hr. The solvent was removed using the SpeedVac apparatus and the crude reaction mixtures were redissolved in DMSO and transferred using a liquid handler to a lmL 96-well plate to give a final theoretical concentration of ¨ 10 mM. The reactions were analyzed and positive product identification was made using LC/MS. The mother stock solution was diluted to 50 nM and assayed for percent inhibition of c-MET at 50nM.

General Procedure 41:

COON
CONITR"
HATU, DMF, CI 70 C, 2hr Cl R'R"NH
fa 0 16 Cl NH2 CI

To an array of 400 L of 0.2 M solution of different amines in DMF in a 96-well plate was added 400 1.1L (0.2 M in DMF) of 6-Amino-5-[(2,6-dichlorobenzyl)oxy]nicotinic acid, 80 p.L of triethylamine (1M

in DMF) and 160 L. of HATU (0.5 M in DMF) and the reactions were stirred at 70 C for 2 hr. The solvent was removed using the SpeedVac apparatus and the crude reaction mixtures were redissolved in DMSO and transferred using a liquid handler to a 1mL 96-well plate to give a final theoretical concentration of ¨ 10 mM. The reactions were analyzed and positive product identification was made using LC/MS. The mother stock solution was diluted to 1 M and assayed General Procedure 42:

[4-(6-Amino-5-hydroxy-pyridin-3-y1)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone: To a solution of [4-(6-Amino-5-benzyloxy-pyridin-3-y1)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone (3.67 g, 8.1 mnnol) in 100 ml ethanol was added 25 ml cyclohexne and 367 mg palladium black.
Reluxed overnight. The solution was filtered and the volatiles were removed.

To the residue was added 60 mL of Me0H, 20 mL cyclohexene and 350 mg Pd black. Refluxed overnight. Filtered and removed volatiles, resuspended in methanol, added 350 mg Pd black and hydrogenated at 1 atm overnight (pressure reactors all busy). Filtered and isolated 3.0 grams of a solid foam. 1H NMR (400 MHz, DMSO-D6) 8 ppm 7.82 (d, J=2.02 Hz, 1 H) 7.58 (d, J=8.34 Hz, 2 H) 7.41 (d, J=8.34 Hz, 2 H) 7.12 (d, J=2.02 Hz, 1 H) 5.74 (s, 2 H) 3.33 (s, 5 H) 3.08 (s, 2 H) 1.95 (m, 8 H) 1.49 (s, 2 H). LC/MS(APCI) 367 m/e (M+1).
To an array of 10x75 mm test tubes were added [4-(6-Amino-5-hydroxy-pyridin-3-y1)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yI)-methanone (0.2 M in DMF, 80 pmol, 1.0 eq.), Cs2CO3 (2 M, 160 pmol, 2.0 equiv) and different alkyl halides (0.2 M in DMF, 88 pmol, 1.1 eq.).The reactions were stirred at room temperature overnight. In order to separate the inorganic salts, the resulting suspension was evaporated and DMF (625 pL) was added. After agitation, the mixture was centrifuged to settle the solid residue, and the supernatant was transferred to a new 10x75 mm test tube. The reactions were analyzed and positive product identification was made using LC/MS. The mother stock solution was diluted to I1.IM
and assayed.
General Procedure 43:

0 rYL o HO
NH, (2R,6S)-444-(6-Amino-5-hydroxy-pyridin-3-y1)-benzoy1]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester: See general procedure IG. Yield 83.5%. 1H NMR (400 MHz, DMSO-D6) oppm 7.81 (d, J=2.27 Hz, 1 H) 7.57 (d, J=8.34 Hz, 2 H) 7.41 (d, J=8.34 Hz, 2 H) 7.12 (d, J=2.02 Hz, 1 H) 5.70 o N N 0 1 ) 2 N Cs2CO3 DMF
2) HCl/dioxane =RX

, HO

R. I .N0 (s, 2 H) 4.07 (s, 2 H) 3.31 (s, 3 H) 1.39 (s, 10 H) 1.03- 1.14 (m, 7 H) To an array of 10x75 mm test tubes were added [4-(6-Amino-5-hydroxy-pyridin-3-y1)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone (0.2 M in DMF, 80 pmol, 1.0 eq.), Cs2CO3 (2 M, 160 pmol, 2.0 equiv) and different alkyl halides (0.2 M in DMF, 88 pmol, 1.1 eq.).The reactions were stirred at room temperature overnight. In order to separate the inorganic salts, the resulting suspension was evaporated and DMF (625 pL) was added. After stirring, the mixture was centrifuged to settle the solid residue, and the supernatant was transferred to a new 10x75 mm test tube. The solid residues were extracted with more DMF (400 pL) and the extracts were combined with the first organic layer.
The DMF was evaporated, and HCI (4 M in dioxane, 2.5 mmol, 31 eq.) was added to the reaction mixture in the receiving test tube. The reaction mixture was stirred at room temperature for 3 hr. The reactions were analyzed and positive product identification was made using LC/MS. The mother stock solution was diluted to 1 pM and assayed.
Example 1(a):
1. To a stirred solution of Cs2CO3 (11.63 g, 35.69 mmol) in DMF (180 mL) under a N2 atmosphere containing 3-hydroxy-4-nitro-pyridine (5 g, 35.69 mmol) was added 2,6-dichlorobenzyl bromide (8.56 g, 35.69 mmol). The mixture was stirred for 6 h at ambient temperature. The reaction was then diluted with Et0Ac (400 mL) and partitioned with H20 (100 mL). The aqueous layer was extracted with Et0Ac (2 x 50 mL). The organic layers were then combined and washed with H20 (2 x 50 mL) and brine (1 x 50 mL). The organics were dried over Na2SO4, filtered and concentrated to dryness under vacuum to yield 3-(2,6-dichloro-benzyloxy)-2-nitro-pyridine (10.5 g, 98.4%) as a white solid.
2. To a stirred mixture of AcOH (650 mL) and Et0H (500 mL) was suspended 3-(2,6-dichloro-benzyloxy)-2-nitro-pyridine (37.4 g, 0.11 mol) and iron chips (69.4 g, 0.11 mol). The reaction was heated slowly to reflux and allowed to stir for 1 hr. The reaction was cooled to room temperature then filtered through a pad of celite. The resulting filtrate was neutralized with conc. NH4OH (600 mL) and then extracted with Et0Ac (3 x 500 mL). The combined organic extracts were washed with saturated NaHCO3 (2 x 100 mL), H20 (2 x 100 mL) and brine (1 x 100 mL) then dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (32.4 g, 0.11 mol, 99%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) 6 7.56 (m, 3H), 7.46 (dd, 2H), 7.36 (d, 1H), 6.62 (dd, 1H), 6.18 (br s, 2H, NH2), 5.24 (s, 2H); MS ni/z 270 [M+11.
3. A stirring solution of 3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (32.4 g, 0.11 mol) in acetonitrile was cooled to 0 C using an ice bath. To this solution was added N-bromosuccininnide (19.5 g, 0.11 mol) portionwise. The reaction was stirred at 0 C for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in Et0Ac (500 mL) and partitioned with H20 (250 mL). The organic was then washed with sat'd NaHCO3 (2 x 200 mL) and brine (1 x 200 mL).
Activated charcoal was added to the organic layer and warmed to reflux. The solution was then cooled to room temperature and filtered through a pad of celite. The organic was then concentrated to dryness under vacuum to one third the original volume. The solids were then filtered off to yield 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (22.0 g, 0.07 mol, 64%) as a tan solid.
The remaining filtrate was concentrated under vacuum to yield crude 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (12.1g, 0.04 mol, 35%) as a brown solid.

Example 1(b): 3-Benzylm-5-bromo-pyridin-2-ylamine was prepared following procedure 1 from 3-benzyloxy-pyridin-2-ylamine as a tan solid in 65% yield.
Example 1(c): 5-Bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(2,6-difluoro-benzyloxy)-2-nitro-pyridine was prepared in 99%
yield. 1H NMR (400 MHz, DMSO-d6) 6 8.14 (m, 2H), 7.79 (dd, 1H), 7.52 (m, 1H), 7.16 (m, 2H), 5.37 (s, 2H); MS m/z 266 [M+]. 3-(2,6-Difluoro-benzyloxy)-pyridin-2-ylamine was prepared in 100% yield. 1H NMR
(400 MHz, DMSO-d6) 6 7.88 (s, 2H), 7.64 (dd, 1H), 7.57 (m, 2H), 6.84 (dd, .1H), 5.24 (s, 2H); MS
m/z 237 [M+1]. 5-Bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamine was prepared in 91% yield.
Example 1(d): 5-Bromo-3-(2-bromo-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(2-bromo-benzyloxy)-2-nitro-pyridine intermediate was prepared in 99% yield as a white solid. 3-(2-bromo-benzyloxy)-pyridin-2-ylamine was prepared in 100% yield as a solid. 5-Bromo-3-(2-bromo-benzyloxy)-pyridin-2-ylamine was obtained in 37% yield as a tan solid.
Example 1(e): 5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(2-chloro-6-fluoro-benzylog)-2-nitro-pyridine was prepared in 90% yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.15 (m, 2H), 7.80 (m, I H), 7.50 (m, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 5.39 (s, 2H). 3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine was prepared in 88% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) 67.70-7.15 (m, 5H), 6.45 (m, 1H), 5.45 (br s, 2H), 5.06 (s, 2H). 5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine was prepared in 81% yield.
Example l(f): 5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(2-chloro-4-fluoro-benzyloxy)-2-nitro-pyridine was prepared in 91% yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 68.08 (m, 2H), 7.75 (m, H), 7.63 (m, 1H), 7.55 (m, I H), 7.25 (m, 1H), 5.45 (s, 21-1). 3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine was prepared in 100% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) 6 7.70 (m, 2H), 7.47 (m, 1H), 7.20 (m, 1H), 7.08 (m, 1H), 6.45 (m, IH), 5.62 (br s, 2H), 5.08 (s, 2H). 5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine was prepared in 63% yield.
Example 1(g): 5-Bromo-3-(2,4-dichloro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(2,4-Dichloro-benzyloxy)-2-nitro-pyridine was prepared in 96%
yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 6 8.05-7.50 (m, 6H), 5.39 (s, 2H); MS (m/z) 299 (M+1). 3-(2,4-Dichloro-benzyloxy)-pyridin-2-ylamine was prepared in 98% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) 6 7.65-6.25 (m, 6H), 5.85 (br s, 2H), 5.06 (s, 2H). 5-Bromo-3-(2,4-dichloro-benzyloxY)-pyridin-2-ylamine was prepared in 65% yield.
Example 1(h): 2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile was prepared following procedure 1. 2-(2-Nitro-pyridin-3-yloxymethyl)-benzonitrile was prepared in 91% yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 6 8.15-7.55 (m, 1H), 5.50 (s, 2H). 2-(2-Amino-pyridin-3-yloxymethyl)-benzonitrile was prepared in 86% yield as a tan solid. 1H NMR
(400 MHz, DMSO-d6) 6 7.95-6.45 (m, 7H), 5.65 (br s, 2H), 5.20 (s, 2H). 2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile was prepared in 77% yield.
Example I(i): 5-Bromo-3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(2-trifluoronnethyl-benzyloxy)-2-nitro-pyridine was prepared in 92% yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 6 8.05-7.58 (m, 7H), 5.45 (s, 2H). 3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine was prepared in 80% yield as a tan solid. 5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine was prepared in 43% yield as a solid.
Example 1(j): 5-Bromo-3-(4-tert-butyl-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(4-tert-butyl-benzyloxy)-2-nitro-pyridine was prepared in 80%
yield as an oil. 1H NMR
(400 MHz, DMSO-d6) 6 8.10-7.30 (m, 7H), 5.30 (s, 2H), 1.25 (s, 9H). 3-(4-tert-Butyl-benzyloxY)-pyridin-2-ylamine was prepared in 100% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) 6 7.45-6.25 (m, 7H), 5.58 (br s, 2H), 5.05(s, 2H), 1.25 (s, 9H). 5-Bromo-3-(4-tett-butyl-benzyloxy)-pyridin-2-ylamine was prepared in 55% yield as a solid.
Example 1(k): 5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(2-Chloro-benzyloxy)-2-nitro-pyridine was prepared in 89% yield as an off-white solid.
1H NMR (400 MHz, DMSO-d6) 6 8.10-7.40 (m, 7H), 5.40 (s, 2H). 3-(2-Chloro-benzyloxy)-pyridin-2-ylamine was prepared in 100% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) 6 8.65-6.45 (m, 7H), 5.62 (br s, 2H), 5.10(s, 2H). 5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine was prepared in 22%
yield as a solid.
Example 1(1): 5-Bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. 3-(2-chloro-3,6-difluoro-benzyloxy)-2-nitro-pyridine intermediate was prepared in 99% yield as an off white solid. 1H NMR (CDCI3, 300 MHz) 05.31 (s, 2H), 7.02-7.09 (dt, 1H, J, 4, 8), 7.17-7.23 (dt, 1H, J, 4.5, 8.4), 7.54-7.58 (dd. 1H, J, 4.5, 8.4), 7.71-7.68 (dd, 1H, J,1.21, 8.4), 8.14-8.16 (dd, 1H, J, 1.23, 4.5). 3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine was prepared in 100% yield as a light yellow solid. 1H MR (CDCI3, 300 MHz) 6 4.6-4.8.(brs, 2H), 5.2 (s, 2H), 7.0-7.08 (dt, 1H, J, 4.1, 9.0), 7.09-7.12 (dd, 1H, J, 1.0, 7.8), 7.15-7.22 (dt, 1H, J, 4.8, 8.0), 7.69-7.71 (dd, 1H, J, 1.2, 5.1). 5-Bromo-3-(2-chloro3,6-difluoro-benzyloxy)-pyridin-2-ylamine was obtained in 64%
yield as a tan solid.
Example 1(m): 5-Bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1 starting from 3-hydroxy-4-nitro-pyridine and 1-bromomethy1-3-fluoro-2-trifiuoromethyl-benzene.
Example 1(n):
1. 2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred in THF (150 mL, 0.5M) at 0 C using an ice bath for 10 min. Lithium aluminum hydride (2.75 g, 0.072mol) was slowly added. The reaction was stirred at ambient temperature for 3 hr. The reaction was cooled in ice bath, and water (3 mL) was added drop wisely followed by adding 15% NaOH (3 mL) slowly. The mixture was stirred at ambient temperature for 30 min. 15% NaOH (9 mL), MgSO4 were added and the mixture filtered to remove solids. The solids were washed with THF (50 mL) and the filtrate was concentrated to give 1-(2,6-Dichloro-3-fluoro-pheny1)-ethanol (14.8 gm, 95% yield) as a yellow oil.
1H NMR (400 MHz, DMS0-d6) 6 1.45 (d, 3H), 5.42 (m, 2H), 7.32 (m, 1H), 7.42 (m, 1H).

CI CI
ri OH DEAD/PPh3/THF ON

2. To a stirred solution of triphenyl phosphine (8.2 g, 0.03 mol) and DEAD
(13.65 mL of a 40%
solution in toluene) in THF (200 mL) at 0 C was added a solution of 1-(2,6-dichloro-3-fluoro-pheny1)-ethanol (4.55 g, 0.021 mol) and 3-hydroxy-nitropyridine (3.35 g, 0.023 mol) in THF (200 mL). The resulting bright orange solution was stirred under a nitrogen atmosphere at ambient temperature for 4 hours at which point all starting materials had been consumed. The solvent was removed, and the crude material was dry loaded onto silica gel, and eluted with ethyl acetate-hexanes (20:80) to yield 3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (6.21 g, 0.021 mol, 98%) as a pink solid. 1H NMR
(CDCI3, 300 MHz) M.8-1.85 (d, 3H), 6.0-6.15 (q, 1H), 7.0-7.1 (t, 1H), 7.2-7.21 (d, 1H), 7.25-7.5 (m, 2H), 8.0-8.05(d, 1H).
3. 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1.
To a stirred mixture of AcOH (650 mL) and Et0H (500 mL) was suspended 3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (9.43 g, 0.028 mol) and iron chips (15.7 g, 0.28 mol). The reaction was heated slowly to reflux and allowed to stir for 1 hr. The reaction was cooled to room temperature then diethyl ether (500 mL) and water (500 mL) was added. The solution was carefully neutralized by the addition of sodium carbonate. The combined organic extracts were washed with sat'd NaHCO3 (2 x 100 mL), H20 (2 x 100 mL) and brine (1 x 100 mL) then dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.04 g, 0.027 mol, 99%) as a light pink solid. 1H NMR (CDCI3, 300 MHz) 01.8-1.85 (d, 3H), 4.9-5.2 (bra, 2H), 6.7-6.84 (q, 1H), 7.0-7.1 (m, 1H), 7.2-7.3 (m, 1H), 7.6-7.7 (m, 1H).
4. 5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine was prepared following procedure 1. A stirring solution of 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.07 g, 0.03 mol) in acetonitrile was cooled to 0 C using an ice bath. To this solution was added NBS (5.33 g, 0.03 mol) portionwise. The reaction was stirred at 0 C for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in Et0Ac (500 mL), and purified via silica gel chromatography. The solvents were then removed in vacuo to yield 5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (5.8 g, 0.015 mol, 51%) as a white crystaline solid.
Example 1(o):
F 1 = I MeMgCl/THF F OH

1. 2-Chloro-3,6-difluorobenzaldehyde (1.0 molar equivalent) was dissolved in THF (0.2M) and stirred at 0 C for 5 min. The corresponding methylmagnesium chloride solution (1.1 molar equivalent) was added .The reaction was warmed up gradually to ambient temperature and stirred for 2 hr.
Methanol, and IN HCI was added to the mixture and diluted with ethyl acetate.
The mixture was washed with water, brine, dried over MgSO4, filtered, and concentrated to give 1-(2-chloro-3,6-difluoro-phenyI)-ethanol as oil. 1H NMR (400 MHz, DMSO-d6) 6 1.42 (d, 3H), 5.21 (m, 1H), 5.42 (m, 1H), 7.09 (m, 1H), 7.18 (m, 1H).
2. 5-bromo-341-(2-chloro-3,6-difluoro-pheny1)-ethoM-pyridin-2-ylamine was prepared following the same procedure as Example 1(n) starting from 1-(2-chloro-3,6-difluoro-phenyl)-ethanol and 3-hydroxy-nitropyridine.
Example II(a): To an ice cooled solution of (2,6-dichloro-phenyl)-methanol (5 g, 28.2 mmol) in anhydrous tetrahydrofuran (200 mL) was added sodium hydride (1.13 g, 28.2 mmol, 60% disp.) slowly under nitrogen atmosphere. After stirring for 30 minutes, 3,5-dibromo-pyrazin-2-ylamine (7.08 g, 28.2 mmol) in anhydrous tetrahydrofuran (50 mL) was added via an addition funnel.
Once the addition was complete the ice bath was removed and the reaction was refluxed under nitrogen and monitored by reversed phase HPLC. After 18 hr HPLC showed that the majority of the starting 3,5-dibromo-pyrazin-2-ylamine had been consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated in vacuum until 50 mL remained. The mixture was diluted with ethyl acetate (200 mL) and extracted with 50% brine (2 x 200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuum. The crude product was purified using a silica gel column eluting with 1:1 ethyl acetate/dichloromethane to yield 5-bromo-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine as a white solid (8.17 g, 83% yield).
Example 11(b): 5-Bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine was prepared following procedure 2 from (2-chloro-3,6-difluoro-phenyl)-methanol and 3,5-dibromo-pyrazin-2-ylamine.
Example II(c):
1. 2-Chloro-3, 6-difluorobenzaldehyde (1.0 molar equivalent) was dissolved in THE (0.2M) and stirred at 0 C for 5 min. The corresponding methylmagnesium chloride solution (1.1 molar equivalent) was added .The reaction was warmed up gradually to ambient temperature and stirred for 2 hr.
Methanol and IN HCI were added to the mixture and diluted with ethyl acetate.
The mixture was washed with water, brine, dried over MgSO4, filtered, and concentrated to give 1-(2-chloro-3,6-difluoro-pheny1)-ethanol as oil. 1H NMR (400 MHz, DMSO-d6) 6 1.42 (d, 3H), 5.21 (m, 1H), 5.42 (m, 1H), 7.09 (m, 1H), 7.18 (m, 1H).
2. 5-bromo-341-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2-chloro-3,6-difluoro-pheny1)-ethanol and 3,5-dibromo-pyrazin-2-ylamine.
Example 11(d):
1. 1-(2-Chloro-3,6-difluoro-phenyl)-2-methyl-propan-1-ol was prepared following the procedure of Example II(c) using isopropylmagnesium chloride. 1H NMR (400 MHz, DMSO-d6) 6 0.63 (d, 3H), 1.06 (d, 3H), 2.19 (m, 1H), 4.59 (m, 1H), 5.54 (d, 1H), 7.21 (m, 1H), 7.36 (m, 1H).
2. 5-bromo-3-[1-(2-chloro-3,6-difluoro-pheny1)-2-methyl-propoxyl-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2-chloro-3,6-difluoro-pheny1)-2-methyl-propan-1-01 and 3,5-dibromo-pyrazin-2-ylamine.
Example II(e):

1. 2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred in THF (150 mL, 0.5M) at 0 C using an ice bath for 10 min. Lithium aluminum hydride (from Aldrich, 2.75 g, 0.072mol) was slowly added. The reaction was stirred at ambient temperature for 3 h. The reaction was cooled in ice bath, and water (3 mL) was added drop wisely followed by adding 15% NaOH (3 mL) slowly. The mixture was stirred at ambient temperature for 30 min. 15% NaOH (9 mL), MgSO4 were added and the mixture filtered to remove solids. The solids were washed with THF (50 mL) and the filtrate was concentrated to give 1-(2,6-Dichloro-3-fluoro-phenyl)-ethanol (14.8 gm, 95% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 6 1.45 (d, 3H), 5.42 (m, 2H), 7.32 (m, 1H), 7.42 (m, 1H).

2. 5-Bromo-341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2,6-dichloro-3-fluoro-pheny1)-ethanol and 3,5-dibromo-pyrazin-2-ylamine.

Example 11(f): 5-Bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylamine was prepared following procedure 2 from (3-fluoro-2-trifluoromethyl-phenyl)-methanol and 3,5-dibromo-pyrazin-2-ylamine.

Example 1-1: A mixture of 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (exa'mple 1(a), 100 mg, 0.29 mmol), 4-(4,4,5,5-tetramethy1-1,3-2-dioxabordan-2-y1) phenol (86 mg, 0.35 mmol), bis(triphenylphosphine) palladium(11) chloride (8 mg, 0.009 mmol) and sodium carbonate (91 mg, 0.87 mmol) in ethylene glycol dimethyl ether (10 mL) and water (0.5 mL) was heated to reflux under nitrogen for 18 hours. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The mixture was washed with water, brine, dried over Na2SO4, and purified on silica column to afford 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-phenol as light pine crystals (89 mg, 85% yield).

Example 1-2:

1. To a mixture of 4-(4,4,5,5-tetramethy1-1,3-2-dioxabordan-2-y1) phenol (5.00 g, 22.72 mmol) and 0s2003 (16.29 g, 49.98 mmol) in DMF (100 mL) were added 4-(2-chloroethyl)morpholine hydrochloride (4.65 g, 24.99 mmol) and K1 (0.2 g, 0.6 mmol). The mixture was stirred at 65 C oil bath OH CI

o I Nk) =Cs2CO3/KI HCI DMF
7L_i<o o -B.
.77*B.

for overnight and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate (600 mL), and partitioned with water. The water layer was extracted with ethyl acetate (2X50 mL). The combined ethyl acetate solution was washed with brine (5X100 mL), dried over Na2SO4, filtered, condensed, and dried in high vacuum to provide 4-{244-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenoxy]-ethy1}-morpholine (6.8 g, 90% yield) as an off-white solid. 1H NMR

(400 MHz, DMSO-d6) 6 7.55 (d, 2H), 6.90 (d, 2H), 4.07 (t, 2H), 3.54 (m, 4H), 2.65 (t, 2H), 2.43 (m, 4H).

2. 3-(2,6-Dichloro-benzyloxy)-544-(2-morpholin-4-yl-ethoxy)-pheny1]-pyridin-2-ylamine was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (example 1(a)) and 4-{2-[4-(4,4,5,5-tetramethyl-[1,3,21dioxaborolan-2-y1)-phenoxy]-ethy1}-morpholine (prepared in part 1) following procedure 3 as a white solid.
Example 1-3:
I. OH+ CI Cs2CO3/KI
rN) HCI DMF c)3, _.7<0 0 .6. LO 0-'0 1. 3-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenoxy]-ethylymorpholine was prepared following the same procedure as 4-(244-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenoxyyethylymorpholine in Example 1-2 using 3-(4,4,5,5-tetramethy1-1,3-2-dioxabordan-2-y1) phenol in 92% yield as a white wax solid. 1H NMR (400 MHz, DMSO-d6) 67.28 (t, 1H), 7.22 (dt, 1H), 7.14 (d, 1H), 7.04 (ddd, 1H), 4.06 (t, 2H), 3.56 (m, 4H), 2.49 (t, 2H), 2.45 (m, 4H).
2. 3-(2,6-Dichloro-benzyloxy)-543-(2-morpholin-4-yl-ethoxy)-phenyll-pyridin-2-ylamine was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (example 1(a)) and 3-{2-[4-(4,4,5,5-tetramethy141,3,21dioxaborolan-2-y1)-phenoxy]-ethy1}-morpholine prepared in part 1 following procedure 3 as a light yellow solid.
Example 1-4:

:r 0 0 Pdc126:Ippf) CH2Cl2 \ >. \ 101 N 0 0 KOAc/DMS0 1. To a mixture of 4-bromoindole (9.80g, 50 mmol), pinacole diborate (13.97g, 55 mmol), and KOAc (14.72g, 150 mmol) in DMSO (200 mL) was added palladium catalyst PdC12(dppf)*CH2C12 (1.22g, 1.5 mmol). The system was degassed, and then charged with nitrogen for three times. The mixture was stirred at 80 C oil bath under nitrogen for 22 hours. TLC showed the complete disappearance of the starting material 4-bromoindole. The mixture was cooled to room temperature, and then poured to water (1 L). The product was extracted with ethyl acetate for three times. The combined extracts were washed by brine for five times to remove DMSO solvent, and then dried over Na2SO4. During the washing step, the catalyst may precipitate out, which was removed by filtration. The ethyl acetate solution was filtered and condensed. The residue was purified on a silica gel column eluting with Et0Ac-hexane (9:1). The first fraction provided the side product indole (1.25g, 21% yield), Rf 0.55 (Et0Ac-Hexane 5:1). The second fraction provided 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-y1)-1H-indole as a white solid (8.01g, 66%), Rf 0.46 (Et0Ac-Hexane 5:1). 1H NMR (300 MHz, DMSO-d6):
611.03 (bs, 1H, N-H)), 7.49 (d, J 7.7 Hz, 1H, H-5), 7.38 (dd, J 0.9 Hz, J 7.0 Hz, 1H, H-7), 7.38 (t, J
2.6Hz, 1H, H-2), 7.06 (dd, J 7.7 Hz, J 7.0 Hz, 1H, H-6), 6.73 (bd, J 2.2 Hz, 1H, H-3), 1.32 (s, 12H, 4CH3); MS (m/e): 244 (M+H)+.

2. 3-(2,6-dichloro-benzyloxy)-5-(1H-indo1-4-y1)-pyridin-2-ylamine was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (Example 1(a)) and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-y1)-1H-indole following procedure 3. The first fraction was identified to be 3-(2,6-dichloro-benzyloxy)-5-(1H-indo1-4-y1)-pyridin-2-ylamine.
Example 1-5: The same experiment was performed as Example 4, and the second fraction was identified as 3-[2-chloro-6-(1H-indo1-4-y1)-benzyloxy]-5-(1H-indol-4-y1)-pyridin-2-ylamine.
Example 1-6: 246-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-A-pyrrole-1-carboxylic acid tett-butyl ester was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (Example 1(a)) and N-Boc pyrrole-2-boronic acid following procedure 3.
Example 1-7: To a mixture of 2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-311]-pyrrole-1-carboxylic acid tert-butyl ester (Example 6, 30 mg, 0.069 mmol) in ethanol/water (2:1, 10 mL) was added sodium carbonate (100 mg, 0.95 mmol). The mixture was refluxed overnight. The reaction was cooled to ambient temperature and extracted with ethyl acetate. The mixture was washed with water, brine, dried over Na2SO4, and purified on a silica gel column to afford 3-(2,6-dichloro-benzyloxy)-5-(1H-pyrrol-2-y1)-pyridin-2-ylamine.
Examples 1-8 to 1-12: The compounds of Examples 1-8 to 1-12 were prepared according to procedure 3 using 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and: 4-fluorophenyl boronic acid (Example 1-8); phenyl boronic acid (Example 1-9); 2-fluorophenyl boronic acid (Example 1-10); 3-fluorophenyl boronic acid (Example 1-11); and 4-(4,4,5,5-tetramethy141,3,21dioxaborolan-2-y1)-phenylamine (Example 1-12).
Example 1-13: To a solution of 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (100 mg, 0.28 mmol) in methylene chloride (5 mL) at 0 C, was added methanesulfonyl chloride (0.021 mL, 0.28 mmol) and 4-methylmorpholine (0.16 mL). The mixture was stirred at room temperature for 2 hr, and diluted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified with a silica gel column eluting with hexane-ethyl acetate (5:1) to give N-{446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yll-pheny1}-methanesulfonamide.
Example 1-14: To a solution of 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (100 mg, 0.28 mmol) in acetonitrite (3 mL) at 0 C, was added pyridine (0.035 mL, 1.5 eq.) and acetic anhydride (0.03 mL, 0.28 mmol). The mixture was stirred at room temperature over night, and the precipitate was filtered to provide N-{446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-acetamide as a white solid.
Examples 1-15 to 1-35: The compounds of Examples 1-15 to 1-35 were prepared according to procedure 3 from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and: 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenol (Example 1-15); 4-methoxyphenyl boronic acid (Example 1-16); 3-aminobenzeneboronic acid (Example 1-17); 4-trifluoromethoxybenzeneboronic acid (Example 1-18); 2-hydroxybenzene boronic acid (Example 1-19); 2-phenoxyphenylboronic acid (Example 1-20); 3,4-difluorophenylboronic acid (Example 1-21); (3-isopropyl)phenylboronic acid (Example 1-22); (2-trifluoromethylphenyl)boronic acid (Example 1-23); (2-methoxyphenyl)boronic acid (Example 1-24); (4-trifluoromethylphenyl)boronic acid (Example 1-25); [(2-methylsulfonylamino)phenyl]boronic acid (Example 1-26); 4-hydroxymethylphenylboronic acid (Example 1-27); 3,4-methylenedioxyphenylboronic acid (Example 1-28); 2-trifluoromethoxyphenylboronic acid (Example 1-29); 4-methylthiophene-2-boronic acid (Example 1-30); 2-benzyloxyphenylboronic acid (Example 1-31); 3-methoxyphenylboronic acid (Example 1-32); 1-(tert-butoxycarbonyl)indole-2-boronic acid, and the tert-butoxycarbonyl group was removed using 20% trifluoroacetic acid in dichloromethane (Example 1-33); (3-fluoro-4-benzyloxyphenyl)boronic acid (Example 1-34); and 4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-benzoic acid (Example 1-35).
Example 1-36: To a solution of 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-benzoic acid (50 mg, 0.13 mmol), HOBT (21 mg, 0.156 mmol), and EDC (30 mg, 0.156 mmol) in DMF (2 mL) was added N, N-diethylethylenediamine (0.022 mL, 0.156 mmol). The reaction was stirred at room temperature for 24 hr, then diluted with Et0Ac, and partitioned with H20. The organic was separated and the aqueous was extracted with Et0Ac. The organic layers were combined, washed with saturated NaHCO3, and concentrated to dryness under vacuum. The material was purified using column chromatography (silica gel, 99:1 to 95:5 CH2C12/Me0H) to give 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-N-(2-diethylamino-ethyl)-benzamide (45 mg, 72% yield) as a white solid.
Examples 1-37 and 1-38: The compounds of Examples 1-37 and 1-38 were prepared from 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yli-benzoic acid and N, N-diethyl-1,3-propanediamine (Example 1-37) and 1-methylpiperazine(Example 1-38), following procedure 4.
Example 1-39:

Olt 0 0 HOBT/EDC 0 ,0 H,./Pd/C B61-16/THF
Psc_l_ri? TEA/DMF cfl\lyg OH H
1. A mixture of (+)-carbobenzyloxy-D-proline (1.5 g, 6 mmol), EDC (2.3 g, 12 mmol), HOBt (800 mg, 6 mmol), TEA (1.5 mL) and pyrrolidine (853 mg, 12 mmol) in DMF (20 mL) was stirred at rt for 18 hr. The reaction was diluted with water and sodium bicarbonate, extracted with dichloromethane (3x).
The combined DCM was concentrated and purified on a silica gel column to give (R)-2-(pyrrolidine-1-carbony1)-pyrrolidine-1-carboxylic acid benzyl ester. (R)-2-(pyrrolidine-1-carbony1)-pyrrolidine-1-carboxylic acid benzyl ester was hydrogenated using Pd/C in methanol at ambient temperature for 20 hr to provide pyrrolidin-1-y1-(R)-pyrrolidin-2-yl-methanone. To a solution of pyrrolidin-1-y1-(R)-pyrrolidin-2-yl-methanone (1.2 g, 7.1 mmol) in THF (10 mL) at 0 C was added B2H6 (10 mL, 10 mmol). The mixture was heated to reflux for 16 hr. The reaction was acidified with HC1 and concentrated. The residue was basified to pH 10 with 2N NaOH and extracted with 5% methanol in DCM. The organic layer was concentrated and purified on a silica gel column to give 800 mg (73%) of (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.
2. {446-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone was prepared from 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yly benzoic acid and (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Examples 1-40 to 1-45: The compounds of Examples 1-40 to 1-45 were prepared according to procedure 4 from 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-benzoic acid and: (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-40); 4-pyrrolidin-1-yl-piperidine (Example 1-41); 4-piperidine ethanol (Example 1-42); (3S)-(3-dimethylamino-pyrrolidine (Example 1-43); (3R)-(3-dimethylamino-pyrrolidine (Example 1-44); and (S)-3-cyclopropylaminomethyl-piperidine (prepared according to the procedures for (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine in example 1-39) (Example 1-45).
Example 1-46:

CI HO NH3 +ç15 --31.0 CN¨Nr¨N.HO NH2 1. To a solution of epichlorohydrin (from Aldrich, Milwaukee, 3.91 mL, 50.0 mmol) in Et0H (100 mL) was added pyrrolidine (4.18 mL, 50.0 mmol) at room temperature. The mixture was stirred at 55-60 C for 20 hr, then refluxed for 3 hr. The solvent was removed under reduced pressure and crude 1-chloro-3-pyrrolidin-1-yl-propan-2-ol was obtained as an oil (10 g). This oily product was dissolved in 7 M ammonia in Me0H (40 mL) and stirred at room temperature overnight. Then another 30 mL of 7M
ammonia in Me0H was added and the mixture was stirred at 40 C overnight. NMR
showed that the starting material disappeared completely. The solvent was removed and the residue was dissolved in 2 N HCI and then lyophilized to give 10.8 g of oil salt product, which was dissolved in Me0H-H20 at 0 C
and the resin (AG1-X8, hydroxide form) was added in portions with stirring until the pH of the solution is above 9Ø After filtration, the filtrate was evaporated under reduced pressure to give the free amine 1-amino-3-pyrrolidin-1-yl-propan-2-ol as yellowish oil (8.6 g). This crude product was used for the reaction without further purification.
2. 4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-N-(2-hydroxy-3-pyrrolidin-1-yl-propy1)-benzamide was prepared from 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3111-benzoic acid and 1-amino-3-pyrrolidin-1-yl-propan-2-ol following procedure 4.
Examples 1-47 to 1-52: The compounds of Examples 1-47 to 1-52 were prepared according to procedure 4 from 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yli-benzoic acid and: 3-fluoro-1-(2S)-pyrrolidin-2-ylmethyl-piperidine (prepared according to the procedures for (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine) (Example 1-47); 1-cyclopropyl-piperazine (Example 1-48); (R)-2-[(cyclopropylmethyl-amino)-methy1]-pyrrolidine (prepared according to the procedures for (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine) (first fraction, Example 1-49; second fraction, Example 1-50); N-(2-hydroxy-3-pyrrolidin-1-yl-propyI)-N-methyl amine (prepared according to the same procedure as 1-amino-3-pyrrolidin-1-yl-propan-2-ol (Example 1-51); and (2S)-2-[(3R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyrrolidine (prepared according to the procedure for (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine) (Example 1-52).
Example 1-53: 3-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-benzoic acid was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-benzoic acid following procedure 3.

Example 1-54: {3-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1}-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone was prepared from 346-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-benzoic acid and (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Example 1-55:
OH 0 0"Thr 0 +
-B. <0 0 *KO .6.

1. To a solution of 4-(4,4,5,5-tetramethyl-[1,3]clioxolan-2-y1)-phenol (10.0 g, 45.5 mmol) and Cs2CO3 (23.5 g, 68.25 mmol) in DMF (60 mL) was added ethyl a-bromoacetate (11.6 g, 68.25 mmol).
The mixture was stirred at room temperature for 24 hours, then diluted with ethyl acetate, washed with water, dried over Na2SO4. After filtration and evaporation, the residue was dried under high vacuum to provide [4-(4,4,5,5-tetramethy141,3]dioxolan-2-y1)-phenoxy]-acetic acid ethyl ester (12.52 g, 90% yield) as an oil.
2. A mixture of 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (Example 1(a)) (2.2 g, 6.3 mmol), [4-(4,4,5,5-tetramethyl-[1,3]clioxolan-2-y1)-phenoxy]-acetic acid ethyl ester (2.9 g, 1.5 eq.), bis(triphenylphosphine)palladium(11) chloride (136 mg) and sodium carbonate (1.93 g, 3.0 eq.) in ethylene glycol dimethyl ether (30 mL), DMF (5 mL) and water (8 mL) was heated to 90-100 C under nitrogen for 7 hr. The reaction was cooled to rt and diluted with ethyl acetate. The mixture was washed with water, brine, dried and purified on silica column to afford {4-p-amino-5-(2,6-dichloro-berayloxy)-pyridin-3-yll-phenoxyyacetic acid ethyl ester. This ester was treated with sodium carbonate and water at rt overnight. The reaction was diluted with ethyl acetate. The mixture was washed with water, brine, dried and purified on silica column to afford 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-phenoxy}-acetic acid.
Example 1-56: 2-{446-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-A-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-A-ethanone was prepared from 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-ylyphenoxy}-acetic acid and (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Example 1-57: 2-{446-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yll-ethanone was prepared from 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-acetic acid and (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Example 1-58: 3-(2,6-Dichloro-benzyloxy)-5-(1H-indo1-5-y1)-pyridin-2-ylamine was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and indole-5-boronic acid following procedure 3.
Example 1-59: To a solution of 3-(2,6-Dichloro-benzyloxy)-5-(1H-indo1-5-y1)-pyridin-2-ylamine (example 1-58, 200 mg, 0.52 mmol) in acetic acid (4 mL) and trifluoroacetic acid (1 mL) was added 1-methy1-4-piperidone (0.32 mL, 2.6 mmol). The solution was refluxing for over night, and evaporated.
The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, and condensed. The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95:5:0.1) to provide 3-(2,6-dichloro-benzyloxy)-543-(1-methy1-1,2,3,6-tetrahydro-pyridin-4-y1)-1H-indo1-5-y1]-pyridin-2-ylamine (103.5 mg, 41% yield) as an orange crystalline solid.
Example 1-60: To a de-gassed solution of 3-(2,6-dichloro-benzyloxy)-543-(1-methy1-1,2,3,6-tetrahydro-pyridin-4-y1)-1H-indo1-5-y11-pyridin-2-ylamine (example 1-61, 130 mg, 0.27 mmol) in methanol (50 mL) and acetic acid (5 mL) was added 10% Pd/C (50 mg). The solution was degassed and charged with hydrogen for three times, and then was stirred under hydrogen balloon for over night. The mixture was 'filtered through a celite pad, washed with methanol, and then condensed.
The residue was dissolved in ethyl acetate, washed with sat. NaHCO3 and brine, dried over Na2SO4, and condensed.
The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95:5:0.1) to provide 3-(2,6-dichloro-benzyloxy)-543-(1-methyl-piperidin-4-y1)-1H-indo1-5-y1]-pyridin-2-ylamine as a white solid.
Examples 1-61-1-68: The compounds of Examples 1-61 to 1-68 were prepared according to procedure 5 from 3-(2,6-Dichloro-benzyloxy)-5-(1H-indo1-5-y1)-pyridin-2-ylamine and: morpholine (Example 1-61); piperidine (Example 1-62); pyrrolidine (Example 1-63);
diethylamine (Example 1-64);
pyrrolidin-3-yl-carbamic acid tert-butyl ester (Example 1-65); 2,6-dimethyl-morpholine following (Example 1-66); (R)-pyrrolidin-3-yl-acetamide (Example 1-67); and piperazin-1-yl-ethanone (Example 1-68).
Example 1-69: 3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(1H-indo1-5-y1)-pyridin-2-ylamine was prepared from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and indole-5-boronic acid following procedure 3.
Examples 1-70 to 1-75: The compounds of Examples 1-70 to 1-75 were prepared according to procedure 5 from 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(1H-indo1-5-y1)-pyridin-2-ylamine and: piperazin-1-yl-ethanone (Example 1-70); 2,6-dimethyl-morpholine (Example 1-71); (3S)-pyrrolidin-3-yl-acetamide (Example 1-72); piperidine (Example 1-73); morpholine (Example 1-74); and pyrrolidine (Example 1-75).
Example 1-76:

HN

Br KOAc/ DMSO 40 N o z---d PdC12 (dppf).CH2C112 13, 1. To a stirred solution of ethyl 5-bromo-1H-indole-2-carboxylate (5g, 18.6mmol) in DMSO
(75mL, 0.25M), 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi-1,3,2-dioxaborolane (11.2g, 44.3mmol), potassium acetate (5.5g, 56.0 mmol), and [bis(diphenylphosphino)ferrocene]
dichloropalladium II (1.23mmol) were added. The mixture was de-gassed and charged with nitrogen for three times, and then heated at 80 C
under nitrogen for overnight. The reaction was cooled to ambient temperature and diluted with ethyl acetate (2x100mL). The mixture was washed with water (1x50 mL), brine (1x50mL), dried over MgSO4, and purified on a silica gel column to afford ethyl 5-(4,4,5,5-tetramethy1-1, 3,2-dioxaborolan-2-y1)-1H-indole-2-carboxylate as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 6 1.31 (t, 3H), 4.32 (m, 2H), 7.18 (s, 1H), 7.42 (d, 1H), 7.54 (d, 1H), 8.05 (s, 1H), 11.96 (s, 1H); MS m/z 315 (M+1).
2. 5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yI]-1H-indole-2-carboxylic acid ethyl ester was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-y1)-1H-indole-2-carboxylic acid ethyl ester following procedure 3.
Example 1-77: To a mixture of ethyl 5-{6-amino-5- [(2,6-dichlorobenzyl) oxy]
pyridin-3-yI}-1H-indole-2-carboxylate (2.5 g, 5.5mmol) in methanol:water (60mL:20mL), lithium hydroxide (0.65g, 27.1mmol) was added. The reaction was heated to reflux for overnight. Most of the solvent was evaporated and the mixture was acidified, and stirred for 10 min. The precipitate was filtered out and washed with water to yield 5-{6-amino-5-[(2,6-dichlorobenzyl)oxy]pyridin-3-y1}-1H-indole-2-carboxylic acid as tan solid.
Examples 1-78 to 1-85: The compounds of Examples 1-78 to 1-85 were prepared according to procedure 4 from 5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-1H-indole-2-carboxylic acid and: N-methylpiperazine (Example 1-78); (3R)-3-dimethylamino-pyrrolidine (Example 1-79); (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (prepared as in example 1-39) (Example 1-80); 2-pyrrolidin-1-yl-ethylamine (Example 1-81); 2-morpholin-4-yl-ethylamine (Example 1-82); (S)-pyrrolidin-3-yl-carbamic acid led-butyl ester (Example 1-83), followed by de-protection of the Boc-group in 20 %
trifluoroacetic acid in dichloromethane (Example 1-84); 2-hydroxy-3-pyrrolidin-1-yl-propylamine (Example 1-85).
Example 1-86: 4-(6-Amino-5-benzyloxy-pyridin-3-y1)-phenol was prepared from 3-benzyloxy-5-bromo-pyridin-2-ylamine and 4-(4,41,5,5-tetramethy1-1,3-2-dioxabordan-2-y1) phenol following procedure 3.
Example 1-87: 3-Benzyloxy-5-phenyl-pyridin-2-ylamine was prepared from 3-benzyloxy-5-bromo-pyridin-2-ylamine and phenylboronic acid following procedure 3.
Example 1-88: 3-(3-Methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine was prepared according to procedure 6.
Examples 1-89 to 1-105: The compounds of Examples 1-89 to 1-105 were prepared according to procedure 6 from: 2-chloro-4-fluoro-benzylbromide (Example 1-89); 2-chlorobenzylbromide (Example I-90); 2,5-dichlorobenzylbromide (Example 1-91); 2-chloro-5-trifluoromethyl benzylbromide (Example 1-92);
2,4-Dichloro-5-fluoro-benzylbromide (Example 1-93); 2-chloro-3-trifluoromethyl-benzylbromide (Example 1-94); 2-chloro-3,6difluoro¨benzylbromide (Example 1-95); 3,4-dichloro-benzylbromide (Example 1-96); 2-bromomethyl-benzonitrile (Example 1-97); 2-chloro-6-fluoro-3-methyl-benzylbromide (Example 1-98); 2-bromomethy1-1,3,4-trifluoro-benzene (Example 1-99); 2-bromomethy1-1,3-difluoro-benzene (Example I-100); 2-bromomethy1-1,3-difluoro-4-methyl-benzene (Example 1-101); 2-bromomethy1-4-chloro-1,3-difluoro-benzene (Example 1-102); 2-bromomethy1-1-chloro-3-fluoro-benzene (Example 1-103); 4-bromomethy1-2-fluoro-1-methoxy-benzene (Example 1-104); and 1-bromomethy1-3-nitro-benzene, followed by reduction of the nitro group to amino and reaction with methanesulfonyl chloride (Example I-105).

Example 1-106: 544-(2-Morpholin-4-yl-ethoxy)-pheny1]-3-(3-nitro-benzyloxy)-pyridin-2-ylamine was synthesized according to procedure 7.
Examples 1-107 to 1-110: The compounds of Examples 1-107 to 1-110 were prepared according to procedure 7 from: 1-bromomethyl-naphthalene (Example 1-107); 2-bromomethy1-3-chloro-1,4-difluoro-benzene (Example 1-108); 2-bromo-N-(4-isopropyl-phenyl)-2-phenyl-acetamide (Example 1-109); and 3-bromomethy1-5-chloro-benzo[b]thiophene (Example 1-110).
Example 1-111: (4-[6-Amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y1]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y11-methanone was synthesized according to procedure 8.
Examples 1-112 to 1-117: The compounds of Examples 1-112 to 1-117 were prepared according to procedure 8 from: 2-bromomethy1-1-fluoro-3-trifluoromethyl-benzene (Example 1-112); 2-bromomethy1-4-fluoro-1-trifluoromethyl-benzene (Example 1-113); 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (Example 1-114); 1-bromo-2-bromomethyl-benzene (Example 1-115); 1-bromomethy1-3-fluoro-2-trifluoromethyl-benzene (Example 1-116); and 2-bromomethy1-3-chloro-1,4-difluoro-benzene (Example 1-117).
Examples 1-118 to 1-121: The compounds of Examples 1-118 to 1-121 were prepared according to procedure 3 from 5-bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamine and:
4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-y1)-phenol (Example 1-118); 4-{244-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenoxy]-ethy1}-morpholine (Example 1-119); 4-(4,4,5,5-tetramethy141,3]dioxolan-2-y1)-1H-indole (Example 1-120); and 4-(4,4,5,5-tetramethy141,3]dioxolan-2-y1)-benzoic acid (Example 1-121).
Example 1-122: {4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-311]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-A-methanone was prepared from 446-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-y1]-benzoic acid and (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Example 1-123: (4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-ylypheny1}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone was prepared from 446-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yli-benzoic acid and (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Example 1-124: (446-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yll-phenoxy}-acetic acid ethyl ester was prepared from 5-bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamine and of [4-(4,4,5,5-tetramethy141,3]dioxolan-2-y1)-phenoxy]-acetic acid ethyl ester following procedure 3.
Example 1-125: {4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-acetic acid ethyl ester (1.0 g, 2.41 mmol) was treated with sodium carbonate (1.28 g, 12.05 mmol) and water (10 mL) at 90-100 C overnight. The reaction was cooled to rt and diluted with ethyl acetate. The mixture was washed with water, brine, dried and purified on silica column to afford 4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-y1]-phenoxy}-acetic acid.
Example 1-126: 2-{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-y1]-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-ethanone was prepared from 446-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yll-phenoxy}-acetic acid and (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Example 1-127: 2-{446-Amino-542,6-difluoro-benzyloxy)-pyridin-3-y1]-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-ethanone was prepared from 446-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yI]-phenoxy}-acetic acid and (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Examples 1-128 to 1-134: The compounds of Examples 1-128 to 1-134 were prepared according to procedure 3 from 4-(4,4,5,5-tetramethyl-(1,3]dioxolan-2-y1)-phenol and: 5-bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine (Example 1-128); 5-bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine (Example 1-129); 5-bromo-3-(2,4-dichloro-benzyloxy)-pyridin-2-ylamine (Example 1-130); 2-(2-amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (Example 1-131); 5-bromo-3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine (Example 1-132); 5-bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine (Example 1-133); and 5-bromo-3-(4-tert-butyl -benzyloxy)-pyridin-2-ylamine (Example 1-134).
Example 1-135:

N-Methyl Morpholine 1. To a solution of 4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-21)-phenylamine (5.00 g, 22.8 mmol) in methylene chloride (100 mL) and 4-methylmorpholine (16 mL) at 0 C was added methanesulfonyl chloride (2.1 mL, 28 mmol). The mixture was stirred at room temperature for 2 hr, and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to provide N44-(4,4,5,5-tetramethy141,3,2idioxaborolan-2-y1)-pheny1]-methanesulfonamide as a white solid (6.32 g, 93% yield). MS rniz 298 (M+1).
2. N-{446-Amino-5-(2-cyano-berrzyloxy)-pyridin-3-ylyphany1}-methanesulfonamide was prepared following procedure 3 from 2-(2-Amino-5-bromo-pyridin-3-yloxymethy1)-benzonitrile and N44-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-pheny1]-methanesullonamide.
Example 1-136: 10% NaOH solution (25 mL) was added to N-{446-amino-5-(2-cyano-benzyloxy)-pyridin-3-yli-phenyl}methanesulfonamide (Example 1-135, 650 mg, 1.65mmol) in ethylene glycol (55 mL). The mixture was heated to reflux and allowed to stir for 24 hr. The reaction was cooled to room temperature. Most of the solvent was evaporated and the mixture was acidified. The precipitated solid was filtered out to afford 242-Amino-5-(4-methanesulfonylamino-pheny1)-pyridin-3-yloxymethyll-benzoic acid as light brown solid. The filtrate was neutralized and extracted with Et0Ac (5 x 20 mL). The organic layer was combined, dried over MgSO4, and concentrated to yield 242-Amino-5-(4-methanesulfonylamino-pheny1)-pyridin-3-yloxymethyll-benzamide as an off-white solid.
Example 1-137: 242-Amino-5-(4-methanesulfonylamino-pheny1)-pyridin-3-yloxymethylFbenzoic acid was prepared as in Example 1-136.
Example 1-138 to 1-140: The compounds of Examples 1-138 to 1-140 were prepared according to procedure 4 from 2-[2-amino-5-(4-methanesulfonylamino-pheny1)-pyridin-3-yloxymethyl]-benzoic acid and: N-methyl-piperazine (Example 1-138); 2-hydroxyethylamine (Example 1-139);
and isobutylamine (Example 1-140).

Example 1-141: 5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine (Example 1(e), 9.00 9, 27.0 mmol), 4-carboxybenzeneboronic acid (4.41 g, 27.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.99 g , 0.9 mmol), potassium carbonate (13.1 g, 95.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 C to 98 C over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and many small impurities. The mixture was cooled to 45 C. The solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 mL of water. The filtrate was cooled in an ice bath and acidified to pH 7.5 with acetic acid using a pH
meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 2.5 g of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1]-benzoic acid and a second compound as a brown solid in a ratio of about 1:1 by 1H-NMR. This material was discarded. -The filtrate was acidified to pH 6.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 3.6 g (36 % yield) of 446-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yli-benzoic acid as a brown solid containing a 5-10 %
impurity by 1H-NMR.
Examples 1-142 to 1-149: The compounds of Examples 1-142 to 1-149) were prepared according to procedure 4 from 4-E6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-y1]-benzoic acid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-142); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-143); (3S)-3-dimethylamino-pyrrolidine (Example 1-144); (S)-pyrrolidin-3-yl-carbamic acid Jeri-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-145); N-methylpiperazine (Example 1-146); 1-piperazin-1-yl-ethanone (Example 1-147); 2-morpholin-411-ethylamine (Example 1-148); 3-morpholin-4-yl-propylamine (Example 1-149).
Example 1-150: 5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine (4.50 g, 14.3 mmol), 4-carboxybenzeneboronic acid (2.62 g, 15.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.56 g, 0.5 mmol), potassium carbonate (6.90 g, 50 mmol), dimethylformamide (36 mL), and water (18 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 82 to 93 C over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed product at Rf 0.3 and a few small impurities. The mixture was cooled to 45 C. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and discarded. The combined filtrate was diluted with 216 mL of water and 4 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes with 3 g of Celite and 3 g of Norit. The solids were collected by vacuum filtration through a pad of Celite and washed with 10 mL of water. The solids were discarded.
The combined filtrate was cooled in an ice bath and acidified to pH 7 with acetic acid using a pH meter.

The solids were collected by vacuum filtration, washed with 20 mL of ethanol:water 1:1 and dried under vacuum to give 2.7 g (53 % yield) of 446-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1]-benzoic acid.
Examples 1-151 to 1-159: The compounds of Examples 1-151 to 1-159 were prepared according to procedure 4 from 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-y1]-benzoic acid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-151); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-152); (3S)-3-dimethylamino-pyrrolidine (Example 1-153); pyrrolidin-3-yl-carbamic acid tett-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-154); 4-pyrrolidin-1-yl-piperidine (Example 1-155); N-methylpiperazine (Example 1-156); 1-piperazin-1-yl-ethanone (Example 1-157); 2-morpholin-4-yl-ethylamine (Example 1-158); and 3-morpholin-4-yl-propylamine (Example 1-159).
Example 1-160: 2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 29.6 mmol), 4-carboxybenzeneboronic acid (5.4 g, 32.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.8 g, 70.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 90 C over a period of 2 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and an impurity at Rf 0.5. The mixture was cooled to 45 C. The sticky solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N
potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 20 mL of water. The solids were discarded. The filtrate was cooled in an ice bath acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL water and dried under vacuum to give 8.5 g (83 %
yield) of 446-amino-5-(2-cyano-benzyloxy)-pyridin-3-yll-benzoic acid as a very dark solid.
Examples 1-161 to 1-170: The compounds of Examples 1-161 to 1-170 were prepared according to procedure 4 from 4[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-y1]-benzoic acid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-161); (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-162); (3S)-3-dimethylamino-pyrrolidine (Example 1-163); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-164); 4-pyrrolidin-1-yl-piperidine (Example 1-165); N-methylpiperazine (Example 1-166); 1-piperazin-1-yl-ethanone (Example I-167); 1-methyl-piperidin-4-ylamine (Example 1-168); 2-Morpholin-4-yl-ethylamine (Example 1-169); and 3-morpholin-4-yl-propylamine (Example 1-170).
Example 1-171: 5-Bromo-3-(2,4-dichloro-benzyloxy)-pyridin-2-ylamine (6.96 g, 20.0 mmol), 4-carboxybenzeneboronic acid (3.98 g, 24.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.74 g, 0.66 mmol), potassium carbonate (9.7 g, 70 mmol), dimethylformamide (35 mL) and water (17 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 95 C over a period of 9 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and impurities at Rf 0.5 and 0.3. The mixture was cooled to room temperature and allowed to stand over for about 48 hr. The solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and saved. The filtrate was diluted with 210 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 mL of water to give about 1 g of a mixture of product and a spot running with starting material. This mixture was discarded. The filtrate was cooled in an ice bath and acidified to pH 5-6 with about 10 mL of acetic acid. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 2.9 g (37 % yield) of 4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yI]-benzoic acid as a brown solid.
Examples 1-172 to 1-181: The compounds of Examples 1-172 to 1-181 were prepared according to procedure 4 from 446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-y1]-benzoic acid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-172); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-173); (3S)-3-dimethylamino-pyrrolidine (Example 1-174); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-175); 4-pyrrolidin-1-yl-piperidine (Example 1-176); N-methylpiperazine (Example 1-177); 1-piperazin-1-yl-ethanone (Example 1-178); 1-methyl-piperidin-4-ylamine (Example 1-179); 2-morpholin-4-yl-ethylamine (Example 1-180); and 3-morpholin-4-yl-propylamine (Example 1-181).
Example 1-182: 5-Bromo-3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine (5.80 g, 16.7 mmol), 4-carboxybenzeneboronic acid (3.05 g, 18.4 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.62 g, 0.6 mmol), potassium carbonate (8.10 g, 58 mmol), dimethylformamide (47 mL) and water (23 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 93 C over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed product at Rf 0.6 and a few small impurities. The mixture was cooled to 45 C. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 300 mL of water and 4 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes with 3 g of Celite and 3 g of Norit. The solids were collected by vacuum filtration through a pad of Celite and washed with 10 mL of water. The solids were discarded. The filtrate was cooled in an ice bath and acidified to pH 7.3 with acetic acid using a pH
meter. The solids were collected by vacuum filtration, washed with 20 mL of ethanol:water 1:1 and dried under vacuum to give 4.5 g (69 % yield) of 446-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yll-benzoic acid as a brown solid.%
Examples 1-183 to 1-192: The compounds of Examples 1-183 to 1-192 were prepared according to procedure 4 from 446-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-y1]-benzoic acid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-183); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-184); (3S)-3-dimethylamino-pyrrolidine (Example 1-185); pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-186); 4-pyrrolidin-1-yl-piperidine (Example 1-187); N-methylpiperazine (Example 1-188); 1-piperazin-1-yl-ethanone (Example 1-189); 1-methyl-piperidin-4-ylamine (Example 1-190); 2-morpholin-411-ethylamine (Example 1-191); and 3-morpholin-4-yl-propylamine (Example 1-192).

Example 1-193: 2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 26.8 mmol), 4-carboxybenzeneboronic acid (4.9 g, 30.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.1 g, 95 mmol), dimethylformamide (72 mL), and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 96 C over a period of 2 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.8, product at Rf 0.5 and an impurity at Rf 0.4. The mixture was cooled to 45 C and filtered to remove the solids. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and 4 g of Celite and 2 g of Norit were added. The solids were collected by vacuum filtration through 4 g of Celite, washed with 30 mL of ethanol:water 1:1 and discarded The filtrate was cooled in an ice bath and acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL
water and dried under vacuum to give 8.1 g (80 % yield) 446-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-y1]-benzoic acid as a dark solid.
Examples 1-194 to 1-201: The compounds of Examples 1-194 to 1-201 were prepred according to procedure 4 from 446-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-y111-benzoic acid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-194); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-195); (3S)-3-dimethylamino-pyrrolidine (Example 1-196); N-methylpiperazine (Example 1-197);
1-piperazin-1-yl-ethanone (Example 1-198); 1-methyl-piperidin-4-ylamine (Example 1-199); 2-morpholin-4-yl-ethylamine (Example 1-200); and 3-morpholin-4-yl-propylamine (Example 1-201).
Example 1-202: 5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine (9.00 g, 27.0 mmol), 4-carboxybenzeneboronic acid (4.41 g, 27.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.99 g, 0.9 mmol), potassium carbonate (13.1 g, 95 mmol), dimethylformamide (72 mL), and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 98 C over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and a few small impurities. The mixture was cooled to 45 C. The solids were collected by vacuum filtration, washed with 20 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12-13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 mL of water to give about 1 g of a mixture which was discarded.
The filtrate was cooled in an ice bath and acidified to pH 6.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 3.6 g (36 % yield) 4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-y11-benzoic acid as a brown solid.
Examples 1-203 to 1-210: The compounds of Examples 1-203 to 1-210 were prepared according to procedure 4 from 446-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yll-benzoic acid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-203); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-204); (3S)-3-dimethylamino-pyrrolidine (Example 1-205); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-206); N-methylpiperazine (Example 1-207); 1-piperazin-1-y1)-ethanone (Example 1-208);
2-morpholin-4-yl-ethylamine (Example 1-209); and 3-morpholin-4-yl-propylamine (Example 1-210).
Example 1-211: 4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yI]-benzoic acid methyl ester was prepared following procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid as an off-white solid in 55%
yield. 1H NMR
(CDC13, 300 MHz) P3.94 (s, 3H), 4.79 (brs, 2H), 5.29-5.30 (d, 2H, J, 1.6), 7.06-7.19 (dt, 1H, J, 4.1, 9.0), 7.2-7.26 (m, 1H), 7.37-7.38 (d, 1H, 1.8), 7.58-7.61 (m, 2H), 8.01-8.02 (d, 2H, J, 1.8), 8.08-8.11 (m, 2H).
To a stirred solution of 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid methyl ester (2.5 g, 6 mmol) in warm isopropanol (300 mL) was added H20 (100 mL) containing LiOH
(0.74 g, 31 mol). The reaction immediately turned orange and was left to stir at room temperature for 18 hr. The reaction was diluted with Et0Ac (200 mL) and brine (50 mL). The organic was separated off and the aqueous was extracted with Et0Ac (2 x 50 mL). The organic layers were combined and washed with brine (2 x 25 mL), dried with Na2SO4 and concentrated to dryness under vacuum to yield 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y11-benzoic acid (2.4 g, 6 mmol, 99%) as an off-white solid.
Examples 1-212 to 1-224: The compounds of Examples 1-212 to 1-224 were prepared according to procedure 4 from 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-benzoic acid and: N-methylpiperazine (Example 1-212); 4-pyrrolidin-1-yl-piperidine (Example 1-213); piperidin-4-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-214); 3,5-dimethyl-piperazine (Example 1-215); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-216); (3S)-3-dimethylamino-pyrrolidine (Example 1-217); (R)-pyrrolidin-3-yl-carbamic acid (6d-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-218); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-219); 1-methyl-piperidin-4-ylamine (Example 1-220); 2-pyrrolidin-1-yl-ethylamine (Example 1-221); 3-pyrrolidin-1-yl-propylamine (Example I-222); 2-morpholin-4-yl-ethylamine (Example 1-223); and 3-morpholin-4-yl-propylamine (Example 1-224).
Example 1-225: 3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yI]-benzoic acid was prepared using the same procedure as 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-benzoic acid from from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 3-methoxycarbonylbenzeneboronic acid.
Examples 1-226 to 1-239: The compounds of Examples 1-226 to 1-239 were prepared according to procedure 4 from 346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-benzoic acid and: N-methylpiperazine (Example 1-226); 4-pyrrolidin-1-yl-piperidine (Example 1-227); piperidin-4-yl-carbamic acid tert-butyl ester, and then followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-228); 3,5-dimethyl-piperazine (Example 1-229); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-230); (3S)-3-dimethylamino-pyrrolidine (Example 1-231);
(R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-232); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-233); 1-methyl-piperidin-4-ylamine (Example 1-234); 2-pyrrolidin-1-yl-ethylamine (Example 1-235); 3-pyrrolidin-1-yl-propylamine (Example 1-236); 2-morpholin-4-yl-ethylamine (Example 1-237); 3-morpholin-4-yl-propylamine (Example 1-238); and 1-[4-(2-amino-ethyl)-piperazin-1-y1]-ethanone (Example 1-239).
Example 1-240:

NH, 401 0 (Et)3N 1101 0 DCM ,B.

1. 4-(4,4,5,5-Tetramethy1-1,3,2-dioxaborolan-2-yl)aniline (5 g, 22.8 mmol) was dissolved in DCM (100 mL, 0.2M), triethylamine (15 mL, 5.0 molar equivalent) was added to the mixture. The reaction was stirred at 0 C for 5 min. 3-chloropropane-1-sulfonyl chloride (4.2 g, 23.0 mmol) was added portion wise. The reaction was stirred at 0 C for 1 hr and brought gradually to room temperature, heated to reflux at 70 C for 2 hr. The mixture was cooled to room temperature, diluted with Et0Ac and water.
The organic layer was washed with brine, dried over MgS0.4, filtered, and concentrated. The residue was purified through a silica column to afford 2-[4-(4,4,5,5-tetramethy1-1, 3,2-dioxaborolan-2-yl)phenygisothiazolidine 1,1-dioxide as off-white solid (5.2 g, 70% yield). 1H
NUR (400 MHz, DMSO-d6) 7.62 (d, 2H), 7.18 (d, 2H), 3.76 (t, 2H), 3.53 (t, 2H), 2.41 (t, 2H), 1.28 (s, 12H).
2. 3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-1A6-isothiaz.olidin-2-y1)-pheny1]-pyridin-2-ylamine was prepared following procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 244-(4,4,5,5-tetramethy1-1, 3,2-dioxaborolan-2-yl)phenyl]isothiazolidine 1,1-dioxide.
Example 1-241: 3-(2,6-Dichloro-benzyloxy)-544-(1,1-dioxo-1A6-isothiazolidin-2-y1)-pheny9-pyridin-2-ylamine was prepared following procedure 3 from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and 244-(44,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenylpso-thiazolidine 1,1-dioxide.
Example 1-242: 5-[4-(1,1-dioxo-1A6-isothiazolidin-2-y1)-pheny1]-3-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-2-ylamine was prepared according to procedure 8.
Example 1-243: 2-Diethylamino-ethanesulfonic acid {446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yll-pheny1}-amide was synthesized according to procedure 9.
Examples 1-244 to 1-266: The compounds of Examples 1-244 to 1-266 were prepared following procedure 9.
Examples 1-267 to 1-269: The compounds of Examples 1-267 to 1-269 were prepared according to procedure 3, with purification by reversed phase preparative HPLC eluting with acetonitrile-water-trifluoroacetic acid system and obtained as trifluoroacetic acid salts, from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and: 2-(dimethylaminomethyl)-phenylboronic acid (Example 1-267);

3-(pyrrolidin-1-y1)-phenylboronic acid (Example 1-268) and N44-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenylymethanesulfonamide (Example 1-269).
Example 1-270: 546-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-ylythiophene-2-carboxylic acid was prepared following procedure 3 starting from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 5-carboxythiophene-2-boronic acid.
Examples 1-271 to 1-276: Examples 1-271 to 1-276 were prepared according to procedure 4 from 546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-ylphioPhene-2-carboxylic acid and: N-methylpiperazine (Example 1-271); (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-272); 1-methyl-piperidin-4-y1)-amine (Example 1-273); 3,5-dimethyl-piperazine (Example 1-274); 2-pyrrolidin-1-yl-ethylamine (Example 1-275); and 4-pyrrolidin-1-yl-piperidine (Example 1-276).
Example 1-277: 446-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-ylybenzoic acid was prepared using the same procedure as 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid from 5-bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid.
Examples 1-278 to 1-285: Examples 1-278 to 1-285 were prepared according to procedure 4 from 4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoic acid and: 4-pyrrolidin-1-yl-piperidine (Example 1-278); 1-methyl-piperidin-4-ylamine (Example 1-279); 3,5-dimethyl-piperazine (Example 1-280); 3-dimethylamino-pyrrolidine (Example 1-281); (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-282); 2-morpholin-4-yl-ethylamine (Example 1-283); N-methylpiperazine (Example 1-284);
and 4-acetyl-piperazin-1-y1)-ethylamine (Example 1-285).
Examples 1-286 to 1-289: The compounds of Examples 1-286 to 1-289 were prepared following procedure 2.
Example 1-290: 4-{6-Amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyridin-3-y1}-benzoic acid was prepared using the same procedure as 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yly benzoic acid from 5-bromo-3-0-(2,6-dichloro-3-fluoro-pheny1)-ethoxyypyridin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid.
Examples 1-291 to 1-296: The compounds of Examples 1-291 to 1-296 were prepared according to procedure 4 from 4-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-benzoic acid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example 1-291); 1-methyl-piperidin-4-ylamine (Example I-292); (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 1-293); 4-pyrrolidin-1-yl-piperidine (Example 1-294); N-methyl-piperazine (Example 1-295); and 3,5-dimethyl-piperazine (Example 1-296).
Examples 1-297 to 1-299: The compounds of Examples 1-297 to 1-299 were prepared following procedure 9.
Examples 1-300 to 1-661 were prepared according to the procedures referenced in the Tables herein, except as specifically described in the following paragraphs. When multiple procedures are referenced in the Tables separated by "/", the indicated procedures were performed sequentially.
Example 1-311: 3-{6-Amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-benzoic acid was prepared using the same procedure as 4[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-Pyridin-3-y1]-benzoic acid from 5-bromo-3-0-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-2-ylamine and 3-methoxycarbonylbenzeneboronic acid.
Example 1-312: 3-{6-Amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-yll-pheny1)-(4-methyl-piperazin-1-y1)-methanone was prepared following procedure 4 starting from 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-benzoic acid and 1-methyl-piperidin-4-ylamine.
Example 1-330: 4-{6-Amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-3-y1}-benzoic acid was prepared using the same procedure as 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-benzoic acid from 5-bromo-341-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid.
Example 1-331: 4-{6-Amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide was prepared following procedure 4 starting from 4-{6-amino-5-0-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-3-y1}-benzoic acid and the corresponding amine.
Example 1-342: 3-{6-Amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-3-y1}-benzoic acid was prepared using the same procedure as 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y0-benzoic acid from 5-bromo-341-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyridin-2-ylamine and 3-methoxycarbonylbenzeneboronic acid.
Example 1-343: (3-{6-Amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyridin-3-y1}-pheny1)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-melhanone was prepared following procedure 4 starting from 3-{6-amino-541-(2-chloro-3,6-difluoro-pheny1)-ethoxy3-pyridin-3-y1}-benzoic acid and the corresponding amine.
Example 1-359:
1. Preparation of 2-hydroxy-7-mm-4-azonia-spiro[3.5]nonane: To a solution of morpholine (17.4 mL, 0.2 mol, 1.0 eq.) in ethanol (20 mL) was added epichlorohydrin (16.1 ml, 1.03 eq.) from the addition funnel. The reaction was cooled with an ice water bath and gradually raised to room temperature. After 24 hr, the reaction was concentrated at 50 C until no more distillate could be condensed. The resulting oil was stored at room temperature for 24-48 hr or until a significant mass of crystals was observed. The slurry was diluted with acetone and filtered. The solids were dried under high vacuum. This provided 20g of crystalline product. The mother liquors could be concentrated and the crystallization process repeated in increase recovery.

OH

1. Ethanol NaH/DMF
+ C
2 Acetone 0 =
0 0 \.... Step 2 Step 1 ON

Br OH 1..0 Pd(PPI13)2C12 + ON NaHCO2 CI

I

CI

2. Preparation of 1-Morpholin-4-y1-344-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenoxyl-propan-2-ol: 4-(4,4,5,5-Tetramethy141,3,2]dioxaborolan-2-y1)-phenol (440 mg, 2mmol) was added to a stirred suspension of NaH (96mg, 2eq) in DMF (10mL) at 0 C. After 1 hr, 2-hydroxy-7-oxa-4-azonia-spiro[3.5]nonane (714mg, 2eq.) was added. The mixture was stirred at room temperature overnight. The reaction mixture was poured into sat'd NH4CI solution, and extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4 and condensed to dryness. The crude product was purified with a silica gel column eluting with 2% methanol in methylene chloride to afford 220mg of product as a pink solid (30%). 1H NMR (400 MHz, DMSO-d6): 6 7.58 (d, J = 8.2 Hz, 2H), 6.915 (d, J = 7.8 Hz, 2H), 4.89 (d, J = 2.0 Hz, 1H), 3.98 (m, 3H), 3.55 (m, 4H), 2.40 (m, 6H), 1.27 (s, 12H). MS (m/e): 364 [M+H]

(100%).

3. 1-(4-{6-Amino-541-(2,6-dichloro-3-fiuoro-pheny1)-ethoxy]-pyridin-3-ylyphenoxy)-3-morpholin-4-yl-propan-2-ol was prepared following procedure 3 starting from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine and 1-morpholin-4-y1-344-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenoxy]-propan-2-ol.

Example 1-371: 4-Methyl-piperazine-1-carboxylic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-amide was prepared according to procedure 10.

Example 1-386: 3-16-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]pyridin-3-y1}-benzoic acid was prepared using the same procedure as 4-(6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y11-benzoic acid from 5-bromo-341-(2,6-dichloro-pheny1)-ethoxy]-pyridin-2-ylamine and methoxycarbonylbenzeneboronic acid.

Example 1-387: (3-{6-Amino-541-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-y1)-pheny1)-((3R,5S)-3,5-dimethyl-piperazin-1-y1)-methanone was prepared following procedure 4 starting from 3-{6-amino-5-[1-(2,6-dichloro-pheny1)-ethoxy]-pyridin-3-y1}-benzoic acid and 3,5-dimethyl-piperazine.

Example 399: 4-16-Amino-541-(2,6-dichloro-pheny1)-ethoxy]-pyridin-3-y1}-benzoic acid was prepared using the same procedure as 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-benzoic acid from 5-bromo-341-(2,6-dichloro-phenyl)-ethoxy]-pyridin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid.

Example 400: 4-{6-Amino-541-(2,6-dichloro-pheny1)-ethoxyl-pyridin-3-yll-N-(2-pyrrolidin-1-yl-ethyl)-benzamide was prepared following procedure 4 starting from 4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-y1}-benzoic acid and 2-pyrrolidin-1-yl-ethylamine.

Example 1-454:

QN

Br Zn(CN)2/DMF

. ON

Pd2(dba)3/DPPF = NH2 CI

To a solution of 5-bromo-341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-2-ylamine (5.00 g, 13.15 mmol) in DMF (73 mL) and water (1 mL) was added Zn(CN)2 (4.50 g, 26.3 mmol), Pd2(dba)3 (0.602 g, 0.65 mmol), and DPPF (0.86 g, 1.55 mmol). The mixture was degassed and charged with nitrogen for three time, and then stirred under nitrogen at 100 C for 3 hr.
The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with a solution of sat.

NH4CI-conc. NH4OH-water (4:1:4), then dried over MgSO4. The crude product was purified on a silica gel column eluting with ethyl acetate-hexanes (1:4) to provide 6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile as a white solide (4.15 g, 97% yield).

Example 1-455: 6-Amino-541-(2,6-dichloro-3-cyano-pheny1)-ethoxy]-nicotinonitrile was obtained as a side product from the preparation of 6-Amino-5-0-(2,6-dichloro-3-fluoro-pheny0-ethoxyl-nicotinonitrile.

Example 1-456: 5-Aminomethy1-341-(2,6-dichloro-3-fluoro-pheny1)-sthoxyypyridin-2-ylamine was prepared with the reduction of 6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-nicotinonitrile. To a solution of borane in THF (1.0 M, 16.8 mL, 16.8 mmol) was added 6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]nicotinonitrile (785 mg, 2.41 mmol) in anhydrous THF (8 mL) at 0 C under nitrogen. The reaction solution was stirred under nitrogen at 0 C for 5 hr, and then HCI
solution (6N, 12 mL) was added slowly followed with the addition of water (12 mL) and methanol (80 mL).
The mixture was stirred for overnight. After evaporation of solvents, the residue was partitioned between dichloromethane and NaOH solution (1 N). The water layer was extracted for three times, and the combined extracts were dried over MgSO4. After filtration, evaporation and high vacuum dry, a white solid product was obtained (750 mg, 94% yield).

Example 1-457: (R)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid {6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-ylmethy1}-amide was prepared with the same procedure as Step 4 in procedure 11.

Example 1-462: (S)-1-{6-Amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-ethane-1,2-diol was prepared as follow: To a solution of asymmetic dihydroxylation-mix ci (2.33 g) in a 1:1 mixture of t-BuOH and water (8 mL each) cooled to 0 C was added 341-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-5-vinyl-pyridin-2-ylamine (500 mg, 1.67 mmol). The reaction mixture was stirred at 0 C until consumption of the starting material. Three more loadings of AD-mix a was added periodically to increase the reaction rate. Water was added (5 mL) and the mixture was extracted with Et0Ac (3 x 20 mL). The combined organic layer was dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC to provide (S)-1-{6-amino-541-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyridin-3-y1}-ethane-1,2-diol (320 mg, 53% yield).
Example 1-463: (R)-1-{6-Amino-5-0-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyridin-3-y1}-ethane-1,2-diol was prepared with the same procedure as Example 1-462 with AD-mix a.

Examples 11-1 to 11-6: The compounds of Examples 11-1 to 11-6 were prepared according to the Suzuki coupling procedure 3 from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine and: 4-(4,4,5,5-tetramethy141 ,3,2]dioxaborolan-2-y1)-phenol (Example 11-1);
244-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyllisothiazolidine 1,1-dioxide (Example 11-2); 3-{244-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenoxy]-ethyl)-morpholine (Example 11-3); 4-{244-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenoxyl-ethylymorpholine (Example 11-4); 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenylamine (Example 11-5); and 4-(4,4,5,5-tetramethy141,3,21dioxaborolan-2-y1)-benzoic acid (Example 11-6).
Example 11-7: {445-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yll-pheny1)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone was prepared following the amidation procedure 4 from 4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-y1]-benzoic acid and (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.
Example 11-8: {445-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-y1]-pheny1}-(4-pyrrolidin-1-yl-piperidin-1 -y1)-methanone was prepared following the amidation procedure 4 from 445-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yli-benzoic acid and 4-pyrrolidin-1-yl-piperidine.
Examples 11-9 to 11-32: The compounds of Examples 11-9 to 11-32 were prepared following the Suzuki coupling procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine and the following compounds prepared according to the procedure in Example 1-243:
2-morpholin-4-yl-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-9); 2-piperidin-1-yl-ethanesulfonic acid [4-(4,4,515-tetramethy141,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-10); 2-(4-hydroxy-piperidin-1-y1)-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-11); 2-pyrrolidin-1-yl-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-12); 2-[(3R)-3-Hydroxy-pyrrolidin-1-y11-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,21dioxaborolan-2-y1)-phenyl]-amide (Example 11-13); 2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-y1]-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,21dioxaborolan-2-y1)-phenyl]-amide (Example 11-14); 2-(cyclopropylmethyl-amino)-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-15); 2-dimethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-pheny11-amide (Example 11-16); 2-diethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-17); 2-(4-acetyl-piperazin-1-y1)-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-18); 244-(2-hydroxy-acety1)-piperazin-1-y1]-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-19); 2-cyclopropylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-20); 2-[(3R)-2-Hydroxymethyl-pyrrolidin-1-y1]-ethanesulfonic acid [3-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-21); 2-(4-Hydrm-piperidin-1-y1)-ethanesulfonic acid [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenyll-amide (Example 11-22); 2-(4-acetyl-piperazin-1-y1)-ethanesulfonic acid [3-(4,4,5,5-tetramethy141,3,21dioxaborolan-2-y1)-pheny1]-amide (Example 11-23); 2-piperidin-1-y1 -ethanesulfonic acid [3-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenylFamide (Example 11-24); 2-diethylamino-ethanesulfonic acid [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-25); 2-morpholin-4-yl-ethanesulfonic acid [3-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenyl]-amide (Example 11-26); 2-pyrrolidin-1-yl-ethanesulfonic acid [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-27); 2-dimethylamino-ethanesulfonic acid [3-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenyl]-amide (Example 11-28);
244-(2-hydroxy-acety1)-piperazin-1-yll-ethanesulfonic acid [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-29); 2-(cyclopropylmethyl-amino)-ethanesulfonic acid [3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-y1)-phenyl]-amide (Example 11-30);
2-[(3R)-3-hydroxy-pyrrolidin-1-y1]-ethanesulfonic acid [3-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-pheny1]-amide (Example 11-31); and 2-cyclopropylamino-ethanesulfonic acid [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenylFamide (Example 11-32).
Example 11-33: 445-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-benzoic acid was prepared following the Suzuki coupling procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-y1)-benzoic acid.
Example 11-34: {445-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yli-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-y1]-methanone was prepared following the amidation procedure 4 from 445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-211]-benzoic acid and (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.

Examples 11-35 to 11-46: The compounds of Examples 11-35 to 11-46 were prepared according to the amidation procedure 4 from 445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-benzoic acid and: 2-pyrrolidin-1-yl-ethylamine (Example 11-35); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 11-36); 1-[4-(2-amino-ethyl)-piperazin-1-y1]-ethanone (Example 11-37); 3-pyrrolidin-1-yl-propylamine (Example 11-38);

(3S)-3-dimethylamino-pyrrolidine (Example 11-39); (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boo-group with trifluoroacetic acid in dichloromethane (Example 11-40); 3,5-dimethyl-piperazine (Example 11-41); 4-pyrrolidin-1-yl-piperidine (Example 11-42); 3-morpholin-4-yl-propylamine (Example 11-43); 1-methyl-piperidin-4-ylamine (Example 11-44); 2-morpholin-4-yl-ethylamine (Example 11-45); and N-methylpiperazine (Example 11-46).
Example 11-47: 345-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-benzoic acid was prepared following the Suzuki coupling procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine (Example 11(b)) and 3-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-benzoic acid (Aldrich, Milwaukee).

Examples 11-48 to 11-60: The compounds of Examples 11-48 to 11-60 were prepared according to the amidation procedure 4 from 345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-benzoic acid and: N-methylpiperazine (Example 11-48); (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 11-49); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 11-50); 3,5-dimethyl-piperazine (Example 11-51); 3-morpholin-4-yl-propylamine (Example 11-52); 4-pyrrolidin-1-yl-piperidine (Example 11-53); (3S)-3-dimethylamino-pyrrolidine (Example 11-54); 2-pyrrolidin-1-yl-ethyl amine (Example 11-55); 1-methyl-piperidin-4-ylamine (Example 11-56); (2S)-pyrrolidin-1-ylmethyl-pyrrolidine (Example 11-57); 2-morpholin-4-yl-ethylamine (Example 11-58); 2-(4-Acetyl-piperazin-1-y1)-ethylamine (Example 11-59); and 3-pyrrolidin-1-yl-propylamine (Example 11-60).
Example 11-61: 3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(1H-indo1-5-y1)-pyrazin-2-ylamine was prepared from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine and indole-5-boronic acid following procedure 3.
Examples 11-62 to 11-68: The compounds of Examples 11-62 to 11-68 were prepared according to procedure 5 from 3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(1H-indo1-5-y1)-pyrazin-2-ylamine and:
pyrrolidine (Example 11-62); diethylamine (Example 11-63); 1-piperazin-1-yl-ethanone (Example 11-64);
2,6-dimethyl-morpholine (Example 11-65); N-(S)-pyrrolidin-3-yl-acetamide (Example 11-66); piperidine (Example 11-67); and morpholine (Example 11-68).
Example 11-69: 341-(2-Chloro-3,6-difluoro-pheny1)-2-methyl-propoxy1-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine was prepared following the Suzuki coupling procedure 3 from 5-bromo-341-(2-chloro-3, 6-difluoro-phenyl)-2-methyl-propoxyi-pyrazin-2-ylamine and 4-{244-(4,4, 5,5-tetramethy141 ,3,2]dioxaborolan-2-y1)-pheno,cyl-ethyl}-morpholine.
Example 11-70: (341-(2-Chloro-3,6-difluoro-pheny1)-ethoxy]-544-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine, compound with trifluoro-acetic acid, was prepared following the Suzuki coupling procedure 3 from 5-bromo-341-(2-chloro-3,6-difluoro-pheny1)-2-methyl-propoxy]-pyrazin-2-ylamine and 4-{244-(4,4,5,5-tetramethy141,3,21dioxaborolan-2-y1)-phenoxy]-ethy1}-morpholine. The product was purified with a reversed phase 0-18 preparative HPLC eluting with acetonitrile-water-trifluoroacetic acid and obtained as a trifluoroacetic acid salt.
Examples 11-71 to 11-83: The compounds of Examples 11-71 to 11-83 were prepared according to the Suzuki coupling procedure 3 from 5-bromo-341-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyrazin-2-ylamine and: 4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenoxyl-ethylymorpholine, followed by purification with a reversed phase 0-18 preparative HPLC eluting with acetonitrile-water-trifluoroacetic acid and obtained as a trifluoroacetic acid salt (Example 11-71); N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenyll-methane-sulfonamide (Example 11-72); 2-pyrrolidin-1-y1 -ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,21dioxaborolan-2-y1)-phenyll-amide (prepared as in Example 1-243) (Example 11-73); 2-(4-hydroxy-piperidin-1-y1)-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenyll-amide (prepared as in Example 1-243) (Example 11-74); 2-piperidin-1-yl-ethanesulfonic acid [4-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1)-phenyTamide (prepared according to the procedure in Example 1-243) (Example 11-75); 2-(cyclopropylmethyl-amino)-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenyfl-amide (prepared as in Example 1-243) (Example II-76); 2-[(3R)-3-Hydroxy-pyrrolidin-l-y1]-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (prepared as in Example 1-243) (Example 11-77); 2-[(2S)-2-Hydroxymethyl-pyrrolidin-l-y1]-ethanesulfonic acid [4-(4,4,5,5-tetramethy1-[l,3,2]dioxaborolan-2-y1)-pheny1]-amide (prepared as in Example 1-243) (Example 11-78); 2-dimethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenyll-amide (prepared as in Example 1-243) (Example 11-79); 2-morpholin-4-yl-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-y1)-phenyTamide (prepared as in Example 1-243) (Example 11-80); 2-diethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-pheny1]-amide (prepared as in Example 1-243) (Example 11-81); 2-cyclopropylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-y1)-pheny1]-amide (prepared as in Example 1-243); and 3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yI)-benzoic acid (Example 11-83).
Examples 11-84 to 11-88: The compounds of Examples 11-84 to 11-88 were prepared according to the amidation procedure 4 from 3-{5-amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid and: (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 11-84); (R)-pyrrolidin-3-yl-carbamic acid iert-butyl ester, followed by de-protection of Boc-group with trifluoroacetic acid in dichloromethane (Example 11-85); (2R)-2-pyrrolidin-l-ylmethyl-pyrrolidine (Example 11-86); 2-(4-acetyl-piperazin-1-y1)-ethylamine (Example 11-87); and (2S)-pyrrolidin-1-ylmethyl-pyrrolidine (Example 11-88).
Example 11-89: 3-{5-Amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid was prepared following the Suzuki coupling procedure 3 from 5-bromo-341-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-ylamine and 3-(4,4,5,5-letramethy141,3,21dioxaborolan-2-y1)-benzoic acid.
Example 11-90: 3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1)-N-(1-methyl-piperidin-4-y1)-benzamide was prepared following the amidation procedure 4 from 3-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1)-benzoic acid and 1-methyl-piperidin-4-ylamine.
Example 11-91: 3-{5-Amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-(3-pyrrolidin-l-yl-propy1)-benzamide was prepared following the amidation procedure 4 from 3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid and 3-pyrrolidin-1-yl-propylamine.
Example 11-92: (3-{5-Amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxyl-pyrazin-2-y1}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone was prepared following the amidation procedure 4 from 3-15-amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid and 4-pyrrolidin-l-yl-piperidin-1-ylamine.
Example 11-93: 4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-y1]-benzoic acidwas prepared following the Suzuki coupling procedure 3 from 5-bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylamine and 3-(4,4,5,5-tetramethy141 ,3,2]dioxaborolan-2-y1)-benzoic acid.
Example 11-94: 445-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yli-N-(2-morpholin-4-yl-ethyl)-benzamide was prepared following the amidation procedure 4 from 445-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yll-benzoic acid and 2-morpholin-4-yl-ethylamine.

Example 11-95: 445-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-y1]-N-(1-methyl-piperidin-4-y1)-benzamide was prepared following the amidation procedure 4 from 445-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yll-benzoic acid and 1-methyl-piperidin-4-ylamine.
Examples 11-96 to 11-211 were prepared according to the procedures referenced in the Tables herein, except as specifically described in the following paragraphs.
Example 11-108: 4-{5-Amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid was prepared using the same procedure as 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1j-benzoic acid from 5-bromo-3-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-pyrazin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid.
Example 11-109: 4-{5-Amino-641-(2-chloro-3,6-difluoro-pheny1)-ethoxyl-pyrazin-2-y1}-N-(3-pyrrolidin-1-yl-propy1)-benzamide was prepared following procedure 4 starting from 4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-y1}-benzoic acid and 3-pyrrolidin-1-yl-propylamine.
Example 11-121: 345-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-y11-benzoic acid using the same procedures a 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-benzoic acid from 5-bromo-3-(3-fluoro-2-trifiuoromethyl-benzyloxy)-pyrazin-2-ylamine and methoxycarbonylbenzeneboronic acid.
Example 11-122: {3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone was prepared following procedure 4 starting from 345-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yll-benzoic acid and 4-pyrrolidin-1-yl-piperidin-1-ylamine.
Example 11-145: 4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid was prepared using the same procedure as 4-p-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-benzoic acid from 5-bronno-341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid.
Example 11-148: 4-{5-Amino-641-(2,6-dichloro-3-fluoro-pheny1)-ethoxy]-pyrazin-2-y1}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide was prepared following procedure 4 starting from 4-{5-Amino-6-[1-(2,6-dichloro-3-fiuoro-phenyl)-ethoxy]-pyrazin-2-y1}-benzoic acid and (R)-2-hydroxy-3-pyrrolidin-1-yl-propylamine.
Example 11-156: 4-{5-Amino-641-(2,6-dichloro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid was prepared using the same procedure as 446-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-benzoic acid from 5-bromo-341-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-ylamine and 4-methoxycarbonylbenzeneboronic acid.
Example 11-157: (4-{5-Amino-641-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-y1}-pheny1)-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone was prepared following procedure 4 starting from 4-{5-Amino-6-[1-(2,6-dichloro-pheny1)-ethoxy]-pyrazin-2-yI}-benzoic acid and 4-pyrrolidin-1-yl-piperidin-1-ylamine.
Example 11-168: 3-{5-Amino-641-(2,6-dichloro-pheny1)-ethoxy]-pyrazin-2-y1}-benzoic acid was prepared using the same procedure as 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-benzoic acid from 5-bromo-341-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-ylamine and 3-methoxycarbonylbenzeneboronic acid.

Example 11-169: 3-{5-Amino-641-(2,6-dichloro-pheny1)-ethoxy]-pyrazin-2-y1)-N-(1-methyl-piperidin-4-y1)-benzamide was prepared following procedure 4 starting from 3-{5-amino-641-(2,6-dichloro-pheny1)-ethoxyl-pyrazin-2-ylybenzoic acid and 1-methyl-piperidin-4-ylamine.
Example 11-193: 545-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-thiophene-2-carboxylic acid was prepared following procedure 3 starting from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine and 5-carboxythiophene-2-boronic acid.
Example 11-194: {545-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylythiophen-2-y1}-(4-methyl-piperazin-1-y1)-methanone was prepared following procedure 4 starting from 545-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-y1]-thiophene-2-carboxylic acid and 4-methyl-piperazin-1-ylamine.
Examples L-1 to L-176 were prepared according to procedure 40. In Table 5, the compounds are grouped into sections, with each section having a letter designation.
Example numbers are assigned left to right by rows. For example, in Section A, the compounds in the top row, from left to right, are Examples L-1 to L-4, and the compounds in the second row are, from left to right, Examples L-5-L-8. % Inhibition is the percent c-MET inhibition at 50nM.
Examples L-177 to L-352 were prepared according to procedure 41. In Table 6, the compounds are grouped into sections, with each section having a letter designation.
Example numbers are assigned left to right by rows. % Inhibition is the percent c-MET inhibition at 1pM.
Examples L-353 to L-548 were prepared according to procedure 42. In Table 7, the compounds are grouped into sections, with each section having a letter designation.
Example numbers are assigned left to right by rows. % Inhibition is the percent c-MET inhibition at 1 pM.
Examples L-549 to L-636 were prepared according to procedure 43. In Table 8, the compounds are grouped into sections, with each section having a letter designation.
Example numbers are assigned left to right by rows. % Inhibition is the percent c-MET inhibition at 1 pM.
BIOLOGICAL EXAMPLES
It will be appreciated that, in any given series of compounds, a range of biological activities will be observed. In its presently preferred aspects, this invention relates to novel compounds capable of modulating, regulating and/or inhibiting protein kinase activity. The following assays may be employed to select those compounds demonstrating the optimal degree of the desired activity.
Assay Procedures The following in vitro assay may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs.
Similar assays can be designed along the same lines for any PK using techniques well known in the art. A literature reference is provided (Technikova-DObrova Z, Sardanelli AM, Papa S FEBS Lett. 1991 Nov 4; 292: 69-72).
The general procedure is as follows: compounds and kinase assay reagents are introduced into test wells. The assay is initiated by addition of the kinase enzyme. Enzyme inhibitors reduce the measured activity of the enzyme.

In the continuous-coupled spectrophotometric assay the time-dependent production of ADP by the kinase is determined by analysis of the rate of consumption of NADH by measurement of the decrease in absorbance at 340 nm. As the PK produces ADP it is re-converted to ATP by reaction with phosphoenol pyruvate and pyruvate kinase. Pyruvate is also produced in this reaction. Pyruvate is subsequently converted to lactate by reaction with lactate dehydrogenase, which simultaneously converts NADH to NAD. NADH has a measurable absorbance at 340 nm whereas NAD
does not.
The presently preferred protocol for conducting the continuous-coupled spectrophotometric experiments for specific PKs is provided below. However, adaptation of this protocol for determining the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art.
HGFR Continuous-coupled Spectrophotometric Assay This assay analyzes the tyrosine kinase activity of HGFR on the Met-2 substrate peptide, a peptide derived from the activation loop of the HGFR.
Materials and Reagents:
1. HGFR enzyme from Upstate (Met, active) Cat. # 14-526 2. Met-2 Peptide (HGFR Activation Loop) Ac-ARDMYDKEYYSVHNK (MW = 1960).
Dissolve up in 200 mM HEPES, pH 7.5 at 10 mM stock.
3. 1 M PEP (phospho-enol-pyruvate) in 200 mM HEPES, pH 7.5 4. 100 mM NADH (B-Nicotinamide Adenine Dinucleotide, Reduced Form) in 200mM
HEPES, pH 7.5 5. 4 M MgCl2 (Magnesium Chloride) in ddH20 6. 1 M DTT (Dithiothreitol) in 200 mM HEPES, pH 7.5 7. 15 Units/mL LDH (Lactic Dehydrogenase) 8. 15 Units/mL PK (Pyruvate Kinase) 9. 5M NaCI dissolved in ddH20 10. Tween-20 (Protein Grade) 10% Solution 11. 1 M HEPES buffer: (N[2-Hydroxethyllpiperazine-N-(2-ethanesulfonic acid]) Sodium Salt. Dissolve in ddH20, adjust pH to 7.5, bring volume to 1 L. Filter at 0.1 pm.
12. HPLC Grade Water; Burdick and Jackson #365-4, 1 X 4 liters (or equivalent) 13. 100% DMSO (SIGMA) 14. Costar # 3880 ¨ black clear flat bottom half area plates for Ki determination and %
inhibition 15. Costar # 3359 ¨ 96 well polypropylene plates, round bottom for serial dilutions 16. Costar # 3635 ¨ UV-plate clear flat bottom plates for % inhibition 17. Beckman DU-650 w/ micro cell holders 18. Beckman 4-position micro cell cuvette Procedure:
Prep Dilution Buffer (DB) for Enzyme (For 30 mL prep) 1. DB final concentration is 2 mM DTT, 25 mM NaC12, 5 mM MgCl2, 0.01% Tween-20, and 50 mM HEPES buffer, pH 7.5.

2. Make up 50 mM HEPES by adding 1.5 mL 1 M HEPES into 28.1 mL of ddH20.
Add rest of the reagents. Into 50 mL conical vial, add 60 uL of 1M DTT, 150 uL 5M
NaCl2, 150 uL

1M MgC12, and 30 uL of 10% Tween-20 to give total volume of 30 mL.

3. Vortex for 5-10 seconds 4. Aliquot out DB at 1 mL/tube and label tubes as "DB HGFR"

5. Note: This can be prepared and stored ahead of time.

6. Freeze un-used aliquots in microcentrifuge tubes at -20 C freezer.

Prep Compounds 1. For compound dilution plate, add 4 uL of 10 mM stock into column 1 of plate, and bring volume to 100 uL with 100% DMSO.

2. Set up the Precision 2000 dilution method. A final concentration of 200 uM
compound in 50%

DMSO, 100 mM HEPES (1:2 serial dilution).

Prep Coupled Enzymatic Buffer:

1. Final concentration in assay:

Reagent (Stock Conc.) Final Conc. In Assay a. PEP (1 M) 1 mM

b. NADH (100 mM) 300 uM

c. MgC12 (4 M) 20 mM

d. DTT (1 M) 2 mM

e. ATP (500 mM) 300 uM

f. HEPES 200 mM (pH 7.5) 100 mkti g. Pyruvate Kinase (PK) 15 units/mL

h. Lactic Dehydrogenase (LDH) 15 units/mL

i. Met-2 peptide (10 mM) 0.500 mM

j. HGFR 50 nM

2. Fora 10 mL reaction buffer add 10 uL of 1M PEP, 33 uL of 100 mM NADH, 50 uL of 4M MgCl2, 20 uL of 1M DTT, 6 uL of 500 mM ATP, and 500 uL of 10 mM Met-2 peptide into 100 mM
HEPES buffer pH 7.5 and vortex/mix.

3. Add coupling enzymes, LDH and PK, into reaction mix. Mix by gentle inversion.

Running samples 1. Spectrophotometer seettings:

i. Absorbance wavelength (A): 340 nm ii, Incubation time: 10 min iii. Run time: 10 min iv. Temperature: 37 C

2. Add 85 pL of CE reaction mix into each well of assay plate.

3. Add 5 pL of diluted compound into a well of the assay plate.

4. Add 5 pL of 50% DMSO for negative control into last column of assay plate.
5. Mix with multi-channel pipettor or orbital shaker.
6. Pre-incubate for 10 minutes at 37 C.
7. Add 10 pL of 500 nM HGFR to each well of assay plate; the final HGFR
concentration is 50 nM
in a total final volume of 100 pL.
8. Measure activity for 10 minutes at A = 340 nm and 37 C.
The following in vitro assays may be used to determine the level of activity and effect of the different compounds of the present invention on one or more of the PKs.
Similar assays can be designed along the same lines for any PK using techniques well known in the art.
Several of the assays described herein are performed in an ELISA (Enzyme-Linked lmmunosorbent Sandwich Assay) format (Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay,"
Manual of Clinical Immunology, 2d ed., Rose and Friedman, Am. Soc. Of Microbiology, Washington, D.C., pp. 359-371). General procedure is as follows: a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added. The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody recognizing the substrate of the enzymatic phosphorylation reaction. Non-substrate components of the cell lysate are washed away and the amount of phosphorylation on the substrate is detected with an antibody specifically recognizing phosphotyrosine compared with control cells that were not contacted with a test compound.
The presently preferred protocols for conducting the ELISA experiments for specific PKs is provided below. However, adaptation of these protocols for determining the activity of compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of knowledge of those skilled in the art.
Other assays described herein measure the amount of DNA made in response to activation of a test kinase, which is a general measure of a proliferative response. General procedure for this assay is as follows: a compound is introduced to cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand known to activate the receptor is added. After incubation at least overnight, a DNA
labeling reagent such as 5-bromodeoxyuridine (BrdU) or H3-thymidine is added. The amount of labeled DNA
is detected with either an anti-BrdU antibody or by measuring radioactivity and is compared to control cells not contacted with a test compound.
MET TRANSPHOSPHORYLATION ASSAY
This assay is used to measure phosphotyrosine levels on a poly(glutamic acid:tyrosine, 4:1) substrate as a means for identifying agonists/antagonists of met transphosphorylation of the substrate.
Materials and Reagents:
1. Corning 96-well ELISA plates, Corning Catalog # 25805-96.
2. Poly(glu-tyr), 4:1, Sigma, Cat. No; P 0275.
3. PBS, Gibco Catalog # 450-1300EB

4. 50 mM HEPES
5. Blocking Buffer: Dissolve 25 g Bovine Serum Albumin, Sigma Cat. No A-7888, in 500 mL PBS, filter through a 4 pm filter.
6. Purified GST fusion protein containing the Met kinase domain, SUGEN, Inc.
7. TBST Buffer.
8. 10% aqueous (MilliQue H20) DMSO.
9. 10 mM aqueous (dH20) Adenosine-5'-triphosphate, Sigma Cat. No. A-5394.
10. 2X Kinase Dilution Buffer: for 100 mL, mix 10 mL 1M HEPES at pH 7.5 with 0.4 mL 5%
BSA/PBS, 0.2 mL 0.1 M sodium orthovanadate and 1 mL 5M sodium chloride in 88.4 mL dH20.
11. 4X ATP Reaction Mixture: for 10 mL, mix 0.4 mL 1 M manganese chloride and 0.02 mL
0.1 M ATP in 9.56 mL dH20.
12. 4X Negative Controls Mixture: for 10 mL, mix 0.4 mL 1 M manganese chloride in 9.6 mL
dH20.
13. NUNC 96-well V bottom polypropylene plates, Applied Scientific Catalog # S-14. 500 mM EDTA.
15. Antibody Dilution Buffer: for 100 mL, mix 10 mL 5% BSA/PBS, 0.5 mL 5%
Carnation Instant Milk in PBS and 0.1 mL 0.1 M sodium orthovanadate in 88.4 mL TBST.
16. Rabbit polyclonal antophosphotyrosine antibody, SUGEN, Inc.
17. Goat anti-rabbit horseradish peroxidase conjugated antibody, Biosource, Inc.
18. ABTS Solution: for 1 L, mix 19.21 g citric acid, 35.49 g Na2HPO4 and 500 mg ABTS with sufficient dH20 to make 1 L.
19. ABTS/H202: mix 15 mL ABST solution with 2i.LL H202 five minutes before use.
20. 0.2 M HCI
Procedure:
1. Coat ELISA plates with 2 pg Poly(Glu-Tyr) in 100 pL PBS, hold overnight at 4 C.
2. Block plate with 150 pL of 5% BSA/PBS for 60 min.
3. Wash plate twice with PBS then once with 50 mM Hepes buffer pH 7.4.
4. Add 50 pl of the diluted kinase to all wells. (Purified kinase is diluted with Kinase Dilution Buffer. Final concentration should be 10 ng/well.) 5. Add 25 pL of the test compound (in 4% DMSO) or DMSO alone (4% in dH20) for controls to plate.
6. Incubate the kinase/compound mixture for 15 minutes.
7. Add 25 pL of 40 mM MnCl2to the negative control wells.
8. Add 25 pL ATP/ MnCl2 mixture to the all other wells (except the negative controls).
Incubate for 5 min.
9. Add 25 j.tL 500 mM EDTA to stop reaction.
10. Wash plate 3x with TBST.

11. Add 100 pt rabbit polyclonal anti-Ptyr diluted 1:10,000 in Antibody Dilution Buffer to each well. Incubate, with shaking, at room temperature for one hour.
12. Wash plate 3x with TBST.
13. Dilute Biosource HRP conjugated anti-rabbit antibody 1: 6,000 in Antibody Dilution buffer. Add 100 pL per well and incubate at room temperature, with shaking, for one hour.
14. Wash plate 1X with PBS.
15. Add 100 .1 of ABTS/H202 solution to each well.
16. If necessary, stop the development reaction with the addition of 100 I
of 0.2M HCI per well.
17. Read plate on Dynatech MR7000 ELISA readqr, with the test filter at 410 nM and the reference filter at 630 nM.
BrdU INCORPORATION ASSAYS
The following assays use cells engineered to express a selected receptor and then evaluate the effect of a compound of interest on the activity of ligand-induced DNA
synthesis by determining BrdU
incorporation into the DNA.
The following materials, reagents and procedure are general to each of the following BrdU
incorporation assays. Variances in specific assays are noted.
General Materials and Reagents:
1. The appropriate ligand.
2. The appropriate engineered cells.
3. BrdU Labeling Reagent: 10 rnIVI, in PBS, pH7.4(Roche Molecular Biochemicals, Indianapolis, IN).
4. FixDenat: fixation solution (Roche Molecular Biochemicals, Indianapolis, IN).
5. Anti-BrdU-POD: mouse monoclonal antibody conjugated with peroxidase (Chemicon, Temecula, CA).
6. TMB Substrate Solution: tetramethylbenzidine (TMB, ready to use, Roche Molecular Biochemicals, Indianapolis, IN).
7. PBS Washing Solution: 1X PBS, pH 7.4.
8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co., USA).
General Procedure:
1. Cells are seeded at 8000 cells/well in 10% CS, 2mM Gln in DMEM, in a 96 well plate.

Cells are incubated overnight at 37 C in 5% CO2.
2. After 24 hours, the cells are washed with PBS, and then are serum-starved in serum free medium (0%CS DMEM with 0.1% BSA) for 24 hours.
3. On day 3, the appropriate ligand and the test compound are added to the cells simultaneously. The negative control wells receive serum free DMEM with 0.1%
BSA only; the positive control cells receive the ligand but no test compound. Test compounds are prepared in serum free DMEM with ligand in a 96 well plate, and serially diluted for 7 test concentrations.

4. After 18 hours of ligand activation, diluted BrdU
labeling reagent (1:100 in DMEM, 0.1%
BSA) is added and the cells are incubated with BrdU (final concentration is 10 pM) for 1.5 hours.
5. After incubation with labeling reagent, the medium is removed by decanting and tapping the inverted plate on a paper towel. FixDenat solution is added (50 p1/well) and the plates are incubated at room temperature for 45 minutes on a plate shaker.
6. The FixDenat solution is removed by decanting and tapping the inverted plate on a paper towel. Milk is added (5% dehydrated milk in PBS, 200 p1/well) as a blocking solution and the plate is incubated for 30 minutes at room temperature on a plate shaker.
7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution is added (1:200 dilution in PBS, 1% BSA, 50 p1/well) and the plate is incubated for 90 minutes at room temperature on a plate shaker.
8. The antibody conjugate is removed by decanting and rinsing the wells 5 times with PBS, and the plate is dried by inverting and tapping on a paper towel.
9. TMB substrate solution is added (100 p1/well) and incubated for 20 minutes at room temperature on a plate shaker until color development is sufficient for photometric detection.' 10. The absorbance of the samples are measured at 410 nm (in "dual wavelength" mode with a filter reading at 490 nm, as a reference wavelength) on a Dynatech ELISA plate reader.
HGF-Induced BrdU Incorporation Assay Materials and Reagents: 1. Recombinant human HGF (Cat.
No. 249-HG, R&D Systems, Inc. USA).
2. BxPC-3 cells (ATCC CRL-1687).
Remaining Materials and Reagents, as above.
Procedure:
1. Cells are seeded at 9000 cells/well in RPMI 10% FBS in a 96 well plate. Cells are incubated overnight at 37 C in 5% CO2.

2. After 24 hours, the cells are washed with PBS, and then are serum starved in 100 11.1_ serum-free medium (RPM! with 0.1% BSA) for 24 hours.

3. On day 3, 25 pi containing ligand (prepared at 1 p,g/mL
in RPM' with 0.1% BSA; final HGF conc. is 200 ng/mL) and test compounds are added to the cells. The negative control wells receive 25 tL serum-free RPM' with 0.1% BSA only; the positive control cells receive the ligand (HGF) but no test compound. Test compounds are prepared at 5 times their final concentration in serum-free RPMI
with ligand in a 96 well plate, and serially diluted to give 7 test concentrations. Typically, the highest final concentration of test compound is 100 M, and 1:3 dilutions are used (i.e. final test compound concentration range is 0.137-100 p.M).
4. After 18 hours of ligand activation, 12.5 111. of diluted BrdU labeling reagent (1:100 in RPMI, 0.1% BSA) is added to each well and the cells are incubated with BrdU
(final concentration is 10 01) for 1 hour.
5. Same as General Procedure.

6. Same as General Procedure.
7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution (1:100 dilution in PBS, 1% BSA) is added (100 uL/well) and the plate is incubated for 90 minutes at room temperature on a plate shaker.
8. Same as General Procedure.

9. Same as General Procedure.
10. Same as General Procedure.
In Vivo Animal Models XENOGRAFT ANIMAL MODELS
The ability of human tumors to grow as xenografts in athymic mice (e.g., Balb/c, nu/nu) provides a useful in vivo model for studying the biological response to therapies for human tumors. Since the first successful xenotransplantation of human tumors into athymic mice, (Rygaard and Povlsen, 1969, Acta Pathol. Microbial. Scand. 77:758-760), many different human tumor cell lines (e.g., mammary, lung, genitourinary, gastro-intestinal, head and neck, glioblastoma, bone, and malignant melanomas) have been transplanted and successfully grown in nude mice. The following assays may be used to determine the level of activity, specificity and effect of the different compounds of the present invention.
Three general types of assays are useful for evaluating compounds:
cellular/catalytic, cellular/biological and in vivo. The object of the cellular/catalytic assays is to determine the effect of a compound on the ability of a TK to phosphorylate tyrosines on a known substrate in a cell. The object of the cellular/biological assays is to determine the effect of a compound on the biological response stimulated by a TK in a cell. The object of the in vivo assays is to determine the effect of a compound in an animal model of a particular disorder such as cancer.
Suitable cell lines for subcutaneous xenograft experiments include C6 cells (glioma, ATCC #
CCL 107), A375 cells (melanoma, ATCC # CRL 1619), A431 cells (epidermoid carcinoma, ATCC # CRL
1555), Calu 6 cells (lung, ATCC # HTB 56), PC3 cells (prostate, ATCC # CRL
1435), SKOV3TP5 cells, S114 (NIH3T3 fibroblast cell line genetically engineered for cMet and HGF
expressions from NCI), U-87MG (human malignant glioma, ATCC HTB 14) and NIH 313 fibroblasts genetically engineered to overexpress EGFR, PDGFR, IGF-1R or any other test kinase. The following protocol can be used to perform xenograft experiments:
Female athymic mice (BALB/c, nu/nu) are obtained from Simonsen Laboratories (Gilroy, CA).
All animals are maintained under clean-room conditions in Micro-isolator cages with Alpha-dri bedding.
They receive sterile rodent chow and water ad libitum.
Cell lines are grown in appropriate medium (for example, MEM, DMEM, Ham's F10, or Ham's F12 plus 5% - 10% fetal bovine serum (FBS) and 2 mM glutamine (GLN)). All cell culture media, glutamine, and fetal bovine serum are purchased from Gibco Life Technologies (Grand Island, NY) unless otherwise specified. All cells are grown in a humid atmosphere of 90-95% air and 5-10% CO2 at 37 C. All cell lines are routinely subcultured twice a week and are negative for mycoplasma as determined by the Mycotect method (Gibco).

Cells are harvested at or near confluency with 0.05% Trypsin-EDTA and pelleted at 450 x g for min. Pellets are resuspended in sterile PBS or media (without FBS) to a particular concentration and the cells are implanted into the hindflank of the mice (8 - 10 mice per group, 2 - 10 x 106 cells/animal).
Tumor growth is measured over 3 to 6 weeks using venier calipers. Tumor volumes are calculated as a 5 product of length x width x height unless otherwise indicated. P values are calculated using the Students t-test. Test compounds in 50 - 100 1..1 excipient (DMSO, or VPD:D5W) can be delivered by IP injection at different concentrations generally starting at day one after implantation.
Met Phosphorylation - Cellular Assay Materials and Reagents:
10 1. Falcon 10 cm culture dishes.
2. A549 lung carcinoma cells.
3. F12K growth medium (with 2% FBS + 2mM glutamine.
4. F12K assay medium (with 0.1% BSA).
5. Fisher cell scrapers.
6. Lysis buffer (HNTG, 1 mM sodium orlhovanidate, 1 mM PMSF and 2mM sodium fluoride).
7. 1.5 mL Eppendorf tubes.
8. Eppendorf microcentrifuge.
9. BCA assay reagents A and B (#23223 and 23224, Pierce).
10. Sample tube rotator.
11. Gel blot container rotator.
12. 5X sample buffer.
13. Novex pre-cast tris-glycine 8% acrylamide gels.
14. Bio-Rad electrophoresis chamber.
15. SDS-PAGE buffer.
16. TBS (pH 7.6) + 0.1% Triton X-100 (TBST), with and wihtout 5% milk.
17. Western blot transfer buffer.
18. Osmonics nitrocellulose paper.
19. Bio-Rad Transblot paper.
20. Gel transfer apparatus.
21. Anti-phosphotyrosine (mouse monoclonal).
22. Bio-Rad Kaleidoscope Prestained Standards (161-0324).
23. Anti-h-met (C-28) rabbit polyclonal, conjugated and non-conjugated with agarose (#sc-161 AC and sc-161, Santa Cruz Biotechnology, Inc.).
24. Donkey and anti-rabbit lg-HRP (NA 934, Amersham).
25. Sheet anti-mouselg-HRP (NA 931, Amersham).
26. SuperSignal West Pico Chemiluminescent Substrate (#34080, Pierce).
27. Saran Wrap.
28. Kodak BioMax exposure cassette.

29. Fuji X-ray film.
30. Kodak film developer.
Procedure:
1. Plate cells in 10 cm dishes with growth medium with 2% FBS + 2mM
glutamine. Grow to near confluency.
2. Serum starve cells overnight in assay medium with 0.1% BSA.
3. Add drug to the plates, one dose per plate, usually in a 2-flod titration.
Add asay medium (with the same DMSO concentration as the drugs) for no drug.
4. Incubate plates 4-5 hours with the drug, then add HG, 50 ng/mL for 10 minutes.
5. Wash plates once with PBS, add 400 I lysis buffer, and scrape off the cells. Collect in 1.5 mL Eppendorf tubes.
6. After about 10-20 minutes in the lysis buffer, centrifuge lysates in a microcentrifuger at full speed (14,000g) and collect the supernatants in a separate Eppendorf tube.
7. Determine protein concentration with the BCA assay reagents.
8. Adjust sample concentration to 0.5 mg protein in 0.4 mL using lysis buffer.
9. Add 15 IA anti-h-met AC for immunoprecipitation, rotate samples for 2 hours at 4 C.
10. Wash samples 3 times with lysis buffer and resuspend in 35 I 5X sample buffer.
11. Boil sample at 100 C for 10 minutes and microcentrifuge at highest setting for 30 minutes to pellet the agarose beads.
12. Load 15 I each to 2 gels, one for anti-phosphorylation and the other for anti-h-met.
Also load 10 I of prestained standards, one lane per gel.
13. Run gel around 100-125 V, then transfer gel to nitrocellulose either overnight at 70 mAmps or 1 hour at 500 mAmps.
14. Block membranes on rotator for 1 hour in TBS + 0.1% Triton X-100 (TBST) +
5% PBS.
All steps from this point are at room temperature unless otherwise. unless otherwise noted.
15. Add 0.8 g/rnL antiphosphotyrosine and 0.25 Ilg/mL anti-h-met on rotator either for 2 hours or overnight.
16. Wash membranes 3 times 5 minutes each in TBST on rotator.
17. Add HRP-conjugated antibodies )sheep anti-mouse for the antiphosphotyroeins; donkey anti-rabbit for the nati-h-met) at 1:5000 for approximately 45 minutes on rotator.
18. Wash membranes 3 times for 5 minutes each in TBST on rotator.
19. Add the 2 reagents in th3e SuperSignal kit together in equal volumes (3 mL
+ 3 mL for each blot), rotate for 1 -2 minutes.
20. Wrap blots in Saran Wrap and tape securely inside the exposure cassette.
21. In the darkroom with only the safety light on, place a sheet of film inside the cassette.
After an allotted time, remove film and place in the developer machine for automatic processing.
Experiment with the exposure time to get proper exposure.
TABLES

,PCT/US2004/005495 Table 1 No. Structure Name Met IC50 1H-NMR MS m/z (M+1) (IAM) Br CI ,i, 5-Bromo-3-(2,6-dichloro-(400 MHz, DMSO-d6) 6 7.62 1(a)a I e-L _ 5.3 (m, 1H), 7.56 (m, 2H), 7.46 (m, 349 b nzyloxy)-Pyridin-2-ylamine 2H), 5.80 (s, 2H), 5.22 (s, 2H) .' CI

(400 MHz, DMSO-d6) 6 7.56 (d, *I Br J = 2 Hz, 1H), 7.47 (d, J = 7.2 3-Benzyloxy-5-bromo- Hz, 2H), 7.38 (m, 2H), 7.32 (d, 1(b) >20 280 pyridin-2-ylamine J = 7.2 Hz, 1H), 7.26 (d, J = 2 Hz, 1H), 5.95 (s, 2H), 5.14 (s, NH, 2H) Br (400 MHz, DMSO-d6) 6 7.60 (d, / 5-Bromo-3-(2,6-difluoro-F 40% at 1H), 7.52 (m, 1H), 7.40 (d, 1H), 315 (w) 1(c) -.. IN benzyloxy)-pyridin-2-20 M 7.18 (m, 2H), 5.81 (br. S. 2H), * NH2 ylamine 5.12 (s, 2H) F

40) r (400 MHz, DMSO-d6) 6 7.65 5-Bronno-3-(2-bromo-(m, 2H), 7.60 (d, 1H), 7.42 (m, 357 (,11+) 1(d) Br benzyloxy)-pyridin-2->20 ..-N 2H), 7.30 (d, 1H), 5.94 (s 2H), O2"( ylamine N}-6 5.13 (s, 2H) Tr 5-Bromo-3-(2-chloro-6- (400 MHz, DMSO-d6) 6 7.80-1(e) fluoro-benzyloxy)-pyridin->20 7.30 (m, 5H), 5.80 (br s, 2H), 331 2-ylamine 5.15 (s, 2H) 4111127. F

Br 5-Bromo-3-(2-chloro-4- (400 MHz, DMSO-d6) 6 7.80-fluoro-benzyloxy)-pyridin- 7.20 (m, 5H), 5.95 (br s, 2H), 331 al 0 2-ylamine 5.10 (s, 2H) F W-- a r 5-Bromo-3-(2,4-dichloro- (400 MHz, DMSO-d6) 6 7.80-,.

1(g) 1 benzyloxy)-pyridin-2-7.50 (m, 5H), 6.20 (br s, 2H), 348 N

1110 0 ." ylamine 5.20 (s, 2H) CI CI

Br 2-(2-Amino-5-bromo- (400 MHz, DMSO-d6) 6 7.90-1(h) pyridin-3-yloxymethyly 7.30 (m, 6H), 5.90 (br s, 2H), 304 (M+) a o I benzonitrile 5.20 (s, 2H) Br 5-Bronno-3-(2-(400 MHz, DMSO-d6) 6 7.80-trifluoromethyl-10) 7.30 (m, 6H), 6.00 (br s, 2H), 347 I
benzyloxy)-pyridin-2-5.25 (s, 2H) NH2 ylamine r (400 MHz, DMSO-d6) 6 7.50-5-Bromo-3-(4-tert-butyl- '7.20 (m, 6H), 5.85 (br s, 2H), 335 (M+) 0 , N benzyloxy)-pyridin-2-io 0 ylamine 5.05 (s, 2H), 1.25 (s, 9H) NH, No.
Structure Name Met IC60 MS m/z (11M) (M+1) 5-Bromo-3-(2-chloro-(400 MHz, DMSO-d6) 6 7.70-1(k) ...... io ylamine 5.15 (s, 2H) benzyloxy)-pyridin-2-7.20 (m, 6H), 5.90 (br s, 2H), N
NH, (CDCI3, 300 MHz) 6 4.7-4.8 Br 5-Bromo-3-(2-chloro-3,6-(brs, 2H), 5.21 (s, 2H), 7.03-1(1) I
I
difluoro-benzyloxy)-5.3 7.10 (dt, 1H, J, 4.1, 9.1), 7.17-F
IP 0 Aµl NH, pyridin-2-ylamine 7.25 (m, 2H), 7.75-7.76 (d, J, F
1.86).
,Br 5-Bromo-3-(3-fluoro-2-cF3 1trifluoromethyl-1(m) F

=
o 'N benzyloxy)-pyridin-2-ylamine Br (CDCI3, 300 MHz) 6.1.85-1.95 I
F rak.
o I ..,N
5-Bromo-3-[1-(2,6-(d, 3H), 4.7-5.0 (brs, 2H), 5.9-1(n) IP
NH, dichloro-3-fluoro-phenyI)-6.01 (q, 1H), 6.8-6.95 (d, 1H), ci ethoxyj-pyridin-2-ylamine 7.01-7.2 (t, 1H), 7.4-7.45 (m, ' i H), 7.8-7.85 (d, 1H).
Br 5-Bromo-3-[1-(2-chloro-1(o) ci ....(-1-3,6-difluoro-phenyI)-ethoxyl-pyridin-2-ylamine F
F
NH, Br ci N).=
5-Bromo-3-(2,6-dichloro-(400 MHz, DMSO-d6) 6 5.45 (s, II(a) le (2.1y,.N benzyloxy)-pyrazin-2->20 2H), 6.45 (s, 2H), 7.50 (m, 3H), ylannine 7.63 (s, 'I H) CI
(300 MHz, CDCI3) 6 7.7 (s, 1H), N; 5-Bromo-3-(2-chloro-3,6-7.23-7.16 (m, 1H), 7.09-7.01 II(b) F
jt r,i difluoro-benzyloxy)->20 0- y pyrazin-2-ylamine (m, 1H), 5.53 (s, 2H), 4.72 (s, F
NH, 2H) Br F
N.,T,1 5-Bromo-3-[1-(2-chloro-(400 MHz, DMSO-d5) 6 1.75 (d, /I ''''3,6-difluoro-phenyI)-3H), 6.26(m, 1H), 6.46 (s, 2H), II(c) 0-y"
181/ 267 ethoxyl-pyrazin-2-..
Gt6 ........., I
(m, 1H), 7.41 (m, 1H), 7.52 NH, ...1 a ylamine (s, 1H) F
II

(400 MHz, DMSO-d6) 6 0.92 (d, 5-Bromo-3-[1-(2-chloro-F
N '=
3,6-difluoro-phenyl)-2-3H), 1.17 (m, 3H), 2.57 (m, 1H), II(d) oAl%"
methyl-propoxyi-pyrazin-18.1 5.75 (d, 1H), 6.49 (s, 2H), 7.24 01 a 2-ylamine (m, 1H), 7.40 (m, 1H), 7.54 (s, 1H) F

No. Structure Name Met ICso 1H-NMR MS m/z (j1M) (M+1) Br (400 MHz, DMSO-d6) 6 1.74 (d, 1 re-Li 5-Bromo-341-(2,6- 0.24/ 3H), 6.40 (m, 1H), 6.52 (br s, dichloro-3-fluoro-phenyI)-11(e) it ethoxyl-pyrazin-2- 0.66/ 2H), 7.30 (m, 1H), 7.48 (m, 1H), 382 4µI' - ci NH2 ylamine 1.3 7.56 (s, 1H); MS
m/z 382 F (M+1).

Br N.,Li 5-Bromo-3-(3-fluoro-2-.. ji,, trifluoromethyl-NO F ,-N

0 o benzyloxy)-pyrazin-2-NH, ylamine Table 2 No.
Structure Name Met 1C60 Procedure 1H-NMR .
MS miz (I1M) (1.14-1-1) *IA
.

4-[6-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 59.36 (s, 1H, OH), 7.77 (s, see 1H), 7.54 (dõ./ .= 5.2 Hz, 2FI), 7.43 (m, 4H), 6.78 benzyloxy)-pyridin-3-y1]-0.279 ,, examples (d, J = 5.2 Hz, 2H), 5.49 (br. s, 2H, NH2), 5.30 dish 0 1 phenol (5, 2H, CH2).
up ci NH, _ -eN......5 ' ) .
(400 MHz, DMSO-d6) 57.81 (d, J = 1.2 Hz, 1H), 3-(2,6-Dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-0.58 see 7.53 (m, 31-I), 7.48 (m, 3H), 6.97 (d, 2H), 5.53 (br.
examples s, 2H, NH2), 5.31 (s, 2H, CH2), 4.08 (t, 2H), 3.55 phenyl]-pyridin-2-ylamine I
(t, 4H), 2.68 (t, 2H), 2.46 (t, 4H).
1 -ir grik, 0 qua 0 NH
(400 MHz, DMSO-d6) 57.89 (d, J = 1.2 Hz, 1H), 1-...-6 3-(2,6-Dichloro-benzyloxy)-5-7.54 (d, J = 5.2 Hz, 2H), 7.51 (d, J = 1.2 Hz, 1H), see a'2 examples [3-(2-morpholin-4-yl-ethoxy)-0.59 7.44 (dd, 1H), 7.28 (dd, 1H), 7.18 (m, 2H), 6.83 ip (dd, 1H), 5.65 (br. s, 2H), 5.33 (s, 2H), 4.12 (t, phenyl]-pyridin-2-ylamine NI-I., 2H), 3.55 (t, 6H), 2.68 (t, 2H), 2.46 (t, 2H) ,46, 11 Wir I
3-(2,6-Dichloro-benzyloxy)-5-(400 MHz, DMSO-d6) 511.18 (5, 1H, NH), 7.87 see (d, 1H), 7.5 (d, 2H), 7.46 (d, 2H), 7.36 (m, 1H), Cl 1 '' (1H-indo1-4-y1)-pyridin-2-1.4 examples 7.33 (m, 1H), 7.12 (t, 1H), 7.03 (d, 1H), 6.49 (d, giii ylamine 1H), 5.61 (br. s, 2H, NH2), 5.31 (a, 2H, CH2).
NH
411111" ci , I:1 rip IW- / 3-[2-Chloro-6-(1H-Indo1-4-y1)-\ IP
, -...
benzyloxy]-5-(1H-indo1-4-y1)-4.71 see pyridin-2-ylamine examples 11111-1 Cl NF.I
N-boo 2-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y1]-see I
>20 isyl '''.
p rrole-1-carboxylic acid tert-examples c.-,,--butyl ester Cl -,, NH

(400 MHz, DMSO-d6) ii 11.05 (s, 1H), 7.85 (s, 3-(2,6-Dichloro-benzyloxy)-5-,.."
(1H-pyrrol-2-y1)-pyridin-2-4.25 see 1H), 7.58 (s, 1H), 7.55 (5, 1H), 7.50 (m, 2H), 6.75 ylamine examples (s, 1H), 6.35 (s, 1H), 6.05 (s, 1H), 5.50 (br. s, 411111" Cl 2H), 5.30 (5, 2H).
F
IP
3-(2,6-Dichloro-benzyloxy)-5-(400 MHz, DMSO-d6) 57.89 (s, 1H), 7.69 (m, (4-fluoro-phenyl)-pyridin-2-8.01 examplessee 2H), 7.58 (m, 3H), 7.48 (m, 1H), 7.23 (m, 2H), ii.
i , N
ylamine 5.70 (br. s, 2H), 5.35 (s, 2H).

-4.--- CI

.
(400 MHz, DMSO-d6) 57.89 (d, J = 2 Hz, 1H), 3-(2,6-Dichloro-benzyloxy)-5-3.3 see 7.63 (d, J = 6.8 Hz, 2H), 7.57 (d, J = 2 Hz, 1H), a ci 1 '...t1 phenyl-pyridin-2-ylamine examples 7.54 (m, 2H), 7.43 (m, 1H), 7.40 (m, 2H), 7.26 (m, 1H), 5.68 (br. s, 2H), 5.34 (s, 2H).
44F-P a * F

3-(2,6-Dichloro-benzyloxy)-5-(400 MHz, DMSO-d6) 57.76 (d, 1H), 7.55 (m, see I
I(2-flu examples oro-pheny1)-phenyl)-2-6.09 2H), 7.54 (m 1H), 7.46 (m, 2H), 7.32 (m, 1H), lamine 7.25 (m, 2H), 5.78 (br. s, 2H), 5.28 (s, 2H).
0 o ci "1-6 .
No.
Structure Name Met 1C50 Procedure MS m/z (1-LIVI) (M+1) , 3-(2,6-Dichloro-benzyloxy)-5-(400 MHz, DMS0-(16) 57.95 (d, 1H), 7.58-7.44 a I '-' (3-fluoro-phenyl)-pyridin-2-13.8 see examples (m, 7H), 7.17 (m 1H), 5.78 (br. s, 2H), 6.35 (s, to 010 , N
ylamine les 2H).
NH , NH, 5-(4-Amino-phenyl)-3-(2,6-(400 MHz, DMSO-d6) 57.75 (d, 1H), 7.54 (dd, see 4H), 7.47 (m, 1H), 7.40 (d, 1H), 7.29 (dd, 2H), dichloro-benzyloxy)-pyridin-2- 0.606 a -..
examples 6.60 (dd, 2H), 5.44 (br. s, 2H), 5.31 (s, 2H), 5.15 .... N

I
ylamine NH, (br s, 2H).
40a 9,0H, N-(4-(6-Amino-5-(2,6-(400 MHz, DMSO-d6) 6 9.70 (s, 1 H), 7.86 (d, 1H), ylj-phenyl}-examples (m, 2H), 7.22 (dd, 2H), 5.63 (br. s, 2H), 5.33 (s, dichloro-benzyloxy)-pyridin-3.
see 7.59 (m, 1H), 7.58 (m, 2H), 7.55 (m, 1H), 7.45 0.44 6:- ' methanesulfonamide =
2H), 2.95 (s, 3H).
a NH, ,Z6 SO
N-(446-Amino-5-(2,6-(400 MHz, DMSO-c16) 59.94 (s, 1H), 7.86 (d, 1H), N-(446-Amino-5-(2,6-see 7.59 (m, 1H), 7.57 (m, 2H), 7.54 (m, 2H), 7.48 dichloro-benzyloxy)-pyridin-3- >20 examples (m, 2H), 5.61 (br. s, 2H), 5.33 (s, 2H), 2.04 (s, I .."' y1J-phenyl}-acetamide 3H).

ci NH, OH

IIIP
346-Amino-5-(26-dichloro-(400 MHz, DMSO-d6) 67.83 (s, 1H), 7.55 (dd, see 2H), 7.46 (m 2H), 7.19 (m, 1H), 7.10 (m, 1H), I '' benzyloxy)-pyridin-3-y1j-1.34 examples 7.04 (m, 1H), 6.98 (m, 1H), 6.69 (m, 1H), 5.67 la 0 '"
phenol (br. s, 2H), 5.33 (s, 2H).

mr- ci NH, ...CH, 3-(2,6-Dichloro-benzyloxy)-5-(400 MHz, DMSO-d6) 57.83 (s, 1H), 7.62-7.54 see (4-methoxy-pheny1)-pyri examles din-2- 6.65 (m, 4H), 6.97 (dd, 2H), 6.66 (dd, 2H), 5.58 (br. s, p ylamine 2H), 5.33 (s, 2H), 3.77 (s, 3H).
io NH2 5-(3-Amino-phenyI)-3-(2,6-(300 MHz, CDCI3) 57.84 (d, 1H), 7.68 (m, 1H), see 7.45 (m, 1H), 7.36 (t, 1H), 7.28 (d, 1H), 7.22 (m, dichloro-benzyloxy)-pyriclin-2- 1.07 I
',,, ylamine .
examples 1H), 6.93 (d, 1H), 6.86 (d, 1H), 6.64 (dd, 1H), at ,..
5.34 (s, 2H), 4.73 (br s, 2H), 4.12 (br s, 2H).
a NH, F
3-(2,6-Dichloro-benzyloxy)-5-see (300 MHz, CDCI3) 57.95 (d, 1H), 7.49-7.24 (m, (3-trifluoromethoxy-phenyl)->20429 .
I
pyridin-2-ylamine examples 7H), 7.17 (m, 1H), 5.39 (s, 2H), 4.81 (bra, 2H).
ilt 0 '"
a NH, .WP
IP

2-(6-Amino-5-(2,6-dichloro-(300 MHz, CDC13) 57.81 (d, 1H), 7.66 (m, 2H), see =benzyloxy)-pyridin-311)-2.16 7.52 (m, 1H), 7.37 (d, 1H), 7.26 (m, 3H), 6.99 (m, I
examples ' H), 5.32 (s, 2H), 4.77 (bra, 2H) a NH, 40 0 40 3-(2,6-Dichloro-benzyloxy)-5-(300 MHz, CDC13) 57.88 (d, 1H), 7.66 (m, 2H), 1-20 .
I
(2-phenoxy-phenyl)-pyridin-2- >20 exaseemples 7.45 (m, 3H), 7.34 (m, 2H), 7.26 (m, 3H), 7.07 ylamine (m, 2H), 6.93 (, 211), 5.16 (s, 2H), 4.66 (br s, 2H).
WO a NH, No. Structure Name Met 1C50 Procedure 1H-NMR MS m/z (1-1M) (M+1) aik... F

lir 3-(2,6-Dichloro-benzyloxy)-5-see (300 MHz, CDCI3) 67.89 (d, 1H), 7.40 (d, 2H), 1-21 (3,4-difluoro-phenyl)-pyridin-14.3 examples 7.26 (m, 5H), 5.37 (s, 2H), 4.80 (br s, 2H).
= I 2-ylamine rai 0 ,... N

NH, 1r a 3-(2,6-Dichloro-benzyloxy)-5-(300 MHz, CDCI3) 67.96 (d, 1H), 7.40-7.15 (m, (110 see 1-22 (3-isopropyl-phenyl)-pyridin-15.9 examples 8H), 5.38 (s, 2H), 4.73 (br s, 2H), 2.98 (m, 1H), 387 2-ylamine 1.31 (d, 6H).
= I
ii 0 :"H2 41111-3-P a -(300 MHz, CDCI3) 67.76 (d, J = 8.7 Hz, 1H), 3-(2,6-Dichloro-benzyloxy)-5-F
see 7.69 (s, 1H), 7.58 (t, J = 7.3 Hz, 1H), 7.47 (t, J =
1-23 . (2-trifluoromethyl-phenyl)->20 I .
examples 7.4 Hz, 1H), 7.38 (d, J = 7.4 Hz, 2H), 7.27 (m, pyridin-2-ylamine 2H), 7.17 (s, 1H), 5.29 (s, 2H), 4.78 (br s, 2H).
140 0 :õ N
a 116 0-- 3-(2,6-Dichloro-benzyloxy)-5-(300 MHz, CDCI3) 67.89 (s, 1H), 7.41-7.24 (m, see 1-24 . (2-methoxy-pheny1)-pyridin-2-11.5 examples 6H)' 7.02 (m, 2H), 5.32 (s, 2H), 4.69 (br s, 2H), 375 Iylamine 3.84 (s, 3H).

:F6 W" a F F
F

40 3-(2,6-Dichloro-benzyloxy)-5-see (300 MHz, CDCI3) 67.98 (d, J = 1.8 Hz, 1H), 1-25 (4-trifluoromethyl-phenyl)->20 examples 7.66 (m, 3H), 7.36 (m, 3H), 7.29 (m, 2H), 7.89 (s, 413 " pyridin-2-ylamine 1H), 5.38 (s, 2H), 4.93 (br s, 2H) I 'r=I

S :õ a 40 , 1i--0 N-(246-Amino-5-(2,6- =
dichloro-benzyloxy)-pyridin-3- see (300 MHz, CDCI3) 6 8.75 (br s, 1H), 7.70-7.14 1-26 =
>20 dill 0 I ...- N ylj-phenyl}-examples (m, 9H), 5.31 (s, 2H), 8.16 (bra, 2H), 3.16 (s, 3H) methanesulfonamide NH, WI a _ OH

{446-Amino-5-(2,6-dichloro-(300 MHz, CDCI3) 67.84 (d, J = 1.8 Hz,1H), 7.66 see 1-27 benzyloxy)-pyridin-3-y11-2.5 examples (m, 2H), 7.63-7.18 (m, 6H), 5.36 (s, 2H), 4.75 (d, 375 = phenyl}-methanol 2H), 4.73 (br s, 2H), 2.5 (br, 1H) taw 0 ..-N

lir a NH, -IP 5-Benzo[1,31dioxo1-5-y1-3-(300 MHz, CDCI3) 67.88 (d, J = 1.5 Hz,1H), 7.37 see 1-28. (2,6-dichloro-benzyloxy)-8.5 examples (m' 2H), 7.29 (m, 2H), 6.99 (d, 2H), 6.87 (d, 1H), 389 =-.
ilk a ' 1 N pyridin-2-ylamine 5.99 (s, 2H), 5.36 (s, 2H), 4.74 (br s, 2H) o NH, q"...

0.4r 3-(2,6-Dichloro-benzyloxy)-5-F see (300 MHz, CDCI3) 67.82 (s,1H), 7.47-7.25 (m, 1-29 . ,, (2-trifluoromethoxy-phenyl) >20 I pyridin-2-ylamine examples 8H), 5.33 (s, 2H), 4.82 (bra, 2H) o '1'1 110 a NH, .

No. Structure Name Met 1O60 Procedure 1H-NMR MS
m/z (M+1) (1-41) -(300 MHz, ODO13) 67.96 (d, J = 1.9 Hz, 1H), 3-(2,6-Dichloro-benzyloxy)-5-see 7.37 d, J = 8.5 Hz, 2H), 7.29 (m, 2H), 7.00 (d, J 365 1-30 (4-methyl-thiophen-2-y1)- 3.5 examples = 1.1 Hz, 1H), 6.80 (s, 1H), 5.34 (s, 21-1), 4.80 (br I pyridin-2-ylamine 0.. ' N s, 2H), 2.28 (s, 3H) uiiiri 01 NH, 10 . ii 5-(2-Benzyloxy-phenyl)-3-(300 MHz, CDO13) 67.90 (d, J = 1.7 Hz, 1H), see 1-31= 'w (2,6-dichloro-benzyloxy)- >20 7.49 (d, J = 1.7 Hz, 1H), 7.31 (m, 10H), 7.06 (m, 451 Pa ,N I
examples pyridin-2-ylamine 2H), 5.06 (s, 2H), 4.77 (br s, 211).

a NH, 0 0., (300 MHz, ODC13) 67.96 (d, J = 1.7 Hz, 1H), 3-(2,6-Dichloro-benzyloxy)-5-see 7.39-7.11 (m, 4I-1), 7.13 (d, J = 7.7 Hz, 2H), 7.07 375 1-32 . (3-methoxy-phenyl)-pyridin-2. 4.01 Iexamples (t, J = 2.1 Hz, 1H), 6.88 (dd, J = 8.2 Hz, 2.1 Hz, ylamine ' N 111), 5.36 (s, 2H), 4.78 (br s, 2H), 3.87 (s, 3H).

iii- a0 (300 MHz, ODO13) 68.47 (br s, 1H), 8.04 (s, 1H), FIN , 3-(2,6-(26-benzyloxy)-5-see 7.70 (d, J = 5.5 Hz, 1H), 7.62-7.11 (m, 61-1), 6.71 384 1-33 (1H-indo1-2-y1)-pyridin-2 - 7.5 examples (d, J = 1.3 Hz, 11-I), 6.66 (dd, J = 7.7 Hz, 2.1 Hz, ci 1 '` ylamine 1H), 5.29 (s, 211), 4.73 (br s, 2H).
0 Al . ci "1-12 5-(4-Benzyloxy-3-fluoro- (400 MHz, DMSO-d6) 6 5.20 (s, 211), 5.32 (s, 2H), F see 1-34 [100 phenyl)-3-(2,6-dichloro- 13.5 examples 5.65 (s, 2H), 7.25 (t, 1H), 7.33 (m, 111), 7.39 (m, 469 benzyloxy)-pyridin-2-ylamine 3H), 7.46 (m, 3H), 7.51 (m, 4H), 7.88 (s, 1H) .

IP a NFL, _ (400 MHz, DMSO-d6) 67.98 (s, 1H), 7.92 (d, J =

4-[6-Amino-5-(2,6-dichloro-10 see 5.6 Hz, 2H), 7.75 (d, J = 4.8 Hz, 2H), 7.55 (d, J = 390 1-35 ben4loxy)-pyridin-3-y11- 12.8 examples 6.2 Hz, 1H), 7.54 (dd, 2H), 7.45 (m, 1H), 5.8 (br.

benzoic acid s, 2H), 5.34 (s, 211).

40 a 'N
CI NIFI , Z'N5"

r)(400 MHz, DMSO-d6) 6 8.45 (s, 1H), 7.97 (d, J =

0 NH 446-Amino-5-(2,6-dichloro-1.2 Hz, 111), 7.86 (d, J = 5.6 Hz, 2H), 7.73(d, J =
benzyloxy)-pyridin-3-yI]-N-(2- 0.99 see examples 5.6 Hz, 2H), 7.60 (d, J = 1.2 Hz, 1H), 7.54 (d, 487 * diethylamino-ethyl)-J = 5.2 Hz, 211), 7.44 (dd, 1H), 5.77 (br. s, 211), benzamide .-, 5.34 (s, 2H), 3.3 (m, 4H), 2.6 (m, 411), 0.99 (t, 6H) io. cio -N

NEL, r ....õ..

(400 MHz, DMSO-d6) 5 8.60 (s, 11-1), 7.96 (d, J =

N
0 if 446-Amino-5-(2,6-dichloro- 1.2 Hz, 1H), 7.85 (d, J = 5.6 Hz, 111), 7.75 (d, J =

benzyloxy)-pyridin-31 1]-N-(3- see 5.6 Hz, 111), 7.70 (d, J = 1.2 Hz, 111), 7.60 (m, 1-37 0.82 diethylamino-propy1)- examples 111), 7.55 (m, 2H), 7.45 (m, 2H), 5.70 (br. s, 211), benzamide 5.35 (s, 211), 3.3 (m, 4H), 2.6 (m, 4H), 1.7 (m, i 2H), 1.0 (t, 6H) rip o 'I' 41135 a "2 No. Structure Name Met 1C66 Procedure 1H-NMR
MS rrilz (PM) (M+1) _ _ -rir ., N.,..1 (400 MHz, DMSO-d6) 5 7.95 (d, J = 2 Hz, 1H), {4-16-Amino-5-(2,6-dichloro- 7.72 (dd, J = 6, 1.6 Hz, 2H), 7,59 (d, ../ = 1.6 Hz, benzyloxy)-pyridin-3-yli- see 1H), 7.57 (d, J = 1.2 Hz, 1H), 7.55 (s, 1H), 7.43 471 1-38 *
1.02 phenyl}-(4-methyl-piperazin- examples (dd, J = 6, 1.2 Hz, 1H), 7.40 (dd, J = 6, 1.6 Hz, aN 1-yI)-methanone 2H), 5.76 (br. s, 2H), 5.35 (s, 2H), 3.6 (m, 4H), I
difit 0 ..41 2.3 (m, 4H), 2.2 (5, 3H).

up c, NH, _ 0 ch.

{4-[6-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 57.96 (d, 1H), 7.72 (dd, o CO benzyloxy)-pyridin-3-yli- 0.062/

see 2H), 7.59 (m, 2H), 7.54 (m, 2H), 7.47 (m, 2H), 1-39 phenyI}-[(2R)-2-pyrrolidin-1- 0.11/
0.2 examples 5.76 (br. s, 2H), 5.36 (s, 2H), 4.35 (m, 1H), 3.5 ylmethyl-pyrrolidin-1-y11- (Xi 0.04) (d, 2H), 3.0 (m, 4H), 1.7-2.0 (m, 10H).
methanone 0 Chiral t {446-Amino-5-(2,6-dichloro- (400 MHz, DMSO-d6) 67.93 (d, 1H), 7.68 (dd, O .. l0 benzyloxy)-pyridin-3-y11- 2H), 7.57 (d, 1H), 7.54 (dd, 2H), 7.47 (m, 2H), see 1-40 phenyl}-[(2S)-2-pyrroliclin-1-0.21 examples 7.44 (m, 1H), 5.74 (br. s, 2H), 5.34 (s, 2H), 3.45 526 ylmethyl-pyrrolidin-110- (m, 1H), 3.3 (m, 4H), 2.46 (m, 2H), 1.95 (m, 2H), methanone 1.84 (m, 4H), 1.63 (m, 4H).

r.......0 O niõ.1 (400 MHz, DMSO-d6) 0 7.95 (d, 1H), 7.70 (dd, (4-16-Amino-5-(2,6-dichloro-2H), 7.55 (d, 1H), 7.48 (dd, 2H), 7.41 (m, 1H), benzyloxy)-pyridin-3-yli- see 0.35 examples 7.39 (m, 2H), 5.76 (br. s, 2H), 5.35 (s, 2H), 3.0 525 illi pheny1}-(4-pyrrolidin-1-yl-(m, 4H), 2.6 (m, 4H), 2.25 (s, 1H), 1.89 (m, 4H), piperidin-1-yI)-methanone = I N.
1.66 (m, 4H) 0 Asi a NI-6 O Nria.-OH
(400 MHz, DMSO-d6) 5 7.94 (d, 1H), 7.71 (dd, (446-Amino-5-(2,6-dichloro-2H), 7.70 (d, 1H), 7.59 (dd, 2H), 7.55 (m, 1H), benzyloxy)-pyridin-3-y11- see 1-42 lb 0.56 7.45 (m, 2H), 5.76 (br. s, 2H), 5.35 (s, 2FI), 4.35 500 phenyl}-(2-(2-ethyl)-ethyl) examples (t, 2H), 3.60 (m, 1H), 3.44 (m, 2H), 3.0 (m, 2H), piperldin-1-y11-methanone 1.68 (m, 2H), 1.40 (m, 2H), 1.37 (m, 2H) \ _ .

O t(131 (446-Amino-5-(26-dichloro-(400 MHz, DMSO-d6) 5 7.95 (d, 1H), 7.75 (dd, benzyloxy)-pyridin-3-y1}- 2H), 7.57 (d, 1H), 7.55 (dd, 2H), 7.48 (m, 1H), see 1-43 0 phenyI}-[(3S)-3-0.47 7.46 (m, 2H), 5.76 (br. s, 2H), 5.35 (s, 2H), 3.60 485 examples dimethylamino-pyrrolidin-1- (m, 1H), 3.0 (m, 2H), 2.2 (s, 3H), 2.1 (s, 3H), 1.15 yll-methanone (m, 2H) = 1 ch, 0 -""

4....k. a NH, \

O I0 (446-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 5 7.95 (m, 1H), 7.72 (m, benzyloxy)-pyridin-3-y11-see 2H), 7.60 (m, 1H), 7.55 (m, 2H), 7.46 (m, 3H), 1-44 phenyl}-[(3R)-3-0.65 *
examples 5.76 (br. s, 2H), 5.35 (s, 2H), 3.50 (m, 3H), 3.0 dimethylamino-pyrrolidin-1-(m, 2H), 2.1 (s, 3H), 2.05 (5, 3H), 1.1 (m, 2H) yli-methanone = I
riiii 0 ,N

NFL, _ 1 W a e-to {446-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 57.94 (d, 1H), 7.77 (m, benzyloxy)-pyridin-3-y1}- 2H), 7.57 (m, 2H), 7.55 (m, 1 H), 7.46 (dd, 1H), see 1-45 rz . phenyl}-[(3S)-3-0.77 examples 7.39 (m, 2H), 5.79 (s, 2H), 5.35 (s, 2H), 4.4 (m, 526 cyclopropylaminomethyl- 1H), 3.6 (m, 1H), 2.6-3.0 (m, 4H), 1.4-1.8 (m, piperidln-1-yll-methanone 8H), 0.8 (m, 2H).

No. Structure Name Met 1O60 Procedure MS miz (PM) (M+1) -. r-ra (400 MHz, DMSO-d6) 55.45 (m, 1H), 7.99 (d, ti 0. 4-(6-Amino-5-(2,6-dichloro-2H), 7.88 (m, 2H), 7.75 (m, 2 H), 7.61 (d, 1H), 41 benzyloxy)-pyridin-3-y11-N-(2- 0.2 see 1-46 c5.Tho 7.57 (m, 21-0, 7.46 (dd, 1H), 5.79 (s, 2H), 5.36 (s, hydroxy-3-pyrrolidln-1-yl-examples 2H), 4.8 (m, 1H), 3.75 (m, 1H), 3.44 (m, 1H), 3.18 propy1)-benzamide N.
(m, 1H), 2.53 (m, 4H), 2.40 (m, 1H), 1.67 (m, 4H) 0¨F
.:
(4-(6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-see 1-47 pheny1)-[(2S)-2-(3-fluoro- 0.42 examples 1110 piperidin-1-ylmethyl)-. pyrrolidin-1-y11-methanone is..Nik I

VI a NH., ' {4-16-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-see 1.67 phenyl}-(4-cyclopropyl-examples = I s' piperazin-1-y1)-methanone .0a :H:

NH {446-Amino-5-(2,6-dichloro-b benzyloxy)-pyridin-3-y1F
(400 MHz., DMSO-d6) 6 7.92 (d, 1FI), 7.67 (m, pheny1)-[(2R)-2-see 2H), 7.54 (m, 2H), 7.49 (m, 2H), 7.43 (m, 2H), 0.37525 a ((cyclopropylmethyl-amino)-examples 5.73 (s, 2H), 5.32 (a, 2H), 4.2 (m, 1H), 3.5 (m, methyl]-pyrrolidin-1-y1)-1H), 3.28 (m, 4H), 2.0-1.7 (m, 6H), 1.18 (m, 4H) ¨ / methanone a CrilF1_, 0 446-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 58.16 (d, 1H), 7.61 (d, benzyloxy)-pyridin-3-y1]-N-1H), 7.38 (m, 2H), 7.23-7.18 (m, 41-1), 7.09 (m, see 1-50 4_401 .
cyclopropylmethyl-N-(2R)- 0.29 1H), 5.44 (s, 2H), 4.98 (s, 2H), 4.05 (m, 1H), 3.2 525 examples pyrrolidin-2-ylmethyl-(m, 1H), 3.1 (m, 1H), 2.93 (m, 8H), 2.78 (m, 2H), benzamide 2.10 (m, 4H) o (400 MHz, DMSO-d6) 57.90 (m, 1H), 7.76 (m, 4-(6-Amino-5-(2,6-dichloro-1H), 7.63 (m, 2H), 7.52 (d, 2 H), 7.50 (m, 2H), benzyloxy)-pyridin-3-01-N-(2- 'Le`a 1-51 C-a-,c, 1 0.71 examples 7.40 (m, 1H), 5.69 (s, 2H), 5.30 (s, 2H), 3.70 (m, see hydroxy-3-pyrrolidin-1-yl-1H), 2.96 (s, 3H), 2.44 (m, 4H), 2.34 (m, 4H), Yu, propyI)-N-methyl-benzamide 1.75 (m, 4H).

,i,H -0 {446-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 57.96 (d, 1H), 7.70 (m, o (,..._ benzy1oxy)-pyridin-3-A-2H), 7.60 (m, 1H), 7.57 (m, /H), 7.55 (m, 3H), ti,...J phenyl}-{(25)-2-((3R)-3-0.53 (3R)-3-see 7.46 (m, 1H), 5.78 (s, 2H), 5.37 (s, 2H), 4.3 (m, a 41) hydroxy-pyrrolidin-1-examples 1H), 3.6 (m, 4H), 3.2 (m, 4H), 1.9 (m, 4H), 1.24 ylmethyli-pyrrolidin-1-y1}-(m, 4H).
(1¨\* a \ / methanone T

IP H 3-(6-Amino-5-(2,6-dichloro-(400MHz, DMSO-d6) 58.13 (m, 1H), 7.91 (d, 1-53 i benzyloxy)-pyridin-3-y11- 16 1H), 7.98(m, 2H), 7.56(dd, 2H), 7.54(m, 2H), examplessee I -N benzoic acid 7.47(m, 1H),5.76(s, 2H), 5.36(s, 2H) I* 0 ct NH, _ No.
Structure Name Met 1C60 Procedure MS m/z O- LM) (M+1) _ --.
7 60 (346-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-y11-(400MHz, DMSO-d6) 07.93 (d, 1H), 7.74 (m, pheny1)-[(2R)-2-pyrrolidin-1-2.5 *
see 2H), 7.56 (m, 3H), 7.46 (m, 2H), 7.36 (m, 1H), ylmethyl-pyrrolidin-1-y1]-examples 5.74 (s, 2H), 5.35 (s,2H), 4.40 (m, 1H), 3.40 (d, folC
NH, methanone "
2H), 3.0 (m, 4H), 1.7-2.0 (m, 10H) ci ¨
......roli (446-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 07.81 (d, 1H), 7.56 (m, benzyloxy)-pyridin-3-y1]-2.41 see2H), 7.48 (m, 4 H), 6.87 (m, 2H), 5.53 (s, 2H), ,.... I
examples N
phenoxy)-acetic acid 5.32 (s, 2H), 4.33 (s, 2H) 1101 ., a NH

t b d14.ch 1or b-einzy 2-{4-[6-Amino-5-(2,6-10-pyridin-3.
(400 MHz, DMSO-d6) 07.77 (d, 1H), 7.52 (d, a ylj-pheno)ry)-1-((2R)-2-f 0.53 see 1H), 7.47 (m, 3H), 7.41 (m, 2H), 6.88 (m, 2H), pyrrolidin-1-ylmethyl-xy examples 5.51 (s, 2H), 5.28 (s, 2H), 4.67 (s, 2H), 4.20 (m, a \ N
pyrrolidin-1-y11-ethanone 1H), 3.42 (m, 2H), 1.82 (m, 4H), 1.96 (m, 10H).
_ ("
2-{4-[6-Amino-5-(2,6-(400 MHz, DMSO-d6) 07.82 (d, 1H), 7.57 (d, *¨\...2--1 dichloro-benzyloxy)-pyridin-3-1H), 7.52 (m, 3H), 7.45 (m, 2H), 6.93 (m, 2H), 1-57 ,F4a Ili c't "". yl see -570.5 5.56 (s, 2H), 5.33 (s, 2H), 4.72 (s, 2H), 4.20 (m, pyrrolidin-1-ylmethyl-examples1H), 3.5 (m, 2H), 2.52 (m, 6H), 1.85 (m, 4H), 1.66 C----r= \--t a PJ
pyrrolidin-1-y1)-ethanone (m, 4H) H \

3-(2,6-Dichloro-benzyloxy)-5-(400 MHz, DMSO-d6) 6 11.05 (s, 1H, NH), 7.87 see (d, 1H), 7.76 (m, 1H), 7.57 (m, 3H), 7.40-7.48 (m, (1H-indo1-5-y1)-pyridin-2-4.3 CI
N
ylamine examples 2H), 7.34 (m, 2H), 6.44 (m, 1H), 5.49 (br. s, 2H, (tC:0 ..--NH2), 5.36 (s, 2H, CH2) NH, H \ /
(400 MHz, DMSO-d6) 6 11.35 (d, 1H, NH), 7.95 Up N-... 3-(2,6-Dichloro-benzyloxy)-5-(s, 1H), 7.89 (d, 1H), 7.55 (m, 4H), 7.45 (m, 2H), .
--,.
[3-(1-methy1-1,2,3,6-see tetrahydro-pyridin-4-yI)-1H-1.57 examples 7.39 (dd, 1H), 6.25 (m, 1H), 5.54 (br. s, 2H, NH2), indo1-5-yll-pyridin-2-ylamine 5.37 (a, 2H, CH2), 3.77 (m, 2H), 3.32 (m, 2H), Jr a 1= .1H
2.82 (m, 2H), 2.80 (s, 3H).
H
\
(400 MHz, DMSO-d3) 510.9 (d, 1H, NH), 7.90 (d, 1.1 N... 3-(2,6-Dichloro-benzyloxy)-5-[3-(1-methyl-piperidin-4-y1)-1H), 7.80 (s, 1H), 7.55 (m, 4H), 7.46 (m, 2H), 3.04 see 7.32 (dd, 1H), 5.50 (br. s, 2H, NH2), 5.38 (s, 2H, 481 1H-indo1-5-yll-pyridin-2-examples O
ylamine CH2), 3.32 (m, 2H), 3.02 (m, 2H), 2.90 (m, 1FI), fl* a NEI
2.67 (s, 3H), 2.10 (m, 2H), 1.98 (m, 2H).
H \
3(26-Dichloro-benzyloxy)-5--(400 MHz, DMSO-d6) 02.31 (m, 4H), 3.55 (m, iN¨ \

IP \-0/ (3-rn'orpholin-4-1H-1H-1.19 see 4H), 3.66 (s, 2H), 5.26 (s, 2H), 5.45 (s, 2H), 7.22 examples (s, 1H), 7.34 (m, 2H), 7.48 (m, 2H), 7.57 (m, 2H), ""
-1 '..
indo1-5-y1)-pyridin-2-ylamine 7.80 (s, 1H), 7.85 (s, 1H), 10.92 (br s, 1H) ak. o illy ri NI-I
, H \

(300 MHz, CDC13) 01.43 (m, 2H), 1.60 (m, 4H), 3-(2,6-Dichloro-benzyloxy)-5-see 2.50 (m, 4H), 3.76 (s, 2H), 4.65 (br s, 2H), 5.40 (3-piperidin-1-ylmethy1-1H-1.41 examples (s' 2H), 7.19 (s, 1H), 7.27 (m, 1H), 7.38 (m, 5H), =
I
indo1-5-y1)-pyridin-2-ylamine 7.87(s, 1H), 8.01 (d, J= 1.7 Hz, 1H), 8.17 (bra, 0 ,N
1H) Si 1,11-1 a _ _ H
\ 0 IP
3-(2,6-Dichloro-benzyloxy)-5-(300 MHz, CDC13) 6 1.79 (m, 4H), 2.62 (m, 4H), (3-pyrrolidin-1-ylmethy1-1H-1.34 see 3.88 (s, 2H), 4.64 (br s, 2H), 5.40 (s, 2H), 7.21 (d, indo1-5-y1)-pyridin-2-ylamine examples J = 2.3 Hz, 1H), 7.26 (m, 1H), 7.38 (m, 5H), 7.84 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 8.10 (bra, 1H) a "2 ---.--No.
Structure Name Met 1C50 Procedure MS rn/z (1-1M) (M+1) H
( i 3-(2,6-Dichloro-benzyloxy)-5-(300 MHz, CDCI3) 6 1.13 (t, 6H), 2.64 (q, 4H), see 3.88 (s, 2H), 4.66 (br s, 2H), 5.37 (s, 2H), 7.19 (d, (3-diethylaminomethy1-1H-3.23 indo1-5-y1)-pyridin-2-ylamine examples J = 1.7 Hz, 1H), 7.26 (m, 1H), 7.37 (m, 5H), 7.86 I
a (s, 11-1), 8.00 (d, J = 1.7 Hz, 11-1), 8.44 (br s, 11-1) a _ KAA..(14546-Amino-5-(2 (300 MHz, CDCI3) 6 1.39 (s, 9H), 2.22 (m, 1H), dichloro-benzyloxy)-pyridin-3-..
,6-2.40 (m, 1H), 2.58 (m, 1H), 2.68 (m, 1H), 2.99 _ O
,..W
y1]-1H-indo1-3-ylmethyly see (m, I H), 3.82 (d, 1H), 3.88 (d, 1H), 4.16 (m, IH), RP
(3R)-pyrrolidin-3-yI)-6.3 examples 4.65 (bra, 2H), 4.81 (m, 1H), 5.41 (s, 2H), 7.17 (d, J = 2.1 Hz, 1H), 7.26 (m, 1H), 7.38 (m, 5H), I
carbamic acid tert-butyl ester 7.81 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 8.09 (br s, IH) LLµ=-(ci (300 MHz, CDCI3) 6 1.13 (d, J = 6.3 Hz, 6H), "
\

3-(2,6-Dichloro-benzyloxy)-5-1.80 (t, J = 10.7 Hz, 2H), 1.94 (br s, 1H), 2.84 (d, [3-(2,6-dimethyl-morpholin-4->20 see J = 10.5 Hz, 2H), 3.72 (m, 4H), 4.68 (br s, 2H), ylmethyI)-1H-Indol-5-y11-examples 5.39 (s, 2H), 7.16 (d, J = 2.2 Hz, 1H), 7.26 (m, ' I ''' pyridin-2-ylamlne 1H), 7.38 (m, 5H), 7.89 (s, 1H), 8.10 (d, J = 1.7 , N
IP
a =
NH, Hz, 1H), 8.32 (br s, IH) HNI's :

(300 MHz, CDCI3) 61.86 (s, 3H), 2.31 (m, 2H), dichloro-benzyloxy)-pyridin-3-' 2.59 (m, 1H), 2.70 (m, 1H), 2.99 (m, 1H), 3.82 (d, dis,õ \
1.-- "-I
N-(1-{546-Amino-5-(2,6-IIPP-y11-1H -indo1-311methyly 1.79 see 1H) 3.90 (d, 1H), 4.42 (m, 1H), 4.68 (br s, 2H), examples 5.40 (s, 2H), 5.91 (m, IH), 7.15 (d, J = 2.2 Hz, acetamide (3R)-pyrrolidin-3-yI)-1H), 7.26 (m, 2H), 7.38 (m, 5H), 7.82 (s, 1H), .

8.00(d, J = 1.8 Hz, 1H), 8.33 (bra, 1H) WI a NH, ,....
"
1-(44546-Amino-5-(2,6-.3¨
(300 MHz, CDCI3) 62.01 (s, 3H), 2.51 (m, 4H), \ µq---.5 (10 dichloro-benzyloxy)-pyridin-3- 2.18 see 3.44 (m, 2H), 3.63 (m, 2H), 3.78 (s, 2H), 4.68 (br yI]-1H-indol-3-ylmethyl)-examples s' 2H), 5.40 (s, 2H), 7.17 (d, J = 2.2 Hz, I H), 7.26 (m, 1H), 7.38 (m, 5H), 7.88 (s, 1H), 8.00 (d, 1,,,,, piperazin-1-yI)-ethanone J = 1.8 Hz, I H), 8.34 (br s, I H) , HN \
161 3-(2-Chloro-3,6-difluoro-see .õ
benzyloxy)-5-(1H-Indol-5-y1)-I ._,.14 pyridin-2-ylamine examples Ili CI NH2 F
0)L.
0 1-(4-(546-AmIno-5-(2-chloro-3,6-difluoro-benzyloxy)-H \
(300 MHz, CDCI3) 6 2.08 (s, 3H), 2.49 (m, 4H), ' pyridin-3-y1]-1H-lndo1-3-0.8 see 3.48 (m, 2H), 3.61(m, 2H), 3.80 (s, 2H), 4.68 (s, I-I), 7.20 (m, 2H), 7.41 ylmethylypiperazin-1-y1)-examples 2H), 5.30(s, 2H), 7.02 (m, I
I ""

(m, 3H), 7.89(s, I H), 8.06 (s, 1H), 8.63 (s, 1H) ethanone F
H \ ?:-__)'"== 3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[3-(2,6-(300 MHz, CDCI3) 6 1.37 (d, 6H), 1.92 (m, 2H), (1110 dimethyl-morpholin-4-2.71 see 2.95 (m, 2H), 3.87(m, 4H), 4.68 (s, 2H), 5.34 (s, ylmethyl)-1H-Indol-5-y1]-i a0 examples 2H), 7.08 (m, I H), 7.27 (m, 2H), 7.48 (m, 3H), 7.89(s, 11-1), 7.98 (s, 1H), 8.21 (br s, 1H) ii ' N
Alp NH, pyridin-2-ylamine F

No. Structure Name Met IC60 Procedure 1H-NMR MS m/z (1-trvi) (M+1) n...fl 1. N-(1-(546-Amino-5-(2-(300 MHz, CDCI3) 61.71 (m, 1H), 1.81(5, 3H), RP chloro-3,6-difluoro-2.31 (m, 2H), 2.48 (m, 1H), 2.79(m, 2H), 3.11 (m, 1-72 , benzyloxy)-pyridin-3-yI]-1H-0.95 1H), 3.98 (m, 2H), 4.68 (s, 2H), 6.31 (s, 2H), 7.06 526 1 ''' examplessee 0 NH: indo1-3-ylmethyl)-(35)-(m, 1H), 7.20 (m, 2H), 7.45 (m, 4H), 7.86 (s, 1H), pyrrolidin-3-y1)-acetamide 7.98(s, 1H), 8.38 (s, 1H) F

H\

. e--\ 3-(2-Chloro-3,6-difluoro-.(300 MHz, CDCI3) 61.64 (m, 2H), 1.64 (m, 4H), L./ benzyloxy)-5-(3-piperidin-1-see 2.56(m, 4H), 3.80 (s, 2H), 4.68 (s, 2H), 5.30(s, 1-73 -.
0.74 I ylmethy1-1H-indo1-5-y1)-examples 2H), 7.08 (m, 1H), 7.20 (m, 2H), 7.45 (m, 3H), pyridin-2-ylamine 7.86(s, 1H), 7.89 (s, 1H), 8.49 (br s, 1H) NH , H \

C\ 3-(2-Chloro-3,6-difluoro-(300 MHz, CDCI3) 62.72 (m, 4F1), 3.80 (m, 6H), 40 0' benzyloxy)-5-(3-morpholin-4- 1.4 see 4.70 (s, 2H), 5.33 (d, 2H), 7.07 (m, 1H), 7.20 (m, I -` ylmethy1-1H-indol-5-y1)-examples 1H), 7.35-7.55 (m, 4H), 7.86 (s, 1H), 8.00 (d, 1H), 0 ""
pyridin-2-ylamine 8.23 (s, 1H) 40 a NH, F
-H \ 0 3-(2-Chloro-3,6-difluoro-(300 MHz, CDCI3) 6 1.86 (m, 4H), 2.79 (m, 4H), 40 benzyloxy)-5-(3-pyrrolidin-1-see 4.01 (s, 2H), 4.63 (s, 2H), 5.30 (d, 2H), 7.05 (m, 0.7 F ylmethy1-1 H-indo1-5-y1)-examples 1H), 7.18 (m, 1H), 7.30-7.60 (m, 4H), 7.80 (s, I '' pyridin-2-ylamine 1H), 8.00 (d, 1H), 8.64 (s, 1H) fi- 0 '14 a F

0 r-H \

546-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 6 1.34 (t, 3H), 4.34 (m, benzylm)-pyridin-3-yI]-1H- see >20 2H), 5.34 (s, 2H), 5.58 (s, 2H), 7.16 (s, 1H), 7.52 456 indole-2-carboxylic acid examples (m, 6H), 7.84 (d, 2H), 11.84 (s, 1H) = I ethyl ester iiiiõ, 0 -N

WI a NH., 0, `-µ--OH

H \

546-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 6 5.46 (a, 2H), 5.53 (s, 2H), see 1-77 11101 benzyloxy)-pyridin-3-y11-1H-1.62 6.66 (s, 1H), 7.33 (d, 1H), 7.44 (m, 2H), 7.54 (m, 428 indole-2-carboxylic acid examples 3H), 7.72 (s, 1H), 7.86 (s, 1H), 11.12 (s, 1H) oI ---..

-- "

mr, ci NH, O r- \

\--P¨
H \
(546-Amino-5-(26-dichloro-(400 MHz, DMSO-d6) 62.21 (s, 3H), 2.36 (m, benzyloxy)-pyridin-3-y1]-1H- see 4H), 3.74 (m, 4H), 5.35 (s, 2H), 5.53 (s, 2H), 6.78 1-78 1:40 0.18 indo1-2-y1}-(4-methyl- examples (s, 1H), 7.50 (m, 6H), 7.81 (s, 1H), 7.88 (s, 1H), , piperazin-1-yI)-methanone 11.56 (s, 1 H) I

0 r N

ill li.- a NH, O 0,11--=

(546-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 6 1.80 (m, 1H), 2.12 (m, H \

benzyloxy)-pyridin-3-y1]-1H-1H), 2.21 (s, 6H), 2.74 (m, 1H), 3.25 (m, 1H), see 1-79 indo1-2-y1}-[(3R)-3-0.18 3.53 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 5.36 (s, 524 examples dimethylamino-pyrrolidin-1-2H), 5.54 (s, 2H), 6.98 (s, 1H), 7.46 (m, 3H), 7.56 I I yll-methanone (m, 3H), 7.86 (m, 2H),11.53 (s, 1H) , *
I 0 N NH, No. Structure Name Met 1C50 Procedure.
11-1-NMR MS nilz (11M) (M+1) . -.

(400 MHz, DMSO-d6) 5 1.80 (m, 1H), 2.12 (m, NS (546-Amino-5-(2,6-dichloro-H benzyloxy)-pyridin-3-y11-1H-1H), 2.21 (s, 6H), 2.74 (m, 1H), 3.25 (m, 1H), 1-80 indo1-2-y1)-[(2R)-2-pyrrolidin- 0.079 3.53 (m, 1H), 3.78 (m, 11-I), 4.02 (m, 1H), 5.36 (s, 524 examplessee 1-ylmethyl-pyrrolidin-1-y11-2H), 5.54 (s, 2H), 6.98 (s, 1H), 7.46 (m, 3H), 7.56 methanone (m, 3H), 7.86 (m, 2H),11.53 (s, 1H) ikii , 0 N., _ 1.1 0 tL

,ii... 5-[6-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 5 1.66 (m, 4H), 2.51 (m, [I, benzyloxy)-pyndin-3-y1]-1H-see 4H), 2.58 (t, 2H), 3.39 (m, 2H), 7.11 (s, 1H), 7.45 1.2 indole-2-carboxylic acid (2- examples (m, 2H), 7.55 (m, 3H), 7.60 (m, 1H), 7.82 (s, 1H), pyrrolidin-1-yl-ethyl)-amide 7.88 (s, 1H), 8.45 (t, 1H), 11.56 (s, 1H) 1 :'N

" \ \--\ 5-[6-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 62.41 (m, 6H), 3.39 (m, SI k_o) benzyloxy)-pyridin -3-y11-1H-see 2H), 3.58 (m, 4H), 7.11 (s, 1H), 7.45 (m, 2H), 1 .8 indole-2-carboxylic acid (2- examples 7.55 (m, 4H), 7.82 (s, 1H), 7.88 (s, 1H), 8.42 (t, morpholin-4-yl-ethyl)-amide 1H), 11.52 (s, 1H) 6C0 I :::

. _2 H I \ (1-{546-Amino-5-(2,6-(400 MHz, DMSO-d6) 6 1.38 (s, 9H), 1.64 (m, dichloro-benzyloxy)-pyridin-3-1H), 1.98 (m, 2H), 3.18 (m, 2H), 3.78 (m, 2H), y11-1H-indole-2-carbonyl}-- see 5 5.37 (s, 2H), 5.53 (s, 2H), 6.92 (m, 1H), 7.26 (m, 596 (3S)-pyrrolidin-314)- examples 1H), 7.48 (m, 2H), 7.56 (m, 3H), 7.61 (m, 1H), 0L- carbamic acid tert-butyl c:
7.86 (m, 2H), 11.52 (s, 1H) & :FIN, ester . to,NFI, H I \
{5-[6-Amino-5-(2,6-dichloro-(400 MHz, DMSO-d6) 62.20 (m, 2H), 2.68 (m, 10 benzyloxy)-pyridin-3-yI]-1 H -see 0.14 1H), 3.84 (m, 4H), 5.56 (s, 2H), 7.52 (m, 6H), 496 indo1-2-y1)4(3S)-3-amino- examples 7.94 (m, 5H), 8.62 (m, 2H) 6c0 I :-IiN pyrrolidin-1-y1I-methanone . -.1.5 s--\_,C3 546-Amino-5-(2,6-dichloro-(400 MHz:, DMSO-c13) 6 1.67 (m, 4H), 2.37 (m, benzyloxy)-pyridin-3-y1)-1H-1H), 2.52 (m, IN), 3.31 (m, 1H), 3.62 (m, 4H), see 1-85 indole-2-carboxylic acid (2-0.7 examples 3.46 (m, 1H), 3.76 (m, 1H), 5.38 (s, 2H), 5.52(s, 554 hydroxy-3-pyrrolidin-1-yl-2H), 7.14 (s, 1H), 7.46 (m, 2H), 7.56 (m, 4H), propyI)-amide 7.86 (m, 2H), 8.48 (t, 1H), 11.58 (s, 1H) OH

(400 MHz, DMS0-4) 69.4 (s, 11-1), 7.74 (d, J = 2 1-86 4-(6-Amino-5-benzyloxy-8.7 see Hz, 1H), 7.52 (d, J =
7.2 Hz, 21-I), 7.38 (m, 4H), 293 WI pyridin-3-yI)-phenol examples 7.32 (m, 2H), 6.8 (d, J = 7.2 Hz, 2H), 5.69 (s, 0 I ..-N
2H), 5.22 (s, 2H) . NH, (400 MHz, DMSO-d6) 7.84 (d, 1H), 7.56 (d, 2H), 3-Benzyloxy-5-phenyl-pyridin. see examples 7.51 (d, 2H), 7.38 (m, 5H), 7.31 (t, 1H), 7.25 (t, 277 tip , 2-ylamine I
1H), 5.83 (br s, 2H), 5.24 (s, 2H) 0 . .- N

.
(400 MHz, DMS0-4) 7.85 (d, 1H), 7.56 (m, 2H), 1-88 \= # 3-(3-Nlethoxy-benzyloxy)-5-see 7.38 (m, 3H), 7.28 (m, 2H), 7.08 (m, 2H), 6.86 307 ' I phenyl-pyridin-2-ylamlne examples (m, 11-1), 5.84 (br s, 2H), 5.21 (s, 2H), 3.75 (s, 31-1) 0 "

_ No. Structure Name Met 1C60 Procedure 1H-NMR
MS m/z (Mil) (I-LM) _ 3-(2-Chloro-4-fluoro- (400MHz, DMSO-d6) 57.88 (5, 1H), 7.79 (m, see 1-89 ')\I a .-- I benzyloxy)-5-phenyl-pyridin- 17 1H), 7.59 (m, 2H), 7.51 (dd, 1 H) , 7.40 (m, 3H), examples NH, (400MHz, DMSO-d6) 57.88 (d, 1H), 7.73 (m, 3-(2-Chloro-benzyloxy)-5- 48% at see 1-90 (1a 1H), 7.68 (m, 2H), 7.50 (m, 1H), 7.38 (m, 5H), I phenyl-pyridin-2-ylamine 20 uM examples 7.26 (m, 1H), 5.57 (5, 2H), 5.30 (5,2H) - -( 400MHz, DMSO-d6) 57.89 (d, 1H), 7.85 (d, 3-(2,5-Dichloro-benzyloxy)-5- 48% at see 1H), 7.59 (m, 2H), 7.53 (d, 1H), 7.46 (d, 1H), 7.39 345 1-91 a Ilik a .-1 phenyl-pyridin-2-ylamine 20 uM examples (m, 3H), 7.26 (m, 1H), 5.95 (5, 2H), 5.30 (5,2H) 0 '' "

NFL, _ (400MHz, DMSO-de) 6 8.15 (5, 1H), 7.89 (d, 1H), F _- 3-(2-Chloro-5-trifluoromethyl-1-92 FF lif a , benzyloxy)-5-phenyl-pyridin- >20 see7.76 (d, 2H), 7.59 (m, 2H), 7.48 (d, 1H), 7.39 (m, examples cq 2-ylamine 2H), 7.26 (m, 1H), 5.90 (s, 2H), 5.36 (5,2H) NH, a 3-(2,4-Dichloro-5-fluoro- (400MHz, DMSO-de) 6 7.95 (d, 1H), 7.88 (m, 1-93 F . CI .õ,.
benzyloxy)-5-phenyl-pyridin- >20 see 2H), 7.60 (m, 2H), 7.44 (d, 1H), 7.39 (m, 2H), 364 i examples 0 -.. N 2-ylamine 7.26 (m, 1H), 6.01 (s, 2H), 5.24 (5,2H) NH, F F Ili F MI;111' 3-(2-Chloro-3-trifluoromethyl-(400MHz, DMSO-d6) 58.10 (d, 1H), 7.89 (d, 1H), see 1-94 benzyloxy)-5-phenyl-pyridin. >20 exam les 7,85 (m, 1H), 7.60 (m, 3H), 7.45 (d, 1H), 7.39 (m, Cci .......
p i 2-ylamine 2H), 7.26 (m, 1H), 5.93 (5, 2H), 5.37 (5,2H) a .. N

NH, 3-(2-Chloro-3,6-difluoro- (400MHz, DMSO-de) 07.89 (d, 1H), 7.57 (m, a , see 1-95 benzylm)-5-phenyl-pyridin- 0.64 examples 4H), 7.40 (m, 3H), 7.26 (m, 1 H), 5.72 (2, 2H), IN
F 0 2-ylamine 3.28 (s,2H) NFL, a a 0 (400MHz, DMSO-d6) 6 7.86 (d, 1H), 7.84 (d, 1H), 3-(3,4-Dichloro-benzyloxy)-5- see 7.65 (m, 1H), 7.67 (m, 3H), 7.39 (m, 3H), 7.26 1-96 q ,.. 16.2 1 phenyl-pyridin-2-ylamine examples (m, 1H), 5.96 (s, 2H), 5.24 (5,2H); MS m/z =-=-.. N

345[M+1].

Hz , (400MHz, DMSO-d6) 6 7.90 (dd, 2H), 7.82 (d, 2-(2-Amino-5-phenyl-pyridin- see 1H), 7.75 (m, 1H), 7.56 (m, 3H), 7.48 (d, 1H), 1-97 '. -- 1 12.2 3-yloxymethyl)-benzonitrile examples 7.40 (m, 2H), 7.26 (m, 1H), 5.85 (5, 2H), 5.39 (5,2H) NH., 40 3-(2-Chloro-6-fluoro-3-(400MHz, DMSO-d5) 57.88 (d, 1H), 7.61 (m, see 1-98 methyl-benzyloxy)-5-phenyl- 7.6 2H), 7.53 (d, 1H), 7.43 (m, 3H), 7.25 (m, 2H), a examples 1 pyridin-2-ylamine 5.65 (5, 21-I), 5.27 (5,2H), 2.34 (s, 3H) *0 NH, r _ (400MHz, DMSO-d6) 57.89 (d, 1H), 7.61 (m, 5-Phenyl-3-(2,3,6-trifluoro- see 3H), 7.52 (d, 1H), 7.40 (m, 2H), 7.25 (m, 2H), F
I benzOxY)-pyridin-2-ylamine 3'9 examples 0 -.1,1 5.75 (s, 2H), 5.26 (5,2H) F ill No. Structure Name Met IC50 Procedure 1H-NMR MS in/z (11M) (M+1) (400MHz, DMSO-c16) 67.88 (d, 1H), 7.61 (m, 3-(2,6-Difluoro-benzyloxy)-5- see 9.3 examples 2H), 7.51 (m, 2H), 7.40 (m, 2H), 7.26 (m, 11-1), 314 I N phenyl-pyridin-2-ylamine 7.18 (m, 2H), 5.69 (s, 2H), 5.23 (s,2H) F NH, SO 3-(2,6-Difluoro-3-methyl-(400MHz, DMSO-d6) 67.88 (d, 1H), 7.60 (m, see 1-101 F N. benzyloxy)-5-phenyl-pyridin-12 examples 2H), 7.51 (d, 1H), 7.40 (m, 3H), 7.27 (m,1H), 7.07 328 I ,N 2-ylamine (m, 1H), 5,68 (s, 2H), 5.21 (s,2H) lir F NN

Ol 3-(3-Chloro-2,6-difluoro-examples see (400MHz, DMSO-d6) 67.88 (d, 1H), 7.74 (m, 1-102 F N.. benzyloxy)-5-phenyl-pyridin-9.6 1H), 7.61 (m,2H), 7.51 (d, 1H), 7.40 (m, 2H), 7.27 347 a rik6 0 , N I 2-ylamine (m,2H), 5.76 (s, 2H), 5.26 (s, 2H) glill F NH, 10 3-(2-Chloro-6-fluoro-(400MHz, DMSO-d6) 67,88 (d, 1H), 7.61 (m, 1-103 . benzyloxy)-5-phenyl-pyridin-7.91 examseeples 2H)' 7.52 (d, 1H), 7.49 (m,1H), 7.40 (m, 3H), 7.30 329 I ,-N 2-ylamine (m, 2H), 5.67 (s, 2H), 5.27 (s, 2H) 310 F NH, * 3-(3-Fluoro-4-methoxy-(400 MHz, DMSO-de) 67,84 (d, 1H), 7.56 (m, examples see 1-104 benzyloxy)-5-phenyl-pyridin-15 1H), 7.43 (d, 1H), 7.38 (m,3H), 7.26 (m, 2H), 7.10 325 F 0 I ".',- N 2-ylamine (m, 2H), 5.58 (s, 2H), 5.15 (s, 2H) _ ¨0 110 NH, so N43-(2-Amino-5-phenyl-(400 MHz, DMSO-d5) 69,76 (s, 1H), 7.85 (d, J =

pyridin-3-yloxymethyl)- see 1.8 Hz, 1H), 7.57 (d, 2H), 7.36 (m, 5H), 7.28 (m, >20 R ti --- 1 phenyll-examples 2H), 7.15 (d, 1H), 5.85 (bra, 2H), 5.22 (s, 2H), -g-- 0 0 '"N methanesulfonamide 2.96 (s, 3H) NH, _ ,Ni = ) (DMSO-de) 02.50 (m, 4H), 2.69 (m, 2H), 3.57 (t, 544-(2-Morpholin-4-yl- see 4H), 4.09 (t, 2H), 5.37 (s, 2H), 5.85 (s, 2H),6.96 1-106 ethoxy)-phenyI)-3-(3-nitro-12.6 examples (d, 2H), 7.38 (d, 1H), 7.48 (d, 2H), 7,69 (t, 1H), 451 benzyloxy)-pyridin-2-ylamine 7.81 (d, 1H), 8.01 (m, 1H), 8.17 (m, 1H), 8.36 (m, 1H) NO2 0 0L.-0 NH, _ . X 544-(2-Morpholin-4-yl-(DMSO-d6) 62.50 (m, 4H), 2.69 (t, 2H), 3.57 (t, ethoxy)-phenyl]-3- see 4H), 4.10 (t, 2H), 5.66 (s, 2H), 5.67 (s, 2H), 6.97 7.7 * (naphthalen-1-ylmethoxy)-examples (d, 2H), 7.49-7.61 (m, 5H), 7.78-7.82 (m, 2H), pyridin-2-ylamine 7.88-7.98 (m, 2H), 8.20 (dd, 1H) go 0 -110 NH, r_.0 =) 3-(2-Chloro-3,6-difluoro-(400 MHz, CDC13) 62.60 (m, 4H), 2.83 (t, 2H), benzyloxy)-544-(2-morpholin. see 3.74 (t, 4H), 4.16 (t, 2H), 4.63 (s, 2H), 5.27 (d, 0.21 4-yl-ethoxy)-phenyl]-pyridin- examples 2H), 6.98 (d, 2H), 7.02-7.10 (m, 1H), 7.16-7.22 2-ylamine (m, 1H), 7.30 (2, 2H), 7.44 (d, 2H), 7.91 (d, 1H) = I

Ft alliwp F NH, No. Structure Name Met 1050 Procedure 1H-NMR MS m/z (PM) (M+1) _ ' tC) '' = .f. 2-(2-Amino-544-(2-(400 MHz, DMSO-d6) 6 1.15 (d, 611), 2.50 (m, morpholin-4-yl-ethoxy)-411), 2.68 (m, 2H), 2.77-2.89 (m, 1H), 3.57 (t, see 1-109 * IP phenyli-pyridin-3-yloxy)-N-(4->20 examples 6H), 4.08 (t, 2H), 6.15 (s, 1H), 6.20 (s, 211), 6.93 568 o isopropyl-phenyl)-2-phenyl-(d, 211), 7.17 (d, 1H), 7.30-7.44 (m, 3H), 7.48(d, \ I acetamide 2H), 7.68 (d, 2H), 7.79 (d, 1H) NH, ,Ni .-1 3-(5-Chloro-(400 MHz, DMSO-d6) 62.50 (m, 411), 2.70 (m, benzo[b]thiophen-3-211), 3.58 (t, 4H), 4.11 (t, 2H), 5.46 (s, 2H), 5.82 see 1-110 = ylmethoxy)-544-(2-2.4 examples (s, 2H), 6.98 (d, 2H), 7.43 (dd, 1H), 7.50-7.56 (m, 496.5 morpholin-4-yl-ethoxy)-311), 7.80(d, 1H), 8.05(d, 1H), 8.11 (d, 111), 8.16 a phenyl]-pyridin-2-ylamine (s, 1H) * \ NH, S

C) 0 N CD {446-Amino-5-(4-tluoro-2-(400 MHz, DMSO-d5) 67.94 (s, 2H), 7.71 (m, trifluoromethyl-benzylo>cy)-see 4H), 7.44 (m, 3H), 5.92 (s, 2H), 5.36 (s, 2H), 4.21 1-111 40 pyriclin-3-yll-phenyl}-[(2R)-2- 1.51 examples (m, 1H), 3.52 (m, 2H), 2.69 (m, 5H), 1.96 (m, pyrrolidin-1-ylmethyl-211), 1.84 (m, 3H), 1.68 (m, 4H) pyrrolidin-1-y11-methanone 0 F NH, F F

O N (446-Amino-5-(2-fluoro-6-(400 MHz, DMSO-d6) 67.94 (s, 1H), 7.69 (m, trifluoromethyl-benzyloxy)-see 5H), 7.59 (s, 1H), 7.50 (m, 2H), 5.72 (s, 2H), 5.26 1-112 pyridin-311]-pheny1)-[(2R)-2-0.15 examples (s, 211), 4.16 (m, 1H), 3.47 (m, 2H), 2.63 (m, 5H), pyrrolidin-1-ylmethyl-pyrrolidin-1-y1j-methanone 1.96 (m, 2H), 1.86 (m, 3H), 1.68 (m, 4H) F

CD

O N {446-Arnin0-5-(541101.0-2-(400 MHz, DMSO-c16) 67.95 (s, 111), 7.85 (m, trifluoromethyl-benzyloxy)- see 2H), 7.63 (m, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 1-113 pyridin-3-y1]-phenyl}-[(2R)-2-1.27 examples 6.04 (s, 2H), 5.36 (s, 211), 4.16 (m, 1H), 3.44 (m, 543 pyrrolidin-1-ylmethyl-2H), 2.62 (m, 5H), 1.96 (m, 211), 1.85 (m, 3H), pyrrolidin-1-yli-methanone 1.66 (m, 4H) F

C (4-(6-Amino-5-[1-(2-(400 MHz, DMSO-d6) 67.85 (d, 1H), 7.81 (s, 1H), trifluoromethyl-phenyl)-7.76 (m, 2H), 7.41 (m, 5H), 7.03 (s, 1H), 6.16 (s, see 1-114 ethoxyl-pyridin-3-y1}-phenyl)- 0.33 examples 211), 5.81 (m, 1H), 4.10 (m, 1H), 3.41 (m, 211), 539 , 0 [(2R)-2-pyrrolidin-1-ylmethyl- 2.59 (m, 5H), 1.94 (m, 2H), 1.82 (m, 3H), 1.64 (d, pyrrolidin-1-yll-methanone 3H), 1.48 (m, 4H) =
Or F NH2 F F

, , No. Structure Name Met IC60 Procedure 1H-NMR MS m/z (M+1) (1-1M) ?

(400 MHz, DMSO-d6) 67.74 (s, 1H), 7.68 (m, . 10{446-Amino-5-(2-bromo-benzyloxy)-pyridin-3-yli-see 3H), 7.45 (m, 5H), 7.31 (m, 1H), 5.92 (s, 21-1), 1-115 IP phenyll-[(2R)-2-pyrrolidin-1- 1.75 examples 5.25 (s, 2H), 4.16 (m, 1H), 3.43 (m, 2H), 2.62 (m, ylmethyl-pyrrolidin-1-yI]-5H), 1.94 (m, 2H), 1.82 (m, 3H), 1.65 (m, 41-1) methanone I
ip o NH, CD

0 N C) {446-Amino-5-(3-fluoro-2-(400 MHz, DMSO-c16) 67.92 (s, 1H), 7.66 (m, trifluoromethyl-benzyloxy)-see 4H), 7.46 (m, 4H), 5.89 (s, 2H), 5.39 (s, 2H), 4.19 1-116 pyridin-3-y11-pheny1}-1(2R)-2- 0.025 (10 examples (m, 1H), 3.50 (m, 2H), 2.54 (m, 5H), 1.95 (m, pyrrolidin-1-ylmethyl-2H), 1.83 (m, 3H), 1.64 (m, 4H) --, pyrrolidin-1-y1]-methanone ift- 0 'N

''''' OF, NH, F

CD

0 N {446-Amino-5-(2-chloro-3,6-(400MHz, DMSO-d6) 67.95 (d, 1H), 7.69 (d, 2H), difluoro-benzyloxy)-pyridin-3-see 7.58 (m, 2H), 7.50 (d, 2H), 7.40 (m, 1H), 5.81 (s, 1-117 ilo yli-phenyl}-[(2R)-2-pyrrolidin- 0.063 examples 2H), 5.29 (s, 2H), 4.35 (m, 1H), 3.5 (d, 2H), 2.87 1-ylmethyl-pyrrolidin-1-y11-(d, 2H), 2.71 (d, 2H), 1.7-2.0 (m, 10H) 1 -- methanone c F* NH, F

=H

1.1 446-Amino-5-(2,6-difluoro-(400 MHz, DMSO-d6) 69.38 (s, 1H), 7.77 (d, J =

see 1-118benzyloxy)-pyridin-3-y1]-3.79 2 Hz 1H), 7.52 (m, 2H), 7.40 (m, 3H), 7.17 (m, 329 F / , examples , 1,1 phenol 2H), 6.79 (m, 2H), 5.53 (br. s, 2H), 5.20 (s, 2H) 110 NH, F

(400 MHz, DMSO-d3) 6 7.81 (d, J = 2 Hz, 1H), , 3-(2,6-Difluoro-benzyloxy)-5-see 7.51 (m, 3H), 7.45 (d, J = 2 Hz, 1H), 7.17 (m, 1-119 (1H-Indo1-4-y1)-pyridin-2-5.8 j, .,.F ," , examples 2H), 6.98 (m, 2H), 5.58 (s, 2H), 5.21 (a, 2H), 4.10 , 14 ylamine (t, 2H), 3.57 (t, 4H), 2.69 (t, 2H), 2.48 (t, 4H) ULF "1-6 ,0 (400 MHz, DMSO-d6) 611.18 (s, 1H), 7.86 (d, J
) 3-(2,6-Difluoro-benzyloxy)-5-= 2 Hz, 1H), 7.52 (m, 1H), 7.44 (d, J = 2 Hz, 1H), see 1-120 [4-(2-morpholin-4-yl-ethoxy)-examples 7.36 (dd, 1H), 7.34 (m, 1H), 7.18 (m, 211), 7.13 352 phenyll-pyridin-2-ylamine (dd, 1H), 7.02 (dd, 1H), 6.49 (m, 1H), 5.66 (s, F
2H), 5.22 (s, 211) I
1/66 0 ...,N

Mr F NH, (400 MHz, DMSO-d6) 612.85 (s, 1H), 7.94 (d, J

446-Amino-5-(2,6-difluoro-I*
see = 2Hz, 1H), 7.89 (dd, 211), 7.71 (dd, 2H), 7.55 (d, 1-121 benzyloxy)-pyridin-3-y11-.., 1 examples J = 2Hz, 1H), 7.47 (m, 1H), 7.13 (m, 2H), 5.83 (s, F
benzoic acid =-... N
2H), 5.19 (s, 2H) * F NH, 0 a" {416-Amino-5-(2,6-difluoro-(400 MHz, DMSO-d6) 67.94 (d, 1H), 7.68 (dd, = ,6 benzylmry )-pyridin-3-- yfl F
see 2H), 7.56 (m, 1H), 7.51 (m, 3H), 7.18 (m, 2H), 1-122 C- 411 phenyly[(2R)-2-pyrrolidin-1-1.21 examples 5.79 (s, 2H), 5.29 (s, 2H), 3.48 (m, 1H), 2.65 (m, ylmethyl-pyrrolidin-1-y1]-4H), 2.48 (d, 2H), 1.86 (m, 1011) Fkri methanone ' No.
Structure Name ' Met 1050 Procedure MS rnIz (111\11) (M+1) (446-Amino-5-(2,6-difluoro-(400 MHz, DMSO-c16) 67.94 (d, 1H), 7.68 (dd, benzyloxy)-pyridin-3-A-see 2H), 7.56 (m, 1H), 7.51 (m, 3H), 7.18 (m, 2H), phenyl}-[(2S)-2-pyrrolidin-1-1.36 examples 5.78 (s, 2H), 5.24 (s, 2H), 4.6 (m, 1H), 3.5 (m, ylmethyl-pyrrolidin-1-A-methanone 2H), 2.52 (d, 4H), 1.86 (m, 10H) HaN N
#
.--10,......-(446-Amino-5-(2,6-difluoro-benzyloxy)-pyriclin-3-y1]-see (400 MHz, DMSO-d6) 67.81 (d, J .--- 2 Hz, 1H), 7.52 (m, 3H), 7.18 (m, 1H), 6.96 (m, 2H), 6.70 .-phenoxy)-acetic acid ethyl examples (br. s, 2H), 5.23 (s, 2H), 4.79 (5, 2H), 2.68 (q, ester 4H), 1.21 (t, 3H) QC) l'INN, .-'or-i (446-Amino-5-(2,6-difluoro-(400 MHz, DMSO-d6) 67.79 (d, 1H), 7.51 (m, see 1H), 7.47 (m, 1H), 7.44 (m, 2H), 7.17 (m, 2H), benzyloxy)-pyridin-3-yll-14.7 , 1 phenoxyl-acetic acid examples 7.05 (m, 2H), 5.55 (br. s, 2H), 5.21 (5, 2H), 4.25 F
..

(s, 2H) C5C: NH, 0 D''" 2-(4-[6-Amino-5-(2,6-difluoro-(400 MHz, DMSO-d6) 67.81 (d, 1H), 7.51 (m, wb benzy4oxy)-pyridin-3-yll-see 3H), 7.45 (d, 1H), 7.18 (m, 2H), 6.80 (m, 2H), phenoxy)-1-[(2R)-2-pyrrolidin 3.58 examples 5.65 (s, 2H), 5.22 (s, 2H), 4.80 (dd, 2H), 4.29 (m, A
1-ylmethyl-pyrrolidin-1--N
ethanone )-1H), 3.53 (m, 2H), 3.20 (m, 4H), 1.93 (m, 10H) r K.
2-{4-[6-Amino-5-(2,6-difluoro-(400 MHz, DMSO-c16) 67.81 (d, 1H), 7.52 (m, benzyloxy)-pyridin-3-y1)-see 31-1), 7.46 (d, 1H), 7.18 (m, 2H), 7.00 (m, 2H), phenoxy)-1-[(2S)-2-5.43523 examples 5.68 (s, 2H), 5.22 (s, 2H), 4.80 (dd, 2H), 4.60 (m, Ck-cP
pyrrolidin-1-ylmethyl-1H), 3.53 (m, 2H), 3.19 (m, 4H), 1.96 (m, 10H) F
N
pyrrolidin-1-yI]-elhanone =
H

446-Amino-5-(2-chloro-6-(400MHz, DMSO-c16) 69.38 (s, 1H), 7.77 (d, 1H), fluoro-benzyloxy)-pyridin-3-3.99 7.50 (m, 1H), 7.42 (m, 4H), 7.39 (m, 1H), 6.80 F
I
yll-phenol examplessee (m, 2H), 5.50 (s, 2H), 5.24 (s, 2H) 46 o --N
Mr a NH, =
H

4-16-Amino-5-(2-chloro-4-(DMSO-d6) 6 521 (s, 2H), 5.37 (s, 2H), 6.80 (d, see fluoro-benzyloxy)-pyridin-3-examples 2H), 7.26 (t, 1H), 7.34 (a, 1H), 7.41 (d, 2H), 7.50 ,õ, A-phenol (d, 1H), 7.79 (m, 2H), 9.38 (s, 1H) F illo a NI-I
=
H
*
446-Amino-5-(2,4-dichloro-see (DMSO-d6) 5 5.21 (s, 2H), 5.71 (s, 2H), 6.81 (d, benzyloxy)-pyridln-3-A-9/>20 examples 2H), 7.40 (m, 51-1), 7.74 (m, 2H), 9.38 (s, 1H) 0 1 2,, phenol H, a a N
=H
IP
242-Amino-5-(4-hydroxy-(DMSO-d6) 55.35 (s, 2H), 5.68 (s, 2H), 6.77 (d, phenyl)-pyrid -in-39 2H), 7.41 (m, 3H), 7.54 (t, 1H), 7.78 (m, 3H), 7.92 -..
examples see I
N
yloxymethylj-benzonitrile (d, 1H), 9.38 (s, 1H) 110 o :
CM

=
H

4-[6-Amino-5-(2-(400 MHz, DMSO-d6) 6 5.32 (s, 2H), 5.68 (s, 2H), see 6.78 (d, 2H), 7.26 (s, 1H), 7.36 (d, 2H), 7.57 (t, trifluoromethyl-benzyloxy)-3.67 pyridin-3-A-phenol examples 1H), 7.72 (t, 1H), 7.78 (m, 2H), 7.86 (m, 1H), 9.38 ii o .--N
(s, 1H) NH, 'M CF, No.
Structure Name Met 1C60 Procedure MS m/z (1-1M) (M+I) _ _ .
=H

4-(6-Amino-5-(2-chloro-(DMSO-d6) 65.25 (s, 2H), 5.69 (s, 2H), 6.78 (d, see benzyloxy)-pyridin-3-y11-13.8 2H), 7.38 (m, 5H), 7.50 (m, 1H), 7.71 (m, 1H), I
phenol examples 7.78 (s, 1H), 9.38 (s, 1H) du 0 ...- N
NH, a OH

IS
4-(6-Amino-5-(4-tert-butyl-(DMSO-c16) 61.26 (s, 9H), 5.16 (s, 2H), 5.63 (s, see ..
benzyloxy)-pyridin-3111-2H), 6.78 (d, 2H), 7.40 (m, 7H), 7.72 (s, 1H), 9.36 I .N
phenol examples (s, 1H) , R, H S*0 N -{416-Amino-5-(2-cyano-benzyloxy)-pyridin-3-y11-see (DMSO-d6) 62.98 (s, 3H), 5.36 (s, 2H), 5.82 (s, 4.18 2H), 7.24 (d, 2H), 7.42 (s, 1H), 7.58 (m, 3H), 7.75 phenyl}-examples I
methanesulfonamide (t, 1H), 7.89 (m, 3H), 9.70 (s, 1H) .44 . ONO Ni-k fi'/
H

2-[2-Amino-5-(4-(DMSO-d6) 6 2.88 (s, 3H), 5.37 (s, 2H), 5.75 (s, methanesulfonylemino-see >20 2H), 7.15 (d, 2H), 7.30 (s, IH), 7.48 (m, 6H), 7.20 phenyl)-pyridin-3-examples 1 '- N
yloxymethy1}-benzamide (d, 1H), 7.80 (s, 1H), 7.90 (s, 1H) i:?/
H St.

2-[2-Amino-5-(4-(DMSO-d6) 6 3.00 (s, 3H), 5.65 (s, 2H),7.26 (d, methanesulfonylamino-see >20 21-1), 7.47 (m, 3H), 7.60 (m, 4H), 7.72 (m, IH), phenyl)-pyridin-3-examples 7.82 (s, IH), 7.94 (d, IH), 9.84 (s, 1H) io OH
yloxymethylj-benzoic acid o HH2 2, pilr'.o N-(4-(6-Amino-5-(2-(4-(DMSO-d6) 6 2.08 (s, 3H), 2.26 (m, 2H), 2.96 (s, methyl-piperazine-1-3H), 3.15 (m, 2H), 3.36 (m, 2H), 3.59 (m, 2H), carbonyl)-benzyloxy}-pyridin->20 5.17 (br s, 2H), 5.78 (s, 2H), 7.23 (d, 2H), 7.28 r,r, -c4-.
3-y1}-phenyl)-examples see (m, 1H), 7.36 (s, 1H), 7.43 (m, 2H), 7.57 (m, 4H), methanesulfonamide 7.84 (s, 1H) 14? ' ,0 2-[2-Amino-5-(4-(DMSO-d6) 62.96 (s, 3H), 3.28 (m, 2H), 3.46 (m, methanesulfonylamino-2H), 4.70 (s, 1H), 5.30 (s, 2H), 5.78 (s, 2H), 7.23 -..
phenyl)-pyridin-3->20 (d, 2H), 7.32 (s, IH), 7.39 (m, IH), 7.47 (m, 2H), examples see yloxymethyll-N-(2-hydroxy-7.53 (m, 2H), 7.62 (d, IH), 7.83 (s, IH), 8.37 (t, Cco N'HN, ethyl)-benzamide 1H), 9.72 (br s, 1H) r..NH
2..
H

2-[2-Amino-5-(4-(DMSO-d6) 60.84 (d, 6H), 1.78 (m, IH), 2.82 (s, methanesulfonylamino-see 3H), 3.03 (t, 2H), 5.28 (s, 2H), 5.72 (s, 2H), 7.

phenyl)-pyridin-3->20 , yloxymethyg-N-isobutyl-N
examples (d, 2H), 7.24 (s, 1H), 7.42 (m, 5H), 7.62 (d, 1H), Cco NH, benzamide 7.79 (s, 1H), 8.41 (t, 1H), 9.68 (s, 1H) 'Jr-NH

No. Structure Name Met ICso Procedure 1H-NMR
MS m/z (11M) (M+1) , O OH

= 446-Amino-5-(2-chloro-6-see (400MHz, DMSO-d6) 6 5.25 (s, 2H, CH2, 5.82 (br ) 1-141 fluoro-benzyloxy)-pyridin-3-examples s, 2H, NH2), 6.30 -8.00 (multiplets, 9H, aromatic) ci yI]-benzoic acid I

0 NH, F

o N {446-Amino-5-(2-(2-6-(300 MHz, CDC's) 57.96 (d, 1H), 7.57 (m, 4H), fluoro-benzyloxy)-pyridin-3-see 7.10 (m, 3H), 7.04(t, 1H), 5.30 (s, 2H), 4.83 (s, 1-142 yll-phenyl}-[(2R)-2-pyrrolidin-0.63 examples 2H), 4.45 (m, 1H), 3.40 (m, 211), 2.90 (m, 4H), 2.2 1-ylmethyl-pyrrolidin-1-y1]-1.5 (m, 10H) = methanone .

P e., O 0 {446-Amino-5-(2-chloro-6-(300 MHz, CDCI3) 57.96 (d, 1H), 7.57 (m, 4H), fluoro-benzyloxy)-pyridin-3- see 7.10 (m, 311), 7.04(t, 1H), 5.30 (s, 2H), 4.83 (s, 1-143 ylj-phenyl)-[(25)-2-pyrrolidin- 13 40 1-ylmethyl-pyrrolidin-1-y11-examples 2H), 4.45 (m, 1H), 3.40 (m, 2H), 2.90 (m, 411), 2.2 1.5 (m, 1011) . methanone 40 F NIFiz \ _ O /131 {446-Amino-5-(2-chloro-6-(300 MHz, CDCI3) 6 7.94 (s, 1H), 7.58 (m, 4H), fluoro-benzyloxy)-pyridin-3-see 7.36 (m, 3H), 7.05(t, 1H), 5.30 (s, 2H), 5.07 (s, 1-144 40 yll-pheny1}4(3S)-3-1.7 examples 2H), 3.9 (m, 1H), 3.6 (m, 2H), 3.4 (m, 1H), 3.0 dimethylamino-pyrrolidin-1-(m, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.8 (m, 2H) ' N

yll-methanone NH.
_ 40 , 0 NI-t, O d {446-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3- see 0.63 yli-phenyl}-[(35)-3-amino- examples . pyrrolidin-1-yI]-methanone 41111" F0 NH, O Njr-(300 MHz, CDCI3) 57.93 (d, J = 1.7 Hz, 1H), {
7.56 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 1-146 161 fluoro-benzyloxy)-pyridin-3-1.94 see 211), 7.28 (m, 311), 7.07 (t, J = 8.8 Hz), 5.30(s, 455 yI]-phenyl}-(4-methyl- examples 2H), 5.05 (br s, 2H), 3.75 (m, 4H), 2.48 (m, 4H), = I piperazin-1-yI)-methanone 2.34 (s, 311) ' lb F

r'NI.

ON) 1-(4-{446-Amino-5-(2-chloro- (300 MHz, CDCI3) 57.91 (d, J = 1.7 Hz, 111), 6-fluoro-benzyloxy)-pyridin-3- see 7.58 (d, J = 8.2 Hz, 211), 7.50 (d, J = 8.2 Hz, 1-147 140 yll-benzoy1}-piperazin-1-y1)-1.45 examples 2H), 7.35 (m, 311), 7.08 (t, J = 8.2 Hz), 5.42 (br s, 484 ethanone 2H), 5.32 (s, 2H), 3.60 (m, 811), 2.14 (s, 311) I

= NC, F

No.
Structure Name Met IC50 Procedure MS rn/z (11M) (M+1) (300 MHz, CDCI3) 67.96 (d, J = 1.7 Hz, 1H), . C..6 4-16-Amino-5-(2-chloro-6-7.85 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, fluoro-benzyloxy)-pyridin-3-see 2F1), 7.30 (m, 2H), 7.24 (d, J = 1.7 Hz, 1H), 7.08 6.4 y11-N-(2-morpholin-4-yl-examples (m, 1H), 6.95 (br t, 1H), 5.32 (s, 2H), 5.06 (br s, ' ethyl)-benzamide 2H), 3.82 (m, 4H), 3.64 (m, 2H), 2.76 (m, 2H), Ai 0 ,N
F
Hit 2.65 (m, 4H) o 11,NO) (300 MHz, CDCI3) 6 8.02 (br t, 1H), 7.95 (d, J =
AO
446-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-5.6 see 1.7 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.59 (d, J =
8.3 Hz, 2H), 7.39 (d, J = 1.7 Hz, 1H), 7.30 (m, yll-N-(3-morpholin-4-yl-examples 2H), 7.08 (m,1H), 6.95 (br t, 1H), 5.32 (s, 2H), .
I , N
propyI)-benzamide 5.10 (br s, 2H), 3.78 (m, 4H), 3.62 (m, 2H), 2.64 tibi 0 NH
(m, 6H), 1.87 (m, 2H) F

446-Amino-5-(2-chloro-(400 MHz, DMSO-c15) 65.30 (s, 2H, CH2), 5.95 see 353 (M-benzyloxy)-pyridin-3-y11-examples (br s, 2H, NH2), 7.36 - 7.95 (multiplets, 10H, 1) 1' benzoic acid aromatic).
' io 0 I ,N

b {446-Amino-5-(2-chloro-(300 MHz, CDCI3) 67.96 (d, J = 1.6 Hz, 1H), benzyloxy)-pyridin-3-y11-see 7.52 (m, 6H), 7.25 (m, 2H), 7.21(d, J = 1.6 Hz, IS
pheny1)-[(2R)-2-pyrrolidin-1- p.87 examples 1H), 5.26 (s, 2H), 4.88 (br s, 2H), 4.32 (m, 1H), ylmethyl-pyrrolidin-1-y11-3.52 (m, 2H), 2.89 (m, 4H), 2.2-1.5 (m, 10H).
.
methanone 1/0 0 NH, <

{446-Amino-5-(2-chloro-(300 MHz, CDCI3) 67.96 (d, J = 1.6 Hz, 1H), benzyloxy)-pyridin-311]-7.52 (m, 6H), 7.25 (m, 2H), 7.21(d, J = 1.6 Hz, see phenyI}-[(2S)-2-pyrrolidin-1-2.3 examoes 1H), 5.26 (s, 2H), 4.88 (br s, 2H), 4.32 (m, 1H), ylmethyl-pyrrolidin-1-y11-3.52 (m, 2H), 2.89 (m, 4H), 2.2-1.5 (m, 10H). MS
methanone raiz 491 [M+11.
a I

...- N
NH, \ _ 0 N1.5 {4-16-Amino-5-(2-chloro-(300 MHz, CDC13) 67.95 (s, 1H), 7.53 (m, 6H), benzyloxy)-pyridin-3-yI]-7.33 (m, 2H), 7.27(s, 1H), 5.26 (s, 2H), 4.94 (br s, phenyl}-[(3S)-3-12.7 see examples 2H), 3.90 (m, 1H), 3.60 (m, 2H), 3.45 (m, 1H), dimethylamino-pyrrolidin-1-2.85 (m, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 1.89 (m, y11-methanone 2H) I
10/ o NH, -IFI, {446-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yI]-see phenyl}-((3S)-3-amino-.
examples pyrrolidin-1-y11-methanone I
i....?.........ro :...:
=

No.
Structure Name Met 1C50 Procedure MS rn/z (iM) (M+1) -......---r......10 o {446-Amino-5-(2-chloro-(300 MHz, CDC13) 57.96 (d, J = 1.8 Hz, 1H), iIi........) benzyloxy)-pyridin-3-y0-7.47 (m, 6H), 7.32 (m, 2H), 7.21(d, J = 1.8 Hz, phenyl}-(4-pyrrolidin-1-yl-1.5 see examples 1H), 5.26 (s, 2H), 4.86 (br s, 2H), 3.95 (m, 4H), 2.55 (m, 4H), 2.30 (m, 1H), 1.95 (m, 2H), 1.76 ' piperidin-1-y1)-methanone (m, 4H), 1.52 (m, 2H).
, N

I* NH, _ 0 Nj....
(4-[6-Amino-5-(2-chloro-(300 MHz, CDC13) 57.94 (d, J = 1.8 Hz, I H), benzyloxy)-pyridin-3-yll-2.1 see 7.49 (m, 6H), 7.32 (m, 2H), 7.21(d, J = 1.8 Hz, phenyl)-(4-methyl-piperazin-examples 1H), 5.27 (s, 2H), 4.00 (br s, 2H), 3.80 (m, 4H), =
I
1-yI)-methanone 2.50 (m, 4H), 2.35 (s, 3H) iial 0 , N
NH, M.'..
t41,.
0 N.õ}
1-(4-(446-Amino-5-(2-chloro-(300 MHz, CDC13) 57.95 (d, J = 1.8 Hz, 1H), benzyloxy)-pyridin-3-yll-3.8 see 7.51 (m, 6H), 7.33 (m, 2H), 7.21(d, J = 1.8 Hz, benzoy1}-piperazin-1-y1)-examples II-I), 5.27 (s, 2H), 4.94 (br s, 2H), 3.65 (m, 8H), ethanone 2.14 (s, 3H) .41 1111r NH, li...---....1 (300 MHz, CDCI3) 57.95 (d, J = 1.8 Hz, I H), SO
C--16 446-Amino-5-(2-chloro-ben4loxy)-pyridin-3-y11-N-(2-7.84 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.51 (m, 1H), 7.43 (m, I H), 7.34 (m, 2H), 7.24(d, 8.9 see morpholin-4-yl-ethyl)-examples J = 1.8 Hz, 1H), 7.01 (bit, 1H), 5.27(s, 21-0, 5.18 =
I - N
benzamide (br s, 2H), 3.77 (m, 4H), 3.61 (m, 2H), 3.25 (m, .
up 0 NH, 2H), 2.70 (m, 2H), 2.60 (m, 4H) .
(300 MHz, CDC13) 6 7.95 (d, J = 1.8 Hz, 1H), ti,,..õr`p,, s--' 4-[6-Amino-5-(2-chloro-7.84 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), benzyloxy)-pyridin-3-yll-N-(3-4.5 see 7.51 (m, 2H), 7.43 (m, 1H), 7.34 (m, 2H), 7.24(d, morpholin-4-yl-propyI)-examples J = 1.8 Hz, 1H), 5.27 (s, 2H), 4.97 (br s, 2H), benzamide 3.75 (m, 4H), 3.59 (m, 2H), 3.25 (m, 2H), 2.57 6.-- .i, (m, 4H), 1.83 (m, 2H).

#
446-Amino-5-(2-cyano-(400 MHz, DMSO-d6) 6 5.35 (s, 2H, CH2), 5.95 see benzyloxy)-pyridin-3-y0-examples (bra, 2H, NH2), 7.50-8.00 (multiplets, 10H, cN

I
benzoic acid aromatic) "N
=

NH, _ ,,b 242-Amino-544-((2R)-2-(300 MHz, CDCI2) 57.99 (d, J = 1.6 Hz, 1H), see pyrrolidin-1-ylmethyl-examples 7.76 (d, J = 7.5 Hz, 2H), 7.50 (m, 6H), 7.24(d, J

pyrrolidine-1-carbonyI)-1.2 -1.6 Hz, 1H), 5.35 (s, 2H), 4.88 (br s, 2H), 4.46 phenylj-pyridin-3-(m, 1H), 3.52 (m, 2H), 3.24 (m, 4H), 2.2-1.5 (m, N
I
yloxymethy1}-benzonitrile 10H) .
0 ' N
NH, rip e 2-{2-Amino-5-144(25)-2-1H NMR (300 MHz, CDCI3) 57.99 (d, J = 1.6 pyrrolidin-1-ylmethyl-Hz, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.50 (m, 6H), pyrrolidine-1-carbonyl) phenyll-pyridin-3-see examples 7.24(d, J = 1.6 Hz, 1H), 5.35 (s, 2H), 4.88 (br s, 2H), 4.46 (m, 1H), 3.52 (m, 2H), 3.24 (m, 4H), 2.2 N
yloxymethyl}-benzonitrile 1.5 (m, 10H).
I
I*
0 ...- N
NH, No.
Structure Name Met 1C50 Procedure MS rn/z (1-IM) (14+1) _ NI......

(300 MHz, CDCI3) 67.98 (s, 1H), 7.76 (d, J = 7.6 2-(2-Amino-5-14-((3S)-3-dimethylamino-pyrrolidine-1-Hz, 21-1), 7.50 (m, 6H), 7.26(s, 1H), 5.36 (s, 2H), carbonyl)-phenyl]-pyridin-3->20 see examples 4.99 (br s, 2H), 3.90 (m, 1H), 3.60 (m, 2H), 3.45 (m, 1H), 2.85 (m, 1H), 2.32 (s, 3H), 2.23 (s, 3H), N
yloxymethy1}-benzonitrile I

N
1.89 (m, 2H) ip ' NH, (300 MHz, CDCI3) 67.98 (d, J = 1.4 Hzõ 1H), 2-(2-Amino-544-((3S)-3-amino-pyrrolidine-1-2.05 see 7.76 (d, J = 7.5 Hz, 2H), 7.50 (m, 6H), 7.24(d, J
= 1.4 Hz, 1H), 5.35 (s, 2H), 4.91 (br s, 2H), 3.70 carbonyl)-phenyl]-pyridin-3-examples N
yloxymethyl)-benzonitrile (m, 4H), 2.15 (m, 1H), 2.23 (s, 2H), 1.25 (m, 1H), I
1.05 (m, 1H) to 0 ..- N
NH, (300 MHz, CDCI3) 67.97 (d, J = 1.7 Hzõ 1H), ;11,J
2-(2-Amino-544-(4-pyrrolidin-7.76 (d, J = 7.5 Hz, 2H), 7.66 (m, 2H), 7.51 (m, 1-yl-piperldine-1-carbonyl)-40 3.9 see 2H), 7.46 (m, 2H), 7.23(d, J = 1.4 Hz, 1H), 5.35 phenyI]-pyridin-3-examples (s, 2H), 4.88 (br s, 2H), 3.95 (m, 4H), 2.55 (m, yloxymethyl)-benzonitrile 4H), 2.30 (m, 1H), 1.95 (m, 2H), 1.76 (m, 41-1), N

' õI'N
1.52 (m, 2H) so 0 tsiFi -rr N.,,....-(300 MHz, CDCI3) 07.96 (d, J = 1.8 Hzõ 1H), 2-(2-Amino-544-(4-methyl-piperazine-1-carbonyI)-see 7.76 (d, J = 7.5 Hz, 2H), 7.66 (m, 2H), 7.51 (m, 3.2 2H), 7.48 (m, 2H), 7.24(d, J = 1.4 Hz, 1H), 5.35 phenyll-pyridin-3-examples N
I
yloxymethylybenzonitrile (s, 2H), 5.01 (bra, 2H), 3.65 (m, 4H), 2.45 (m, 0 ,N
4H), 2.36 (s, 3H) NH, 0,NOlt 245-4-4-Acetyl-piperaE1119-(300 MHz, CDCI3) 07.95 (d, J = 1.7 Hzõ 1H), 1-carbony1)-pheny1]-2-amino-5.7 see 7.76 (d, J = 7.5 Hz, 2H), 7.66 (m, 2H), 7.54 (m, examples 2H), 7.50 (m, 2H), 7.26(d, J = 1.4 Hz, 1H), 5.36 pyridin-3-yloxymethyly N
benzonitrile (s, 2H), 5.27 (bra, 2H), 3.65 (m, 8H), 2.14 (s, 3H) I '' to NH., 11........1 446-Amino-5-(2-cyano-(300 MHz, CDCI3) 67.99 (d, J = 1.8 Hzõ 1 I-I), ipi 1......õ'N.....
7.82 (d, J = 8.3 Hz, 2H), 7.74 (m, 1H), 7.66 (m, 2H), 755 (m, 3H), 7.25(d, J = 1.8 Hz, 1H), 6.18 benzyloxy)-pyridin-3-yI]-N-(1-see N

N
10.8 (d, J = 8.0 Hz, 1H), 5.35 (s, 2H), 4.88 (bra, 2H), I
methyl-piperidin-4-yI)-examples ....
benzamide 4.05 (m, 1H), 2.96 (m, 1H), 2.46 (s, 3H), 2.40 (m, õI

1H), 2.05 (m, 1H), 1.79 (m, 1H), 1.65 (m, 2H), 0.95 (m, 2H) --=
k......---.1 (300 MHz, CDCI3) 6 7.98 (d, J = 1.8 Hzõ 11-1), 4-(6-Amino-5-(2-cyano-7.85 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.4 Hz, 1H), benzylov)-pyridin-3-y1)-N-(2-see 7.66 (m, 2H), 7.57 (m, 3H), 7.27(d, J = 1.8 Hz, 8.6 N
morpholin-4-yl-ethyl)-examples 1H), 7.06 (m, 1H), 5.36 (s, 2H), 5.14 (br s, 2H), I
benzamide 3.78 (m, 4H), 3.63 (m, 2H), 2.73 (m, 2H), 2.63 io . -N
NH, (m, 4H) No. Structure Name Met 1C50 Procedure 1H-NMR
MS m/z (IIA) (M+1) _ . .

0, 11..--..N0-"I
(300 MHz, CDC13) 6 8.01 (d, J ... 1.7 Hzõ 1H), 4-[6-Amino-5-(2-cyano-7.87 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.5 Hz, 1H), (161 benzyloxy)-pyridin-3-y11-N-(3- 17.3 see 7.67 (m, 1H), 7.56 (dõ J = 8.4 Hz, 21-1), 7.45 (m, morpholin-4-yl-propy1)- examples 3H), 7.27(d, J = 1.8 Hz, 1H), 6.36 (s, 2H), 4.89 " 1 ,,,, benzamide (br s, 2H), 3.74 (m, 4H), 3.60 (m, 2H), 2.57 (m, 6H), 1.82 (m, 2H) O OH

446-Amino-5-(2,4-dichloro- (400 MHz, DMSO-de) 55.35 (s, 2H, CH2), 5.90 01 see 1-171 benzyloxyypyridin-3-y11-examples (br s, 2H, NH2), 7.30-8.00 (multiplets, 9H, N benzoic acid aromatic) I

I

"N

gill 0 NH2 CI ....r.-o /4 b (446-Amino-5-(2,4-dichloro-(300 MHz, CDC13) 57.97 (d, J = 1.7 Hz, 1H), benz-yloxyypyridin-3-y1]- 7.47 (m, 6H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, examples see 1-172 io pheny1)-[(2R)-2-pyrrolidin-1-0.61 1H), 7.18(d, J = 1.7 Hz, 1H), 5.21 (s, 2H), 4.85 ylmethyl-pyrrolidin-1-y1F (br s, 2H), 4.42 (m, 1H), 3.50 (m, 2H), 2.84 (m, methanone 4H), 2.2-1.5 (m, 10H) .

gal 0 ilir I-12 <

0 {446-Amino-5-(2,4-dichloro- (300 MHz, CDC12) 07.97 (d, J = 1 . 7 Hz, 1H), O

benzyloxy)-pyridin-311]- 7.47 (m, 6H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, see 1-173 so pheny1)-[(2S)-2-pyrrolidin-1-0.66 examples 1H), 7.18(d, J = 1 . 7 Hz, 1H), 5.21 (s, 2H), 4.85 ylmethyl-pyrrolidin-1-y1]- (bra, 2H), 4.42 (m, 1H), 3.50 (m, 2H), 2.84 (m, methanone 4H), 2.2-1.5 (m, 10H) I \' ail 0 - N

NH, .

aIF=

\ _ rill 0õN {4-[6-Amino-5-(2,4-dichloro-(300 MHz, CDC13) 07.95 (s, 1H), 7.50 (m, 6H), benzylmy)-pyridin-3-y1]- 7.30 (dd, J = 1 . 9 Hz, J = 8.3 Hz, 1H), 7.20(3, see 1-174 io phenyl)-[(33)-3-0.8 examples 1H), 5.21 (s, 2H), 5.07 (br s, 2H), 3.90 (m, 1H), dimethylamino-pyrrolidin-1- 3.62 (m, 2H), 3.46 (m, 1H), 2.85 (m, 1H), 2.32 (s, yli-methanone 3H), 2.23 (s, 3H), 1.89 (m, 2H) = 1 '..

o '1'1 a. H.

O U

{4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-y1]- see 1-175 101 1.2 pheny1)-1(3S)-3-amino- examples pyrrolidin-1111-methanone = 0 I ,ni o. H2 -õ.......0 (300 MHz, CDC13) 57.98 (d, J = 1.8 Hz, 1H), o lc...) (4-[6-Amino-5-(2,4-dichloro- 7.71 (d, J = 3.5 Hz, 1H), 7.50 (m, 5H), 7.30 (dd, benzyloxy)-pyridin-3-y11- see J = 2.0 Hz, J =
8.3 Hz, 1H), 7.18(d, J = 1.8 Hz, 525 1-176 0.85 phenyl}-(4-pyrrolidin-1-yl- examples 1H), 5.22 (s, 2H), 4.83 (br s, 2H), 4.23 (m, 2H), _.

piperidin-1-y1)-methanone 2.78 (m, 2H), 1.95 (m, 2H), 1.76 (m, 3H), 1.25 I , N

(m, 4H), 0.85 (m, 4H) . NH, a ''P

=

No. Structure Name Met 1C60 Procedure 1H-NMR MS tniz (PM) (wl) ON) {446-Amino-5-(2,4-dichloro- (300 MHz, CDCI3) 67.95 (s, 1H), 7.50 (m, 6H), 1-177 SO benzyloxy)-pyridin-3-yI]- 0.79 see 7.30 (dd, J = 1.9 Hz, J = 8.3 Hz, 1H), 7.20(s, 473 phenyl}-(4-methyl-piperazin- examples 1H), 5.21 (s, 2H), 5.07 (br s, 2H), 3.65 (m, 4H), = 1-yI)-methanone 2.45 (m, 4H), 2.36 (s, 3H) 0 I ..1N

a 111011 NI-1, ' o NCY1' (300 MHz, CDCI3) 67.97 (d, J = 1.8 Hz, 1H), 1-(4-{446-Amino-5-(2,4-7.50 (m, 6H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, 1-178 1.1 dichloro-benzyloxy)-pyridin-3- 1.67 see 1H), 7.18(d, J = 1.8 Hz, 1H), 5.22 (s, 2H), 4.87 501 yli-benzoy1}-piperazin-1-y1)- examples (br s, 2H), 3.64 (m, 4H), 3.53 (m, 4H), 2.14 (s, ' I ethanone di 0 Ni.i. 3H) a ' F. "

O 14......., (300 MHz, CDCI3) 67.98 (d, J = 1.8 Hz, 1H), 101 1.........411, 7.81 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 446-Amino-5-(2,4-dichloro-7.46 (m, 2H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, benzyloxy)-pyridin-3-y11-N-(1- see 1-179 = 1.12 1H), 7.18(d, J = 1.8 Hz, 1H), 6.09 (br d, 1H), 5.22 486 I ''' methyl-piperidin-4-yI)- examples 0 " (s, 2H), 4.83 (br s, 2H), 4.05 (m, 1H), 3.06 (m, 0 111 NH, benzamide a 1 H ) , 2.46 (s, 3H), 2.32 (m, 1H), 2.12 (m, 1H), 1.83 (m, 1H), 1.26 (m, 2H), 0.88 (m, 2H) o kl_.¨ (300 MHz, CDCI3) 67.98 (d, J = 1.8 Hz, 1H), 6 4-16-Amino-5-(2,4-dichloro- 7.84 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 0 benzyloxy)-pyridin-3-y1I-N-(2- as see 7.46 (m, 2H), 7.30 (dd, J = 2.0 Hz, J = 8.3 Hz, 502 morpholin-4-yl-ethyl)- examples 1H), 7.20(d, J = 1.8 Hz, 1H), 6.90 (br t, 1H), 5.22 a io, 0 NH. benzamide (s, 2H), 4.91 (br s, 2H), 3.75 (m, 4H), 3.59 (m, 2H), 2.65 (m, 2H), 2.55 (m, 4H) . 1:1_,-õCf (300 MHz, CDCI3) 6 7.99 (d, J = 1.7 Hz, 1H), 416-Amino-5-(2,4-dichloro- 7.87 (d, J = 8.3 Hz, 2H), 7.71 (m, 1H), 7.55 (d, J

benzyloxy)-pyridin-3-y11-N-(3- 2 see = 8.3 Hz, 2H), 7.47 (m, 2H), 7.30 (dd, J = 2.0 Hz, 516 morpholin-4-yl-propyI)- examples J = 8.3 Hz, 1H), 7.21 (d, J =
1.7 Hz, 1H), 5.23 (s, benzamide 2H), 4.91 (br s, 2H), 3.75 (m, 4H), 3.59 (m, 2H), . a 2r I r-I m 2.60 (m, 6H), 1.83 (m, 2H) 0,,0H

446-Amino-5-(2- (400 MHz, DMSO-d6) 6 5.35 (s, 2H, CH2), 5.95 1:10 see 1-182 trifluoromethyl-benzyloxy)-examples (bra, 2H, NH2), 7.40 - 8.00 (multiplets, 10H, 388 (M+) cF, , pyridin-3-yI]-benzoic acid aromatic) ' ,.1,1 NFL

O b {446-Amino-5-(2- 1H NMR (300 MHz, CDCI3) 67.96 (d, J = 1.7 trffluoromethyl-benzyloxy)- Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.7 see 1-183 pyridin-3-y1I-pheny1)4(2R)-2- 0.75 examples Hz, 1H), 7.53 (m, 6H), 7.15 (d, J = 1.7 Hz, 1H), 525 lb pyrrolidin-1-ylmethyl- 5.35 (s, 2H), 4.82 (br s, 2H), 4.42 (m, 1H), 3.50 pyrrolidin-1-y11-methanone (m, 2H), 2.65 (m, 4H), 2.2-1.5 (m, 10H) I
io . Nc6 _ , _ No.
Structure Name Met IC50 Procedure MS raiz (111\4) (M+1) (0 O

{446-Amino-5-(2-(300 MHz, CDCI3) 57.96 (d, J = 1.7 Hz, 1H), trifluoromethyl-benzyloxy)-7.74 (d, J =7.8 Hz, 1E1), 7.68 (d, J = 7.7 Hz, 1H), pyridin-3-y11-phenyl}-[(2S)-2- >20 see examples 7.53 (m, 6H), 7.15 (d, J = 1.7 Hz, 1H), 5.35 (s, , 2H), 4.82 (br s, 2H), 4.42 (m, 1H), 3.50 (m, 2H), pyrrolidin-1-ylmethyl-pyrroliclin-1-y11-methanone 2.65 (m, 4H), 2.2-1.5 (m, 10H) =
, \ _ O
N
{446-Amino-5-(2-(2 r3 (300 MHz, CDCI3) 57.97 (d, J = 2.1 Hz, 1H), trifluoromethyl-benzyloxy)-7.74 (d, J =7.8 Hz, 1H), 7.68 (d, J =7.7 Hz, 1H), pyridin-3-yli-pheny1)-[(3S)-3-1.39 see 7.51 (m, 6H), 7.16 (d, J = 2.1 Hz, 1H), 5.35 (s, examples 2H), 4.88 (br s, 2H), 3.89 (m, 1H), 3.65 (m, 2H), dimethylamino-pyrrolidin-1-3.45 (m, 1H), 2.75 (m, 1H), 2.31 (s, 3H), 2.22 (s, F*
yll-methanone I
3H), 2.11 (m, 1H), 1.89 (m, 1H).
* o 1,":11õ

-NIA, O

[(3S)-3-Amino-pyrrolidin-1-(300 MHz, CDCI3) 67.93 (d, J = 1.4 Hz, 1H), y1]-(446-amino-5-(2-see 7.74 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), trifluoromethyl-benzyloxy)-0.79 examples 7.55 (m, 3H), 7.45 (m, 3H), 7.15 (d, J = 1.4 Hz, pyridin-3-yli-phenyl}-1H), 5.35 (s, 2H), 5.01 (bra, 2H), 3.65 (m, 4H), . 3 ....N

I %.' methanone 2.03 (m, 3H), 1.75 (m, 1H), 0.85 (m, 1H) 0 .

(300 MHz, CDCI3) 57.96 (d, J = 1.8 Hz, 1H), (446-Amino-5-(2-7.74 (d, J = 7.9 Hz, 11-1), 7.66 (m, 1H), 7.60 (m, trifluoromethyl-benzyloxy)-1H), 7.47 (m, 5H), 7.14 (d, J = 1.8 Hz, 1H), 5.35 pyridin-3-y1]-phenyl)-(4-1.01 see examples (s, 2H), 4.81 (bra, 2H), 4.60 (m, 1H), 3.74 (m, pyrrolidin-1-yl-piperidin-1-y1)-1H), 2.96 (m, 2H), 2.65 (m, 2H), 2.22 (m, 11-1), ' I ..",, methanone 1.85 (m, 2H), 1.55 (m, 4H), 1.25 (m, 2H), 0.95 to 0 NH,(m, 2H) re 0........N..õ.1 {446-Amino-5-(2-(300 MHz, CDCI3) 57.95 (d, J = 1.8 Hz, 1H), trliluoromethyl-benzyloxy)-pyridin-3-y1)-phenyl}-(4-1.64 see 7.74(d, J =7.7 Hz, 1H), 7.68 (d, J =7.7 Hz, 1H), examples 7.60 (t, J =7.7 Hz, 1H), 7.48 (m, 5H), 7.14 (d, J

methyl-piperazin-1-yI)-= 1.8 Hz, 1H), 5.35 (s, 2H), 4.89 (br s, 2H), 3.80 i ....' methanone (m, 2H), 3.51 (m, 2H), 2.40 (m, 4H), 2.32 (s, 3H) NH, o o N,rk-(300 MHz, CDCI3) 57.96 (d, J = 1.8 Hz, 1H), 1-(4-{446-Amino-5-(2-7.74 (d, J =7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), trifluoromethyl-benzyloxy)-6.7 pyridin-3-y1]-benzoy1)-examples see mples 7.60 (t, J = 7.7 Hz, 1H), 7.48 (m, 5H), 7.14 (d, J

= 1.8 Hz, 1H), 5.36 (s, 2H), 4.87 (bra, 2H), 3.64 piperazin-1-yI)-ethanone F, 1 ""-r4 (m, 4H), 3.53 (m, 4H), 2.14 (s, 3H) 40 r:iõ
o(300 MHz, CDCI3) 57.98 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 14-01\ 446-Amino-5-(2-7.67 (d, J = 7.6 Hz, 1H), 7.60 (m, 1H), 7.52 (m, trifluoromethyl-benzyloxy)-3.8 see 3H), 7.14 (d, J = 1.8 Hz, 1H), 5.98 (m, 1H), 5.36 pyridin-3-y11-N-(1-methyl-examples (s, 2H), 4.85 (bra, 2H), ), 4.05 (m, 1H), 2.90 (m, ' I N
piperidin-4-y1)-benzamIde 2H), 2.32 (s, 3H), 2.18 (m, 2H), 2.01 (m, 2H), NH, 1.62 (m, 2H) O
it....õ
(300 MHz, CDCI3) 57.98 (d, J = 1.8 Hz, 1H), .
1-..-6 446-Amino-5-(2-7.82 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), trifluoromethyl-benzyloxy)-6.2 see 7.68 (d, J = 7.7 Hz, 1H), 7.60 (tõ J = 7.7 Hz, PYridin-3-y11-N-(2-morpholin-examples 1H), 7.53 (m, 3H), 7.17 (d, J = 1.8 Hz, 1H), 6.83 ,F..:
I
4-yl-ethyl)-benzamide (m, 1H), 5.36 (s, 2H), 4.89 (bra, 2H), 3.74 (m, lir NH.
4H), 3.57 (m, 2H), 2.62 (m, 2H), 2.52 (m, 4H) No.
Structure Name Met IC50 Procedure MS m/z @M)(M+1) , -NC/
(300 MHz, CDCI3) 67.98 (d, J = 1.8 Hz, 1H), 4-16-Amino-5-(2-7.95 (m, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.74 (d, J

IP
trifluoromethyl-benzyloxy)-see = 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.60 (tõ

.
pyridin-3-y1I-N-(3-morpholin-examples J = 7.7 Hz, 1H), 7.53 (m, 3H), 7.17 (d, J = 1.8 it;
. I N

4-yl-propyI)-benzamide Hz, 1H), 5.36 (s, 2H), 4.94 (br s, 2H), 3.75 (m, ...G."
NH, 4H), 3.59 (m, 2H), 2.59 (m, 6H), 1.83 (m, 2H) 4-16-Amino-5-(4-#tertl-butyl-see (400 MHz, DMSO-c15) 6 1.25 (s, 9H, t-butyl), 5.20 benzyloxy)-pyridin-3-y1j-examples (s, 2H, CH2), 5.95 (br s, 2H, NH2), 7.35-8.00 376 (M+) I
benzoic acid (multiplets, 10H, aromatic) NH, <0 (446-Amino-5-(4-tert-butyl-(300 MHz, CDCI3) 67.94 (d, J = 1.7 Hz, 1H), benzyloxy)-pyridin-3-y1j-see 7.49 (m, 8H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s, phenyl}4(2R)-2-pyrrolidin-1-1.89 examples 2H), 4.80 (br s, 2H), 4.48 (m, 1H), 3.48 (m, 2H), ylmethyl-pyrrolidin-1-yI]-methanone 2.62 (m, 4H), 2.2-1.5 (m, 101-1), 1.34 (s, 9H) 0 0 m.c -P
..

(446-Amino-5-(4-tert-butyl-(300 MHz, CDCI3) 67.94 (d, J = 1.7 Hz, 1H), benzyloxy)-pyridin-3-yI]-see 7.49 (m, 8H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s, pheny1)-[(2S)-2-pyrrolidin-1- 3.27 examples 2H), 4.80 (bra, 2H), 4.48 (m, 1H), 3.48 (m, 2H), ylmethyl-pyrrolidin-1-y11-2.62 (m, 4H), 2.2-1.5 (m, 10H), 1.34 (s, 9H) ....,,, methanone _ \
4.16-Amino-5-(4-terf -butyl-(300 MHz, CDCI3) 6 7.94 (d, J = 2.1 Hz, 1H), 7.54 (m, 4H), 7.45 (d, J = 8.3 Hz, 2H), 7.38 (d, J

benzyloxy)-pyridin-3-01-phenyl}-[(3R)-3-4.29 see = 8.3 Hz, 2H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s, examples 2H), 4.84 (br s, 2H), 3.89 (m, 1H), 3.64 (m, 2H), dimethylamino-pyrrolidin-1-1 ' 3.42 (m, 1H), 2.70 (m, 1H), 2.31 (s, 3H), 2.22 (s, , N
yfl-rnethanone iti o 3H), 2.05 (m, 1H), 1.89 (m, 1H), 1.34 (s, 9H) .-(300 MHz, CDCI3) 6 7.93 (d, J = 1.7 Hz, 1H), {416-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yI]-see 7.48 (m, 4H), 7.41 (m, 4H), 7.21 (d, J = 1.7 Hz, 3.8 1H), 5.11 (s, 2H), 4.85 (bra, 2H), 3.80 (m, 2H), phenyl}-(4-methyl-piperazin-examples N
1-yI)-methanone 3.52 (m, 2H), 2.41 (m, 4H), 2.33 (s, 3H), 1.34 (s, * :H, 9H) Cr1.

1-(4-{446-Amino-5-(4-tett-(300 MHz, CDCI3) 67.94 (d, J = 1.8 Hz, 1H), IP
butyl-benzyloxy)-pyridin-3-y11-see 7.50 (m, 8H), 7.21 (d, J = 1.7 Hz, 1H), 5.11 (s, benzoy1)-piperazin-1-y1)-examples 2H), 4.90 (br s, 2H), 3.64 (m, 4H), 3.53 (m, 4H), I ' ethanone 2,14 (s, 3H), 1.34 (s, 9H) Iii0, 41,9 NH, o ¨
--Cil (300 MHz, CDCI3) 67.95 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), ':1 4-(6-Amino-5-(4-tert-butyl-7.44 (d, J = 7.7 Hz, 2H), 7.38 (d, J = 7.7 Hz, 2H), benzyloxy)-pyridin-3-yI]-N-(1-methyl-piperidin-4-yI)-benzamide 2.92 see examples 7.21 (d, J = 1.8 Hz, 1H), 6.05 (m, 1H), 5.11 (s, 2H), 4.80 (br s, 2H), 4.01 (m, 1H), 2.84 (m, 2H), *

NH, 2.33 (s, 3H), 2.20 (m, 2H), 2,10 (m, 2H), 1.62 (m, 2H), 1.34 (s, 9H) No. Structure Name Met 1C60 Procedure MS miz (11M) (M+1) ¨

(300 MHz, CDCI3) 87.95 (d, J = 1.8 Hz, 1H), oxilõ¨e---1 L-' 446-Amino-5-(4-tert-butyl-7.82 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), benzyloxy)-pyridin-3-yll-N-(2- 6.66 see 7.44 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), morpholin-4-yl-ethyl)-examples 7.22 (d, J = 1.8 Hz, 1H), 6.91 (t, J = 4.6 Hz, 1H), uir .-6 benzamide 5.10 (s, 2H), 4.90 (br s, 2H), 3.74 (m, 4H), 3.57 (m, 2H), 2.62 (m, 2H), 2.51 (m, 4H), 1.34 (s, 9H) (300 MHz, CDCI3) 88.01 (t, J = 4.5 Hz, 1H), 7.96 446-Amino-5-(4-tert-butyl-(d, J = 1.8 Hz, 1H), 7.86 (d, J
= 8.3 Hz, 2H), 7.54 benzyloxy)-pyridin-3-yll-N-(3- 6.3 see (d, J = 8.3 Hz, 2H), 7.44 (d, J
= 8.4 Hz, 2H), 7.38 .,, morpholin-4-yl-propyI)-examples (d, J = 8.4 Hz, 2H), 7.24 (d, J = 1.8 Hz, 1H), 5.12 0 benzamide (s, 2H), 4.89 (br s, 2H), 3.74 (m, 4H), 3.59 (m, 2H), 2.55 (m, 6H), 1.82(m, 2H), 1.34 (s, 9H) 1110 446-Amino-5-(2-chloro-4-(400 MHz, DMSO-d6) 85.25 (s, 2H, CH2), 5.80 see fluoro-benzyloxy)-pyridin-3-examples (br s, 2H, NH2), 7.20 - 8.00 (multiplets, 9H, I I --- A-benzoic acid aromatic) 0 N (4-16-Amino-5-(2-chloro-4-(300 MHz, CDCI3) 87.97 (d, J = 1.7 Hz, 1H), fluoro-benzyloxy)-pyridin-3-see 7.52 (m, 6H), 7.20 (m, 1H), 7.05 (m, 1H), 5.21 (s, yli-phenyI}-[(2R)-2-pyrrolidin- 1.48 examples 2H), 4.80 (br s, 2H), 4.45 (m, 1H), 3.52 (m, 2H), 1-ylmethyl-pyrrolidin-1-A-2.76 (m, 4H), 2.2-1.5 (m, 10H) = methanone '-410 a õ NH, F

p 0 µ,-o 0 (446-Amino-5-(2-chloro-4-(300 MHz, CDCI3) 87.97 (d, J = 1.7 Hz, 1H), fluoro-benzyloxy)-pyridin-3-see 7.52 (m, 6H), 7.20 (m, 1H), 7.05 (m, 1H), 5.21 (s, 1-204 lb yli-phenyl}-[(25)-2-pyrrolidin- 2.5 examples 2H), 4.80 (br s, 2H), 4.45 (m, 1H), 3.52 (m, 2H), 1-ylmethyl-pyrrolidin-1 -yIj-2.76 (m, 4H), 2.2-1.5 (m, 10H) . methanone Fio 0 I ''' NH, -j---0 tt.1.%) (446-Amino-5-(2-chloro-4-(300 MHz, CDC13) 87.97 (s, 1H), 7.52 (m, 6H), fluoro-benzyloxy)-pyridin-3-examples 7;20 (m, 1H), 7.04 (m, 1H), 5.21 (s, 2H), 4.95 (br see y1]-pheny1)-[(35)-3-6.1 s 2H), 3.90 (m, 1H), 3.61 (m, 2H), 3.33 (m, 1H), dimethylamino-pyrrolidin-1-2.75 (m, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 2.10 (m, ylj-methanone 1H), 1.89 (m, 1H) = I

140 c) NH, F
_IA

{446-Amino-5-(2-chloro-4-(300 MHz, CDCI3) 87.97 (d, J =
1.8 Hz, 1H), fluoro-benzyloxy)-pyridin-3-1.83 see 7.52 (m, 6H), 7.20 (m, 1H), 7.04 (m, 1H), 5.21 (s, yl[-pheny1)-[(35)-3-amino-examples 211), 4.84 (br s, 2H), 3.84 (m, 4H), 2.15 (m, 1H), ail 0= I pyrrolidin-1-y1]-methanone 1.76 (m, 2H), 1.56 (m, 2H) NH, F Mr =

_ No. Structure Name Met IC Procedure MS m/z (PM) (M+1) _ 0 N(X.

{446-Amino-5-(2-chloro-4-(300 MHz, CDCI3) 67.96 (s, 1H), 7.52 (m, 6H), 10 fluoro-benzyloxy)-pyridin-3-5 see 7.20 (m, 1H), 7.04 (m, 1H), 5.21 (s, 2H), 4.89 (br yll-phenyl}-(4-methyl-examples s, 2H), 3.80 (m, 2H), 3.65 (m, 2H), 2.43 (m, 41-1), ' 1 piperazin-1-yI)-methanone 2.33 (s, 3H) NH, F

tit 0 11....) 1-(4-{446-Amino-5-(2-chloro-(300 MHz, CDCI3) 67.96 (s, 1H), 7.52 (m, 6H), 4-fluoro-benzyloxy)-pyridin-3-see 5.3 7.20 (m, 1H), 7.04 (m, 1H), 5.21 (s, 2H), 4.90 (br y1]-benzoy1}-piperazin-1-y1)-examples s, 2H), 3.67 (m, 4H), 3.53 (m, 4H), 2.22 (s, 3H) = I ,,,, ethanone 0 0 trili F
, L'-'1..."' --10 (300 MHz, CDCI3) 67.99 (d, J = 1.6 Hz, 1H), 446-Amino-5-(2-chloro-4-7.84 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 40 fluoro-benzyloxy)-pyridin-3-see 7.49 (dd, J = 6.0 Hz, 8.5 Hz, 1H), 7.20 (m, 2H), y11-N-(2-morpholin-4-yl-examples 7.04 (m, 1H), 6.82 (m, 1H), 5.22 (s, 2H), 4.85 (br ethyl)-benzamide s, 2H), 3.74 (m, 4H), 3.58 (m, 2H), 2.63 (m, 2H), 11110 NH,2.53 (m, 4H) F

cl 4 NC?
(300 MHz, CDCI3) 68.06 (m, 1H), 7.00 (d, J =
446-Amino-5-(2-chloro-4-1.6 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.55 (d, J =

1-210 fluoro-benzyloxy)-pyridin-3- 5.5 see 8.3 Hz, 2H), 7.49 (dd, J = 6.0 Hz, 8.5 Hz, 1H), yI]-N-(3-morpholin-4-yl-examples 7.20 (m, 2H), 7.04 (m, 1H), 5.22 (s, 2H), 4.85 (br rr,r,4-0 propyI)-benzamide a, 2H), 3.75 (m, 4H), 3.60 (m, 2H), 2.55 (m, 6H), FAN-4' 1.83 (m, 2H) O ON

Sil 446-Amino-5-(2-chloro-3,6-(300 MHz, DMSO-d6) 6 5.21 (s, 2H), 5.71 (s, see 1-211 difluoro-benzyloxy)-pyridin-3- 0.35 examples 2H), 7.31-7.46 (m, 1H), 7.5-7.62 (m, 4H), 7.91-= 1 ."' yI]-benzoic acid 7.94 (m, 3H).

F
mr, F NH, (..'y'' 0 N,....õ) (300 MHz, CDCI3) 07.97 (d, J = 1.6 Hz, 1H), (4-[6-Amino-5-(2-chloro-3,6-examples 7.56 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 1-212 1161 difluoro-benzyloxy)-pyridin-3- 0.063 7.35 (d, J = 1.6 Hz, 1H), 7.20 (m, 1H), 7.06 (m, see yij-pheny1)-(4-methyl-.
1H), 5.29 (a, 211), 4.81 (bra, 2H), 3.79 (m, 211), F 0 , N 1 piperazin-111)-methanone 3.54 (m, 2H), 2.44 (m, 4H), 2.33 (s, 3H) 411115-P F NH, 0,13 (300 MHz, CDCI3) 67.97 (d, J = 1.7 Hz, 111), (446-Amino-5-(2-chloro-36-7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), difluoro-benzyloxy)-pyridin-3-see 7.35 (d, J = 1.6 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 0049.
y1]-phenyl}-(4-pyrrolidin-1-yl-examples 1H), 5.29 (s, 2H), 4.79 (br s, 2H), 4.60 (m, 1H), piperldin-1-y1)-methanone 3.85 (m, 1H), 3.02 (m, 2H), 2.65 (m, 4H), 2.35 F F NH, (m, 1H), 2.05 (m, 4H), 1.65 (m, 4H).

_ ,.......NH., 0 11........) MS (ES+) (446-Amino-5-(2-chloro-3,6-(400 MHz, DMSO-d6) 67.92 (s, 1H), 7.66 (m, m/z 543 * difluoro-benzyloxy)-pyridin-3-see 4H), 7.46 (m, 4H), 5.89 (s, 2H), 5.39 (s, 2H), 4.19 (MH+).
1-214 y1]-phenyl}-(4-amino- 0.1 examples (m, 1H), 3.50 (m, 2H), 2.54 (m, 5H), 1.95 (m, MS m/z F ..... , N piperidin-1-yI)-methanone 2H), 1.83 (m, 3H), 1.64 (m, 4H) [M+11 W F . H2 No. Structure Name Met 1C60 Procedure MS m/z (PM) (M+1) - -ricv1H

0 N..,....õ),,, (400 MHz, DMSO-d6) 57.98 (s, 1H), 7.58 (d, 2H), (4-16-Amino-5-(2-chloro-3,6-7.41 (d, 2H), 7.31 (s, 1H), 7.19 (m, 1H), 7.06 (m, difluoro-benzyloxy)-pyridin-3-see 1-215 40 yll-phenyl)-(3,5-dimethyl- 0.1 examples 1H), 5.31 (s, 211), 4.81 (m, 2H), 4.68 (m, 1H), 3.69 (m, 1H), 2.89 (in, 2H), 2.69 (m, 1H), 2.40 piperazin-1-yI)-methanone F õI , = 0 I N

(m, 111), 1.74 (m, 1H), 1.18 (d, 6H) NH, F

0 (446-Amino-5-(2-chloro-3,6--o (400MHz, DMSO-d6) 57.95 (d, 111), 7.69 (d, 2H), difluoro-benzyloxy)-pyridin-3-see 7.58 (m, 211), 7.50 (d, 2H), 7.40 (m, 1H), 5.81 (s, 1-216 y11-pheny1)-[(2S)-2-pyrrolidin- 0.1 examples 2H), 5.29 (s, 2H), 4.35 (m, 1H), 3.5 (d, 2H), 2.87 110 1-ylmethyl-pyrrolidin-1-yI]-(d, 2H), 2.71 (d, 2H), 1.7-2.0 (m, 10H) methanone F 0 . 0 . NI

F NH' \

O N (4-[6-Amino-5-(2-chloro-3,6-(400 MHz, DMSO-d6) 57.97 (s, 1H), 7.60 (m, difluoro-benzyloxy)-pyridin-3-4H), 7.32 (s, 1H), 7.18 (m, 1H), 7.04 (m, 1H), see 1-217 yll-phenyl)-[(3S)-3- 0.12 examples 5.31 (s, 2H), 4.78 (m, 2H), 3.90 (m, 111), 3.68 (m, dimethylamino-pyrrolidin-1-2H), 3.41 (m, 1H), 2.78 (m, 1H), 2.31 (s, 3H), I y11-methanone 2.24 (s, 311), 2.08 (m, 1H), 1.84 (m, 1H) F difit. I ,ri WI r NH, prt, {446-Amino-5-(2-chloro-3,6-(400 MHz, DMSO-d6) 57.84 (s, 1H), 7.62 (m, difluoro-benzyloxy)-pyridin-3-see 5H), 7.35 (m, 1H), 7.20 (m, 1H), 5.38 (s, 2H), 0.053 yll-phenyl}-[(3R)-3-amino-examples 3.78 (m, 3H), 3.55 (m, 1H), 3.41 (m, 1H), 2.18 . pyrrolidin-1-yll-methanone (m, 1H), 1.82 (m, 1H) 0 , N
F*
F NH, jIH, (446-Amino-5-(2-chloro-3,6-400 MHz, DMSO-d6) 57.84 (s, 1H), 7.62 (m, 51-1), difluoro-benzyloxy)-pyridin-3-see 7,35 (m, 1H), 7.20 (m, 1H), 5.38 (a, 2H), 3.78 (m, 459 0.095 yli-phenyl}--[(3S)-3-amino-examples 3H), 3.55 (m, 1H), 3.41 (m, 1H), 2.18 (m, 1H), pyrrolidin-1-yll-methanone 1.82 (m, 1H) F = I

* , NH, _ = 1:1,,, (400 MHz, DMSO-d6) 57.97 (s, 1H), 7.80 (d, 2H), 40 446-Amino-5-(2-chloro-3,6-7.58 (d, 2H), 7.36 (s, 1H), 7.18 (m, 1H), 7.04 (m, difluoro-benzyloxy)-pyndin-3-see 0.11 1H), 6.01 (d, 1H), 5.28 (s, 2H), 4.78 (s, 2H), 3.98 y11-N-(1-methyl-piperidin-4-examples . I
(m, 1H), 2.85 (m, 2H), 2.31 (s, 3H), 2.18 (t, 2H), F Alb 0 ...- yI)-benzamide 2.10 (m, 211), 1.65 (m, 2H) 41-0 F NH' o L*0 446-Amino-5-(2-chloro-3,6-(400 MHz, DMSO-d6) 57.98 (s, 1H), 7.89 (d, 2H), 40 difluoro-benzyloxy)-pyridin-3-see 7.56 (d, 2H), 7.45 (m, 1H), 7.31 (s, 1H), 7.17 (m, 0.18 yl-N-(2-pyrrolidin-1-yl-ethyl)-examples 1H), 7.01 (m, 111), 5.28 (s, 2H), 4.85 (s, 2H), 3.65 F AL , N benzamide (m, 2H), 2.89 (t, 2H), 2.76 (m, 4H), 1.89 (m, 4H) IP F e NH, . 1(../.......0 446-Amino-5-(2-chloro-3,6-(400 MHz, DMSO-d6) 58.72 (m, 1H), 7.95 (m, difluoro-benzyloxy)-pyridin-3-see 3H), 7.57 (d, 2H), 7.35 (s, 1H), 7.18 (m, 11-1), 7.02 0.19 yll-N-(3-pyrrolidin-1-yl-examples (m, 1H), 6.31 (s, 2H), 4.79 (s, 2H), 3.68 (m, 2H), F ,. 0...-11 propyI)-benzamide 2.89 (m, 6H), 1.97 (m, 6H) Mg. F NH.

, , No.
Structure Name Met 1C50 Procedure MS in&

(Mil) ---' i IP
.-- 446-Amino-5-(2-chloro-3,6-(400 MHz, DMSO-d5) 57.97 (s, 1H), 7.82 (d, 2FI), difluoro-benzyloxy)-pyridin-3- 0.165 see 7.62 (d, 2H), 7.36 (s, 1H), 7.18 (m, 1H), 7.05 (m, =
y1]-N-(2-morpholin-4-yl-examples 1H), 6.81 (m, 1H), 5.28 (s, 2H), 4.79 (s, 2H), 3.78 F
= ..,.

....N
ethyl)-benzamide (m, 4H), 3.58 (m, 2H), 2.63 (t, 2H), 2.51 (m, 4H) 1W. F
NH' _ -(400 MHz, DMS0-(15) 58.04 (m, 1H), 7.96 (s, 446-Amino-5-(2-chloro-3,6-1H), 7.89 (d, 2H), 7.58 (d, 2H), 7.38 (s, 1H), 7.18 difluoro-ben 0.28 zyloxy)-pyridin-3-see (m' 1H), 7.06 (m, 1H), 7.29 (s, 2H), 4.81 (s, 2H), yll-N-(3-morpholin-4-yl-examples 3.76 (m, 4H), 3.61 (m, 2H), 2.59 (t, 2H), 2.54 (m, propyI)-benzamide 4H), 1.79 (m, 2H) N6C,IL
i 346-Amino-5-(2-chloro-3,6-(300 MHz, CDCI3) 6 8.15 (s, 1H), 7.92 (s, 1H), I*
ohl difluoro-benzyloxy)-pyiidin-3- 3.7/0.6 7.84 (d, J = 7.4 Hz, 1H), 7.60 (m, 2H), 7.55 (s, examples see A-benzoic acid 1H), 7.40 (m, 2H), 5.75 (s, 2H), 5.31 (br s, 2H) -.
I
F , 11,õ.
= N

(300 MHz, CDCI3) 57.96 (d, J = 1.7 Hz, 1H), {346-Amino-5-(2-chloro-3,6-7.58 (dd, J = 1.1 Hz, 6.8 Hz, 1H), 7.46 (m, 1H), F
N, difluoro-benzyloxy)-pyridin-3- 0.068 see 7.35 (m' 3H), 7.20 (m, 1H), 7.06 (m, 1H), 5.27 (s, .
I
yll-phenyl}-(4-methyl-examples 2H), 4.81 (br s, 2H), 3.83 (m, 2H), 3.50 (m, 2H), F 411,1. o 'N
piperazin-1-y1)-methanone IP
NH, 2.49 (m, 2H), 2.39 (m, 2H), 2.33 (s, 3H) F

(300 MHz, CDCI3) 57.96 (d, J = 1.8 Hz, 1H), =-tn {346-Amino-5-(2-chloro-3,6-7.57 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.45 (t, J = 7.6 '' difluoro-benzyloxy)-pyridin-3- 0.05 see Hz, 1H), 7.34 (m, 3H), 7.20 (m, 1H), 7.06 (m, 1-227 r 4.õ. . I ri yll-pheny1)-(4-pyrroliclin-1-yl-examples 1H), 5.27 (s, 2H), 4.77 (br a, 2H), 4.60 (m, 1H), Jr r NH
piperidin-1-y1)=methanone 3.80 (m, 1H), 3.02 (m, 2H), 2.60 (m, 2H), 2.30 (m, 1H), 9.95 (m, 2H), 1.85 (m, 4H), 1.65 (m, 4H) ,., ta {3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3- 0.23 see (300 MHz, CD-30D) 6 8.01 (s, 1H), 7.89 (s, 1H), 7.75 (m, 2H), 7.59 (s, 1H), 7.48 (t, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 5.38 (s, 2H), 4.01 (m, 1H), y1I-pheny1)-(4-amino-examples F
a N
3.09 (m, 2H), 2.68 (t, 2H), 1.97 (m, 2H), 1.58 (m, piperldin-1-y1)-methanone F NH, 2H) =1 (300 MHz, CDCI3) 57.96 (d, J = 1.7 Hz, 1H), Mr lyNH {346-Amino-5-(2-chloro-3,6-7.56 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.36 (m, difluoro-benzyloq)-pyridin-3- 0.066/
see 3H), 7.20 (m, 1H), 7.06 (m, 1H), 5.27 (s, 2H), =

r nal. 0 -÷
A-phenyl}-(3,5-dimethyl-0.18 examples 4.62 (br s, 2H), 4.66(m, 1H), 3.65(m, 1H), 3.90 111, F
NH, piperazin-1-yI)-methanone (m, 2H), 2.70 (m, 1H), 2.40 (m, 1H), 1.97 (m, 1H), 1.15 (d, 3H), 0.99 (d, 3H) {346-Amino-5-(2-chloro-3,6-(300 MHz, CDCI3) 57.96 (d, J = 1.7 Hz, 1H), IP

difluoro-benzyloxy)-pyridin-3-7.66 (s, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.45 (m, ....
yll-pheny1)-[(2S)-2-pyrrolidin-0.19 exaseerrinles 2H), 7.36 (d, J = 1.7 Hz, 1H), 7.20 (m, 1H), 7.06 r...6c. ...N
1-ylmethyl-pyrrolidin-1-y11-r (m, 1H), 5.27 (s, 2H), 4.78 (br s, 2H), 4.42 (m, , NH, methanone 1H), 3.45 (m, 2H), 2.68 (m, 4H), 2.2-1.5 (m, 10H) 1 io ND-< {346-Amino-5-(2-chloro-3,6-(300 MHz, CDCI3) 57.96 (s, 1H), 7.68 (d, J = 7.4 I
Hz, 1H), 7.59 (m, 1H), 7.44 (m, 2H), 7.36 (s, 1H), difluoro-benzyloxy)-pyridin-3-see 7.20 (m, 1H), 7.06 (m, 1H), 5.27 (s, 2H), 4.80 (br i i -'-A-phenyI)-[(3S)-3-0.128 F
Al examples s, 2H), 3.90 (m, 1H), 3.61 (m, 2H), 3.41 (m, 1H), dimethylamino-pyrrolidin-1-NH, 2.77 (m, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 2.10 (m, F
yll-methanone 1H), 1.82 (m, 1H) i {3-[6-Amino-5-(2-chloro-3,6-(300 MHz, CD30D) 57.86 (s, 1H), 7.75 (m, 2H), difluoro-benzyloxy)-pyridin-3-see 7.58 (m, 3H), 7.38 (m, 1H), 7.22 (m, 1H), 5.38 (s, 0.12 y1I-phenyl)-[(3R)-3-amino-examples 2H), 4.00-3.56 (m, 5H), 2.40 (m, 1H), 2.12 (m, F
NH' pyrrolidin-1-y1)-methanone 1H) No.
Structure Name Met 1C50 Procedure MS miz (11M) (M+1) 0===NH, (346-Amino-5-(2-chloro-3,6-(300 MHz, CD30D) 67.86 (s, 1H), 7.75 (m, 2H), difluoro-benzyloxy)-pyridin-3-see 7.58 (m, 3H), 7.38 (m, 1H), 7.22 (m, 1H), 5.38 (s, (-233 0.12 F
y11-pheny1}-[(3S)-amino-examples 2H), 4.00-3.56 (m, 5H), 2.40 (m, 1H), 2.12 (m, ,6c 0 l'ii'j'2 pyrrolldin-1-y1)-methanone 11-1).
(300 MHz, CDCI3) 67.96 (d, J = 1.7 Hz, 1H), 11-Cf 346-Amino-5-(2-chloro-3,6-7.94(s, 1H), 7.64(m, 2H), 7.47(t, J = 7.7 Hz, difluoro-benzyloxy)-pyridin-3-see 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.20 (m, 1H), 7.06 0.23 yli-N-(1-methyl-piperidin-4-examples (m, 1H), 6.25 (m, 1H), 5.27 (s, 2H), 4.81 (br s, yI)-benzamide 2H), 3.99 (m, 1H), 2.84 (m, 2H), 2.30 (s, 3H), 2.16 (m, 2H), 2.04 (m, 2H), 1.64 (m, 2H) (300 MHz, CDCI3) 68.02 (s, 1H), 7.96 (d, J = 1.7 Fr--3-(6-Amino-5-(2-chloro-3,6-Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.8 difluoro-benzyloxy)-pyridin-3- 0.
see Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 1.7 1-235 F. 1 -'m yfl-N-(2-pyrrolidin-1-yl-ethyl)-examples Hz, 1H), 7.20 (m, 2H), 7.06 (m, 1H), 5.27 (s, 2H), NH, benzamide 4,83 (br s, 2H), 3.61 (m, 2H), 2.77 (m, 2H), 2.62 (m, 4H), 1.81 (m, 4H) ,...)..1.11.,-..,0 (300 MHz, CDCI3) 68.78 (m, 1H), 8.04 (d, J =
1.6 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.68 (d, J =
346-Amino-5-(2-chloro-3,6-F

r4 7.7 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.45 (t, J =
see (-236 difluoro-benzyloxy)-pyridin-3- 0.28 7.7 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.20 (m, ylj-N-(3-pyrrolidin-1-yl-examples 1H), 7.06 (m, 1H), 5.29 (s, 2H), 4.77 (bra, 2H), propyI)-benzamide 3.61 (m, 2H), 2.77 (m, 2H), 2.66 (m, 4H), 1.87 (m, 2H), 1.80 (m, 4H) (300 MHz, CDCI3) 57.99 (t, J = 1.5 Hz, 1H), 7.97 346-Amino-5-(2-chloro-3,6-(d, J = 1.8 Hz, 1H), 7.66 (m, 2H), 7.49 (t, J = 7.7 difluoro-benzyloxy)-pyridin-3-see 0.35 Hz' 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.20 (m,11-1), yll-N-(2-morpholin-4-yl-examples 7.06 (m, 2H), 5.27 (s, 2H), 4.85 (bra, 2H), 3.72 F.41113 ethyl)-benzamide (m, 4H), 3.59 (m, 2H), 2.63 (m, 2H), 2.52 (m, 4H) (300 MHz, CDCI3) 68.02 (m, 2H), 7.97 (d, J =
-1.1.
1-238 ,i.,---. -,,, 14.-,....õ.,1 346-Amino-5-(2-chloro-3,6-1.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.65 (d, J
difluoro-benzyloxy)-pyridin-3- 0.35 =
see 8,3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.38 (d, J =

yI)-N-(3-morpholin-4-yl-examples 1,8 Hz, 11-1), 7.19 (m, 1H), 7.06 (m, 1H), 5.27 (s, propyI)-benzamide 2H), 4.81 (br s, 2H), 3.66 (m, 4H), 3.59 (m, 2H), 2.55 (m, 2H), 2.49 (m, 4H), 1.81 (m, 2H) r....,,,k N-[2-(4-Acetyl-piperazin-1-(300 MHz, CDCI3) 58.00 (s, 1H), 7.86 (s, 1H), ------,---' y1)-ethyl]-3-16-amino-5-(2-7.67 (dd, 2H), 7.56 (t, 1H), 7.48 (s, 1H), 7.21 (m, see (-239 chloro-3,6-difluoro-0.1 examples 1H), 7.08 (m, 1H), 6.02 (br s, 2H), 5.39 (s, 2H), benzyloxy)-pyridin-3-yI]-benzamide 3.75 (m, 4H), 3.60 (m, 2H), 2.79 (m, 2H), 2.60 (m, 4H), 2.11 (s, 3H) o=-=-'$) tip 3-(2-Chloro-3,6-diflUoro-(400 MHz, DMSO-d3) 67.88 (s, 1H), 7.62 (d, 2H), (240 benzyloxy)-5-14-(1,1-dioxo-0.1 see 7.56 (m, 1H), 7.51 (s, 1H), 7.40 (m, 1H), 7.23 (d, ----.
1X5-isothiazolidin-2-yI)-examples 2H), 5.70 (s, 2H), 5.28 (s, 2H), 3.76 (t, 2H), 3.49 I .14 phenyl)-pyridin-2-ylamine (t, 2H), 2.41 (t, 2H) NH
N
F
cf.-51"

IP
3-(2,6-Dichloro-benzyloxy)-5-(4-(1,1-dioxo-12, 0.067 ,e-see isothiazolidin-2-y1)-phenyll-examples =

I ..' pyridin-2-ylamine o 'N
410) a =

No. Structure Name Met 1C60 Procedure 1H-NMR MS m/z (1-IM) (M+1) -o- ,N

5-[4-(1,1-Dioxo-1k6-1101 isothiazolidin-2-y1)-phenyl]-3-see 0.14 =

, -.. (2-fluoro-6-trifluoromethyl-examples I ,N benzyloxy)-pyridin-2-ylamine CF

Hnrk=kr"-(300 MHz, CDCI3) 67.92 (d, J = 1.8 Hz, 1H), I-, 2-Diethylamino-7.48 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 1.8 Hz, 1H), * ethanesulfonic acid {4-16-see 7.24 (m, 3H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 1-243 amino-5-(2-chloro-3,6-0.043 examples 2H), 4.70 (br s, 2H), 3.22 (t, J = 6.1 Hz, 2H), 3.04 1 ` difluoro-benzyloxy)-pyridin-3-(t, J = 6.1 Hz, 2H), 2.65 (q, J = 7.1 Hz, 4H), 1.10 110# a NH, yll-pheny1}-amide (t, J = 7.1 Hz, 6H) ft A

H -0R-----y-2-Cyclopropylamino-(300 MHz, CDCI3) 87.92 (d, J = 1.8 Hz, 1H), 0 ethanesulfonic acid (4-[6-7.48 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 1.8 Hz, 1H), see 1-244 amino-5-(2-chloro-3,6-0.081 examples 7.24 (m, 3H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 509 difluoro-benzyloxy)-pyridin-3-2H), 4.75 (br s, 2H), 3.25 (s, 4H), 2.17 (m, 1H), iii 0 ' N
a NH, yll-pheny1}-amide 0.9 (m, 1H), 0.50 (m, 2H), 0.40 (m, 2H) F

W

H
V 2-Pyrrolidin-1-yl-(300 MHz, CDCI3) 87.92 (d, J = 1.8 Hz, 1H), 110 ethanesulfonic acid {446-7.48 (d, J = 8.5 Hz, 2H), 7.31 (d, J =1.8 Hz, 1H), see 1-245 amino-5-(2-chloro-3,6-0.082 examples 7.24 (m, 3H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 523 I'-' difluoro-benzi.iloxy)-pyridin-3-2H), 4.72 (bra, 2H), 3.27 (m, 2H), 3.06 (m, 2H), .., N

yli-phenyl}-amide 2.59 (m, 4H), 1.86 (m, 4H) 110 : NH, 1' R
(300 MHz, CDCI3) 87.92 (d, J = 1.8 Hz, 1H), " -g9 2-(4-Hydroxy-piperidin-1-yI)-7.48 (d, J = 8.5 Hz, 2H), 7.32 (m, 2H), 7.24 (m, 0. ethanesulfonic acid (4-(6-see 2H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 2H), 1-246 amino-5-(2-chloro-3,6-0.135 examples 4.74 (br s, 2H), 3.81 (m, 1H), 3.31 (t, 2H), 2.98 (t, I ' difluoro-benzylm)-pyridin-3-At 0 -"
2H), 2.85 (m, 2H), 2.32 (m, 2H), 1.98 (m, 2H), yn-phenyl}
illir c, NH, 1.58 (m, 3H) F

2-Morpholin-4-yl-(300 MHz, DMSO-d6) 6 9.80 (br s, 1H), 7.89 (d, J

ethanesulfonic acid {446-= 1.6 Hz, 1H), 7.59 (m, 3H), 7.52 (d, J = 1.6 Hz, see 1-247 amino-5-(2-chloro-3,6-0.31 examples 1H), 7.26 (d, .1= 8.6 Hz, 2H), 5.72 (br s, 2H), 539 difluoro-benzyloxy)-pyridin-3-5.28 (s, 2H), 3.49 (m, 4H), 3.28 (t, 2H), 2.69 (t, ici 0 1.:H, yll-phenyl)-amide 2H), 2.31 (m, 4H) F

R

H l'-'-'0 .
2-Pipendin-1-yl-(300 MHz, CDCI3) 67.93 (d, J = 1.8 Hz, 1H), * ethanesulfonic acid {446-see 7.48 (d, J = 8.5 Hz, 2H), 7.30 (m, 2H), 7.24 (m, 1-248 amino-5-(2-chloro-3,6-0.114 examples 2H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 2H), 537 difluoro-benzyloxy)-pyridin-3-4.70 (bra, 2H), 3.25 (t, 2H), 2.92 (t, 2H), 2.52 (m, . .... N

y1]-phenyl}
4H), 1.85 (m, 4H), 1.63 (m, 2H) 1: ::C: NH, F

f?

H -g.---,N--I 2-Dimethylamino-(300 MHz, CDCI3) 67.92 (d, J = 1.8 Hz, 1H), ethanesulfonic acid (446-7.48 (d, J = 8.5 Hz, 2H), 7.30 (m, 2H), 7.24 (m, see 1-249 amino-5-(2-chloro-3,6-0.098 examples 2H), 7.20 (m, 1H), 7.07 (m, 1H), 5.28 (s, 2H), 497 F difluoro-benzyloxy)-pyridin-3-4.71 (br s, 2H), 3.20 (t, 2H), 2.88 (t, 2H), 2.32 (s, ihi 0 I . N yll-phenyl}
6H) NN
a ,-, No.
Structure Name Met 1C50 Procedure MS rnik (MM) (M+1) .
=
' co....., 2-(4-Acetyl-piperazin-1-yI)- ethanesulfonic acid {446-(300 MHz, CDCI3) 67.92 (d, J = 1.8 Hz, 111), 7.48 (d, J = 8.5 Hz, 211), 7.30 (m, 2H), 7.24 (m, N I

see 1H), 7.20 (m, 1H), 7.07 (m, 2H), 5.28 (s, 2H), amino-5-(2-chloro-3,6-0.42 "
difluoro-benzyloxy)-pyridin-3-examples 4.80 (br s, 2H), 3.65 (m, 2H), 3.48 (m, 2H), 3.32 NH, yli-phenyl} 1-c. I
(t, 2H), 2.94 (t, 2H), 2.50 (m, 21-1), 2.46 (m, 211), Cc:
2.10 (s, 3H) H i''''...1r,7 2-(Cyclopropylmethyl-amino) (300 MHz, CDCI3) 67.94 (s, 111), 7.48 (m, 2H), AO
ethanesulfonic acid (446.
see 7.31 (m, 3H), 7.21 (m, 1H), 7.18 (m, 1H), 5.28 (s, amino-5-(2-chloro-3,6-0.075 , examples 2H), 4.75 (s, 2H), 3.23 (m, 4H), 2.58 (m, 2H), difluoro-benzyloxy)-pyridin-3-1.00 (m, 1H), 0.56 (m, 211), 0.18 (m, 2H) CCi .
'-' yli-phenyl}-amide I?
H1;'0...0" 2-[(3R)-3-Hydrory-pyrrolidin-(300 MHz, CDCI3) 67.92 (s, 111), 7.43 (m, 211), 1-y11-ethanesulfonic acid {4-see examples 7.31 (m, 3H), 7.19 (m, 1H), 7.05 (m, 1H), 6.28 (s, [6-amino-5-(2-chloro-3,6-0.125 2H), 4.75 (s, 211), 4.45 (m, 1H), 3.29 (m, 2H), difluoro-benzyloxy)-pyridin-3-3.10 (m, 3H), 2.88 (m, 1H), 2.61 (m, 111), 2.30 --"
yll-phenyl}-amide (m, 2H), 1.89 (m, 211) "", F
-H -g-----O 2-[(2S)-2-Hydroxymethy1-pyrrolidin-1-y11-ethanesulfonic acid {446-(300 MHz, CDCI3) 67.89 (s, 1H), 7.45 (m, 2H), 7.30 (m, 3H), 7.21 (m, 1H), 7.08 (m, 1H), 5.31 (s, =

0.097 see amino-5-(2-chloro-3,6-examples 2H), 4.78 (s, 211), 3.55 (m, 2H), 3.36 (t, 1H), 3.11 I "
difluoro-benzyloxy)-pyridin-3-(m, 2H), 2.69 (m, 2H), 2.21 (m, 1H), 1.89 (m, 6H) IP .
NH, yli-phenyl}-amide F

.1,-^y.Th 244-(2-Hydroxy-acety1)-*
'--".-r piperazin-1-y11-OH ethanesulfonic acid {446-(300 MHz, DMS0-(15) 6 9.81 (s, 1H), 7.89 (s, 1H), 7.58 (d, 211), 7.50 (s, 1H), 7.39 (m, 211), 7.24 (d, 0.18 see 1 ' amino-5-(2-chloro-3,6-examples 2H), 5.75 (s, 2H), 5.28 (s, 2H), 4.54 (t, 1H), 4.01 .
, N
difluoro-benzyloxy)-pyridin-3-(d, 2H), 3.29 (m, OH), 2.79 (t, 211), 2.36 (m, 4H) NH, y1]-phenylyamide F
Nr l= 2-(4-Acetyl-piperazin-1-yI)-a, ...õ..7 ethanesulfonic acid {3-[6-(300 MHz, CDCI3) 62.02 (s, 3H), 2.30 (m, 4H), see 2.95 (m, 411), 3.35 (m, 4H), 3.55 (m, 2H), 5.30 (d, 1-255 _5 amino-5-(2-chloro-3,6-0.68 emmples 2H), 5.42 (s, 211), 7.05 (m, 1H), 7.20 (m, 1H), 'T......,, .., di11uoro-bensyloxy)-pyridin-3-7.35 (m, 5H), 8.00 (d, 1H), 10.17 (s, 1H) y1]-phenyl}amide 111---,TO 2-Pyrrolidin-1-yl-(300 MHz, CDCI3) 6 1.60-1.80 (m, 4H), 2.40-2.55 ethanesulfonic acid {3-[6-(m, 4H), 3.02 (t, J = 6.6 Hz, 211), 3.29 (t, J = 6.6 k, : =$:.
amino-5-(2-chloro-3,6-0.23 see examples Hz, 2H), 5.08 (s, 2H), 5.29 (d, J = 1.3 Hz, 2H), F
. N

difluoro-benzyloxy)-pyridin-3-6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.25-7.45 yll-phenyl}-amide (m, 5H), 7.97 (d, J = 1.7 Hz, 1 H) (300 MHz, CDCI3) 6 2.42 (t, J = 4.6 Hz, 4H), 2.90 p3 0 2-Morpholin-4-yl-ethanesulfonic acid {346-(t, J = 6.9 Hz, 2H), 3.31 (t, ..1 = 6.9 Hz, 2H), 3.62 see (t, J = 4.6 Hz, 4H), 5.24 (s, 2H), 5.30 (d, J = 1.3 amino-5-(2-chloro-3,6-1.64 examples Hz, 2H), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), õ, fl difluoro-benzyloxy)-pyridin-3-7.30-7.45 (m, 511), 7.99 (d, J = 1.6 Hz, 1H), 9.38 ..4 yll-phenyl}amide (s, 1H) q ft r -g 2-Diethylamino----- ......--(300 MHz, CDCI3) 6 1.00 (t, 6H), 2.52 (q, 4H), ethanesulfonic acid {3-[6-see 3.02 (t, 2H), 3.25 (t, 2H), 5.19 (s, 2H), 5.29 (d, amino-5-(2-chloro-3,6-1.67 examples 211), 7.05 (m, 1H), 7.20 (m, 1H), 7.35 (m, 5H), , . "

difluoro-benzyloxy)-pyridin-3-F

y1]-phenylyamide 7.98 (d, 111) 2-Dimethylamino-.
_.-- 1 ethanesulfonic acid {346-(300 MHz, CDC13) 6 2.24 (s, 611), 2.85 (t, 2H), amino-5-(2-chloro-3,6-1.5 3.24 (t, 2H), 5.11 (s, 211), 5.29 (d, 2H), 7.07 (m, examples see F
N
difluoro-benzyloxy)-pyridin-3-111), 7.15 (m, 1H), 7.35 (m, 511), 7.98 (d, 1H) is, F 0 NH, y1]-phenyl}
......

No. Structure Name Met 1C53 Procedure MS rdz I

(PM) (M+1) -_ p.9 0 2-Piperidin-1-yl-(300 MHz, CDCI3) 61.30-1.60 (m, 6H), 2.30-2.45 g ethanesulfonic acid {346-(m, 4H), 2.89 (t, J = 6.7 Hz, 2H), 3.28 (t, J = 6.7 see 1-260 amino-5-(2-chloro-3,6- 1.63 Hz, 2H), 5.13(s, 2H), 5.29 (d, J = 1.4 Hz, 2H), exa mples Zi: difluoro-benzyloxy)-pyridin-3-6.95-7.05 (m, 1H), 7.15-7.45 (m, 6H), 7.98 (d, J

y1]-phenyl)amide = 1.6 Hz, 1H) _ 2-[(3R)-3-Hydroxymethyl-(300 MHz, CDC13) 6 1.60-1.8 (m, 4H), 2.05-2.15 pyrrolidin-1-y11-(m, 1H), 2.55-2.75 (m, 2H), 2.95-3.15 (m, 2H), ethanesulfonic acid (346-see 3.25-3.55 (m, 3H), 3.82 (dd, J = 3.0, 11.2 Hz, 1.7 amino-5-(2-chloro-3,6-examples 1H), 4.97 (s, 2H), 5.28 (d, J = 1.6 Hz, 2H), 6.98-., difluoro-benzyloxy)-pyridin-3-7.08 (m, 1H), 7.10-7.20 (m, 1H), 7.25-7.45 (m, y1I-pheny1}-amide 5H), 7.98 (d, J=1.8 Hz, 1H) ,,,,,..
N 9,,A) 2-(4-Hydroxy-piperidin-1-y1)-(300 MHz, DMSO-d6) 6 1.15-1.30 (m, 2H), 1.45-ethanesulfonic acid (346-1.55 (m, 2H), 1.90-2.02 (m, 2H), 2.50-2.70 (m, sexamples ee 1-262 amino-5-(2-chloro-3,6- 1.5 4H), 4.49 (brs, 1H), 5.28 (s, 2H), 5.82 (s, 2H), , -1.- 1 difluoro-benzyloxy)-pyridin-3-7.05-7.10 (m, 1H), 7.20-7.40 (m, 5H), 7.45-7.60 yli-phenyl}amide (m, 1H), 7,83 (d, J = 1.6 Hz, 1H) 244-(2-Hydroxy-acetyl)-(300 MHz, CDCI3) 6 2.36 (m, 4H), 2.92 (t, 2H), piperazin-1-y11-3.14 (m, 2H), 3.32 (t, 2H), 3.54 (m, 2H), 3.60 (br ethanesulfonic acid (346-see 1-263 , 1.14 s, 1H), 4.07 (s, 2H), 5.30 (s, 2H), 5.40 (br s, 2H), amino-5-(2-chloro-3,6-examples 7.06 (m, 1H), 7.24 (m, 2H), 7.34(m, 2H), 7.44 (m, difluoro-benzyloxy)-pyridin-3-2H), 7.99 (d, J = 1.6 Hz, 1H), 9.88 (br s, 1H) yll-phenyl}amide . - g.
(300 MHz, CDC13) 6 1.65 (m, 1H), 2.08 (m, 1H), M....0 2-[(3R)-3-Hydroxy-pyrrolidin-2.22 (m, 1H), 2.46 (m, 1H), 2.76 (m, 1H), 2.87 1-yll-ethanesulfonic acid (3-see (m, 1K), 3.02 (m, 2H), 3.32 (m, 2H), 4.28 (m, 1-264 [6-amino-5-(2-chloro-3,6- 1.097539 ,...1.5c$::, examples 1H), 5.28 (br s, 2H), 5.29(s, 2H), 7.06(m, 1H), difluoro-benzyloxy)-pyridin-3-7.24 (m, 2H), 7.44(m, 5H), 8.00 (d, J = 1.7 Hz, yll-phenyiyamide 1H) , r-A 2-(Cyclopropylmethyl-amino).
(300 MHz, CDCI3) 6 0.02 (m, 2H), 0.39 (m, 2H), ,, Q 14.51m. r A ethanesulfonic acid {346-0.84 (m, 1H), 2.40 (d, 2H), 3.14 (t, 2H), 3.32 (t, see 1-265 amino-5-(2-chloro-3,6- 1 examples 2H), 5.28(s, 2H), 5.38 (br s, 2H), 7.06(m, 1H), difluoro-benzyloxy)-pyridin-3-7.24 (m, 2H), 7.44(m, 5H), 8.00 (d, J = 1.7 Hz, NI, yll-phenyl)amide 1H) _ 2-Cyclopropylamino-(300 MHz, CDCI3) 00.28 (m, 2H), 0.37 (m, 2H), Z 1 ethanesulfonic acid (346-see 2.06 (m, 1K), 3.15-3.40 (m, 4H), 5.30 (d, 2H), 1-266 amino-5-(2-chloro-3,6- 0.9 , examples 5.39 (s, 2H), 7.07 (m, 1H), 7.19 (m, 1H), .1 7.30-difluoro-benzyloxy)-pyridin-3-7.55 (m, 5H), 8.01 (d, 1H) yll-phenyl}amide ¨
3-(2-Chloro-3,6-difluoro-..

ioI N. benzyloxy)-5-(2-dimethylaminomethyl-see 0 ,I1I '' 17A phenyl)-pyridin-2-ylamine;
examples compound with trifluoro-IP ci Nt-I
acetic acid F

40 0 3-(2-Chloro-3,6-difluoro-(400 MHz, DMSO-c16) 51.94 (t, 4H), 3.31 (t, 4H), benzyloxy)-5-(3-pyrrolidin-1-see 5.44 (s, 2H), 6.56 (d, 1H), 6.74 (s, 1H), 6.88 (d, 1-268 yl-phenyl)-pyridin-2-ylamine; 4 -, examples 1H), 7.24 (t, 1H), 7.43 (m, 1H), 7.58 (m, 3H), 7.83 I , TFA compound with trifluoro-ilik o - acetic acid (m, 2H) 4.r. a 141-12 p , ' No. Structure Name Met 1C60 Procedure NMR MS miz (11M) (M+1) HN" ''''P

3,6-difluoro-benzyloxy)-(400 MHz, DMSO-d6) 62.99 (s, 3H), 5.35 (s, 2H), 40 pyridin-3-y11-phenyl}-see 6.72 (br s, 2H), 7.27 (d, 2H), 7.42 (m, 1H), 7.59 TFA methanesulfonamide;
examples (m, 1H), 7.65 (d, 2H), 7.73 (s, 1H), 7.84 (s, 1H), I N compound with trifluoro-9.79(s, 1H) acetic acid ci NH , F

OH

¨ 5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-see yll-thiophene-2-carboxylic examples , I acid NH, tillirl F

examples (300 MHz, CDCI3) 6 8.00 (d, J = 1.8 Hz, 1H), {546-Amino-5-(2-chloro-3,6-7.30 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), difluoro-benzyloxy)-pyridin-3-see 7.20 (m, 1H), 7.10 (d, J = 3.8 Hz, 1H), 7.07 (m, 479 y1]-thiophen-2-y1)-(4-methyl-O 'N40 piperazin-1-yI)-methanone ci 1H), 5.27 (d, J = 1.7 Hz, 2H), 4.82 (br s, 2H), ...*-NH, 3.81 (m, 4H), 2.47 (m, 4H), 2.34 (s, 3H) F P-- \ ¨

c)h_ pl oyrroi d-3i n, -63- -(300 MHz, CDCI3) 68.02 (d, J = 1.8 Hz, 1H), o\- {d5160-Arom_bineon-,_,,5-10(2xy-7.52 (m, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.21 (m, see 1-272 .... s yll-thiophen-2-y1)-[(2R)-2-examples 1H), 7.14 (d, J = 3.9 Hz, 1H), 7.07 (m, 1H), 5.27 pyrrolidin-1-ylmethyl-(d, J = 1.5 Hz, 2H), 4.80 (br s, 2H), 4.50 (m, 1H), pyrrolidin-1-y11-methanone 3.81 (m, 2H), 2.74 (m, 4H), 2.25-1.82 (m, 10H).

O 'N

10 ci MI.

F

i (300 MHz, CDCI3) 68.02 (d, J = 1.8 Hz, 1H), P 546-Amino-5-(2-chloro-3,6-7.42 (d, J = 3.9 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), ¨ difluoro-benzyloxy)-pyridin-3-s see 7.21 (m, 1H), 7.15 (d, J = 3.9 Hz, 1H), 7.07 (m, 1-273 yll-thiophene-2-carboxylic examples 1H), 5.89 (br d, 1H), 5.29 (d, J = 1.5 Hz, 2H), acid (1-methyl-piporidin-4-y1)-4.02 (br s, 2H), 4.05 (m, 1H), 3.03 (m, 2H), 2.80 amide id ., 3H), 2.40 (m, 2H), 1.85 (m, 2H), 1.62 (m, 2H) NH, 0 1.4 _ ?,1/4.___,NH {546-Amino-5-(2-chloro-3,6-(300 MHz, CDC13) 6 8.00 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), s \ difluoro-benzyloxy)-pyridin-3-see 7.21 (m, 1H), 7.10 (d, J = 3.8 Hz, 1H), 7.07 (m, 1-274 yli-thiophen-2-y1}-(3,5-F
examples 1H), 5.28 (d, J = 1.5 Hz, 2H), 4.82 (br s, 2H), I N dimethyl-piperazin-1-y1)-4.38 (m, 2H), 2.98 (m, 2H), 2.65 (m, 2H), 1.68 (br methanone s, 1H), 1.11 (d, J =6.2 Hz, 6H) 0 NH, F

SD ) (300 MHz, CDCI3) 68.00 (d, J
= 1.8 Hz, 1H), tr 546-Amino-5-(2-chloro-3,6-7.82 (br m, 1H), 7.66 (d, J = 3.9 Hz, 1H), 7.29 (d, difluoro-benzyloxy)-pyridin-3-J = 1.8 Hz, 1H), 7.21 (m, 1H), 7.11 (d, J
= 3.9 .,\--.
2.
see 1-275 yl1-thiophene-2-carboxylic examples Hz' 1H), 7.07 (m, 1H), 5.26 (d, J = 1.5 Hz, 2H), acid (2-pyrrolidin-1-yl-ethyl)-4.81 (br s, 2H), 3.71 (m, 2H), 3.02 (m, 2H), 2.95 iii 0 "N amide (m, 2H), 2.01 (m, 4H), 1.97 (m, 2H), 1.11 (d, J =

ci NH, 6.2 Hz, 6H) F

(300 MHz, CDCI3) 6 8.00 (d, J = 1.8 Hz, 1H), . 0-10 {546-Amino-5-(2-(2-3,6-3 7.29 (d, J
= 1.8 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), difluoro-benzyloxy)-pyridin-3-7.20 (m, 1H), 7.09 (d, J = 3.8 Hz, 1H), 7.07 (m, see 1-276 yll-thiophen-2-y11-(4-1H), 5.27 (d, J = 1.5 Hz, 2H), 4.80 (br s, 2H), 533 O I 'N pyrrolidin-1-yl-piperidin-1 -yI)-examples 4.43 (m, 2H), 3.10 (m, 2H), 2.63 (m, 4H), 2.34 (:(: NH, F methanone (m, 1H), 1.99 (m, 2H), 1.83 (m, 4H), 1.63 (m, 2H).

No. Structure Name Met 1C50 Procedure 1H-NMR
MS m/z AO
(M+1) 4-[6-Amino-5-(3-fluoro-2-see 1-277 ,, trifluoromethyl-benzyloxy)-examples ' I pyridin-3-y11-benzoic acid NH, OF, F

rTh.,0 o h,...,1 (300 MHz, CDCI3) 67.97 (d, J = 1.8 Hz, 1H), (446-Amino-5-(3-fluoro-2-7.61-7.42 (m, 6H), 7.21 (d, J = 8.7 Hz, 1H), 7.12 trifluoromethyl-benzyloxy)-see (d, J = 1.8 Hz, 1H), 5.33 (s, 2H), 4.81 (br s, 2H), 543 1-278 0 pyridin-3-y11-pheny1}-(4-examples 4.62 (m, 1H), 3.84 (m, 1H), 2.98 (m, 2H), 2.65 pyrrolidin-1-yl-piperidin-1-yI)-(m, 4H), 2.32 (m, 1H), 1.97 (m, 2H), 1.84 (m, I = methanone 4H), 1.60 (m, 2H) 0 ' NO, F

o (300 MHz, CDCI3) 67.99 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.55 (m, 1H), 7.52 (d, J
upC--"--= 8.3 Hz, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.22 (t, J
trifluoromethyl-benzyloxy)- see = 8.7 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 5.99 (br I `` pyridin-3-yfl-N-(1-methyl- examples nekk 0 '" piperidin-4-yI)-benzamide d, 1H), 5.34 (s, 2H), 4.83 (br s, 2H), 4.04 (m, 1H), 2.87 (m, 2H), 2.34 (s, 3H), 2.20 (m, 2H), 2.05 (m, 2H), 1.63 (m, 2H) rl-y.
O N,), {446-Amino-5-(3-fluoro-2-(300 MHz, CDCI3) 67.98 (s, 1H), 7.61-7.43 (m, trifluoromethyl-benzyloxy)- 6H), 7.22 (t, J
= 8.7 Hz, 1H), 7.13 (d, J = 1.6 Hz, see 1-280 IP pyridin-3-y11-phenyl}-(3,5-examples 1H), 5.33 (s, 2H), 4.82 (bra, 2H), 4.65 (m, 1H), dimethyl-piperazin-1-y1)- 3.65 (m, 1H), 2.90 (m, 2H), 2.68 (m, 1H), 2.42 methanone (m, 1H), 1.60 (m, 1H), 1.12 (d, 3H), 1.00 (d, 3H) 0 , NH, F

\tõ....

(300 MHz, CDCI3) 67.98 (d, J = 2.4 Hz, 1H), . (446-Amino-5-(3-fluoro-2-7.61-7.43 (m, 6H), 7.21 (t, d = 8.8 Hz, 1H), 7.14 trifluoromethyl-benzylo,v)- see (d, J = 2.4 Hz, 1H), 5.33 (s, 2H), 4.57 (bra, 2H), 503 1-281 11101 pyridin-3-y1]-phenyl}-(3-examples 3.89 (m, 1H), 3.65 (m, 2H), 3.42 (m, 1H), 2.70 dimethylamino-pyrrolidin-1-, (m, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 2.14 (m, 1H), . I .....-N yI)-methanone 1.82 (m, 1H) ?

{4-16-Amino-5-(3-fluoro-2- (300 MHz, CDCI3) 67.98 (d, J = 1.4 Hz, 1H), .
trifluoromethyl-benzyloxy)- 7.58-7.43 (m, 6H), 7.20 (t, J = 8.8 Hz, 1H), 7.13 see 1-282 pyridin-3-y1]-pheny1)-[(25)-2-examples (d, J = 1.4 Hz, 1H), 5.34 (s, 2H), 4.81 (bra, 2H), 11001 pyrrolidin-1-ylmethyl-4.46 (m, 1H), 3.50 (m, 2H), 2.77 (m, 4H), 2.30-pyrrolidin-1-y1]-methanone 1.50 (m, 10H) . I -.=+

4011 Cr, N., F

(300 MHz, CDCI3) 68.00 (d, J = 1.2 Hz, 1H), 4-[6-Amino-5-(3-fluoro-2-7.83 (d, J = 8.2 Hz, 2H), 7.56 (m, 1H), 7.55 (d, J
trifluoromethyl-benzyloxy)-1-283 pyridin-3-y11-#NI-(2-see = 8.2 Hz, 2H), 7.45 (d, 1H), 7.20 (t, J = 8.8 Hz, N examples 1H), 7.13 (d, J = 1.4 Hz, 1H), 6.76 (m, 1H), 5.34 I morpholin-4-yl-ethyl)-(s, 2H), 4.85 (br s, 2H), 3.74 (m, 4H), 3.56 (m, benzamide 2H), 2.62 (m, 2H), 2.52 (m, 4H) F

No. Structure Name Met 1D30 Procedure MS m/z (11M) (M+1) Cr (4-[6-Amino-5-(3-fluoro-2-(300 MHz, CDCI3) 5 7.97 (d, J = 1.8 Hz, 1H), trifluoromethyl-benzyloxy)-7.58-7.43 (m, 6H), 7.20 (t, J = 8.8 Hz, 1H), 7.12 see 1-284 pyridin-3-y1j-pheny1}-(4- examples (d, J =
1.8 Hz, 1H), 5.34 (s, 2H), 4.93 (br s, 2H), ...,,, methyl-piperazin-1-yI)-3.80 (m, 2H), 3.56 (m, 2H), 2.44 (m, 4H), 2.33 (s, IL---e' methanone 3H) _ (300 MHz, CDCI3) 68.00 (d, J = 1.2 Hz, 1H), 1....ii. N-E2-(4-Acetyl-piperazin-1-7.82 (d, J = 8.2 Hz, 2H), 7.58 (m, 1H), 7.55 (d, J

1101 I yfl-ethy1]-446-amino-5-(3-(3 = 8.2 Hz, 2H), 7.44 (d, J =
7.8 Hz, 1H), 7.22 (t, J

examples see 1-285 fluoro-2-trifluoromethyl-= 8.8 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 6.72 (m, I '' -,i benzyloxy)-pyridin-3-y1]-1H), 5.34 (s, 2H), 4.85 (br s, 2H), 3.65 (m, 2H), , benzamide 3.60 (m, 2H), 3.50 (m, 2H), 2.65 (m, 2H), 2.51 , (m, 4H), 2.10 (s, 3H) HNt0 2-Piperidin-1-yl-(300MHz, CDCI3) 67.84 (d, 1H), 7.26 (d, 2H), IB ethanesulfonic acid (4-(6-see 7.20 (d, 2H), 7.06 (m, 3H), 7.59 (s, 1H), 4.86 (s, 1-286 amino-541-(2-chloro-3,6-3,6 0.18 N.
examples 2H), 3.25 (m, 2H), 2.89 (m, 2H), 2.49 (m, 4H), I difluoro-pheny1)-ethoxyl-1.83 (d, 3H), 1.62 (m, 4H), 1.48 (m, 2H) IP ci N% pyridin-3-y1}-phenyl)-amide F

HN-g-----0, 2-(4-Hydroxy-piperidin-1-y1)-(300MHz, CDCI3) 67.84 (d, 1H), 7.26 (d, 2H), cil ethanesulfonic acid (4-{6-7.20 (d, 2H), 7.06 (m, 3H), 7.59 (s, 1H), 4.86 (s, see 1-287 amino-541-(2-chloro-3,6- 0.14 examples 2H), 3.76 (m, 1H), 3.25 (m, 2H), 2.89 (m, 2H), difluoro-phenyl)-ethoxy]-2.78 (m, 2H), 2.26 (m, 2H), 1.83 (m, 5H), 1.62 pyridin-3-y1}-phenyl)-amide (m, 2H) NH
IP CI

F

?

I 2-Dimethylamino-(300MHz, CDCI3) 6 7.84 (d, 1H), 7.26 (d, 2H), ethanesulfonic acid see 7.20 (d, 21-1), 7.06 (m, 3H), 7.59 (s, 1H), 4.86 (s, 1-288 (4-(6-amino-541-(2-chloro- 0.15 N.
examples 2H), 3.21 (m, 2H), 2.88 (m, 2H), 2.30 (s, 6H), 3,6-difluoro-phenyl)-ethoxy]-I
2.26 (m, 2H), 1.82 (d, 3H) rib- 0 pyridin-3-y1)-phenyl)amide u11111}1, ci NH2 _ F

HNI'N 2-Cyclopropylamino-(300 MHz, CDCI3) 67.89 (s, 1H), 7.38 (d, 2H), ethanesulfonic acid (4-{6-lb see 7.26 (d, 2H), 7.18 (m, 3H), 5.95 (m, 1H), 4.89 (s, 623 1-289 amino-5-[1-(2-chloro-3,6- 0.16 examples 2H), 3.22 (m, 4H), 2.14 (m, 1H), 1.85 (d, 3H), F1 difluoro-pheny1)-ethoxyl-."
0.50 (m, 2H), 0.38 (m, 2H) pyiidin-3-y1}-pheny1)-amide ci NI-I

4-{6-Amino-5-11-(2,6-1$01 dichloro-3-fluoro-phenyl)-see ethoxyl-pyridin-3-y1}-benzoic examples I '' acid F ifitt, 0 , N

liP CI NH' C) (4-(6-Amino-541-(2,6-0 N dichloro-3-fluoro-pheny1)-(300MHz, CDCI3) 67.84 (d, 1H), 7.52 (d, 2H), ethoxy]-pyridin-3-y1}-see 7.31 (d, 2H), 7.08 (m, 3H), 6.13 (m, 1H), 4.86 (s, phenyI)-((2R)-2-pyrrolidin-1- 0.063 examples 2H), 4.30 (m, 1H), 3.40 (m, 2H), 2.60 (m, 4H), ylmethyl-pyrrolidin-1-yI)-1.82 (d, 3H), 1.70-2.0 (m, 10H) I methanone F iii..... 0 .44 I

up.-_ ' No. Structure Name Met 1C50 Procedure 1H-NMR MS
irt/z (1M) (M+1) = 1:1.., 4-{6-Amino-541-(2,6- (300MHz, CDCI3) 67.84 (d, 1H), 7.78 (d, 2H), UP dichloro-3-fluoro-phenyI)- 7.35 (d, 2H), 7.31 (m, 3H), 6.16 (tert, 1H), 5.90 examples see 1-292 ethoxyl-pyridin-3-y1)-N 0.069 (d, 1H), 4.86 (s, 2H), 4.05 (m, 1H), 2.85 (d, 1H), F ifiFt 0 , N I -(1-methyl-piperidin-4-yI)-2.35 (s, 3H), 2.05 (d, 1H), 2.25 (t, 1H), 1.82 (d, I I 111). a NH2 benzamide 3H), 1.60 (m, 1H), 1.29(m, 2F1), 0.86(m, 2H) T
(3-{6-Amino-541-(2,6- (300MHz, CDCI3) 67.84 (d, 1H), 7.51 (s, 1H), dichloro-3-fluoro-phenyl)- 7.38 (m, 3H), 7.30 (m, 1H), 7.15 (m, 1H), 6.97 (s, see 1-293, ' I N ethoxy]-pyridin-3-y1)- 0.051 1H), 6.15 (m, 1H), 4.94( s, 2H), 3.45-3.89 (m, dp 0 examples NH, phenyl)-[(3R)-3-amino- 4H), 3.20( m, 1H), 2.25(m, 1H), 2.15 (m, 1H), pyrrolidin-1-y1A-methanone 1.82 (d, 3H), 1.34 (m, 2H) 4-D--1; (4-{6-Amino-541-(2,6-(300MHz, CDCI3) 67.84 (d, 1H), 7.70 (m, 1H), dichloro-3-flUoro-phenyl)- 7.45 (m, 1H), 7.30 (s, 2H), 7.08 (t, 1H), 6.92 (d, see 1-294 ethoxyl-pyridin-3-y1)- 0.062 examples 2H), 6.13 (m, 1H), 4.86 (s, 2H), 4.30 (t, 1H), 2.80 phenyI)-(4-pyrrolidin-1-yl- (m, 4H), 1.82 (d, 3H), 1.80 (m, 4H), 1.35 (m, 4H), piperidin-1-y1)-methanone 0.89 (m, 4H) 0 CX (4-{6-Amino-5-[1-(2,6-(300 MHz, CDCI3) 67.89 (s, 1H), 7.71 (d, 2H), dichloro-3-fluoro-phenyl)-see 7.49 (d, 2H), 7.40 (s, 1H), 7.35 (m, 1H), 7.08 (m, 503 1-295 40 ethoxy)-pyridin-3-y1)- 0.079 examples 1H), 6.17 (m, 1H), 4.98 (s, 2H), 4.28 (t, 2H), 3.68 1 -.. pheny1)-(4-methyl-piperazin-(m, 4H), 2.38 (m, 2H), 2.31 (s, 3H), 1.88 (d, 3H) F Av.. 0 1 , N 1-yI)-methanone Cl r = 11.... (4-{6-Amino-541-(2,6-dichloro-3-fluoro-phenyl)-see 1-296 ethoxyl-pyridin-3-y1)- 0.054 0 examples phenyI)-(3,5-dimethyl-piperazin-1-y1)-methanone F I AI 0 Asi WI ci NH _ . -g-----N--- 2-Cyclopropylamino- (300 MHz, CDCI3) 67.79 (s, 1H), 7.30 (m, 3H), ethanesulfonic acid (446- 7.24 (m, 3H), 7.08 (t, 1H), 6.95 (a, 1H), 6.09 (m, 1-297 40 amino-5-[1-(2,6-dichloro-3- 0.164 see 1H), 4.89(a, 2H), 3.21 (m, 4H), 2.12(m, 1H), examples , fluoro-pheny1)-ethoxy)-1.84 (d, 3H), 0.87 (m, 1H), 0.50 (m, 2H), 0.36 (m, F 40 0 . t, I ''' pyridin-3-y1)-phenyl)-amide 2H) 0 NH, fr 2-Dimethylamino-1 ethanesulfonic acid (300 MHz, CDCI3) 67.81 (s, 1H), 7.26 (m, 6H), 1-298 40 (4-{6-amino-541-(2,6- 0.059 see 7.04 (t, 1H), 6.94 (s, 1H), 6.12 (m, 1H), 4.95 (s, dichloro-3-fluoro-phenyl)- examples 2H), 3.21 (t, 2H), 2.85 (t, 2H), 2.31 (s, 6H), 1.85 1 1 ethoxy]-pyridin-3-y1}-pheny1)-(d, 3H) F Ai 0 -*" amide 441.- ci NH, " 1.---'0" " 2-[(3R)-3-Hydroxy-pyrrolidin-(300MHz, CDCI3) 67.84 (d, 1H), 7.30 (m, 5H), 1-y1)1-ethanesulfonic acid (4- 7.10 (t, 1H), 6.89 (s, 1H), 6.10 (tert, 1H), 4.86 (s, 1-299 , {6-amino-5-[1-(2,6-dichloro- 0.062 examples see2H), 4.40 (s, 1H), 3.21 (m, 21-1), 2.88 (m, 3H), 3-fluoro-phenyl)-ethoxy] 2.67 (d, 1H), 2.46 (m, 1H), 2.20 (m, 2H), 2.05 (s, 0 NH 2 -pyridin-3-y1)-phenyl)-amide 1H), 1.85 (d, 3H), 1.25 (s, 1H) it-^r1 N42-(4-Acetyl-piperazin-1-y1) (300MHZ, CDCI3) 67.85 (s, 1H), 7.79 (d, 2H), --y ethy1]-446-amino-511-(2,6- 4 as in 7.42 (d, 2H), 7.30 (dd, 1H), 7.07 (t, 1H), 7.02 (d, 1-300 dichloro-3-fluoro-phenyl)- 0.059 Example I- 1H), 6.81 (bm, 1H), 6.13 (q, 1H), 5.42 (s, 2H), [M+1]
, ethoxyl-pyridin-3-y1)-291 3.80 (m, 2H), 3.62 (m, 2H), 3.53 (m, 2H), 2.68 benzamide (m, 2H), 2.52 (m, 4H), 2.10 (s, 3H), 1.87 (d, 3H).

No.
Structure Name Met 1C50 Procedure MS tniz (11M) (M+1) , =
11,....-0 4-{6-Amino-541-(2,6-(300MHZ, CDCI3) 68.71 (bm, 1H), 7.92 (m, 3H), dichloro-3-fluoro-phenyI)-4 as in ethoxy]-pyridin-3-yI)-N-(3-0.064 Example 1- 7.42 (d, 2H), 7.31 (dd, 1H), 7.06 (t, 1H), 7.01 (s, r.
pyrrolidin-1-yl-propyI)-1H), 6.12 (q, 1H), 4.97 (s, 2H), 3.65 (m, 2H), 3.00 [M+1]
(m, 6H), 2.00 (m, 6H), 1.87 (d, 3H).
U---µ)-a = "-El':
benzamide .
I.,.,..6 4-{6-Amino-541-(2,6-(300MHZ, CDCI3) 6 7.90 (d, 1H), 7.79(d, 2H), dichloro-3-fluoro-phenyl)-4 as in 7.44 (d, 2H), 7.31 (dd, 1H), 7.06 (t, 1H), 7.01 (d, 1-302ethoxyl-pyridin-3-y1)-N-(2-0.071 Example 1- 1H), 6.83 (bm, 1H), 6.12 (q, 1H), 5.05 (s, 2H), I .:N
morpholin-4-yl-ethyl)-291) 3.74 (m, 4H), 3.58 (m, 2H), 2.63 (m, 2H), 2.53 [M+1]
s-1-4-a N", benzamide (m, 4H), 1.87 (d, 3H).
,..X6 (4-{6-Amino-541-(2,6-(300MHZ, CD30D) 6 7.76 (s, 1H),7.54 (m, 1H), dichloro-3-fluoro-phenyl)-4 as in 7.42 (m, 4H), 7.24 (t, 1H), 7.04 (s, 1H), 6.22 (q, ethoxy k l-pyridin-3-y1)-phenyl)- 0.059 Example 1H), 4.82 (s, 2H), 3.76 (m, 1H), 3.68 (m, 2H), [M+1[
((S)-3-amino-pyrrolidin-1-yI)-3.52 (m, 1H), 2.28 (m, 1H), 1.92 (m, 3H), 1.75 I'' methanone (m, 1H), 1.42 (m, 1H).
F
0 "
itr CI
1µ41-12 NH, (4-{6-Amino-541-(2,6-(300MHZ, CD30D) 6 7.76 (s, 1H),7.54 (m, 1H), *
dichloro-3-fluoro-phenyl)-4 as in 7.42 (m, 4H), 7.24 (t, 1H), 7.04 (s, 1H), 6.22(q, ethoxyl-pyridin-3-y1}-phenyl)- 0.072 Example I- IN), 4.82 (s, 2H), 3.76 (m, 1H), 3.68 (m, 2H), [M+1]
((R)-3-amino-pyrrolidin-1-yI)-3.52 (m, 1H), 2.28 (m, 1H), 1.92 (m, 3H), 1.75 I
I -' F
0 ,N
methanone (m, 1H), 1.42 (m, IN).
Ali NH, . 0,..NH, (4-{6-Amino-541-(2,6-dichloro-3-fluoro-phenyl)-4 as in ethoxy}-pyridin-3-y1}-phenyl)-0.18 Example 1-[MO]

I'' (4 -amino-piperidin-1-yI)-I
' ' Ia. 0 '14 methanone a Fill, OH

(4-{6-Amino-5-[1-(2,6-(300MHZ, CD30D) 67.78 (d, 1H), 7.47 (m, 3H), dichloro-3-fluoro-phenyl)-4 as in 7.37 (m, 3H), 6.92 (d, 1H), 6.07 (q, 1H), 5.88 (s, ethoxyi-pyridin-3-y1)-phenyl)- 0.024 Example I- 2H), 4.82 (dd, 1H), 4.15 (d, 1H), 3.53 (m, 2H), rum]

, ((S)-3-hydroxy-pyrrolidin-1-3.42 (m, 1H), 3.15 (m, 1H), 2.43 (m, 1H), 1.85 L
I ,N
yI)-methanone (m, 1H), 1.75 (d, 3H).
"11 , ?hi (446-Amino-541-(2,6-(300MHZ, CD30D) 67.80 (d, 1H), 7.47 (m, 3H), dIchloro-3-fluoro-phenyl)-4 as in 7.37 (m, 3H), 6.92 (d, 1H), 6.07 (q, 1H), 5.89 (s, ethoxyl-pyridin-3-y1}-phenyl)- 0.022 Example I- 2H), 4.82 (dd, 1H), 4.15 (d, 1H), 3.53 (in, 2H), rum]

I
((R)-3-hydroxy-pyrrolidin-1-3.42 (m, 1H), 3.15 (m, 1H), 2.43 (m, 1H), 1.85 L
iaili yI)-methanone (m, 1H), 1.75 (d, 3H).
II" a NH, F
i No.
Structure Name Met IC50 Procedure MS m/z (INI) (M+1) H _ o IND
(4-(6-Amino-5-(1-(2,6-(300MHZ, CD30D) 57.80 (d, 1H), 7.47 (m, 3H), [110 dichloro-3-fluoro-phenyl)-4 as in 7.37 (m, 3H), 6.92 (d, 1H), 6.07 (q, 1H), 5.89 (s, ethoxyl-pyridin-3-y1}-phenyl)- 0.033 Example I- 2H), 4.70 (m, 1H), 4.05 (m, 1H), 3.6 (m, 2H), 3.32 rm+i]
"
_.((R)-2-hydroxymethyl-(m, 1H), 2.43 (m, 1H), 1.85 (m, 3H), 1.75 (d, 3H), I
=

m pyrrolidin-1-y1)-methanone 1.15(m, 1H).
ia. 0 =
NH, 416-. a =
Pl...--r.
4-(6-Amino-5-(1-(2,6-(300MHZ, CDCI3) 59.55 (bm, 1H), 8.80 (t, 1H), .1 dichloro-3-fluoro-phenyl) 4 as in 7.95 (s, 1H), 7.58 (d, 2H), 7.55 (m, 3H), 7.45 (t, 1-309' ethoxyl-pyridin-3-y1}-N-(2-0.04 Example I- 1H), 7.09 (d, 1H), 6.23 (q, I H), 3.60 (q, 2H), 3.22 WA
[M+1]
diethylamino-ethyl)-(m, 5H), 3.09 (m, 1H), 1.85 (d, 3H), 1.22 (dd, '::' benzamide 6H).
F
.
-=
11,....,,,, \
*
Li 4-(6-Amino-541-(2,6-I
dichloro-3-fluoro-phenyl) 4 as in (300MHZ, CDCI3) 58.25 (bm, 1H), 7.90 (d, 1H), 7.82 (s, 2H), 7.34 (d, 2H), 7.25 (m, 1H), 7.04 (t, ethoxyl-pyridin-3-y1}-N-(2-0.12 Example 1-1H), 6.96 (s, 1H), 6.09 (q, 1H), 4.97 (s, 2H), 3.82 [M+1]
' 1 '' pyrrolidin-1-yl-ethyl)-F
benzamide (m, 2H), 3.15 (m, 6H), 2.00 (m, 4H), 1.85 (d, 3H).
Ur ci NH, [100 OH 3-(6-Amino-5-[1-(2,6-3 as in dichloro-3-fluoro-phenyl)-311Example 420 [M-1]

, ethoxy]-pyridin-3-yI}-benzoic ' F

, N
acid NH, (3-{6-Amino-541-(2,6-(300MHZ, CDCI3) 57.86 (s, 1H), 7.41 (m, 3H), =
u, dichloro-3-fluoro-phenyl)-7.30 (m, 3H), 7.07 (t, 1H), 6.99 (s, 1H), 6.12 (q, ethoxy]-pyridin-3-yll-phenyl)- 0.062 1H), 4.99 (s, 2H), 3.89 (m, 2H), 3.50 (m, 2H), [M+1]
(4-methyl-piperazin-1-y1)-2.54 (m, 2H), 2.40 (m, 2H), 2.35 (s, 3H), 1.87 (d, MP 0 NE', methanone 3H).
(300MHZ, CDCI3) 57.89 (s, 1H), 7.73 (2,1H), , 346-Amino-541-(2,6-7.67 (d, I H), 7.49 (d, 1H), 7.42 (t, I H), 7.31 (dd, ,-.1-Lil dichloro-3-fluoro-phenyl)-4 as in 1H), 7.05 (t, 1H), 7.01 (s, 1H), 6.28 (bd, 1H), 6.12 ethoxyl-pyridin-3-yll-N-(1-0.069 Example I-(q, 1H), 4.99 (s, 2H), 4.08 (m, 1H), 3.04 (m, 2H), [M+1]
methyl-piperidin-4-yI)-2.42 (s, 3H), 2.32 (m, 2H), 2.10 (m, 2H), 1.87 (d, 16;(7,. NH, 3H), 3H), 1.80 (m, 2H).
(3-(6-Amino-541-(2,6-(300MHZ, CDCI3) 57.87 (s, 1H), 7.40 (m, 4H), 1--) dichloro-3-fluoro-phenyl)-4 as in 7.29 (dd, 1H), 7.05 (t, IN), 7.00 (s, IH), 6.12 (q, 1-314 , , ethoxy]-pyridin-3-y1}-phenyl)- 0.06 ExampleI-,....&,,õX
((S)-2-pyrrolidin-1-ylmethyl-1H), 4.92 (s, 2H), 3.50 (m, 2H), 3.74 (m, 4H), [M+1]
1.86 (d, 3H), 1.57-2.18 (m, 11H).
pyrrolidin-1-yI)-methanone ..
j-..-1 r-` rk N42-(4-Acetyl-piperazin-1-y1) (300MHZ, CDCI3) 57.88 (s, 1H), 7.83 (s, 1H), g ethyl]-3-{6-amino-5-[1-(2,6-4 as in 7.65 (d, 1H), 7.46 (m, 2H), 7.32 (dd, 1H), 7.06 (t, dichloro-3-fluoro-phenyl)-0.069 Example I- 1H), 7.03 (s, 1H), 6.95 (bt, 1H), 6.12 (q, 1H), 5.08 will ethoxyl-pyridin-3-y1)-(s, 2H), 3.66 (m, 4H), 3.50 (m, 2H), 2.73 (m, 2H), `
F.611 benzamide 2.52 (m, 4H), 2.09 (s, 3H), 1.87 (d, 3H).
_ (3-(6-Amino-541-(2,6-(300MHZ, CDCI3) 57.87 (s, 1H), 7.38 (m, 4H), 0-"N", dichloro-3-fluoro-phenyl)-4 as in 7.28 (m, IH), 7.06 (t, 1H), 6.98 (s, 1H), 6.12 (q, i 1 -..
ethoxy]-pyridin-3-y1}-phenyl)- 0.048 Example I- 1H), 5.05 (s, 2H), 3.82 (m, 2H), 3.72 (m, 2H), [M+11 F'6CLO
N
((S)-3-amino-pyrrolIdin-1-y1)-2.10 (m, 1H), 1.86 (d, 3H), 1.84 (m, 2H).

NH, methanone .

No. Structure Name Met IC50 Procedure 'H-NMR
MS m/z (1-1M) (M+1) () jj 346-Amino-54142,6-I dichloro-3-fluoro-phenyl)-. 4 as in (300MHZ, CDCI3) 67.91 (s, 1H), 7.87 (s, 1H), 7.85 (d, 1H), 7.50 (m, 2H), 7.31 (dd, 1H), 1-317 140 ethoxy]-pyridin-3-yI}-N(3- 0.059 Example!-7.04(m, 2H), 6.13 (q, 1H), 4.93 (s, 2H), 3.64 (m, IM+1]
morpholin-4-yl-propyI)-6H), 2.50 (m, 6H), 1.87 (d, 3H), 1.81 (m, 2H).
benzamide F'6I 1, :ii:

1-318 _.260 (346-Amino-54142,6-(300MHZ, CDCI3) 67.87 (s, 1H), 7.40 (m, 4H), dichloro-3-fluoro-phenyl) 4 as in 7.29 (dd, 1H), 7.05 (t, 1H), 7.00 (s, 1H), 6.12 (q, ,;r1t. ethoxyl-pyridin-3-y1}-phenyl)- 0.13 Example I-1H), 4.92 (s, 2H), 3.50 (m, 2H), 3.74 (m, 4H), [MO]
i ,N ((R)-2-pyrrolidin-1-ylmethyl-1.86 (d, 3H), 1.57-2.18 (m, 11H).
F-C'Cc-i "". pyrrolidin-1-yI)-methanone 10 346-Amino-54142,6-(300MHZ, CDCI3) 67.86 (s, 1H), 7.82 (s, 1H), h dichloro-3-fluoro-phenyl)-4 as in 7.73 (d, 1H), 7.46 (m, 4H), 7.22 (t, 1H), 7.04 (s, 1-319 ethoxyi-pyridin-3-y1}-N(2- 0.1 Example 1- 11-1), 6.95 (bt, 1H), 6.22 (q, 1H), 4.82 (s, 2H), 3.60 .. .

i 1 -...fil [1101.1 F 0 ' N", N pyrrolidin-1-yl-ethyl)-(m, 2H), 2.82 (m, 2H), 2.70 (m, 4H), 1.87 (d, 3H), AI
benzamide 1.82 (m, 2H).
'`o= ci j...Y 346-Amino-54142,6-(300MHZ, CDCI3) 6 8.66 (bt, 1H), 7.90 (s, 1H), i dichloro-3-fluoro-phenyl)-4 as in 7.85 (s, 1H), 7.61 (d, 1H), 7.42 (m, 2H), 7.31 1-320 40 g ethoxy]-pyridin-3-y1}-N4 3- 0.13 Ex ample 1- (dd, 1H), 7.05 (m, 2H), 6.14 (q, 1H), 4.88 (s, 2H), rim+11 I . pyrrolidin-1-yl-propy1)-312 3.65 (m, 2H), 2.71 (m, 2H), 2.56 (m, 4H), 1.87 (d, L

, al . ,N
benzamide 3H), 1.80(m, 2H), 1.71 (m, 4H).

"H.

34 6-Ami54142,6- no-(300MHZ, CDCI3) 67.90 (s, 1H), 7.84 (s, 1H), i r') t1 dichloro-3-fluoro-phenyl)-4 as in 7.66 (d, 1H), 7.46 (m, 2H), 7.32 (dd, 1H), 7.05 1-321 ethoxy]-pyridin-3-yI}-N(2- 0.18 Example I- (m, 2H), 6.88 (bt, 1H), 6.14(q, 1H), 5.04(s, 2H), rum]

morpholin-4-yl-ethyl)-312 3.82 (m, 4H), 3.66 (m, 2H), 2.72 (t, 2H), 2.60 (m, L

benzamide 4H), 1.88 (d, 3H).
"":

(300MHZ, CDCI3) 6 7.86 (s, 1H), 7.41 (m, 3H), 46-Amino-541-(2,6-7.30 (m, 3H), 7.07 (t, 1H), 6.99 (s, 1H), 6.12 (q, OD(8 dichloro-3-fluoro-phenyl)-4 as in 1H), 4.95 (s, 2F1), 4.70 (m, 1H), 3.82 (m, 1H), 1-322 * 1".- e thoh-A-pyridin-3-y1}-pheny1)- 0.071 Example I-3.06 (m, 1H), 2.98 (m, 1H), 2.65 (m, 4H), 2.28 [M+11 (4-pyrrolidin-1-yl-piperidin-1-.1 "8.
(m, 1H), 1.02 (m, 1H), 1.81 (m, 5H), 1.55 (m, y1)-methanone 2H).

(300MHZ, CDCI3) 67.83 (s, 1H), 7.32 (m, 4H), L--7.21 (d, 2H), 7.06 (t, 1H), 6.96 (s, 1H), 5.96 (q, 1-323 amino-5-[1-(2,6-dichloro-3- 0.08 1H), 4.81 (s, 2H), 3.22 (m, 2H), 3.02 (m, 2H), [M+11 1 fluoro-phenyl)-ethoxy]-2.62 (m, 4H), 1.84 (d, 3H), 1.08 (t, 6H).
pyridin-3-yI}-phenyl)-amide _ ft " Ina. 2(4-Hydroxy-piperidin-1-yI)-(300MHZ, CDCI3) 67.81 (s, 1H), 7.31 (m, 3H), '3" ethanesulfonic acid (446-9 as in 7.25 (m, 3H), 7.07 (t, 1H), 6.96 (s, 1H), 6.11 (q, 583 1-324 amino-5-[1-(2,6-dichloro-3- 0.059 Example!- 1H), 4.95(s, 2H), 3.76(m, 1H), 3.25 (t, 2H), 2.92 will -... fluoro-phenyl)-ethoxy]-297 (t, 2H), 2.79 (m, 2H), 2.25 (m, 2H), 1.93 (m, 2H), L
...

NI-1 pyridin-3-y1}-phenyl)-amide 1.86 (d, 3H), 1.62 (m, 2H).

-I?

ii -g------(-1 2-Piperldin-1-yl-(300MHZ, CDCI3) 67.84 (s, 1H), 7.32 (m, 4H), '-= ethanesulfonic acid (446-9 as in 7.21 (d, 211), 7.06 (dd, 1H), 6.96 (s, 1H), 6.11 (q, 1-325 amino-54142,6-[1-3- 0.089 Example I. 1H), 4.88 (s, 2H), 3.24 (t, 2H), 2.89,(t, 2H), 2.48 [Mil]
F...Li, I fluoro-pheny1)-ethoxy]-(m, 4H), 1.86 (d, 3H), 1.62 (m, 4H), 1.49 (m, 2H).

pyridin-3-yll-phenyl)-amide CI Nii ' No. Structure Name Met IC50 Procedure MS :Tr&

(PM) (M+1) ft_ .5- 2-(Cyclopropylmethyl-amino) (300MHZ, CDCI3) 07.83 (s, 1H), 7.28 (m, 6H), ethanesulfonic acid (4-{6-9 as in 7.06 (dd, 1H), 6.96 (s, 1H), 6.11 (q, 1H), 4.91 (s, 1-326 amino-5-(1-(2,6-dicbloro-3- 0.075 Example!- 2H), 3.22(m, 4H), 2.50 (d, 2H), 1.86 (d, 3H), 0.84 [M+1]
,- ' N fluoro-phenyl)-(m, 2H), 0.52 (m, 2H), 0.15 (m, 1H).
pyridin-3-y1}-amide-amide 61,-----0.... 2-((R)-3-Hydroxy-pyrrolidin-1-(300MHZ, CDCI3) 07.83 (s, 1H), 7.32 (m, 5H), yI)-ethanesulfonic acid (4-{6-9 as in 7.05 (m, 3H), 5.95 (q, 1H), 4.84 (s, 2H), 4.43 (m, 1-327 amino-5-[1-(2-chloro-3,6- 0.093 Example!- 1H), 3.25 (m, 2H), 3.02 (m, 3H), 2.84 (m, 1H), 14+1]

difluoro-phenyl)-ethoxy1-286 2.53 (m, 1H), 2.30 (m, 1H), 2.22 (m, 1H), 1.84 (d, L

pyridin-3-y1}-phenyl)-amide 3H), 1.81 (m, 1H).

A
HN-A-----N
2-Cyclopropylamino-(300MHZ, CDCI3) 07.89 (s, 1H), 7.38 (d, 2H), 10 ethanesulfonic acid (446-9 as in 7.24 (m, 2H), 7.18 (m, 3H), 5.95 (q, 1H), 4.89 (s, 1-328 amino-541-(2-chloro-3,6- 0.16 Example I- 2H), 3.22 (m, 4H), 2.14 (m, 1H), 1.85 (d, 3H), [M+1]
I..1.; difluoro-phenyI)-ethoxy]-286 0.50 (m, 2H), 0.38 (m, 2H).
pyridin-3-y1}-phenyl)-amide 1101 010 NH, F

rl HNN'''' .A.,L.' L. 2-Diethylamino-(300MHZ, CDCI3) 07.84 (s, 1H), 7.34 (d, 2H), V-- ethanesulfonic acid (4-{6-9 as in 7.23 (m, 3H), 7.02(m, 3H), 5.96(q, 1H), 4.81 (s, 1-329 amino-541-(2-chloro-3,6- 0.095 Example 1-2H), 3.22 (m, 2H), 3.02 (m, 2H), 2.62 (m, 4H), [M+11 difluoro-phenyl)-ethoxy]-1.84 (d, 3H), 1.08 (t, 6H).
pyridin-3-y1}-phenyl)-amide Air ci NH, lb 4-{6-Amino-541-(2-chloro-3 as in 1-330' 3,6-difluoro-phenyl)-ethoxyl-Example [M+'1]
I N pyridin-3-y1}-benzoic acid let 010 NH, F

4-(6-Amino-541-(2-chloro-(300MHZ, CDCI3) 07.91 (s, 1H), 7.80 (d, 2H), , 7.46 (d, 2H), 7.05 (m, 3H), 6.87 (m, 1H), 5.97 (q, 517 0.13 pyridin-3-yI}-N-(2-morpholin-1H), 4.97 (s, 2H), 3.75 (m, 4H), 3.58 (m, 2H), [M+13 du . I -;11 4-yl-ethyl) 2.60 (m, 6H), 1.84 (m, 3H).
WI ci NH, F

(300MHZ, CDCI3) 07.90 (s, 1H), 7.78 (d, 2H), 110 C..õ,õ1 --11' 4-(6-Amino-5-[1-(2-chloro-4 as in 7.45 (d, 2H), 7.05 (m, 4H), 5.98 (q, 1H), 4.90 (s, 1-332[M+11 3,6-difluoro-phenylyethoxy]- 0.079 Example!- 2H), 4.00 (m, 1H), 2.88 (m, 2H), 2.32 (s, 3H), pyridin-3-yI}-N-(1-methyl-331 2.18 (m, 2H), 2.08 (m, 2H), 1.84 (d, 3H), 1.57 (m, r,. 0 AV I piperidin-4-yI)-benzamide 2H).

4111111" ci NH' F

(-)N

0 N (4-(6-Amino-541-(2-chloro-(300MHZ, CDCI3) 07.90 (s, 1H), 7.54 (m, 2H), 3,6-difluoro-phenyl)-ethoxy]-4 as in 7.42 (d, 2H), 7.05 (m, 3H), 5.98 (q, 1H), 4.86 (s, 541 1-333 pyridin-3-y1}-phenyl)-((R)-2- 0.067 Example 1-* pyrrolidin-1-ylmethyl-331 2H), 3.50 (m, 2H), 3.74 (m, 4H), 1.84 (d, 3H), LM+1]
1.57-2.18 (m, 11H) pyrrolidin-1-yI)-methanone *0 ", _ F

No.
Structure Name Met IC50 Procedure MS rniz (11M) (M+1) PH, (4-(6-Amino-541-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-4 as in (300MHZ, CDCI3) 67.68 (m, 5H), 7.25 (m, 3H), pyridin-3-y1}-phenyl)-((R)-3-0.089 Example I- 6.27 (m, 1H), 4.88 (s, 2H) 473, 3.75 (m, 5H), 3.31 (m, rui+fi amino-pyrrolidin-1-yI)-2H), 2.44 (m, 1H), 2.17 (m, 1H), 1.93 (m, 3H).
' ' I

0 ..-1,1 methanone Ail WI a NH, F
(LN, H
O
N....,..J., (4-(6-Amino-541-(2-chloro-(300MHZ, CDCI3) 67.90 (s, 1H), 7.42 (m, 4H), 3,6-difluoro-phenyl)ethoxy]-pyridin-3-y1)-phenyl)-4 as in 7.05 (m, 3H), 5.97 (q, 1H), 4.86 (s, 2H), 4.62 (m, 0.09 Example I- 1H), 3.65 (m, 1H), 2.88 (in, 2H), 2.68 (m, 1H), (M+1]
((3R,5S)-3,5-dimethyl-2.41 (m, 1H), 1.84 (d, 3H), 1.64 (m, 1H), 1.05 (m, 0 I isi piperazin-1-yI)-methanone 6H).

NH, F
-4-{6-Amino-541-(2-chloro-3,6-difluoro-phenylyethoxy]-4 as in (300MHZ, CDCI3) 69.00 (s, 1H), 7.92 (s, 1H), 7.83 (d, 2H), 7.42 (d, 2H), 7.09 (m, 2H), 7.01 (m, 0.09 Example I-pyridin-3-yI)-N-(3-pyrrolidin-1-1H), 5.96 (q, 1H), 4.89 (s, 2H), 3.60 (m, 2H), 2.75 [M+1]
yl-propy1)-benzam I ' ide (m, 2H), 2.62 (m, 4H), 1.85 (m, 7H).
Lir I NH, F
0, I

tO
(4-(6-Amino-5-[1-(2-chloro-(300MHZ, CDCI3) 57.90 (s, 1H), 7.53 (m, 2H), 3,6-difluoro-phenyl)-ethoxy]-4 as in IP
pyridin-3-y1}-phenyl)-((S)-2-0.09 Example I- 7.43 (d, 2H), 7.05 (m, 3H), 5.98 (q, 1H), 4.86 (s, 2H), 4.45 (m, 1H), 3.58 (m, 2H), 3.00 (m, 4H), [M+1]
pyrrolidin-1-ylmethyl-1.84 (d, 3H), 1.70-2.18 (m, 10H) F
pyrrolidin-1-yI)-methanone I

..-N
0 CI NH, F
--r-N-(4-(6-Amino-541-(2-chloro-(101 3,6-difluoro-pheny1)-ethoxyl-4 as in (300MHZ, CDCI3) 57.90 (s, 1H), 7.44 (m, 4H), pyridin-3-y1)-phenyl)-(4-0.077 Example I- 7.07 (m, 3H), 5.95 (q, 1H), 4.87 (s, 2H), 3.60 [M+11 F"..
methyl-piperazin-1-yI)-(m, 4H), 2.43 (m, 4H), 2.33 (s, 3H), 1.84 (d, 3H).

0 I ..,N
methanone 1161 ci I*6 F
r....M.,0 O
IV.......) (4-(6-Amino-5-[1-(2-chloro-(300MHZ, CDCI3) 57.90 (s, 1H), 7.42 (m, 4H), 3,6-difluoro-phenyl)-ethoxik 4 as in 0.062 Example I- 7.02 (m, 3H), 6.00 (q, 1H), 4.87 (s, 2H), 4.64 (m, pyridin-3-y1)-phenyl)-(4-1H), 3.85 (m, 1H), 2.99 (m, 2H), 2.67 (m, 4H), [MO]
pyrrolidin-1-yl-piperidin-1-yI)-"11 methanone 2.38 (m, 1H), 1.90 (m, 9H), 1.62 (m, 2H).
i,-IW" 01 NH' F

4-{6-Amino-541-(2-chloro-.
4 as in (300MHZ, CDCI3) 67.91 (s, 1H), 7.86 (d, 2H), 3,6-difluoro-phenyl)-ethoxy]-7.45 (d, 2H), 7.10 (m, 3H), 7.01 (m, 1H), 5.98 (q, 0.086 Example I-I N
pyridin-3-yI)-N-(2-pyrrolidin-1-1H), 4.90 (s, 2H), 3.60 (m, 2H), 2.80 (m, 2H), EM+1]
, N

c, N
yl-ethyl)-benzamide 2.68 (m, 4H), 1.85 (m, 7H).
40 = H, No.
Structure Name Met 1C50 Procedure MS rn/z (11M) (M+1) -ji-i, 0 L.) (4-{6-Amino-541-(2-chloro-(300MHZ, CDCI3) 57.76 (s, 1H), 7.67 (m, 211), 3,6-difluoro-phenyl)-ethoxy}-4 as in 7.59 (d, 2H), 7.42 (s, 1H), 7.32 (m, 1H), 7.20 (m, pyridin-3-y1}-phenyl)-((S)-3-0.075 Example I- 1H), 6.27 (m, 1H), 4.86 (s, 211), 3.75 (m, 5H), N.
amino-pyrrolidin-111)-3.31 (m, 2H), 2.44 (m, 111), 2.14 (m, 1H), 1.95 [m+1}
I
methanone (m, 3H).
0 'N

NH, CI
F
, 3-{6-Amino-541-(2-chloro-as in 3,6-difluoro-phenyl)-ethoxy]-=
Example 1 o [M+1]
pyridin-3-yI}-benzoic acid 40 . N",, F
I
(3-{6-Amino-541-(2-chloro-(300MHZ, CDCI3) 57.88 (s, 1H), 7.43 (m, 211), " 3,6-difluoro-phenyl)-ethoxyl-7.30 (m, 211), 7.10 (m, 2H), 6.95 (m, 1H), 5.97 (q, 1-343pyridin-3-y1)-phenyl)-0.16 1H), 4.87 (s, 2H), 4.65 (m, 1H), 3.60 (m, 1H), ((3R,5S)-3,5-dimethyl-2.72 (m, 3H), 2.41 (m, 1H), 2.01 (s, 1H), 1.84 (d I '' [M+11 At c= ='"
, W-- CI
"", piperazin-1-y1)-methanone 3H), 1.17 (m, 311), 0.98 (m, 3H).
F
(3-{G-Amino-541-(2-chloro-=
(300MHZ, CDCI3) 57.65 (m, 5H), 7.42 (s, 1H), 3,6-difluoro-phenyl)-ethoxy}-4 as in 7.32 (m, I H), 7.20 (m, 111), 6.27 (m, 1H), 4.85 (s, 1:=344 pyridin-3-yll-phenyl)-((R)-3-0.12 Example g,õ.õ
amino-pyrrolidin-1-y1)-2H), 3.75 (m, 511), 3.31 (m, 21-1), 2.44 (m, 111), [M+1]
2.16 (m, 1H), 1.93 (m, 3H).
methanone F

(300MHZ, CDCI3) 57.90 (s, 1H), 7.78 (s, 1H), 6 346-Amino-541-(2-chloro-4 as in 7.67 (d, 1H), 7.45 (m, 2H), 7.00 (m, 3H), 6.15 y 3,6-difluoro-phenyl)-ethoxy1-0.2 Example (bd, 1H), 5.98 (q, 1H), 4.08 (m, 111), 2.97 (m, I ....
t pyridin-3-y1}-11-(1-methyl-[M+11 211), 2.38 (s, 3H), 2.27 (m, 2H), 2.10 (m, 211), 40 o -41 piparldin-4-y1)-benzamide , 1.84 (d, 3H), 1.74 (m, 2H).
el NH
F
(3-{6-Amino-541-(2-chloro-(300MHZ, CDCI3) 57.88 (s, 1H), 7.42 (m, 3H), 3,6-difluoro-phenyl)-ethoxy}-4 as in 7.30 (m, 2H), 7.09 (m, 2H), 7.00 (m, 111), 5.95 (q, o I .1'N
pyridin-3-y1}-phenyl)-(4-0.19 Example 111), 4.87 (s, 2H), 3.83 (m, 211), 3.47 (m, 2H), [MO]
methyl-piperazin-1-y1)-"H.

2.51 (m, 2H), 2.33 (m, 5H), 1.84 (d, 311).
methanone F

3-(6-Amino-541-(2-chloro-(300MHZ, CDCI3) 58.69 (s, 1H), 7.91 (m, 2 7.
=
11), 4 as in 3,6-difiuoro-phenyl)-ethoxyl-65 (d, 1H), 7.42 (m, 211), 7.00 (m, 3H), 5.99 (q, 0.21 Example ce.:0-=,, 5.-:,1 pyridin tm+ii yl-propy1)-benzamIde 2.63 (m, 4H), 1.84 (d, 311), 1,77 (m, 6H).
F
=

' 3-(6-Amino-541-(2-chloro-4 as in (300MHZ, CDCI3) 57.91 (s, 1H), 7.86 (s, 1H), , 3,6-difluoro-phenyl)-ethoxyl-7.70 (d, 111), 7.50 (m, 211), 7,00 (m, 4H), 5.99 (q, 0.2 Example 1H), 4.86 (s, 2H), 3.60 (m, 2H), 2.78 (m, 2H), [M+1]
pyridin-3-yI}-N-(2-pyrrolidin-1-X; NEI
yl-ethyl) 2.63 (m, 4H), 1.85 (m, 7H).
( No.
Structure Name Met 1C50 Procedure MS m/z (I-IM) (M+1) (3-[6-Amino-5-[1-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-4 as in 7.28 (m, 1H), 7.20 (m, 1H), 6.27 (m, 1H), 4.85 (s, 473 (300MHZ, CDCI3) 67.70 (m, 511), 7.42 (s, 1H), 1-349Al ,e-k 0 '"
pyridin-3-y1)-phenyl)-((S)-3- 0.13 Example 211), 3.75 (m, 511), 3.31 (m, 2H), 2.66 (m, 1H), IM+1]
qtr. ci NH, amino-pyrrolidin-1-yI)-2.44 (m, 111), 1.93 (m, 3H).
F
methanone a 3-{6-Amino-541-(2-(2-(300MHZ, CDCI3) 67.91 (s, 1H), 7.84 (s, 1H), 4 as in 7.65 (d, 1H), 7.46 (m, 2H), 7.05 (m, 3H), 6.83 3,6-difluoro-phenyl)-0.39 Example (bs, 1H), 5.97 (q, 1H), 4.91 (s, 2H), 3.74 (m, 4H), ,..-1..- 3:
pyridin-3-y1)-N-(2-morpholin-[M+1]

3.58 (m, 2H), 2.63 (m, 2H), 2.62 (m, 4H), 1.84 0 . N-4 4-yl-ethyl)-benzamide (m, 3H).
. 0 %.3 (3-{6-Amino-541-(2-chloro-.
N
(300MHZ, CDCI3) 67.88 (s, 1H), 7.45 (m, 4H), pi 3,6-difluoro-phenyl)-ethoxyl-4 as in 7.05 (m, 3H), 5.98 (q, 1H), 4.86 (s, 2H), 4.45 (m, 1-351pyridin-3-y1)-pheny1)-((R)-2-0.23 Example I '''' pyrrolidin-1-ylmethyl-1H), 3.64 (m, 1H), 3.44 (m, 1H), 2.64 (m, 411) [M+1]

....N
1.83 (d, 311), 1.70-2.18 (m, 10H) 1.I .0 NH, pyrrolidin-l-y1)-methanone F
co (346-Amino-541-(2-chloro-(300MHZ, CDCI3) 6 7.88 (s, 1H), 7.45 (m, 4H), 3,6-difluoro-pheny1)-ethoxy)-4 as in 7.09 (m, 3H), 5.98 (q, 1H), 4.86 (s, 2H), 4.45 (m, pyridin-3-y1}-phenyl)-((S)-2-0.15 Example 1H), 3.45 (m, 2H), 2.75 (m, 4H), 1.84 (d, 311), [M+1) pyrrolidin-l-ylmethyl-( 1.70-2.18 (m, 10H) pyrrolidin-1-yI)-methanone \
, Nr:25 ) =
TM 341-(2-Chloro-3,6-difluoro-phenyl)-ethoxy1-544-(2-0.23 Example 1 morpholin-4-yl-ethoxy)-3 as in phenyl]-pyridin-2-ylamine lbNH2 TFA
CI
_ FOf _ ......,-.0 WA c, I -[1-(2-Chloro-3,6-difluoro-3 as in pheny1)-ethoxy]-5-13-(2-0.22 Example I.
I A,, morpholin-4-yl-ethoxy)-ISCI
NH, WA
phenyl]-pyridin-2-ylamine F
CN..........."..
(400 MHz, DMSO-d6): d 7.74 (d, J = 2.0 Hz, 1H), 341-(26-Dichloro-3-fluoro-3 as in 7.53 (m, 1H), 7.44 (m, 2H), 7.32 (d, J = 9.0 Hz, phenyl)-ethoxy1-544-(2-0.068Example 1.2H), 7.00 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 1.6 Hz , rm+i]
M
pyrrolldin-1-yl-etho-CI , /

1H), 6.11 (m, 1H), 5.79 (s, 211), 4.30 (m, 2H), 3.5 L
phenyll-pyridin-2-ylamine (m, 6H), 1.90 (m, 4H), 1.807 (d, J = 6.7 Hz, 3H).
F

CI
',..

(400 MHz, DMSO-d6): d 7.73 (s, 1H), 7.54 (m, 3-[1-(2,6-Dichloro-3-fluoro-9A.
phenyl)ethoxy]-5-{4I2-(1-3 as in 1H), 7.44 (m, 211), 7.284 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.6 Hz, 211), 6.88 (s, IN, pyridine-H), 6.10 methyl-pyrrolidin-2-y1)-0.079 Example "(m, 1H), 5.78 (s, 2H), 4.7 (m, 111), 3.3 (m, 2H), [M+1]

ethoxy]-phenyl}-pyridin-2-3.1 (m, 2H), 2.77 (s, 311), 2.3 (m, 6H), 1.81 (d, J
ylamine = 6.2 Hz, 311).
CI

... N
F 1 iirk 0 CI
NH, IIAPP

, No. Structure Name Met 1C50 Procedure MS m/z (M+1) (11M) (..
_ Of ON.,..) 341-(2,6-DichlorO-3-fluoro-(400 MHz, DMSO-d6): d 7.72 (d, 1H), 7.53 (m, ' ilki 3 as in phenyl)-ethoxy1-544-(2-1H), 7.44 (m, 1H), 7.33 (m, 2H), 7.03 (m, 3H), 506 0.13 morpholin-4-yl-ethoxy)-Example 1.6.23 (q, 1H), 4.35 (m, 2H), 3.95 (m, 1H), 3.0-3.8 [M+11 I ' I c, (m, 9H), 1.851 (d, 3H).
phenyll-pyridin-2-ylarnine , 1 : WI

I F

0..._,..¨õ,...-..1 (400 MHz, DMSO-d6): d 7.82 (d, 1H), 7.53 (q, 341-(2,6-(2,6-3-fluoro-1H), 7.46 (t, 1H), 7.33 (t, 1H), 7.03 (m, 3H), 6.95 ,,, phenyl)-ethoxy]-543-(2-(2 3 as in 1-358 1,0 1 -2,,,, 0.22 (dd, 1H), 6.24(q, 1H), 4.38 (m, 2H), 3.96 (m, 2H), ,,,,,,,,, morpholin-4-yl-ethoxy)-Example 1-2 3.75 (m, 2H), 3.61(m, 2H), 3.5(m, 2H), 3.25(m, L".. '1 o NN2 phenyll-pyridin-2-ylamine F

2H), 1.851 (d, 3H).

(----N.--y" =

(400 MHz, DMSO-d6): d 7.73 (d, J = 1.6 Hz, 1H), 0.....,1 OH Am.., 1-(4-(6-Amino-541-(2,6 -7.56 (m, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.28 (d, J =

IP dichloro-3-fluoro-phenyl)-6.7 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 6.88 (d, J =

ethoxy]-pyridin-3-yI)- 0.045 2.0 Hz, 1H), 6.11 (m, 1H), 5.75 (s, 2H), 4.88 (d, [M+l]

...... NI phenoxy)-3-morpholin-4-yl-F

J = 2.0 Hz, 1H), 3.96 (m, 3H), 3.57 (t, J = 4.3 Hz, propan-2-ol NH, 4H), 2.42 [m, 6H), 1.81 (d, J =
6.7 Hz, 3H).
. CI

r iN.,.....,-..
(400 MHz, DMSO-d6): d 7.73 (d, J = 1.6 Hz, 1H), 3-[1-(2,6-Dichloro-3-fluoro- 0.7.56 (m, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.28 (d, J =

3 as in i phenyl)-544-(2-[4 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 494 033 Example 1 diethylamino-ethoxy)-phenyl].
1.6 Hz, 1H), 6.11 (m, 1H), 5.75 (s, 2H), 4.02 (t, J
[M+l]

pyridin-2-ylamine = 6.2 Hz, 2H), 2.756 (m, 2H), 2.55 (m, 4H), 1.81 F aim 0 `... N
(d, J = 6.7 Hz, 3H), 0.99 (t, J = 7.0 Hz , 6H).

WI 01 "H, _ (400 MHz, DMSO-d6): d 7.73 (d, J = 2.0 Hz, 1H), CT, 4...6. 3-(1-(2,6-Dichloro-3-fluoro-7.53 (m, 1H), 7.44 (t, J = 8.6 Hz, 1H), 7.27(d, J =

i mep phenyl)-ethoxy]-544-(1-3 as in 6.7 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.87 (d, 3 =

1-361 methyl-piperidin-3- 0.043 Example 1.1.6 Hz, 1H), 6.10 (m, 1H), 5.75 (s, 2H), [M+1]

I ylmethoxy)-phenyl]-pyridin-2-2 3.831(m, 2H), 2.81(m, 1H), 2.62 (s, 1H), 2.153 (s, F 0 N ylamine 3H), 1.95 (m, 3H), 1.81 (d, J = 6.7 Hz, 3H), 1.72 n, NH_ (m, 4H).

----r ),N.........--...

(400 MHz, DMSO-d6): d 7.73 (d, J = 2.0 Hz, 1H), 3-[1-(2,6-Dichloro-3-fluoro-7.53 (m, 1H), 7.44 (t, J = 8.6 Hz, I H), 7.27 (m, 3 as in 110 pheny1)-ethoxy1-544-(2-2H), 6.91 (m, 2H), 6.88 (d, J = 2.0 Hz , 1H), 6.11 0.052 Example 1. 2 diisopropylamino-ethoxy)-(m, 1H), 5.74 (s, 2H), 3.88 (t, J = 6.7 Hz, 2H), [M+1]

pheny1]-phenyl]-2-ylamine 3.02 (m, 2H), 2.76 (t, J = 6.7 Hz, 2H), 1.81 (d, J ==, a F ichn 0 1 0 *--. N
6.7 Hz, 3H), 0.986 (m, 12H).

NH, W.1 -0, (400 MHz, DMSO-d6): d 7.66 (d, J = 1.6 Hz, 1H), 341-(2,6-Dichloro-3-fluoro-7.49 (m, 1H), 7.377 (t, J = 8.2 Hz, 1H), 7.20 (m, 0 phenyl)-ethoxy]-544-(1-2H), 6.87 (m, 2H), 6.81 (d, J = 1.6 Hz , 1H), 6.04 0.052 methyl-piperidin-4-yroxy)-(m, 1H), 5.68 (s, 2H), 4.30 (m, 1H), 2.55 (m, 2H), [M+11 a 1 phenyll-pyridin-2-ylamine 2.12 (m, 5H), 1.84 (m, 2H), 1.74 (d, J = 6.7 Hz, ,, N
3H), 1.57 (m, 2H).

F Alm tip ao R_.

HN-',0 N-(446-Amino-5[1-(2-chloro=
3 as in 40 3,6-difluoro-phenyl)-0.1 Example I-pyridin-3-y1)-phenyl)-[M+1]
F
I '-.

methanesulfonamide if& 0 -N

44' a "H=

F

=

No. Structure Name Met 1C50 Procedure MS miz (1-1M) (M+1) 341-(2-Chloro-3,6-difluoro-11101 phenyl)-ethoxy1-544-(1,1-3 as in 1-365 dioxo-1Iambda*6* 0.14 Examplel-r 1 -- -isothiazolidin-2-y1)-phenyl]-EM+1]

Ai. 0 --N pyridin-2-ylamine IIIW 01 NH, fl H 1,---N-(4-{6-Amino-541-(2,6-(300MHZ, CDCI3) 69.75 (s, 1H), 7.88(d, 1H), ' 3 as in IP dichloro-3-fluoro-phenyl)-7.55 (q, 1H), 7.45 (t, 1H), 7.35 (d, 2H), 7.18 (d, 1-366 I ethoxyl-pyridin-3-y1}-phenyl)- 0.076 Example I-135 2H), 6.9 (d, 1H), 6.10 (q, 1H), 5.85 (s, 2H), [M+11 0 I --" methanesulfonamide 2.99(s, 3H),1.80 (d, 3H).
11101 . NH, .

F

341-(2,6-Dichloro-3-fluoro-(300MHZ, CDCI3) 6 7.80 (d, 1H), 7.55 (q, 1H), 1-367 I I '.. phenyl)-ethoxy]-5-phenyl- 0.5 3 7.45 (t, 1H), 7.35 (dd, 4H), 7.25 (m, 1H), 6.95 (d, [M+1]
iiii. o ''N pyridin-2-ylamine 1H), 6.12 (q, 1H), 5.85 (s, 2H), 1.80 (d, 3H).

IV a NI-1, F

N-(4-{6-Amino-5-1(R)-1-(2-TEA chloro-3, 3 as in (300MHZ, CDCI3) 6 9.80 (s, 1H), 7.70(d, 1H), IIII 6-difluoro-phenyI)-0.066 Example 1- 7.43 (m, 3H), 7.30 (ddd, 1H), 7.25 (d, 1H), 7.18 ethoxy]-pyridin-3-y1}-phenyl)-IM+1]
135 (m, 2H), 6.10 (q, 1H), 2.95(s, 3H),1.75 (d, 3H).
0 ' N methanesulfonamide NH, F

\

341-(2,6-Dichloro-3-fluoro-=

1-369 I phenyl)-ethoxy1-5-thlophen-3. 0.055 F AIL 0 ..., ..

[M+1]
yl-pyridin-2-ylamine VP a NH, 5-Benzotbithiophen-2-y1-341-s......, (2,6-dichloro-3-fluoro-1.95 1 phenyl)-ethoxyj-pyridin-2-[Mil]

F du ylamine 1111111..- ci NH, HNIN'') 4-Methyl-piperazine-1-(300MHZ, CDCI3) 67.71 (s, 1H), 7.40 (d, 2H), carboxylic acid (4-{6-amino-7.32-7.23 (m, 3H), 7.06 (t, 1H), 6.99(s, 1H), 6.77 1-371 541-(2,6-dichloro-3-fluoro- 0.057 (bs, 1H), 6.11 (q, 1H), 5.62 (s, 2H), 3.60 (m, 4H), [M+1]
pheny1)-ethoxyl-pyricl 0 L--"' 2.57 (m, 4H), 2.40 (s, 3H), 1.87 (d, 3H).
phenyl)-amide ciin-3-y1)- NE', F

,, - 1-(446-Amino-541-(2,6-dichloro-3-fluoro-phenyl)-10 as in 1-372 ethoxy]-pyridin-3-y1)-phenyl)- 0.21 Example I-[M+1]
isi...... N 3-(2-pyrrolidin-1-yl-ethyl)- 371 WI Cl NH, urea F

No. Structure , Name Met IC50 Procedure 1H-NMR MS tn/z (M+1) (A) HNIN^-" 14 1-(4-(6-Amino-5-[1-(2,6- 0.064 Example(300MHZ, CDCI3) 67.68 (s, 2H), 7.45 (m, 2H), 40 dichloro-3-fluoro-phenyl)-10 as in 7.36 (d, 2H), 7.25 (m, 2H), 6.95 (s, 2H), 6.55 (q, I -i ethoxyi-pyridin-3-y1}-pheny1)-1H), 4.86 (s, 2H), 3.63 (t, 2H), 3.31 (m, 3H), 1.87 [M+1) I
nalt, 0 , N 3-(2-hydroxy-ethyl)-urea (d, 3H).

Illp ci NH, F

i.../.
NNJ--- 1-(4-{6-Amino-541-(2,6-10 as in (300MHZ, CDCI3) 67.88 (s, 1H), 7.55 (m, 3H), 1/0 dichloro-3-fluoro-phenyl)-7.35 (d, 2H), 7.23 (m, 3H), 6.95 (s, 1H), 6.55 (q, 548.2 .1-374 ethoxy]-pyridin-3-y1}-pheny1)- 0.062 Example 1- 1H), 4.86 (s, 2H), 3.71 (t, 2H), 3.31 (m, 6H), 2.51 [M+1]

3-(2-morpholin-4-yl-ethyl)- 371 (m, 4H), 1.86 (d, 3H).
. urea 4=-"' GI N".

HNINO... NH (R)-3-Amino-pyrrolidine-1-10 as in (300MHZ, CDCI3) 67.65 (m, 4H), 7.31 (m, 3H), carboxylic acid (4-{6-amino-503.8 7.19(m, 2H), 6.37 (m, 1H), 4.87(s, 2H), 3.95 (m, 1-375 541-(2,6-dichloro-3-fluoro-0.053 Example 1-1H), 3.80 (m, 1H), 3.60 (m, 2H), 3.31 (m, 2H), [M+1]
phenyl)-ethoxyl-pyridin 371 2.45 (m, 1H), 2.18 (m, 1H), 1.95 (d, 3H).
10 I ''' -3-yll-phenyl)-amide F

HNI 0.....NH, (S)-3-Amino-pyrrolidine-1- 10 as in (300MHZ, CDCI3) 07.85 (m, 4H), 7.31 (m, 3H), 40 carboxylic acid (4-{6-amino-504.1 7.19 (m, 2H), 6.37 (m, 1K), 4.87 (s, 2H), 3.95 (m, 1-376 541-(2,6-dichloro-3-fluoro-0.052 Example I-1H), 3.80 (m, 1H), 3.60 (m, 2H), 3.31 (m, 2H), [M+11 I phenyl)-ethoxyl-pyridin 2.45 (m, 1K), 2.18 (m, 1H), 1.95 (d, 3H).

-3-y1}-phenyl)-amide 40 c, = NH, F

I -Crp 1-(4-{6-Amino-541-(2,6-dichloro-3-fluoro-phenyl)- 10 as in 1-377 ethoxyl-pyridin-3-y1}-phenyl)- 0.04 Example 1-[M+1]
3-(1-methyl-piperidin-4-yI)- 371 c?.=-xl--0 -"
urea F

T 0,-H p 1-(4-{6-Amino-541-(2-chloro-40 3,6-difluoro-phenyl)-ethoxy]-10 as in 1-378 pyridin-3-y1}-phenyl)-3-(1-0.038 Example 1-[M+1]
I :. N

Ail 0 methyl-piperidin-4-yI)-urea iiir a NH, F

I
H 9.õ .., (R)-3-Amino-pyrrolidine-1-10 carboxylic acid (4-{6-amino-10 as in HO

1-3795-[1-(2-chloro-3,6-difluoro-0.069 Example I-I[M+l] phenyl)-ethoxy)-pyridin-3-y1}-O --"
phenyI)-amide ICC.1: NH.

F

NH, ni.m.h 0"-. 2 (S)-3-Amino-pyrrolidine-1-WI HCI carboxylic acid (4-(6-amino-10 as in 1-3805-[1-(2-chloro-3,6-difluoro-0.075 Example I-[M+1]

1 , N phenyl)-ethoxy}-pyridin-3-y1}-IP a 0 NH, phenyl)-amide F

No. Structure Name Met 1C50 Procedure MS in/z (PM) (N1+1) jr,ori 1-(4-{6-Amino-541-(2-chloro-10 as in (300MHZ, CDCI3) 07.69 (d, 2H), 7.37 (d, 2H), 3,6-difluoro-phenyl)-=
0.11 Example- 7.25 (d, 2H), 7.15 (m, 2H), 7.09 (d, 2H), 6.00 (q, pyridin-3-0}-phenyl)-3-(2-1 1H), 4.86 (s, 2H), 3.63 (t, 2H), 3.32(m, 3H), 1.83 [M+11 0 I ,N hydroxy-ethyl)-urea 37, (d, 3H).

HN N, 11 ....", 4-Methyl-piperazine-1-(300MHZ, CDCI3) 07.78 (s, 1H), 7.41 (d, 2H), Ir carboxylic acid (4-{6-amino-10 as in 7.29 (d, 2H), 7.09 (s, 1H), 7.05 (m, 1H), 6.95 (m, 541-(2-chloro-3,6-difluoro-0.082 Example I- 1H), 6.56 (bs, 1H), 6.00 (q, 1H), 5.25 (s, 2H), -. phenyl)-ethoxy}-pyridin-3-y 3.58 (m, 4H), 2.53 (m, 4H), 2.38 (s, 3H), 1.84 (d, [M+1]
0 I ,..= N, 1}-pheny1)-amide 3H).

1110 c, NH

F

HN ti -1-(4-{6-Amino-541-(2-chloro-10 as in 3,6-difluoro-phenyl)-ethoxyl-0.11 Example 1-pyridin-3-y1}-pheny1)-3-(2-[M+1]
0 - N pyrrolidin-1-yl-ethyl)-urea "2 =

1 ......, r--.

1-(4-{6-Amino-541 -(2-chloro-10 asin (300MHZ, CDCI3) 07.83 (d, 1H), 7.29 (m, 5H), 40 3,6-difluoro-pheny1)-7.00 (m, 4H), 5.94 (q, 1H), 4.87 (bs, 2H), 3.67 533.7 0.13 Example ethoxy}- I-. pyridin-311}-pheny1)-3-(2-371 (m, 4H), 3.38 (m, 2H), 2.52 (m, 4H), 1.86 (d, [M+1]
morpholin-4-yl-ethyl)-urea 3H).
j110) a NH=
F

0 N,......4-HN.1,0 (R)-2-Pyrrolidin-1-ylmethyl-(300MHZ, CDCI3) 07.93 (s, 1H), 7.67 (d, 2H), pyrrolidine-1-carboxylic acid 10 as in 7.27 (d, 2H), 6.95 (m, 4H), 6.70 (q, 1H), 4.84 (s, 666.8 (4-{6-amino-541-(2-chloro-0.13 Example I- 2H), 3.85 (m, 1H), 3.75(m, 1H), 3.40 (m, 1H), rm+ii 40 3,6-difluoro-phenyl)-ethoxyj-2.90 (m, 4H), 2.65 (m, 4H), 2.10 (m, 3H), 1.83 (d, '="' pyridin-3-y1}-phenyl)-amide 3H), 1.9-1.7 (m, 3H).

11" a NH=
r o 346-Amino-541-(2,6-3 as in dichloro-phenyl)-ethoxy]-Example I-[M+1]
I N pyridin-3-yll-benzoic acid 1401 NCI, CI

T

(300MHZ, CDCI3) 07.86 (s, 1H), 7.39 (m, 4H), (3-{6-Amino-541-(2,6-7.31 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (m, dichloro-pheny1)-ethoxyl-1H), 4.93 (s, 2H), 4.65 (m, 1H), 3.56 (m, 1H), 1-387---1-- 4-----"---c, .,-,. "
pyridin-3-y1}-pheny1)-0.16 4 2.95 (m, 1H), 2.79 (m, 1H), 2.71 (m, 1H), 2.44 [M+1]
((3R,5S)-3,5-dimethyl-(m, 1H), 1.84 (d, 3H), 1.95 (m, 1H), 1.25 (d, 3H), piperazin-1-yI)-methanone 1.17 (d, 3H).

r (300MHZ, CDCI3) 07.85 (s, 1H), 7.39 (m, 4H), io ,o (3-{6-Amino-541-(2,6-7.32 (d, 2H), 7.15 (t,iH), 7.02 (5, 1H), 6.15 (m, 0 dichloro-phenyl)-ethoxyj-4 as in 1H), 4.90 (s, 2H), 4.65 (m, 1H), 3.65 (m, 1H), 1-388 cl... I 'N
pyridin-3-y1}-phenyl)-(4-0.1 Example 1- 3.05 (m, 2H), 2.80 (m, 1H), 2.65 (m, 4H), 2.30 [M+1]
, NH, pyrrolidin-1-yl-piperidin-1-yI)-387 (m, 1H), 2.05 (m, 1H), 1.86 (d, 3H), 1.81 (m, methanone 3H), 1.52 (m, 4H).

, =
No.
Structure Name Met IC50 Procedure MS intz (11M) (M+1) _ 1-389 cy, _.(j..ar¨.
3-(6-Amino-541-(2,6-(300MHZ, CDCI3) 67.88 (s, 1H), 7.82 (s, 1H), 4 as in 7.69 (d, 1H), 7.45 (m, 3H), 7.32 (d, 2H), 7.15 (t, dichloro-phenyl)-ethoxy]-0.13 Example- 1H), 7.06 (5, 1H), 6.99 (bm, 1H), 6.16 (q' 1H), [M+1j pyridin-3-y1}-N-(2-pyrrolidin-1.
ykethyl)-ethyl) ' N

4.93 (s, 2H), 3.61 (m, 2H), 2.78 (m, 2H), 2.63 (m, a NH, 4H), 1.87 (d, 3H), 1.82 (m, 4H).
-3-(6-Arnino-541-(2,6-(300MHZ, CDCI3) 67.89 (s, 1H), 7.82 (s, 1H), 4 as in 7.65 (d, 1H), 7.48 (m, 3H), 7.32 (d, 2H), 7.15 (t, dichloro-phenyl)-ethoxy].

0.12 Example I- 1H), 7.06 (s, 1H), 6.78 (bm, 1H), 6.16 (q, 1H), pyridin-3-yI}-N-(2-morpholin-[M+l]
4-yl-ethyl)-benzamide 4.95 (s, 2H), 3.73 (m, 4H), 3.59 (m, 2H), 2.62 (m, L
NH, 2H), 2.51 (m, 4H), 1.87 (d, 3H).
,...L.g.., xo (346-Amino-541-(2,6-(300MHZ, CDCI3) 67.861H) (d, , 7.37 (m, 4H), 'L) dichloro-phenyl)-ethoxy}-4 as in' 1H) 02 (s 1H) 15 (t 30 (d 7., 2H), 7., , 7., , 6.15 (m, pyridin-3-y1}-phenyl)-((S)-2-0.098 Example I-pyrrolidin-1-ylmethyl-541[M+1]
1H), 4.91 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), pyrrolidin-l-methanone-methanone 2.70 (m, 4H), 1.84 (d, 3H), 1.70-2.0 (m, 10H) 1-392 llo _N pi^"0 3-(6-Amino-541-(2,6-(300MHZ, CDCI3) 6 8.60 (bm, 1H), 7.89 (s, 1H), dichloro-phenyI)-ethoxy]
pyridin-3-yI}-N-(3-pyrrolid-in-1-4 as in 7.65 (d, 1H), 7.45 (m, 3H), 7.32 (d, 2H), 7.15 (t, yl-propyI)-benzamide 0.072 Example I- 1H), 7.04 (s, 1H), 6.17 (q, 1H), 4.89 (s, 2H), 3.62 (m, 2H), 2.78 (m, 2H), 2.66 (m, 4H), 1.86 (d, 3H), [M+11 11,0;c1 N", 1.83 (m, 2H), 1.79 (m, 4H).
r^-trrL
L) N42-(4-Acetyl-piperazin-1-y1) (300MHZ, CDCI3) 07.88 (s, 1H), 7.81 (s, 1H), ethy11-3-(6-amino-541-(2,6-(2,6 4 as in 7.63 (d, 1H), 7.48 (m, 3H), 7.32 (d, 2H), 7.15 (t, 0.079 Example 1- 1H), 7.06 (s, 1H), 6.69 (bm, 1H), 6.16 (q, 1H), dichloro-phenyl)-ethoxy}-fiv1+11 4.94 (s, 2H), 3.65 (m, 4H), 3.50 (m, 2H), 2.62 (m, 6I ':1 pyridin-3-yI}-benzamide 2H), 2.52 (m, 4H), 2.09 (s, 3H), 1.87 (d, 3H), r rr (300MHZ, CDCI3) 07.89 (s, 1H), 7.73 (s, 1H), q=-' 3-(6-Amino-541-(2,6-7.65 (d, 1H), 7.50(d, 1H), 7.43 (t, 1H), 7.32 (d, dichloro-phenyl) as in 0.061 Example 1-ethoxy]-2H), 7.16 (t, 11-1), 7.04 (s, 1H), 6.15 (m, 1H), 6.05 i pyridin-3-yI}-N-(1-methyl-(bd, 1H), 4.92 (s, 2H), 4.03 (m, 1H), 2.94 (m, 2H), [M+1]
piperidin-4-y1)-benzamide 3872.38 (s, 3H), 2.26 (m, 2H), 2.09 (m, 2H), 1.86 (d, 3H), 1.70 (m, 2H).
(3-{6-Amino-541-(2,6-(300MHZ, CDCI3) 07.85 (s, 1H), 7.40 (m, 4H), 1r, l.,,14,dichloro-phenyl)-elboxy]-4 as in 7.30 (d, 2H), 7.16 (t, 1H), 7.02 (s, 1H), 6.15 (m, pyridin-3-y1}-phenyl)-(4-0.058 Example I- 1H), 4.93 (s, 2H), 3.82 (m, 2H), 3.45 (m, 2H), i methyl-piperazin-1-yI)-2.52 (m, 2H), 2.38 (m, 2H), 2.33 (s, 3H), 1.86 (d, [M+1]
,N

N
methanone 2H). R, T ISO *
(3-{6-Amino-541-(2,6-N
dichloro-phenyl)-ethoxy}-4 as in (300MHZ, CDCI3) 67.86 (d, 1H), 7.37 (m, 4H), I

pyridin-3-y1}-phenyl)-((R)-2-0.18 Example 1-7.30 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (m, ;
pyrrolidin-1-ylmethyl-1H), 4.91 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), [M+1]....--ri pyrrolidin-1-yI)-methanone 2.70 (m, 4H), 1.84 (d, 3H), 1.70-2.0 (m, 10H) so (3-(6-Amino-541 -(2,6-dichloro-phenyl)ethoxy]-4 as in (300MHZ, CD30D) 67.74 (s, 1H), 7.69-7.43 (m, 6H), 7.32 (t, 1H), 7.22 (s, 1H), 6.42 (m, 1H), 4.05-I
pyridin-3-y1}-phenyl)-((S)-3-0.055 Example I-3.60 (m, 4H), 3.50 (m, 1H), 2.50 (m, 1H), 2.18 [M+1]
110 .
"'I, amino-pyrrolidin-1-y1)-387 methanone (m, 1H), 1.90 (d, 3H).
1.01 /40 7 'D' NH, (3-{6-Amino-541-(2,6-dichloro-phenyl)ethoxy]-4 as in (300MHZ, CD30D) 67.74 (s, 1H), 7.69-7.43 (m, 6H), 7.32 (t, 1H), 7.22 (s, 1H), 6.42 (m, 1H), 4.05-pyridin-3-yll-phenyl)-((R)-3-0,072 Example I-I

N
amino-pyrrolidin-1-y1)-3.60 (m, 4H), 3.50 (m, 1H), 2.50 (m, 1H), 2.18 [M+11 , ,-, methanone (m, 1H), 1.90 (d, 3H). 0 MCI

' - 181 -Structure Name Met IC50 Procedure 1H-NMR MS tn/z No.

(M+1) (I-IM) O OH

4-(6-Amino-541-(2,6- 3 as in 1-399 dichloro-phenyl)-ethoxy1-Example I-[M+1]

Ipyridin-3-y1}-benzoic acid N

* H

CI

(300MHZ, CDCI3) 67.89 (s, 1H), 7.79 (d, 2H), V 4-(6-Amino-5-[1-(2,6-7.43 (d, 2H), 7.32 (d, 2H), 7.15 (t, 1H), 7.02 (s, dichloro-phenyl)-01 0.059 4 1H), 6.87 (bm, 1H), 6.15 (q, 1H), 4.93 (s, 2H), 501[M+1]

pyridin-3-y1}-N-(2-pyrrolidin-1.
3.58 (m, 2H), 2.72 (m, 2H), 2.58 (m, 4H), 1.87 (d, i 1 ykethyl)-benzamide . .41 3H), 1.80 (m, 4H).

1401 ci NH, = 11,.....,,,,,`,, (300MHZ, CDCI3) 67.90 (s, 1H), 7.79 (d, 2H), L..,!, 4-(6-Amino-541-(2,6-4 as in 7.44 (d, 2H), 7.32 (d, 2H), 7.15 (t, 1H), 7.03 (s, dichloro-pheny1)-ethoxyl-1-401 110 0.073 Example I- 1H), 6.77 (bm, 1H), 6.15 (q, 1H), 4.95 (s, 2H), pyridin-3-yI}-N-(2-morpholin-[M+11 400 3.74 (m, 4H), 3.57 (m, 2H), 2.61 (m, 2H), 2.52 I " 4-yl-ethyl)-benzamide (m, 4H), 1.87 (d, 3H).

NH, ON

k .1....
(4-16-Amino-541-(2,6- (300MHZ, CDCI3) 67.87 (s, 1H), 7.52 (m, 2H), = tli....../' dichloro-phenyl)-ethoxyl- 4 as in 7.39 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 7.01 (s, pyridin-3-y1)-phenyl)-((S)-2- 0.068 Example I- 1H), 6.15 (q, 1H), 4.91 (a, 2H), 4.45 (m, 1H), 3.41 rhi+13 pyrrolidin-1-ylmethyl- 400 (m, 2H), 2.70 (m, 4H), 1.86 (d, 3H), 1.70-2.0 (m, L

pyrrolidin-1-yI)-methanone 10H) i I" ci 0 to,;:64 III"

O I4.......1 (300MHZ, CDCI3) 67.89 (s, 1H), 7.76 (d, 2H), Alit lir I"I6-Amino-5-[1-(2,6-4 as in 7.42 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 7.02 (s, dichloro-phenyl)-ethoxy]-501[M+1]
1-403 0.062 Example I- 1H), 6.15 (q, 1H), 5.97 (bd, 1H), 4.94 (s, 2H), pyridin-3-yI)-N-(1-methyl-400 4.03 (m, 1H), 2.85 (m, 2H), 2.32 (s, 3H), 2.18 (m, IN piperidin-4-yI)-benzamide 2H), 2.06 (m, 2H), 1.86 (d, 3H), 1.60 (m, 2H).

VI Po a NH, (1-yri O N.........).., (446-Amino-541-(2,6- (300MHZ, CDCI3) 67.88 (s, 1H), 7.41 (m, 4H), dichloro-pheny1)-ethoxyl- 4 as in 7.32 (d, 2H), 7.15 (t, 1H), 7.02 (s, 1H), 6.15 (q, 1-404 I. pyridin-3-y1}-pheny1)- 0.052 Example I- 1H), 4.92 (s, 2H), 4.62 (m, 1H), 3.66 (m, 1H), [M+1) ((3R,5S)-3,5-dimethyl- 400 2.82 (m, 2H), 2.68 (m, 1H), 2.40 (m, 1H), 1.87 (d, 1 piperazin-1-y1)-methanone 3H), 1.65 (m, 1H), 1.15 (d, 3H), 0.98 (d, 3H).

I
0 ...- N

VI a NH, L...õ..N._,C (300MHZ, CDCI3) 67.90 (s, 1H), 7.78 (d, 2H), T N-[2-(4-Acetyl-piperazin-1-y1) 4 as in 7.44 (d, 2H), 7.32 (d, 2H), 7.15 (t, 1H), 7.03 (s, ethy11-446-amino-5-(1-(2,6-(2,6 0.062 Example I- 1H), 6.69 (bm, 1H), 6.15 (q, 1H), 4.96 (s, 2H), [M+1) dichloro-phenyl)-ethoxyj-400 3.66 (m, 2H), 3.61 (m, 2H), 3.50 (m, 2H), 2.62 pyridin-3-y1}-benzamide Uct :H, (m, 2H), 2.52 (m, 4H), 2.10 (s, 3H), 1.87 (d, 3H).

0 11...õ...-.........0 (300MHZ, CDCI3) 68.80 (bm, 1H), 7.90 (s, 1H), 4-{6-Amino-541-(2,6-4 as in 7.79 (d, 2H), 7.40 (d, 2H), 7.31 (d, 2H), 7.15 (t, SO

dichloro-phenyl)-ethoxy)-1-406 0.061 Example I- 1H), 7.02 (s, 1H), 6.15 (q, 1H), 4.91 (s, 2H), 3.62 [M+1]
pyridin-3-yI}-N-(3-pyrrolidin-1=
=
400 (m, 2H), 2.78 (m, 2H), 2.66 (m, 4H), 1.87 (d, 3H), ' 1 '.=
yl-propyI)-benzamide 1.85 (m, 4H), 1.25 (m, 2H).

uur c, NH, No. Structure Name Met 1C50 Procedure MS rniz (M+1) (PM) _ jF12 (4-{6-Amino-54142,6-dichloro-phenylyethoxyF
4 as in (300MHZ, CD30D) 67.74-7.24 (m, 9H), 6.39 (m, 1-407 pyridin-3-y1}-phenyl)4(S)-3- 0.05 Example I- 1H), 4.05-3.60 (m, 4H), 3.60 (m, 1H), 2.50 (m, [M+11 1 I --, aminopyrrolidin-1-yI)-400 1H), 2.18 (m, 1H), 1.90 (d, 3H).

methanone 40 0 N.....HN, HCI

. 0 (446-Amino-54142,6-dichloro-pheny1)-ethoxy]-4 as in (300MHZ, CD30D) 67.74-7.24 (m, 9H), 6.39 (m, 1-408 pyridin-3-y1}-phenyl)4(R)-3- 0.049 Example 1- 1H), 4.06-3.60 (m, 4H), 3.50 (m, 1H), 2.50 (m, [M+1]
1 1 ....--,4 amino-pyrrolidin-1-yI)-400 1H), 2.18 (m, 1H), 1.90 (d, 3H).

iti 0 methanone -"r". a NH' HCI

, N C-- (446-Amino-54142,6-(300MHZ, CDCI3) 67.87 (s, 1H), 7.52 (m, 2H), dichloro-phenyl)ethoxy]-4 as in 7.39 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 7.01 (s, pyridin-3-y1}-phenyl)4(R)-2- 0.081 Example I- 1H), 6.15 (q, 1H), 4.91 (s, 2H), 4.45 (m, 1H), 3.41 rm+11 40 pyrrolidin-1-ylmethyl-400 (m, 2H), 2.70 (m, 4H), 1.86 (d, 3H), 1.70-2.0 (m, pyrrolidin-1-yI)-methanone 10H) i I. CI NI-1 ,.......0 (300MHZ, CDCI3) 67.87 (s, 1H), 7.39 (m, 4H), .
o N......) (446-Amino-54142,6-7.32 (d, 2H), 7.17 (t, 1H), 7.01 (s, 1H), 6.15 (q, dichloro-phenyl)-ethoxy}-4 as in Example 1- 1H), 4.91 (s, 2H), 4.60 (m, 1H), 3.76 (m, 1H), 1-410 0 pyridin-3-y1}-phenyl)-(4- 0.055 541[M+1]
3.00 (m, 2H), 2.60 (m, 4H), 2.28 (m, 1H), 1.95 pyrrolidin-1-yl-piperidin-1-y1)-i (m, 2H), 1.86 (d, 3H), 1.81 (m, 4H), 1.56 (m, I methanone iii LW3' a "112 re 0,N,) (4-{6-Amino-5-[1-(2,6-(300MHZ, CDCI3) 67.87 (s, 1H), 7.40 (m, 4H), dichloro-pheny1)-ethoxyl-4 as in Example I- 7.31 (d, 2H), 7.15 (t, 1H), 7.01 (s, 1H), 6.15 (q, 1-411 0 pyridin-3-y1}-pheny1)44- 0.053 1H), 4.92 (s, 2H), 3.78 (m, 2H), 3.52 (m, 2H), [M+11 methyl-piperazin-1-yI)-i 2.41 (m, 4H), 2.34 (s, 3H), 1.86 (d, 3H).

methanone 40 ci NH, ON

1,....._, (S)-2-Pyrrolidin-1-ylmethyl-11 pyrrolidine-1-carboxylic acid (300MHZ, CDCI3) 6 9.05(br, 1H), 7.70 (s, 1H), II: N)....) (346-amino-54142,6-7.05 (t, 1H), 6.70 (s, 1H), 6.02 (q, 1H), 5.01 (s, 1-412 I I dichloro-3-fluoro-phenyl)- 0.067 11 2H), 4.15 (dd, 2H), 3.75 (m, 2H), 3.25(m, 1H), [M+1]
ethoxyl-pyridin-3-y1}-prop-2-2.75 (m, 3H), 2.45 (m, 3H), 2.05 (m, 1H), 1.78 (d, ` ynyl) 3H), 1.65 (br, 7H).

-amide 1101 a NH, F

cNcf 4-Methyl-piperazine-1-(300MHZ, CDCI3) 6 7.75(s, 1H), 7.30 (m, 2H), carboxylic acid (346-amino-7.05 (t, 1H), 6.75 (s, 1H), 6.02 (q, 1H), 5.01 (s, 1-413 . 5-[142,6-dichloro-3-fluoro- 0.056 11 2H), 4.20 (d, 2H), 3.45 (m, 4H), 2.45 (m, 4H), [M+1}
I phenylyethoxyl-pyridin-3-y a 2.25 (s, 3H), 1.81 (d, 3H).
NH, 1}-prop-2-yny1)-amide il*0 No. Structure Name Met 1C50 Procedure 1H-NMR

(tIM) (M+1) c) Ich,) 4-Pyrrolidin-1-yl-piperidine-1-(300MHZ, CDCI3) 67.75(s, 1H), 7.30 (m, 2H), 4o carboxylic acid (3-(6-amino-7.10 (t, 1H), 6.70 (s, 1H), 6.02 (q, 1H), 5.01 (s, 534 1-414 541-(26-dichloro-3-fluoro-0.058 11 2H), 4.20 (d, 2H), 3.89(d, 1H) 2.89 (t, 2H), 2.55 [M+1]
phenyl)-pyridin-3-y1}- (s, 4H), 2.21 (m, 2H), 1.90(d, 2H),1.81 (d, 3H), prop-2-ynyI)-amide 1.45(m, 2H), 1.25(m, 2H).
ir-jc.: NH, F

(3R,55)-3,5-Dimethyl-1:1,1ral piperazine-1-carboxylic acid (300MHZ, CDCI3) 6 7.75(s, 1H), 7.30 (m, 2H), (346-amino-541-(2,6- 7.05 (t, 1H), 6.75 (s, 1H), 6.02 (q, 1H), 5.01 (s, ...,i 1-415 dichloro-3-fluoro-phenyl)-0.063 11 2H), 4.78(s, 1H), 4.20 (d, 2H), 3.85 (d, 1H), [M+1]
ethoxy] 2.85(m, 4H), 2.45 (t, 1H), 1.89 (s, 3H), 1.01 (d, -pyridin-3-y1)-prop-2-yny1)- 6H).

F amide II 8 Lõ.11, 1-(3-(6-Amino-541-(2,6-(300MHZ, CDCI3) 6 7.75(s, 1H), 7.30 (m, 2H), dichloro-3-fluoro-pheny1)- 7.05 (t, 1H), 6.70 (s, 1H), 6.00 (q, 1H), 5.25(m, 1-416 ethoxy]-pyridin-3-yI)-prop-2-0.051 11 1H), 5.05 (s, 2H), 4.80(d, 1H), 4.15 (d, 2H), 2.75 [MO]
ynyI)-3-(1-methyl-piperidin-4- (d, 2H), 2.20(s, 3H), 2.10 (t, 2H), 1.95(d, 2H), yI)-urea 1.75 (d, 3H), 1.45 (d, 2H).

F

17(3-(6-Amino-541-(2,6- (300MHZ, CDCI3) 6 7.70(s, 1H), 7.30 (m, 2H), dichloro-3-fluoro-phenyl)- 7.05 (t, 1H), 6.70 (s, 1H), 6.00 (q, 1H), 5.30(m, 1-417 ,. ethoxyl-pyridin-3-y1)-prop-2-0.062 11 1H), 5.01 (s, 2H), 4.15 (d, 2H), 3.25 (m, 2H), [MO]
yny1)-3-(3-pyrrolidin-1-yl- 2.50(m, 6H), 1.80(d, 3H), 1.82 (m, 4H), 1.60 (m, propyI)-urea 2H).
, 1-418 cfrx( 0 8 4 LJ 1-(346-Amino-541-(2,6-(300MHZ, CDCI3) 6 7.70(s, 1H), 7.30 (m, 2H), dichloro-3-fluoro-phenyI)- 7.05 (t, 1H), 6.70 (s, 1H), 6.00 (q, 1H), 5.45(s, ethoxyl-pyridin-3-y1)-prop-2- 0.052 11 1H), 5.15 (s, 2H), 4.15 (d, 2H), 3.25 (m, 2H), WO]
ynyI)-3-(2-pyrrolidin-1-yl- 2.60(t, 2H), 2.50(m, 4H), 1.80(d, 3H), 1.70 (s, . NH, ethyl)-urea 4H).
F

.

1-(3-{6-Amino-541-(2,6- (300MHZ, CDCI3) 6 7.73(s, 1H), 7.28 (m, 2H), dichloro-3-fluoro-phenyl)- 7.05 (t, 1H), 6.70 (s, 1H), 6.00 (q, 1H), 5.25(s, 510 1-419 cxj.,:. õõ ethoxyl-pyridin-3-y1}-prop-2-0.055 11 1H), 5.15 (s, 2H), 4.15 (d, 2H), 3.65 (m, 4H), [MO]
yny1)-3-(2-morpholin-4-yl- 3.25(m, 2H), 2.45(m, 6H), 1.80(d, 3H).
ethyl)-urea itirn 0 1-(3-{6-Amino-5-11-(2,6-(300MHZ, CDCI3) 6 7.70(s, 1H), 7.30 (m, 2H), ..41 ' dichloro-3-fluoro-phenyI)-7.05 (t, 1H), 5.70 (s, 1H), 6.00 (q, 1H), 5.10(s, 524 1-420 ethoxyl-pyridin-3-y1}-prop-2- 0.064 11 2H), 4.15 (d, 2H), 3.70 (m, 6H), 3.20(s, 2H), [M+1j - ynyI)-3-(3-morpholin-4-yl-2.50(m, 4H), 1.80(d, 3H), 1.65(m, 2H).
propyI)-urea a (R)-2-Pyrrolidin-l-ylmethyl-ii C pyrrolidine-1-carboxylic acid D
(300MHZ, CDCI3) 6 9.05(br, 1H), 7.70 (s, 1H), (346-amino-541-(2,6- 7.05 (t, 1H), 6.70 (s, 1H), 6.02 (q, 1H), 5.01 (s, 534 1-421 I I dichloro-3-fluoro-phenyl)-0.071 11 2H), 4.15 (dd, 2H), 3.75 (m, 2H), 3.25(m, 1H), [M+l]
ethoxyl-pyridin-3-yll-prop-2- 2.75 (m, 3H), 2.45 (m, 3H), 2.05 (m, 1H), 1.78 (d, ' 3H), 1.65 (br, 7H).
Iynyl) -amide I. a0 :õ

F

NI, 4 3-(1-(2,6-Dichloro-3-fluoro-pheny1)-ethoxyl-5-(3-1-422 010.071 1 dimethylamino-prop-1-ynyI)-[MO]
F rail 0 ,-. N pyridin-2-ylamine IV ci NH, , No.
Structure Name Met IC50 Procedure MS fit&
(IAA
(M+1) /1õ..NH, (3-{6-Amino-641-(2,6-dichloro-3-fluoro-phenyl)-0.062 a ethoxA-pyridin-3-ylyprop-2-.
[M+1) F

N
ynyl)-urea 1M1>III CI
NH, Ijirt N-(3-{6-Amino-541-(2,6-II

(300MHZ, CDCI3) 67.74 (s, 1H), 7.45 (bm, 1H), dichloro-3-fluoro-phenyl)-7.31 (dd, 1H), 7.07 (t, 11-1), 6.73 (s, 1H), 6.00 (q, =
1 '''.
ethoxyypyridin-3-y1)-prop-2-0.016 F
a , N
yny1)-2-piperidin-1-yl-1H), 4.99 (s, 2H), 4.26 (d, 2H), 2.98(s, 2H), 2.46 [M+l]
II1J111- a NH, acetamide (m, 4H), 1.81 (d, 3H), 1.59 (m, 4H), 1.45 (m, 2H).
II
Clo N-(3-{6-Amino-5-[1-(2,6-II

dichloro-3-fluoro-phenyl)-(300MHZ, CDCI3) 67.74 (s, 1H), 7.45 (bm, 1H), 7.31 (m, 2H), 7.08 (t, 1H), 6.71 (s, 1H), 6.00 (q, .
I '"
ethoxyl-pyridin-3-y1}-prop-2-0.027 1H), 5.02 (s, 2H), 4.27 (d, 2H), 3.73 (m, 4H), [M+1]

F iii,h, a , 14 ynyI)-2-morpholin-4-yl-3.05 (s, 2H), 2.54 (m, 4H), 1.81 (d, 3H).

mr a NH, acetamide II ilir9 N-(36-Amino-5-(1-(2,6-(300MHZ, CDCI3) 67.74 (s, 1H), 7.37 (bm, 1H), dichloro-3-fluoro-phenyl)-7.31 (dd, 1H), 7.08 (t, 1H), 6.72 (s, 1H), 6.00 (q, ' I s' ethoxyl-pyridin-3-y1}-prop-2- <0.0091 Al 0 ' N
1H), 5.01 (s, 2H), 4.27 (d, 2H), 3.18 (s, 2H), 2.63 [M+1]
F
yny1)-2-pyrrolidin-1-yl-kw a NH, (m, 4H), 2.01 (m, 2H), 1.81 (d, 3H), 1.80 (m, 2H).
acetamide (300MHZ, CDCI3) 67.71 (s, 1H), 7.45 (bm, I H), oro..0-N-(3-{6-Amino-5-11-(2,6-7.31 (dd, 1H), 7.07 (t, 1H), 6.72 (s, 1H), 5.99 (q, II
dichloro-3-fluoro-phenyl)-1H), 5.06 (s, 2H), 4.42 (m, 1I-1), 4.25 (m, 2H), 1-427.-"
ethoxyl-pyridin-3-y1}-prop-2- 0.011 ynyI)-2-((R)-3-hydroxy-3.21 (s, 2H), 3.00 (m, 1H), 2.80 (m, 1H), 2.71 (m, [M+11 õ
1H), 2.45 (m, 1H), 2.22 (m, 11-1), 1.79 (d, 3H), ILA. NH, pyrrolidin-1-yI)-acetamide 1.78 (m, 2H).

Ulry4^) N-(3-{6-Amino-5-[1-(2,6-(300MHZ, CDCI3) 67.73 (d, 1H), 7.38 (bm, 1H), II
1/4'.-C.OH dichloro-3-fluoro-phenyl) 7.31 (dd, 1H), 7.08 (dd, 1H), 6.72 (d, 1H), 6.00 1-428ethoxyi-pyildin-3-y1}-prop-2-0.012 (q, 1H), 5.03 (s, 2H)õ 4.26 (d, 2H), 3.74 (m, 1H), ynyI)-2-(4-hydroxy-piperidin-3.02 (s, 2H), 2.78 (m, 2H), 2.32 (m, 2H), 1.92 (m, [M+1) a tIH, 1-yI)-acetsimide 4H), 1.80 (d, 3H).
_ Ilyy N-(3-(6-Amino-541-(2,6-(300MHZ, CDCI3) 07.73 (d, 1H), 7.38 (bm, 1H), II
dichloro-3-fluoro-phenyl)-7.31 (dd, 1H), 7.08 (dd, 1H), 6.72 (d, 1H), 6.00 1-429 .
ethoxyl-pyridin-3-y1)-prop-2- 0.022 12 ynyI)-2-dimethylamino-(q, 1H), 4.99 (s, 2H), 4.26 (d, 2H), 2.98 (s, 2H), [M+11 F
2.31 (s, 6H), 1.80 (d, 3H).
a 0 I' acetamide w' CI

NA, , g C N-(3-{6-Amino-541-(2,6-(300MHZ, CDCI3) 67,73 (d, 1H), 7.59 (bm, 1H), I I
dichloro-3-fluoro-phenyl)-7.30 (dd, 1H), 7.07 (dd, 1H), 6.72 (d, 1H), 6.00 1-430.
ethoxy]-pyridin-3-A-prop-2- 0.013 (q, 1H), 4.98 (s, 2H), 4.25 (d, 2H), 3.05 (s, 2H), [M+1]

' -^I
yny1)-2-diethylamino-2.57 (dd, 4H), 1.80 (d, 3H), 1.03 (t, 6H).
mir. a NH, acetamide p 2-(4-Acetyl-piperazin-1-y1)-N-(300MHZ, CDCI3) 67.73 (d, 1H), 7.31 (dd, 1H), -tr-C

.._i 0 N,/ (3-{6-amino-541-(2,6-7.25 (bm, 1H), 7.08 (dd, 1H), 6.71 (d, 1H), 6.00 8 dichloro-3-fluoro-phenyl)-0.027 (q, 1H), 5.04 (s, 211), ,4.27 (d, 2H), 3.66(m, 2H), [M+1]
1 õ

F
ethoxy]pyridin-3-y1)-prop-2-3.52 (m, 2H), 3.08 (s, 2H), 2.78 (m, 211), 2.32 (m, & NH
ynyI)-acetamide , 2H), 2.53 (m, 4H), 2.10 (s, 3H), 1.81 (d, 3H).
a , ii Cr 4-Methyl-piperazine-1-TN
carboxylic acid (3-{6-amino-in (300MHZ, CDCI3) 67.73 (d, 1H), 7.30 (dd, 1H), as I I
5-[1-(2,6-dichloro-3-fluoro-7.07 (t, 1H), 6.78 (d, 1H), 6.01 (q, 1H), 5.01 (s, 1<1 0.61 Example I-I
pheny1)-ethoxyl-pyridin-3-y1)-2H), 4.64 (s, 1H), 3.38 (m, 4H), 2.42 (m, 4H), [M+1]
I
Al.
0 ., N
1,1-dimethyl-prop-2-ynyI)-2.31 (s, 3H), 1.79 (d, 3H), 1.70 (s, 6H).
WII a NH, amide F

No. Structure Name Met IC50 Procedure 1H-NMR MS trilz (WI) (m+i) r), H (3R,5S)-3,5-Dimethyl-ii,N,), piperazine-I-carboxylic acid (300MHZ, CDCI3) 67.74 (s, 1H), 7.30 (dd, 1H), 8 (3-{6-amino-541-(2,6- 7.07 (t, 1H), 6.79 (s, 1H), 6.01 (q, 1H), 4.93 (s, 1-433 dichloro-3-fluoro-phenyl)- Ki 1.5 11 2H), 4.59 (s, 1H), 3.75 (m, 2H), 2.82 (m, 2H), [M+1]
' I " ethoxy]
2.35 (m, 2H), 1.80 (d, 3H), 1.71 (s, 6H), 1.09 (d, Av... 0 ....N

-pyridin-3-yI}-1,1-dimethyl- 6H).
up ci NH2 prop-2-ynyI)-amide L (R)-2-Pyrrolidin-1-ylmethyl-(300MHZ, CDCI3) 68.44 (bs, 1H), 7.72 (d, 1H), pyrrolidine-1-carboxylic acid II yii ....., 7.30 (dd, 1H), 7.07 (t, 1H), 6.79 (s, 1H), 6.01 (q, 562 (3-{6-amino-541-(2,6-1-434 8 dichloro-3-fluoro-phenyl)- Ki 1.22 11 1H), 4.87 (s, 2H), 3.75 (m, 1H), 3.25 (m, 1H), [M+1]
2.68 (m, 2H), 2.56 (m, 2H), 2.40 (m, 1H), 2.05 ethoxy1-pyridin-3-y1}-1,1-.'N (m, 1H), 1.82-1.68 (m, 17H), 1.56 (m, 1H).
dimethyl-prop-2-ynyI)-amide 0 NH, ..

t (S)-2-Pyrrolidin-1-ylmethyl-(300MHZ, CDCI3) 68.44 (bs, 1H), 7.72 (s, 1H), 14 0 pyrrolidine-1-carboxylic acid 7.30 (dd, 1H), 7.07 (t, 1H), 6.79 (s, 1H), 6.01 (q, 1r, (3-(6-amino-541-(2,6-1-435 11 Ki 1.58 11 1H), 4.87 (s, 2H), 3.75 (m, 1H), 3.25 (m, 1H), dichloro-3-fluoro-phenyl)-[M+1]
2.68(m, 2H), 2.56 (m, 2H), 2.40 (m, 1H), 2.05 ethoxy]-pyridin-3-yI}-1,1-(m, 1H), 1.82-1.68 (m, 17H), 1.56 (m, 1H).
dimethyl-prop-2-ynyI)-amide 0 " N

14yll'Hi "1-(3-{6-Amino-5-fl-(2,6- (300MHZ, CDCI3) 67.72 (s, 1H), 7.31 (dd, 1H), II `"'"dichloro-3-fluoro-pheny1)- 7.08 (t, 1H), 6.75 (s, 1H), 6.01 (q, 1H), 5.53 (bm, 538 1-436 , ethoxy]-pyridin-3-yI}-1,1- Ki 1.11 11 1H), 5.00 (a, 2H), 4.66 (bs, 1H), 3.56 (m, 4H), [M+1]
dimethyl-prop-2-ynyI)-3-(2- 3.32 (m, 2H), 2.45 (m, 2H), 2.35 (m, 4H), 1.81 (d, morpholin-4-yl-ethyl)-urea 3H), 1.64 (s, 6H).

N

Y----01-(3-{6-Amino-5-11-(2,6- (300MHZ, CDCI3) 67.72 (s, 1H), 7.31 (dd, 1H), 11 ' dichloro-3-fluoro-phenyl)- 7.08 (t, IH), 6.77 (a, 1H), 6.01 (q, 1H), 5.68 (bm, 1-437 1 ethoxy]-pyridin-3-yI}-1,1- Ki 0.61 11 1H), 5.14 (bs, 1H), 5.01 (s, 2H), 3.30 (m, 2H), I
Iii 0 'N dimethyl-prop-2-ynyI)-3-(2-2.65 (m, 2H), 2.50 (m, 4H), 1.81 (d, 3H), 1.68 (m, [M+1]

'' CI NH. pyrrolidin-1-yl-ethyl)-urea 4H), 1.63 (s, 6H).

F

,...,..0 1 jp-4 Pyrrolidin-i-yl-piperidine-1- (300MHZ, CDCI3) 67.73 (s, 1H), 7.31 (dd, IN), carboxylic acid (3-{6-amino- 7.07(t 1H), 6.79(a, 1H), 6.01 (q, IN), 5.68 (bm, 541-(2,6-dichloro-3-fluoro- 1H), 4.95 (a, 2H), 4.68 (bs, 1H), 3.88 (m, 2H), 562 1-438 Ki 0.72 II
phenyl)-pyridin-3-y1}- 2.82 (m, 2H), 2.58 (m, 4H), 2.28 (m, IN), 1.92 [M+1]

1,1-dimethyl-prop-2-ynyI)- (m, 2H), 1.81 (d, 3H), 1.80 (m, 4H), 1.70 (s, 6H), IP' 01 NH. amide 1.50 (m, 2H).

F

rTh,110 346-Amino-541-(2,6-(300MHZ, CDCI3) 67.85 (d, 1H), 7.31 (dd, 1H), L---) I I dichloro-3-fluoro-phenyl)-7.09 (t, 1H), 6.78 (d, 1H), 6.00 (q, 1H), 5.69 (bd, 410 1-439 i -- ethoxy]-pyridin-3-yI}- Ki 0.46 1H), 5.14 (s, 2H), 4.12 (m, 1H), 1.81 (d, 3H), 1.20 [M+1]
,.,.. propynoic acid (d, 6H).
IP 0 NH, cyclohexylamide ...

I 3-(6-Amino-541-(2,6- (300MHZ, CDCI3) 67.86 (s, 1H), 7.31 (dd, 1H), 11 dichloro-3-fluoro-phenyl)- 7.09 (t, 1H), 6.79 (s, 1H), 6.00 (q, 1H), 5.72 (bd, 450 1-440 ethoxyl-pyridin-3-y1}- Ki 0.43 11 1H), 5.14 (s, 2H), 3.82 (m, 1H), 1.95 (m, 2H), i [M+11 IN propynoic acid 1.80 (d, 3H), 1.72 (m, 2H), 1.65 (m, 2H), 1.38 (m, 11110 CI NH2 isopropylamide 2H), 1.20 (m, 2H).

F

4-(3-Amino-3-methyl-but-1-ii (300MHZ, CD30D) 67.60 (d, 1H), 7.45 (dd, I H), ynyI)-2-[1-(2,6-dichloro-3-382 1-441 Ki 1.06 11 7.25 (t, 1H), 6.66 (d, 1H), 6.06 (q, 1H), 1.84 (d, i 010 fluoro-pheny1)-ethoxyl-[M+I]

3H), 1.66 (s, 6H).
0 phenylamine S

, No. Structure Name Met IC50 Procedure MS m/z -(11M) , (M+1) r`N--oN.........) (4-(6-Amino-541-(3-fluoro-2-(300MHZ, CDCI3) 67.90 (s, 1H), 7.51 (m, 1H), trifluoromethyl-phenyI)-16% at 7.40 (m, 5H), 7.10 (m, 1H), 6.90 (s, 1H), 5.80 (q, ethoxy]-pyridin-3-y1}-pheny1)-1uM 1H), 4.94 (s, 2H), 3.58 (m, 4H), 2.53 (m, 4H), [M+1]
(4-methyl-piperazin-1-yI)-so0 ,N I methanone 2.32 (s, 3H), 1.84 (d, 3H).

F NH, F
F

r...Th...0 0 N,,) (300MHZ, CDCI3) 67.89 (s, 1H), 7.54 (m, 1H), (4-(6-Amino-541-(3-fluoro-2-7.32 (d, 5H), 7.17 (m, 1H), 6.90 (d, 1H), 5.79 (q, trifluoromethyl-phenyl)-1-443 *
ethoxyl-pyridin-3-y1}-phenyl)-13% at 13 1H), 4.93 (s, 2H), 4.60 (m, 1H), 3.80 (m, 1H), 1uM 2.95 (m, 2H), 2.64 (m, 4H), 2.34 (m, 1H), 1.95 [M+1]
(4-pyrrolidin-1-yl-piperidin-(m, 2H), 1.81 (m, 4H),1.73 (d, 3H), 1.56 (m, 2H).

solyI)-methanone F N I
F
-rINI

(4-(6-Amino-541-(3-fluoro-2-(300MHZ, CDCI3) 67.9 (d, 1H), 7.50 (m, 1H), trifluoromethyl-phenyI)-7.36 (m, 5H), 7.11 (m, 1H), 6.90 (s, 1H), 5.81 (q, 10% at ethoM-pyridin-3-y1}-phenyl)-13 1H), 4.93 (s, 2H), 4.62 (m, 1H), 3.66 (m, 1H), 1uM

[M+1]
((3R,5S)-3,5-dimethyl-2.85 (m, 2H), 2.65 (m, 1H), 2.40 (m, 1H), 1.73 (d, piperazin-1-yI)-methanone 3H), 1.10 (m, 7H).

F N
F

-ON

( .,..

0 Nj (4-(6-Amino-541-(3-fluoro-2-(300MHZ, CDCI3) 6 7.90(s, 1H), 7.73(m, 1H), trifluoromethy1-pheny1)-7.53 (m, 3H), 7.34 (d, 2H), 7.13 (m, 1H), 6.90 (s, 15% at 1-445 lb ethoxyj-pyridin-3-y1}-phenyl)-1 uM 13 1H), 5.80 (q, 1H), 4.93 (s, 2H), 4.45 (m, 1H), 3.50 [M+1]
((S)-2-pyrrolidin-1-ylmethyl-(m, 2H), 2.70 (m, 4H), 1.73 (d, 3H), 1.20-2.0 (m, 10H).
Ipyrrolidin-1-yI)-methanone 0 F :
F F

?

(4-(6-Amino-5-0-(3-fluoro-2-(300MHZ, CDCI3) 07.90 (s, 1H), 7.73 (m, 1H), trifluoromethyl-phenyl)-7.53 (m, 3H), 7.34 (d, 2H), 7.13 (m, 1H), 6.90 (s, 12% at ethoxyl-pyridin-3-y1}-pheny1)-luM 13 1H), 5.80 (q, 1H), 4.93 (s, 2H), 4.45 (m, 1H), 3.50 [M+1]
((R)-2-pyrrolidin-1-ylmethyl-(m, 2H), 2.70 (m, 4H), 1.73 (d, 3H), 1.20-2.0 (m, 1 pyrrolidin-1-yI)-methanone 10H).

*FN

_ F F F

r _IN1 (300MHZ, CDCI3) 67.90 (d, 1H), 7.75 (d, 2H), o NH 4-16-Amino-541-(3-fluoro-2-7.72 (m, 1H), 7.52 (m, 1H), 7.48 (d, 2H), 7,10 (m, trifluoromethyl-phenyI)-12% at 1H), 6.89 (d,1H), 6.00 (bd, 1H), 5.80 (q, 1H), 4.93 ethoxy]-pyridin-3-yI)-N-(1-1 uM 13 (s, 2H), 4.02 (m, 1H), 2.85 (m, 2H), 2.31 (s, 3H), [M+1]
methyl-piperidin-4-yI)-2.16 (m, 2H), 2.05 (m, 2H), 1.73 (d, 3H), 1.62 (m, benzamide I N

2H).

0 F NH, ¨ F F

No. Structure Name Met 1050 Procedure 1H-NMR MS rtt/z _ (PM) (M+1) 0 0,........0 4-(6-Amino-541-(3-fluoro-2-(300MHZ, CDCI3) 67.90 (d, 1H), 7.79 (d, 2H), 10 trifluoromethyl-phenyl)-7.55 (m, 2H), 7.48 (d, 2H), 7.13 (m, 1H), 7.08 7% at 1-450 ethoxy]-pyridin-3-y1)-N-(2-13 (bs, 1H), 6.90 (s, 1H), 5.80 (q, 1H), 4.94 (s, 2H), 1uM
[M+1]
I ...- N pyrrolidin-1-yl-ethyl)-3.58 (m, 2H), 2.78 (m, 2H), 2.62 (m, 4H), 1.81 benzamide (m, 4H), 1.72 (d, 3H).

F
F
.

40 c.,0 4.46-Amino-5[1-(3-fluoro-2-(300MHZ, CDCI3) 67.91 (d, 1H), 7.78 (d, 2H), trifluoromethyl-phenyl)-7.51 (m, 2H), 7.39 (d, 2H), 7.10 (m, 1H), 6.91 (d, 12% at 1-451 ethoxy}-pyridin-3-y1)-N-(2-13 1H), 6.78 (bs, 1H), 5.82 (q, 1H), 4.97 (s, 2H), luM
[M+1J
morpholin-4-yl-ethyl)-3.72 (m, 4H), 3.57 (m, 2H), 2.62 (m, 2H), 2.52 benzamide (m, 4H), 1.73 (d, 3H).
IP c'r N112 F

o 11,-......õ0 4-(6-Amino-5-11-(3-fluoro-2-(300MHZ, CDCI3) 68.81 (s, 1H), 7.92 (s, 1H), 40 trifluoromethyl-phenyI)-7.78 (d, 2H), 7.53 (m, 1H), 7.48 (d, 2H), 7.13 (m, 3% at 1-452 ethoxyj-pyridin-3-yI)-N-(3-13 1H), 6.90 (s, 1H), 5.80 (q, 1H), 4.90 (s, 2H), 3.60 1uM
[M+1]
pyrrolidin-1-yl-propyI)-(m, 2H), 2.78 (m, 2H), 2.66 (m, 4H), 1.85 (m, C4F NH, 0 -41 benzamide 6H), 1.73 (d, 3H).

F F
, 4--(6-Amino-541-(3-fluoro-2-(300MHZ, CDCI3) 67.93 (s, 1H), 7.80 (d, 2H), 40 trifluoromethyl-phenyl)- 10% at 7.53 (m, 3H), 7.38 (d, 2H), 7.10 (m, 1H), 6.91 (d, 1-453 ethoxy]-pyridin-3-yI)-N-(3-luM 1H), 5.82 (q, 1H), 4.95 (a, 2H), 3.70 (m, 4H), 3.57 [M+1]
I ,, morpholin-4-yl-propyI)-(m, 2H), 2.54 (m, 6H), 1.81 (M, 2H), 1.73 (d, 3H).
benzamide C? F FF NH, i loro-3-7% at Example 1- (400 MHz, DMSO-d6) 67.93 (s, 1H), 7.56 (m, 1-454 ,, N I fl6u-phenyl)-npoh-e5n4y11)--(e2ih6o-dxylc1h- 1H), 7.46 (t, 1H), 6.88 (br, 2H), 6.76 (a, 1H), 6.02 325 IM-1]
1uM 454 0 0411 nicotinonitrile (q, 1H), 1.77(d, 3H).
isi CI

F

I .4 6-Amino-541-(2,6-dichloro-3.
6% at Example 1- (400 MHz, DMSO-d6) 68.00 (s, 1H), 7.81 (d, 1-455 o N cyano-phenyl)-ethoxy]-332 [M-1]
1uM 455 1H), 7.07 (t, 2H), 5.78 (d, 1H), 1.74(d, 3H).
N nicotinonitrile 41111-1-1. ci III

I '. 5-Aminomethy1-3-[1-(2,6-(400 MHz, DMSO-d6) 67.53 (m, 1H), 7.43 (m, 1-456 N dichloro-3-fluoro-phenyl)-0% at 1 Example 1- 2H), 6.76 (s, 1H), 5.98 (q, 1H), 5.47 (br, 2H), uM 456 [M+1]
ethoxyl-pyridin-2-ylamine 1.74(d, 3H) NH, CI

F

(400 MHz, DMSO-d6) 6 9.58(s,1H), 7.93(s,1H), (R)-2-Pyrrolidin-1-ylmethyl-7.55(m,1H), 7.40(s,1H), 6.59 (dd,1H), 6.80 11,,,N1 D pyrrolidine-1-carboxylic acid 1% at 1 Example 1- (d,1H), 6.060,1H), 4.19(dd,1H), 4.10(dd,1H), 1-457 II (6-amino-541-(2,6-dichloro-uM 457 3.94(dd,1H), 3.85(dd,1H), 3.21(m,2H), [M+1]
3-fluoro-phenyI)-ethoxy]-is 04 0 pyridin-3-ylmethyl)-amide 3.15(m,2H), 3.01(m,2H), 1.98(m,2H), NH, 1.90(m,2H), 1.84(m,2H), 1.78(d,3H), 1.72(br,1H).
a No.
Structure Name Met IC50 Procedure MS m/z (A) (M+1) _ Ni?
r..-0 N-(6-Amino-5-[1 -(2,6-as in (400 MHz, DMSO-d6) 67.51 (m, 1H), 7.43 (t, 2H), I
I
dichloro-3-fluoro-phenyl)-0% at 1 k458 N
., , 6., , 5., , 5., di o ethoxyl-pyridin-3-ylmethyl)-uM Example r 728(m 1H)70(s 1H)96(q 1H)68(s EM+1]

2H), 3.84(d, 2H), 2.68(s, 3H), 1.76(d, 3H) methanesulfonamide 4111112-r CI
F

NH
N-{6-Amino-541-(2,6-as (400 MHz, CDCI3): d 7.49 (s, 1H), 7.29 (m, 1H), in I
---dichloro-3-fluoro-phenyl)-2% at 1 Example r7.06 (t, 1H), 6.71 (s, 1H), 6.03 (q, 1H), 5.49 (bs, IN
erhoxYl-PYriclin-3-ylmethyl)-uM
1H), 4.82 (bs, 2H), 4.29 (dd, 1H), 4.12 (dd, 1H), [M+1]

acetamide 1.96 (s, 3H), 1.83 (d, J 8.0 Hz, 3H).
110 Cl NH, ;
F
N-(6-Amino-5-[1-(2,6-(400 MHz, CDCI3): d 7.69 (d, 2H), 7.29 (m, 4H), as in dichloro-3-fluoro-phenyl)-9% at 1 Example /.7.06 (t, 1H), 6.69 (s, 1H), 5.98 (q, 1H), 4.84 (bs, ethoxyi-pyridin-3-ylmethyl)-4-uM
2H), 4.51 (m, 1H), 3.86 (dt, 2H), 2.43 (s, 3H), [M+1]

CI NH, methyl-benzenesulfonamide 1.83 (d, J 8.0 Hz, 3H).
F
_ 341-(2,6-(2,6-3-fluoro-(400 MHz, CDCI3): d 7.56 (s, 1H), 7.29 (m, 1H), i 7.05 (t, 1H), 6.91 (s, 1H), 6.19 (dd, 1H), 6.07 (q, I
phenyl)-ethoxy]-5-vinyl-Ki 0.68 1H), 5.40 (d, J 16Hz, 1H), 5.02 (d, J 12 Hz, 1H), [M+1]
Ol niN, pyridin-2-ylamine 4.86 (bs, 2H), 1.85 (d, J 8.0 Hz, 3H).
ci F
H
HO, (S)-1-(6-Amino-541-(2,6-(400 MHz, CDCI3): d 7.55 (s, 1H), 7.29 (m, 1H), i --- I
dichloro-3-fluoro-phenyl)-2% at 'I Example I- 7.05 (t, 1H), 6.82 (s, 1H), 6.05 (q, 1H), 4.82 (bs, r&

"
ethoxy[-pyridin-3-yI)-ethane-uM

2H), 4.63 (m, 1H), 3.64 (m, 4H), 1.83 (d, J 8.0 [M+1]
MP CI

1,2-dial Hz, 3H).
F
_ H
HO...
(R)-1-(6-Amino-5-11-(2,6-(400 MHz, CDCI3): d 7.55 (s, 1H), 7.29 (m, 1H), as n i .-dichloro-3-tluoro-phenyl)-2% at 1 Example 1.7 05 (t, 1H), 6.82 (s, 1H), 6.05 (q, 1H), 4.82 (bs, ethoxy]-pyridin-3-yI}-ethane-uM

2H), 4.63 (m, 1H), 3.54 (m, 4H), 1.83 (d, J 8.0 [M+1]
1,2-dial RT., 3H).
N
CI
H' _.
F
(400 MHz, CDCI3): d 7.66 (s, 2H), 7.62 (s, 1H), phenylyethoxy1-5-(1H-.,.

Ki 0.10 7.37 (m, 1H), 7.13 (m, 1H), 7.04 (s, 1H), 6.17 (q, .1 341-(2,6-Dichloro-3-fluoro-IN pyrazol-4-y1)-pyridin-2-[M+1) J 8.0 Hz, 1H), 1.93 (d, J 8.0 Hz, 3H) I
CI
"2 ylamine W--F
NO

r---/
341-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-541-(2-/

(400 MHz, CDCI3): d 7.71 (s, 1H), 7.55 (s, 2H), ,µ
7.37 (m, 1H), 7.06 (m, 1H), 6.87 (s, 1H), 6.09 (m, ovrrolidin-1-v1-ethyfl-1H-Ki 0.34 =
=
=
=
1H), 4.26 (t, J 8.0 Hz, 2H), 2.96 (t, J 8.0 Hz, 2H), [M+1[
:
pyrazol-4-y11-pyridin-2-ylamine 2.55 (m, 4H), 1.87 (d, J 8.0 Hz, 3H), 1.26 (m, 4H) al 0 1'1 CI
NH, ' F

, ---( /-14--( 341-(2,6-Dichloro-3-fluoro-(400 MHz, CDCI3): d 7.76 (s, 1H), 7.54 (s, 1H), --1µ1 phenyl)-ethoxy1-541-(2-7.46 (s, 1H), 7.28 (m, 1H), 7.04 (m, 1H), 6.86 (m, diisopropylamino-ethyl)-1H- Ki 0.47 1H), 6.08 (m, 1H), 4.05 (t, J 8.0 Hz, 2H), 2.83 (t, I
.
pyrazol-4-y1j-pyridin-2-yi 2H), 1.86 (d, J 4.0 Hz, 3H), 0.96 (d, J 8.0 Hz, [M+1]
I
amine 12H).
-4r--- CI
F
_ No. Structure Name Met IC50 Procedure 1H-NMR MS m/z (11M) (M+1) r-7 3-11-(2,6-Dichloro-3-fluoro-(400 MHz, CDCI3): d 7.72 (s, 1H), 7.60 (s, 1H), / , phenylyethoxy]-541-(2-(1 7.50 (s, 1H), 7.38 (m, 1H), 7.13 (m, 1H), 7.05 (s, 1-467 morpholin-4-yl-ethyl)-1H-Ki 0.083 14 1H), 6.19 (m, 1H), 4.61 (m, 2H), 3.89 (m, 4H), 1 0.,....- IN pyrazol-4-y1]-pyridin-2-3.53 (m, 2H), 3.02 (m, 4H), 1.93 (d, J 8.0 Hz, [M+1]

3H).

*ylamine CI NH' F

Br IN 5-Bromo-3-(3-fluoro-2-(400 MHz, DMSO-d6) 67.67 (s, 1H), 7.43 (d, 8% at328 I-468 1101 0 methoxy-benzyloxy)-pyridin-15 1H), 7.40(d, 1H), 7.33(t, 1H), 7.20(m, 1H), 6.00(s, luM
[M+1]
NH, 2-ylamine 2H), 5.19 (s, 2H), 3.96(s, 3H) F I

Br L)., 5-Bromo-341-(3-fluoro-2-(400 MHz, DMSO-d6) 67.51 (s, 1H), 7.25 (d, 7% at342 1-469 0 0"¨y" methoxy-phenyl)-ethoxyl-15 1H), 7.18(m, 1H), 7.09(m, 1H), 6.94(s, 1H), luM
[M+11 NH, pyridin-2-ylamine 6.02(s, 2H), 5.72 (q, 1H), 3.93(s, 3H), 1.57(d, 3H) o F I

.
(I'NH

0 N,......)., {446-Amino-5-(3-fluoro-2-(400 MHz, DMSO-d6) 6 9.24(s, 1H), 8.61(d,1H), methoxy-benzyloxy)-pyridin-1-470 40 3-y11-pheny1)-((3R,55)-3,5-3% at 3 7.96(d, 1H), 7.81(d, 2H), 7.57 (d, 1H), 7.43 (d, 465 1uM 2H), 7.32(t, 1H), 7.18(m, 1H), 5.34(s, 2H), 3.91(s, [M+1) dimethyl-piperazin-1-yI)-IN methanone 3H), 3.39(m, 2H), 2.49(m, 4H), 1.21(m, 6H).

0 1,1[1, F ?

llIFI

0 N..,.....).....

(4-(6-Amino-541-(3-fluoro-2-(400 MHz, DMSO-d6) 6 9.25(d, 1H), 8.64(d,1H), methoxy-phenyl)-ethoxyj- 1% at 7.88(s, 1H), 7.61(d, 2H), 7.53 (d, 2H), 7.46 (s, 1-471 pyridin-3-y1)-phenyl)-3 1H), 7.35(d, 1H), 7.21(1, 1H), 7.13(m, 1H), lphi [11.11+1]
((3R,58)-3,5-dimethyl-6.03(m, 1H), 3.93(s, 3H), 3.38(m, 2H), 2.49 (m, IN
piperazin-1-yI)-methanone 4H), 1.67(d, 3H), 1.20(m, 6H) So NH, . ir I 5-Bromo-3-(3-fluoro-2-(400 MHz, DMSO-d6) 67.59 (s, 1H), 7.36 (d, -,.., N
1-472 110 o isopropoxy-benzyloxy)-Ki 12.1 15 1H), 7.31(d, 1H), 7.25(t, 1H), 7.12(m, 1H), 5.90(s, 356 NH, pyridin-2-yIamine 2H), 5.10(s, 2H), 4.43 (m, 1H),1.26(d, 6H) o F

II-NH

0N.,.1.

(4-[6-Amino-5-(3-fluoro-2-(400 MHz, DMSO-d6) 6 9.45(d, 1H), 8.79(q,1H), isopropoxy-benzyloxy)-7.99(s, 1H), 7.88(s, 1H), 7.80 (d, 2H), 7.58 (d, 1-473 pyridin-3-y1]-phenyl)-Ki 12.7 3 2H), 7.41(d, 1H), 7.32(t, 1H), 7.17(m, 1H), 5.37(s, 493 ((3R,55)-3,5-dimethyl-2H), 4.45(m, 1H), 3.40(m, 2H), 2.49 (m, 4H), I piperazin-1-yI)-methanone 1.28(d, 8H), 1.20 (m, 6H) o ''' "

F..õ...1,_ No.
Structure Name Met 1C50 Procedure MS nilz (RM) (M+1) NH, (400 MHz, DMSO-d6) 6 7.66(d, 1H), 7.55(q, 1H), 5-(4-Amino-phenyl)-3-f1-(2,6-7.43 (t, 1H), 7.02 (d, 2H), 6.81(s, 1H), 6.56(d, I
.-dichloro-3-fluoro-phenyl) 21-1), 6.08(q, 1H), 5.60(s, 2H), 5.08(s, 2H), 1.78(d, a 0 '..NHI:
3H) ethoxy]-pyridin-2-ylamine '411111.2" CI
F
.Thor (4-{6-Amino-541-(2,6-dichloro-3-fluoro-phenyl)-as in (400 MHz, CDCI3): d 7.82 (s, 1H), 7.30 (m, 3H), 7.06 (m, IH), 6.95 (m, 3H), 6.12 (q, I H), 4.80 (m, ethoxyj-pyridin-3-y1)---Ki 0.20 Example 1.2H), 4.66 (s, 2H), 3.82 (s, 3H), 1.86 (d, J 8.0 Hz, I

o N "
phenoxy)-acetic acid methyl 3H).
ester * a ", F
....--TOH
*
(4-16-Amino-541-(2,6-as in (400 MHz, CDCI3): d 7.70 (s, 1H), 7.50 (m, 2H), I
dichloro-3-fluoro-phenyl)-7.45 (m, 2H), 7.20 (m, 2H), 6.85 (m, 2H), 6.05 (q, ,.
...... IN
ethoxyl-pyridin-3-y1)-Ki 0.20 Example 1.1H), 5.72 (s, 2H), 4.49 (s, 2H), 3.82 (s, 3H), 1.75 NH, phenoxy)-acetic acid (d, J 8.0 Hz, 3H).
F
(LN1H
161.'rN
d2i-c(411-11o6ro-A-3m-flinuoo-r50--Ip1h4e2n6y1-)-(400 MHz, CDCI3): d 7.48 (s, 1H), 7.35 (m, 1H), q÷-.
ethoxy]-pyridin-3-yI)-7.20 (m, 2H), 7.12 (m, 2H), 7.01 (m, 2H), 6.20 (q, Ki 0.027 1H), 4.73 (m, 3H), 4.10 (m, 1H), 3.36 (m, 1H), phenoxy)-I-((3R,5S)-3,5-i ..., IN
dimethyl-piperazin-1-yI)-3.13 (m, 2H), 2.84 (m, IH), 1.94 (d, J 8.0 Hz, 3H), 1.34 (m, 6H).
1$
ethanone NH CI
, F
.....)(0--0.
2-(4-{6-Amino-541-(2,6-(400 MHz, CDCI3): d 7.48 (s, 1H), 7.36 (m, IN), _.' dichloro-3-fluoro-phenyl)-7.21 (d, 2H), 7.19 (m, 2H), 7.10 (m, 2H), 7.01 (m, ethoxy]-pyridin-3-yI)-Ki 0.041 2H), 6.20 (q, 1H), 4.65 (m, 2H), 4.55 (m, 1H), phenoxy)-14(R)-3-hydroxy-3.69 (m, 3H), 3.48 (m, 1H), 2.10 (m, 3H), 1.92 di o N. "
pyrrolidin-1-y1)-ethanone (m, 5H).
mr, 1 NI-12 F
r---Trio- 442-(4-{6-Amino-541-(2,6-/yKL) dichloro-341uoro-pheny1)-(400 MHz, CDCI3): d 7.50 (s, 1H), 7.36 (m, 1H), ethoxy]-pyridin-3-yI)-7.22 (d, 2H), 7.19 (m, 2H), 7.15 (m, 2H), 7.00 (m, phenoxy)-acetyll-piperazine- Ki 0.16 2H), 6.20 (q, 1H), 4.75 (s, 2H), 3.57 (m, 4H), 3.45 (m, 4H), 1.93 (d, J 8.0 Hz, 3H), 1.47 (s, 9H).
carboxylic acid tert-butyl 1-=C=10: 'al, ester .
F
2-(4-(6-Amino-541-(2,6-(400 MHz, CDCI3): d 7.48 (s, 1H), 7.36 (m, 1H), dichloro-3-fluoro-phenyl)-7.20 (d, 2H), 7.15 (m, 2H), 7.00 (d, 2H), 6.20 (q, IP
ethoxyi-pyridin-3-y1)-phenoxy)-1-((R)-2-pyrrolidin-1H), 4.68 (s, 2H), 4.46 (m, 1H), 4.04 (m, 1H), 3.93 (m, 1H), 3.60 (m, 1H), 3.52 (m, 1H), 3.50 I
.-- 1 I -ylmethyl-pyrrolidin-1-y1)-(m, 1H), 3.12 (m, IN), 3.09 (m, 1H), 2.83 (m, ip, 0 N "
ethanone 1H), 1.93 (d, J 8.0 Hz, 3H), 2.16-1.66 (m, 10H).
uici 1 N

No. Structure Name Met 1C50 Procedure MS rn/z (WA) (M+1) 0 .,r 1 5-Bromo-3-(341uoro-6,7,8,9-(400 MHz, DMSO-d6) 5 7.57 (d, 1H), 7.16(m, 15 N tetrahydro-5H-3H), 6.95(dt, 1H), 6.07(d, 2H), 5.63(d, 1H), 1-481 0-..
benzocyclohepten-5-yloxy)-2.10(m, 2H), 2.16(m, 2H), 1.86 (m, 1H),1.77(m, NH, pyridin-2-ylamine 2H), 1.34(m,1H).
*

F

(1-NH
0 N,......A.... {446-Amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-* benzocyclohepten-5-yloxy)-pyridin-3-y1]-pheny1)-) I ((3R,55)-3,5-dimethyl-Eii--0 ''= N piperazin-1-yI)-methanone ilD

) 3-(3-Fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5.

[4-(2-pyrrolidin-1-yl-ethoxy)-I
) E N phenyl]pyridin-2-ylamine N

F

W

HNIrCH, 0 N-{446-Amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylo xy)-pyridin-3-y11-phenyl}-ll 0 , N methanesulfonamide NH, 1 i 1/fr F

3-(3-Fluoro-6,7,8,9-tetrah dro-5H-Y
1-485 --, IN
benzocyclohepten-5-yloxy)-5.

337 [M-1]

IIIP NI-I2 (1H-pyrazo1-4-y1)-pyridin-2-Ilir ylamine F

Br .,.-1 1 5-Bromo-341-(2-chloro-3-(400 MHz, CDCI3): d 7.68 (s, 1H), 7.24 (m, 3H), 1-486 io 0 N fluoro-pheny1)-ethoxyl-0% at 1 15 6.69 (s, 1H), 5.64 (q, 1H), 4.78 (bs, 2H), 1.68 (d, uM
NH, pyridin-2-ylamine J 8.0 Hz, 3H).
CI

F

(400 MHz, CDCI3): d 7.50 (s, 1H), 7.30 (m, 2H), 341-(2-Chloro-3-fluoro-101 phenyl)-ethoxy]-544-(2-7.20 (m, 3H), 7.00 (s, 1H), 6.95 (m, 2H), 5.90 (q, Ki 3.30 3 1H), 4.36 (m, 2H), 3.85 (m, 2H), 3.55 (m, 2H), ) pyrrolidin-1-yl-ethoxy)-I
2.95 (m, 2H), 2.10 (m, 4H), 1.82 (d, J 8.0 Hz, 0 ."N phenyl]-pyridln-2-ylamine 3H). ci F

No. Structure i Name Met 1C50 Procedure 1H-NMR MS rn/z (11M) (M+1) . . -(CDCI3) d 5.15 (br s, 2H), 5.19 (s, 2H), 7.17 (m, I ....N 1H), 7.34-7.46 (m, 5H), 7.64 (d, J = 8 Hz, 1H), 5'-Benzyloxy-[2,31bipyridinyl-1-488 >20 16 7.70 (td, J = 7.8, 1.9 Hz, 1H), 7.86 (d, J = 1.6 Hz, 278 IN 6'-ylamine 1H), 8.22(d, J = 2 Hz, 1H), 8.63 (d, J = 4 Hz, 0 0 ' NH, 1H).

(CDCI3) d 5.17 (s, 2H), 5.27 (bra, 2H), 7.19 (d, J

= 2 Hz, 1H), 7.33 (dd, J = 7.8, 4.6 Hz, 1H), 7.35-5-Benzyloxy-[3,3Pipyridinyl-1-489 >20 16 7.44 (m, 5H), 7.70 (dt, J = 2, 8 Hz, 1H), 7.85 (d, J 278 I 6-ylamine = 2 Hz, 1H), 8.56 (dd, J = 1.6, 4.8 Hz, 1H), 8.71 ta o N
NH, (d, J = 2 Hz, 1H).
_ (CDCI3) d 6.22 (s, 2H), 6.15 (bra, 2H), 7.21 (s, 3-Benzyloxy-5-pyrimidin-5-yl-1-490 ,, >20 16 I H), 7.43 (m, 5H), 7.77 (s, 1H), 8.81 (s, 2H), 9.20 279 ....... NI pyridin-2-ylamine (s, 1H).

NR, 1 ',.....N (CDCI3) d4.40 (br s, 2H), 4.94 (br s, 2H), 5.13 (s, 2H), 6.58 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 1.6 5-Benzyloxy-13,31bipyridinyl-1-491 >20 16 Hz, 1H), 7.35-7.44 (m, 5H), 7.56 (dd, J = 2.4, 8.4 293 6,6'-diamine IN Hz, 1 H), 7.77 (d, J = 1.6 Hz, 1H), 8.13 (d, J =2 Hz, 1H).

(CDCI3) d 5.33 (s, 2H), 5.99 (bs, 2H), 7.22-7.26 I ---N5'-(2-Chloro-benzyloxy)- (m, 1H), 7.29-7.37 (m, 2H), 7.42-7.51 (m, 2H), 1-492 8.24 I -, [2,31131pyridiny1-6'-ylamine 7.63 (d, 1H), 7.72 (dt, 1H), 7.99 (d, IH), 5.13 (d, I , N
1 H), 8.65 (dd, 1H).
IP o NH, I ,,N
5-(2-Chloro-benzyloxy)-1-493 4.6 =
[3,31bipyridiny1-6-ylamine 3-(2-Chloro-benzyloxy)-5-I-494 1 pyrimidin-5-yl-pyridin-2- 19.3 -4) ylamine ,,, NH, I ',N 5-(2-Chloro-benzyloxy)-1-495 4.31 13,3pipyridiny1-6,6'-diamine Oil no-IIN, ..-N (CDCI3) d 5.18 (s, 2H), 5.48 (bs, 2H), 7.19-7.22 5'-(4-Chloro-benzyloxy)-1-496 -.. (2,3lbipyridiny1-6'-ylamlne 14 16 (m, 1H), 7.38 (s, 4H), 7.63-7.65 (m, 1H), 7.73 (dt, 312 I 1H), 7.89 (d, 1H), 8.17 (d, 1H), 8.63 (d, 1H).
ilk e$:

NH:CI "411.7.
_ 1-497 .- 5-(4-Chloro-benzyloxy)- 14.1 I [3,3pipyridiny1-6-ylamine Ai 0 'IF:

CI =-=

---;,-, No. Structure Name Met 1C50 Procedure 1H-NMR MS tn/z (1-IM) (Mil) :: =-=-=µ=.;

3-(4-Chloro-benzyloxy)-5-1-498 Pyrimidin-5-yl-pyridin-2- >20.0 16 a o? ylamine Nt-6 ci -111147-NH, I ') .
5-(4-Chloro-benzyloxy)->20.0 16 [3,3]bipyridinyl-6,6'-diamine CI

I ':N 5-(2-Chloro-3,6-difluoro-(CDCI3) 5 5.39 (s, 2H), 6.19 (bs, 2H), 7.08 (dt, 1-500 F .',.
benzyloxy)42,31bipyridiny1-6- 1.8 16 1H), 7.21-7.28 (m, 2H), 7.65 (d, 1H), 7.77 (dt, ilk o I -41 ylamine 1H), 8.13 (d, 1H), 8.67 (dd, 1H) GI "

F

5-(2-Chloro-3,6-difluoro-1-501benzyloxy)-[3,3]bipyridiny1-6- 0.282 F i,. .--- ylamine 0).N

411111kili F

1 N;

5-(2-Chloro-3,6-difluoro-1-502 I benzyloxy)-[3,41bipyridinyl-6- 0.211 16 I '''' F ilk 0 ,N
ylamine 41110 F NH, NN

3-(2-Chloro3,6-difluoro-1-503 1 benzyloxy)-5-pyrimidin-5-yl- 2.15 16 F 4011, 0 I
pyridin-2-ylamine 'N

MO F NH, NH, I ;5-(2-Chloro-3,6-difluoro-1-5041 benzyloxy)-[3,3]bipyridinyl- 0.209 16 F rift. 0 ,N 6,6'-diamine VP F NH, ,,, (CDCI3) d 5.47 (s, 2H), 5.76 (bs, 2H), 7.21-7.25 6-(21,6-Dichloro-benzyloxy)-(m, 1H) 7.27-7.32 (m, 1H), 7.37-7.41 (m, 2H

2.84 16 ), I ',''N

346[2,3bipyridiny1-6'-ylamine 7.66 (d, 1H), 7.75 (dt, 1H), 8.06 (d, 1H), 8.17 (d, 1H), 8.66 (dd, 1H).

I '.) 5-(2,6-Dichloro-benzyloxy)-2.71 16 I '''. 13,31bipyridinyl-6-ylamine mr, ei NH, iN.........., 5-(2,6-Dichloro-benzyloxy)-1.3 16 [3,41bipyridiny1-6-ylamine No. Structure Name Met IC50 Procedure MS in&

(PM) (M+1) ,I.N1 3-(2,6-Dichloro-benzyloxy)-5-1-508 I 1 ''' pyrimidin-5-yl-pyridin-2- 10.3 16 iiii 0 ...41 ylamine 41111111-kil a isill NH, 1 .......-`N

5-(2,6-Dichloro-benzyloxy)-0.578 16 I [3,Thipyridinyl-6,6'-diamine qr.- 01 NH, - _ (CDCI3) d 1.87 (d, J = 6.6 Hz, 3H), 4.60 (br s, 2H), 4.96 (br s, 2H), 6.11 (q, J = 6.6 Hz, 1H), ' 5-0 -(2,6-Dichloro-3-fluoro-1-510 phenyl)-ethoxy]-0.0167 16 6.56 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 7.06 (t, J =

8.5 Hz, 1H), 7.31 (dd, J = 4.8, 8.7 Hz, 1H), 7.48 F Av. 0 ,, N I [3,Thipyridiny1-6,6'-diamine (dd, J = 1.8, 8.4 Hz, 1H), 7.75 (s, 1H), 8.05 (s, 01 NH, 1H).

(CDCI3) d 1.87 (d, J = 6.6 Hz, 3H), 2.37 (s, 3H), ......N," , N {6'-Amino-5'41-(2,6-dichloro-2.39 (br s, 2H), 2.56 (br s, 2H), 3.43 (br s, 2H), 3-fluoro-phenyl)ethoxyl-3.86 (br s, 2H), 5.13 (br s, 2H), 6.21 (q, J = 6.7 1-511 1 ,- 1 [2,3lbipyridiny1-4-y1}-(4- 0.0742 16 Hz, 1H), 7.04 (dd, J = 8.1, 8.7 Hz, 1H), 7.10 (dd, F ,,L 0 N methyl-piperazin-1-yI)-J = 1.2,5.1 Hz, 1H),7.29 (dd, J = 5.1, 9.3 Hz, IP c, NH, methanone 1H), 7.48 (a, 1H), 7.57 (d, J = 1.5 Hz, 1H), 8.24 (d, J =1.8 Hz, 1H), 8.65 (dd, J = 0.6, 4.8 Hz, 1H).

(CDCI3) d 1.87 (d, J = 6.6 Hz, 3H), 2.36 (s, 3H), ..,...N,..1 (6'-Amino-5T-(2,6-dichloro-2.46 (m, 2H), 2.58 (m, 2H), 3.66 (m, 2H), 3.89 3-fluoro-phenyl)-ethoxyl-(m, 2H), 5.08 (br s, 2H), 6.17 (q, J = 6.6 Hz, 1H), 1-512 1 .. 1 [2,31bipyridiny1-6-y1)-(4- 0.0629 16 7.05 (dd, J = 8.1,8.8 Hz, 1H), 7.31 (dd, J = 5.0, F i& o ' N methyl-piperazin-1-yI)-8.9 Hz, 1H), 7.46 (dd, J = 0.8, 7.7 Hz, 1H), 7.51 qiur ci N, methanone (d, J = 1.8 Hz, 1H), 7.55 (dd, J = 0.8, 8.0 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H).

(CDCI3) d 1.88 (d, J = 6.6 Hz, 3H), 2.38 (s, 3H), ,NO 1 ...õN {6'-Amino-5'41-(2,6-dichloro-2.44 (m, 2H), 2.56 (m, 2H), 3.52 (m, 2H), 3.87 3-fluoro-phenyl)-etho41-(m, 2H), 5.05 (bra, 2H), 6.12 (q, J = 6.7 Hz, 1H), 1-513 , .- [3,3']bipyridiny1-5-y1}-(4- 0.034 16 6,97(d, J = 1.8 Hz, 1H), 7.08 (dd, J = 8.1, 8.7 Hz, F Al 0 ........ k methyl-piperazin-1-yI)-1H), 7.33 (dd, J = 5.0, 8.9 Hz, 1H), 7.72 (t, J =
methanone 2.1 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 8.54 (d, J =
WI a NH, 1.8 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H).

rN' 0 N....) (CDCI3) d 1.88 (d, J = 6.9 Hz, 3H), 2.39 (s, 3H), {6'-Amino-5'-[1-(2,6-dichloro-2.52 (br s, 2H), 2.61 (bra, 2H), 3.74 (bra, 2H), 3-fluoro-phenyl)-ethoxy1-3.89 (br s, 2H), 5.02 (bra, 2H), 6.12 (q, J = 6.7 1-514 [3,3lbipyridiny1-6-y1)-(4- 0.0213 16 Hz, 1H), 6.97 (d, J = 1.2 Hz, 1H), 7.08 (t, J = 8.4 I -- methyl-piperazin-1-yI)-Hz, 1H), 7.33 (dd, J =
4.8, 8.7 Hz, 1H), 7.68 (d, J
F Al ,., k methanone = 9 Hz, 1H), 7.76 (dd, J = 1.8, 8.4 Hz, 1H), 7.89 4111111" ci NI-1.2 (d, J = 1.5 Hz, 1H), 8.59 (d, J = 1.5 Hz, 1H).

(CDCI3) d 1.88 (d, J = 6.9 Hz, 3H), 2.39 (s, 3H), {6-Amino-541-(2,6-dichloro-2.51 (m, 2H), 2.61 (m, 2H), 3.67 (m, 2H), 3.90 , I 5,,3-fluoro-phenyl)-ethoxy]-(m, 2H), 5.08 (br s, 2H), 6.14 (q, J
= 6.7 Hz, 1H), 1-515 [3,41bipyridiny1-2'-y1)-(4- 0.0387 16 7.05 (s, 1H), 7.06 (dd, J = 7.8, 9 Hz, 1H), 7.32 (d, F ,. L methyl-piperazin-1-yI)-J = 5.1 Hz, 1H), 7.34 (dd, J = 5.0, 7.7 Hz, 1H), io 0 õõ4 methanone 7.66 (d, J = 1.2 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), a --, 8.53 (d, J = 5.1 Hz, 1H).

(CDCI3) d 1.83 (d, J = 6.6 Hz, 3H), 4.55 (br s, 541-(2-Chloro-3,6-difluoro-2H), 4.87 (br s, 2H), 5.95 (q, J = 6.5 Hz, 1H), 1-516phenyI)-ethoxy]-0.0393 16 6.55 (d, J = 8.4 Hz, 1H), 6.93-7.12 (m, 3H), 7.48 F AI F I [3,3lbipyridiny1-6,6'-diamine (dd, J = 1.8, 8.4 Hz, 1H), 7.76 (s, 1H), 8.09 (s, 1H).

_ No.
Structure Name Met IC50 Procedure MS m/z (AM) (M+1) `=N="1 1,,,.N o (CDCI3) d 1.84 (d, J = 6.6 Hz, 3H), 2.39 (s, 3H), {6'-Amino-5'41-(2-chloro-3,6-2.53 (br s, 4H), 3.63 (br s, 2H), 3.82 (br s, 2H), I
difluoro-phenyl)-ethoxy]-5.09 (br s, 2H), 6.06 (q, J = 6.5 Hz, 1H), 6.93-[2,31bipyridiny1-5-y1)-(4-0.131 ,.
methyl-piperazin-1-yI)-7.10 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.69 (d, J
i , F
,- 14 methanone = 7.8 Hz, 1H), 7.76 (dd, J = 2.1, 8.4 Hz, 1H), 8.28 1.1 (d, J = 1.5 Hz, 1H), 8.66 (d, J = 1.5 Hz, 1H).

F
NH
{6'-Amino-5'41-(2-chloro-3,6-(CDCI3) d 1.84 (d, J = 6.6 Hz, 3H), 2.40 (s, 3H), difluoro-phenyl)-ethoxy]-2.45 (br s, 2H), 2.61 (br s, 2H), 3.48 (br s, 2H), 3.89 (br s, 2H), 5.13 (br s, 2H), 6.06 (q, J = 6.6 [2,Thipyridiny1-4-y1)-(4-0.209 methyl-piperazin-1-yI)-Hz, 1H), 6.93-7.10 (m, 2H), 7.12 (dd, J = 1.2, 5.1 ,.. N

L'r methanone Hz, 1H), 7.52 (s, 1H), 7.68 (d, J = 1.2 Hz, 1H), F

8.24 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 4.8 Hz, 1H).
(CDCI3) d 1.84 (d, J = 6.6 Hz, 3H), 2.38 (s, 3H), -..
.
(6'-Amino-5'41-(2-chloro-3,6-2.49 (m, 2H), 2.60 (m, 2H), 3.70 (m, 2H), 3.91 difluoro-phenyI)-ethoxy]-(m, 2H), 5.01 (br s, 2H), 6.02 (q, J = 6.6 Hz, 1H), --[2,31bipyridiny1-6-y1)-(4-0.466 6.93-7.12 (m, 2H), 7.49 (dd, J = 0.8, 7.7 Hz, 1H), F

...,. IN
methyl-piperazin-1-yI)-7.58 (dd, J = 0.9, 8.1 Hz, 1H), 7.62 (d, J = 1.8 Hz, .

F
NH, methanone 1H), 7.78 (t, J = 7.8 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H).

'N
{6-Amino-5'41-(2-chloro-3,6-(CDCI3) d 1.85 (d, J = 6.6 Hz, 3H), 2.44 (s, 3H), , difluoro-phenyl)-ethoxy]-2.57 (m, 4H), 3.59 (m, 2H), 3.91 (m, 211), 5.02 (br [3,31bipyridiny1-5-y1}-(4-0.134 s, 2H), 5.97 (q, J = 6.4 Hz, 1H), 6.96-7.14(m, N

methyl-piperazin-1-y1)-3H), 7.74 (s, 1H), 7.87 (bra, 1H), 8.57 (bra, 1H), F
methanone 8.71 (bra, 1H).

MIll- F

1.,...N 0 {6'Amino-5(1-(2-chloro-3,6-(CDCI3) d 1.86 (d, J = 6.6 Hz, 3H), 2.45 (s, 3H), ' _.,,,1 difluoro-phenyl)-ethoxy]-2.62 (br s, 2H), 2.69 (bra, 2H), 3.82 (bra, 2H), 3.95 (br s, 2H), 4.97 (bra, 2H), 5.98 (q, J = 6.5 [3,3]bipyridiny1-6-y1)-(4-0.0716 Hz, 1H), 6.96-7.14 (m, 3H), 7.71 (d, J = 8.1 Hz, i .,.

I
methyl-piperazin-1-yI)-F
NH, 1H), 7.79 (dd, J = 2.3, 8.3 Hz, 1H), 7.90 (d, J =

F Ail 0 ',... N
methanone 2.1 Hz, 1H), 8.62 (d, J = 1.5 Hz, 1H).
Mr N.,...
(CDCI3) d 1.86 (d, J = 6.6 Hz, 3H), 2.45 (a, 3H), ,0 1, {6-Amino-541-(2-chloro-3,6-2.62 (bra, 2H), 2.70 (br a, 2H), 3.77 (br a, 2H), difiuoro-phenyl)ethoxy]-3.96 (bra, 2H), 5.03 (bra, 2H), 5.99 (q, J = 6.7 ., [3,41bipyridiny1-2'11)-(4-0.0626 Hz, 1H), 6.96-7.14 (m, 2H), 7.16 (d, J = 1.8 Hz, F divi 0 .... iN
methyl-piperazin-1-yI)-1H), 7.36 (dd, J = 2.0, 5.3 Hz, 1H), 7.71 (d, J =

lir F

methanone 1.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 8.45 (d, J =
4.8 Hz, 1H).
(CDCI3) d 1.87 (d, J = 6.6 Hz, 3H), 5.20 (bra, F iii,i, 5ph'-[e1n-y(21),..6;Dhoicxyhlio_ro-3-fluoro-I ''.
[2,31bipyridiny1-6'-ylamine cr.---N
0.0677 2:1): 96..323Hz, ,,,JH=), 67..751H(zd, ,1:1=), 87..104H z(t,,iJR=),87.4.5H9z(d, , 1H), 7.15 (dd, J = 4.8, 6.6 Hz, 1H), 7.29 (dd, J =

J = 1.2 Hz, 1H), 7.67 (td, J = 7.8, 1.8 Hz, 1H), WI ci NH, 8.24 (d, J = 1.5 Hz, 1H), 8.60 (d, J = 3.9 Hz, 1H).
(CDCI3) d 1.84 (d, J = 6.9 Hz, 3H), 5.14 (br s, 5'41-(2-Chloro-3,6-difluoro-2H), 6.08 (q, J = 6.5 Hz, 1H),6.93-7.10 (m, 2H), I
, ---phenyl)-ethoxy]-0.612 7.16 (dd, J = 5.1, 6.6 Hz, 1H), 7.54 (d, J = 8.1 Hz, F AI
0 ' ,N
[2,31bipyridiny1-6'-ylamine 1H), 7.65-7.70 (m, 2H), 8.24 (s, 1H), 8.62 (d, J =

F
NH, 4.2 Hz, 1H) 41111111)11 'N
......

(CDCI3) d 1.87 (d, J =6.6 Hz, 3H), 5.37 (br s, 541-(2-Chloro-3,6-difluoro-2H), 6.00 (q, J = 6.5 Hz, 1H), 6.97-7.15 (m, 3H), I
1 -.' phenyl)-ethoxyl-0.0777 7.34 (dd, J = 4.7, 7.7 Hz, 1H), 7.69 (d, J = 7.8 Hz, F lil 'N
[3,31bipyridiny1-6-ylamine 1H), 7.82 (s, 1H), 8.56 (d, J = 3.9 Hz, 1H), 8.65 quir F
NI-L, (S, 1H).

No. Structure Name Met 1C50 Procedure MS tat (1-tM) (M+1) 3-[1-(2-Chloro-3,6-difluoro-(CDC13) d 1.87 (d, J =6.6 Hz, 3H), 5.16 (br s, 1-526 1 phenyl)-ethoxy]-5-pyrimidin- 0.552 16 2H), 6.98 (q, J = 6.5 Hz, 1H), 6.96-7.14 (m, 3H), ":1:" 5-yl-pyridin-2-ylamine 7.86 (s, 1H), 8.77 (s, 2H), 9.14 (s, 1H).
' * , o .H.

(CDC13) d 1.87 (d, J = 6.6 Hz, 3H), 2.38 (s, 3H), {6'-Amino-5'41-(2,6-dichloro-2.51 (brs, 4H), 3.62 (br s, 2H), 3.81 (br s, 2H), I 3-fluoro-pheny1)-ethoxyl-.., N
5.13 (br s, 2H), 6.21 (q, .1= 6.7 Hz, 1H), 7.04 (t, J

[2,3]blpyridiny1-5-y1)-(4- 0.0385 = 8.4 Hz, 1H), 7.30 (dd, J = 4.8, 8.7 Hz, 1H), 7.75 I methyl-piperazin-1-y1)-i (dd, J = 1.9, 8.2 Hz, 1H), 8.28 (s, 1H), 8.64 (s, F . 0 ".. N methanone 1H).
, lip a NH, N

I ;
(CDC13) d 1.84 (d, J = 6 Hz, 3H), 5.13 (br s, 2H), 541-(2-Chloro-3,6-difluoro-5.97 (q, J = 6.5 Hz, 1H), 6.95-7.10 (m, 2H), 7.12 1-528 I phenyl)-ethoxyl- 0.0659 F Alt. 0 I ...-N [3,41bipyridiny1-6-ylamine (d, J = 1.6 Hz, 1H), 7.30 (d, J = 6 Hz, 2H), 7.95 lip F NH , (d, J = 2 Hz, 1H), 8.58 (d, J = 5.6 Hz, 2H).

5-Benzyloxy-3-[1-(2-chloro-(CDC13) d 1.84 (d, 3H), 4.88 (s, 2H), 5.89 (q, 1-529 ? 3,6-difluoro-pheny1)-ethoxy]- 2.58 17 1H), 6.79 (d, 1H), 6.+1 (d, 1H), 7.01 (dt, 1H), 7.11 1 pyridin-2-ylamine 7.17 (m, 1H), 7.28-7.40 (m, 5H).
F ===... N CF,CO,H

4 F NH, P

F , :41 ... N 1 341-(2-Chloro-3,6-difluoro-1-530 40 0 pheny1)-ethoxy1-5-(2-ethyl- 4.08 F NH, butoxy)-pyridin-2-ylamine .F,1<.F

1 0., F

OH

I .....1. I 341-(2-Chloro-3,6-difluoro-1-531 F 40 . `,.. N phenyI)-ethoxy]-5-(3-methyl- 2.4 NH 2 butoxy)-pyridin-2-ylamine F

F
1 0,,,H

OH

I 4' 11 3-[1-(2-Chloro-3,6-difluoro-1-532 F 0 0 -... 1.1 pheny1)-ethoxy]-5-butoxy- 1.94 NH 2 pyridin-2-ylamine F

F
F

OH

I 41.......IN
F 341-(2-Chloro-3,6-difluoro-1-533 pheny1)-ethoxy]-5-propoxy- 0.672 IPI NH, F pyridin-2-ylamine F
F

OH

=

No. Structure Name Met1Cro Procedure 1H-NMR MS rn/z (11M) .

P

, 4)- 1 341-(2-Chloro-3,6-difluoro-F ---.. t4 pheny1)-ethoxy]-5-1-534 . o 5.97 17 ra-1.2 cyclohexylmethoxy-pyridin-2-F ylamine 1 o./Fier OH

H

F io ......N

6-Amino-5-[1-(2-chloro-3,6-NH, 1-535 F difluoro-phenyl)-ethoxy]- 0.54 17 F F pyridin-3-ol 1 0..)1F

OH

?

3-[1-(2-Chloro-3,6-difluoro-i 41 phenylyethoxy]-5-(2-1-536 r 1 7.5 17 ilo F o -` N cyclohexyl-ethoxy)-pyridin-2-IND.I2 ylamine 1 0?F

(\ ---I
F ,... I 3-[1-(2-Chloro-3,6-difluoro-- o '= N
1-537 IP NH2 phenyfl-ethoxy]-5-isobutoary- 1.2 17 F pyridin-2-ylamine OH

.

\ ;

3-[1-(2-Chloro-3,6-difluoro-t .-.. ....-1., phenyl)-ethoxy]-5-1-538 F iii IP i,h. 2.8 17 phenethyloxy-pyridin-2-NH, ylamine F

10/ p OH

p_ , 341-(2-Chloro-3,6-difluoro-1.539 F ilo F O4I
phenyl)-ethoxy]-5-(pyridin-2- 3.2 17 ylmethoxy)-pyridin-2-ylamine 1 0.y1(FF

OH

-198..

No. Structure Name Met 1C50 Procedure 111-NMR
MS tnlz (M) (M+1) -p_ I .41 F 0 ',.. 341-(2-Chloro-3,6-difluoro-1-540 SS NH., phenyl)-ethoxy]-5-(pyridin-4- 0.8 F ylmethoxy)-pyridin-2-ylamine . F

OH

rY
0 N.,.....-(446-Amino-5-11-(2,6- (300MHZ, CDC13) 6 7.89 (s, 1H), 7.40 (m, 4H), dichloro-3-fluoro-pheny1)- 4 as in 0 Example I-7.35 (dd, 1H), 7.08 (t, 1H), 7.02 (s, 1H), 6.17 (q, 567 1-541 ethoxyl-pyridin-3-y1)-pheny1)- 0.079 1H), 4.98 (s, 2H), 3.82 (m, 2F1), 3.62 (m, 2H), (4-methyl-plperazin-1-y1)- 291 I 1 s'hi 2.52 (m, 4H), 1.88 (d, 3H).
F ai 0 ' methanone "'"---CINil, Table 3 No. Structure Name Ki (pM) 1H-NMR
MS m/z Procedure or 1 (%) (M+H) cH, ' r-I-N E, (400 MHz, DMSO-D6) d ppm 0.84 (s, 3 H) 0.93-0 N........k. (4-{6-Amino-541-(2,6-1.10 (m, 3 H) 1.80 (d, J=6.57 Hz, 3 H) 2.30 (s, 2 crt dichloro-3-fluoro-phenyI)- H) 2.55 -2.74 (m, 2 H) 3.38- 3.49 (m, 1 H) 4.32 1-542 * ethoxyi-pyridin-3=y1)-phenyl)-0.023 (s, 1 H) 5.96 (s, 2 H) 6.14 (q, J=6.57 Hz, 1 H) F,6eI CH, , ((3R,5S)-3,5-dimethyl-7.00 (d, J=1.77 Hz, 1 H) 7.36 (m, 2 H) 7.45 (m, 3 ... ' , N piperazin-1-yI)-methanone H) 7.56 (dd, J=8.97, 4.93 Hz, 1 H) 7.88 (d, cr NN
J=1.77 Hz, 1 H) ri=H'NEi (400 MHz, DMSO-D6) d ppm 0.84 (s, 3 H) 0.93-0 (4-{6-Amino-541-(2,6-1.10 (m, 3 H) 1.80 (d, J=6.57 Hz, 3 H) 2.30 (s, 2 dichloro-3-fluoro-phenyl)- H) 2.55 - 2.74 (m, 2 H) 3.38 - 3.49 (m, 1 H) 4.32 1-543 ethoxy]-pyridin-3-y1)-pheny1)-1.5 (s, 1 H) 5,96 (s, 2 H) 6.14 (q, J=6.57 Hz, 1 H) ((3R,55)-3,5-dimethyl- 7.00 (d, J=1.77 Hz, 1 H) 7.36 (m, 2 H) 7.45 (m, 3 piperazin-1-yI)-methanone H) 7,56 (dd, J=8.97, 4.93 Hz, 1 H) 7.88 (d, iLe..1, ci NH, J=1.77 Hz, 1 H) F

N. 110 (400 MHz, DM50-D6) d ppm 1.80 (d, J=6.82 Hz, 5-{6-Amino-541-(2,6-3 H) 6.01 (s, 2 H) 6.17 (q, J=6.57 Hz, 1 H) 7.05 dichloro-3-fluoro-phenyl)-(d, J=1.77 Hz, 1 H) 7.44 (t, J=8.72 Hz, 1 H) 7.55 a,Z=13 I ' ethoxyl-pyridin-3-y11-2-fluoro-F
(m, 2 H) 7.79 (m, 1 H) 7.89 (d, J=1.77 Hz, 1 H) ' N benzonitrile . ,........,...0 III..
7.97 (dd, J=6.06, 2.27 Hz, 1 H) II
(400 MHz, DMSO-D6) d ppm 1.49 - 1.65 (m, 2 H) OH 4-(4-(6-Amino-541-(2,6- 1.75 -1.86 (m, 3 H) 1.86 - 1.98 (m, 3 H) 2.53 (s, dichloro-3-fluoro-phenyl)- 1 H) 2.88 (s, 2 H) 2.99 (s, 2 H) 5.84 (s, 2 H) 6.11 ethoxy]-pyridin-3-y1}-phenyl)- (d, J=6.57 Hz, 1 H) 6.93 (s, 1 H) 7.28 - 7.38 (m, ,_. piperidin-4-ol J=8.08 Hz, 2 H) 7.39 - 7.50 (m, J=8.21, 8.21 Hz, 11..Aci NH, 3 H) 7.57 (dd, J=8.72, 4.93 Hz, 1 H) 7.81 (s, 1 H) (400 MHz, DMSO-D6) d ppm 1.43 - 1.56 (m, 4 H) ' 0 0 .
(4-{6-Amino-541-(2,6- 1.61(d, J=3.79 Hz, 4 H) 1.81 (d, J=6.57 Hz, 3 H) dichloro-3-fluoro-phenyl)- 3.51 (s, 2 H) 5.94 (s, 2 H) 6.15 (d, J=6.82 Hz, 1 0.057 ethoxyl-pyridin-3-y1)-pheny1)- H) 7.00 (d, J=1.77 Hz, 1 H) 7.28 - 7.41 (m, 2 H) piperidin-i-yl-methanone 7.40 - 7.50 (m, 3 H) 7.57(dd, J=9.09, 5.05 Hz, 1 a NH, H) 7.87 (d, J=2.02 Hz, 1 H) O (400 MHz, DMSO-D6) d ppm 1.73 - 1.93 (m, 7 H) 3.39 - 3.52 (m, 4 H) 5.96 (s, 2 H) 6.07 - 6.20 (m, ' dMic-{11610-Arom-31n-flou-50-ro[1--p(2h,e6n-y1)-0.067 J=6.82 Hz, 1 H) 6.99 (d, J=1.77 Hz, 1 H) 7.39 -ethoxyl-pyridin-3-y1}-phenyl)-7.47 (m, 3 H) 7.52 (d, 2 H) 7.56 (dd, J=9.09, 5.05 k Hz, 1 H) 7.82 - 7.92 (m, J=1.77 Hz, 1 H) F' '' pyrrolidin-1-yl-methanone N.

(400 MHz, CHLOROFOP,M-D) d ppm 1.77 - 1.88 4-{0-Amino-541-(2,6-(m, 3 H) 2.11 (a, 3 H) 3.91 (c, 3 H) 4.90 (a, 2 H) 100 dichloro-3-fluoro-phenyI)-CH, 6.02 (d, J=6.82 Hz, 'I H) 6.69 (d, J=1.77 Hz, 1 H) 1-548 ethoxyl-pyridin-3-y11-3-17%

7.00 - 7.09 (m, 1 H) 7.14 (d, J=7.83 Hz, 1 H) 7.26 I H' is, methyl-benzoic acid methyl - 7.31 (m, 1 H) 7.59 (d, J=1.77 Hz, 1 H) 7.83 (dd, ester ID ci NH, J=7.96, 1.39 Hz, 1 H) 7.88 (s, 1 H) H,c5...j.

(400 MHz, DMSO-D6) d ppm 0.84 - 0.96 (m, 6 H) n cõ, 341-(2,6-DIchloro-3-fluoro-1.44 -1,61 (m, 2 H) 1.72 - 1.83 (m, 3 H) 2.58 -phenyl)-ethoxy]-544-[4 2.70 (m, 2 H) 2.71 -2.84 (m, 4 H) 5.76 - 5.92 (m, 1-549 (dimethyl-piperazIn-1-0.095503 2 H) 6.02 - 6.18 (m, 1 H) 6.88 - 7.01 (m, 1 H) ylmethyl)-pheny1]-pyridin-2-7.25 (d, 2 H) 7.32 (d, 2 H) 7.38 - 7.49 (m, 1 H) F...151Ø- N ylamine 7.50 - 7.64 (m, 2 H) 7.76 - 7.88 (m, 1 H) . till, (400 MHz, DMSO-D6) d ppm 0.77 - 0.91 (m, 3 H) (4-{6-Amino-541-(2,6-1.00 (s, 3 H) 1.75 (d, J=6.82 Hz, 3 H) 2.16 - 2.30 dIchloro-3-fluoro-phenyl)-(m, J=12.63 Hz, 3 H) 2.64 - 2.76 (m, 3 H) 3.54 (s, 1-550 E6c,,, ..CH, ethoxy]-pyridin-3-yI)-3,5-15%

6 H) 4.25 - 4.40 (m, 1 H) 5.69 (s, 2 H) 5.91 (q, dimethoxy-phenyl)-(dimethyl-J=6.74 Hz, 1 H) 6.54 - 6.67 (m, 3 H) 7.37 - 7.43 piperazin-1-y1)-methanone (m, 1 H) 7.43 - 7.51 (m, 1 H) 7.51 -7.60 (m, 1 H) koLa ", H35_0 (400 MHz, DMSO-D6) d ppm 0.80 - 0.96 (m, 3 H) 1.06 (s, 3 H) 1.80 (d, J=6.57 Hz, 3 H) 2.26 - 2.42 0 IN ..../1"C I'l (4-{6-Amino-5-(1-(2,6-(m, J=1.52 Hz, 2 H) 2.61 -2.85 (m, J=1.77 Hz, 3 F ,. dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-311)-2-fluoro- 0.091 H) 4.35 - 4.47 (m, J=6.32 Hz, 1 H) 6.06 (s, 2 H) 6.16 (q, J=6.57 Hz, 1 H) 7,02 (s, 1 H) 7,27 - 7.40 I H, phenyl)-(dimethyl-piperazin-(m, 3 H) 7.40 - 7.49 (m, J=8.72, 8.72 Hz, 2 H) F&c. 1-yI)-methanone NH6 7.51 -7.62 (m, J=8.84, 5.05 Hz, 1 H) 7.93 (s, 1 ci H) No.
Structure Name 1(1 ( M) MS m/z Procedure or 1 (%) (M+H) H.3_14 11.....)=*cH. (4-(6-AmIno-541-(2,6-(400 MHz, DMS0-06) d ppm 0.83 - 1.00 (m, 3 H) 1.02 - 1.17 (m, 3 H) 1.78 (d, 3 H) 2.70 - 2.98 (m, dichloro-3-fluoro-phenyl)-6 H) 4.36 -4.50 (m, 1 H) 6.01 - 6.10 (m, 2 H) 1-552ethoxy]-pyridin-3-y1}-3-fluoro- 0.2237 6.10- 6.22 (m, 1 H) 6.96 - 7.04 (m, 1 H) 7.06-I
N. ....:SC
phenyl)-(dimethyl-piperazin-7.15 (m, 1 H) 7.16- 7.23 (m, 1 H) 7.30 - 7.39 (m, F rd,... 0 N
1-yI)-methanone 1 H) 7.40 - 7.49 (m, 1 H) 7.50 - 7.59 (m, 1 H) LW a 7.86 - 7.98 (m, 1 H) (400 MHz, DMSO-D6) d ppm 0.88 (s, 3 H) 1.01 (4-(6-Amino-5-[1-(2,6-(s, 3 H) 1.77 (d, J=6.57 Hz, 3 H) 1.98 (s, 3 H) dichloro-3-fluoro-phenyI)-2.31 (s 1 H) 2.73 (s, 3 H) 3.50 (s, 2 1-1) 4,35 (s, 1 ethoxy]-pyridin-3-y1}-3-0.2593 H) 5.89' (s, 2 H) 6.00 (q, J=6.57 Hz, 1 H) 6.60 (s, F.,Arti methyl-pheny1)-(dimethyl-piperazin-1-yI)-methanone 1 H) 7.01 -7.12 (m, J=7.83 Hz, 1 H) 7.12 - 7.28 '0'`,zi "I"
(m, 2 H) 7.37 - 7.63 (m, 3H) ?(' (400 MHz, DMSO-D6) d ppm 1.00- 1.31 (m, 4 ,,c5c.cI.,.. (446-Amino-541-(2,6-0H, H) 1.87 (d, J=6.82 Hz, 3 H) 3.37 - 3.40 (m, 6 H) dichloro-3-fluoro-phenyI)-3.55 - 3.65 (m, 2 H) 6.01 -6.05 (m, 2 H) 6.21 (q ethoxy)-pyridin-3-ylyphenyly 0.140719 J=6.57 Hz, 1 H) 7.07 (d, J=1.77 Hz, 1 H) 7.45 - ' a2R,65)-2,6-dimethyl-7.55 (m, 5 H) 7.63 (dd, J=8.84, 5.05 Hz, 1 H) morpho1in-4-ylymethanone 7.92 - 7.98 (m, 1 H) (400 MHz, DMSO-D6) d ppm 1.36 (t, J=6.82 Hz, 3 H) 1.95 (d, J=6.57 Hz, 3 1-1) 4.08 -4.16 (m, 2 H) ?
341-(2,6-Dichloro-3-fluoro-5.91 -5.95 (m, 2 H) 6.16 (q, J=6.57 Hz, 1 H) 7.08 H, 1 ''CH, phenyl)ethoxy1-5-(2-ethoxy-22% -7.13 (m, 2 H) 7.19 (d, J=7.83 Hz, 1 H) 7.27 (dd, F Ira 0 -''' phenyl)pyridin-2-ylamine J=7.58, 1.77 Hz, 1 H) 7.40 (t, J=8.59 Hz, 1 H) Rir 0, NH, 7.62 (t, J=8.59 Hz, 1 H) 7.73 (dd, J=9.09, 5.05 Hz, 1 H) 7.84 (d, J=1.77 Hz, 1 H) (400 MHz, DMSO-D6) d ppm 1.82 (d, J=6.57 Hz, o 3 H) 3.57 - 3.58 (m, 3 H) 3.74 - 3.75 (m, 3 H) 341-(2,6-Dichloro-3-fluoro-5.82 - 5.86 (m, 2 H) 6.03 (q, J=6.57 Hz, 1 H) 6.72 phenyl)-ethoxy1-5-(2,5-bli, 0.5746 (d, 1=3.23 Hz, 1 H) 6.84 (dd, J=8.84, 3.03 Hz, 1 dimethoxy-phenylypyridin-2-H) 6.89 (d, J=1.77 Hz, 1 H) 6.98 (d, J=9.09 Hz, 1 F lip 0 ' N
ylamine H) 7.50 (t, J=8.59 Hz, 1 H) 7.61 (dd, J=8.84, 4.80 4" ci "11-Hz, 1 1-1) 7.66 (d, J=1.77 Hz, 1 H) ,...oH, (400 MHz, DMSO-D6) d ppm 1.83 (d, J=6.82 Hz, 3 H) 3.64 - 3.67 (m, 3 H) 3.81 -3.84 (m, 3 H) SO3-(1-(2,6-Dichloro-3-fluoro-0-c1.6 phenyl)-5-(2,4-(2,4 5.74 - 5.78 (m, 2 H) 6.03 (q, J=6.57 Hz, 1 H) 6.59 0.2172 (dd, J=8.34, 2.27 Hz, 1 H) 6.64 (d, J=2.53 Hz, 1 19 ,,ZI' dimethoxy-phenylypyridin-2-H) 6.88 (d, J=1.77 Hz, 1 H) 7.10 (d, J=8.34 Hz, 1 F

H) 7.53 (t, J=8.59 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 ' ' oi NH=
H) 7.63 (dd, J=8.84, 5.05 Hz, 1 H) (400 MHz, DMSO-D6) d ppm 1.81 (d, J=6.82 Hz, itc-c, SO 0.0H, 311-(2,6-Dichloro-3-fluoro-3 H) 3.58 - 3.59 (m, 6 H) 5.68 - 5.69 (m, 2 H) pheny1)-ethoxy1-5-(2,6-5.96 (q, J=6.82 Hz, 1 H) 6.63 (d, J=1.77 Hz, 1 H) I N3 , 2'%0 F

I .., dimethoxy-phenyl)-2-6.71 (d, J=8.34 Hz, 2 H) 7.26 (t, J=8.34 Hz, 1 H) so ci 0 ,,, ylamine 7.42 (d, J=1.52 Hz, 1 H) 7.52 (t, J=8.59 Hz, 1 H) 7.61 (dd, J=8.84, 5.05 Hz, 1 H) 3-[1-(2,6-Dichloro-3-fluoro-(400 MHz, DMSO-D6) d ppm 1.78 (d, J=6.57 Hz, 1-559 It 3 H) 5.91 - 5.99 (m, 3 H) 6.59 - 6.60 (m, 1 H) =
\ I F F phenylyethoxy1-5-(2-(2 .
4%
7.26 (d, J=7.58 Hz, 1 H) 7.42 - 7.48 (m, 2 H) 7.50 CI CH3 4*
tnfluoromethyl-phenyl)-pyridin-2-ylamine -7.58 (m, 2 H) 7.65 (t, J=7.33 Hz, 1 H) 7.75 (d, F
J=7.83 Hz, 1 H) (400 MHz, DMS0-06) d ppm 1.79 (d, J=6.82 Hz, 5-(2-Chloro-phenyl)-341-(2,6.
3 H) 5.96 - 6.03 (m, 3 H) 8.75 (d, J=1.77 Hz, 1 H) dichloro-3-fluoro-phenyl)-24%

1(54 ethoxyl-pyridin-2-ylamine 7.27 - 7.38 (m, 3 H) 7.42 - 7.49 (m, 2 H) 7,52 -' 7.57 (m, 2 I-1) H.
3-[1-(2,6-Dichloro-3-fluoro-(400 MHz, DMSO-D6) d ppm 1.74 (d, J=6.82 Hz, a __.(' i of phenyl)-5-(2-3 H) 5.92 - 5.98 (m, 3 H) 6.74 (d, J=1.77 Hz, 1 H) 14%

F7--(C1 CFI, .
trifluoromethoxy-phenyly 7.29 - 7.43 (m, 5 H) 7.50 (dd, J=9.09, 5.05 Hz, 1 pyridin-2-ylamine H) 7.56 (d, J=1.77 Hz, 1 H) [
1-(2-(6-AmIno-541-(2,6-(400 MHz, DMS0-06) d ppm 1.83 (d, J=6.82 Hz, 0#1 o 3 H) 1.92 - 1.93 (m 3 H) 6.01 - 6.07 (m, 3 H) CH., dichloro-3-fluoro-phenyly ,, _ _ ' 10.59 (d, J-2.02 Hz, 1 H) 7.26 (d, J=7.83 Hz, 1 H) I CH' 1 ethm)-pyridin-3-y1)-pheny1)-A

ethanone 7.45 (t, J=7.33 Hz, 1 H) 7.48- 7.51 (m, 1 H) 7.52-F
44m- a NH, 7.58 (m, 3 H) 7.61 (dd, J=8.84, 5.05 Hz, 1 H) No.
Structure Name Ki ( M) MS m/z Procedure or! (%) (M+H) (400 MHz, DMSO-D6) d ppm 1.71 (d, J=6.57 Hz, . F

341-(2,6-Dichloro-3-fluoro-3 H) 5.88 - 5.90 (m, 2 H) 5.96 (q, J=6.82 Hz, 1 H) I CH, 1 `, phenyl)-ethoxy]-5-(2-fluoro-0,4322 6.76 - 6.78 (m, 1 H) 7.10 - 7.16 (m, 2 H) 7.19-F Al, 0 ". N
phenyI)-pyridin-2-ylamine 7.28 (m, 2 H) 7.36 (t, J=8.59 Hz, 1 H) 7.47 (dd, IW' a "".
J=8.84, 4.80 Hz, 1 H) 7.60 - 7.63 (m, 1 H) (400 MHz, DMSO-D6) d ppm 1.79 (d, J=6.57 Hz, 3 H) 4.20 (t, J=5.05 Hz, 2 H) 5.03 (t, J=5.56 Hz, 1 =
(2-{6-Amino-541-(2,6-H) 5.82 - 5.83 (m, 2 H) 6.02 (q, J=6.57 Hz, 1 H) OH dichloro-3-fluoro-phenyl)-0, 6.68 (d, J=1.77 Hz, 1 H) 7.01 (dd, J=7.58, 1.52 I
CI-6 I '.-ethoxy]-pyridin-3-y1)-phenyl)-21" Hz, 1 H) 7.25 (dt, J=7.58, 1.52 Hz, 1 H) 7.31 (dt, F
010 NH, ....1,1 methanol J=7.33, 1.26 Hz, 1 H) 7.46 (t, J=8.59 Hz, 1 H) glAg 7.49 - 7.53 (m, 2 H) 7.56 (dd, J=8.84, 5.05 Hz, 1 H) (400 MHz, DMSO-D6) d ppm 1.65 (d, J=6.57 Hz, * CH, 3-0-(2,6-Dichloro-3-fluoro-3 H) 1.80 -1.80 (m, 3 H) 5.67 - 5.69 (m, 2 H) Cl CH, i '`, phenyl)-ethoxy]-5-o-tolyl-25% 5.86 (q, J=6.57 Hz, 1 H) 6.45 (d, J=1.77 Hz, 1 H) F Ai. 0 ' NH, ,1 pyridin-2-ylamine 6.86 - 6.90 (m, 1 H) 7.00 - 7.09 (m, 3 H) 7.29-a 7.35 (m, 2 H) 7.42 (dd, J=8.84, 5.05 Hz, 1 H) (400 MHz, DMSO-D6) d ppm 1.84 (d, J=6.57 Hz, 9 3-[1-(2,6-Dichloro-3-fluoro-3 H) 3.65 - 3.66 (m, 3 H) 5.83 - 5.84 (m, 2 H) PO
6.04 (q, J=6.57 Hz, 1 H) 6.93 (d, J=1.77 Hz, 1 H) CH, Phenyl)-ethoxy]-5-(2-I

0.2779 7.00 (dt, J=7.33, 1.01 Hz, 1 H) 7.08 (d, J=7.83 1 , -methoxy-phenyl)-pyridin-2-F 10 0 '"
ylamine Hz, 1 H) 7.19 (dd, J=7.58, 1.77 Hz, 1 H) 7.28-CI

7.34 (m, 1 H) 7.53 (t, J=8.84 Hz, 1 H) 7.61 -7.66 (m, 2 H) (400 MHz, DMSO-D6) d ppm 1.57 - 1.58 (m, 3 341-(2,6-Dichloro-3-fluoro-H) 1.79 (d, J=6.82 Hz, 3 H) 1.97 - 1.98 (m, 3 H) H,C
CH, phenyl)-ethoxy]-5-(2,6-5.73 - 5.75 (m, 2 H) 5.98 (q, J=6.57 Hz, 1 H) 6.41 1-567 I R.
0%

-' I ''.
dimethyl-phenyl)-pyridin-2-(d, J=1.77 Hz, 1 H) 6.99 - 7.11 (m, 3 H) 7.25 (d, F ailk, 0 , N

ylamine J=1.77 Hz, 1 H) 7.44 (t, J=8.59 Hz, 1 H) 7.54 (dd, 111 a "1-6 J=8.84, 5.05 Hz, 1 H) (4-{6-Amino-541-(2,6-Anal. Calcd for C24 H22 C12 F N3 03: C, 58.79;
dichloro-3-fluoro-phenyl)-0.0525 H, 4.52; N, 8.57. Found: 0, 58.39; H, 4.72; N, ethoxyi-pyridin-3-yll-phenyl)-8.24.
r'1 .,.
morpholin-4-yl-methanone .
(4-(6-Amino-541-(2,6-----c", dichloro-3-fluoro-phenyl)-Anal. Calcd for C26 H26 CI3 F N4 02: C, 56.59;

ethoxyl-pyridin-3-y1}-2-chloro- 0.0478 H, 4,75; N, 10.15. Found: C, 52.83; H, 5.16; N, phenyl)-((3R,58)-dimethyl-8.79. 1.1eq of H20; 1.3 eq AcOH
piperazin-1-yI)-methanone X
4-(6-Amino-541-(2,6-dl,,,r, ichloro-3-fluoro-phenyI)-Anal. Calcd for C27 H29 0I2 F N4 02: C, 61.02;
N
ethoxyj-pyridin-3-y1}-2-0.225 H, 5.50; N, 10.54. Found: C, 55.99; H, 5.79; N, methyl-phenyl)-((3R,5S)-F'64"
dimethyl-piperazin-1-y1)-_ 9.01. 1.2eq of H20; 1.5eq of AcOH
. "N

methanone (400 MHz, CHLOROFORM-D) d ppm 1.09 (d, 341-(2,6-DIchloro-3-fluoro-J=6.32 Hz, 6 H) 1.80 (d, J=6.82 Hz, 3 H) 1.88 -pheny1)-ethoxy]-544-1.98 (m, 2 H) 2.78 - 2.90 (m, 2 H) 3.59 - 3.70 (m, ((2R,65)-2,6-dimethyl-0,2204 2 H) 3.86 -3.95 (m, 2 H) 5.12 - 5.16 (m, 2 H) I
morpholin-4-ylmethyl)-6.06 (q, J=6.57 Hz, 1 H) 6.94 -7.04 (m, 2 H) 7.25 H,..., F lit 0 N
phenyl]-pyridln-2-ylamine (dd, J=8.84, 4.80 Hz, 1 H) 7.28 - 7.34 (m, 2 H) I" ci 7.36 - 7.44 (m, 2 H) 7.77 (d, J=1.52 Hz, 1 H) NrD
(400 MHz, CHLOROFORM-D) d ppm 1.80 (d, 341-(2,6-Dichloro-3-fluoro-J=6.57 Hz, 3 H) 2.51 -2.58 (m, 4 H) 3.58 - 3.60 phenyl)-ethoxy]-5-(4-(m, 2 H) 3.75 (t, J=4,55 Hz, 4 H) 5.27 - 5.31 (m, 2 0.0554 morpholin-4-ylmethyl-H) 6.06 (q, J=6.57 Hz, 1 H) 6.95 (d, J=1.52 Hz, 1 phenyl)-pyridin-2-ylamine H) 7.00 (t, J=8.08 Hz, 1 H) 7.22 - 7.29 (m, 3 H) a NN, 7.33 - 7.37 (m, 2 H) 7.74 (d, J=1.77 Hz, 1 H) CH, (400 MHz, DMSO-D6) d ppm 1.64 (d, J=6.57 Hz, 341-(2,6-Dichloro-3-fluoro-3 H) 2.08 - 2.10 (m, 6 H) 5.65 - 5.68 (m, 2 H) phenyl) -phenyI)-pyridin-2-pheny1)-ethoxy1-5-(35-, 5.93 (q, J=6.57 Hz, 1 H) 6.69 - 6.71 (m, 2 H) 6.75 I c"' 1 ylamine - 6.78 (m, 2 H) 7.28 (t, J=8.59 Hz, 1 H) 7.40 (dd, F raki, RIM a NH, J=9.09, 4.80 Hz, 1 H) 7.62 (d, J=1.77 Hz, 1 H) - zuz -No. Structure Name Ki (AM) 1H-NMR
MS m/z Procedure or I (%) (M+H) (400 MHz, DMSO-D6) d ppm 1.78 (d, J=6,57 Hz, 3 H) 2.27 - 2.28 (m, 3 H) 5.80 - 5.84 (m, 2 H) 110. cit .
341-(26-Dichloro-3-flUoro- 6.08 (q, J=6.57 Hz, 1 H) 6.88 (d, J=1.77 Hz, 1 H) 1-574 I cH, 1 phenyl)-ethoxy]-5-m-tolyl-7.02 (d, J=7.33 Hz, 1 H) 7.09 -7.15 (m, 2 H) 7.21 F Ai 0 'N pyridin-2-ylamine (t, J=7.58 Hz, 1 H) 7.41 (t, J=8.59 Hz, 1 H) 7.54 a NH=
(dd, J=9.09, 5.05 Hz, 1 H) 7.77 (d, J=1.77 Hz, 1 H) 0- N= (400 MHz, DMSO-D6) d ppm 1.60 (d, J=6.57 Hz, 1101 0'CH.3 3-[1-(2,6-Dichloro-3-fluoro- 3 H) 3.55 (d, J=14.91 Hz, 6 H) 5.57 - 5.60 (m, 2 phenyI)-ethoxy]-5-(3,4- H) 5.90 (q, J=6.57 Hz,1 H) 6.63 (d, J=2.02 Hz, 1 H) 6.65 (d, J=1.77 Hz, 1 H) 6.68 - 6.76 (m, 2 H) .

F,. T.H1 IdImethoxy-pheny1)-pyridin-2-0 '" ylamine 7.23 (t, J=8.59 Hz, 1 H) 7.36 (dd, J=4.80, 4.04 Cl "N2 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) (400 MHz, DMSO-D6) d ppm 1.83 (d, J=6.57 Hz, 5-Bipheny1-3-y1-3-[1-(2,6-3 H) 5.92 -595. (m, 2 H) 6.16 (q, J=6.57 Hz, 1 H) 1-576 dichloro-3-fluoro-phenyl)-7.01 (d, J=1.52 Hz, 1 H) 7.38 - 7.59 (m, 9 H) 7.69 ethoxyl-pyridin-2-ylamine (d, J=7.33 Hz, 2 H) 7.93 (d, J=1.52 Hz, 1 H) H2N __, (400 MHz, DMSO-D6) d ppm 1.84 (d, J=6.57 Hz, , / 5-(3,5-Bis-trifluoromethyl-3 H) 6.16 - 6.24 (m, 3 H) 7.03 (d, J=1.77 Hz, 1 H) F ! -341-(2,6-(2,6 -3-1-577 phenyl) 7.45 (t, J=8.59 Hz, 1 H) 7.54 (dd, J=9.09, 5.05 fluoro-pheny1)-ethoxyl-Hz, 1 H) 7.92 -7.95 (m, 1 H) 8.00 - 8.02 (m, 2 H) F CI F F pyridin-2-ylamine F 8.08 (d, J=2.02 Hz, 1 H) CI 3-[1-(2,6-Dichloro-3-fluoro- (400 MHz, DMSO-D6) d ppm 1.87 (d, J=6.57 Hz, SO
3 H) 6.09 -6.12 (m, 2 H) 6.22 (q, J=6.57 Hz, 1 H) phenyl)-ethoxy]-5-(3,4-7.04 (d, J=1.77 Hz, 1 H) 7.46 - 7.53 (m, 2 H) 7.62 I CI-I.i Al dichloro-phenyI)-pyridin-2-F
(dd, J=9.09, 5.05 Hz, 1 H) 7.66 - 7.70 (m, 2 H) ylamine 7.96 (d, J=2.02 Hz, 1 H) a "1-6 eft (400 MHz, DMSO-D6) d ppm 1.76 (d, J=6.57 Hz, 3 H) 2.54 -2.55 (m, 3 H) 5.90 - 5.94 (m, 2 H) IN 1-(3-(6-Amino-541-(2,6-6.10 (q, J=6.57 Hz, 1 H) 6.93 (d, J=1.77 Hz, 1 H) dichIoro-3-fluoro-phenyl)-7.39 (t, J=8.59 Hz, 1 H) 7.46 (t, J=7.83 Hz, 1 H) a H, 1 -- ethoxyl-pyridin-3-y1}-phenyl)-7.51 (dd, J=9.09, 5.05 Hz, 1 H) 7.63 (d, J=8.34 F a . 'N ethanone Hz, 1 H) 7.76 (d, 1=7.83 Hz, 1 H) 7.81 -7.83 (m, 'I H) 7.85 (d, J=2.02 Hz, 1 H) F .",. F
(400 MHz, DMSO-D6) d ppm 1.82 (d, J=6.57 Hz, 3-11-(2,6-Dichloro- 3-fluoro-UP
3 H) 6.06 -6.10 (m, 2 H) 6.18 (q, J=6.57 Hz, 1 H) phenyI)-ethoxy]-5-(3,5-1-580 CI CI-6 ,... .
7.01 (d, J=1.77 Hz, 1 H) 7.06 - 7.19 (m, 3 H) 7.45 F 0 I -N difluoro-phenyI)-pyridin-2-(t, J=8.84 Hz, 1 H) 7.58 (dd, J=9.09, 5.05 Hz, 1 ylamine H) 7.95 (d, J=2.02 Hz, 1 H) CI

' cl 341-(2,6-Dichloro-3-fluoro- (400 MHz, DM30-D6) d ppm 1.90 (d, J=6.132 Hz, phenyl)-elhoxy]-5-(2,5- 3 H) 6.10 (q, J=6.57 Hz, 1 H) 6.17 - 6.19 (m, 2 H) F0I N dichloro-phenyI)-pyridin-2-6.84 (d, J=1.77 Hz, 1 H) 7.44 - 7.51 (m, 2 H) 7.56 c, NR, ylamine (t, J=8.59 Hz, 1 H) 7.59 - 7.70 (m, 3 H) A, (4-{6-Arnino-541-(2,6-dichloro-4-tfifluoromethyl-pheny1)-ethoxy]-pyridin-3-y1)-Passed CHN 1.0eq AcOH

phenyI)-((3R,5S)-3,5-PfroC!.:' NI:: dimethyl-piperazin-1-yI)-methanone (400 MHz, DMSO-D6) d ppm 1.35 (t, J=6.82 Hz, ,t(CH, 3 H) 1.82 (d, J=6.57 Hz, 3 H) 3.99 - 4.09 (m, 2 H) 5.88 - 5.91 (m, 2 H) 6.13 (q, J=6.57 Hz, 1 H) 6.80 401 341-(2,6-Dichloro-3-fluoro-(dd, J=8.08, 2.27 Hz, 1 H) 6.84 (t, J=2.02 Hz, 1 1-583 phenyl)-ethoxy]-5-(3-ethoxy-H) 6.92 (d, J=1.77 Hz, 1 H) 6.96 (d, J=7.58 Hz, 1 F I '' phenyl)-pyridin-2-ylamine gii 0 -N
H) 7.26 (t, J=7.83 Hz, 1 H) 7.46 (t, J=8.59 Hz, 1 mr- ci NI-1, H) 7.57 (dd, J=8.84, 5.05 Hz, 1 H) 7.83 (d, J=1.77 Hz, 1 H) ,,. CI
(400 MHz, DMSO-D6) d ppm 1.87 (d, J=6.57 Hz, IW--5-(3-Chloro-phenyl)-341-(2,6. 3 H) 6.03 - 6.06 (m, 2 H) 6.18 - 6.24 (m, 1 H) 1-584 a It 1 ", dichloro-3-fluoro-phenyl)-7.02 (d, J=2.02 Hz, 1 H) 7.35 (td, J=6.82, 1.77 F r a 1 0 'N ethoxyl-pyridln-2-ylamine Hz, 1 H) 7.41 -7.53 (m, 4 H) 7.62 (dd, J=8.84, NH' 5.05 Hz, 1 H) 7.93 (d, J=2.02 Hz, 1 H) .
No.
Structure Name Ki (AM) MS m/z Procedure or I (%)_ (M+H) F
0 CH, (400 MHz, DMSO-D6) d ppm 1.58 (d, J=6.57 Hz, 341-(2,6-Dichloro-3-fluoro-3 H) 2.01 -2.02 (m, 3 H) 5.62 - 5.64 (m, 2 H) phenyl)-5-(4-fluoro-3-5.89 (q, J=6.82 Hz, 1 H) 6.68 (d, J=1.77 Hz, 1 H) CI
H, 1 methyl-phenyl)-pyridin-2-6.90 (t, J=8.84 Hz, 1 H) 6.96 - 7.04 (m, 2 H) 7.22 F i&
0 '1'1 ylamine (t, J=8.59 Hz, 1 H) 7.34 (dd, J=9.09, 5.05 Hz, 1 Rip c, NH, H) 7.56 (d, J=1.77 Hz, 1 H) 341-(2,6-Dichloro-3-fluoro-(400 MHz, DMSO-D6) d ppm 1.84 (d, J=6.57 Hz, /
F
phenyl)-ethoxYl-5-(3-3 H) 6.05 - 6.07 (m, 2 H) 6.14 - 6.21 (m, 1 H) F trifluoromethyl-phenyl)-6.99 (d, J=1.77 Hz, 1 H) 7.46 (t, J=8.59 Hz, 1 H) F
pyridin-2-ylamine cH, Olt F
7.56 (dd, J=8.84, 5.05 Hz, 1 H) 7.59 - 7.65 (m, 3 CI
H) 7.76 -7.80 (m, 1 H) 7.95 (d, J=1.77 Hz, 1 H) (400 MHz, DMSO-D6) d ppm 1.82 (d, J=6.57 Hz, 341-(2,6-Dichloro-3-fluoro-3 H) 5.98 - 6.00 (m, 2 H) 6.13 - 6.20 (m, 1 H) I
Hs 1 ..phenyl)-ethoxy]-5-(3-fluoro-6.99 (d, J=1.77 Hz, 1 H) 7.05 - 7.11 (m, 1 H) 7.21 F 110 . -,1 phenyl)-pyridin-2-ylamine -7.27 (m, 2 H) 7.39 - 7.49 (m, 2 H) 7.59 (dd, a NH=
J=9.09, 5.05 Hz, 1 H) 7.90 (d, J=2.02 Hz, 1 H) H,N , N
341-(2,6-Dichloro-3-fluoro-(400 MHz, DMSO-D6) d ppm 1.60 (d, J=6.57 Hz, /
phenyl)-ethoxy]-5-(3-3 H) 5.80 -5.84 (m, 2 H) 5.90 -5.98 (m, 1 H) CH, X; trifluoromethoxy-phenyl)-' =
, 6.73 (d, J=2.02 Hz, 1 H) 7.00 - 7.07 (m, 2 H) 7.20 ot a F
pyridin-2-ylamine -7.30 (m, 3 H) 7.34 (dd, J=8.84, 4.80 Hz, 1 H) 7.68 (d, J=1.77 Hz, 1 H) 0-=-µ0 (400 MHz, DMSO-D6) d ppm 1.82 (d, J=6.57 Hz, 5-Benzo[1,3]dioxo1-5-y1-3[1-.
3 H) 5.81 -5.83 (m, 2 H) 6.03 - 6.04 (m, 2 H) phenyl)-ethoxy]-pyridin-2-(2,6-dichloro-3-fluoro-6.10 - 6.17 (m, 1 H) 6.83 - 6.96 (m, 4 H) 7.46 (t, =
Hs '' F iiii,..
I ,,,, J=8.84 Hz, 1 H) 7.58 (dd, J=9.09, 5.05 Hz, 1 H) ylamine MP a NH, 7.76 (d, J=2.02 Hz, 1 H) OH
(400 MHz, DMSO-D6) d ppm 1.95 (d, J=6.82 Hz, IP
3 H) 5.98 - 6.00 (m, 2 H) 6.22 - 6.28 (m, 'I H) 3-{6-Amino-541-(2,6-6.78 - 6.81 (m, 1 H) 6.89 - 6.93 (m, 2 H) 7.04 (d, 1-590 . H, N-- dichloro-3-fluoro-phenyl)-J=1.77 Hz, 1 H) 7.29 (t, J=8.08 Hz, 1 H) 7.58 (t, F 410 o "N
ethoxy]-pyridin-3-yI)-phenol J=9.09, 8.59 Hz, 1 H) 7.71 (dd, J=8.84, 4.80 Hz, CI
NEI' 1 H) 7.89 (d, J=1.77 Hz, 1 H) 9.55 - 9.57 (m, 1 H) (400 MHz, DMSO-D6) d ppm 1.83 (d, J=6.57 Hz, io OH
(3-{6-Amino-541-(2,6-3 H) 4.52 (d, J=5.31 Hz, 2 H) 5.16 - 5.22 (m, 1 H) dichloro-3-fluoro-phenyl)-5.88 - 5.90 (m, 2 H) 6.11 -6.17 (m, 1 H) 6.96 (d, Cl I .:'N
ethoxyi-pyridin-3-y1)-phenyl)-J=1.52 Hz, 1 H) 7.20 - 7.28 (m, 2 H) 7.31 -7.36 methanol (m, 2 H) 7.46 (t, J=8.84 Hz, 1 H) 7.53 (dd, ci NH, J=9.09, 5.05 Hz, 1 H) 7.83 (d, J=1.77 Hz, 1 H) (400 MHz, Dmso-Da) d ppm 1.88 (d, J=6.57 Hz, u=
346-Amino-541-(2,6-3 H) 6.10 -6.12 (m, 2 H) 6.24 (q, J=6.57 Hz, 1 H) c..3,__ 0 = /
dichloro-3-fluoro-phenyI)-7.12 (d, J=1.77 Hz, 1 H) 7.51 (t, J=8.59 Hz, 1 H) CI%
/ -N ethoxy]-pyridin-3-yI)-7.60 - 7.68 (m, 2 H) 7.77 (d, J=7.83 Hz, 1 H) 7.81 F
a benzonitrile (d, J=8.08 Hz, 1 H) 7.94 -7.96 (m, 1 H) 8.00 (d, J=1.77 Hz, 1 H) (400 MHz, DMSO-D6) d ppm 1.83 (d, J=6.57 Hz, c'.cH
341-(2,6-Dichloro-3-fluoro-3 H) 3.79 - 3.80 (m, 3 H) 5.91 -5.92 (m, 2 H) ' 6.11 -6.18 (m, 1 H) 6.81 -6.84 (m, 1 H) 6.86-phenyl)-ethoxy]-5-(3-6.89 (m, 1 H) 6.93 (d, J=1.52 Hz, 1 H) 6.97 - 7.01 F.,6c f:' '',,i methoxy-pheny1)-pyridin-2-o (m, 1 H) 7.29 (t, J=8.34, 7.83 Hz, 1 H) 7.46 (t, N,õ.
ylamine ci ..
J=8.84 Hz, 1 H) 7.59 (dd, J=9.09, 5.05 Hz, 1 H) 7.85 (d, J=1.77 Hz, 1 H) cr..... a (400 MHz, DMSO-D6) d ppm 1.83 (d, J=6.57 Hz, phenyl)-ethoxy]-5-(3,5-7.00 (d, J=1.77 Hz, 1 H) 7.44 - 7.49 (m, 4 H) 7.58 F
341-(2,6-Dichloro-3-fluoro-3 H) 6.10 - 6.12 (m, 2 H) 6.16 - 6.22 (m, 1 H) ,1,1 dichloro-phenyl)-pyridin-2-(dd, .1=9.09,5.31 Hz, 1 H) 7.95 (d, J=2.02 Hz, 1 . NH, ylamine H) c"(400 MHz, DMSO-D6) d ppm 1.80 (d, J=6.82 Hz, 3-[1-(2,6-Dichloro-3-fluoro-3 H) 1.90 - 1.93 (m, 3 H) 2.24 - 2.27 (m, 3 H) phenyl)-ethoxy]-5-(2,5-5.81 -5.83 (m, 2 H) 6.00 (q, J=6.82, 6.32 Hz, 1 1-595 I H.405 '1 '.
dimethyl-phenyl)-pyridin-2-H) 6.57 (d, J=1.77 Hz, 1 H) 6.79 - 6.82 (m, 1 H) F 40 0 ' "
ylamine 6.98 - 7.03 (m, 1 H) 7.10 (d, J=7.83 Hz, 1 H) 7.45 NH, Cl - 7.52 (m, 2 H) 7.58 (dd, J=8.84, 5.05 Hz, 1 H) No.
Structure Name Ki ( M) MS m/z Procedure or I (%) (M+H) a (400 MHz, DMSO-D6) d ppm 1.79 (d, J=6.57 Hz, I-I,c., ill 5-(5-Chloro-2-methoxy-3 H) 3.61 -3.63 (m, 3 H) 5.89 - 5.91 (m, 2 H) 5.97 - 6.03 (m, 1 H) 6.86 (d, J=1.77 Hz, 1 H) 7.06 phenyl)-341-(2,6-(2,6-3-a ci-' fluoro-pheny1)-ethoxyl-L
(d, J=8.84 Hz, 1 H) 7.15 (d, J=2.78 Hz, 1 H) 7.29 pyridin-2-ylamine .
I
F
, N
(dd, J=8.84, 2.53 Hz, 1 H) 7.49 (t, J=8.59 Hz, 1 CI

H) 7.59 (dd, J=9.09, 5.31 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H) (400 MHz, DMSO-D6) d ppm 1.83 (d, J=6.57 Hz, 5-(3-Chloro-4-fluoro-phenyI)-3 H) 5.98 -6.00 (m, 2 H) 6.14 - 6.20 (m, 1 H) 341-(2,6-dichloro-3-fluoro-6.98 (d, J=1.77 Hz, 1 H) 7.42 - 7.45 (m, 2 H) 7.47 õ
phenyl)-ethoxy]-pyridin-2-(d, J=8.59 Hz, 1 H) 7.55 - 7.60 (m, 2 H) 7.87 (d, ylamine J=2.02 Hz, 1 H) F
(400 MHz, DMSO-D6) d ppm 1.79 (d, J=6.57 Hz, IP
3-(1-(2,6-Dlchloro-3-fluoro-3 H) 3.59 - 3.60 (m, 3 H) 5.88 - 5.91 (m, 2 H) , CH3 pheny1)-ethoxy1-5-(5-fluoro-2-6.00 (q, J=6.82 Hz, 1 H) 6.90 (d, J=1.77 Hz, 1 H) I
H' I -methoxy-phenyl)-pyridin-2-6.99 - 7.10 (m, 3 H) 7.48 (t, J=8.84 Hz, 1 H) 7.59 rik , N
ylamine (dd, J=9.09, 5.31 Hz, 1 H) 7.64 (d, J=2.02 Hz, 1 F

VP- ci NH, H) Ha (400 MHz, DMSO-D6) d ppm 1.20- 1.25 (m, 6 CH, 3-[1-(2,6-Dichloro-3-fluoro-H) 1.83 (d, J=6.57 Hz, 3 H) 2.86 - 2.94 (m, 1 H) phenyl)-ethoxy]-5-(3-5.88 - 5.91 (m, 2 H) 6.13 (q, J=6.32 Hz, 1 H) 6.89 =
Fi. I "-isopropyl-phenyl)-pyridin-2-(d, J=1.77 Hz, 1 H) 7.11 -7.15 (m, 2 H) 7.23-F *
0 ' "
ylamine 7.31 (m, 2 H) 7.47 (t, J=8.59 Hz, 1 H) 7.58 (dd, CI
NH' J=8.84, 4.80 Hz, 1 H) 7.83 (d, J=2.02 Hz, 1 H) HPI ....N
(400 MHz, DMSO-D6) d ppm 1.83 (d, J=6.57 Hz, I
5-(3-Chloro-4-trifluoromethyl-3 H) 6.11 -6.13 (m, 2 H) 6.17 (q, J=6.57 Hz, 1 H) a o N rib, phenyl)-3-[1-(2,6-dichloro-3-6.99 (d, J=1.77 Hz, 1 H) 7.46 (t, J=8.84 Hz, 1 H) 478.90 C112:(-1:cH, CIF
µ411 fluoro-phenyl)-ethoxy]-7.56 (dd, J=9.09, 5.05 Hz, 1 H) 7.68 (d, J=1.77 , ' pyridin-2-ylamine Hz, 1 H) 7.72 (d, J=8.59 Hz, 1 H) 7.80 (dd, F
J=8.34, 1.77 Hz, 1 H) 7.95 (d, J=2.02 Hz, 1 H) H,N ...., (400 MHz, DMSO-D6) d ppm 1.83 (d, J=6.57 Hz, 4-(6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-g......z, CH N. / 41t ethoxy]-pyridin-3-yI)-3 H) 6.13 - 6.22 (m, 3 H) 7.06 (d, J=1.77 Hz, 1 H) 7.45 (t, J=8.59 Hz, 1 H) 7.57 (dd, J=9.09, 5.05 , Hz, 1 H) 7.63 (d, J=8.59 Hz, 2 H) 7.84 (d, J=8.59 ('FliscI
s."'N benzonitrile Hz, 2 H) 7.97 (d, J=1.77 Hz, 1 H) ' 3-[1-(2,6-Dichloro-3-fluoro-(400 MHz, DMSO-D6) d ppm 1.82 (d, J=6.82 Hz, phenyl)-ethoxy1-5-(3,4-3 H) 5.96 - 6.00 (m, 2 H) 6.17 (q, J=6.57 Hz, 1 H) 6.99 (d, J=1.77 Hz, 1 H) 7.22 - 7.27 (m, 1 H) 7.41 r 7 I TH3 Iro-`1, difluopheny1)-pyridin-2--7.52 (m, 3 H) 7.58 (dd, J=9.09, 5.05 Hz, 1 H) 'Crylamine .
1111, 7.87 (d, J=2.02 Hz, 1 H) 0 NJ.CI4, (400 MHz, DM50-D6) d ppm 1.73 (m, 1 H) 1.80 (446-Amino-541-(2,6-(d, J=6.82 Hz, 3 H) 1.84 (m, 1 H) 2.26 (d, dichloro-3-fluoro-phenyl)-J=21.98 Hz, 2 H) 2.53 (m, 2 H) 2.63 (m, 2H) 3.40 1 ' 2, ethoxy].pyridin-3-y1)-phenyl)- 0.0095 (m, 2 H) 3.60 (m, 2 H) 5.95 (s, 2 H) 6.14 (d, ....L...r, 1 (4-methyl-[1 ,4]diazepan-1-y1).
J=6.57 Hz, 1 H) 6.99 (s, 1 H) 7.36 (d, J=7.58 Hz, F
, i I' methanone 2 H) 7.44 (m, 3 H) 7.57 (dd, J=8.97, 4.93 Hz, 1 H) 7.86 (d, J=1.77 Hz, 1 H) (4-(6-Amino-541-(2,6-(400 MHz, DMSO-D6) d ppm 1.81 (t, .1=6.19 Hz, Ni Hz 2 H) 3.45 (m 2 H) 3.7 (m 2 H) 5.96 (s 2 H) dichloro-3-fluoro-phenyl)-3 H) 1.90 (m, 2 H) 2.96 (m, 2 H) 3.10 (d, J=36.88 ethoxy]-pyridin-3-y1)-phenyl)- 0.031 ' ' 6.14 (q, J=6.82 Hz, 1 H) 6.99 (d, J=1.52 Hz, 1 H) H. 1 [1,4]diazepan-1-yl-7.44 (m, 5 H) 7.56 (dd, J=8.97, 4.93 Hz, 1 H) methanone 7.87 (d, J=1.77 Hz, 1 H) .$ Cr (400 MHz, DMSO-D6) d ppm 1.80 (d, J=6.57 Hz, (4-(6-Amino-541-(2,6-3 H) 2.72 (m, 4 H) 3.36 (m, 2 H) 3.52 (m, 2 H) dichloro-3-fluoro-phenyl)-5.96 (s, 2 H) 6.14 (q, J=6.74 Hz, 1 H) 6.99 (d, 0.0475 ethoxy)-pyridin-3-y1)-phenyl)-J=1.77 Hz, 1 H) 7.37 (m, 2 H) 7.44 (m, 3 H) 7.57 piperazIn-1-yl-methanone (dd, J=8.97, 4.93 Hz, 1 H) 7.87 (d, J=1.77 Hz, 1 H) ,cH., (400 MHz, CHLOROFORM-D) d ppm 1.83 (d, J=6.57 Hz, 3 H) 4.84 (s, 2 H) 5.03 (d, J=11.12 CI
H, 341-(2,6-Dichloro-3-fluoro-Hz, 1 H) 5.38 (d, J=17.43 Hz, 1 H) 6.06 (q, phenyI)-ethoxy]-5-vinyl-'-..

"
0.655 J=6.82 Hz, 1 H) 6.49 (dd, J=17.68, 10.86 Hz, 1 pyridin-2-ylamlne H) 6.90 (d, J=1.77 Hz, 1 H) 7.04 (dd, J=8.84, IIIV a 7.83 Hz, 1 H) 7.29 (dd, J=8.84, 4.80 Hz, 1 H) F
7.55 (d, J=1.77 Hz, 1 H) No.
Structure Name Ki (pm) MS m/z Procedure or 1 (%) (M+H) _pH
Ho 0-0 (446-Amino-541-(2,6-(400 MHz, DMSO-D6) d ppm 1.81 (d, J=6.82 Hz, 3 H) 3.28 (m, 2 H) 3.54 (m, 2 H) 3.97 (d, J=4.04 dichloro-3-fluoro-phenyI)-Hz 2 H) 4.08 (d, J=4.29 Hz, 2 H) 5.10 (br, 2 H) ethoxy]-pyridin-3-y1}-phenyi)-0.0 -9 5.98 (d, 2 H) 7.00 (d, J=1.77 Hz, 1 H) 7.45 (m, 3 ((3R,45)-3,4-dihydroxy-Fa .4 pyrrolidin-1-yI)-methanone H) 7.48 (m, 2 H) 7.57 (dd, J=8.97, 4.93 Hz, 1 H) C'CNH, 7.88 (d, J=1.77 Hz, 1 H) l (400 MHz, DMSO-D6) d ppm 1.34(m, 1 H) 1.74 ti..,..õ
5-[(1-Benzyl-pyrrolidin-3-(d, J=5.94 Hz, 3 H) 1.78 (m, 1 H) 2.08 (m, 1 H) ylaminoymethy1]-3[1-(2,6-2.40 (m, 2 H) 2.54 (m, 1 H) 2.89 (m, 1 H) 3.33 (s, dichloro-3-fluoro-phenyl)-0%
2 H) 3.49 (s, 2 H) 5.52 (s, 2 H) 5.94 (q, J=6.57 ethoxyl-pyridin-2-ylamine Hz, 1 H) 6.68 (s, 1 H) 7.27 (m, 5 H) 7.36 (m, 1 H) 7.39 (m, 1 H) 7.48 (m, 1 H) Fly 0....14--CHH
(400 MHz, DMSO-D6) d ppm 1.80 (d, J=6.57 Hz, 4-{6-Amino-541-(2,6-3 H) 2.87 (m, 1 H) 3.43 (m, 1 H) 3.81 (m, 2 H) dichloro-3-fluoro-phenyl)-0.045 4.74 (m, 1 H) 6.00 (s, 2H) 6.13 (q, J=6.48 Hz, 1 ethoxy]-pyridin-3-y1)-N-H) 6.96 (dd, J=6.57, 1.77 Hz, 1 H) 7.45 (m, 3 H) azetidin-3-yl-benzamide NN
7.54 (dd, J=8.97, 4.93 Hz, 1 H) 7.87 (m, 3 H) c, % CH, 0,-4-{6-Amino-5-[1-(2,6-(400 MHz, CHLOROFORM-D) d ppm 1.87 (d, -N:
J=6.82 Hz, 3 H) 2.72 (s, 6 H) 4.99 (s, 2 H) 6.12 dichloro-3-fluoro-phenyl)-(q, J=6.57 Hz, 1 H) 6.99 (d, J=1.77 Hz, 1 H) 7.07 ethoxy]-pyridin-3-yI)-N,N-0.069 (m, 1 H) 7.32 (dd, J=8.84, 4.80 Hz, 1 H) 7.50 (m, ly. I
dimethyl-F

"
2 H) 7.76 (d, J=8.59 Hz, 2' H) 7.91 (d, J=1.77 Hz, .
benzenesulfonamide "H, 1 H) 9,4 (400 MHz, Me0D) d ppm 1.72 (d, J=6.57 Hz, 3 341-(2,6-Dichloro-3-fluoro-H) 3.69 (s, 3 H) 4.78 (s, 2 H) 6.13 (q, J=6.57 Hz, .3,r.Z
phenyl)-ethoxy]-5-(6-1 H) 6.71 (dd, J=8.84, 2.27 Hz, 1 H) 6.88 (d, methoxy-1H-benzoimidazol-J=2.02 Hz, 1 H) 7.04 (m, 1 H) 7.26 (m, 2 H) 7.40 -P
2-yI)-pyridin-2-ylamine (d, J=1.77 Hz, 1 H) 8.03 (d, J=2.02 Hz, 1 H) O
"H.
341-(2,6-Dichloro-3-fluoro-(400 MHz, Me0D) d ppm 1.78 (d, J=6.57 Hz, 3 phenyl)-ethoxy]-5-(6-H) 3.51 (s, 3 H) 3.75 (s, 3 H) 6.10 (q, J=6.32 Hz, No-4:
methoxy-1-methy1-1H-1 H) 6.90 (m, 1 H) 6.92 (m, 1 H) 7.13 (m, 1 H) =
II
benzoimidazo1-2-y1)-pyridin-2.
7.35 (m, 2 H) 7.80 (d, J=7.33 Hz, 1 H) .
".
ylamine õ.......
ii,.0 % lij sulfony1)-pheny11-pyridin-2-J8.97, 4.93 Hz, 1 H) 7.54 (d, J=8.34 Hz, 2 H) 341-(2,6-(2,6-3-fluoro-(400 MHz, Me0D) d ppm 1.83 (m, 2 H) 1.67 (d, 0---ri"
J=6.57 Hz, 31-1) 2.66 (m, 4 H) 3.35 (m, 2 H) 3.40 phenyl)-ethoxy]-544-(4-(m, 2 H) 6.20 (q, J=6.65 Hz, 1 H) 7.02 (d, J=1.77 methyl-{1,4]diazepane-1-!
H, Hz, 1 H) 7.20 (t, J=8.59 Hz, 1 H) 7.43 (dd, ...e..,...i. , =
F
0 ' N
ylamine 011.
I

7.77 (d, J=8.59 Hz, 2 H) 7.81 (d, J=1.26 Hz, 1 H) ci (400 MHz, DMS0-06) d ppm 1.82 (d, J=6.57 Hz, ,:, m2 r=.._ dichloro-3-fluoro-pheny1)-646-Amino-541-(2,6-3 H) 3.92 (s, 3 H) 5.96 (s, 2 H) 6.17 (q, J=6.48 Hz, 1 H) 7.03 (d, J=1.77 Hz, 1 H) 7.35 (dd, ethoxy]-pyridin-3-yI)-1-J=8.59, 1.26 Hz, 1 H) 7.44 (t, J=8.72 Hz, 1 H) F...151":' methy1-1H-Indazole-3-carboxylic acid amide 7.56 (m, 2 H) 7.91 (d, J=2.02 Hz, 1 H) 8.03 (d, NH, J=8.59 Hz, 1 H) _N.crt, (400 MHz, CHLOROFORM-D) d ppm 1.84 (d, (o 341 -(2,6-Dichloro-3-fluoro-J=6.82 Hz, 3 H) 3.89 (s, 3 H) 4.76 (s, 2 H) 6.05 phenyI)-ethoxy]-5-(1-methyl-ci ci-L
.
(q, J=6.57 Hz, 1 H) 6.84 (d, J=1.77 Hz, 1 H) 7.03 ' 1H-pyrazol-4-y1)-pyridin-2-it N

,.., (m, 1 H) 7.28 (dd, J=8.97, 4.93 Hz, 1 H) 7.40 (s, F
. - ylamine 1 H) 7.53 (s, 1 H) 7.74 (d, J=1.77 Hz, 1 H) (4rifl u -{-Arommethyl-phenyI)-H) 7.72 (t, J7.96 Hz, 3 H) 7.47 - 7.57 (m ino-5-[1-(2-(400 MHz, DMSO-D6) d ppm 9.29 (d, J=9.60 Hz, t6o 1 H) 8.63 (d, J=10.86 Hz, 1 H) 7.84 - 7.94 (m, 2 =
6 H) ethoxyl-pyridin-3-y1}-phenyl)-%
' =

7.35 (s, 1 H) 5.97 - 6.05 (m, 1 H) 3.37 (s, 2 H) Fi&r::, (3,5-dimethyl-piperazin-1-yI)-1.69 (d, J=6.06 Hz, 3 H) 1.15 (s, 5 H) 1.06 (s, 1 methanone NH, H) CH, (400 MHz, DMSO-D6) d ppm 9.26 (s, 2 H) 8.64 c..t.5;1.fi (4-{6-Amino-541-(3-(s, 2 H) 7.93 (s, 2 H) 7.84 (d, J=1.52 Hz, 2 H) ' trifluoromethyl-phenyl)-7.81 (d, J=7.58 Hz, 2 H) 7.66 (s, 2 H) 7.60 (d, ethoxy]-pyridin-3-y1)-pheny1)-2%
J=8.34 Hz, 5 H) 7.53 - 7.59 (m, 2 H) 7.46 (d, (3,5-dimethyl-piperazIn-1-y1)-J=8.34 Hz, 4 H) 6.01 (q, J=6.32 Hz, 2 H) 3.32 (s, F
F6...,, methanone 4 H) 3.03 (s, 1 H) 2.75 (s, 1 H) 1.61 (d, J=6.32 io NH, Hz, 5 H) 1.13 (s, 7 H) N
7-[4-(3,5-Dimethyl-(400 MHz, DMSO-D6) d ppm 8.53 (s, 2 H) 8.33 c".
piperazine-l-carbonyl)-(d, J=2.02 Hz, 2 H) 7.84 (d, J=2.02 Hz, 2 H) 7.80 pheny11-2-phenyl-41-1-0%
(d, J=3.34 Hz, 5 H) 7.36 - 7.42 (m, 12 H) 5.93 (s, pyrido{3,2-b][1,4]oxazin-3-2 H) 4.55 (s, 1 H) 3.73 (s, 3 H) 3.40 (s, 6 H) 1.19 one (s, 10 H) No.
Structure Name Ki ( M) MS m/z Procedure or 1 (%)_ (M+H) CH, rkNH
(400 MHz, DMSO-D6) d ppm 7.97 (d, J=1.77 Hz, 1,1 0,1, Hs {416-Amino-5-(3-fluoro-2-1 H) 7.79 (s, 1 H) 7.66 - 7.74 (m, 3 H) 7.48 (d, trifluoromethyl-benzyloxy)-J=1.77 Hz, 2 H) 7.41 (d, J=8.34 Hz, 2 H) 7.24 (s, pyridin-3-y1j-phenyl}-(3,5-16%
1 H) 5.91 (s, 1 H) 5.40 (s, 2 H) 3.61 (s, 1 H) 2.61 - 504 dimethyl-piperazin-1-yI)-2.70 (m, 3 H) 2.33 (s, 1 H) 2.17 (s, 1 H) 1.95 -F..F.Fr ......

'N
methanone 2.06 (m, 1 H) 1.47 (s, 1 H) 1.23 (s, 7 F1) 1.00 (s, 3 NH, H) 0.80 - 0.92 (m, 6 H) rr;
{446-Amino-5-(2,6-difluoro-(400 MHz, DMSO-D6) d ppm 8.02 (s, 1 H) 7.96 (s, 1 H) 7.85 (d, J=8.34 Hz, 2 H) 7.51 - 7.62 (m, 3 benzyloxy)-pyridin-3-y11-5%
H) 7.23 (t, J=8.08 Hz, 2 H) 5.43 (s, 2 H) 4.09 (s, 1 pheny1)-(3,5-dimethyl-H) 3.37 (s, 1 H) 1.40 (s, 9 H) 1.14 (d, J=2.27 Hz, piperazin-1-yI)-methanone ac4o:
3 H) 1.08 (d, J=16.42 Hz, 3 H) loxy-(4-(6-Amino-5-benzY-(3 (400 MHz, DMSO-D6) d ppm 9.35 (s, 1 H) 8.70 pyridin-3-yI)-phenyl],5-(3,5 N&
(s, 1 H) 7.96 (s, 2 H) 7.78 (d, J=8.59 Hz, 4 H) 6%
7.55 (d, J=8.08 Hz, 5 H) 7.42 (t, J=7.20 Hz, 2 H) dimethyl-piperazin-1-yI)-7.35 (t, J=7.33 Hz, 1 H) 5.40 (s, 2 H) 3.39 (s, 2 H) methanone 3.16 (s, 1 H) 1.20 (s, 4 H) (400 MHz, DMSO-D6) d ppm 7.95 (d, J=1.77 Hz, (4-{6-Amino-541-(2-chloro-1 H) 7.57 (d, J=8.34 Hz, 2 H) 7.52 (s, 1 H) 7.45 3,6-difluoro-phenyl)-ethoxy]- 0.375 (d, J=8.08 Hz, 3 H) 7.25 (d, J=1.77 Hz, 1 H)6.11 pyridin-3-y1}-phenyl)-(4-ethyl-(s, 1 H) 5.95 (s, 2 H) 3.62 (s, 1 H) 3.49 (s, 1 H) piperazin-1-yI)-methanone 2.44 (s, 2 H) 2.41 (d, J=7.07 Hz, 4 H) 1.85 (d, 005c: NH, J=6.32 Hz, 3 H) 1.06 (t, J=7.20 Hz, 3 H) rpr--011, (400 MHz, DMSO-D6) d ppm 7.91 (d, J=2.02 Hz, 1 H) 7.65 (d, J=8.34 Hz, 2 H) 7.53 (d, J=7.33 Hz, (4-(6-Amino-5-benzyloxy-2 H) 7.44 (d, J=1.77 Hz, 1 H) 37-77.
.42 (m, 3 H) õõ, pyridin-3-y1)-pheny1]-(4-ethyl- 7%

7.32 (t, J=7.33 Hz, 1 H) 5.94 (s, 2 H) 5.25 (s, 2 H) - '"

piperazin-1-y1)-methanone 3.60 (s, 1 H) 3.38 (s, 1 H) 2.30 - 2.41 (m, 5 H) cro ,,,, 0.99 (t, J=7.20 Hz, 3 H) rt";.õ
(400 MHz, DMSO-D6) d ppm 9.40 (s, 1 H) 8.77 ....1-.., {416-Amino-5-(2-methyl-benzyloxy)-pyridin-3-yI]-(s, 1 H) 7.98 (d, J=1.52 Hz, 1 H) 7.77 -7.88 (m, 4 0%
H) 7.37 (d, J=8.34 Hz, 2 H) 7.53 (d, J=7.33 Hz, 1 pheny1)-(3,5-dimethyl-H) 7.21 -7.31 (m, 3 H) 5.37 (s, 2 H) 3.39 (s, 2 H) piperazin-1-yI)-methanone 2.37 (s, 3 H) 1.20 (s, 4 H) 3-{2-Amino-544-(4-pyrrolidin-(400 MHz, DMSO-D6) d ppm 9.78 (s, 1 H) 8.12 -0 (s, 1 H) 7.92 - 7.98 (m, 2 H) 7.88 (d, J=7.58 Hz, 1 1-yl-piparldins-1-carbonyl)-H) 7.74 - 7.83 (m, 3 H) 7.59 (t, J=7.71 Hz, 2 H) phenyl]-pyridin-3-6%

I
7.40 (d, J=8.34 Hz, 2 H) 5.47 (s, 2 H) 3.86 (s, 3 yloNymethylybenzoic acid i H) 3.50 (0, 2 H) 3.41 (s, 1 H) 3.10 (s, 2 H) 2.00 H, . so e methyl ester (s, 3 H) 1.85 (s, 2 H) 1.53 (s, 2 H) ' &
3-{2-Amino-544-(3,5-(400 MHz, DMSO-D6) d ppm 9.31 (s, 2 H) 8.67 ' dimethyl-piperazine-1-(s, 2 H) 8.12 (s, 2 H) 7.92 - 7.99 (m, 4 H) 7.88 (d, carbonyl)-phenyll-pyridin-3-0%
J=7.83 Hz, 2 H) 7.75 - 7.84 (m, 6 H) 7.53 -7.63 yloxymethylybenzoic acid (m, 6 H) 5.48 (s, 4 H) 3.81 - 3.91 (m, 6 H) 3.39 ,, methyl ester (s, 4 H) 3.13 (s, 1 H) 1.20 (s, 7 H) (400 MHz, DMSO-D6) d ppm 9.91 (s, 1 H) 7.95 {446-Amino-5-(2-methyl-(d, J=1.52 Hz, 1 H) 7.85 (s, 1 H) 7.80 (d, J=8.34 k--) ==8.34 benzyloxy)-pyridin-3-y1)-6%
Hz, 2 H) 7.21 -7.31 (m, 3 H) 5.36 (s, 2 H) 4.56 Hz, 2 H) 7.53 (d, J7.07 Hz, 1 H) 7.49 (d, J
pheny1)-(4-pyrrolidin-1-yl-(s, 1 H) 3.68 (s, 1 H) 3.51 (s, 2 H) 3.41 (s, 1 H) 6, I
piperidin-1-y1)-methanone 3.10 (s, 3 H) 2.82 (s, 1 I-1) 2.37 (s, 3 H) 1.99 (s, 3 NH, H) 1.79 - 1.90 (m, 2 H) 1.56 (s, 2 H) (400 MHz, DMSO-D6) d ppm 7.90 (d, J=1.52 Hz, o lr,..) [4-(6-Amino-5-1 H) 7.79 (d, J=8.34 Hz, 3 H) 7.66 (s, 1 H) 7.44-7.55 (m, 21-I) 4.03 (d, J=6.06 Hz, 2 H) 3.83 (s, 1 cyclohexylmethoxy-pyridin-3-7%
H) 3.67 (s, 1 H) 3.51 (s, 2 H) 3.39 (s, 1 H) 3.09 yI)-phenyl]-(4-pyrrolidin-1-yl-(s, 2 H) 2.82 (s, 1 H) 2.14 (s, 2 H) 1.99 (s, 3 H) piperidin-1-y1)-methanone 1.79 - 1.91 (m, 5 H) 1.64 -1.76 (m, 3 H) 1.54 (s, i....c...i 2 H) 1.20 - 1.30 (m, 2 H) 1.07 (d, J=11.62 Hz, 2 \ --) NH, H) No.
Structure Name Ki (p.M) MS m/z Procedure or 1 (%) (M+H) (400 MHz, DMSO-D6) d ppm 9.76 (s, 1 H) 8.51 (t, J=5.56 Hz, 1 H) 7.86 (d, J=1.52 Hz, 2 H) 7.79 0 4-(1-(2-Amino-544-(4-(d, J=8.34 Hz, 2 H) 7.63 (dd, J=14.40, 8.34 Hz, 5 pyrrolidin-1-yl-piperidine-1-H) 7.45 (d, J=8.34 Hz, 2 H) 7.04 (t, J=7.96 Hz, 'I

carbonyl)-phenyl]-pyridin-3-7%
H) 6.55- 6.65 (m, 3 H) 6.00 (d, J=6.32 Hz, 1 H) "Gr'llier ''' yloxy)-ethyl)-(2-(3-hydroxy-3.49 (s, 2 H) 3.34 - 3.45 (m, 3 H) 3.09 (s, 3 H) phenyl)-ethyl]benzamide 2.75 (s, 1 H) 2.65 - 2.74 (m, 2 H) 2,13 (s, 1 H) 1.99 (s, 3 H) 1.78 - 1.89 (m, 2 H) 1.65 (d, J=6.32 Hz, 3 H) 1.52 (s, 2 H) (400 MHz, DMSO-D6) d ppm 9.80 (s, 1 H) 8.62 (t, J=5.81 Hz, 1 H) 7.85 (d, J=1.26 Hz, 1 H) 7.78 Cir) 4-(1-(2-Amino-544-(4-(d, J=8.34 Hz, 3 H) 7.62 (dd, J=12.63, 8.34 Hz, 5 pyrrolidin-1-yl-piperidine-1-H) 7.39 - 7.49 (m, 4 H) 7.21 -7.30 (m, 1 H) 5.98 itire .
carbonyl)-phenyli-pyridin-3-3%
(d, J=6.32 Hz, 1 H) 3.65 (s, 1 H) 3.40 - 3.51 (m, yloxy)-ethy1)42-(2,6-dichloro-J=6.63, 6.63, 6.63, 6.63 Hz, 4 H) 3.03 - 3.15 (m, ., pheny1)-ethyll-benzamide H) 2.82 (s, 1 H) 2.13 (s, 1 H) 1.98 (s, 3 H) 1.78 -6C:
1.89 (m, 2 H) 1.65 (d, J=6.06 Hz, 3 H) 1.53 (s, 2 H) 4-(1-(2-Amino-544-(4-(400 MHz, DMSO-D6) d ppm 7.75 - 7.82 (m, 2 H) 7.56 -7.67 (m, 4 H) 7.39 - 7.49 (m, 6 H) 4.27 (d, pyrrolidin-1-yl-piperidine-1-J=4.80 Hz, 2 H) 3.92 (s, 1 H) 3.49 (s, 2 H) 3.37 carbonyl)-phenyll-pyridin-3-3%

(s, 2 H) 3.07 (s, 3 H) 2.12 (s, 1 H) 1.92 - 2.04 (m, di-g4) yloxy)-ethyl)-(1-benzyl-' 4 H) 1.79 - 1.91 (m, 2 H) 1.71 (d, J=11.87 Hz, 1 piperidin-4-y1)-benzamide H) 1.59- 1.68 (m, 3 H) 1.51 (s, 2 H) (400 MHz, DMSO-D6) d ppm 8.39 (s, 1 H) 7.77-0 4-(1-(2-Amino-544-(4-7.85 (m, 3 H) 7.61 (t, J=8.08 Hz, 6 H) 7.43 (d, C
pyrrolidin-1-yl-plperidine-1-J=8.34 Hz, 2 H) 5.96 (s, 1 H) 3.69 (s, 2 H) 3,49 oarbony1)-phenyl]-pyridin-3-0%
(s, 3 H) 3.39 (s, 2 H) 3.30 (t, J=6.95 Hz, 3 H) 3.14 yloxy)-ethy1)43-(2-oxo-- 3.22 (m, 4 H) 3.09 (s, 3 H) 2.18 (t, J=8.08 Hz, 2 eu,,--11-rert'' pyrrolidln-1-y1)-propyl]-H) 2.00 (s, 3 H) 1.86 (ddd, J=15.28, 7.58, 7.45 benzamide Hz, 4 H) 1.65 (t, J=6.06 Hz, 5 H) 1.52 (s, 2 H) c3,---mi, (400 MHz, DMSO-D6) d ppm 9.85 (s, 1 H) 7.91 (d, J=1.77 Hz, 1 H) 7.58 (dd, J=8.97, 4.93 Hz, 1 dichloro-3-fluoro-pheny1)-H) 7.50 - 7.55 (m, 4 H) 7.44 - 7.50 (m, 1 H) 7.13 e(4t4ho6xyll-plyn:id-51n--(31--y(21)-,6p-heny1)- 0.0472 (d, J=1.52 Hz, 1 H) 6.27 (q, J=6.57 Hz, 1 H) 3.48 v i , H
N
(4-ethyl-piperazin-1-y1)-(s, 2 H) 3.15 (q, J=7.07 Hz, 3 H) 3.06 (s, 2 H) W NH' methanone 1.84 (d, J=6.57 Hz, 3 H) 1.22 (t, J=7.33 Hz, 3 H) F
{446-Amino-5-(2,6-dichloro-(400 MHz, DMSO-D6) d ppm 9.29 (s, 2 H) 8.66 (s, 2 H) 7.91 - 8.00 (m, 51-1) 7.85 (d, J=6.02 Hz, 5 benzyloxy)-pyridin-3-y1J-10% H) 7.54 - 7.61 (m, 10 H) 7.48 - 7.53 (m, 3 H) 5.48 pheny1)-(3,5-dimethyl-(s, 5 H) 4.6i (s, 1 H) 1.21 (d, J=4.55 Hz, 9 H) piperazin-1-y1)-methanone 1.15 (s, 5 H) i(6-Amino-3-aza-(400 MHz, DMSO-D6) d ppm 8.14 (d, J=3.54 Hz, . A-..7 bcyclo[3.1 .0]hex-3-y1)-(4-(6-3 H) 7.87 (s, 1 H) 7.58 (dd, J=8.97, 4.93 Hz, 1 H) amino-5-[1-(2,6-dichloro-3-0.0554 7.44 - 7.53 (m, 5 H) 7.12 (s, 1 H) 6.25 (s, 1 H) .i.
fluoro-phenyl)-ethoxy]-3.95 (d, J=11.87 Hz, 1 H) 3.69 (s, 2 H) 1.96 (d, pyridin-3-y1)-pheny1)-J=13.39 Hz, 2 H) 1.84 (d, J=6.57 Hz, 3 H) methanone (400 MHz, DMSO-D6) d ppm 8.20 (d, J=2.27 Hz, ......., CJ
1 H) 7.83 (d, J=1.77 Hz, 1 H) 7.79 (dd, J=8.59, 541-(2,6-(2,6-3-fluoro-2.53 Hz, 'I H) 7.61 (dd, J=8.97, 4.93 Hz, 1 H) , phenyl)-ethoxy1-6'-(2-7.49 (t, J=8.84 Hz, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 0.109 morpholln-4-yl-ethoxy)-6.88 (d, J=8.59 Hz, 1 H) 6.18 (q, J=6.82 Hz, 1 H) Ha I
[3,31131pyridlnyl-6-ylamine 5.92 (s, 2 H) 4.41 (t, J=5.81 Hz, 2 H) 3.61 (m, 4 F
H) 2.72 (t, J=5.81 Hz, 2 H) 2.47 - 2.52 (m, 4 H) ci NH.
1.85 (d, J=6.57 Hz, 3 H) ' (400 MHz, DMSO-D6) d ppm 7.42 -7.52 (m, 2 H) -"--0 6'-Amino-5'41-(2,6-dichloro-7.25 - 7.35 (m, 2 H) 7.22 (t, J=8.72 Hz, 1 H) 6.64 3-fluoro-phenyl)-ethoxy)-1-(2-(d, J=1.52 Hz, 1 H) 6.19 (d, J=9.35 Hz, 1 H) 5.89 40,, 0.692 pyrrolidin-1-yl-ethyl)-1H-(q, J=6.74 Hz, 1 H) 5.58 (s, 2 H) 3.72 -3.84 (m, 2 ' [3,31bipyridiny1-6-one H) 2.42 - 2.53 (m, 2 H) 1.57 (d, J=6.57 Hz, 3 H) ,, NH, 1.39 - 1.50(m, 4 H) No.
Structure Name Ki (p.M) 'H-NMR
MS m/z Procedure or I (%) (M+H) (400 MHz, DMSO-D6) d ppm 7.98 (d, J=2.53 Hz, ..-,....0 1 H) 7.62 (d, J=2.02 Hz, 1 H) 7.57 (dd, J=8.59, 541-(Z6-(Z6-3-fluoro-2.53 Hz, 1 H) 7.40 (dd, J=8.97, 4.93 Hz, 1 H) .;.
phenyI)-ethoxy]-6'-(2-0.094 7.27 (t, J=8.72 Hz, 1 H) 6.77 (d, J=1.77 Hz, 1 H) pyrrolidin-1-yl-ethoxy)-6.66 (d, J=8.59 Hz, 1 H) 5.97 (q, J=6.57 Hz, 1 H) FT, . 44 [3,3'1bipyridinyl-6-ylamine 5.70 (s, 2 H) 4.17 (t, J=5.81 Hz, 2 H) 2.56 - 2.65 (m, 2 H) 1.63 (d, J=6.82 Hz, 3 H) 1.46- 1,54(m, 4 H) 0.97 - 1.09 (m, 1 H) (400 MHz, DMSO-D6) d ppm 7.71 (dd, J=9.60, 1.77 Hz, 2 H) 7.46 - 7.56 (m, 2 H) 7.42 (t, J=8.72 H
61-Amino-541-(2,6-dichloro-Hz, 1 H) 6.84 (s, 1 H) 6.39 (d, J=9.35 Hz, 1 H) uoro-phenyl)-ethoxy]-142-6.10 (q, J=6.57 Hz, 1 H) 5.79 (s, 2 H) 3.98 -4.08 (1-methyl-pyrrolidin-2-y1)-0.513505 (m, 4 H) 3.81 -3.92 (m, 2 H) 2.85 - 2.92 (m, 2 H) F,,, 1,1 ethy1]-1H-[3,31bipyridiny1-6-2.14 - 2.18 (m, 7 H) 1.93- 2.05 (m, 5 H) 1.84-,,..4,4..c, NH, one 1.89 (m, 2 H) 1.76 - 1.82 (m, 4 H) 1.52 - 1.63 (m, 6 H) 1.26 - 1.38 (m, 2 H) 1.08 - 1.18 (m, 6 H) (400 MHz, Me0D) d ppm 7.62 (d, J=1.52 Hz, 1 H) 7.25 - 7.31 (m, 2 H) 7.19 - 7.25 (m, 2 H) 6.73 (4-{6-Amino-541-(2,4,6-(s, 2 H) 6.65 (d, J=1.77 Hz, 1 H) 5.65 (q, J=6.57 trimethyl-phenyl)-ethoxyl-Hz, 1 H) 4.46 -4.57 (m, 1 H) 3.61 -3.73 (m, 1 H) pyridin-3-y1)-phenyl)-(4-2.96 - 3.07 (m, 1 H) 2.73 - 2.84 (m, 1 H) 2.50-pyrrolidin-1-yl-piperidin-1-y1)-2.59 (m, 4 H) 2.23 - 2.31 (m, 7 H) 2.10 (s, 3 H) .64 methanone 1.92- 2.04(m, 1 H) 1.77 - 1.88 (m, 1 I-1) 1.69-H,C
CH, ", 1.76 (m, 4 H) 1.66 (d, J=6.82 Hz, 3 H) 1.29- 1.40 (m, 2 H) (400 MHz, Me0D) d ppm 7.66 (d, J=2.02 Hz, 1 ..,,.10 H) 7.28 - 7.39 (m, 4 H) 7.12 - 7.23 (m, 2 H) 7.07 (4-{6-Amino-541-(2-(2-6-fluoro-phenyI)-ethoxy]-(d, J=1.77 Hz, 1 H) 6.92 - 7.02 (m, 1 H) 5.97 (q, J=6.06 Hz, 1 H) 4.44 - 4.56 (m, 1 H) 3.62 - 3.74 pyridin-3-y1)-pheny1)-(4-(m, 1 H) 2.96 - 3.03 (m, 1 H) 2.72 - 2.84 (m, 1 H) Yo' '' pyrrolidin-1-yl-piperidin-1-y1)-methanone 2.48 - 2.59 (m, 4 H) 2.20 - 2.31 (m, 111) 1.91 -2.02 (m, 1 H) 1.78 - 1.89 (m, 1 H) 1.66 - 1.77 (m, , NH, 8 H) 1.28 - 1.40 (m, 2 H) (400 MHz, DMSO-D6) d ppm 7.61 (d, J=1.77 Hz, IP
341-(2,6-Dichloro-3-fluoro-1 H) 7.38 (dd, J=8.97, 4.93 Hz, 1 H) 7.20 - 7.29 1-642phenyI)-ethoxy]-5-(4-fluoro-(m, 3 H) 6.99 - 7.07 (m, 2 H) 6.76 (d, J=1.77 Hz, .l F a H30 --,. IN
phenyl)-pyridin-2-ylamine , a 1 H) 5.95 (q, J=6.65 Hz, 1 H) 5.70 (s, 2 H) 1.62 ac? "2 (d, J=6.57 Hz, 3 H) (500 MHz, DM50-D6) d ppm 7.73 (s, 1 H) 7.73-. 0 0,, 6'-Amino-5'41-(2,6-dichloro-7.46 (m, 5 H)7.09 (d, J=1.55 Hz, 1 H) 6.42 (d, 3-fluoro-phenyI)-ethoxy]-1H- 0.04323 J=9.5 Hz, 1 H) 6.29 (q, J=6.65 Hz, 1 H) 1.34 (d, [3,31bipyridiny1-6-one J=6.60 Hz, 3 H) .,.,,, (300 MHz, CDCI3-D1) d ppm 8.54 (d, 2 H) 7.80 5'-Bromo-541-(2,6-dichloro-(m, 2 H) 7.33 (m, 1 H) 7.08 (m, 1 H) 6.93 (s, 1 H) 3-fluoro-phenyl)-ethoxyl-0.1958 6.12 (q, J = 6.7 Hz, 1 H) 5.041 (br. s, 2 H) 1.88 [M+2]
[3,3lbipyridiny1-6-ylamine (d, J = 6.7 Hz, 3 H) 11,c. õCH, (300 MHz, CDCI3-D1) d ppm 7.83 (d, J = 1.87 341-(2,6-Dichloro-3-fluoro-Hz, 1 H) 7.28 (m, 4 H) 7.04 (m, 1 H) 6.98 (d ,J =
phenyl)-ethoxy]-5-(4-0.1572 1.76 Hz , 1 H) 6.75 (m, 2 H) 6.11 (q, J = 6.7 Hz, 1 F,6cts. , ,, dimethylamino-phenyl)-H) 4.76 (br. s, 2 H) 2.97 (s, 6 H) 1.85 (d, J = 6.7 NH, pyridin-2-ylamine Hz, 3 H) 5-[1-(2,6-Dichloro-3-fluoro-(300 MHz, CDCI3-D1) d ppm 8.10 (s, 1 H) 7.77 0-cF;
(s, 1 H) 7.50 (m, 1 H) 7.30 (m, 1 H) 7.09 (m, 2 H) MS 408 Ha ...V''.
phenyl)-ethoxy]-2'-methoxy-0.099 6.92 (m' 1 H) 6.06 (d, J = 6.7 Hz, 1 H) 4.91 (br. s, m/z F.'6(1.0 " [3,31b1pyridiny1-6-ylamine a 2 H) 3.87 ( s, 3 H) 1.83 (d, J = 6.7 Hz, 3 H) HN
(300 MHz, CDCI3-D1) d ppm 8.21 (s, 1 H) 7.93 311 -(2,6-DIchloro-3-fluoro-(m, 1 H) 7.64 (m, 1 H) 7.43 (m, 1 H) 7.32-7.21 phenyl)-5-(1H-indol- 0.1664 (m, 3 H) 7.09-7.024 (m, 2 H) 6.58 (m, 1 H) 6.16 F.lyN
5-y1)-pyridin-2-ylamine (m, 1 H) 4.80 (s, 2 H) 3.50 (s, 2 H) 1.87 (d, a ,m, J=6.69 Hz, 3 H) .3:s.._ (4-{6-Amino-541-(2,6-(300 MHz, CDC13-D1) d ppm 7.87 (s, 1 H) 7.42 dichloro-phenyl)-propoxy].
(m, 4 H) 7.30 (m, 3 H) 7.16 (m, 1 H) 7.05 (s, 1 H) pyridin-3-y1}-phenyl)-(3,5-0.5533 5.92 (m, 1 H) 4.97 (s, 2 H) 4.61 (br. s, 1 H) 3.65 dimethyl-plperazin-1-y1)-(br. s, 2 H) 2.85 (br. s, 3 H) 2.49 (br. s, 1 H) 2.41 methanone (m, 3 H) 2.19 (m, 1 H) 1.08 (m, 6 H) No. Structure Name Ki (IA) MS m/z Procedure or 1 (%)_ (M+H) 0--,Pl L.,. [4-(6-Amino-5-benzyloxy- .
' (400 MHz, DMSO-D6) d ppm 7.92 (d, J=1.77 Hz, pyridin-3-y1)-phenyl]-(4-1 H) 7.68 (d, J=8.34 Hz, 2 H) 7.53 (d, J=7.07 Hz, 29% 2 H) 7.37 - 7.46 (m, 5 H) 7.33 (m, 1 H) 5.96 (s, 2 pyrrolidin-1-yl-piperidin-1-y1)-0 N methanone H) 5.25 (s, 2 H) 3.49 (s, 2 H) 3.09 (s, 2 H) 2.00 ^ I
ma, (s, 2 H) 1.84 (s, 2 H) 1.56 (s, 1 H) sr-A
(300 MHz, CDCI3-D1) d ppm 8.25 (d, J = 1.79 3-(2,6-Dichloro-3-fluoro-1-650 y-1 benzyloxy)-5-thiazol-2-yl- 0.3627 Hz 1 H) 7.76 (d, J = 3.30 Hz) 7.36-7.26 (m 3 H) F N
7.20 (m , 1 H) 7.05 (m, 1H) 6.17 (q, J = 6.7 Hz, 1 pyridin-2-ylamine ci NH, H) 5.09 (br. s, 2 H) 1.86 (d, J = 6.7 Hz, 3 H) ,-.., (400 MHz, DMSO-D6) d ppm 7.93 (d, J=1.52 Hz, x,) (4-{6-Amino-541-(2-fluoro-6-trifluoromethyl-pheny1)-1 H) 7.74 - 7.82 (m, 3 H) 7.71 m, 3 H) 7.62 - 7.67 1-651 ethoxy]-pyridin-3-y1)-phenyl)- 1.5258 (m, 3 H) 7.47 (m, 4 H) 7.38 (m, 1 H) 5.43 (s, 2 H) 3.67 (br. s, 2 H) 3.51 (br. s, 3 H) 3.40 (br. s, 1 H) (4-pyrrolidin-1-yl-piperidin-1-. 4 YD-methanone3.09 (br. s, 2 H) 2.00 (br.
s, 3 H) 1.83 (br. s, 2 H) 1.53 (br. s, 2 H) r=k H3C-N , N 3-(2,6-Dichloro-3-fluoro-(300 MHz, CDCI3-D1) d ppm 7.90 (d, J = 1.67 benzyloxy)-5-(1-methyl-1H-Hz, 1 H) 7,30 (m, 2H) 7.05 (m, 3 H) 6.91 (d, J =

11%

F N, I .,'N imidazol-2-y1)-pyridin-2-0.98 Hz, 1 H) 6.10 (q, J = 6.7 Hz, 1 H) 4.99 (br. s, a- NH, ylamine 2 H) 3.57 (s, 3 H) 1.83 (d, J = 6.7 Hz, 3 I-1) (400 MHz, DMSO-D6) d ppm 7.92 (s, 1 H) 7.90 {446-Amino-5-(2,4,6-ISF-cs-Lx.icyt`"' (s, 1 H) 7.84 (d, J=8.34 Hz, 2 H) 7.50 (d, J=8.34 a trimethyl-benzyloxy)-pyridin -1-653 c., 2% Hz, 2 H) 6.92 (s, 2 H) 5.27 (s, 2 H) 3.51 (br. s, 8 ., 0 3-y1Fpheny1}-(4-pyrrolidin-1-H) 3.09 (br. s, 3 H) 2.32 (s, 6 H) 2.25 (s, 3 H) yl-piperidin-1-yI)-methanone 1.99 (br. s, 2 H) 1.84 (br. s, 2 H) 1.55 (br. s, 2 H) {446-Amino-5-(2,3,5,6-(400 MHz, DMSO-D6) d ppm 9.75 (s, 1 H) 7.88 'H
c".' tetramethyl-benzyloxy)-(s, 2 H) 7.79 (d, J=8.34 Hz, 2 H) 7.45 (d, J=8.08 1-654 ,,,,. AI . 41 LA ,,--, pyridin-3-yli-pheny1)-(4- 9% Hz, 3 H) 6.97 (s, 1 H) 5.28 (s, 2 H) 3.64 (s, 1 H) . ID pyrrolidin-1-yl-piperidin-1-yI)-3.45 (s, 2 H) 3.34 (s, 1 H) 3.04 (s, 3 H) 2.15 (s, methanone 12 H) 1.94 (s, 3 H) 1.79 (s, 2 H) 1.50 (s, 2 H) (400 MHz, DMSO-D6) d ppm 7.83 (d, J=2.02 Hz, 1 H) 7.48 (d, J=8.34 Hz, 3 H) 7.33 (d, J=8.34 Hz, {4-[6-Amino-5-(2,4,6-trifluoro=
3 H) 7.24 (d, J=1.77 Hz, 1 H) 7.12 - 7.22 (m, 2 H) 1-655 r"-crr,iort , 0, benzyloxy)-pyridin-3-y1]-5.86 (m, 1 H) 5.76 (s, 2 H) 4.19 (br. s, 1 H) 3.65 0 phenyl}-(4-pyrrolidln-1-y1-(br. s, 1 H) 2.96 (br. s, 2 H) 2.16 (br. s, 1 H) 1.83 piperidin-1-yI)-methanone (br. s, 2 H) 1.69 (br. s, 5 H) 1.60 (d, J= 5.67 Hz, 5 H) 1.30 (br. s, 2 H) (400 MHz, DMSO-D6) d ppm 7.89 (d, J=1.77 Hz, , (4-(6-Amino-541-(2-fluoro-6-1 H) 7.57 - 7.66 (m, 3 H) 7.41 -7.49 (m, 2 H) trifluoromethyl-pheny1)-la 7.36 (d, J=8.08 Hz, 2 H) 7.19 (d, J=1.77 Hz, '1 H) 1-656 , . 0 0, ethoxyl-pyridin-3-y1)-phenyl)-5.85 (s, 2 H) 5.80 (s, 1 H) 4.21 (s, 1 H) 3.57 (br.
., , 0 (4-pyrrolidin-1-yl-piperidin-1-s, 1H) 3.02 (s, 2 H) 2.22 (s, 1 H) 1.80 (br. s, 2H) yI)-methanone 1.78 (d, J=6.3 Hz, 3 H) 1.66 (s, 4 H) 1.34 (s, 2 H) ask ci (400 MHz, DMSO-D6) 8 ppm 8.82 (br. s, 1 H) 1111111.cH, 6-Amino-5-[1-(2,6-dichloro-3-7.97 (d, J=1.77 Hz, 1 H) 7.52 -7.57 (m, 1 H) 1-657 NH flUoro-phenyl)-ethoxy]-N- 7.46 (t, J=8.72 Hz, 1 H) 7.05 (d, J=1.26 Hz, 1 H) CI
Orj'.=a- a-6 methyl-nicotinamidine 6.73 (br. s, 1 H) 6.06 (quart., J=6.57 Hz, 1 H) H,N N' 2,91 (s, 3 H) 1.78 (d, J=6.57 Hz, 3 H) (400 MHz, DMSO-D6) 8 ppm 9.07 (br. s, 1 H) a 6-AmIno-541-(2,6-dichloro-3-7.94 (d, J=1.52 Hz, 1 H) 7.53 (m, 1 I-1) 7.47 (m, 1 fluoro-phenyl)-ethoxy]-N-(2-H) 6.97 (s, 1 H) 6.77 (br. s, 1 H) 6.06 (s, 1 H) 1-658 (Ct"."' NH

456 39 .
I morpholin-4-yl-ethyl)-3.55 (quart, J=4.29 Hz, 2 H) 3.54 (m, 2 H) 3.47 NaN "1/4_,0 nicotinamidine (m, 2 H) 2.54 (t, J=6.06 Hz, 2 H) 2.42 (s, 3 H) 1.78 (d, J=6.82 Hz, 3 H) (400 MHz, DM50-D6) d ppm 9.84 (s, 1 H) 7.91 ../ID
(d, J=1.52 Hz, 1 H) 7.78 - 7.88 (m, 1 H) 7.65 -.X0 (4-{6-Amino-541-(2,4,5-7.75 (m, 3 H) 7.57 (dd, J=10.23, 3.66 Hz, 1 H) trifluoro-phenyl)-propoxy]-7.46 (d, J=8.34 Hz, 2 H) 5.91 - 5.98 (m, 1 H) 3.50 1-659 pyridin-3-y1)-(4-(4-pyrrolidin-1-yl-piperidin-1-y1)-(s, 2 H) 3.40 (s, 1 H) 3.09 (s, 2 H) 2.09 (dt, J=14.08, 6.98 Hz, 2 H) 1.99 (s, 2 H) 1.92 (dt, i:')?'' ,04 -, N methanone J=13.90, 6.95 Hz, 2 H) 1.83 (s, 2 H) 1.55 (s, 2 H) 0.92 (t, J=7.33 Hz, 3 H) No.
Structure Name Ki ( M) MS m/z Procedure or! (%) (M+H) ..,,0 NMR (400 MHz, DMSO-D6) d ppm 9,84 (s, 1 H) X,...) (4-{6-Amino-541-(6-chloro-2-7.95 (s, 2 H) 7.65 (d, J=8.34 Hz, 2 H) 7.53 - 7.60 fluoro-3-methyl-phenyl)-(m, 2 H) 7.48 (s, 1 H) 7.32 -7.42 (m, 2 H) 6.25 ethoxyl-pyridin-3-y1}-phenyl)-(q, J=6.48 Hz, 1 H) 3,58 (s, 2 H) 3.49 (s, 1 H) (4-pyrrolidin-1-yl-piperidin-1-3.18 (d, J=5.05 Hz, 3 H) 2.27 (d, J=1.52 Hz, 5 H) y1)-methanone 2.01 -2.13 (m, 4 H) 1.89(d, J=6.57 Hz, 5 H) 1.64 a NH, (s, 2 H) (400 MHz, DMSO-D6) d ppm 10,14 (s, 1 H) 8.12 3-(1-(2-Amino-5-(4-(4-(s, 1 H) 7.93 (s, 1 H) 7.76 - 7.87 (m, 4 H) 7.72 (s, 1 H) 7.65 (d, J=8.34 Hz, 2 H) 7.53 (ddd, J=15.92, pyrrolidin-1-yl-piperidine-1-7.83, 7.58 Hz, 2 H) 7.40 - 7.47 (m, 3 H) 6.03 -carbony1)-pheny1]-pyridin-3-6.10 (m, 1 H) 4.55 (s, 1 H) 3,64 (s, 1 H) 3.47 (s, 2 H.V.

yloxy)-ethyl)-benzoic acid H) 3.38 (s, 1 H) 3.07 (s, 3 H) 2.13 (s, 1 H) 1.98 NH, (s, 3 H) 1.78 - 1.89 (m, 3 H) 1.65(t, J=5.68 Hz, 3 H) 1.56 (s, 2 H) 1.31 (d, J=6.57 Hz, 2 H) ' Table 4 No. Structure Name Met 1060 Procedure 'H-NMR
MS m/z (FIK

(M+1) =H

AO 445-Amino-6-(2,6-dichloro-(400 MHz, DMSO-c16) 65.61 (s, 211), 6.09 (s, 211).
see benzyloxy)-pyrazin-2-y1]- 1.35 examples 6.79 (d, 2H), 7.45 (t, 1H), 2.56 (d, 2H), 7.76 (d, phenol 21-1), 7.99 (s, 1H), 9.46 (s, 1H) ii;.õ11, WI 0 NH, 0'.1--)'=

3-(2,6-Dichloro-benzyloxy)-5-(400 MHz, DMSO-d6) 62.41 (m, 2H), 3.51 (m, 110 [4-(1,1-dioxo-12,6-see 2H), 3.76 (m, 2H), 5.62 (s, 2H), 6.28 (s, 2H), 7.22 11-2 .
0.825 isothiazolidin-2-y1)-phenyll-examples (m, 2H), 7.48 (m, 1H), 7.56 (m, 211), 7.94 (m, pyrazin-2-ylamine 2H), 8.14 (s, 1H) i=-= oli:=11 LW' a NFL, .

(400MHz, DMSO-d6) 6 2.45 (m, 4H), 2.71 (t, t,...0 3_,2,6 k -Dichloro-benzyloxy)-5-see 2H), 3.56 (t, 411), 4.15 (t, 2H), 5.61 (s, 2H), 6.32 11-3 [3-(2-morpholin-4-yl-ethoxy)- 0.74 examples (s, 2H), 6.86 (d, 1H), 7.29 (t, 1H), 7.46 (m, 2H), iii oly" phenyl]-pyrazin-2-ylamine 7.52 (m, 1H), 7.55 (s, 111), 7.57 (d, 1H), 8.16 (s, ''''r-- a ", 1H) ,,CY

=) (400 MHz, DMSO-c16) 62.45 (m, 4H), 2.71 (m, 3-(2,6-Dichloro-benzyloxy)-5-see 2H), 3.59 (t, 411), 4.11 (t, 211), 5.64 (s, 2H), 6.18 11-4 * [4-(2-morpholin-4-yl-ethoxy)- 1.25 examples (s, 2H), 6.97 (d, 2H), 7.46 (t, 1H), 7.56 (d, 211), phenyl]-pyrazin-2-ylamine 7.86 (d, 211), 8.06 (s, 1H) Nit ol'r' MP a NH,, * 5-(4-Amino-phenyl)-3-(2,6-(400 MHz, DMSO-d6) 65.19 (s, 211), 5.59 (s, 211), examples see 11-5 = ,.
dichloro-benzyloxy)-pyrazin- 0.94 5.96 (s, 21-1), 6.60 (d, 2H), 7.45 (t, 1H), 7.56 (d, 361 N 2-ylamine 2H), 7.62 (d, 2H), 7.91 (s, 1H) toNH, 4110 445-Amino-6-(2,6-dichloro-see (400 MHz, DMSO-c16) 6 5.64 (s, 2H), 6.52 (s, 2H), benzyloxy)-pyrazin-2-y13- 1.75 examples 7.46 (m, 1H), 7.56 (m, 2H), 7.96 (d, 2H), 8.07 (d, benzoic acid 2H), 8.27 (s, 1H) Oil al NH., ceD

{445-Amino-6-(2,6-dichloro-. 1-D benzyloxy)-pyrazin-2-y11-(400 MHz, DMSO-d6) 6 1.79 (m, 10H), 2.64 (m, phenyl}-[(2R)-2-pyrrolidin-1- 0.24 examplessee 4H), 3.45 (m, 311), 5.64 (s, 2H), 6.42 (s, 2H), 7.49 526 IP ylmethyl-pyrrolidin-1-y1]-(m, 3H), 7.58 (m, 2H), 7.98 (d, 2H), 8.00 (s, 1H) methanone = -...

Ai. o 'N
moki. a NH, 0 IV..J IX
(400 MHz, DMSO-d6) 6 1.37 (m, 2H), 1.66 (m, {4-[5-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-y1]-see 411), 1.85 (m, 211), 2.32 (m, 211), 2.52 (m, 4H), 11-8 *
0.56 3.04 (m, 21-1), 3.92 (m, 1H), 5.62 (s, 2H), 6.42 (s, phenyl)-(4-pyrrolldin-1-14-examples 211), 7.40 (d, 211), 7.46 (t, 1H), 7.58 (m, 2H), 8.00 piperidin-1-yI)-methanone (d, 2H), 8.21 (s, 1H) ma" a NH, , H p,----0 2-Morpholin-4-yl-(300 MHz, CDC13) 62.50 (t, 411), 2.92 (t, 2H), ethanesulfonic acid {445-see 3.29 (t,2H), 3.72 (t, 211), 4.81 (s, 2H), 5.67 (d, 11-9 amino-6-(2-chloro-3,6- 1.26 = , difluoro-benzyloxy)-pyrazin-2. examples 2H), 7,05 (m, 1H), 7.20 (m, 1H), 7.28 (d, 2H), F ii o ' ylj-phenyl}-amide 7.90 (d, 2H), 8.04 (s, 1H) '''' _ .

No. Structure Name Met 1050 Procedure 'H-NMR
MS m/z (MM) (M+1) I?

2-Piperidin-1-yl-(300 MHz, CDCI3) 61.60 (m, 2H), 1.63 (m, 4H), ethanesulfonic acid {445 see2.49 (m, 4H), 2.90 (t, 2H), 3.26 (t, 2H), 4.85 (s, 11-10 amino-6-(2-chloro-3,6-1.2 , examples 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), = difluoro-benzyloxy)-pyrazin-2.
F
7.29 (d, 2H), 7.89 (d, 2H), 8.04 (s, 1H) 1101 F NH,ylj-pheny1}-amide V' 2-(4-Hydroxy-piperidin-1-yI)-(300 MHz, 00013) 6 1.63 (m, 2H), 1.90 (m, 2H), ethanesulfonic acid {445-see 2.27 (t, 2H), 2.80 (m, 2H), 2.92 (t, 2H), 4.86 (s, 11-11 amino-6-(2-chloro-3,6-0.65 examples 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, 1H), difluoro-benzyloxy)-pyrazin-2.
F...,6col 7.28 (d, 2H), 7.90 (d, 2H), 8.04 (s, 1H) NH, y11-phenylyamide ¨

, k0 2-Pyrrolidin-1-yl-(300 MHz, CDCI3) 61.83 (m, 4H), 2.56 (m, 4H), ethanesulfonic acid {45 see3.04 (t, 2H), 3.28 (t, 2H), 4.91 (s, 2H), 5.67 (d, 11-12 amino-6-(2-chloro-3,6-0.58 examples 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.27 (d, 2H), -... difluoro-benzyloxy)-pyrazin-2.

F du.7.88 (d, 2H), 8.03 (s, 1H) . yq-phenyl}-amide 2-[(3R)-3-Hydroxy-pyrrolidin- (300 MHz, CDCI3) 6 1.85 (m, 1H), 2.25 (m, 2H), 1-ylyethanesulfonic acid {4- 2.55 (m, 1H), 2.84 (d, 1H), 3.02 (m, 3H), 3.26 (m, see 11-13 . [5-amino-6-(2-chloro-3,6-1.59 examples 2H), 4.43 (m, 1H), 4.82 (s, 2H), 5.67 (d, 2H), 7.05 ,10 difluoro-benzyloxy)-pyrazin-2.
(m, 1H), 7.20 (m, 1H), 7.35 (d, 2H), 7.88 (d, 2H), 1 * N "

F H2 ylyphenylyamide 8.04 (s, 1H) .....OH

,j....--.6 2-[(2S)-2-Hydroxymethyl-examples (i3H0)0, MHz, CDCI3) 61.85 (m, 4H), 2.20 (m, 1H), pyrrolidin-1-yI]-2.70 (m, 2H), 3.05 (m, 2H), 3.30-3.70(m, 3H), ethanesulfonic acid {445- see . 3.95 (m, 'I H), 4.79 (s, 2H), 5.67 (d, 2H), 7.05 (m, 554 amino-6-(2-chloro-3,6-7.20 (m, 1H), 7.32 (d, 2H), 7.88 (d, 2H), 8.05 ,6c)..t: difluoro-benzylm)-pyrazin-2.
(a, i H) yI]-pheny1)-amide li rkir'v 2-(Cyclopropylmethyl-amino).
1FINMR (300 MHz, CDCI3) 60.14 (m, 2H), 0.52 ethanesulfonic acid {445-see (m, 2H), 0.95 (m, 1H), 2.50 (d, 2H), 3.21(m, 4H), 11-15 amino-6-(2-chloro-3,6-1.28 examples 4.86 (s, 2H), 5.67 (d, 2H), 7.05 (m, 1H), 7.20 (m, difluoro-benzyloxy)-pyrazin-2.
F,Ar,e1c.
1H), 7.30 (d, 2H), 7.89 (d, 2H), 8.04 (s, 1H) ylypheny1}-amide Z.....,,,,,,, NH, ' " on 2-Dimethylamino-(300 MHz, CDCI3) 02.30 (s, GH), 2.86 a, 2H), ethanesulfonic acid {445-see 3.21 (t, 2H), 4.83 (s, 2H), 5.67 (d, 2H), 7.05 (m, 11-16 amino-6-(2-chloro-3,6-0.91 examples 1H), 7.18(m, IN), 7.26(d, 2H), 7.88(d, 2H), 8.05 difluoro-benzyloxy)-pyrazin-2-(s, I H) yq-phenyl)-amide ' * F :HI:

2-Diethylamino-(300 MHz, CDCI3) 6 1.08 (t, 6H), 2.61 (q, 4H), ethanesulfonic acid {4-[5-see 3.03 (t, 2H), 3.23 (t, 2H), 4.80 (s, 2H), 5.67 (d, 11-17 amino-6-(2-chloro-3,6-0.46 examples 2H), 7.05 (m, 1H), 7.19 (m, 1H), 7.27 (d, 2H), difluoro-benzyloxy)-pyrazin-2.

j' 7.88 (d, 2H), 8.04 (s, 1H) :5C

yq-phenyl) F.1 NH, .4,---..----1 2-(4-Acetyl-piperazin-1-y1)-(300 MHz, CDCI3) 62.08 (s, 3H), 2.46 (m, 4H), "----ro ethanesulfonic acid {445-see 2.93 (t, 2H), 3.30 (t, 2H), 3.47 (t, 2H), 3.62 (t, 2H), 11-18 amino-6-(2-chloro-3,6-1.5 examples 4.82 (s, 2H), 5.67 (s, 2H), 7.05 (m, 1H), 7.20 (m, difluoro-benzyloxy)-pyrazin-2-1.....6colf At, 1H), 7.28 (d, 2H), 7.91 (d, 2H), 8.05 (s, 1H) y1]-phenyl}

_ it 2-[4-(2-Hydroxy-acetyI)-"1-----Cco piperazin-1-y11-(300 MHz, CDCI3) 62.48 (t, 4H), 2.93 (t, 2H), Lct, ethanesulfonic acid {4-[5- see 3.30 (m, 4H), 3.55 (brs, 1H), 3.67 (t, 2H), 4.14 (s, 597 0.45 amino-6-(2-chloro-3,6- examples 2H), 4.84 (s, 2H), 5.67 (s, 2H), 7.05 (m, 1H), 7.20 r...6c0.1...t...:
difluoro-benzyloxy)-pyrazin-2. (m, 1H), 7.27 (d, 2H), 7.92 (d, 2H), 8.05 (s, 1H) ylj-phenyl)-amide No.
Structure Name Met 050 Procedure 'H-NMR
MS m/z (11M) (M+1) f? A
H 1,----N
2-Cyclopropylamino-(300 MHz, CDC13) 80.37 (m, 2H), 0.49 (m, 2H), ethanesulfonic acid {445 see2.14 (m, 1H), 3.24 (m, 4H), 4.93 (s, 211), 5.67 (d, amino-6-(2-chloro-3,6-1.29 examples 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.28 (d, 211), difluoro-benzyloxy)-pyrazin-2=
F Al N
7.90 (d, 2H), 8.03 (s, 1H) , yll-phenyl}-amide ri 1.,(9.-...S
2-[(3R)-3-Hydroxymethyl-(300 MHz, CDC13) 61.60-2.0 (m, 5H), 2.15 (m, pyrrolidin-1-y11-1H), 2.55-2.70 (m, 2H), 2.90-3.15 (m, 2H), 3.3-115c "2 ethanesulfonic acid {315-1.38 see amino-6-(2-chloro-3 3.62 (m, 2H), 3.89 (dd, J = 3.0, 11.3 Hz, 111), ,6-examples difluoro-benzyloxy)-pyrazin-2.
4.92 (s, 2H), 5.66 (s, 2H), 6.95-7.60 (m, 5H), 7.55 =
7.70 (m, 2H), 7.77 (s, 1H), 8.10 (s, 1H) yll-phenyl}-amide (300 MHz, CDC13) 61.40-1.60 (m, 211), 1.75-1.88 g 2(4-Hydroxy-piperidin-1-yI)-ethanesulfonic acid {345-(m, 2H), 2.21 (t, J = 9.0 Hz, 2H), 2.65-2.75 (m, see 21-1), 2.85-2.95 (m, 21-1), 3.20-3.35 (m, 2H), 3.69 11-22 ,,6c.of.-, amino-6-(2-chloro-3,6-0.7 examples (m, 1H), 5.17 (s, 211), 5.68 (s, 2H), 6.92-7.02 (m, difluoro-benzyloxy)-pyrazin-2.
111), 7.08-7.20 (m, 1H), 7.30-7.45 (m, 2H), 7.69 yll-phenyl}-amide (s, 111), 7.76 (d, J = 7.5 Hz, 1 H), 8.14 (s, 1H) (300 MHz, CDC13) 62.03 (s, 3H), 2.30-2.40 (m, 71- 2-(4-Acetyl-piperazin-1-y1)-ethanesulfonic acid {345-2H), 2.75-2.85 (m, 2H), 3.20-3.40 (m, 4H), 3.45-t---"C
see 3.55 (m, 2H), 5.35 (s, 21-1), 5.68 (s, 2H), 6.95-7.02 =

amino-6-(2-chloro-3,6-2.79 ,...6c.....itr difluoro-benzylm)-pyrazin-2.
examples (m, 1H), 7.05-7.20 (m, 11-1), 7.30-7.45 (m, 211), 7.64 (s, 1H), 7.76 (d, J = 7.3 Hz, 1H), 8.13 (s, yI]-phenyl)-amide 1H), 8.52 (s, 1H) 2-Piperidin-1-yl-11-24 ,.,6c.....1/4 42-chloro-3,6-3.5 see amino-6 (300 MHz, CDC13) 61.30-1.60 (m, 6H), 2.30-2.45 ethanesulfonic acid {3-[5-(m, 4H), 2.75-2.90 (m, 2H), 3.15-3.30 (m, 2H), examples 5.10 (s, 21-1), 5.66 (s, 2H), 6.95-7.05 (m, 1H), 7.10 difluoro-benzyloxy)-pyrazin-2.
7.20 (m, 1H), 7.25-7.40 (m, 211), 7.60-7.75 (m, yli-phenylyamide 2H), 8.10 (s, 1H) -r 2-Diethylamino-(300 MHz, CDC13) 80.95-1.05 (m, 6H), 2.45-2.55 ethanesulfonic acid {3-[5-see (m, 4H), 2.95-3.10 (m, 2H), 3.15-3.25 (m, 2I1), 11-25 õ.6c, _.-=
amino-6-(2-chloro-3,6-3.7 examples 5.11 (s, 2H), 5.67(s, 2H), 6.90-7.15 (m, 2H), 7.20, . "

difluoro-benzyloxy)-pyrazin-2=
7.40 (m, 2H), 7.55-7.70 (m, 2H), 8.10 (s, 1H) yI]-phenyl}-amide 2-Morpholin-4-yl-(300 MHz, CDC13) 62.30-2.50 (m, 2H), 2.30-3.00 ethanesulfonic acid {3-5-(m, 2H), 3.20-3.40 (m, 2H), 3.50-3.75 (m, 4H), see amino-842-(2-3,6-3.3 3.21 (s, 2H), 5.67 (a, 2H), 6.95-7.08 (m, 1H), 7.10 examples ,..õ&.....,,..1..r.:,, difluoro-benzyloxy)-pyrazin-2.
7.20 (m, 1H), 7.30-7.50 (m, 2H), 7.67 (s, 1H), yI]-phenyl}-amide 7.74 (d, .1 = 7.5 Hz, 1 H), 8.12 (s, 1H) 2-Pyrrolidin-1-yl-(300 MHz, CDCI3) 6 1.62-1.82 (m, 4H), 2.40-2.55 g ethanesulfonic acid {3-[5-see (m, 411), 2.92-3.00 (m, 2H), 3.25-3.35 (m, 211), . ..1-amino-642-chloro-3,6-2 1.8 5.24 (s, 21-1), 5.67 (s, 21-1), 6.95-7.08 (m, 1H), 7.10 difluoro-benzyloxy)-pyrazIn-2.
examples 7.20 (m, 1H), 7.25-7.40 (m, 2H), 7.63 (s, 1H), yI]-phenyl}-amide 7.73 (d, J = 7.1 Hz, 1 H), 8.12 (s, 1H) _ ethanesulfonic {3.15.
(300 MHz, CDC13) 62.27 (s, 6H), 2.86 (t, J = 6.4 U.
1.-2e-thpaninee see Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 5.08 (s, 2H), 11-28 Flice:
amino-6-(2-chloro-3,6-2.28 examples 5.67 (s, 2H), 7.00-7.45 (m, 4H), 7.65-7.75 (m, difluoro-benzyloxy)-pyrazin-2.
,-5 211), 8.11 (s, 1H) ylj-pheny1)-amide (300 MHz, CDC13) 62.43 (t, 4H), 2.92 (t, 2H), li'N
piperazin-14]-3.20 (t, 2H), 3.33 (t, 2H), 3.54 (br s, 1H), 3.61 (t, ethanesulfonic acid {345-see 11-29 , i g amino-6-(2-chloro-3,6-1.82 examples 2H), 4.08 (s, 2H), 5.18 (br s, 2H), 5.67 (s, 211), difluoro-benzyloxy)-pyrazin-2=
7.00-7.45 (m, 4H), 7.65-7.75 (m, 211), 8.11 (s, --(=,- l', 11-1) yI]-phenyl}-amide No. Structure , Name Met IC50 Procedure 'H-NMR
MS m/z (PM) (M+1) 11.2,11 g 1 2-(Cyclopropylmethyl-amino) (300 MHz, CDCI3) 60.07 (m, 2H), 0.44 (m, 2H), ethanesulfonic acid {345-0.89 (m, 1H), 2.45 (d, 2H), 3.16 (t, 2H), 3.29 (t, see 11-30 ,,6c. amino-6-(2-chloro-3,6- 1.84 examples 2H), 5.27 (br s, 2H), 5.67 (s, 2H), 7.07 (m, 1H), difluoro-benzyloxy)-pyrazin-2.
7.20 (m, 1H), 7.41 (m, 2H), 7.65 (s, 1H), 7.77 (m, y1]-phenyl}-amide 1H), 8.12 (s, 1H) F.
r1 2-[(3R)-3-Hydroxy-pyrrolidin-(300 MHz, CDCI3) 6 1.80 (m, 1H), 2.20 (m, 2H), 1-y1Fethanesulfonic acid {3-2.50 (m, 1H), 2.70-3.20 (m, 5H), 3.32 (m, 2H), see 11-31 [5-amino-6-(2-chloro-3,6- 2.16 ' ' 4 35 (m 1H) 5 12 (s 2H) 5 68 (s 2H)' 7.05 (m' 540 examples' ' ' ' ' ' ,...acoly.. difluoro-benzyloxy)-pyrazin-2.
1H), 7.20 (m, 1H), 7.40 (m, 2H), 7.73 (m, 2H), yll-phenyl}-amide 8.15 (s, 1H) ..

V---'1-9. 2-Cyclopropylamino-(300 MHz, CDCI3) 60.25-0.50 (m, 4H), 2.09 (m, ethanesulfonic acid {3-[5-see 1H), 3.15-3.40 (m, 4H), 5.37 (s, 2H), 5.68 (s, 2H), 11-32 =.6(,,,, amino-6-(2-3,6-3,6- 2.13 .. difluoro-benzyloxy)-pyrazin-2-examples 7.07 (m, 1H), 7.18 (m, 1H), 7.42 (m, 2H), 7.62 (m, 1H), 7.77 (m, 1H), 8.13 (s, 1H) yI]-phenyl}-amide 0 445-Amino-6-(2-chloro-3,6-see 11-33 difluoro-benzyloxy)-pyrazin-2.

N
examples yll-benzoic acid ArN

= CI NH2 F
-?

O 'IND (445-Amino-6-(2-chloro-3,6-(300 MHz, CDCI3) 6 1.5-2.2 (m, 10 H), 2.65 (m, difluoro-benzyloxy)-pyrazin-2.
see 4H), 3.50 (m, 2H), 4.42 (m, 1H), 4.86 (br s, 2H), 11-34 yll-phenyl}-[(2R)-2-pyrrolidin- 0.15 la examples 5.68 (d, J = 1.3 Hz, 2H), 7.05 (m, 1H), 7.19 (m, 1-ylmethyl-pyrrolidin-1-yI]-1H), 7.57 (m, 2H), 7.96 (d, 2H), 8.12 (s, 1H) N ", methanone o)LrN

1111 a N", F

= 1-J 4-[5-Amino-6-(2-chloro-3,6-(300 MHz, CDC13) 01.87 (m, 4H), 2.73 (m, 4H), difluoro-benzyloxy)-pyrazin-2. 0.13 see 2.85 (t, 2H), 3.64 (m, 2H), 4.91 (s, 2H), 5.68 (d, 11-35 , yn-N-(2-pyrrolidin-i-yl-ethyl)- examples 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.89 (d, 2H), r ,.,,,. . . rl benzamide 7.99 (d, 21-1), 13.13 (s, 1H) IP F Ha NH., . 6 {4-[5-Amino-6-(2-chloro-3,6-(300 MHz, CD30D) 6 1.80-2.40 (m, 2H), 2.24 (s, 11-36 Ilio difluoro-benzyloxy)-pyrazin-2. 0.37 see 3H), 3.30-3.90 (m, 5H), 5.71 (s, 2H), 7.25 (m, yli-phenyl}-[(3S)-3-amino-examples 1H), 7.35 (m, 1H), 7.60 (m, 2H), 8.03 (d, 2H), . -.. pyrrolidin-1-y1Fmethanone 8.10 (s, 1H) F AI 0.1.rN

1111" F M-6 ...$:,,"17 Nbe-(2-(4-Acetyl (300 MHz, CDCI3) 62.10 (s, 3H), 2.52 (m, 4H), ===="y- y1)-ethyl]-445-amino-6-(2-see 2.66 (t, 2H), 3.40-3.80 (m, 6H), 4.94 (s, 2H), 5.68 545 11-37 chloro-3,6-difluoro- 1.35 examples (s, 2H), 6.75 (brs, 1H), 7.05 (m, 1H), 7.20 (m, -eptyyraz1-piipne-2ra-yziI]n--1-1H), 7.84 (d, 2H), 8.00 (d, 2H), 8.14 (s, 1H) benzamide 11,0 445-Amino-6-(2-chloro-3,6-(300 MHz, CDCI3) 61.91 (m, 6H), 2.72 (m, 4H), difluoro-benzyloxy)-pyrazin-2.
see 2.82 (t, 2H), 3.61 (m, 2H), 4.93 (s, 2H), 5.69 (d, 0.58 ylj-N-(3-pyrrolidin-1-yl-examples 2H), 7.05 (m, 1H), 7.20 (m, 1H), 7.89 (d, 2H), F..6c i propy1)-benzamide 7.97 (d, 2H), 8.12 (s, 1H), 8.73 (s, 1H) , No.
Structure Name Met 1050 Procedure MS m/z (IVA
(M+1) -\ _ {445-Amino-6-(2-chloro-3,6-(300 MHz, CDC13) 61.70-2.10 (m, 1H), 2.24 (s, difluoro-benzyloxy)-pyrazin-2.
3H), 2.34 (s, 3H), 2.60-2.90 (m, 1H), 3.30-4.00 yl3-pheny1)-[(3S)-3-0.67 see (m, 4H), 4.90 (s, 2H), 5.68 (d, 2H), 7.10 (m, 1H), dimethylamino-pyrrolidin-1-examples 7.20 (m, 1H), 7.60 (m, 2H), 7.97 (d, 2H), 8.13 (s, =
-, yll-methanone 1H) F r, 0 'N
IP F
NH' pH, {445-Amino-6-(2-chloro-3,6-(300 MHz, CD30D) 61.80-2.40 (m, 2H), 2.24 (s, *
difluoro-benzyloxy)-pyrazin-2.
see 3H), 3.30-3.90 (m, 5H), 5.71 (s, 2H), 7.25 (m, y1]-phenyll-[(3R)-3-0.46 examples 1H), 7.35 (m, 1H), 7.60 (m, 2H), 8.03 (d, 211), .
dimethylamino-pyrrolidln-1-8.10 (s, 1H) F Alt. crel,,,r.N
ylFmethanone togs F
NH, N....XI

{445-Amino-6-(2-chloro-3,6-(300 MHz, CDC13) 60.9-1.2 (m, 6H), 2.2-3.2(m, *
difluoro-benzyloxy)-pyrazin-2-0.48 see 61-1), 4.91 (s, 211), 5.68 (s, 2H), 7.10 (m, 1H), 7.20 ylj-phenyl}-(3,5-dimethyl-examples (m, 111), 7.48 (d, 2H), 7.97 (d, 211), 8.12 (s, 1H) =
,, piperazin-1-yI)-methanone F
NH, , {4-[5-Amino-6-(2-chloro-3,6-(300 MHz, CDC13) 6 1.60-3.40 (m, 17H), 4.89 (s, difluoro-benzyloxy)-pyrazin-2-see 0.33 21-1), 5.68 (d, 211), 7.10 (m, 111), 7.20 (m, 1H), yli-phenyl)-(4-pyrrolidin-1-yl-examples 7.47 (d, 2H), 7.96 (d, 2H), 8.11 (s, 1H) piperidin-1-yI)-methanone 4". F
"2 .X1-.../.....0 4-[5-Amino-6-(2-chloro-3,6-(300 MHz, CDC13) 6 1.83 (m, 2H), 2.60 (m, 6H), Xdifluoro-benzyloxy)-pyrazin-2. 0.59 see 3.61 (m, 2H), 3.76 (m, 4H), 4.93 (s, 211), 5.70 (d, yI]-N-(3-morpholin-4-yl-examples 21-1), 7.05 (m, 1H), 7.20 (m, 1H), 7.88 (d, 2H), :
propyI)-benzamide 8.00 (d, 211), 8.14 (s, 1H) , o 9,, (300 MHz, CDC13) 6 1.80 (m, 2H), 2.07 (m, 2H), L.-.11-=
y1]-N-(1-methyl-piperidin-4- 445-Amino-6-(2-chloro-5,6-2.22 (m, 2H), 2.34 (s, 31-1), 2.88 (m, 2H), 4.04 (m, difluoro-benzyloxy)-pyrazin-2. 0.5 examples see 2H), 4.92 (s, 2H), 5.69 (d, 2H), 6.03 (d, 1H), 7.05 (m, 1H), 7.20 (m, 1H), 7.82 (d, 2H), 7.98 (d, 2H), F
vit..N
y1)-benzamide 8.13 (s, 1H) UPI F

0 11,,,trm C---6 4-[5-Amino-6-(2-chloro-3,6-(300 MHz, CD30D) 62.68 (m, 611), 3.60 (m, 2H), difluoro-benzyloxy)-pyrazin-2.
see 1.11 375 (m, 4H), 5.72 (s, 2H), 7.25 (m, 11-1), 7.35 (m, yI]-N-(2-morpholin-4-yl-examples .
11-1), 7.88 (d, 2H), 8.05 (d, 211), 8.12 (s, 1H) F thi 0 ethyl)-benzamide 0 N,r"
{445-Amino-6-(2-chloro-3,6-(300 MHz, C0C13) 62.39 (s, 3H), 2.48 (m, 411), (001 difluoro-benzyloxy)-pyrazin-2. 0.88 see 3.69(m, 4H), 4.89 (s, 21-1), 5.69(s, 2H), 7.08 (m, ylj-phenyl}-(4-methyl.
examples 111), 7.20 (m, 1H), 7.52 (d, 2H), 7.95(d, 2H), 8.08 .piperazin-1-yI)-methanone (s, 1H) F Aii,i, 0 Ikr'::N
IP F
NH, =
ION H 3-[5-Amino-6-(2-chloro-3,6-see difluoro-benzyloxy)-pyrazin-2.

F
awl' 12cN
ylFbenzoic acid examples MP' F
NH, ;

No. Structure Name Met 1C30 Procedure 1H-NMR MS m/z (PM) (M+1) _ 0, (315-Amino-6-(2-chloro-3,6-(300 MHz, CDCI3) 62.33 (s, 3H), 2.46 (m, 4H), difluoro-benzyloxy)-pyrazin-2. see 3.68(m, 4H), 4.86 (br s, 2H), 5.67(s, 2H), 7.08 11-48 2.85 ylj-pheny1)-(4-methyl- examples (m, 1H), 7.20 (m, 1H), 7.35 (d, 1H), 7.47 (t, 1H), FC OjigL' piperazin-1-y1)-methanone 7.95(m, 2H), 8.10 (s, 1H) F _ {345-Amino-6-(2-chloro-3,6- (300 MHz, CD30D) 62.12 (m, 1H), 2.44 (m, 1H), difluoro-benzyloxy)-pyrazin-2= see 3.52-4.05 (m, 5H), 5.77(s, 2H), 7.24 (m, 1H), 11-49 1.02 yll-phenyl)-[(3R)-3-amino- examples 7.38 (m, 1H), 7.54 (m, 2H), 8.02 (s, 1H), 8.12 (m, Fa-",-,3 pyrrolldin-1-yI]-methanone 211) , j,[3'ILO-NH, {3-15-Amino-6-(2-chloro-3,6-(300 MHz, CD30D) 62.12 (m, 1H), 2.44 (m, 1H), difluoro-benzyloxy)-pyrazin-2= see 3.52-4.05 (m, 5H), 5.77(s, 214 7.24 (m, 1H), 11-50 0.91 yll-pheny1)-[(3S)-3-amino- examples 7.38 (m, 1H), 7.54 (m, 2H), 8.02 (s, 1H), 8.12 (m, pyrrolidin-111)-methanone 2H) F

(300 MHz, CDCI3) 60.99 (br d, 3H), 1.15 (br d, . r la . . , c , ) , 7... {3-[5-Amino-6-(2-chloro-3,6-3H), 2.42 (m, 1H), 2.70 (m, IN), 2.84 (m, 1H), difluoro-benzyloxy)-pyrazin-2. see 2.93 (m, 1H), 3.66(m, 1I-1), 4.67 (m, 1H), 4.92 (br 1151 2'56 yll-phenyl}-(3,5-dimethyl- examples s, 2H), 5.66(s, 2H), 7.05 (m, 1H), 7.20 (m, 1H), piperazin-1-y1)-methanone 7.35 (m, 1H), 7.47 (t, 1H), 7.97(m, 2H), 8.10 (s, 1H) 0,.)-4------0 (300 MHz, CDCI3) 61.82 (m, 2H), 2.50 (m, 4H), 345-Amino-6-(2-chloro-3,6-2.56 (m, 2H)' 3.67(m, 6H), 4.88 (br s, 2H), 5.68 difluoro-benzyloxy)-pyrazin-2= 4.2 see (s' 211), 7.05 (m, 1H), 7.19 (m, 1H), 7.48 (t, 1H), 519 yg-N-(3-morpholin-4-yl- examples 7.70 (d, 1H), 7.90 (n, 1H), 8.06(d, 1H), 8.14 (s, propyI)-benzamide 1H), 8.38 (t, J = 1.6 Hz, 1H) (300 MHz, CDC13) 0 1.60 (m, 2H), 1.30 (m, 4H), 1.86 (m, 2H), 2.00 (m, 2I-1), 2.32 (m, 1H), 2.61 :1)1101-0 1 , (m, 4H), 2.56 (m, 2H), 3.00 (m, 2H), 3.82(m, 1H), difluoro-benzyloxy)-pyrazin-2= see 11-53 '-6c-=1/4' 0.83 examples 4.66 (m, 11-1), 4.93 (br a, 2H), 5.66 (s, 2H), 7.06 528 yll-phenyl)-(4-pyrrolidin-1-yl-(m, 1H), 7.18 (m, 1H), 7.32 (dt, 1H), 7.46 (t, 1H), piperidin-1-y1)-methanone 7.70 (d, 1H), 7.97 (m, 2H), 8.09(d, J = 3.6 Hz, 1H) 0...õ( {345-Amino-6-(2-chloro-3,6- (300 MHz, CDC13) 01.85 (m, 1H), 2.10 (m, 1H), dIfluoro-benzyloxy)-pyrazin-2. 2.21 (s, 3H), 2.31 (s, 3H), 2.75 (m, 1H), 3.42 (m, see 11-54 ,c5c-, yll-phenyl}-[(3S)-3- 1.45 1H), 3.64 (m, 2H), 3.92 (m, 1H), 4.93 (br s, 2H), 488 examples dimethylamino-pyrrolidin-1- 5.67 (s, 211), 7.06 (m, 1H), 7.18 (m, 1H), 7.46 (m, yll-methanone 2H), 7.97 (m, 111), 8.09(m, 2H) 1::,...F.T-.....0 (300 MHz, CDC13) ii 1.82 (m, 4H), 2.69 (m, 411), 345-Amino-6-(2-chloro-3,6- 2.84 (m, 2H), 3.65 (m, 2H), 4.93 (bra, 2H), 5.68 difluoro-benzyloxy)-pyrazin-2. see (s, 2H), 7.06 (m, iH), 7.18 (m, 1H), 7.22 (m, 1H), 488 11-55 '6" 1.6 y1FN-(2-pyrrolidin-1-yl-ethyl)-ethyl) examples 7.49 (t, J = 7.7 Hz, 1H), 7.77 (d, J =7.8 Hz, 111), benzamide 8.04 (dt, J =7.9 Hz, 1.5 Hz, 1H), 8.13 (s, 1H), 8.38(t, ,/ = 1.5 Hz, 1H) (300 MHz, CDCI3) 61.71 (m, 2H), 2,11(m, 2H), grfr-trCi- 345-Amino-6-(2-chloro-3,6-2.28 (t, 2H), 2.95 (m, 2H), 4.11 (m, 1H), 4.89 (s, difluoro-benzyloxy)-pyrazin-2= 0.9 see 11-56 -Tx... ce-Lc.
2H), 5.69(s, 21-1), 6.28 (m, 1H), 7.08 (m, III), 7.18 488 yg-N-(1-methyl-piperidin-4- examples (m, 1H), 7.45(t, 1H), 7.68 (d, 1H), 8.06 (d, 1H), yI)-benzamide 8.11 (s, 1H), 8.35 (s, 1H) . e-0 (3-[5-Amino-6-(2-chloro-3,6- (300 MHz, CDCI3) 62.02 (m, 10H), 2.75(m, 4H), Zo difluoro-benzyloxy)-pyrazin-2. see 3.49 (m, 2H), 4.51 (m, 1H), 4.89 (s, 2H), 5.69(s, 11-57 ylj-phenyl}-[(2S)-pyrrolidin-1- 0.63 examples 2H), 7.08 (m, 1H), 7.20 (m, 1H), 7.48 (m, 211), F ylmethyl-pyrrolldln-1-y1]-7.98(m, 1H), 8.07(m, 1H), 8.11 (s, 1H) methanone ti--,-0 345-Amino-6-(2-chloro-3,6- (300 MHz, CD30D) 6 2.51 (m, 4H), 2.65(t, 2H), difluoro-benzyloxy)-pyrazin-2. 2.5 see 3.58 (t, 2H), 3.69 (m, 4H), 5.72 (s, 2H), 7.20 (m, y1)-N-(2-morpholln-4-yl- examples 111), 7.35 (m, 1H), 7.52 (t, 1H), 7.76 (d, 1H), 8.12 Fl6c...krn , NH, ethyl)-benzamide (m, 2H), 8.41(s, 1H) 03. N42-(4-Acetyl-piperazin-1- y1)-ethyl)-345-amino-6-(2-(300 MHz, CD300) 62.08 (s, 3H), 2.59 (m, 6H), see 3.57 (m, 611), 5.71 (s, 2H), 7.21 (m, 1H), 7.37 (m, 545 11-59 chloro-3,6-difluoro- 2.77 examples 1H), 7.50 (t, 1H), 7.75 (d, 1H), 8.08 (m, 21-1), benzyloxy)-pyrazin-2-yI]-benzamide 8.39(s, 1H) _ No. Structure Name Met IC50 Procedure MS Ink (P.M) (M+1) (300 MHz, CDCI3) 61.79 (m, 411), 1.88 (t, 211), 345-Amino-6-(2-chloro-3,6-2.65 (m, 4H), 2.78 (t, 2H), 3.65 (m, 2H), 4.86 (s, difluoro-benzy1oxy)-pyrazin-2.
see 11-60 ....6,..e.

1), 5.69(s, 2H), 7.06 (m, 111), 7.21 (m, 111), ,-.= yll-N-(3-pyrrolidin-1-yl-examples 7.45(t, 111)7.68 (d, 1H), 8.06 (d, 111), 8.16 (s, propyI)-benzamide , 1H), 8.40 (s, 1H), 8.69 (m, 1H) - H \

3-(2-Chloro-3,6-difludro-see 11-61 benzyloxy)-5-(1H-Indol-5-y1)-.'s:2.N
examples 0 pyrazin-2-ylamine 110 Cl "Fl=
F

H. 0 3-(2-Chloro-3,6-difluoro-(300 MHz, CDCI3) 6 1.78 (m, 4H), 2.66 (m, 4H), IP
benzyloxy)-5-(3-pyrrolidin-1- 0.35 see 3.89 (s, 2H), 4.89 (s, 2H), 5.69(s, 21-1), 7.08 (m, N. ylmethy1-1H-indo1-5-y1)-examples 1H), 7.18 (m, 2H), 7.39 (d, 111), 7.79(d, 1H), 8.08 AI 'F.6 pyrazin-2-ylamine (s, 1H), 8.18 (s, 11-1), 8.79(s, 1H) 0 41111". a H \ ( 3-(2-Chloro-3,6-difluoro-3(300 Mliz, CDCI3) 61.11 (m, 611), 2.69 (m, 4H), IP benzyloxy)-5-(3-see .80 (s, 2H), 4.69(s, 2H), 5.77 (5, 2H), 7.02 (m, 0.73 diethylaminomethy1-1H-examples 1H), 7.21 (m, 2H), 7.45 (d, 1H), 7.89(d, 1H), 8.22 Ai ol'r:" indo1-5-y1)-pyrazin-2-ylamine (m, 3H) ...ro a NH, F

11 \ C.53L 1-(4-(545-Amino-6-(2-chloro-(300 MHz, CDCI3) 62.08 (s, 311), 2.55 (m, 411), 3,6-difluoro-benzyloxy)-3.45 (m, 2H), 3.64(m, 2H), 3.81 (s, 211), 4.78 (s, COI
see 11-64 pyrazin-2-y1]-1H-indo1-3- 1.5 examples 211), 5.71(s' 2H), 7.08 (m, 111), 7.18 (m, 211), 7.31 ' ylmethyl)-piperazin-l-y1)-(d, 1H), 7.79(d, 1H), 8.04 (s, 1H), 8.22 (s, 1H), - N
ethanone 8.49(s, 1H) ip a elt12 -" ?N-D. 3b-e(n2zy-Ciholxyo7-53463.-d(2fli6u-oro-(300 MHz, CDCI3) 61.11 (d, 6H), 1.98 (m, 211), see 2.98 (m, 2H), 3.37(m, 4H), 4.75 (s, 2H), 5.78 (s, 11-65 dimethyl-morpholin-4- 2.4 examples 211), 7.08 (m,11-1), 7.27 (m, 2H), 7.48 (d, 111), ylmethyl)-1H-indo1-5-y1]-, oi=-i"3 pyrazin-2-ylamine 7.39(d, 11-1), 8.19 (s, 1H), 8.28 (5, 211) Mr a H

F

(300 MHz, CDC13) 6 1.69 (m, 1H), 1.88(s, 3H), " C)"r N-(1-{545-Amino-6-(2-2.39 (m, 21-1), 2.75 (m, 2H), 3.08(m, 1H), 3.95 (m, chloro-3,6-difluoro-see 211), 4.50 (m, 1H), 4.79 (s, 211), 5.78 (s, 2H), 6.01 11-66 benzyloxy)-pyrazin-2-y1]-1H- 0.55 examples (m, 1H), 7.05 (m, 1H), 7.18 (m, 211), 7.42 (d, 1H), i-........1....r.: indo1-3-ylmethy1}-(3S)-7.79(d, 111), 8.12 (s, 111), 8.21 (s, 111), 8.28 (s, pyrrolidin-3-yI)-acetamide F
11-1) H.

(300 MHz, CDC13) 61.49 (m, 2H), 1.71 (m, 4H), 40 0 3-(2-Chloro-3,6-difluoro-2.66(m, 4H), 3.89 (s, 2H), 4,79 (s, 211), 5.69(s, benzyloxy)-5-(3-pipendin-1-see 11-67 N.
0.51 examples 2H), 7.08 (m' 1H), 7.18 (m, 1H), 7.31 (s, 1H), ylmethy1-1H-indo1-5-y1)-Au. 0 .'" N pyrazin-2-ylamine 7.42 (d, 1H), 7.78(d, 1H), 8.08 (s, 1H), 8.18(s, IP- a 1-6 111), 8.69 (bra, 1H) _ -11.3._.. \ , 3-(2-Chloro-3,6-difluoro-(300 MHz, CDCI3) 62.72 (m, 41-1), 3.80 (m, 6H), benzyloxy)-5-(3-morpholin-4-see 4.73 (s, 2H), 5.73 (s, 2H), 7.06 (m, 1H), 7.20 (m, 1.15 ylmethy1-1H-indol-5-y1)-examples 11-1), 7.46 (d, 1H), 7.80 (dd, 1H), 8.12 (s, 1H), )ITH N, pyrazin-2-ylamine 8.25 (s, 1H) F

No.
Structure Name Met IC60 Procedure MS m/z (11M) (M+1) ,,NCY
.) 3-[1-(2-Chloro-3,6-difluoro-(400 MHz, DMSO-d6) 00.89 (d, 3H), 1.19 (d, (001 phenyl)-2-methyl-propoxy]-5-[442-(2-4-yl-ethoxy)- 10.58 see 3H), 2.47 (m, 4H), 2.56 (m, 1H), 2.68 (t, 2H), 3.56 examples (t, 4H), 4.07 (t, 2H), 5.96 (d, 1H), 6.28 (s, 2H), F
\
phenyll-pyrazin-2-ylamine 6.89 (d, 2H), 7.26 (m, 1H), 7.38 (m, 1H), 7.63 (d, ' 2H), 7.95 (s, 1H) o 16 a NH, F
) 34142-Chloro-3,6-difluoro-pheny1)-ethoxy]-54442-(400 MHz, DMSO-d6) 6 1.78 (d, 3H), 3.21 (m, morpholin-4-yl-ethoxy)-0'51 see ' =
2H), 3.51 (m, 2H), 3.54 (m, 2H), 3.74 (m, 2H), WA phenyl]-pyrazin-2-ylamine;
examples 3.98 (m, 21-1), 4.38 (t, 2H), 6.34 (bra, 2H), 6.42 compound with trifluoro-(m, 1H), 6.97 (d, 2H), 7.25 (m, 1H), 7.38 (m, 1H), acetic acid 7.66 (d, 2H), 7.86 (s, 1H) *a NEI.
No, 34142,6-Dichloro-3-fluoro-=
phenyl)ethoxyl-54442-(400 MHz, DMSO-d6) 61.79 (d, 3H), 3.21 (m, morpholin-4-yl-ethoxy)-0.3 see 2H), 3.46 (m, 2H), 3.57 (m, 2H), 3.74 (m, 2H), 17A phenyl)-pyrazin-2-ylamine;
examples 3.95 (m' 2H), 4.36 (t, 2H), 6.34 (br s, 2H), 6.49 a -,.
compound with trifluoro-(m, 1H), 6.94 (d, 2H), 7.37 (t, 1H), 7.48 (m, 1H), acetic acid 40 7.66 (d, 2H), 7.98 (s, 1H) a NH, HN'8**0 SO
N-(445-Amino-6-0-(2-chloro-3,6-difluoro-phenyl)-see (400 MHz, DMSO-d6) 6 1.78 (d, 3H), 2.96 (s, 3H), 6.41 (m, 3H), 7.15 (d, 2H), 7.26 (m, 1H), 7.37 (m, 3...T.....:N
ethoxyl-pyrazin-2-y1}-pheny1)-examples methanesulfonamide 1H), 7.64 (d, 2H), 8.00 (s, 1H), 912 (s, 1H) 1.1 oi "1-1.
F
f?
H rg-----0 2-Pyrrolidin-1-yl-ethanesulfonic acid (445-(300 MHz, CDCI3) 01.84 (m, 7H), 2.56 (m, 4H), amino-641-(2-chloro-3,6-see 3.04 (m, 2H), 3.25 (m, 2H), 4.94 (bra, 2H), 6.71 difluoro-phenyl)-ethoxy]-examples (q, 11-1), 6.95 (m, 2H), 7.21 (d, 2H), 7.72 (d, 2H), 11.2:
pyrazin-2-y1}-phenyl)amide 7.96 (s, 1H) 'fil, F
2(4-Hydroxy-piperidin-1-y1)-(300 MHz, CDC13) 01.60 (m, 2H), 1.82 (m, 5H), ethanesulfonic acid (445-2.23 (m, 2H), 2.77 (m, 2H), 2.89 (t, 2H), 3.26 (t, examples see amino-6-[1-(2-chloro-3,6-2H), 3.74 (m, 1H), 5.07 (bra, 2H), 6.70 (q, 04"
difluoro-phenyl)-ethoxy]-1H),7.00 (m, 2H), 7.24 (d, 2H), 7.73 (d, 2H), 7.94 C
H, pyrazin-2111-pheny1)-amide (s, 1H) F
I?
H 1-------p0 2-Piperldin-1-yl-ethanesulfonic acid (445-(300 MHz, CDCI3) 6 1.49 (m, 2H), 1.61 (m, 4H), amino-6-[1-(2-chloro-3,6-see 1.83 (d, 3H), 2.50 (m, 4H), 2.86 (m, 2H), 3.20 (m, 0jkN
difluoro-phenyl)-ethoxy)-examples 2H), 4.95 (br s, 2H), 6.70 (q, 1K), 7.00 (m, 2H), ;

'-W. ct NH, pyrazin-2-y1)-phenyl)-amide 7.24 (d, 2H), 7.74 (d, 2H), 7.96 (s, 1H) F
ft HN-g--"tr'v 24Cyclopropylmethyl-amino) 1:
ethanesulfonic acid (445-amino-64142-[1-3,6-see difluoro-phenyl)-ethoxy].
(300 MHz, CDC13) 6 0.14 (m, 2H), 0.50 (m, 2F1).
0.95 (m, 1H), 1.82 (d, 31-1), 2.49 (m, 2H), 3.20 (m, 4H), 4.73 (br s, 1H), 5.02 (bra, 2H), 6.71 (q, 11-1), examples 7.00 (m, 2H), 7.25 (d, 2H), 7.74 (d, 2H), 7.96 (s, 416 crlyN
pyrazin-2-y1)-phenyl)-amide 1H) ILO a NH.
, No.
Structure Name Met 1C50 Procedure MS m/z (11M) (M+1) 2-[(3R)-3-Hydroxy-pyrrolidin-(300 MHz, CDC13)15 1.79 (m, 1H), 1.82 (d, 3H), 1-yI]-ethanesulfonic acid (4-2.26 (m, 2H), 2.54 (m, 1H), 2.82 (m, 1H), 2,98 see {5-amino-6-(1-(2-chloro-3,6-(m, 2H), 3.08 (m, 111), 3.26 (m, 2H), 4.44 (m, õ ..
rd, elyti difluoro-phenyl)-ethoxy].
examples1H), 4.94 (br s, 1H), 6.70 (q, 1H), 7.00 (m, 2H), illp .
NH, pyrazin-2-yll-phenyl)-amide 7.29 (d, 2H), 7.73 (d, 2H), 7.96 (s, 1H) F
.OH
pyrrolidin-1-y11-2-[(2S)-2-Hydroxymethyl-(300 MHz, CDCI3) 5 1.79 (m, 4H), 1,82 (d, 3H), ethanesulfonic acid (4-{5-see 2.15 (m, 111), 2.66 (m, 2H), 2.98 (m, 2H), 3.35 amino-641-(2-chloro-3,6-examples (m, 111), 3.48 (m, 1H), 3.54 (m, 1H), 3.92 (m, 1:-::
1H), 4.97 (bra, 1H), 6.70 (q, 1H), 7.00 (m, 2H), "
pyrazin-2-y1}-phenyl)-amide ' 7.28 (d, 2H), 7.71 (d, 21-1), 7.95 (s, 1H) C:10.:11 2 difluoro-pheny1)-ethoxy]-F
I?
H
,C) I
2-Dimethylamino-ethanesulfonic acid (4-{5-(300 MHz, CDCI3) 5 1.82 (d, 311), 2.29 (s, 6H), amino-6-[1-(2-chloro-3,6-IP
see 2.85 (t, 2H), 3.21 (t, 2H), 5.00 (br s, 2H), 6.71 (q, N ""==

eity-N
difluoro-phenyI)-ethoxy]-examples 1H), 7.00 (m, 211), 7.23 (d, 211), 7.74 (d, 2H), 7.96 pyrazin-2-y1}-phenyl)-amide (s, 1H) 40 cr Nt-L

H
c.,02-Morpholin-4-yl-ethanesulfonic acid (445-(300 MHz, CDCI3) 5 1.82 (d, 3H), 2.48 (m, 4H), amino-6-[1-(2-chloro-3,6-see 2.90 (m, 2H), 3.27 (m, 211), 3.71 (m, 4H), 4.92 (br 554 difluoro-phenyI)-ethoxy]-examples s, 2H), 6.71 (q, 1H), 7.00 (m, 211), 7.24 (d, 2H), pyrazin-2-y1}-pheny1)-amide 7.74 (d, 2H), 7.97 (s, 111) WI 01 "2 F
R
Hreg.------C-2-Diethylamino-(300 MHz, CDCI3) 51.07 (t, 6H), 1.82 (d, 311), *
ethanesulfonic acid (4-{5-see 2.60 (q, 4H), 3.02 (t, 2H), 3.22 (t, 2H), 4.95 (br s, amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-examples 211), 6.71 (q, 1H), 7.00 (m, 2H), 7.22 (d, 211), 7.74 nip 0 pyrazin-2-y1}-phenyl)-amide (d, 2H), 7.96 (s, 1H) F
A A
HN-t-----N--Si 2-Cyclopropylamino-ethanesulfonic acid (4-(5-(300 MHz, CDCI3) 00.38 (m, 2H), 0.50 (m, 2H), amino-641-(2-chloro-3,6-see 9.82 (d, 311), 2.15 (m, 111), 3.24 (m, 4H), 4.93 (br difluoro-phenyI)-ethoxy]-examples s, 21-1), 6.71 (q, 1H), 7.00 (m, 2H), 7.21 (d, 2H), pyrazin-2-y1}-pheny1)-amide 7.74 (d, 2H), 7.97 (s, 111) F

345-Amino-641-(2,6-dichloro-3-fluoro-phenyl)-see 1.36 9 -, ethoxyi-pyrazin-2-y1}-benzoic examples F 46 o'y"
acid IW"' ci NH, Xto....NH, d(3-(5-Amino-641-(2,6-(300MHz, Me0D) 57.84 (d, 1H), 7.71 (m, 211), ichloro-3-fluoro- hen I -P
Y ) see 7.38 (m, 3H), 7.10 (m, 1H), 6.60 (m, 1H), 4.86 (s, ethoxyl-pyrazin-2-y1)-pheny1)- 0.069 examples 211), 4.20 (m, 111), 3.45-3.89 (m, 4H), 1.82 (d, '&0"
[(3S)-3-amino-pyrrolldin-1-3H), 1.34 (m, 1H), 0.89 (m, 111) ., NH, yI)-m-ethanone (345-Amino-641-(2,6-dichloro-3-fluoro-phenyI)-(300MHz, Me0D) 57.84 (d, 111), 7.71 (m, 2H), see 7.38 (m, 3H), 7.10 (m, 1H), 6.60 (m, 1H), 4.86 (s, [(3R)-3-amino-pyrrolidin-1-F
examples 2H), 4.20 (t, 1H), 3.45-3.89 (m, 4H), 1.82 (d, 3H), yI)-m-ethanone ethoxy]-pyrazin-2-y1}-phenyl)- 0.11 1.34 (m, 1H), 0.89 (m, 1H) r 0 (345-Amino-641-(2,6-(300MHz, CDCI3) 5 8.04 (d, 1H), 7.84 (d, 2H), '9 dichloro-3-fluoro- hen I -P
Y) 7.30 (d, 2H), 7.15 (tert, 1H), 6.99 (t, 1H), 5.89 (m, see ethoxyj-pyrazin-2-y1}-pheny1)- 0.15 1H), 4.89 (s, 2H), 4.44 (s, 1H), 3.89 (m, 1H), 3.65 examples F
[(2R)-2-pyrrolidin-1-ylmethyl-(m, 1H), 3.30 (m, 2H), 2.85 (m, 3H), 1.82 (d, 3H), ..6cic...,.......14,::
pyrrolidin-1-yI)-methanone 0.89-2,20 (m, 9H) , No. Structure Name Met IC50 Procedure MS m/z OA

(M+1) ,Cfj( N-(2-(4-Acetyl-piperazin-1-(300MHz, CDCI3) 68.04 (d, 1H), 7.99 (s, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.34 (m, 2H), 7.15 (t, see 11-87 Y(21),-6e-3(2,6-13o4ro5--3a-{5 -6- -(1- 0.186 1H), 6.72 (tert, 111), 4.89 (s, 211), 4.56 (m, 6H), examples phenyl)-ethoxy]-pyrazin-2-y1}-3.21 (d, 3H), 2.60 (t, 1H), 2.55 (dd, 1H), 2.09 (s, ...3:11.1 benzamide 311), 1.80 (d, 4H) 1-40 (3-{5-Amino-6-[I-(2,6-(300MHz, Me0D) 68.04 (d, 1H), 7.84 (d, 2H), 9 dichloro-3-fluoro-phenyl)-7.35 (m, 3H), 7.20 (m, 1H), 6.60 (m, 1H), 4.89 (s, examples see ethoxy]-pyrazin-2-y1}-phenyl)- 0.17 211), 4.44 (s, 1H), 3.59 (m, 1H), 3.30 (m, 1H), 559 F [(25)-2-pyrrolidin-1-ylmethyl-3.25 (s, 2H), 3.16 (m, 3H), 1.82 (d, 3H), 0.89-pyrrolidin-1-y1)-methanone 2.32 (m, 9H) I

345-AMIn0-6-(1-(2-OhlOr0-see 11-89 3,6-difluoro-phenyl)-ethoxyj-examples pyrazin-2-yI)-benzoic acid F ii.l...h. elYN

111, F NH, \ H

40 b 3-{5-Amino-6-[I-(2,6-(300 MHz, CDCI3) 68.20 (s, 1H), 8.08 (s, 1H), dichloro-3-fluoro-phenyl)-7.89 (d, 1H), 7.75 (d, 1H), 7.44 (t, 1H), 7.01 (m, examples see 11-90 , 0 Ijiym * , g ethoxy)-pyrazin-2-yI}-N-(1- 0.21 2H), 6.78 (m, 1H), 6.20 (s, 1H), 4.98 (s, 2H), 4.09 502 ' methy4-piperldin-4-y1)-(m, 1H), 2.97 (m, 2H), 2.39 (s, 3H), 2.29 (t, 2H), benzamide 2.12 (m, 2H), 1.90 (d, 3H), 1.79 (m, 2H) a 1"

F

3-(5-Amino-641-(2,6-(300 MHz, CD30D) 68.15 (s, 111)7.96 (s, 1H), 1 dichloro-3-fluoro-phenyl)-see 7.80 (d, 1H), 7.61 (d, 1H), 7.35 (m, 2H), 7.09 (t, ethoxy]-pyrazin-2-yI}-N-(3- 0.15 examples 1H), 6.69(m, 1H), 3.44 (t, 2H), 2.55 (m, 6H), 1.88 , . --- pyrrolidin-1-yl-propyI)-(d, 311), 1.80 (m, 611) F benzamide _ ilr"40......, (3-(5-Amino-6-[1-(2,6-(300 MHz, CD-30D) 67.96 (s, IN), 7.76 (d, 1H), Li dichloro-3-fluoro-phenyl)-7.65 (m, 1H), 7.41 (m, 2H), 7.21 (d, i H), 7.12 (t, see 11-92 ''64-1-A,C
ethoxy]-pyrazin-2-y1}-pheny1)- 0.15 1H), 6.61 (m, 1H), 4.68 (m, 2H), 3.62 (m, 1H), 558 examples (4-pyrrolidin-1-yl-piperidin-1-3.05 (m, 211), 2.69 (m, 6H), 2.45 (m, 2H), 2.12 yI)-methanone (m, 211), 1.86 (d, 3H), 1.48(m, 2H) 4-(5-Amino-6-(3-fluoro-2-see trifluoromathyl-benzyloxy)-examples F, 1 ", pyrazin-2-y1]-benzoic acid F 40 o'lyN

NH, 1,,O 4-[5-Amino-6-(3-fluoro-2-(300MHz, CDCI3) 68.14 (s, 1H), 7.92 (d, 2H), 101 trifluoromethyl-benzyloxy)-see 7.84 (d, 211), 7.50 (m, 1H), 7.42 (m, 111), 7.20 (m, 0.22 pyrazin-2-yll-N-(2-morpholin-examples 1H), 6.75 (s, 1H), 5.70 (s, 2H), 4.97 (s, 2H), 3.74 A ... : 1; 4-yl-ethyl)-benzamide (m, 4H), 3.58 (m, 2H), 2.62 (m, 2H), 2.52 (s, 4H) IP cF, NH2 F

_ (300MHz, CDCI3) 68.14 (s, 111), 7.92 (d, 2H), IS ...C1-= 4-.[5-Amino-6-(3-fluoro-2-7.84 (d, 2H), 7.50 (m, 1H), 7.42 (m, 1H), 7.20 (m, tnfluoromethyl-benzyloxy)-see 0.081 111) 6.04 (d 1H) 5.75 (s 211) 5.01 (s 2H) 4.0 pyrazin-2-yI]-N-(1-methyl-examples ' " " ' ' (m, 1H), 2.85 (d, 2H), 2.30 (s3H), 2.20 (t, 2H), plperidin-4-yI)-benzamide 2.12 (d, 211), 1.59 (m, 211) il _ XN O NH, _ r j...9 3-(5-AmIno-641-(2,6-(300MHZ, CD30D) 68.18 (s, 1H), 7.98 (s, 1H), dichloro-3-fluoro-phenyl)-4 as in 7.80 (d, 1H), 7.61 (d, 1H), 7.35 (m, 211), 7.12 (t, ethoxy]-pyrazIn-2-y1}-N-(3- 0.15 Example II- 1H), 6.75 (q, 1H), 3.44 (t, 211)2.55 (m, 611), , pyrrolidin-1-yl-propyI)-1.88 (d, 3H), 1.80 (m, 6H).
benzamide F' 61, AroõN

No.
Structure Name Met IC0 Procedure MS rniz (j1M) (M+1) (300MHZ, CDCI3) 58.38 (s, 1H), 8,18 (s, 2H), Cr--10 3-{5-Amino-6-11-(2-chloro-.
4 as in 7.92 (m, 2H), 7.48 (t, 1H), 7.02 (m, 2H), 6.78 (q, 3,6-difluoro-pheny1)-ethoxyl-0.35 Example 11- 1H), 4.96 (s, 2H), 3.72 (m, 2H), 3.18 (m, 2H), pyrazin-2-yI)-N-(3-pyrrolidin-2.83 (m, 2H), 2.22 (m, 2H), 2.08 (m, 4H), 1.83 CX:::j"CHN.
1-yl-propyI)-benzamide (d, 3H), 1.70 (m, 2H).
(300MHZ, CDCI3) 58.20 (s, 1H), 8.08 (s, 1H), * b 3-(5-Amino-6-[1-(2-chloro-4 as in 7.89 (d, 1H), 7.75 (d, 1H), 7.44 (t, 1H), 7.01 (m, 3,6-difluoro-pheny 021 Example II-1)-ethoxy]-2H), 6.78 (q, 1H), 6.20 (bd, 1H), 4.98 (s, 2H)' N .

N , .
\
pyrazin-2-yI}-N-(1-methyl-4.09 (m, 1H), 2.97 (m, 2H), 2.39 (s, 3H), 2.29 0)(yN
piperidin-4-y1)-benzamide (m, 2H), 2.12 (m, 2H), 1.90 (d, 3H), 1.79 (m, 411" ci , H).
r ( (300MHZ, CDCI3) 58.19 (s, 1H), 8.09 (s, 1H), a 3-{5-Amino-641-(2-chloro-4 as in 7.88 (d, 1H), 7.78 (d, 1H), 7.48 (t, 1H), 7.06 3,6-difluoro-pheny1)-ethoxyl-0.18 Example II- (bm, 1H), 6.96 (m, 2H), 6.75 (q, 1H), 5.08 (s, pyrazin-2-y1)-N-(2-pyrrolidin-2H), 3.68 (m, 2H), 2.88 (m, 2H), 2.68 (m, 4H), 1-yl-ethyl)-benzamide N", 1.86 (m, 7H).
1:7-Cle.:
I0 3-{5-Amino-641-(2-chloro-(300MHZ, CDCI3) 58.17 (s, 1H), 8.08 (s,11-1), ti 4 as in 7.88 (d, 1H), 7.68 (d, 1H), 7.48 (t, 1H), 6.98 (m, 3,6-difluoro-pheny1)-ethoxyl-0.31 Example 11- 2H), 6.80 (bt, 1H), 6.74 (q, 1H), 5.02 (s, 2H), pyrazin-2-y1)-N-(2-m orpholin-3.76 (m, 4H), 3.68 (m, 2H), 2.68 (m, 2H), 2.58 N

.,.:
4-yl-ethyl)-benzamide (m, 4H), 1.85 (d, 3H).
T.
N12-(4-Acetyl-yiperazin-1-y1) (300MHZ, CDCI3) 58.16 (s, 1H), 8.03 (s, 1H), fi'"='"`"
ethy11-3-(5-amino-641-(2-4 as in 7.86 (d, 1K), 7.68 (d, 1H), 7.40 (t, 1H), 6.98 (m, chloro-3,6-difiuoro-phenyI)-0.64 Example 11- 3H), 6.71 (q, 1H), 5.13 (s, 2H), 3.69 (m, 4H), ethoxy]-pyrazin-2-yI)-3.51 (m, 2H), 2.80 (m, 2H), 2.66 (m, 4H), 2.08 S, 11,,"
benzamide (s, 3H), 1.83 (d, 3H).

io L,...... (3-{5-Amino-6-(1-(2-chloro-(300MHZ, CDCI3) 68.02 (s, 1H), 7.82 (m, 2H), 3,6-difluoro-phenyl)ethoxy]-4 as in 7.41 (t, 1H), 7.28 (m, 1H), 6.95 (m, 2H), 6.71(q, ' pyrazin-2-y1)-phenyl)-(4-Example II-1H), 5.00 (s, 2H), 3.85 (m, 2H), 3.46 (m, 2H), )IN
methyl-piperazin-1-yI)-2.36 (m, 4H), 2.33 (s, 3H), 1.83 (d, 3H).

*"1", methanone ci F.
(3-(5-Amino-641-(2-chloro-(300MHZ, CDCI3) 68.02 (s, 1H), 7.80 (m, 2H), 3,6-difluoro-phenyl)-ethoxyl-4 as in 7.41 (t, 1H), 7.29 (m, 1H), 6.95 (m, 2H), 6.69 (q, 1-i pyrazin-2-y1}-(4-(4-Example II-1H), 4.97 (s, 2H), 4.72 (m, 1H), 3.83 (m, 1H), IS

pyrrolidin-1-yl-piperidin-i-yI)-2.81 (m, 7H), 1.83 (d, 3H), 2.10-1.70 (m, 8H). .,).Y.1:::
methanone F
(345-Amino-6[1-(2-chloro-(300MHZ, CDCI3) 58.03 (s, 1H), 7.80 (m, 2H), 3,6-difiuoro-phenyI)-etho)ry]-4 as in 7.41 (t, 1H), 7.29 (m, 1H), 6.95 (m, 2H), 6.70 (q, r pyrazin-2-y1}-phenyl)-Example 11- 1H), 5.00 (s, 2H), 4.68 (m, 1H), 3.56 (m, 1H), oll';
((3R,5S)-3,5-dimethyl-2.75 (m, 3H), 2.42 (m, 1H), 1.83 (d, 3H), piperazin-1-y1)-methanone 1.57(m, 1H), 1.15 (m, 3H), 0.96 (m, 3H). 110 ci F
,NID
(3-(5-Amino-6-[1-(2-chloro-(300MHZ, CDCI3) 58.04 (s, 1H), 7.83 (m, 2H), op.
NLJ
3,6-difluoro-phenyl)-ethoxy]-4 as in 7.39 (m, 2H), 6.98 (m, 2H), 6.70 (q, 1H), 5.00 pyrazin-2-y1)-phenyl)-((S)-2-Example 11- (s, 2H), 4.47 (m, 11-1), 3.50 (m, 2H), 3.00 (m, )I,N
pyrrolidin-1-ylmethyl-5H), 2.30 (m, 3H), 2.00 (m, 5H), 1.83 (d, 3H), pyrrolidin-1-yI)-methanone 1.53 (m, 1H).
lb . -4 SO o H. (3-(5-Amino-6-0-(2-chloro-3,6-difluoro-pheny1)-ethoxy]-4 as in (300MHZ, CDCI3) 58.02 (s, 1H), 7.83 (m, 2H), Example 11- 7.40 (m, 2H), 6.98 (m, 2H), 6.70 (q, 1H), 4.98 pyrazin-2-y1}-Phenyl)-((R)-3-(s, 2H), 3.75 (m, 4H), 3.61-3.15 (m, 1H), 2.15 0 1:-c"
arnino-pyrrolidin-1-y1)-(m, 1H), 1.85 (d, 3H), 1.95-1.75 (m, 31-1).

0 ci NH, methanone F

No. Structure Name Met 1050 Procedure MS m/z (M+1) (1-iM) ¨

ci (345-Amino-641-(2-chloro-(300MHZ, CDCI3) 68.02 (s, 1H), 7.83 (m, 211), 3,6-difluona-phenyl)-ethoxy]-4 as in 7.40 (m, 211), 6.98 (m, 2H), 6.70 (q, 1H), 4.98 pyrazin-2-y1}-phenyl)-((S)-3-Example II-(s, 21-1), 3.75 (m, 4H), 3.61-3.15 (m, 111), 2.15 amino-pyrrolidin-1-yI)-(m, 111), 1.85 (d, 3H), 1.95-1.75 (m, 3H).
methanone 1101 ci :cN

, F

01 445-Amino-6[1-(2-chloro-3 as in 3,6-difluoro-phenyl)-ethoxyl-Example 1-N ,..

pyrazin-2-yI)-benzoic acid Ail 0-4-r"

quir ci NH, ,, Il......"...,0 (300MHZ, CDCI3) 68.28 (bm, 1H), 8.04 (m, 445-Amino-641-(2-chloro-4 as in 3H), 7.84 (d, 2H), 6.95 (m, 2H), 6.71 (q, 1H), 3,6-difluoro-pheny1)-ethoxyl-Example 11- 5.03 (s, 2H), 3.85 (m, 2H), 3.72 (m, 2H), 3.18 109 (m, 2H), 2.82 (m, 2H), 2.25 (m, 4H), 2.08 (m, Al. O''IN 1-yl-propyI)-benzamide Liir ci NN, 2H), 1.87 (d, 3H).

F

0 N........) (445-Amino-6-[1-(2-chloro-(300MHZ, CDCI3) 67.99 (s, 1H), 7.78 (d, 2H), 3,6-difluoro-phenyl)-ethoxy]-4 as in 7.43 (d, 2H), 7.29 (m, 1H), 6.85 (t, 1H), 6.94 (q, pyrazin-2-y1}-phenyl)-(4-0.16 Example 11-1H), 5.07 (s, 2H), 3.75 (m, 2H), 3.50 (m, 2H), methyl-piperazin-1-yI)-2.43 (m, 4H), 2.33 (s, 3H), 1.84 (d, 3H).
!Cr'N methanone IS CI NH.

F
, 0.0 (300MHZ, CDCI3) 68.02 (a, 1H), 7.81 (d, 2H), (4-(5-Amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-4 as in 7.40 (d, 2H), 6.99 (m, 2H), 6.71 (q, 1H), 5.02 (s, pyrazin-2-y1}-phenyl)-(4-0.17 Example 11- 2H), 4.64 (m, 111), 3.85 (m, 1H), 2.99 (m, 2H), pyrrolidin-1-yl-piperidin-1-yI)-109 2.67 (m, 4H), 2.38 (m, 1H), 1.90 (m, 9H), 1.62 i".. ....cN methanone (m, 2H).

Lir CI NH.

F

,a, 4-(5-Amino-641-(2-chloro-(300MHZ, CDCI3) 6002 (a, 1H), 7.81 (d, 2H), 3,6-di fluoro-phenyI)-phenyl)-4 as in 7.38 (d, 2H), 6.99 (m, 211), 6.71 (q, 1H), 4.99 (s, pyrazin-2-y1}-phenyl)-0.19 Example II- 211), 4.65 (m, 1H), 3.65 (m, 1H), 2.88 (m, 211), ((3R,5S)-3,5-dimethyl-109 2.68 (m, 1H), 2.41 (m, 1 H), 1.84 (d, 3H), 1.64 ' 1 ' (m, 1H), 1.18 (s, 3H), 1.05 (a, 3H).
...1..f..N piperazin-1-yI)-methanone INI ci NH, r -k.,....,' (4-(5-Amino-641-(2-chloro-orxiõ...., (300MHZ, CDCI3) 68.07 (s, 1H), 7.81 (d, 211), 3,6-difluoro-phenyl)-ethoxyy 4 as in 7.53 (d, 2H), 6.95 (m, 2H), 6.69 (q, 1H), 4.99 (s, pyrazin-2-y1)-phenyl)-((S)-2- 0.18 Example II-2H),4.45 (m, 1H), 3.55 (m, 2H), 2.95 (m, 4H), pyrrolidin-1-ylmethyl-1.90-2.3 (m, 9H),1.82 (d, 3H), 1.65 (m, 1H).

pyrrolidin-1-yI)-methanone F

a CD (445-Amino-641-(2-(2-(300MHZ, CDCI3) 68.02 (s, 1H), 7.81 (d, 2H), c;:::

3,6-difluoro-phenyl)-ethoxyl-4 as in 7.53 (d, 211), 6.95 (m, 211), 6.69 (q, 1H), 4.99 (s, pyrazin-2-y1}-phenyl)-((R)-2- 0.13 Example 11- 2H),4.45 (m, 111), 3.55 (m, 2H), 2.95 (m, 4H), pyrrolidin-1-ylmethyl-109 2.21 (m, 311), 1.92 (m, 6H),1.82 (d, 3H), 1.59 pyrrolidin-1-yI)-methanone (m, 1H).

F

No.
Structure Name Met IC50 Procedure MS m/z (11M) (M+1) ,NH, (4-(5-Amino-641-(2-chloro-(300MHZ, CD30D) 68.02 (s, 1H), 7.81 (d, 2H), 3,6-difluoro-phenyl)-ethoxyl-4 as in 7.53 (d, 2H), 7.01 (m, 2H), 6.69 (q, 1H), 4.91 (s, pyrazin-2-y1)-phenyl)-((R)-3-0.078 Example II- 2H),3.85 (m, 1H), 3.71 (m, 2H), 3.55 (m, 1H), amino-pyrrolidin-1-y1)-2.18 (m, 1H), 1.85 (d, 3H), 1.75 (m, 1H), 1.42 N
methanone (m, 3H).
o'Y'l NH, F
O
il......., ' to 1..,4.....
4-{5-Amino-6-[1-(2-chloro-4 as in (300MHZ, CDCI3) 68.06 (s, 1H), 7.82 (m, 4H), 3,6-difluoro-phenyl)-ethoxy]-7.00 (m, 2H), 6.72 (m, 2H), 5.04 (s, 211), 4.09 0.19 Example II-F
pyrazin-2-yI)-N-(1-methyl-piperidin-4-y1)-benzamide (m, 1H), 2.97 (m, 2H), 2.39 (s, 3H), 2.29 (m, o'cill 2H), 2.12 (m, 2H), 1.90 (d, 3H), 1.79 (m, 2H).
110 ci NH, F
O
it....,-....0 AO
4-{5-Amino-6-[1-(2-chloro-4 as in (300MHZ, CDCI3) 68.06 (s, 1H), 7.82 (m, 4H), 36-difluoro-phenyl)-ethoxyl-7.00 (m, 2H), 6.72 (m, 2H), 5.04 (s, 2H), 3.68 , 0.11 Example II-pyrazin-2-yI)-N-(2-pyrrolidin-(m, 211), 2.88 (m, 2H), 2.68 (m, 4H), 1.86 (m, 0-cil 1-yl-ethyl)-benzamide 7H).
I.1 ci NH, F
o 11N'' ..,,I) 445-Amino-641-(2-chloro-(300MHZ, CDCI3) 68.06 (s, 1H), 7.82 (m, 4H), 4 as in 36-difluoro-phenyl)-7.00 (m, 2H), 6.72 (m, 2H), 5.04 (s, 2H), 3.75 , 0.26 Example II-F
...c pyrazin-2-y1)-N-(2-morpholin-(m, 4H), 3.56 (m, 2H), 2.62 (t, 2H), 2.52 (m, O
,N
4-yl-ethyl)-benzamide 4H), 1.83 (d, 3H).
.I ci m-6 F
o t,...., " 1 N42-(4-Acetyl-piperazin-1-y1) 1.--N,,, ethyl]-4-{5-amino-6-[1-(2-4 as in (300MHZ, CDCI3) 68.06 (s, 1H), 7.82 (m, 41-1), II
21-1) 70 (m 2H) 00 (m, , .
, , chloro-3,6-difluoro-phenyl)-0.48 Example II- 7.
5.03 (s, 2H), 3.62 (m, 411), 3.50 (m, 2H), 2.65 (t, 2H), 2.52 (m, ethoxy]-pyrazin-2-yI)-fa, 0)1y 4H), 2.10 (s, 3H), 1.83 (d, 3H).
benzamide ci "H=
_ N
244-(2-Hydroxy-acety1)-(300MHZ, CDCI3) 67.96 (s, 1H), 7.75 (d, 211), 1.,_.. .,<, piperazin-1-y1)-3 as in 7.24 (m, 3H), 7.08 (m, 111), 6.95 (m, 1H), 6.70 ct, ethanesulfonic acid (445-0.19 Example I- (q, 1H), 5.02 (s, 2H), 4.14 (s, 211), 3.64 (m, 3H), amino-6-[1-(2-chloro-3,6-3.25 (m, 4H), 2.91 (m, 2H), 2.44 (m, 4H), 1.83 difluoro-pheny1)-ethoxyy (d, 3H).
pyrazin-2-y1)-phenyl)amide 345-Amino-6-(3-fluoro-2-3 as in 11-121trifluoromethyl-benzyloxy)-Example I-,e-N
pyrazin-2-y1]-benzoic acid ral. 0 I" CF, NH, F
(300MHZ, CDCI3) 68.09 (s, 1H), 7.88 (m, 2H), (345-Amino-6-(3-fluoro-2-7.56 (m, 1H), 7.44 (t, 1H), 7.34 (d, 1H), 7.21 (t, '---/-1D trifluoromethyl-benzyloxy)-4 as in 1H), 5.69 (s, 2H), 4.92 (s, 2H), 4.70 (m, 1H), pyrazin-2-y1]-phenyl)-(4-0.19 Example II-O
3.82 (m, 1H), 3.06 (m, 1H), 2.98 (m, 1H), 2.65 1."
pyrrolidin-1-yl-piperidin-1-y1)-(m, 4H), 2.28 (m, 1H), 1.02 (m, 1H), 1.81 (m, (111?c, methanone 5H), 1.55 (m, 211).
,---r--3 345-Amino-6-(3-fluoro-2-(300MHZ, CDCI3) 68.34 (s, 1H), 8.14 (s, 1H), q trifluoromethyl-benzyloxy)-4 as in 8.01 (d, 1H), 7.68 (d, 1H), 7.53 (m, 1H), 7.50 (t, 11-123pyrazin-2-yI]-N-{2-[ethyl-(2-0.45 Example 11- 1H), 7.45 (d, 1H), 7.21 (t, 1H), 6.79 (bm, 1H), Ar.N
methoxy-ethyl)-aminol-ethyl)-5.72 (s, 2H), 4.92 (s, 2H), 3.72 (m, 4H), 3.61 C?C:, "", benzamide (m, 2H), 2.66 (m, 21-1), 2.55 (m, 4H).

No.
Structure Name Met 1055 Procedure MS m/z (11M) (M+1) _ Ai Nr`i (345-Amino-6-(3-fluoro-2-(300MHZ, 000I3) 6 8.10 (s, 1H), 7.90 (m, 2H), W
`---,"=-trifluoromethyl-benzyloxy)-4 as in 7.60-7.20 (m, 5H), 5.70 (s, 2H), 4.91 (s, 2H), pyrazIn-2-y11-phenyl}-(4-0.23 Example II-3.85 (m, 2H), 3.50 (m, 2H), 2.52 (m, 2H), 2,32 methyl-piin-1-yI)-0:c"
me peraz (m, 2H), 2.33 (s, 3H).

qr OF, NH, methanone F
(300MHZ, 000I3) 6 8.85 (bm, 1H), 8.34 (s, 1H), 345-Amino-6-(3-(3-2-4 as in 8.13 (s, 1H), 7.95 (d, 1H), 7.60 (d, 1H), 7.56 (m, trifluoromethyl-benzyloxy)-0.22 Example II- 1H), 7.45 (m, 2H), 7.20 (t, 1H), 5.72 (s, 2H), pyrazin-2-y11-N-(3-pyrrolidin-4.92 (s, 2H), 3.61 (m, 2H), 2.72 (m, 2H), 2.57 cco,...174,4:
1-yl-propyI)-benzamide (m, 4H), 1.82 (m, 2FI), 1.76 (m, 4H).
(300MHZ, CDCI3) 68.28 (s, 1H), 8.14 (s, 1H), N42-(4-Acetyl-piperazin-1-y1) 7.99 (d, 1H), 7.67 (d, 1H), 7.58 (m, 1H), 7.52 (t, Il-- ---4 as in ethy1]-345-amino-6-(3-fluoro-1H), 7.42 (d, 1H), 7.22 (t, 1H), 6.75 (bm, 1H), 0.65Examplel II-2-trifluoromethyl-benzyloxy)-5.72 (s, 2H), 4.95 (s, 2H), 3.62 (m, 4H), 3.47 PC.:..trN
pyrazin-2-y13-benzamide (m, 2H), 2.63 (m, 2H), 2.52 (m, 4H), 2.08 (s, F NH, .
3H).
F
r. . . . . . . . 0 4,...,1 {445-Amino-6-(3-fluoro-2-(300MHZ, CDCI3) 68.10 (s, 1H), 7.88 (d, 2H), 7.52 (m, 1H), 7.44 (d, 2H), 7.42 (m, 1H), 7.20 (t, trifluoromethyl-benzyloxy)-pyrazin-2-yli-phenyl)-(4-4 as in 0.047 Example II- 1H), 5.71 (s, 2H), 5.05 (s, 2H), 4.62 (m, 1H), 3.82 (m, 1H), 3.06 (m, 1H), 2.98 (m, 1H), 2.65 pyrrolidin-1-yl-piperidin-1-yI)-i:CrN
methanone (m, 4H), 2.28 (m, 1H), 1.02 (m, 1H), 1.81 (m, -5H), 1.55 (m, 2H).
OF, "11 r-N.-0 N,) (445-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-4 as in (300MHZ, 00013) 00.08 (s, 1H), 7.88 (d, 2H), 7.55-7.40 (m, 4H), 7.21 (t, 1H), 5.72 (s, 2H), pyrazin-2-yli-phenyl)-(4-0.15 Example 11-5.01 (s, 2H), 3.82 (m, 2H), 3.50 (m, 2H), 2.50 methyl-piperazin-1-yI)-di o),I r,,, (m, 2H), 2.32 (m, 2H), 2.33 (s, 3H).
methanone CF, NH, F
C
I,,.

{445-Amino-6-(3-fluoro-2-(300MHZ, 00013) 0 8.11 (s, 1H), 7.80(d, 2H), trifluoromethyl-banzyloxy)-4 as in 7.68 (m, 3H), 7.42 (d, 1H), 7.22 (t, 1H), 5.72 (s, pyrazin-2-yI]-phenyl)-((S)-2-0.052 Example 11-pyrrolidin-1-ylmethyl-2H), 4.92 (s, 2H), 3.50 (m, 2H), 3.74 (m, 4H), 1.84 (d, 3H), 1.57-2.18 (m, 11H).
pyrrolidin-1-y1)-methanone :=11,:iN

OF, NH
r (345-Amino-641-(2,6-(300MHZ, CDCI3) 68.02 (s, 1H), 7.79 (m, 2H), `-,". dichloro-3-fluoro-phenyl)-4 as in 7.40 (t, 1H), 7.29 (m, 1H), 7,01 (t, 1H), 6.81 (q, q s-..
ethoxy)-pyrazin-2-y1}-phenyl)- 0.17 Example 11- 1H), 5.06 (s, 2H), 3.85 (m, 2H), 3.46 (m, 2H), F ,.., Al,. N
(4-methyl-piperazin-1-yI)-2.51 (m, 2H), 2.35 (m, 2H), 2.33 (s, 3H), 1.84 methanone (d, 3H).

.
(300MHZ, 000I3) 6 8.02 (s, 1H), 7.78 (m, 2H), 7.39 (t, 1H), 7.24 (m, 1H), 7.01 (t, 1H), 6.81 (q, z.r.--ri-, (3-(5-Amino-6-[1-(2,6-d1ch1oro-3 -fluo-phen y1)-4 as In 1H), 5.07 (s, 2H), 4.71 (m, 1H), 3.56 (m, 1H), I
ethoxyl-pyrazin-2-y1)-phenyl)- 0.12 Examplell-2.96 (m, 1H), 2.82 (m, 1H), 2.66 (m, 1H), 2.42 ' ilk X"
((3R,5S)-3,5-dimethyl-(m, 1H), 1.84 (d, 3H), 1.74 (m, 1H), 1.22 (d, Mr piperazin-1-yI)-methanone NH, ci 3H), 1.00 (d, 3H).
r 345-Amino-641-(2,6-(300MHZ, CD30D) 68.16 (s, 1H), 7.99 (s, 1H), dichloro-3-fluoro-phenyl)-4 as In 7.82 (d, 1H), 7.66 (d, 1H), 7.42 (m, 2H), 7.15 (t, ethoxyl-pyrazin-2-y1)-N-(1-0.13 Example II- 1H), 6.74 (q, 1H), 3.95 (m, 1H), 2.98 (m, 2H), F
A k . 0 :c "
methyl-piperldin-4-y1)-2.34 (s, 3H), 2.25 (m, 2H), 2.01 (m,. 2H), 1.84 benzamide (d, 3H), 1.73 (m, 2H).

No. Structure Name Met IC50 Procedure 'H-NMR
MS m/z (PM) (M+1) ) 345-Amino-641-(2,6-(300MHZ, CD30D) 58.17 (5, 11-1), 7.99 (s, IH), IP11 dichloro-3-fluoro-phenyI)-4 as In 7.82 (d, 1H), 7.66 (d, IH), 7.38 (m, 2H), 7.12 (t, 11-133 ethoxy]-pyrazin-2-yI)-N-(2- 0.17 Example 11- 1H), 6.72 (q, 1H), 3.64 (m, 2H), 2.86 (m, 2H), 1 ==== pyrroliclin-1-yl-ethyl)-84 2.75(m, 4H), 2.25 (m, 2H), 2.01 (m,. 2H), 1.84 benzamide (m, 7H).
Air a NH, -Nrj.?
3-{5-Amino-641-(2,6-as in 7(300MHZ, CDCI3) 58.13 (s, 1H), 8.03 (s, 1H), N dichloro-3-fluoro-phenyl)-4 85 (d, IH), 7.67 (d, 1H), 7.42 (t, 1H), 7.28 (dd, 11-134 ethoxy]-pyrazin-2-yll-N-(2- 0.21 Example 11- 1H), 7.00 (t, 1H), 6.86 (q, 1H), 6.84 (bm, 1H), 21 x N morpholin-4-yl-ethyl)-84 5.11 (s, 2H), 3.72 (m, 4H), 3.61 (m, 2H), 2.63 benzamide (m, 2H), 2.53 (m, 4H), 1.84 (d, 3H).

_ (0) 3-{5-Amino-641-(2,6-(300MHZ, CDCI3) 58.19 (s, 1H), 8.06 (s, 1H), dichloro-3-fluoro-phenyl)- 4 as in 7.87 (d, 1H), 7.70 (bm,. 1H), 7.67 (d, 1H), 7.42 11-135 II ethoxy]-pyrazin-2-yI)-N-(3- 0.26 Example II- (t, 1H), 7.28 (dd, 1H), 7.01 (t, 1H), 6.86 (q, 1H), morpholin-4-yl-propyl)-84 5.11 (s, 2H), 3.64 (m, 6H), 2.54 (m, 2H), 2.48 benzamide (m, 4H), 1.84 (m, 5H).

(345-Amino-641-(2,6-aA dichloro-3-fluoro-phenyI)-4 as in 11-136 eot h. co;PY
-m2-y0 1}-pheny1)- 0.15 Example 11- s (4-propyilanin piperidin-1-yI)-methanone -....1.0 ifrra 345-Amino-641-(2,6-dichloro-3-fluoro-pheny1)- 4 as in 11-137 ethoxy]-pyrazin-2-y1)-N-((S)- 0.3 Example II-2-hydroxy-3-morpholin-4-yl-propyI)-benzamide Hoy) 345-Amino-641-(2,6-dichloro-3-fluoro-pheny1)- 4 as in 11-138 ii)11 ethoxyl-pyrazin-2-y1}-N-((R)- 0.13 Example II-2-hydroxy-3-pyrrolidin-1-yl-propyI)-benzamide (300MHZ, 00013) 57.86 (s, 1H), 7.41 (m, 3H), (3-(6-Amino-541-(2,6-7.30 (m, 3H), 7.07 (t, 1H), 6.99 (s, 1H), 6.12 (q, 0, dichloro-3-fluoro-phenyl)-4 as in 31H0)6, 4(m.951(Hs,),22H)9,84(.m70 ,(imii,),121,53(.m82,(imm,,121,8 559 11-139 0 ethoxyl-pyridin-3-y1}-phenyl)- 0.071 Example 11-(4-pyrrolidin-1-yl-piperidin-1-(rn, 1H), 1.02 (m, 1H), 1.81 (m, 5H), 1.55 (m, yI)-methanone 2H).

4-----y---- 2-Diethylamino- ethanesulfonic acid (4-(5-(300MHZ, CDCI3) 57.89 (s, 1H), 7.70 (d, 2H), L--3 as in 7.28 (m, 2H), 7.21 (d, 2H), 7.01 (t, IH), 6.82 (q' 11-140 amino-6-[1-(2,6-dichloro-3- 0.35 Example I-fluoro-phenyl)-ethoxyl-243 1H), 5.05 (s, 21-1), 3.22 (m 2H), 3.00 (m, 2H), ' F ip 0:c" pyrazin-2-y1}-phenyl)-arnide 2.55 (m, 4H), 1.83 (d, 3H), 1.60 (d, 6H).
-...4.-= . NH, ,,t,'",t,",, 2-(4-Hydroxy-piperidin-111)-(300MHZ, CDCI3) 57.95 (s, 1H), 7.71 (d, 2H), õ ethanesulfonic acid (4-(5-3 as in 7.28 (m, 2H), 7.21 (d, 2H), 7.01 (t, 1H), 6.82 (q, 11-141 amino-6-[1-(2,6-dichloro-3- 0.21 Example 1- 1H), 5.00 (s, 2H), 3.78 (m, 1H), 3.25 (t, 2H), "lL, fluoro-phenyl)-ethoxy]-243 2.90 (t, 2H), 2.82 (m, 2H), 2.25 (m, 2H), 1.90 pyrazin-2-y1)-amide-amide (m, 2H), 1.84 (d, 3H), 1.60 (m, 2H).

1? 2-Dimethylamino-H01"-"T' ethanesulfonic acid (300MHZ, CDCI3) 57.89 (s, 1H), 7.70 (d, 2H), (4-{5-amino-641-(2,6- 3 as in IS
7.28 (m, 2H), 7.21 (d, 2H), 7.01 (t, 1H), 6.82 (q, 11-142 dichloro-3-f 0.22 Example I-1uoro-p lheny1)-ethoxy]-243 1H), 5.05 (s, 2H), 3.20 (m, 2H), 2.85 (m, 2H), F Ai oii.:r.;.ti pyrazin-2-y1) 2.28 (s, 3H), 1.83 (d, 3H).

"H. -phenyl)-amide No.
Structure Name Met IC50 Procedure MS m/z (I-IM) (M+1) _.
24(R)-3-Hydroxy-pyrroliclin-1-(300MHZ, CDCI3) 67.93 (s, 1H), 7.89 (d, 2H), yI)-ethanesulfonic acid (445-3 as in 7.27 (m, 4H), 7.00 (t, 1H), 6.84 (q, 1 H), 5.03 (s, amino-6(142,6-dichloro-3-0.19 Example 1- 2H), 4.43 (m, 1H), 3.25 (m, 2H), 3.02 (m, 3H), .
F--6(1-0-c"
fluoro-phenyl)-ethoxy1-2.84 (m, 1H), 2.53 (m, IH), 2.30 (m, 1H), 2.22 pyrazin-2-y1}-phenyl)-amide (m, 1H), 1.84 (d, 3H), 1.81 (m, 1H).
CI

I?

"
"O 2-Pyrrolidin-1-(01 ylethanesulfonic acid (445-3 as in (300MHZ, CDCI3) 67.94 (s, I H), 7.69 (d, 2H), 7.27 (m, 2H), 7.19 (d, 2H), 7.04 (t, 1H), 6.82 (q' amino-6-(1(2,6-dichloro-3-0.36 Example 1- 1H), 5.01 (s, 2H), 3.28 (m, 2H), 3.08 (m, 2H), isr:
fluoro-phenyl)-ethoxy]-2.60 (m, 4H), 1.88 (m, 7H).

F Ail . ,N
pyrazin-2-y1)-phenyl)-amide I" ci "8, 445-Amino-6-[142,6-3 as in dichloro-3-fluoro-phenyl)-1.56 Example l-icN
ethoxyl-pyrazin-24}-benzoic o acid a NE1' F

4-(5-Amino-6-[1-(2,6-TFA dichloro-3-fluoro-phenyl)-4 as in ethoxy]-pyrazin-2-yI}-N((R)-0.15 Example II-cc.i.x..,..
2-hydroxy-3-pyrrolidin-1-yl-propyI)-benzamide ci ""2 ' ,11 (445-Amino-64142,6-dichloro-3-fluoro-pheny1)-4 as in ethoxy]-pyrazin-2-y1}-phenyl)- 0.13 Example 11-I
(4-cyclopropylamino-piperidin-1-y1)-methanone F
. li 0II 0 445-Amino-64142,6-dichloro-3-fiuoro-phenyl)-4 as in TFA

othoxy]-pyrazin-2-yI}-N-((S)-0.12 Example II-, 2-hydroq-3-pyrrolidin-1-yl-propy1)-benamide e "".
F

.
......x..õ, '=
445-Amino-6-(142,6-=
dichloro-3-fluoro-phenyl)-4 as in ethoxy]-pyrazin-2-yI}-N((R)-0.13 Example 11-alui X,õ
2-hydroxy-3-morpholin-4-yl-NH, propyI)-benzamide ir ci F
0 11,,,, =

L.) 445-Amino-6-[142,6-(300MHZ, CDCI3) 68,01 (s, 1H), 7.78 (m, 4H), N.õ.
i d chloro-3-fluoro-phenyl)-4 as in 7.28 (m, 1H), 6.95 (t, 1H), 6.80 (q, IH), 5.95 ethoxyl-pyrazin-2-y1)-N(1-0.068 Example 11- (bd, 1H), 5.07 (s, 2H), 4.05 (m, IH), 2.85 (m, 01 -..
methyl-piperidin-4-yI)-2I-1), 2.32 (s, 3H), 2.21 (m, 2H), 2.08 (m, 2H), F
benzamide 1.85 (d, 3H), 1.68 (m, 21-1).
ci iiii 1,,...
(445-Amino-6-(142,6-A.}
(300MHZ, CDCI3) 68.00 (d, IH), 7.75 (d, 2H), dichloro-3-fluoro-phenyl)-4 as in 7.51 (d, 2H), 7.28 (m, 1H), 7.00 (t, 1H), 6.90 (q, .
ethoxy]-pyrazin-2-y1)-phenyl)- 0.18 Example 11-((S)-2-pyrrolidin-1-ylmethyl-1H), 5.05 (s, 2H), 4.45 (in, 1H), 3.41 (m, 2H), pyrrolidin-1-yI)-methanone 2.70 (m, 4H), 1.84 (d, 3H), 1.70-2.0 (m, 101-1) F al . X41 41112.P IN
NH, No. Structure Name Met 1050 Procedure MS m/z (1-LM) (M+1) ,0 (300MHZ, CDCI3) 67.00 (s, 1H), 7.75 (d, 2H), = ,. li.,) (4-(5-AmIno-641-(2,6-7.40 (d, 2H), 7.28 (m, 1H), 6,99 (t, 1H), 6.76 (q, dichloro-3-fluoro-phenyI)-4 as in 1H), 5.04 (s, 2H), 4.64 (m, 1H), 3.84 (m, 1H), 11-152 ethoxy}-pyrazin-2-y1)-pheny1)- 0.11 Example II-3.02 (m, 2H), 2.60 (m, 4H), 2.30 (m, 1H), 1.92 (4-pyrrolidin-1-yl-piperidin-1-(m, 1H), 1.81 (m, 6H), 1.69 (m, 2H), 1.62 (m, yI)-methanone 2H).

F.la....1..X.N ci ".

- 11 , . 4-(5-Amino-6-11-(2,6-(300MHZ, CDCI3) 58.05 (s, 1H), 7.79 (m, 5H), dichloro-3-fluoro-phenyl)-4 as In [110 7.25 (m, 1H), 6.95 (t, 1H), 6.83 (q, 1H), 5.10 (s, 11-153 ethoxyl-pyrazin-2-y1}-N-(2- 0.102 Example II-2H), 3.74 (m, 4H), 3.49 (m, 2H), 2.63 (m, 2H), ' morpholin-4-yl-ethyl)-F,LXN

2.52 (m, 4H), 1.85 (d, 3H).
benzamide k,....1.....0 NH2 rY
0 N..õ....-(4-(5-Amino-641-(2,6-(300MHZ, CDCI3) 57.99 (s, 1H), 7.78 (d, 2H), dichloro-3-fluoro-phenyl)-4 as in 7.43 (d, 2H), 7.29 (m, 1H), 6.85 (t, 1H), 6.94 (q, 11-154 1101 ethoxyl-pyrazin-2-y1}-phenyl)- 0.16 Example 11-1H), 5.07 (s, 2H), 3.75 (m, 2H), 3.50 (m, 2H), (4-methyl-piperazin-1-yI)-2.43 (m, 4H), 2.33 (s, 3H), 1.84 (d, 3H).
F methanone ill O'cil lir CI NH, (I-NH
0 N........A.... (4-(5-Amino-641-(Z6-(300MHZ, CDCI3) 58.02 (s, 1H), 7.79 (d, 2H), 7.40 (d, 2H), 7.28 (m, 1H), 6.98 (t, 1H), 6.84 (q, dichloro-3-fluoro-phenyl)-4 as in 1H), 5.04 (s, 2H), 4.65 (m, 1H), 3.56 (m, 1H), 11-155 101 ethoxy}-pyrazIn-2-y1}-pheny1)- 0.095 Example II-2.85 (m, 2H), 2.70 (m, 1H), 2.44 (m, 1H), 1.84 ((3R,5S)-3,5-dimethyl-(d, 3H), 1.65 (m, 1H), 1.13 (m, 3H), 1.00 (m, F 0 , NI piperazin-1-yI)-methanone 3H).

up! ei NH, 3110 445-Amino-641-(2,6-3 as in dichloro-phenyl)-ethoxyl-Example I-ci NI --- pyrazin-2-y1}-benzoic acid alai. 0-1---r"

tiolv .1 N H2 ...Th....0 0-.......rj,J (4-(5-Amino-6-[1-(2,6-(300MHZ, CDCI3) 6 8.05 (s, 1H), 7.82 (d, 2H), dichloro-phenylyethoxyl-4 as in 7.50 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 6.90 (q, 11-157 pyrazin-2-y1)-phenyl)-(4- 0.16 Example 11-1H), 5.05 (s, 2H), 2.98 (br, 2H), 2.60 (a, 4H), pyrrolidln-1-yl-piperidin-111)-2.25 (br, 2H), 1.89 (d, 3H), 1.2-1.98(6r, 8H).
I -- methanone (300MHZ, CDCI3) 58.16 (s, 1H), 7.89 (d, 2H), L6 4-(5-Amino-641-(2,6-4 as in 7.75 (d, 2H), 7.32 (m, 2H), 7.15 (t, 1H), 6.91 (q, 40 dichloro-phenyl)-ethoxy)-0.32 Example II- 1H), 6.78 (m, 1H), 5.10 (s, 2H), 3.74 (m, 4H), pyrazin-2-y1)-N-(2-morpholin-157 3.63 (m, 2H), 2.65 (m, 2H), 2.54 (m, 4H), 1.85 4-yl-ethyl)-benzamide (d, 3H).
AP

we' a NH.

NH

0 N,),. (4-(5-Amino-6-[I-(2,6-(300MHZ, CDCI3) 68.05 (s, 1H), 7.82 (d, 2H), dichloro-phenyl)-ethoxy]-4 as In 7.50 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 6.90 (q, pyrazin-2-y1}-phenyl)- 0.14 Example II-1H), 5.05 (s, 2H), 4.60(s, 1H), 4.30(t, 1H), 3.60 11-159 =
((3R,5S)-3,5-dimethyl-157 (s, 1H), 2.70 (m, 411), 1.89 (d, 3H), 0.8-1.2(br, piperazin-1-y1)-methanone 6H).

IW : NH, 0 KI, (300MHZ, CDCI3) 58.16 (s, 1H), 7.90 (d, 2H), 4-{5-Amino-641-(2,6-4 as in 7.83 (d, 2H), 7.32 (t, 2H), 7.16 (t, 1H), 6.84 (q, dichloro-phenyl)-ethoxyl-0.12 Example II- 1H), 6.00 (d, 1H), 5.08 (s, 2H), 4.05 (m, 1H), pyrazin-2-y1}-N-(1-methyl-157 2.81 (m, 2H), 2.35 (s, 3H), 2.21 (m, 2H), 2.08 plperldin-4-y1)-benzamide dui 0.cN

(m, 211), 1.84 (d, 3H), 1,60 (m, 2H).

Ur NH, CI

No. Structure Name Met 1050 Procedure MS m/z (M+1) OAK

?
.

(4-(5-Amino-641-(Z6-O 'TND
(300MHZ, CDCI3) 68.05 (s, I H), 7.82 (d, 2H), dichloro-phenyl)-ethoxyl- 4 as in 7.50 (d, 2H), 7.26 (d, 2H), 7.15 (t, 1H), 6.90 (q, 11-161 pyrazin-2-y1)-phenyl)-((R)-2- 0.16 Example II-IH), 5.05 (s, 2H), 4.30 (t, 1H), 3.50 (m, 2H), SI pyrrolidin-1-ylmethyl-2.65 (m, 411), 1.86 (d, 3H), 1.70-2.0 (m, 10H) pyrrolidin-1-y1)-methanone I rjiN
6. 0 NI.1 .111-7" ci ON

I
,..r (4-(5-Amino-6-[1-(2,6-O IL, (300MHZ, CDCI3) 6 8.05 (s, 1H), 7.82 (d, 2H), dichloro-phenyl)-ethoxy]- 4 as in 7.50 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 6.90 (q, 11-162 pyrazin-2-y1)-phenyl)-((S)-2- 0.14 Example II-1H), 5.05 (s, 2H), 4.45 (m, 1H), 3.41 (m, 2H), pyrrolidin-1-ylmethyl- 157 2.70 (m, 4H), 1.86 (d, 3H), 1.70-2.0 (m, 10H) pyrrolidin-1-y1)-methanone 1.,_1 ecrl tir ci NH' o NiCf (4-(5-Amino-6-[1-(2,6-(300MHZ, CDCI3) 68.05 (s, 1H), 7.82 (d, 2H), dichloro-pheny1)-ethoxy1- 4 as in 7.50 (d, 2H), 7.31 (d, 2H), 7.15 (t, 1H), 6.90 (q, * pyrazin-2-y1)-pheny1)-(4-0.15 Example 11-1H), 5.05 (s, 2H), 3.60 (m, 4H), 2.45 (m, 411), methyl-piperazin-1-yI)- 157 2.31 (s, 3H), 1.89 (d, 3H) methanone "- ci "1", twi, o,0 (4-(5-Amino-641 -(2,6-(300MHZ, CD30D) 67.89 (m, 3H), 7.60 (m, dichloro-phenyl)-ethoxyj- 4 as in 2H), 7.40 (m, 2H), 7.25 (m, I H), 6.74 (m, 1H), 11-164 pyraz1n-2-y1)-phenyl)-((R)-3- 0.15 Example 11-4.90(s, 211), 4.05-3.60 (m, 4H), 3.50 (m, 2H), aminopyrrolidin-1-yI)- 157 2.50 (m, 1H), 2.18 (m, IH), 1.90 (d, 311).

methanone NH, Hc, NH, 0 6 (445-Amino-641-(2,6-dichloro-pheny1)-ethoxyy (300MHZ, CD300) 67.89 (m, 3H), 7.60 (m, 4 as in pyrazin-2-y1}-phenyl)-((S)-3- , i Examplen.
2H), 7.40 (m, 2H), 7.25 (m, 11-1), 6.74 (m, 11-1), 411 aminopyrrolidin-1-yI)-"' ' 4.90(s, 2H), 4.05-3.60 (m, 4H), 3.50 (m, 2H), methanone hydrogen 2.50 (m, 1H), 2.18 (m, 1H), 1.90 (d, 3H).
i 12.c.:n chloride NH, 4-(5-Amino-6-[1-(2,6-(300MHZ, CDCI3) 68.01 (s, 1H), 7.80 (m, 4H), 4 as in dichloro-phenyl)-ethoxy1- Example II- 157 7.31 (dt, 2H), 7.16 (t, 1H), 6.84 (m, 2H), 5.04 (s, 0.11 pyrazin-2-y1)-N-(2-pyrr01idin-2H), 3.55 (m, 2H), 2.71 (m, 2H), 2.57 (m, 4H), i 1-yl-ethyl)-benzamide 1.84 (d, 3H), 1.83 (m, 411).

r& eic"

oxi:L.....,..0 (300MHZ, CDCI3) 68.80 (s, 1H), 8.10 (s, 1H), 4-(5-Amino-641-(2,6-4 as in 7.80 (m, 4H), 7.21 (d, 2H), 7.16 (t, 1H), 6.84 (q, dichloro-phenyl)-ethoxy]-0.22 Example 11- 1H), 5.04 (s, 2H), 3.55 (m, 2H), 2.71 (m, 211), pyrazin-2-y1)-N-(3-pyrrolidin-1 FX:
157 2.57 (m, 4H), 1.84 (m, 4H), 1.83 (d, 3H), 1.81 1-yl-propyI)-benzamide (m, 2H).

1101 e, T4E1 =

3-(5-Amino-641-(2,6- 3 as in dichloro-phenyl)-ethoxy]- Example I-CI N "--pyrazin-2-y1}-benzoic acid 211 .....kt,,,N

CI

(300MHZ, CDCI3) 68.16 (s, 1H), 8.03 (s, 1H), 345-Amino-641-(2,6-7.88 (d, 1H), 7.70 (d, 1H), 7.42 (t, 1H), 7.28 (d, 4 as in dichloro-phenyl)-ethoxyl-2H), 7.10 (t, 1H), 6.94 (q, 1H), 6.15 (bd, 1H), i 0.18 Example II-pyrazin-2-y1)-N-(1-methyl-5.08 (s, 2H), 4.05 (m, 1H), 2.91 (m, 2H), 2.35 piperidin-4-yI)-benzamide (s, 3H), 2.21 (m, 2H), 2.08 (m, 2H), 1.84 (d, ci IIFI
3H), 1.68 (m, 2H).

, No. Structure Name Met 1050 Procedure MS rniz (M+1) (11M) i (300MHZ, CDCI3) 68.15 (s, 1H), 8.02 (s, 1H), 40 11^-.0 3-(5-Amino-641-(2,6-4 as in 7.85 (d, 1H), 7.71 (d, 1H), 7.40 (t, 1H), 7.28 (d, dichloro-phenyl)-ethoxy]-0.33 Example 11- 2H), 7.10 (m, 2H), 6.90 (q, 1H), 5.10 (s, 2H), pyrazin-2-y1)-N-(2-pyrrolidin-3.64 (m, 2H), 2.80 (in, 2H), 2.64 (m, 4H), 1.85 6 1-yl-ethy-benzamide l) (m, 7H).

er NH, I
(300MHZ, CDCI3) 68.04 (s, 1H), 7.79 (m, 2H), /00 fr (3-{5-Amino-641-(2,6-NH dichloro-phenyl)-ethoxy)-4 as in 7.40 (t, 1H), 7.28 (m, 3H), 7.11 (t, 1H), 6.86 (q, pyrazin-2-y1)-phenyl)- 0.36 Example II- 1H), 5.05 (s, 2H), 4.69 (m, 1H), 3.56 (m, IH), ((3R,5S)-3,5-dimethyl-169 2.95 (m, 1H), 2.79 (m, 1H), 2.71 (m, 1H), 2.44 piperazin-1-yI)-methanone (m, 1H), 1.84 (d, 3H), 1.25 (d, 3H), 1.17 (d, 3H).

W" a ".

a (300MHZ, CDCI3) 68.16 (s, 1H), 8.03 (s, 1H), EP
4 as in 7.89 (d, 1H), 7.69 (d, 1H), 7.43 (t, 1H), 7.28 (d, [I'' 0 345-Amino-641-(2,6-' dichloro-pheny1)-ethoxyl-0.48 Example 11- 2H), 7.10 (t, 1H), 6.91 (q, 1H), 6.88 (m, 1H), pyrazin-2-yll-N-(2-morpholin-5.10 (s, 2H), 3.74 (m, 4H), 3.63 (m, 2H), 2.65 4-yl-ethyl)-benzamide (m, 2H), 2.54 (m, 4H), 1.85 (d, 3H).

' (3-(5-Amino-641-(2,6-(300MHZ, CDCI3) 68.01 (d, 1H), 7.87 (m, 2H), dichloro-phenyl)-ethoxyl-4 as in 7.37 (m, 2H), 7.28 (m, 2H), 7.11 (t, 1H), 6.90 0.18 Example II- (m, 1H), 5.05 (s, 2H), 4.45 (m, 1H), 3.41 (m, pyrazin-2-y1)-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-169 2H), 2.70 (m, 4H), 1.84 (d, 3H), 1.70-2.0 (m, .

pyrrolidin-1-yI)-methanone 10H) a "H=

(300MHZ, CDCI3) 67.99 (s, 1H), 7.78 (m, 2H), (345-Amino-641-(2,6-7.39 (t, 1H), 7.28 (in, 3H), 7.08 (t, 1H), 6.87 (q, L,1 dichloro-phenyl)-ethoxy]-4 as in 1H), 5.04 (s, 2H), 4.64 (m, 1H), 3.84 (in, 1H), tJ pyrazi n-2-y1)-phenyl)-(4-0.17 Ex ample II-1 j.... ro.i.-rriZ:

3.02 (in, 2H), 2.60 (in, 4H), 2.30 (m, IH), 1.92 pyrrolidin-1-yl-piperidin-1-y1)-(in, IH), 1.81 (in, 6H), 1.69 (m, 2H), 1.62 (m, Uct NH, methanone 2H).

011, (300MHZ, CDCI3) 6 8.06(s, 1H), 7.89 (d, 2H), L.,N..Ø N42-(4-Acetyl-Acetyl-1-y1) 4 as in 7.75 (d, 2H), 7.31 (dt, 2H), 7.11 (t, 1H), 6.91 (q, ethyl]-4-(5-amino-6-[1-(2,6-0.28 Example 11- 1H), 6.78 (m, 1H), 5.12 (s, 2H), 4.25 (t, 1H), dichloro-phenyl)-ethoxyl-169 3.60 (in, 3H), 3.45 (m, 1H), 2.65 (t, 2H), 2.50 pyrazin-2-y1)-benzamide (m, 3H), 2.05(s, 2H),1.85 (d, 3H).

ii- a NH, (300MHZ, CDCI3) 68.16 (s, 1H), 8.03 (s, 1H), Or( N42-(4-Acetyl-piperazin-1-y1) 7.99 (d, 1H), 7.69 (d, 1H), 7.43 (t, 1H), 7.28 (d, [r-- ethyl]-3-{5-amino-6-[1-(2,6-4 as ,in ,. 2H), 7.11 (t, 1H), 6.91 (q, 1H), 6.78 (m, 1H), 0.35 Exam! it-dichloro-phenyl)-etho41-5.12 (s, 2H), 3.65 (m, 411), 3.49 (m, 2H), 2.68 16'9e pyrazin-2-yI)-banzamide (in, 2H), 2.54 (in, 4H), 2.09 (s, 3H), 1.85 (d, 6;lcri';-:

3H).

(3-(5-Amino-G-(1-(2,6-ichIor o- p heny0.et1.0xy i .
(300MHZ, CDCI3) 08.01 (d, 1H), 7.87 (in, 2H), 6 ' 0 c1 4 as in 7.37 (in, 2H), 7.28 (m, 2H), 7.11 (t, 1H), 6.90 pyrazin-2-y1)-phenyl)-((R)-2- 0.33 Example II- (m, 1H), 5.05 (s, 2H), 4.45 (m, 1H), 3.41 (m, pyrrolidin-1-ylmethyl-pyrroli 169 2H), 2.70 (m, 4H), 1.84 (d, 3H), 1.70-2.0 (n, nail Xr, din-1-yI)-methanone 10H) 11.178 &:, 4-----tr-s, (300MHZ, 000I3) 68.48 (m, IH), 8.22 (t, 1H), 3-15-Amino-641-(2,6-8.05 (s, 1H), 7.91 (dt, 1H), 7.66 (d, 1H), 7.40 (t, 4 as in dichloro-pheny1)-ethoxyl-1H), 7.28 (d, 2H), 7.10 (t, 1H), 6.94 (q, IH), 0.34 Example II-pyrazin-2-yll-N-(3-pyrrolidin-5.04 (s, 211), 3.62 (in, 2H), 2.71 (m, 2H), 2.57 1-yl-propyI)-benzamide (in, 4H), 1.84 (d, 3H), 1.83 (m, 2H), 1.81 (m, 4H).

so ro...,N,.,, (345-Amino-641-(2,6- dichloro-phenyl)-ethoxy]-(300MHZ, CD300) 67.83 (m, 3H), 7.48 (m, 4 as in 2H), 7.37 (m, 2H), 7.23 (m, 1H), 6.74 (in, 1H) 0.11 Example 11 -11-179 , pyrazin-2-y1)-phenyl)-((S)-3-' 4.05-3.60 (m, 4H), 3.50 (m, 1H), 2.50 (in, 1H), amino-pyrrolldin-1-yI)-60)1yFH"

2.18 (m, 1H), 1.90 (d, 3H).

methanone HUI

(3-(5-Amino-641-(2,6-I
= dichloro-phenyl)-ethoxy]-(300MHZ, CD30D) 67.83 (m, 3H), 7.48 (m, 4 as in pyrazin-2-y1}-pheny1)-((R)-3-2H), 7.37 (m, 2H), 7.23 (m, 1H), 6.74 (m, 1H), Example 11-180 1 ri, ==== amino-pyrrolidin-1-yI)-4.05-3.60 (in, 41-1), 3,50 (in, III), 2.50 (in, 1H), methanone hydrochloride 2.18 (m, 1H), 1.90 (d, 3H).
Y

11:=r:" salt a ", - No. Structure Name Met 1050 Procedure MS m/z (jW) (M+1) HG! 0 I (3-(5-Amino-641-(2,6-(300MHZ, CDCI3) 6 8.00 (s, 1H), 7.80 (m, 2H), IW L.,N,. dichloro-phenyl)-ethoxy1-4 as In 7.40 (t, 1H), 7.28 (m, 3H), 7.11 (t, 1H), 6.87 (q, pyrazin-2-y1}-phenyl)-(4- 0.25 Example 0- 1H), 5.05 (s, 2H), 4.64 (m, 1H), 3.87 (m, 2H), methyl-piperazin-1-yI)-169 3.45 (m, 2H), 2.53 (m, 2H), 2.36 (m, 1H), 2.34 itil 0;%N

Air 0 NH, methanone (s, 3H), 1.84 (d, 3H).

_ H r"---1-(4-(5-Amino-6-[1-(2-chloro-(300MHZ, CDCI3) 57.93 (s, 11-1), 7.68 (d, 2H), 10 as in 40 3,6-difluoro-pheny1)-ethoxyl-7.38 (s, 2H), 6.95 (m, 4H), 6.70 (q, 1H), 4.94 (s, 3,1 0.18 Example 1-pyrazin-2-y1}-phenyl)-3-(2-2H), 3.75 (m, 4H), 3.46 (m, 2H), 2.69 (m, 4H), ' :cH

morpholin-4-yl-ethyl)-urea 2.25 (m, 2H), 1.85 (d, 3H).

ClC

, QVC) H )40 (R)-2-Pyrrolidin-1-ylmethyl-(300MHZ, 00013) 57.83 (s, 1H), 7.40 (d, 2H), pyrrolidine-1-carboxylic acid 10 as in 7.27 (d, 2H), 6.95 (m, 3H), 5.95 (q, 1H), 4.85 (s, 11-183 (4-(5-amino-6-[1-(2-chloro- 0.21 Example 1- 2H), 3.85 (m, 1H), 3.75 (m, 1H), 3.40 (m, 1H), 3,6-difluoro-phenyl)-ethoxyl-371 2.90 (m, 4H), 2.65 (m, 4H), 2.10 (m, 3H), 1.85 pyrazin-2-y1}-phenyl)-amide (d, 3H), 1.9-1.7 (m, 3H).

o'cN

40 a NI-6 F

1 ..........,0 li.:1 ti (300MHZ, CDCI3) 57.91 (s, 1H), 7.80(bs, 1H), 1-(4-(5-Amino-841-(2-chloro-10 as in 7.69 (d, 2H), 7.46 (d, 2H), 7.35 (bm, 1H), 7.05 3,6-difluoro-phenyl)-ethoxy]-11.-184 0.18 Example 1-(m, 2H), 6.72 (q, 1H), 4.86 (s, 2H), 3.58 (m, pyrazin-2-y1}-phenyl)-3-(2-c.
371 2H), 3.19 (m, 4H), 3.12 (m, 2H), 2.16 (m, 4H), pyrrolidin-1-yl-ethyl)-urea õH.
2.51 (s, 3H), 1.81 (d, 3H).

HAN, "Th 4-Methyl-piperazine-1-(300MHZ, CDCI3) 57.95 (s, 1H), 7.69 (d, 2H), carboxylic acid (4.45-amino-10 as in WI
.39 (d, 2H), 7.01-6.91 (m, 2H), 6.70 (m, 2H)' 11-185 6-(1-(2-chloro-3 0.1 5037,6-difluoro-Example 1- 4.90 (s, 2H), 3.61 (m, 4H), 2.58 (m, 4H), 2.41 F 2.1.1:-.. N l (s, 3H), 1.81 (d, 3H).
phenyl)-amide i 6 0 NH
411.12-.P. CI

c HN1r",....AH

1-(4-(5-Amino-611 -(2-chloro-10 as in (300MHZ, 00013) 6 7.78 (z, 1H), 7.60 (d, 2H), 40 3,6-difluoro-pheny1)-ethoxy]-0.21 Example I- 7.35 (d, 2H), 7.15 (m, 4H), 6.55 (q, 1H), 4.86 pyrazin-2-y1)-phenyl)-3-(2-371 (s, 2H), 3.64 (t, 2H), 3.31 (t, 3H), 1.82 (d, 3H).
,c-N hydroxy-ethyl)-urea * ci NH, F

' "13--NH2 (S)-3-Amino-pyrrolidine-1-(300MHZ, CDCI3) 57.71 (s, 1H), 7.65 (d, 2H), carboxylic acid (4-{5-amino-10 as in 7.53 (d, 2H), 7.15 (m, 3H), 6.77 (m, 1H), 4.87 IP

(2-chloro-3,6-difluoro- 0.082 Example I-(s, 2H), 3.95 (m, 1H), 3.80 (m, 1H), 3.65 (m, phenyl)-ethoxy]-pyrazin-2-y1}-371 2H), 3.31 (m, 2H), 2.57 (m, 1H), 2.20 (m, 1H), 1.'r ' ni phenyl)-amIde 1.95 (d, 3H).

F

HAP' 1-(4-(5-Amino-611-(2-chloro-10 as In 40 3,6-difluoro-phenyl)-ethoxy l-0.054 Example I-pyrazin-2-y1)-phenyl)-341-(1 0.1..TN methyl-piperidin-4-y1)-urea CICIC: NH=

F

' -No. Structure Name Met IC50 Procedure MS m/z ' (M+1) _ (PM) HNIN..,.1 µ,. i.,,N, 4-Methyl-piperazine-1-(300MHZ, CDCI3) 07.94 (s, 1H), 7.66 (d, 2H), carboxylic acid (4-{5-amino- 10 as in WP
7.37 (d, 2H), 7.24 (m, 1H), 6.95 (t, 1H), 6.81 (m' 11-189 641-(2,6-dichloro-3-fluoro-0.074 Example I- 2H), 4.95 (s, 2H), 3.68 (m, 4H), 2.73 (m, 4H), I til .', phenyl)-ethoxy]-pyrazin-2-y1)-2.51 (s, 3H), 1.83 (d, 3H).
ni& el- phenyl)-amide Lip-P ci NH, F

me11,4,,,,CH

1-(4-(5-Amino-641-(2,6-INI
10 as in (300MHZ, CDCI3) 07.84 (s, 1H), 7.60 (m, 4H), dichloro-3-fluoro-phenyl)-11-190 ethoxyl-pyrazin-2-y1}-phenyl)- 0.28 Example I- 7.33 (m, 3H), 7.15 (m, 1H), 6.70 (q, 1H), 4.86 i I **--_.
371 (s, 2H), 3.64 (t, 2H), 3.31 (m, 3H), 1.82 (d, 3H).
iii ey-N 3-(2-hydroxy-ethyl)-urea ir ci NH, NI
(S)-3-Amino-pyrrolidine-1-carboxylic acid (4-{5-amino- 10 as in MCI
11-191 641-(2,6-dichloro-3-fluoro- 3 Example I-phenyl)-ethoxy]-pyrazin-2-y1)- 371 phenyl)-amide , -0- 1-(4-(5-Amino-641 -(2,6-dichloro-3-fluoro-phenyI)- 10 as in 11-192 ethoxyl-pyrazin-2-y1}-phenyl)- 0.052 Example 1-3-(1-methyl-plperidin-4-y1)- 371 Y, urea F

OH

545-Amino-6-(2-chloro-3,6-N.. s 3 as in difluoro-benzyloxy)-pyrazin-2.

Example I-yI]-thiophene-2-carboxylic acid rai o^y-N

F

: NO.4¨

',. s (545-Amino-6-(2-chloro-3,6-(300MHZ, CDCI3) 6 8.01 (s, 1H), 7.35 (s, 1H), 4 as in difluoro-benzyloxy)-pyrszin-2 0.62 Example II 7.27 (s, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 5.63 yI]-thiophen-2-y1)-(4-methyl-- (s, 1H), 4.87 (m, 1H), 3.80 (m, 4H), 2.48 (m, so piperazin-1-yI)-methanone 4H), 2.34 (s, 3H).

o )YI,4 NH, - F
o {545-Amino-6-(2-chloro-3,6-(300MHZ, CDCI3) 08.01 (s, 1H), 7.35 (d, 1H), ,.....\--difluoro-benzyloxy)-pyrazin-2. 4 as in 7.24 (d, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 5.63 11-195yI]-thiophen-2-y1)-(4-0.51 Example II- (s, 2H), 4.88 (m, 2H), 4.42 (m, 4H), 3.05 (t, 4H), Ø1:" pyrrolidin-1-yl-piperidin-1-y1)-194 2.63 (m, 2H), 2.35 (m, 1H), 2.00 (m, 2H), 1.82 NH, methanone (m, 2H), 1.60 (m, 2H).

F

0 ist NH

{545-Amino-6-(2-chloro-3,6-(300MHZ, CDCI3) 08.01 (s, 1H), 7.35 (d, 1H), difluoro-benzylory)-pyrazin-2. 4 as in 7.24 (d, 1H), 7.07 (m, 1H), 7.01 (m, 1H), 5.63 11-196 5-\-- y11-thlophen-2-y1)-((3R,53)- 0.55 Example II-N
(s, 2H), 4.88 (m, 2H), 4.35 (m, 2H), 2.93 (m, 3,5-dimethyl-piperazin-1-y1)- 194 0-'1%."
2H), 2.60 (m, 2H), 1.10 (d, 6H).
methanone 101 NH., CI

F
_ _ o (545-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2. 4 as in (300MHZ, CDCI3) 08.03 (s, 1H), 7.52 (d, 1H), .... s ylj-thlophen-2-y1)-((R)-2-0.8 Example II- 7.38 (d, 1H), 7.07 (m, 1H), 7.01 (m, 111), 5.63 pyrrolidin-1-ylmethyl- 194 (s, 2H), 4.88 (m, 2H), 4.5-0.60 (m, 17H).

pyrrolidin-1-yI)-methanone :1;m 6 o ' -411112.r. CI

F

.

No. Structure Name Met 1050 Procedure 1H-NMR MS m/z (AM) (M+1) d5-111ro5u-oArn.lbneioiy (300MHZ, CDCI3) 58.03 (s, 1H), 7.45 (d, 1H), Ixy )-py 4 as in 7.38 (d, 1H), 7.20 (m, 1H), 7.05 (m, 1H), 6.58 11-198 yl1-thiophene-2-carboxylic 0.7 Example 11- 510 (m, i .H), 5.65 (s, 2H), 4.89 (m, 2H), 3.75 (m, acid (2-morpholin-4-yl-ethyl)- 194 411), 3.55 (m, 2H), 2.61 (m, 2H), 2.50 (m, 4H) o..cN amide qr.- ci NH, r'N' 0 N.,..) X. 341-(2,6-dichloro-3-(DMSO-d6+TFA /300 MHz) 88.64 (s, 1H), 8.29 fluorophenyl)ethoxy]-5-{5-[(4-4 as in (s, 111), 7.96 (d, 1H), 7.81 (d, 1H), 7.51 (m, 1H), 11-199 ' 1 methylpiperazin-1- 0.15 Example 11- 7.35 (m, 1H), 6.63 (q, 1H), 4.69-4.25 (m, 1H), 505 F dui elyN yl)carbonyl]pyridin-2-194 4.08-3.69 (m, 1H), 3.58-3.01 (m, 6H), 2.82 (s, 4111IJI1 a NH. yl}pyrazin-2-amine 3H), 1.84 (d, 311).
trifluoroacetate ovk .
H

F = N 341-(2,6-Dichloro-3-fluoro-11-200iikk 01-)----I'L phenyl)-ethoxy]-5-pyridin-4- 0.045 3 u I I I IP a NH, yl-pyrazin-2-ylamine F
OyT<F

OH

H

F rii; 0; 341-(2,6-Dichloro-3-fluoro-11-201 phenyl)-5-(1H-pyrrol- 0.22 lir a 14= 2-yI)-pyrazin-2-ylamine F

OH

I ::N (6-(5-Amino-641-(2,6-dichloro-3-fluoro-phenyI)- 16 as in 11-202 ri -, ethoxyj-pyrazin-2-0)-pyridin- 0.15 Example I- 505 F du 0,1:101 3-y1)-(4-methyl-piperazin-1-WI a M-6 yI)-methanone F

OlikF p OH

--NCjiji (245-Amino-641 -(2,6- (DMSO-d6+TFA /300 MHz) 8 8.68 (d, 1H), 8.34 I I'ji dichloro-3-fluoro-phenyl)- 16 as in (s, 111), 7.62 (s, 1H), 7.52-7.27 (m, 311), 6.57 (q, 505 11-203 F Ca 0'Th.'"N ethoxA-pyrazin-2-y1)-pyridin- 0.18 Example 1-ql-P CI NH2 4-yI)-(4-methyl-piperazin-1- 488 1H), 4.66 (m, 1H), 3.70-2.91 (m, 7H), 2.86 (s, 3H), 1.82 (d, 3H).
yI)-methanone F
01,5<F

H

*1)L (6-(5-Amino-641 -(26- (DMSO-d6+TFA /300 MHz) 8 8.24 (s, 1H), 7.96 dichloro-3-fluoro-phenyl)- 16 as in (dd, 1H), 7.79 (d, 11-1), 7.53 (m, 2H), 7.35 (dd, 11-204 r`6'..)",1:: ethoxyl-pyrazin-2-yI)-pyridin- 0.22 Example 1- 1H), 6.61 (q, 1H), 4.60 (br, 1H), 4.12 (br, 1H), 505 2-yI)-(4-methyl-piperazin-1- 488 3.61-3.30 (m, 3H), 3.24-3.04 (m, 3H), 2.83 (s, yI)-methanone 3H), 1.84 (d, 3H).

1' No.
Structure Name Met 1C50 Procedure MS m/z (11M) (M+1) ,...-, -kJ' 1 '',,.
(5-(5-Amino-641-(2,6-(DMSO-d6+TFA /300 MHz) 89.07 (s, 1H), 8.77 dichloro-3-fluoro-phenyI)-16 as in (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.53 (br, 1H), F,A,LojyN
ethml-pyrazin-2-y1}-pyridin-0.1 Example I- 7.44 (m, 1H), 7.32 (m, 11-), 6.58 (q, 1H), 4.63 u.....04,c, NH, 3-yI)-(4-methyl-piperazin-1-(br, 111), 3.74 (br, 1H), 3.61-3.15 (m, 4H), 3.06 yI)-methanone (m, 2H), 2.83 (s, 3H), 1.81 (d, 3H).
OH

(4-(5-Amino-641-(2,6-(DMSO-d6+TFA /300 MHz) 8 8.63 (d, 1H), 8.39 dichloro-3-fluoro-phenyl)-16 as in (s, 111), 8.01 (s, 1H), 7.93 (d, 1H), 7.43 (m, IH), -..

F.iaj: 0 ,t:
ethoxyl-pyrazin-2-y1}-pyridin-0.1 Example I- 7.28 (dd, 1H), 6.58 (q, 1H), 4.63 (m, 1H), 3.92 2-yI)-(4-methyl-piperazin-1-(m, 1H), 3.64-3.13 (m, 4H), 3.11-2.96 (m, 2H), yI)-methanone 2.84 (s, 3H), 1.81 (d, 311).
OH
Oi xlrl' 0 6-(5-Amino-641-(2,6-(DMSO-d6+TFA /300 MHz) 8 9.76 (br, 1H), dichloro-3-fluoro-phenyl)-16 as in 8.96 (m, 2H), 8.37 (s, 1H), 8.26 (d, 1H), 7.80 (d, ethoxyl-pyrazin-2-y1}-N-(2-Example- 1H), 7.51 (m, 1H), 7.37 (dd, 1H), 6.61 (q, 1H), morpholin-4-yl-ethyl)-4.00 (d, 2H), 3.74-3.50 (m, 6H), 3.34 (m, 2H), nicotinamide 3.16 (m, 2H), 1.83 (d, 3H).
...gie, ?...........r''-----p 545-Amino-641-(2,6-(DMSO-d6+TFA /300 MHz) 8 9.16 (m, 1H), dichloro-3-fluoro-phenyl)-16 as in 9.09 (s, 1H), 9.03 (s, 1H), 8.83 (s, 1H), 8.28 (s, ,...J.,....71._,, ethoxy]-pyrazin-2-y1)-N-(2-0.038 Example I- 1H), 7.47 (m, 1H), 7.32 (dd, 1H), 6.66 (q, 1H), ....,-.1.....
T., morpholin-4-yl-ethyl)-4.00 (d, 211), 3.77-3.50 (m, 6H), 3.35 (m, 211), nicotinamide 3.16 (m, 2H), 1.83 (d, 3H).
0,)4 6.
(DMSO-d6+TFA /300 MHz) 8 9.74 (br, IH), 6-{5-Amino-641-(2,6-8.97 (s, 1H), 8.84 (m, IH), 8.36 (s, 1H), 8.26 (d, dichloro-3-fluoro-phenyl)-16 as in Z.,,cli.õ
ethoxyl-pyrazin-2-y1)-N-(3-Example I-1H), 7.79 (d, 1H), 7.50 (m, IH), 7.37 (dd, 1H), O, morpholin-4-yl-propyI)-6.61 (q, 1H), 3.97 (d, 2H), 3.64 (t, 2H), 3.50-0.,,,.1....
,.
3.30 (m, 4H), 3.23-2.98 (m, 4H), 1.92 (m, 2H), nicotinamide 1.83 (d, 3H).
5-(5-Amino-641-(2,6-(DMSO-d6+TFA /300 MHz) 8 9.88 (br, 1H), F
C
II

dichloro-3-fluoro-pheny1)-16 as in 8.86 (s, 1H), 8.30 (s, 1H), 7.68-7.40 (m, 2H), l'''Cr.
ethoxy]-pyrazin-2-y1)-N-(3-0.022 Example 1- 7.32 (m, 1H), 6.67 (q, 1H), 3.97 (d, 2H), 3.66 (t, morpholin-4-yl-propyI)-2H), 3.43 (m, 411), 3.25-2.97 (m, 4H), 1.96 (br, nicotinamide 2H), 1.83 (d, 3H).
OH
*60-<
(645-Amino-641-(2,6-(DMSO-d6+TFA /300 MHz) 8 9.70 (br, 1H), dichloro-3-fluoro-phenyl)-16 as in 8.65 (s, 1H), 8.38 (s, 111), 7.95 (d, 111), 7.80 (d, 11-211 F,ext.....kr-S
ethoxy1-pyrazin-2-yll-pyridin-Example 1- 1H), 7.53 (m, 1H) 7.39 (dd, 1H), 6.62 (q, 1H), NH, 3-y1)-(4-isopropyl-piperazin-1.

4.57 (br, 1H), 3.85 (br, 1H), 3.60-3.05 (m, 7H), yI)-methanone 1.83 (d, 3H), 1.26 (d, 6H).
..?:,F

Table 5 Section A: Examples L-1 to L-16 .; Co) ,...,N C") ,..)N

HN
HN.1-HNC
HNI

el 0 ... N', ,..." 1 N..: I
H2N -,.. ' = H2N

=
=
0 so CI
o C ail ci C I a& CI
F
F
F 44112"

% inhIbltion=58 % inhibition=59 % inhibition=63 % inhibitlon=47 ,yIH
t::H

HNx HN) HNfC

HNI

N" , 4 40 0 N-- =, 4111 H] --, ' --.. I --... ' p N' ' 1-12N H2N

I =
-,.
= =

CI 4.6 CI a CI so CI CI)Ir.CI
, F 41111"' F F

F

% inhibition=68 % inhibition=69 % Inhlbition=66 % InhIbitIon=72 p--N: 1 HN) HN
HN HN"' rib o iii o a 0 iii 0 N,,, I N.,, I ..w.....
Iti I ..-.49".
I
1-12N H,FI
H,N
H2N =
= ' =
- =

CI CI ei 40 a 01 40 01 ci 40 CI

% inhibition=64 % inhibition=67 % Inhibition=67 % inhibilion=52 r5H

* *
(0 ;
HN"' HN
HN
HN) 6, 0 N' le N" , 411 N"

---. I -...

.11211 -... ' =
= =
=

CI 40 a a 40 a 0, 40 CI

F F
F
F

% inhIbitIon=76 % inhlbition=72 % InhIbItion=67 % Inhibition=83 Section B: Examples L-17 to L-32 e =

Cf4 HN HN
N
FIN OH

. 0 isi 0 is 0 N' 4P
N- i N" 1 ...... I
N ' I
,.., ' ,.. ' -.. ' * =
=
=

Cl 40 Cl 011,01 Cl 40 Cl a 40 a F F
F
F

%Inhibition=76 % inhibitlon=66 %InhIbillon=84 %
inhibition=69 =H
OyNFI2 Ito 0, 1,-,r0H
Oy-r-NH

HIµrj HNs"k".2 HN) ib o FIN
ip 0 N" 1 00 0 N' I

-.... ' N-H2N N"
H2N ''' , I
,. I
ci 40 01 0 H2N .
ci di 0 0 H2N =
0 1..õ CI
ci ab, ci F
F lir F 41gPi'' % inhibition=86 %Inhibition=94 % inhibition.--72 %
inhibition=71 _ N.õ

a HNI N
HN
N

iik o op --o is 0 N-- i N." I
*
, I
N --... ' H2N '''' = =
= H2N 'I" .
=

CI rai CI CI rik CI
CI 16,1 CI
ci ao a F "IV F 411"
F '111"
F

% inhibition=77 % inhibition=92 % inhibltion=74 ,^:3 inhibition=64 _ 5!
9\1õ./ 1,-õr0H
nil' 4- ...-N----['NJ HN

dm o lip 0 N- 1 101 0 NI, So 0 N ' 'III N ' 1 ".114'.
--. I
,.. I
-,, .... ' H2N

H 2N = 2 =

o a Cl ci a ai CI
CI 40 ci a 40 ci F lir F 411111;r F F

% Inhibition=l36 % intibltlon=80 % inhibltion=85 %Inhibition=92 DEMANDES OU BREVETS VOLUMINEUX

LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.

JUMBO APPLICATIONS / PATENTS

THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional volumes please contact the Canadian Patent Office.

Claims (35)

CLAIMS:
1. A compound of formula 1 wherein:
Y is N or CR12;
R1 is selected from C6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heteroalicyclic; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R2 is hydrogen;
R3 is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)n OR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)n R4, -NR4C(O)R5, -(CR6R7)n C(O)OR4, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(0)NR4R5, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R8 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S;
or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally substituted by one or more R8 groups;
each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic) or -O-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
A1 is -(CR9R10)n-A2 except that:
(i) when Y is N and R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, A1 is -(CR9R10)n-A2 and n is not zero; and (ii) when Y is N and R2 is H and A1 is m-chlorobenzyl, R1 is not unsubstituted piperazine;
each R9 and R10 is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)n OR4, -CN, -C(O)R4, -0C(O)R4, -NR4C(O)R5, -(CR6R7)n C(O)OR4, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(O)NR4R5; R9 and R10 may combine to form a C3-12 cycloalkyl or 3-12 membered heteroalicyclic; and each hydrogen in R9 and R10 is optionally substituted by one or more R3 groups;

A2 is C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups;
each R11 is independently halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic), -O-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -0-C1-12 alkyl which may be partially or fully halogenated, -CO, -SO
and -SO2;
R12 is hydrogen;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
2. The compound of claim 1, wherein Y is N, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
3. The compound of claim 1, wherein Y is CR12, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
4. The compound of claim 1, wherein the compound has formula 1a wherein A2 is C6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
5. The compound of claim 4, wherein R1 is selected from C6-12 aryl and 5-12 membered heteroaryl, and each hydrogen in R1 is optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
6. The compound of claim 4, wherein A2 is substituted by at least one halogen atom, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
7. The compound of claim 4, wherein R9 and R1 are independently C1-4 alkyl, and A2 is phenyl substituted by at least one halogen atom, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
8. The compound of claim 1, wherein R1 is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
9. A compound of formula 2 wherein:
R1 is selected from C6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heteroalicyclic; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R2 is hydrogen;
R3 is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R5, -S(O)2OR4, -NO2,-NR4R5, -(CR6R7)n OR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)n R4, -NR4C(0)R5, -(CR6R7)n C(O)OR4, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(O)NR4R5, each hydrogen in R3 is optionally substituted by one or more R5 groups, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S;
or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally substituted by one or more R8 groups;
each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic) or -O-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
A1 is -(CR9R10)n-A2;
each R9 and R10 is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)n OR4, -CN, -C(O)R4, -OC(O)R4, -NR4C(O)R5, -(CR6R7)n C(O)OR4, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(O)NR4R5; R9 and R10 may combine to form a C3-12 cycloalkyl or 3-12 membered heteroalicyclic; and each hydrogen in R9 and R10 is optionally substituted by one or more R3 groups;
A2 is C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups;
each R11 is independently halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic), -O-(CH2),(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -0-C1-12 alkyl which may be partially or fully halogenated, -CO, -SO and -SO2;
R12 is hydrogen;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
10. The compound of claim 9, wherein the compound has formula 2a wherein A2 is C6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
11. The compound of claim 10, wherein R1 is selected from C6-12 aryl and 5-12 membered heteroaryl, and each hydrogen in R1 is optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
12. The compound of claim 10, wherein A2 is substituted by at least one halogen atom, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
13. The compound of claim 10, wherein R9 and R10 are independently C1-4 alkyl, and A2 is phenyl substituted by at least one halogen atom, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
14. The compound of claim 9, wherein R1 is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group, and each hydrogen in R1 is optionally substituted by one or more groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
15. A compound of formula 3 wherein:
R1 is selected from C6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heteroalicyclic; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R2 is hydrogen;
R3 is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R6, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)n OR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)n R4, -NR4C(O)R6, -(CR6R7)n C(O)OR4, -C(=NR6)NR4R6, -NR4C(O)NR6R6, -NR4S(O)p R6 or -C(0)NR4R6, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R6, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R6, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S;
or any two of R4, R6, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R6, R6 and R7 is optionally substituted by one or more R8 groups;
each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic) or -O-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
A1 is -(CR9R10)n-A2 except that:
(i) when R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, A1 is -(CR9R19)n-A2 and n is not zero; and (ii) when R2 is H and A1 is m-chlorobenzyl, R1 is not unsubstituted piperazine;
each R9 and R10 is independently hydrogen, halogen, C1-12 alkyl, C3-2 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R6, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)n OR4, -CN, -C(0)R4, -OC(O)R4, -NR4C(O)R5, -(CR6R7),C(O)OR4, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(O)NR4R5; R9 and R10 may combine to form a C3-12 cycloalkyl, or 3-12 membered heteroalicyclic; and each hydrogen in R9 and R19 is optionally substituted by one or more R3 groups;
A2 is C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups;
each R11 is independently halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic), -O-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -0-C1_12 alkyl which may be partially or fully halogenated, -CO, -SO
and -SO2;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
16. The compound of claim 15, wherein the compound has formula 3a wherein A2 is C6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
17. The compound of claim 16, wherein R1 is selected from C6-12 aryl and 5-12 membered heteroaryl, and each hydrogen in R1 is optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
18. The compound of claim 16, wherein A2 is substituted by at least one halogen atom, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
19. The compound of claim 16, wherein R9 and R19 are independently C1-4 alkyl, and A2 is phenyl substituted by at least one halogen atom, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
20. The compound of claim 15, wherein R1 is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group, and each hydrogen in R1 is optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
21. A compound of formula 4 wherein:

R1 is selected from C6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heteroalicyclic; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R3 is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6.12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(0)mR4, -SO2NR4R5, -S(O)2OR4, -NO2,-NR4R5, -(CR6R7)n OR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)n R4, -NR4C(O)R5, -(CR6R7)n C(O)OR4, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(O)NR4R5, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S;
or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally substituted by one or more R8 groups;
each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -O-C1-12 alkyl, -O-(CH2)C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic) or -O-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
each R9 and R13 is independently hydrogen, halogen, C1-12 alkyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)OR4, -CN, -C(O)R4, -OC(O)R4, -NR4C(O)R5, -(CR6R7)C(O)OR4, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(0)NR4R5; R9 and R10 may combine to form a C3-12 cycloalkyl or 3-12 membered heteroalicyclic; and each hydrogen in R9 and R10 is optionally substituted by one or more R3 groups;
A2 is C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups;
each R11 is independently halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic), -O-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -O-C1.12 alkyl which may be partially or fully halogenated, -CO, -SO
and -SO2;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
22. The compound of claim 21, wherein A2 is C6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
23. A compound of formula 5 wherein:
R1 is selected from C6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heteroalicyclic; and each hydrogen in R1 is optionally substituted by one or more R3 groups;
R3 is halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R5, -S(O)2OR4, -NO2, -NR4R5, -(CR6R7)n OR4, -CN, -C(O)R4, -OC(O)R4, -O(CR6R7)nR4, -NR4C(O)R5, -(CR6R7)n C(0)0R4, -C(=NR6)NR4R5, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(O)NR4R5, each hydrogen in R3 is optionally substituted by one or more R8 groups, and R3 groups on adjacent atoms may combine to form a C6-12 aryl, 5-12 membered heteroaryl, C3..12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R4, R5, R6 and R7 is independently hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R4, R5, R6 and R7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S, or any two of R4, R5, R6 and R7 bound to the same carbon atom may be combined to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R4, R5, R6 and R7 is optionally substituted by one or more R8 groups;

each R8 is independently halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -CN, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2),(3-12 membered heteroalicyclic) or -O-(CH2)n(5-12 membered heteroaryl); and each hydrogen in R8 is optionally substituted by one or more R11 groups;
each R9 and R10 is independently hydrogen, halogen, C1-12 alkyl, C3.12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S(O)m R4, -SO2NR4R5, -S(O)20R4, -NO2,-NR4R5, -(CR6R7)n OR4, -CN, -C(O)R4, -OC(O)R4, -NR4C(O)R5, -(CR6R7)n C(O)OR4, -NR4C(O)NR5R6, -NR4S(O)p R5 or -C(O)NR4R5; R9 and R19 may combine to form a C3-12, cycloalkyl or 3-12 membered heteroalicyclic; and each hydrogen in R9 and R19 is optionally substituted by one or more R3 groups;
A2 is C6-12 aryl, 5-12 membered heteroaryl, C3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A2 is optionally substituted by one or more R3 groups; except that when R2, R9 and R19 are all H and A2 is m-chlorophenyl, R1 is not unsubstituted piperazine;
each R11 is independently halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -O-C1-12 alkyl, -O-(CH2)n C3-12 cycloalkyl, -O-(CH2)n C6-12 aryl, -O-(CH2)n(3-12 membered heteroalicyclic), -O-(CH2)n(5-12 membered heteroaryl) or -CN, and each hydrogen in R11 is optionally substituted by one or more groups selected from halogen, -OH, -CN, -C1-12 alkyl which may be partially or fully halogenated, -O-C1-12 alkyl which may be partially or fully halogenated, -CO, -SO
and -SO2;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and p is 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
24. The compound of claim 23, wherein A2 is C6_12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R3 groups, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
25. A compound selected from the group consisting of: 446-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol; 3-(2,6-dichloro-benzyloxy)-5[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(1H-indo1-4-yl)-pyridin-2-ylamine; 3-[2-chloro-6-(1H-indo1-4-yl)-benzyloxy]-5-(1H-indol-4-yl)-pyridin-2-ylamine; 2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pyrrole-1-carboxylic acid tert-butyl ester; 3-(2,6-dichloro-benzyloxy)-5-(1H-pyrrol-2-yl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(4-fluoro-phenyl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(2-fluoro-phenyl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-fluoro-phenyl)-pyridin-2-ylamine; 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine;
N-{4[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide;
N-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-acetamide; 3-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol; 3-(2,6-dichloro-benzyloxy)-5-(4-methoxy-phenyl)-pyridin-2-ylamine; 5-(3-amino-phenyI)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-trifluoromethoxy-phenyl)-pyridin-2-ylamine; 246-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol; 3-(2,6-dichloro-benzyloxy)-5-(2-phenoxy-phenyl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-(3,4-difluoro-phenyl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-isopropyl-phenyl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(2-methoxy-phenyl)-pyridin-2-ylamine;
3-(2,6-dichloro-benzyloxy)-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine; N-{2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl-phenyl}-methanesulfonamide; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenylymethanol; 5-benzo[1,3]dioxol-5-y1-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(2-trifluoromethoxy-phenyl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(4-methyl-thiophen-2-yl)-pyridin-2-ylamine; 5-(2-benzyloxy-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-methoxy-phenyl)-pyridin-2-ylamine;
3-(2,6-dichloro-benzyloxy)-5-(1H-indol-2-yl)-pyridin-2-ylamine; 5-(4-benzyloxy-fluoro-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine; 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid; 416-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-diethylamino-ethyl)-benzamide; 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(3-diethylamino-propyl)-benzamide; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;
{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;
{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pheny1}-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pheny1}-[(3R)-3-dimethylamino-pyrrolidin-1 -yl]-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-cyclopropylaminomethyl-piperidin-1-yl]-methanone; 416-amino-5-(216-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-(3-fluoro-piperidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-cyclopropyl-piperazin-1-yl)-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-{(2R)-2-[(cyclopropylmethyl-amino)-methyl]-pyrrolidin-1-yl}-methanone, 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-cyclopropylmethyl-N-(2R)-pyrrolidin-2-ylmethyl-benzamide; 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propy1)-N-methyl-benzamide; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-{(2S)-R3R)-3-hydroxy-pyrrolidin-1-ylmethyl]-pyrrolidin-1-yl}-methanone, 3-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid; {3-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2 R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-acetic acid;
2-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone; 2-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl}-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone; 3-(2,6-dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;
3-(2,6-dichloro-benzyloxy)-5-(3-piperidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;
3-(2,6-dichloro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;
3-(2,6-dichloro-benzyloxy)-5-(3-diethylaminomethyl-1H-indol-5-yl)-pyridin-2-ylamine;
(1-{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3R)-pyrrolidin-3-yl)-carbamic acid tert-butyl ester; 3-(2,6-dichloro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyridin-2-ylamine; N-(1-{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3R)-pyrrolidin-3-yl)-acetamide; 1-(4-{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-ylmethyl}-piperazin-1-yl)-ethanone; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine; 1-(4-{5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-piperazin-1-yl)-ethanone; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyridin-2-ylamine, N-(1-{5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3S)-pyrrolidin-3-yl)-acetamide; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-piperidin-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine; 5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylic acid ethyl ester; 516-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylic acid; {5-[6-amino-5-(216-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-(4-methyl-piperazin-1-yl)-methanone; {516-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; 5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide; 5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; (1-{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carbonyl}--(3S)-pyrrolidin-3-yl)-carbamic acid tert-butyl ester; {5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone; 5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl1-1H-indole-2-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide; 4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenol; 3-benzyloxy-5-phenyl-pyridin-2-ylamine; 3-(3-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine;
3-(2-chloro-4-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-benzyloxy)-phenyl-pyridin-2-ylamine; 3-(2,5-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-5-trifluoromethyl-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2,4-dichloro-5-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-3-trifluoromethyl-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-316-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(3,4-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 2-(2-amino-5-phenyl-pyridin-3-yloxymethyl)-benzonitrile; 3-(2-chloro-6-fluoro-3-methyl-benzyloxy)-5-phenyl-pyridin-2-ylamine; 5-Phenyl-3-(2,3,6-trifluoro-benzyloxy)-pyridin-2-ylamine; 3-(2,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2,6-difluoro-3-methyl-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(3-chloro-2,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine; 3-(2-chloro-6-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine;
3-(3-Fluoro-4-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine; N43-(2-amino-5-phenyl-pyridin-3-yloxymethyl)-phenyl]-methanesulfonamide; 5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-nitro-benzyloxy)-pyridin-2-ylamine; 5-[4-(2-morpholin-4-yl-ethoxy)-phenyl1-3-(naphthalen-1-ylmethoxy)-pyridin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine, amino-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-yloxy}-N-(4-isopropyl-phenyl)--2-phenyl-acetamide; 3-(5-chloro-benzo[b]thiophen-3-ylmethoxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; {4-6-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y1]-pheny1}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(5-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; (4-{6-amino-5-[ 1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-bromo-benzyloxy)-pyridin-3-yl}-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; 446-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenol; 3-(2,6-difluoro-benzyloxy)-5-(1H-indo1-4-yl)-pyridin-2-ylamine;
342,6-difluoro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;

amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-acetic acid ethyl ester;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-acetic acid; 2-{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone; 2-{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone; 446-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenol; 4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenol; 446-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenol; 212-amino-5-(4-hydroxy-phenyl)-pyridin-3-yloxymethyl]-benzonitrile; 446-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenol; 446-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenol; 416-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenol; N-{4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide; 2-[2-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzamide; 2-[2-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzoic acid; N-(4-{6-amino-5-[2-(4-methyl-piperazine-1-carbonyl)-benzyloxy]-pyridin-3-yl}-phenyl)-methanesulfonamide; 2-[4-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-N-(2-hydroxy-ethyl)-benzamide; 2-[4-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-N-isobutyl-benzamide; 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid; {4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; 1-(4-{4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone; 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide; 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoic acid; {4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone;
{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; {4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; 1-(4-{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone; 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide; 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid; 2-{2-amino-5-[4-((2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethylybenzonitrile; 2-{2-amino-5444(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile;

amino-5-[4(3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile; 2-{2-amino-5-[4-(3S)-3-amino-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile; 2-{2-amino-514-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethylybenzonitrile; 2-{2-amino-5-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile; 2-{5-[4-(4-acetyl-piperazine-1-carbonylyphenyl]-2-amino-pyridin-3-yloxymethylybenzonitrile; 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;
4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;
4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl-N-(3-morpholin-4-yl-propyl)-benzamide; 4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid;
{4-[6-amino-5-(2 ,4-dichloro-benzyloxy)-pyridin-3-A-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone, {4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yI]-methanone; {4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-amino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; {4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; 1-(4-{4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone; 4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; 4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide; 4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoic acid; {4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yI]-methanone; {4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; [(3S)-3-amino-pyrrolidin-1-yI]-{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-methanone; {4[-6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; {4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; 1-(4-{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone; 4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide; 4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;
4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide; 4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoic acid;
{4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; 1-(4-{4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone; 4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide; 4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-y(-ethyl)-benzamide; 4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide; 4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid; {4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; 1-(4-{4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3yl]-benzoyl}-piperazin-1-yl)-ethanone; 4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-A-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-A-N-(3-morpholin-4-yl-propyl)-benzamide;
4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)-(4-methyl-piperazin-1-yl)-methanone; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)-(4-amino-piperidin-1-yl)-methanone; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone; {4-[6-amino-5-(2-chIoro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone; {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone; 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide; 4-[6-amino-5-(2-chIoro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 416-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;
3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; {3-[6-amino-5-(2-chIoro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-amino-piperidin-1-yl)-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone; {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-amino-pyrrolidin-1-yl]-methanone; 3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide; 3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl)-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; 3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;
N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzamide; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-1.lambda.6-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-[4-(1,1-dioxo-1.lambda.6-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine; 5-[4-(1,1-dioxo-1.lambda.6-isothiazolidin-2-yl)-phenyl]-3-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-2-ylamine;
2-diethylamino-ethanesulfonic acid {4-[6-amino-5-(2-chIoro-3,6-difluoro-benzyloxy)-pyridin-3-yl-phenyl}-amide; 2-cyclopropylamino-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-Pyrrolidin-1-yl-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-(4-hydroxy-piperidin-1-yl)-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-morpholin-4-yl-ethanesulfonic acid {4-[6-amino-5-(2-chIoro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-Piperidin-1-yl-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-dimethylamino-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-[(3R)-3-hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-[(2S)-2-hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-[4-(2-hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-(4-acetyl-piperazin-1-yl)-ethanesuIfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-Pyrrolidin-1-yI-ethanesulfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-morpholin-4-yl-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-311]-phenyl}-amide; 2-diethylamino-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-311]-phenyl}-amide; 2-dimethylamino-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-311]-phenyl}-amide; 2-Piperidin-1-yl-ethanesulfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide; 2-[(3R)-3-hydroxymethyl-pyrrolidin-1-yl]-ethanesuIfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl1-phenylyamide; 2-(4-hydroxy-piperidin-1-yl)-ethanesuIfonic acid {316-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl1-phenyl}-amide; 244-(2-hydroxy-acetyl)-piperazin-1-yl1-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-311]-phenylyamide; 2-[(3R)-3-hydroxy-pyrrolidin-111]-ethanesuIfonic acid {3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenylyamide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid {316-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl1-phenyl}-amide; 2-cyclopropylamino-ethanesulfonic acid {346-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenylyamide; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(2-dimethylaminomethyl-phenyl)-pyridin-2-ylamine; compound with trifluoro-acetic acid; 3-(2-chloro-316-difluoro-benzyloxy)-5-(3-pyrrolidin-1-yl-phenyl)-pyridin-2-ylamine; compound with trifluoro-acetic acid; N-{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-4-phenyl}-methanesulfonamide; compound with trifluoro-acetic acid; 546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylic acid; {546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-(4-methyl-piperazin-1-yl)-methanone; {546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; 546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylic acid (1-methyl-piperidin-4-yI)-amide; {5-[6-amino-5-(2-chloro-3,6-difIuoro-benzyloxy)-pyridin-3-yl]thiophen-2-yl)-(3,5-dimethyl-piperazin-1-yl)-methanone; 546-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylic acid (2-pyrrolidin-1-yl-ethyI)-amide; {5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y1]-thiophen-2-yI}-(4-pyrrolidin-1-yI-piperidin-1-yI)-methanone; 4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yI]-benzoic acid;
{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 446-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yI)-benzamide; {4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yI]-phenyl}-(3,5-dimethyl-piperazin-1-yI)-methanone; {4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3-dimethylamino-pyrrolidin-1-yI)-methanone; {4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yIl-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yI]-methanone; 4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl-N-(2-morpholin-4-ykethyl)-benzamide; {4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-A-phenyl1-(4-methyl-piperazin-1-yI)-methanone;
N42-(4-acetyl-piperazin-1-yl)-ethyl]-4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzamide; 2-Piperidin-1-yI-ethanesulfonic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenylyamide; 2-(4-hydroxy-piperidin-1-yI)-ethanesulfonic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yI}-phenyl)-amide; 2-dimethylamino-ethanesulfonic acid (4-{6-amino-5-[1-(2-chIoro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yI}-phenyl)-amide;

cyclopropylamino-ethanesulfonic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yI}-phenylyamide; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-benzoic acid; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-phenyI)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yI)-methanone;
4-{6-amino-511-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-N-(1-methyl-piperidin-4-yl)-benzamide; (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[(3R)-3-amino-pyrrolidin-1-yl)]-methanone; (4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyj-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyFpyridin-3-yI}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;

cyclopropylamino-ethanesulfonic acid (4-{6-amino-5-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-amide; 2-dimethylamino-ethanesulfonic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-amide;
2-[(3R)-3-hydroxy-pyrrolidin-1-yl)]-ethanesulfonic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-amide; and pharmaceutically acceptable salts, hydrates and solvates thereof.
26. A compound selected from the group consisting of: 4-[5-amino-6-(216-dichloro-benzyloxy)-pyrazin-2-yl]-phenol; 3-(2,6-dichloro-benzyloxy)-5-[4-(1,1-dioxo-1.lambda.6-isothiazolidin-2-yl)-phenyl]-pyrazin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine; 3-(2,6-dichloro-benzyloxy)-514-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine; 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine; 445-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-benzoic acid; {415-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; {4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;

morpholin-4-yl-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide; 2-piperidin-1-yl-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide; 2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide; 2-pyrrolidin-1-yl-ethanesulfonic acid {445-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-dimethylamino-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-diethylamino-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide; 2-[4-2-Hydroxy-acety1)-piperazin-1-yl]-ethanesulfonic acid {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-cyclopropylamino-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-211]-phenylyamide;

[(3R)-3-Hydroxymethyl-pyrrolidin-1-yl]-ethanesuIfonic acid {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-A-phenylyamide; 2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid {3[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl)-amide; 2-piperidin-1-yl-ethanesulfonic acid {3{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyll-amide; 2-diethylamino-ethanesulfonic acid {3{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyll-amide; 2-morpholin-4-yl-ethanesulfonic acid {3{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl1-phenylyamide;

pyrrolidin-1-yl-ethanesulfonic acid {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-dimethylamino-ethanesulfonic acid {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-phenylyamide; 2-[4-(2-Hydroxy-acetyl)-piperazin-1-ylFethanesulfonic acid {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid {315-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyll-amide; 2-[(3R)-Hydroxy-pyrrolidin-1-yl]-ethanesuIfonic acid {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl1-phenylyamide; 2-cyclopropylamino-ethanesulfonic acid {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenylyamide; 4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yll-benzoic acid; {4-[5-amino-6-(2-chloro-3,6-difIuoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(2R)-2-pyrro1idin-1-ylmethyl-pyrrolidin-1-yl]-methanone; 4{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-A-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone; N12-(4-acetyl-piperazin-1-yl)-ethyl]-4{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzamide; 4{4-[5-amino-6-(2-chioro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide;{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl1-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone; {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone; {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;
4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-morpholin-4-yl-propyl)-benzamide; 4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide; 4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; {4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;
3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoic acid; {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone; {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone; {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone; 3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-morpholin-4-yl-propyl)-benzamide; {3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;
{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone; 345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;
{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(2S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone; 345-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; N42-(4-acetyl-piperazin-1-yl)-ethyl]-3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzamide;
3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyrazin-2-ylamine;
3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-diethylaminomethyl-1H-indol-5-yl)-pyrazin-2-ylamine; 1-(4-{5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-1H-indol-3-ylmethyl}-piperazin-1-yl)-ethanone; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyrazin-2-ylamine; N-(1-{5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-1H-indol-3-ylmethyl}-(3S)-pyrrolidin-3-yl)-acetamide; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-piperidin-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine; 3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;
3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine; compound with trifluoro-acetic acid; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;
compound with trifluoro-acetic acid; N-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy}-pyrazin-2-yl}-phenyl)-methanesulfonamide; 2-pyrrolidin-1-yl-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;
2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid (4-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-amide; 2-piperidin-1-yl-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide, 2-(cyclopropylmethyl-amino)-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 2-dimethylamino-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 2-morpholin-4-yl-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 2-diethylamino-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 2-cyclopropylamino-ethanesulfonic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;
3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acid;
(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(3S)-3-amino-pyrrolidin-1-yl)-m-ethanone; (3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(3R)-3-amino-pyrrolidin-1 -yl)-m-ethanone; (3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl]-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; N42-(4-acetyl-piperazin-1-yl)-ethyl]-3-{5-amino-641 -(2 ,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-ybenzamide; (3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; 3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acid; 3-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; 3-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;
(3-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoic acid; 4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-A-N-(2-morpholin-4-yl-ethyl)-benzamide; 415-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide; and pharmaceutically acceptable salts, hydrates and solvates thereof.
27. A compound selected from the group consisting of: (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl]-phenyl)-(4-methyl-piperazin-1-yl)-methanone, N42-(4-acetyl-piperazin-1-yl)-ethyl]-4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-N-(2-morpholin-4-yl-ethyl)-benzamide; (4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-y1)-methanone; (4-{6-amino-541-(2,6-dichloro-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;
(4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl]-phenyl)-(4-amino-piperidin-1-yl)-methanone; (4-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone; (4-{6-amino-541 -(2,6-dich loro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-((R)-3-hydroxy-pyrrolidin-1-y1)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy)-pyridin-3-yl}-phenyl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-diethylamino-ethyl)-benzamide; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyI)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid; (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; (3-{6-amino-5-[1-(2,6-dichIoro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-ylmethyl-pyrrolidin-1-yl)-methanone; N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-benzamide; (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yI)-methanone; 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-morpholin-4-yl-propyl)-benzamide; (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;
3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 2-diethylamino-ethanesulfonic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-amide; 2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; 2-piperidin-1-yI-ethanesulfonic acid (4-{6-amino-5[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; 2-(cyclopropylmethyl-amino)-ethanesulfonic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; 2-((R)-3-Hydroxy-pyrrolidin-1-yI)-ethanesulfonic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; 2-cyclopropylamino-ethanesuIfonic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide, 2-diethylamino-ethanesuIfonic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-amide; 4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid; 4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;
(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone; (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;
4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; (4-{6-amino-5-[1-(2-chIoro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (4-{6-amino-5-[1-(2-chIoro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy}-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 4-{6-amino-5-[1-(2-chloro-3,6-difIuoro-phenyl)-ethoxyl-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;
(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone; 3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid; (3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; (3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone; 3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; (3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; 3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; (3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;
3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; (3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-ylmethyl-pyrrolidin-1-yl)-methanone; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-{4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-3-morpholin-4-yl-propan-2-ol; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-5-[4-(2-diethylamino-ethoxy)-phenyl]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-diisopropylamino-ethoxy)-phenyl]-pyridin-2-ylamine; 3-yl-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-pyridin-2-ylamine; N-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(1,1-dioxo-1.lambda.6-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine; N-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-phenyl-pyridin-2-ylamine; N-(4-{6-amino-5-[(R)-1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-thiophen-3-yl-pyridin-2-ylamine; 5-benzo[b]thiophen-2-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;
4-methyl-piperazine-1-carboxylic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; 1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea; 1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea; (R)-3-amino-pyrrolidine-1-carboxylic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; (S)-3-amino-pyrrolidine-1-carboxylic acid (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; 1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea; 1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea;
(R)-3-amino-pyrrolidine-1-carboxylic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; (S)-3-amino-pyrrolidine-1-carboxylic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-amide;
1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea; 4-methyl-piperazine-1-carboxylic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; 1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide; 3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid; (3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; (3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl)-N-(2-morpholin-4-yl-ethyl)-benzamide;
(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; 3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-yl)-N-(3-pyrrolidin-1-yl-propyl)-benzamide; N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide;
3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; (3-{6-amino-5-[1-(2,6-dichIoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (3-{6-amino-5-[1-(2,6-dichIoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;
(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone; (3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy}-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone; 4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid; 4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; (4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; 4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; (4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;
N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide; 4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; (4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-aminopyrrolidin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-prop-2-ynyl)-amide;
4-methyl-piperazine-1-carboxylic acid (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-prop-2-ynyl)-amide; 4-pyrrolidin-1-yl-piperidine-1-carboxylic acid (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide;
(3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide; 1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-prop-2-ynyl)-3-(1-methyl-piperidin-4-yl)-urea; 1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(3-pyrrolidin-1-yl-propyl)-urea; 1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(2-morphoIin-4-yl-ethyl)-urea; 1-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyI)-ethoxy]-pyridin-3-yI}-prop-2-ynyl)-3-(3-morpholin-4-yI-propyl)-urea; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-prop-2-ynyl)-amide; 341-(2,6-dichIoro-3-fIuoro-phenyl)-ethoxyl-5-(3-dimethylamino-prop-1-ynyl)-pyridin-2-ylamine; (3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-prop-2-ynyl)-urea; N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yIl-prop-2-ynyl)-2-piperidin-1-yl-acetamide;
N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-prop-2-ynyl)-2-morpholin-4-yl-acetamide; N-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy}-pyridin-3-yI}-prop-2-ynyl)-2-pyrrolidin-1-yl-acetamide; N-(3-16-amino-511-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-prop-2-ynyl)-2-((R)-3-hydroxy-pyrrolidin-1-yI)-acetamide; N-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-prop-2-ynyl)-2-(4-hydroxy-piperidin-1-y0-acetamide; N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yI}-prop-2-ynyl)-2-dimethylamino-acetamide; N-(3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yI}-prop-2-ynyl)-2-diethylamino-acetamide; 2-(4-acetyl-piperazin-1-yI)-N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]pyridin-3-01-prop-2-ynyl)-acetamide;

methyl-piperazine-1-carboxylic acid (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yI}-1,1-dimethyl-prop-2-ynyl)-amide; (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amide; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yI}-1,1-dimethyl-prop-2-ynyl)-amide; (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (3-{6-amino-541-(2,6-dichloro-3-fIuoro-phenyI)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amide; 1-(3-{6-amino-511-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-1,1-dimethyl-prop-2-ynyl)-3-(2-morpholin-4-O-ethyl)-urea; 1-(3-{6-amino-5-[1-(2,6-dichIoro-3-fIuoro-phenyI)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-3-(2-pyrrolidin-1-ykethyl)-urea; 4-pyrrolidin-1-yI-piperidine-1-carboxylic acid (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-1,1-dimethyl-prop-2-ynyl)-amide; 3-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yI}-propynoic acid cyclohexylamide; 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y1}-propynoic acid isopropylamide; 4-(3-amino-3-methyl-but-1-ynyl)-241-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-phenylamine; (4-{6-amino-5-0-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxyFpyridin-3-y1}-phenyl)-(4-methyl-piperazin-1-y1)-methanone; (4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1y1)-methanone; (4-{6-amino-541-(3-fluoro-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-yll-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; (4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-yll-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide; 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyp-benzamide; 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-yl)-N-(3-pyrrolidin-1-yl-propy1)-benzamide; 4-{6-amino-541-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl)-N-(3-morpholin-4-yl-propy1)-benzamide; 6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyFnicotinonitrile;

amino-541-(2,6-dichloro-3-cyano-phenyl)-ethoxy]-nicotinonitrile; 5-aminomethy1-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid {6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethylyamide; N-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethylymethanesulfonamide; N-16-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-ylmethy1}-acetamide; N-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-ylmethyl}-4-methyl-benzenesulfonamide; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine; (S)-1-{6-amino-511-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-ethane-1,2-diol; (R)-1-{6-amino-541-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-ethane-1,2-diol; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyridin-2-ylamine, 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-511-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yll-pyridin-2-ylamine;

- 314 -3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-diisopropylamino-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine; {4-[6-amino-5-(3-fluoro-2-methoxy-benzyloxy)-pyridin-3-yl[-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(3-fluoro-2-methoxy-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; {4-[6-amino-5-(3-fluoro-2-isopropoxy-benzyloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; 5-(4-amino-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-acetic acid methyl ester; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-acetic acid; 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-ethanone; 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((R)-3-hydroxy-pyrrolidin-1-yl)-ethanone; 4-[2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenoxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester; 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethanone;
{4[-6-amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; 3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine; N-{4-[6-amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide; 3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-(1H-pyrazol-4-yl)-pyridin-2-ylamine; 3-[1-(2-chloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine; 5'-benzyloxy-[2,3']bipyridinyl-6'-ylamine, 5-benzyloxy-[3,3']bipyridinyl-6-ylamine; 3-benzyloxy-5-pyrimidin-5-yl-pyridin-2-ylamine; 5-benzyloxy-[3,3']bipyridinyl-6,6'-diamine; 5'-(2-chloro-benzyloxy)-[2,3]bipyridinyl-6'-ylamine; 5-(2-chloro-benzyloxy)-[3,3]bipyridinyl-6-ylamine; 3-(2-chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;
5-(2-chloro-benzyloxy)-[3,3']bipyridinyl-6,6'-diamine; 5'-(4-chloro-benzyloxy)-[2,3']bipyridinyl-6'-ylamine; 5-(4-chloro-benzyloxy)-[3,3']bipyridinyl-6-ylamine; 3-(4-chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine; 5-(4-chloro-benzyloxy)-[3,3']bipyridinyl-6,6'-diamine; 5'-(2-chloro-3,6-difluoro-benzyloxy)-[2,3']bipyridinyl-6'-ylamine; 5-(2-chloro-3,6-difluoro-benzyloxy)-[3,3]bipyridinyI-6-ylamine; 5-(2-chloro-3,6-difluoro-benzyloxy)-[3,4']bipyridinyl-6-ylamine; 3-(2-chloro3,6-difluoro-benzyloxy)-5-pyrimidin-5-yI-pyridin-2-ylamine; 5-(2-chloro-3,6-difluoro-benzyloxy)-[3,3]bipyridinyl-6,6'-diamine; 5'-(2,6-dichloro-benzyloxy)-[2,3]bipyridinyI-6'-yIamine;
5-(2,6-dichloro-benzyloxy)-[3,3pipyridinyl-6-ylamine; 5-(2,6-dichloro-benzyloxy)-[3,4']bipyridinyl-6-ylamine; 3-(2,6-dichloro-benzyloxy)-5-pyrimidin-5-yI-pyridin-2-ylamine; 5-(2,6-dichloro-benzyloxy)-[3,3']bipyridinyl-6,6'-diamine; 5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3]bipyridinyl-6,6'-diamine; {6'-amino-5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3']bipyridinyl-4-yl}-(4-methyI-piperazin-1-yI)-methanone; {6'-amino-5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3']bipyridinyl-6-yI}-(4-methyl-piperazin-1-yl)-methanone; {6'-amino-5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3]bipyridinyl-5-yI}-(4-methyl-piperazin-1-yI)-methanone; {6'-amino-5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3]bipyridinyl-6-yI}-(4-methyl-piperazin-1-yl)-methanone; {6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,4']bipyridinyl-2'-yI)-(4-methyl-piperazin-1-yI)-methanone; 5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3]bipyridinyl-6,6'-diamine; {6'-amino-5'-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3]bipyridinyl-5-yI)-(4-methyl-piperazin-1-yI)-methanone; {6'-amino-5'-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3]bipyridinyl-4-yI}-(4-methyl-piperazin-1-yl)-methanone; {6'-amino-5'-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3]bipyridinyl-6-yI)-(4-methyl-piperazin-1-yI)-methanone; {6'-amino-5'-[1 -(2-chloro-3,6-difluoro-phenyl)-ethoxyl-[3,3]bipyridinyl-5-yI)-(4-methyl-piperazin-1-yI)-methanone;
{6'-amino-5'-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3']bipyridinyl-6-yl)-(4-methyl-piperazin-1-yl)-methanone; {6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,4']bipyridinyl-2'-yI}-(4-methyl-piperazin-1-yI)-methanone; 5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3]bipyridinyl-6'-ylamine; 5'-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3]bipyridinyl-6'-ylamine; 5-[-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3']bipyridinyl-6-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-pyrimidin-5-yI-pyridin-2-ylamine; {6'-amino-5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-[2,3']bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone; 5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,4']bipyridinyl-6-ylamine; 5-benzyloxy-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(2-ethyl-butoxy)-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(3-methyl-butoxy)-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-butoxy-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-propoxy-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-cyclohexylmethoxy-pyridin-2-ylamine; 6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyridin-3-ol; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(2-cyclohexyl-ethoxy)-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-isobutoxy-pyridin-2-ylamine, 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-5-phenethyloxy-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(pyridin-2-ylmethoxy)-pyridin-2-ylamine; 3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(pyridin-4-ylmethoxy)-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; 5-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-fluoro-benzonitrile;
4-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-piperidin-4-ol;
(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-piperidin-1-yl-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-pyrrolidin-1-yl-methanone; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-3-methyl-benzoic acid methyl ester; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(dimethyl-piperazin-1-ylmethyl)-phenyl]-pyridin-2-ylamine, (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3,5-dimethoxy-phenyl)-(dimethyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-fluoro-phenyl)-(dimethyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-fluoro-phenyl)-(dimethyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-3-methyl-phenyl)-(dimethyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-[1,4]diazepan-1-yl)-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[1,4]diazepan-1-yl-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperazin-1-yl-methanone; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,4S)-3,4-dihydroxy-pyrrolidin-1-yl)-methanone; 5-[(1-benzyl-pyrrolidin-3-ylamino)-methyl]-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-2-ylamine; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-azetidin-3-yl-benzamide; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N,N-dimethyl-benzenesulfonamide; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1H-benzoimidazol-2-yl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1-methyl-1H-benzoimidazol-2-yl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(4-methyl-[1,4]diazepane-1-sulfonyl)-phenyl]-pyridin-2-ylamine; 6-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1-methyl-1H-indazole-3-carboxylic acid amide; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-ylamine; 5-(3-chloro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-fluoro-3-methyl-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-fluoro-phenyI)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-trifluoromethoxy-phenyl)-pyridin-2-ylamine; 5-benzo[1,3]dioxol-5-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenol; (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanol; 3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-benzonitrile; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-methoxy-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dichloro-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dimethyl-phenyl)-pyridin-2-ylamine; 5-(5-chloro-2-methoxy-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 5-(3-chloro-4-fluoro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(5-fluoro-2-methoxy-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-isopropyl-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dichloro-phenyl)-pyridin-2-ylamine; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzonitrile; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-difluoro-phenyl)-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]pyridin-3-yl}-phenyl)-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-ethoxy-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dimethoxy-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,4-dimethoxy-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,6-dimethoxy-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine; 5-(2-chloro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-trifluoromethoxy-phenyl)-pyridin-2-ylamine; 1-(2-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-ethanone; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-fluoro-phenyl)-pyridin-2-ylamine; (2-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-methanol; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-o-tolyl-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-methoxy-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,6-dimethyl-phenyl)-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-morpholin-4-yl-methanone; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-chloro-phenyl)-((3R,5S)-dimethyl-piperazin-1-yl)-methanone; 4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyridin-3-yl}-2-methyl-phenyl)-((3R,5S)-dimethyl-piperazin-1-yl)-methanone; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-((2R,6S)-2,6-dimethyl-morpholin-4-ylmethyl)-phenyl]-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-morpholin-4-ylmethyl-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dimethyl-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-m-tolyl-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dimethoxy-phenyl)-pyridin-2-ylamine; 5-biphenyl-3-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 5-(3,5-bis-trifluoromethyl-phenyl)-3-[ 1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 3-[1-[2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dichloro-phenyl)-pyridin-2-ylamine; 1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-ethanone; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-difluoro-phenyl)-pyridin-2-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dichloro-phenyl)-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-4-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-ethoxy-phenyl)-pyridin-2-ylamine; (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;
(4-{6-amino-5-[1-(3-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone; 7-[4-(3,5-dimethyl-piperazine-1-carbonyl)-phenyl]-2-phenyl-4H-pyrido[3,2-b][1,4]oxazin-3-one; {4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone; {4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone; [4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(3,5-dimethyl-piperazin-1-yl)-methanone; (4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-ethyl-piperazin-1-yl)-methanone; [4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-ethyl-piperazin-1-yl)-methanone; {4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone; 3-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethylybenzoic acid methyl ester; 3-{2-amino-5-[4-(3,5-dimethyl-piperazine-1-carbonyl)-phenyl]-pyridin-3-yloxymethylybenzoic acid methyl ester; {4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; [4-(6-amino-5-cyclohexylmethoxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;
4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[2-(3-hydroxy-phenyl)-ethyl]benzamide; 4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[2-(2,6-dichloro-phenyl)-ethyl]-benzamide; 4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-(1-benzyl-piperidin-4-yl)-benzamide; 4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)43-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide; (4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-ethyl-piperazin-1-yl)-methanone; {4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone; (6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanone; 5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-6'-(2-morpholin-4-yl-ethoxy)-(3,3]bipyridinyl-6-ylamine; 6'-amino-5'11-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H-[3,3]bipyridinyl-6-one;
5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-6'-(2-pyrrolidin-1-yl-ethoxy)-(3,3]bipyridinyl-6-ylamine; 6'-amino-5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-112-(1-methyl-pyrrolidin-2-yl)-ethylj-1H-[3,31bipyridinyl-6-one; (4-{6-amino-5-[1-(2,4,6-trimethyl-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; (4-{6-amino-5-[1-(2-chloro-6-fluoro-phenyl)-ethoxyFpyridin-3-yll-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-fluoro-phenyl)-pyridin-2-ylamine; 6'-amino-5'-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1H-[3,3]bipyridinyl-6-one; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-dimethylamino-phenyl)-pyridin-2-ylamine; 5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-2'-methoxy-[3,31bipyridinyl-6-ylamine; 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-indo1-5-yl)-pyridin-2-ylamine; (4-{6-amino-5-[1-(2,6-dichloro-phenyl)-propoxy]-pyridin-3-yll-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone; [4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 3-(2,6-dichloro-3-fluoro-benzyloxy)-5-thiazol-2-yl-pyridin-2-ylamine; (4-{6-amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 3-(2,6-dichloro-3-fluoro-benzyloxy)-5-(1-methyl-1H-imidazol-2-yl)-pyridin-2-ylamine; (446-amino-5-(2,4,6-trimethyl-benzyloxy)-pyridin-3-yl1-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; {-[16-amino-5-(2,3,5,6-tetramethyl-benzyloxy)-pyridin-3-yll-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;
{446-amino-5-(2,4,6-trifluoro-benzyloxy)-pyridin-3-ylj-phenyll-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; (4-{6-amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxyl-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-N-methyl-nicotinamidine; 6-amino-5[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-N-(2-morpholin-4-yl-ethyl)-nicotinamidine; (4-{6-amino-5[1-(2,4,5-trifluoro-phenyl)-propoxy]pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; (4-{6-amino-5[1-(6-chloro-2-fluoro-3-methyl-phenyl)-ethoxy]pyridin-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 3-(1-{2-amino-5[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]pyridin-3-yloxy}-ethyl)-benzoic acid; and pharmaceutically acceptable salts, hydrates and solvates thereof.
28. A compound selected from the group consisting of: 3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; 3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide; N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yI}-benzamide; (3-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy)-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (3-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; (3-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; (3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone; (3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone; 4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acid; 4-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;
(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (4-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;
(4-{5-amino-6[1-(2-chIoro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone; 4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; 4-{5-amino-641-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; N-[2-(4-acetyl-piperazin-1-yl)-ethyl1-4-{5-amino-6[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-benzamide; 2[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid (4-{5-amino-6[1-(2-chIoro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-amide;
3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoic acid; {3[-5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yI]-phenyl}-(4-pyrrolidin-1-yI-piperidin-1-yI)-methanone; 345-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-{2-[ethyl-(2-methoxy-ethyl)-amino]-ethylybenzamide; {345-amino-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone; 345-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide; N12-(4-acetyl-piperazin-1-yl)-ethyl]-3[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzamide; {445-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yI)-methanone; (445-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl}-phenyl}-(4-methyl-piperazin-1-yl)-methanone; {415-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yI]-phenyl}-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yI)-methanone; (3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; 3-{5-amino-6-[1-(2,6-dichIoro-3-fluoro-phenyI)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; 3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;
3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-morpholin-4-yl-propyl)-benzamide; (3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy}-pyrazin-2-yl}-phenyl)-(4-cyclopropylamino-piperidin-1-yl)-methanone; 3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((S)-2-hydroxy-3-morpholin-4-yl-propyl)-benzamide; 3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide; (3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 2-diethylamino-ethanesulfonic acid (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-amide; 2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 2-dimethylamino-ethanesulfonic acid (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 2-((R)-3-Hydroxy-pyrrolidin-1-yl)-ethanesulfonic acid (4-{5-amino-6[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-amide; 2-pyrrolidin-1-ylethanesulfonic acid (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-amide; 4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-benzoic acid; 4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide; (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-cyclopropylamino-piperidin-1-yl)-methanone; 4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((S)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide; 4-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((R)-2-hydroxy-3-morpholin-4-yl-propyl)-benzamide; 4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl)-N-(1-methyl-piperidin-4-yl)-benzamide;
(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; 4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-yl}-benzoic acid; (4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; (4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R, 5S)-3,5-dimethyl-piperazin-1-yI)-methanone; 4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide; (4-15-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; (4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-((R)-3-aminopyrrolidin-1-yl)-methanone;
(4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-((S)-3-aminopyrrolidin-1-yl)-methanone hydrogen chloride; 4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; 3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-ylybenzoic acid; 3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;
3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; (3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; 3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide; (3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; N42-(4-acetyl-piperazin-1-yl)-ethyl]-4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide;
N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]pyrazin-2-yl}-benzamide; (3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; 3-{5-amino-6-[1-(2 ,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide; (3-{5-amino-6-[1-(2 ,6-dichloro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone, (3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxyypyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone hydrochloride salt; (3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone; 1-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea; (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 1-(4-{5-amino-6-[1-(2-chloro-3 ,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea; 4-methyl-piperazine-1-carboxylic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 1-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl)-phenyl)-3-(2-hydroxy-ethyl)-urea;
(S)-3-amino-pyrrolidine-1-carboxylic acid (4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 1-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl-pyrazin-2-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea; 4-methyl-piperazine-1-carboxylic acid (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 1-(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyypyrazin-2-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea; (S)-3-amino-pyrrolidine-1-carboxylic acid (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide; 1-(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea; 5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophene-2-carboxylic acid; {5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; {5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone; {5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; 5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophene-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yllpyrazin-2-amine trifluoroacetate; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-pyridin-4-yl-pyrazin-2-ylamine; 341-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrrol-2-yl)-pyrazin-2-ylamine; (6-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; (2-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy)-pyrazin-2-yl}-pyridin-4-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl-pyrazin-2-yl}-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; (4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone; 6-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-nicotinamide;
5-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-nicotinamide; 6-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-morpholin-4-yl-propyl)-nicotinamide; 5-{5-amino-641-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yll-N-(3-morpholin-4-yl-propyl)-nicotinamide; (6-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone; and pharmaceutically acceptable salts, hydrates and solvates thereof.
29. A pharmaceutical composition comprising a compound, salt, solvate or hydrate of any one of claims 1 to 28 and a pharmaceutically acceptable carrier.
30. A pharmaceutical composition for use in the treatment of abnormal cell growth in a mammal, comprising a therapeutically acceptable amount of a compound, salt, hydrate or solvate of any one of claims 1 to 28 and a pharmaceutically acceptable carrier.
31. The composition of claim 30, wherein the abnormal cell growth is cancer.
32. The composition of claim 31, wherein the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, and combinations thereof.
33. The composition of claim 31, wherein the cancer is selected from gastrointestinal stromal tumors, renal cell carcinoma, breast cancer, colorectal cancer, non-small cell lung cancer, neuroendocrine tumors, thyroid cancer, small cell lung cancer, mastocytosis, glioma, sarcoma, acute myeloid leukemia, prostate cancer, lymphoma, and combinations thereof.
34. The composition of claim 30, prepared for the administration with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, anti-androgens and mixtures thereof.
35. Use of a compound, salt, solvate or hydrate of any one of claims 1 to 28 for the treatment of abnormal cell growth in a mammal.
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Families Citing this family (188)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4695588B2 (en) * 2003-02-26 2011-06-08 スージェン， インク． Amino heteroaryl compounds as protein kinase inhibitors
WO2005082411A1 (en) * 2004-02-23 2005-09-09 Sugen, Inc. Method of treating abnormal cell growth using c-met and-tor inhibitors
AU2005217325B2 (en) 2004-02-27 2007-11-29 Eisai R & D Management Co., Ltd. Novel pyridine derivative and pyrimidine derivative (1)
US7470701B2 (en) * 2004-03-30 2008-12-30 Novartis Vaccines And Diagnostics, Inc. Substituted 2,5-heterocyclic derivatives
EP1735278B1 (en) * 2004-04-01 2010-01-06 Eli Lilly And Company Histamine h3 receptor agents, preparation and therapeutic uses
US8008301B2 (en) 2004-04-01 2011-08-30 Eli Lilly And Company Histamine H3 receptor agents, preparation and therapeutic uses
CA2577061C (en) * 2004-08-23 2014-02-18 Eli Lilly And Company Histamine h3 receptor agents, preparation and therapeutic uses
RU2007106863A (en) * 2004-08-26 2008-08-27 Пфайзер Инк. (US) Enantioselective bioconversion for the preparation of intermediate compounds of a tyrosine kinase protein inhibitor
CA2578075A1 (en) * 2004-08-26 2006-03-02 Pfizer Inc. Aminoheteroaryl compounds as protein tyrosine kinase inhibitors
GEP20094845B (en) * 2004-08-26 2009-11-25 Pfizer Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
ME01788B (en) * 2004-08-26 2011-02-28 Pfizer Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
GT200600042A (en) * 2005-02-10 2006-09-27 Aventis Pharma Inc BIS ARILO AND HETEROARILO COMPOUNDS REPLACED AS SELECTIVE ANTAGONISTS OF 5HT2A
US20090163476A1 (en) * 2005-03-03 2009-06-25 Sirtris Pharmaceuticals, Inc. N-Phenyl Benzamide Derivatives as Sirtuin Modulators
RU2007146444A (en) * 2005-05-13 2009-06-20 Лексикон Фармасьютикалз, Инк. (Us) POLYCYCLIC COMPOUNDS AND WAYS OF THEIR APPLICATION
ES2431050T3 (en) 2005-08-04 2013-11-22 Sirtris Pharmaceuticals, Inc. Benzothiazoles and thiazolopyridines as modulators of sirtuin
US8088928B2 (en) * 2005-08-04 2012-01-03 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US7855289B2 (en) * 2005-08-04 2010-12-21 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8093401B2 (en) * 2005-08-04 2012-01-10 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
RS52902B (en) 2005-08-24 2014-02-28 Eisai R & D Management Co. Ltd. NEW PYRIDINE DERIVATIVES AND PYRIMIDINE DERIVATIVES (3)
DK1959955T3 (en) * 2005-12-05 2011-02-07 Pfizer Prod Inc Method of Treating Abnormal Cell Growth
WO2007066185A2 (en) * 2005-12-05 2007-06-14 Pfizer Products Inc. Polymorphs of a c-met/hgfr inhibitor
PE20070978A1 (en) * 2006-02-14 2007-11-15 Novartis Ag HETEROCICLIC COMPOUNDS AS INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASES (PI3Ks)
CA2645137A1 (en) 2006-03-07 2007-09-13 James F. Blake Heterobicyclic pyrazole compounds and methods of use
JP2009533327A (en) * 2006-03-22 2009-09-17 バーテックス ファーマシューティカルズ インコーポレイテッド C-MET Kinase Inhibitors for Treating Proliferative Diseases
US8168383B2 (en) 2006-04-14 2012-05-01 Cell Signaling Technology, Inc. Gene defects and mutant ALK kinase in human solid tumors
US7700339B2 (en) 2006-04-14 2010-04-20 Cell Signaling Technology, Inc. Gene defects and mutant ALK kinase in human solid tumors
US7601716B2 (en) 2006-05-01 2009-10-13 Cephalon, Inc. Pyridopyrazines and derivatives thereof as ALK and c-Met inhibitors
JP2009538317A (en) * 2006-05-26 2009-11-05 バイエル ヘルスケア リミティド ライアビリティ カンパニー Drug combinations using substituted diarylureas for cancer treatment
US20110053931A1 (en) * 2006-06-08 2011-03-03 John Gaudino Quinoline compounds and methods of use
US7683060B2 (en) 2006-08-07 2010-03-23 Incyte Corporation Triazolotriazines as kinase inhibitors
ATE535520T1 (en) 2006-08-23 2011-12-15 Eisai R&D Man Co Ltd SALT OF A PHENOXYPYRIDINE DERIVATIVE OR CRYSTAL THEREOF AND METHOD FOR THE PRODUCTION THEREOF
US7790885B2 (en) * 2006-08-31 2010-09-07 Eisai R&D Management Co., Ltd. Process for preparing phenoxypyridine derivatives
WO2008042867A2 (en) * 2006-09-29 2008-04-10 Emiliem Inc. Modulators of multiple kinases
EP2684874B1 (en) 2006-10-23 2017-05-17 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and C-met inhibitors
GB0621607D0 (en) * 2006-10-31 2006-12-06 Chroma Therapeutics Ltd Inhibitors of c-Met
SI3034075T1 (en) 2006-11-22 2018-12-31 Incyte Holdings Corporation Imidazotriazines and imidazopyrimidines as kinase inhibitors
BRPI0719991A2 (en) 2006-12-14 2014-03-18 Bayer Schering Pharma Ag DIHYDROPYRIDINE DERIVATIVES USEFUL AS PROTEIN KINASE INHIBITORS
EP2123627B1 (en) * 2007-01-19 2013-11-20 Ube Industries, Ltd. Process for producing aromatic amine having aralkyloxy or heteroaralkyloxy group
ES2531002T3 (en) * 2007-01-19 2015-03-09 Xcovery Inc Kinase Inhibitor Compounds
DK2076289T3 (en) 2007-04-13 2015-02-09 Dana Farber Cancer Inst Inc Methods for treating cancer resistance to ErbB drugs
CA2682354C (en) * 2007-04-16 2016-12-13 Abbott Laboratories 7-nonsubstituted indole mcl-1 inhibitors
US8263585B2 (en) 2007-05-04 2012-09-11 Novartis Ag Organic compounds
TW200916472A (en) * 2007-06-20 2009-04-16 Sirtris Pharmaceuticals Inc Sirtuin modulating compounds
SG183036A1 (en) 2007-07-17 2012-08-30 Plexxikon Inc Compounds and methods for kinase modulation, and indications therefor
CN101765591B (en) * 2007-07-26 2013-11-27 诺华股份有限公司 Pyrimidine derivatives useful for treatment of inflammatory or allergic conditions
JP5973131B2 (en) 2007-09-13 2016-08-23 コデクシス， インコーポレイテッド A ketoreductase polypeptide for the reduction of acetophenone
MX2010004487A (en) * 2007-10-23 2010-05-05 Allergan Inc Therapeutic substituted lactams.
EP2215066A1 (en) * 2007-11-01 2010-08-11 Sirtris Pharmaceuticals, Inc. Amide derivatives as sirtuin modulators
US20110009381A1 (en) * 2007-11-08 2011-01-13 Sirtis Pharmaceuticals, Inc. Solubilized thiazolopyridines
JP2009132660A (en) 2007-11-30 2009-06-18 Eisai R & D Management Co Ltd Composition for treating esophageal cancer
WO2009073224A1 (en) * 2007-12-07 2009-06-11 Ambit Biosciences Corp. Methods of treating certain diseases using pyrimidine derivatives
US20090227556A1 (en) * 2008-01-31 2009-09-10 Eisai R&D Management Co., Ltd. Receptor tyrosine kinase inhibitors comprising pyridine and pyrimidine derivatives
JPWO2009096198A1 (en) * 2008-02-01 2011-05-26 一般社団法人ファルマＩｐ New biaryl derivatives
EP2265270A1 (en) * 2008-02-04 2010-12-29 OSI Pharmaceuticals, Inc. 2-aminopyridine kinase inhibitors
AR070317A1 (en) 2008-02-06 2010-03-31 Osi Pharm Inc FURO (3,2-C) PIRIDINE AND HAVING (3,2-C) PIRIDINES
EP2248810A4 (en) * 2008-02-18 2011-05-25 Eisai R&D Man Co Ltd Method for producing phenoxypyridine derivative
US20110092452A1 (en) * 2008-03-05 2011-04-21 The Regents Of The University Of Michigan Compositions and methods for diagnosing and treating pancreatic cancer
US8268834B2 (en) * 2008-03-19 2012-09-18 Novartis Ag Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme
FR2928924B1 (en) 2008-03-21 2010-04-23 Sanofi Aventis POLYSUBSTITUTED DERIVATIVES OF 6-HETEROARYL-IMIDAZO-1,2-A! PYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2928923B1 (en) 2008-03-21 2010-04-23 Sanofi Aventis POLYSUBSTITUTED DERIVATIVES OF 2-HETEROARYL-6-PHENYL-IMIDAZO-1,2-A! PYRIDINES, THEIR PREPARATION AND THEIR USE IN THERAPEUTICS
FR2928922B1 (en) 2008-03-21 2010-04-23 Sanofi Aventis DERIVATIVES OF POLYSUBSTITUTED 2-ARYL-6-PHENYL-IMIDAZO-1,2-A! PYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
WO2009151800A1 (en) * 2008-05-07 2009-12-17 Merck & Co., Inc. Soluble epoxide hydrolase inhibitors, compositions containing such compounds and methods of treatment
CL2009001250A1 (en) 2008-05-21 2010-02-05 2-Fluoro-n-methyl-4- [7- (quinolin-6-ylmethyl) imidazol [1,2-b] [1,2,4] 1,2,4] triazin- dihydrochloric and dibenzenesulfonic acid salt 2-yl] benzamide; intermediate compounds; preparation processes; pharmaceutical composition; and use to treat cancer, atherosclerosis, pulmonary fibrosis, kidney disease, among others.
CN102098917B (en) * 2008-06-19 2016-03-16 艾科睿控股公司 Substituted pyridazine carboxamide compounds as kinase inhibitor compounds
MX2011002082A (en) * 2008-08-29 2011-06-20 Genentech Inc Diagnostics and treatments for vegf-independent tumors.
WO2010046780A2 (en) * 2008-10-22 2010-04-29 Institut Pasteur Korea Anti viral compounds
AT507187B1 (en) 2008-10-23 2010-03-15 Helmut Dr Buchberger INHALER
US8592448B2 (en) * 2008-11-20 2013-11-26 OSI Pharmaceuticals, LLC Substituted pyrrolo[2,3-b]-pyridines and -pyrazines
WO2010077624A1 (en) * 2008-12-09 2010-07-08 Merck Sharp & Dohme Corp. Biaryl carboxamides
SI3354650T1 (en) 2008-12-19 2022-06-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
WO2010071853A1 (en) 2008-12-19 2010-06-24 Sirtris Pharmaceuticals, Inc. Thiazolopyridine sirtuin modulating compounds
JP2012102018A (en) * 2009-03-03 2012-05-31 Astellas Pharma Inc Amide compound
TW201100441A (en) 2009-06-01 2011-01-01 Osi Pharm Inc Amino pyrimidine anticancer compounds
DE102009056886A1 (en) 2009-12-03 2011-06-09 Bayer Schering Pharma Aktiengesellschaft cMet inhibitors for the treatment of endometriosis
BR112012019302B1 (en) 2010-02-03 2022-06-21 Incyte Holdings Corporation Imidazo[1,2-b][1,2,4]triazines as c-met inhibitors, composition comprising them and in vitro methods of inhibiting c-met kinase activity, of inhibiting the hgf/ c-meth kinase in a cell and to inhibit the proliferative activity of a cell
US8916593B2 (en) 2010-05-04 2014-12-23 Pfizer Inc. Alkoxy-substituted 2-aminopyridines as ALK inhibitors
CA2798763A1 (en) 2010-05-12 2011-11-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
JP2013526540A (en) 2010-05-12 2013-06-24 バーテックス ファーマシューティカルズ インコーポレイテッド Compounds useful as ATR kinase inhibitors
US9062008B2 (en) * 2010-05-12 2015-06-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
EP2569315A1 (en) 2010-05-14 2013-03-20 OSI Pharmaceuticals, LLC Fused bicyclic kinase inhibitors
AR081039A1 (en) 2010-05-14 2012-05-30 Osi Pharmaceuticals Llc QUINASA FUSIONED BICYCLE INHIBITORS
US9526648B2 (en) 2010-06-13 2016-12-27 Synerz Medical, Inc. Intragastric device for treating obesity
US10420665B2 (en) 2010-06-13 2019-09-24 W. L. Gore & Associates, Inc. Intragastric device for treating obesity
US10010439B2 (en) 2010-06-13 2018-07-03 Synerz Medical, Inc. Intragastric device for treating obesity
US8628554B2 (en) 2010-06-13 2014-01-14 Virender K. Sharma Intragastric device for treating obesity
MX2012014776A (en) 2010-06-25 2013-01-29 Eisai R&D Man Co Ltd Antitumor agent using compounds having kinase inhibitory effect in combination.
WO2012007836A1 (en) 2010-07-16 2012-01-19 Purdue Pharma .Lp. Pyridine compounds as sodium channel blockers
WO2012042421A1 (en) 2010-09-29 2012-04-05 Pfizer Inc. Method of treating abnormal cell growth
JP6023062B2 (en) 2010-10-08 2016-11-09 エックスカバリー ホールディング カンパニー エルエルシー Substituted pyridazine carboxamide compounds
WO2012074951A1 (en) 2010-11-29 2012-06-07 OSI Pharmaceuticals, LLC Macrocyclic kinase inhibitors
GB201021103D0 (en) * 2010-12-13 2011-01-26 Univ Leuven Kath New compounds for the treatment of neurodegenerative diseases
AU2012214085B2 (en) 2011-02-11 2015-07-09 Nicoventures Trading Limited Inhaler component
MX2013009551A (en) * 2011-02-24 2013-09-06 Jiangsu Hanson Pharmaceutical Co Ltd Phosphorus containing compounds as protein kinase inhibitors.
US9145390B2 (en) 2011-03-03 2015-09-29 Concert Pharmaceuticals, Inc. Derivatives of pyrazole-substituted amino-heteroaryl compounds
JO3438B1 (en) * 2011-04-13 2019-10-20 Epizyme Inc Aryl- or heteroaryl-substituted benzene compounds
WO2012152741A1 (en) 2011-05-10 2012-11-15 Bayer Intellectual Property Gmbh Bicyclic (thio)carbonylamidines
US20140088114A1 (en) 2011-05-16 2014-03-27 OSI Pharmaceuticals ,LLC Fused bicyclic kinase inhibitors
WO2012178125A1 (en) 2011-06-22 2012-12-27 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
CA2842841C (en) * 2011-07-27 2016-04-19 Nanjing Allgen Pharma Co. Ltd. Spirocyclic molecules as protein kinase inhibitors
AU2012291744A1 (en) 2011-08-02 2014-02-20 Pfizer Inc. Crizotinib for use in the treatment of cancer
MX373340B (en) 2011-09-30 2020-05-13 Vertex Pharma TREATMENT OF PANCREATIC CANCER AND NON-SMALL CELL LUNG CANCER WITH ATR INHIBITORS.
KR102013133B1 (en) 2011-09-30 2019-08-22 버텍스 파마슈티칼스 인코포레이티드 Processes for making compounds useful as inhibitors of atr kinase
DK2822953T5 (en) 2012-03-06 2017-09-11 Pfizer Macrocyclic derivatives for the treatment of proliferative diseases
AU2013203824A1 (en) 2012-03-16 2013-10-03 Purdue Pharma L.P. Substituted pyridines and pryimidines as sodium channel blockers
CN104582795B (en) 2012-04-05 2018-04-20 沃泰克斯药物股份有限公司 Compounds useful as ATR kinase inhibitors and combination therapy thereof
WO2013152252A1 (en) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
RU2699546C2 (en) * 2012-04-13 2019-09-06 Эпизайм, Инк. Combined therapy for cancer treatment
CN103387535B (en) * 2012-05-10 2016-06-01 广东东阳光药业有限公司 The alkynes yl pyridines compound replaced and using method and purposes
WO2013177092A1 (en) * 2012-05-23 2013-11-28 Sunshine Lake Pharma Co., Ltd. Substituted alkynyl pyridine compounds and methods of use
GB201211310D0 (en) 2012-06-26 2012-08-08 Chroma Therapeutics Ltd CSF-1R kinase inhibitors
CN112755193A (en) 2012-06-26 2021-05-07 德玛医药 Method of treating malignancies with anti-tyrosine kinase inhibitors using dianhydrogalactitol or a derivative thereof
AU2013318618B2 (en) 2012-09-24 2017-04-06 Ventana Medical Systems, Inc. Method of identifying treatment responsive non-small cell lung cancer using anaplastic lymphoma kinase (ALK) as a marker
WO2014055756A1 (en) 2012-10-04 2014-04-10 Vertex Pharmaceuticals Incorporated Method for measuring atr inhibition mediated increases in dna damage
WO2014081816A1 (en) * 2012-11-21 2014-05-30 Concert Pharmaceuticals, Inc. Fluoro-derivatives of pyrazole-substituted amino-heteroaryl compounds
SMT202100425T1 (en) 2012-12-07 2021-09-14 Vertex Pharma 2-amino-n-(piperidin-1-yl-pyridin-3-yl) pyrazolo[1,5alpha]pyrimidine-3-carboxamid as inhibitor of atr kinase
EP2935257B1 (en) 2012-12-20 2018-02-07 Purdue Pharma LP Cyclic sulfonamides as sodium channel blockers
WO2014098176A1 (en) 2012-12-21 2014-06-26 エーザイ・アール・アンド・ディー・マネジメント株式会社 Amorphous form of quinoline derivative, and method for producing same
JP6200520B2 (en) * 2013-02-02 2017-09-20 正大天晴薬業集団股▲ふん▼有限公司 Substituted 2-aminopyridine protein kinase inhibitor
WO2014143240A1 (en) 2013-03-15 2014-09-18 Vertex Pharmaceuticals Incorporated Fused pyrazolopyrimidine derivatives useful as inhibitors of atr kinase
WO2014168986A1 (en) 2013-04-08 2014-10-16 Brown Dennis M Therapeutic benefit of suboptimally administered chemical compounds
CN105264380B (en) 2013-05-14 2017-09-05 卫材R&D管理有限公司 Biomarkers for predicting and evaluating responsiveness of endometrial cancer subjects to lenvatinib compounds
WO2015034729A1 (en) * 2013-09-05 2015-03-12 Calitor Sciences, Llc Substituted pyridine compounds and methods of use
WO2015036898A2 (en) * 2013-09-10 2015-03-19 Shilpa Medicare Limited Novel salts of crizotinib and their preparation
RU2550346C2 (en) 2013-09-26 2015-05-10 Общество с ограниченной ответственностью "Отечественные Фармацевтические Технологии" ООО"ФармТех" New chemical compounds (versions) and using them for treating oncological diseases
AU2013402175B2 (en) 2013-09-30 2017-09-07 Handok Inc. Novel triazolopyrazine derivative and use thereof
US20160280798A1 (en) 2013-11-06 2016-09-29 The United States Of America, As Represented By The Secretary Department Of Health & Human Service Alk antibodies, conjugates, and chimeric antigen receptors, and their use
PT3077397T (en) 2013-12-06 2020-01-22 Vertex Pharma 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof
CA2934251C (en) 2013-12-20 2024-01-02 3-V Biosciences, Inc. A combination of heterocyclic modulators of lipid synthesis and chemotherapeutic drugs in treatment of cancer
CN103755627B (en) * 2014-01-09 2016-02-17 定陶县友帮化工有限公司 The synthetic method of 2-amino-3-hydroxyl-5-chloropyridine
US10231965B2 (en) 2014-02-20 2019-03-19 Ignyta, Inc. Molecules for administration to ROS1 mutant cancer cells
CA2943329A1 (en) 2014-03-24 2015-10-01 Genentech, Inc. Cancer treatment with c-met antagonists and correlation of the latter with hgf expression
US10730866B2 (en) 2014-04-07 2020-08-04 Purdue Pharma L.P. Indole derivatives and use thereof
EP3137074B1 (en) 2014-04-29 2020-08-05 Emory University Prostaglandin receptor ep2 antagonists, derivatives, compositions, and uses related thereto
WO2015172747A1 (en) * 2014-05-16 2015-11-19 Zhaoyin Wang Spirocyclic molecules as mth1 inhibitors
SI3152212T1 (en) 2014-06-05 2020-06-30 Vertex Pharmaceuticals Inc. Radiolabelled derivatives of a 2-amino-6-fluoro-n-(5-fluoro-pyridin-3-yl)- pyrazolo(1,5-a)pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, the preparation of said compound and different solid forms thereof
SG10201811175WA (en) 2014-06-17 2019-01-30 Vertex Pharma Method for treating cancer using a combination of chk1 and atr inhibitors
CN106661064B (en) * 2014-08-07 2019-10-15 江苏豪森药业集团有限公司 A new crystal form of anticancer compound and its preparation method and use
US10112939B2 (en) 2014-08-21 2018-10-30 Bristol-Myers Squibb Company Tied-back benzamide derivatives as potent rock inhibitors
MX394386B (en) 2014-08-28 2025-03-24 Eisai R&D Man Co Ltd VERY PURE QUINOLINE DERIVATIVE AND METHOD FOR ITS PRODUCTION.
BR112017007708B8 (en) 2014-10-13 2023-10-24 Atrin Pharmaceuticals LLC Macrocyclic compound and pharmaceutical composition
GB2535427A (en) 2014-11-07 2016-08-24 Nicoventures Holdings Ltd Solution
UY36391A (en) * 2014-11-05 2016-06-01 Flexus Biosciences Inc MODULATING COMPOUNDS OF INDOLAMINE ENZYME 2,3-DIOXYGENASE (IDO1), ITS SYNTHESIS METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
JP6902466B2 (en) * 2014-11-07 2021-07-14 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン Inhibitors of myocardin-related transcription factors and serum response factor (MRTF / SRF) -mediated gene transcription and how to use them
CN107207471B (en) 2014-12-02 2020-06-26 伊尼塔公司 Combination for the treatment of neuroblastoma
JP6852848B2 (en) 2015-01-13 2021-03-31 国立大学法人京都大学 Preventive and / or therapeutic agent for amyotrophic lateral sclerosis
MX385403B (en) 2015-02-25 2025-03-18 Eisai R&D Man Co Ltd METHOD FOR SUPPRESSING THE BITTERNESS OF A QUINOLINE DERIVATIVE.
MA41598A (en) * 2015-02-25 2018-01-02 Constellation Pharmaceuticals Inc PYRIDAZINE THERAPEUTIC COMPOUNDS AND THEIR USES
KR20250020678A (en) 2015-03-04 2025-02-11 머크 샤프 앤드 돔 엘엘씨 Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer
JP2018521021A (en) 2015-06-11 2018-08-02 バジリア・ファルマスーチカ・インターナショナル・アーゲーＢａｓｉｌｅａ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ａｇ Efflux pump inhibitors and their therapeutic use
SG11201710198YA (en) 2015-06-16 2018-01-30 Eisai R&D Man Co Ltd Anticancer agent
US10405627B2 (en) * 2015-07-14 2019-09-10 Michael Charles Boland, III Luggage with fold out table
WO2017030161A1 (en) 2015-08-20 2017-02-23 エーザイ・アール・アンド・ディー・マネジメント株式会社 Tumor therapeutic agent
HK1258570A1 (en) 2015-09-30 2019-11-15 Vertex Pharmaceuticals Inc. Method for treating cancer using a combination of dna damaging agents and atr inhibitors
GB2542838B (en) 2015-10-01 2022-01-12 Nicoventures Trading Ltd Aerosol provision system
MX2018007266A (en) 2015-12-18 2018-11-09 Ignyta Inc Combinations for the treatment of cancer.
WO2017161004A1 (en) * 2016-03-15 2017-09-21 University Of South Florida PKCδ INHIBITOR FORMULATIONS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS
US10301324B2 (en) 2016-04-12 2019-05-28 Atrin Pharmaceuticals LLC Ataxia telengiectasia and rad3-related (ATR) inhibitors and methods of their use
US10779980B2 (en) 2016-04-27 2020-09-22 Synerz Medical, Inc. Intragastric device for treating obesity
EP3463355B1 (en) * 2016-05-26 2024-08-28 Sonic Master Limited Modulators of dux4 for regulation of muscle function
TWI646094B (en) 2016-06-01 2019-01-01 大陸商貝達藥業股份有限公司 Crystal form of inhibitory protein kinase active compound and application thereof
WO2018110669A1 (en) 2016-12-15 2018-06-21 Ono Pharmaceutical Co., Ltd. Activator of trek (twik related k+ channels) channels
CN106866627B (en) * 2017-01-24 2021-09-14 南方医科大学 3- (1- (aminopyridinyloxy) ethyl) benzamide derivative and synthetic method and application thereof
EP3581183B1 (en) 2017-02-08 2023-11-29 Eisai R&D Management Co., Ltd. Tumor-treating pharmaceutical composition
CN110831597A (en) 2017-05-16 2020-02-21 卫材R&D管理有限公司 Treatment of hepatocellular carcinoma
EP3654982A4 (en) 2017-07-18 2021-04-14 Nuvation Bio Inc. 1,8-NAPHTHYRIDINONE COMPOUNDS AND THEIR USES
SG11202000418XA (en) 2017-07-18 2020-02-27 Nuvation Bio Inc Heterocyclic compounds as adenosine antagonists
IL271759B2 (en) 2017-07-19 2024-01-01 Ignyta Inc Pharmaceutical preparations that include anthraxtinib
EP3697390A1 (en) 2017-10-17 2020-08-26 Ignyta, Inc. Pharmaceutical compositions and dosage forms
CN107794282B (en) * 2017-11-20 2020-12-25 浙江工业大学 Preparation method and strain of crizotinib chiral intermediate
WO2019154665A1 (en) * 2018-02-07 2019-08-15 Basf Se New pyridine carboxamides
SG11202008705TA (en) * 2018-03-15 2020-10-29 Fujian Haixi Pharmaceuticals Co Ltd Heteroaryl compounds as kinase inhibitor
CN110372664A (en) * 2018-04-13 2019-10-25 华东理工大学 Selective JAK2 inhibitor and its application
WO2019206049A1 (en) * 2018-04-25 2019-10-31 Zhuhai Yufan Biotechnologies Co., Ltd Hpk1 inhibitors, preparation method and application thereof
CN110396087A (en) * 2018-04-25 2019-11-01 珠海宇繁生物科技有限责任公司 HPK1 kinase inhibitor, preparation method and application thereof
CN108947895B (en) * 2018-08-22 2021-09-24 肇庆中彩机电技术研发有限公司 Compound with anticancer activity
CN113924095A (en) * 2019-01-18 2022-01-11 诺维逊生物股份有限公司 Heterocyclic compounds as adenosine antagonists
CA3126704A1 (en) * 2019-01-18 2020-07-23 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
WO2020150676A1 (en) 2019-01-18 2020-07-23 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
WO2020191208A1 (en) 2019-03-20 2020-09-24 Emory University Prostaglandin receptor ep2 antagonists, derivatives, and uses related thereto
WO2020228747A1 (en) 2019-05-14 2020-11-19 Teligene Ltd Substituted macrocycles useful as kinase inhibitors
KR102426921B1 (en) * 2019-09-24 2022-07-29 주식회사 이노보테라퓨틱스 Heteroarylamidopyridinol derivatives and pharmaceutical composition for use in preventing or treating autoimmune diseases containing the same as an active ingredient
CN112552293A (en) * 2019-09-25 2021-03-26 珠海宇繁生物科技有限责任公司 PROTAC small molecular compound and application thereof
KR102344185B1 (en) * 2020-02-26 2021-12-27 계명대학교 산학협력단 Novel Pim Kinase Inhibitor and Uses Thereof
CN113493437B (en) * 2020-04-03 2022-07-26 中国药科大学 Compound containing benzimidazole structure and preparation method and application thereof
WO2021196655A1 (en) * 2020-04-03 2021-10-07 中国药科大学 Compound containing benzimidazole structure, preparation method therefor and application thereof
EP4433445A1 (en) * 2021-11-15 2024-09-25 The Broad Institute, Inc. Compounds, compositions, and methods for inducing antimicrobial intracellular activity and for preventing and treating microbial infections
CN119451699A (en) 2022-07-04 2025-02-14 中外制药株式会社 Concomitant medication
EP4582104A1 (en) 2022-08-30 2025-07-09 Chugai Seiyaku Kabushiki Kaisha Combination drug

Family Cites Families (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4725601A (en) 1985-06-04 1988-02-16 Fujisawa Pharmaceutical Co., Ltd. Certain imidazo[1,2-a]pyridines useful in the treatment of ulcers
US4966849A (en) 1985-09-20 1990-10-30 President And Fellows Of Harvard College CDNA and genes for human angiogenin (angiogenesis factor) and methods of expression
US5217999A (en) 1987-12-24 1993-06-08 Yissum Research Development Company Of The Hebrew University Of Jerusalem Styryl compounds which inhibit EGF receptor protein tyrosine kinase
GB8827305D0 (en) 1988-11-23 1988-12-29 British Bio Technology Compounds
CA2078214C (en) 1990-04-02 1995-03-28 Robert Lee Dow Benzylphosphonic acid tyrosine kinase inhibitors
US5302606A (en) 1990-04-16 1994-04-12 Rhone-Poulenc Rorer Pharmaceuticals Inc. Styryl-substituted pyridyl compounds which inhibit EGF receptor tyrosine kinase
ES2108120T3 (en) * 1991-05-10 1997-12-16 Rhone Poulenc Rorer Int MONO- AND BICYCLE BIS ARYLIC AND HETEROARILIC COMPOUNDS INHIBITING EGF AND / OR PDGF TYPHOSINE KINASE.
EP0586608A1 (en) 1991-05-29 1994-03-16 Pfizer Inc. Tricyclic polyhydroxylic tyrosine kinase inhibitors
FI941572A7 (en) 1991-10-07 1994-05-27 Oncologix Inc Combination and method of use of anti-erbB-2 monoclonal antibodies
GB9201693D0 (en) 1992-01-27 1992-03-11 Smithkline Beecham Intercredit Compounds
DE69334351D1 (en) 1992-02-06 2011-05-12 Novartis Vaccines & Diagnostic Biosynthetic binding protein for tumor markers
CA2140440A1 (en) 1992-08-06 1994-02-17 Ellen M. Dobrusin 2-thioindoles (selenoindoles) and related disulfides (selenides) which inhibit protein tyrosine kinases and which have antitumor properties
US5330992A (en) 1992-10-23 1994-07-19 Sterling Winthrop Inc. 1-cyclopropyl-4-pyridyl-quinolinones
ES2309119T3 (en) 1992-10-28 2008-12-16 Genentech, Inc. USE OF ANTIGONISTS OF THE VEGF CELLULAR GROWTH FACTOR.
US6177401B1 (en) 1992-11-13 2001-01-23 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften Use of organic compounds for the inhibition of Flk-1 mediated vasculogenesis and angiogenesis
GB9226855D0 (en) 1992-12-23 1993-02-17 Erba Carlo Spa Vinylene-azaindole derivatives and process for their preparation
US5455258A (en) 1993-01-06 1995-10-03 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamic acids
US5521190A (en) * 1993-05-27 1996-05-28 Fmc Corporation Insecticidal pterdines and 8-deazapteridines
JPH07109260A (en) 1993-10-12 1995-04-25 Fuji Photo Film Co Ltd Production of 5-amino-2-nitropyridine derivative and 5-diamond-3-hydroxypyridine derivative
IL112248A0 (en) 1994-01-25 1995-03-30 Warner Lambert Co Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them
US5863949A (en) 1995-03-08 1999-01-26 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
DE69519751T2 (en) 1995-04-20 2001-04-19 Pfizer Inc., New York ARYLSULFONAMIDO-SUBSTITUTED HYDROXAMIC ACID DERIVATIVES AS INHIBITORS OF MMP AND TNF
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US5880141A (en) 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
GB9520822D0 (en) 1995-10-11 1995-12-13 Wellcome Found Therapeutically active compounds
GB9624482D0 (en) 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
PT780386E (en) 1995-12-20 2003-02-28 Hoffmann La Roche MATRIX METALOPROTEASE INHIBITORS
JP4464466B2 (en) 1996-03-05 2010-05-19 アストラゼネカ・ユーケイ・リミテッド 4-anilinoquinazoline derivatives
HRP970371A2 (en) 1996-07-13 1998-08-31 Kathryn Jane Smith Heterocyclic compounds
EA199900021A1 (en) 1996-07-13 1999-08-26 Глаксо, Груп Лимитед BICYCLIC HETEROAROMATIC COMPOUNDS AS PROTEINTHYROSINKINASE INHIBITORS
ID19609A (en) 1996-07-13 1998-07-23 Glaxo Group Ltd HETEROSICLIC COMPOUNDS
JP3299975B2 (en) 1996-07-18 2002-07-08 ファイザー・インク Phosphinate-based inhibitors of matrix metalloproteases
EA199900139A1 (en) 1996-08-23 1999-08-26 Пфайзер, Инк. DERIVATIVES OF ARYL SULPHONYLAMINO HYDROXAMIC ACID
ID18494A (en) 1996-10-02 1998-04-16 Novartis Ag PIRAZOLA DISTRIBUTION IN THE SEQUENCE AND THE PROCESS OF MAKING IT
EP0950059B1 (en) 1997-01-06 2004-08-04 Pfizer Inc. Cyclic sulfone derivatives
NZ336840A (en) 1997-02-03 2001-01-26 Pfizer Prod Inc Arylsulfonylamino hydroxamic acid derivatives useful in the treatment of tumor necrosis factor and matrix metalloproteinase mediated diseases
EP0966438A1 (en) 1997-02-07 1999-12-29 Pfizer Inc. N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases
AU722784B2 (en) 1997-02-11 2000-08-10 Pfizer Inc. Arylsulfonyl hydroxamic acid derivatives
SE9700661D0 (en) * 1997-02-25 1997-02-25 Astra Ab New compounds
JP2002511852A (en) 1997-05-07 2002-04-16 スージェン・インコーポレーテッド 2-indolinone derivatives as modulators of protein kinase activity
CA2291709A1 (en) 1997-05-30 1998-12-03 Merck & Co., Inc. Novel angiogenesis inhibitors
DE69838172T2 (en) 1997-08-22 2008-04-10 Astrazeneca Ab OXINDOLYLCHINAZOLE DERIVATIVES AS ANGIOGENESEHEMMER
WO1999016755A1 (en) 1997-09-26 1999-04-08 Merck & Co., Inc. Novel angiogenesis inhibitors
KR100446363B1 (en) 1997-11-11 2004-09-01 화이자 프로덕츠 인코포레이티드 Thienopyrimidine and thienopyridine derivatives useful as anticancer agents
GB9725782D0 (en) 1997-12-05 1998-02-04 Pfizer Ltd Therapeutic agents
GB9800569D0 (en) 1998-01-12 1998-03-11 Glaxo Group Ltd Heterocyclic compounds
GB9800575D0 (en) 1998-01-12 1998-03-11 Glaxo Group Ltd Heterocyclic compounds
GB9801690D0 (en) 1998-01-27 1998-03-25 Pfizer Ltd Therapeutic agents
PA8469401A1 (en) 1998-04-10 2000-05-24 Pfizer Prod Inc BICYCLE DERIVATIVES OF HYDROXAMIC ACID
PA8469501A1 (en) 1998-04-10 2000-09-29 Pfizer Prod Inc HYDROXAMIDES OF THE ACID (4-ARILSULFONILAMINO) -TETRAHIDROPIRAN-4-CARBOXILICO
SE9801526D0 (en) * 1998-04-29 1998-04-29 Astra Ab New compounds
DK2020408T3 (en) 1998-05-29 2013-09-30 Sugen Inc Pyrrole-substituted 2-indolinone as protein kinase inhibitor
US20010002396A1 (en) * 1998-07-16 2001-05-31 Charles Achkar Compositions and methods of treating skin conditions
EA200100766A1 (en) 1999-02-11 2002-02-28 Пфайзер Продактс Инк. QUINOLIN-2-ON-SUBSTITUTED HETEROAARYNE DERIVATIVES USED AS ANTI-TUMOR AGENTS
GB9908410D0 (en) 1999-04-13 1999-06-09 Pfizer Ltd Pyridines
AU5636900A (en) * 1999-06-30 2001-01-31 Merck & Co., Inc. Src kinase inhibitor compounds
HN2001000008A (en) * 2000-01-21 2003-12-11 Inc Agouron Pharmaceuticals AMIDA COMPOSITE AND PHARMACEUTICAL COMPOSITIONS TO INHIBIT PROTEINKINASES, AND THE INSTRUCTIONS FOR USE
CO5280092A1 (en) 2000-02-15 2003-05-30 Sugen Inc INDOLINAS SUBSTITUTED WITH PROTEINQUINASE INHIBITING PIRROLS
DE60114153T2 (en) 2000-02-16 2006-07-06 Neurogen Corp., Branford SUBSTITUTED ARYLPYRAZINE
AU2001271642B2 (en) 2000-07-07 2006-01-05 Paratek Pharmaceuticals, Inc. 7-substituted tetracycline compounds
CA2423050A1 (en) * 2000-09-20 2002-03-28 Ortho-Mcneil Pharmaceutical, Inc. Pyrazine derivatives as modulators of tyrosine kinases
GB0101577D0 (en) 2001-01-22 2001-03-07 Smithkline Beecham Plc Compounds
WO2002064594A2 (en) * 2001-02-12 2002-08-22 F. Hoffmann-La Roche Ag 6-substituted pyrido-pyrimidines
US6825198B2 (en) 2001-06-21 2004-11-30 Pfizer Inc 5-HT receptor ligands and uses thereof
BR0214309A (en) 2001-11-21 2004-10-13 Upjohn Co Substituted aryl-1,4-pyrazine derivatives
JP4695588B2 (en) * 2003-02-26 2011-06-08 スージェン， インク． Amino heteroaryl compounds as protein kinase inhibitors
ME01788B (en) * 2004-08-26 2011-02-28 Pfizer Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
GEP20094845B (en) * 2004-08-26 2009-11-25 Pfizer Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
US9665874B2 (en) 2012-03-13 2017-05-30 American Express Travel Related Services Company, Inc. Systems and methods for tailoring marketing
US10884952B2 (en) 2016-09-30 2021-01-05 Intel Corporation Enforcing memory operand types using protection keys
JP6943759B2 (en) 2017-12-28 2021-10-06 株式会社東海理化電機製作所 Shift device

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