WO2011038579A1

WO2011038579A1 - Compounds and compositions as protein kinase inhibitors

Info

Publication number: WO2011038579A1
Application number: PCT/CN2010/001541
Authority: WO
Inventors: Xinshan Kang; Richard M. Fine; Borris Klebansky; Wei LONG; Cunbo Ma; Haijun Li; Yanping Wang; Yunyan Hu; Yinxiang Wang
Original assignee: Zhejiang Beta Pharma Inc.
Priority date: 2009-09-30
Filing date: 2010-09-30
Publication date: 2011-04-07
Also published as: CN102216300A; CN102216300B

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Flt3, PDGFR, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c- RAF, AbI, Bcr-Abl, Aurora- A, AxI, BMX, CHK2, CSR0, Fes, FGFRi, FGFR3, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2a, SAPK2ss, SAPK3 SAPK4, Syk, Tie2, TrkA and/or TrkB Kinases.

Description

THE DESCRIPTION

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS

This application claims benefit of priority to Chinese priority patent application serial no.

200910177355.7 filed on September 30, 2009, which is hereby incorporated by reference in its entirety.

Technical Field

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Flt3, PDGFR, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c- RAF, Abl, Bcr-Abl, Aurora- A, Axl, BMX, CHK2, cSRC, Fes, FGFRl, FGFR3, IKKa, IR, J K2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2a, SAPK2ss, SAPK3 SAPK4, Syk, Tie2, TrkA and/or TrkB kinases.

Background Art

The protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function. A partial, non-limiting, list of these kinases include: receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGF-R), the nerve growth factor receptor, trkB, Met, and the fibroblast growth factor receptor, FGFR3; non-receptor tyrosine kinases such Abl and the fusion kinase BCR-Abl, Lck, Csk, Fes, Bmx and c-src; and serine/threonine kinases such as b-RAF, c-RAF, sgk, MAP kinases (e.g., MKK4, MKK6, etc.) and SAPK2a, SAPK2P and SAPK3. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting fiom inappropriate activation of the immune and nervous systems.

The novel compounds of this invention inhibit the activity of one or more protein kinases and are, therefore, expected to be useful in the treatment of kinase-associated diseases. l Summary of Invention

The present invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders.

The present invention first provides at least one compound of Formula I, II, or III:

II

or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a chelate thereof, or a non- covalent complex thereof, or a prodrug thereof,

wherein:

X and Y are selected from N or CH, and at least one of them must be N, which can be optionally substituted with a hydrogen;

R₂ is selected from the group consisting of R₇, OR₇, NR₇R₈, S(0)_qR₇, S0₂NR₇¾, NR₇S0₂R₈, C(0)R₇, C(0)OR₇, C(0)NR₇R₈, NR₇C(0)R₈, or NR₇C(0)OR₈; the said q is independently selected from 0, 1, or 2; the said R₇ and R₈ are independently selected from the group consisting of:

(a) C].₆ linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with 5-8 membered heterocycloalkyl having 1-4 heteroatoms selected from the group consisting of O, N and S, and is optionally substituted with halogen up to per-halo;

(b) Ci_-6 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo;

(c) Ci-io linear, branched, or cyclic polyether chain, and is optionally substituted with halogen up to per-halo;

(d) Ci-io linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with 5-8 membered heterocycloalkyl having 1-4 heteroatoms selected from the group consisting of O, N and S, and is optionally substituted with halogen up to per-halo; or

(e) Ci-io linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo;

Ri and R₃ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, arylalkenyl, alkynyl, aryl, arylalkyl, arylalkynyl, aryloxyalkyl, alkoxycarbonylalkynyl, aryloxyalkynyl, arylsulfanylalkyl, arylsulfanylalkynyl, arylsulfonyloxyalkenyl, carboxy, carboxyalkenyl, carboxyalkyl, cycloalkyl, carboxyalkynyl, cyano, cyanoalkenyl, cyanoalkyl, cyanoalkynyl, cycloalkylalkoxyalkynyl, halogen, heteroarylalkenyl, heteroarylalkyl, heteroarylalkynyl, heteroarylcarbonyl, heteroarylcarbonylalkenyl, heteroarylcarbonylalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkyl, heterocyclylalkynyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylakenyl, cycloalkylalkenyl, cycloalkylalkynyl, formylalkenyl, formylalkyl, haloalkyl, heteroaryl, heterocyclylcarbonylalkyl, heterocyclyloxyalkenyl, hydroxyalkenyl, hydroxyalkyl, hydroxyalkynyl, NR_aRb, (NR_aRb)alkenyl, (NR_aR_b)alkyl, (NR_aR_b )alkynyl, (NR_aR_b)carbonyl, (NR_aR_b)carbonylalkenyl, (NR_aR_b)carbonylalkyl, (NR_aRb)carbonylalkynyl, nitro, nitroalkenyl, nitroalkyl, or Nitroalkynyl; and

The said R_a and R_b are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, aryl, alkylcarbonyl, alkylsulfanylalkyl, alkylsulfonyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylsulfonyl, hydroxyalkoxy alkyl, hydroxyalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, heteroaryl, heteroarylalkyl, (NRcRd)alkylcarbonyl,

(NRcRd)carbonyl, (NRcRd)alkyl, or (NRcRd)carbonylalkyl; wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkoxycarbonylalkyl, the arylalkyl, the arylcarbonyl, and the

arylsulfonyl, the cycloalkyl, the cycloalkyl part of the cycloalkylalkyl, the heteroaryl, the heteroaryl part of the heteroarylalkyl, and the heteroarylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, allcoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, halo, haloalkoxy, haloalkyl, hydroxy, nitro, NRcRd, (NRcRd)alkyl, (NRcRd)alkylcarbonyl, (NRcRd)carbonyl, (NRcRd)carbonylalkyl, oxo, or spiroheterocyclyl, wherein the aryl and the aryl part of the arylalkyl can be substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, nitro, or oxo; and

The said Rc and R are independently selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, carboxyalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, hydroxyalkoxy alkyl, hydroxyalkyl, or (NReRf)alkyl; wherein the said aryl, heteroaryl, and

heterocyclyl can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, or nitro; and

The said Re and Rf are independently selected from the group consisting of hydrogen or alkyl;

The said R4 is selected from C6-io aryl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-C_1-6 alkyl, halosubstituted-Ci_-6 alkoxy, C_5-10 heteroaryl-C_0-4 alkyl, or C_3-8 heterocycloalkyl-Co_-4 alkyl; and the said heteroaryl and heterocycloalkyl substituents of R4 are optionally substituted with Q_-6 alkyl or the N-oxide derivatives;

R₅ and R6 are independently selected from hydrogen or Ci-₆ alkyl; or

R₅ and R^, together with the phenyl ring to which R₅ and R^ are attached form a C_6-10 aryl or C_5-10 heteroaryl.

In some embodiments, X is N.

In some embodiments, Y is N.

In some embodiments, R₂ is selected from the group consisting of R₇, OR7, NR ¾, S0₂NR₇R₈, C(0)R₇, C(0)OR₇, C(0)NR₇R₈, NR₇C(0)R₈, or NR₇C(0)OR₈.

In some embodiments, at least one of R₇ and R₈ are independently selected from the group consisting of:

(a) Ci_-5 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with 5-8 membered heterocycloalkyl having 1 -3 heteroatoms selected from the group consisting of O or N, and is optionally substituted with halogen up to per-halo;

(b) C_1-5 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo;

(c) C_1-8 linear, branched, or cyclic polyether chain, and is optionally substituted with halogen up to per-halo;

(d) Ci_-8 linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with 5-8 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of O or N, and is optionally substituted with halogen up to per-halo; or

(e) Ci_-8 linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo.

In some embodiments, at least one of R₇ and R₈ are independently selected from the group consisting of: (a) Ci_-6 linear, branched, or cyclic polyether chain, and is optionally substituted with halogen up to per-halo;

(b) Ci_-6 linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with 5-8 membered heterocycloalkyl having 1-2 heteroatoms selected from the group consisting of O or N, and is optionally substituted with halogen up to per-halo; or

(c) Ci_-6 linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo.

In some embodiments, at least one of R₇ and R₈ are independently selected from C linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with 5-8 membered heterocycloalkyl having 1-2 heteroatoms selected from the group consisting of O or N, and is optionally substituted with halogen up to per-halo..

In some embodiments, at least one of R and Rg are independently selected from C_1-4 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo.

In some embodiments, at least one of Ri and R₃ are independently selected from the group consisting of hydrogen, holagen, or alkyl.

In some embodiments, at least one of Ri and R₃ are independently selected from the group consisting of holagen or Ci_-6 alkyl.

In some embodiments, at least one of Rj and R₃ are independently selected from the group consisting of hydrogen or holagen.

In some embodiments, Ri and R₃ are both hydrogens..

In some embodiments, R4 is selected from C_6-i₀ aryl optionally substituted with 1 to 2 groups independently selected from halogen, halosubstituted-C alkyl, halosubstituted-Ci_-4 alkoxy, C_5-8 heteroaryl-C_0-4 alkyl, or C_3-6 heterocycloalkyl-C_0-4 alkyl; and the said heteroaryl and

heterocycloalkyl substituents of R4 are optionally substituted with CM alkyl or the N-oxide derivatives.

In some embodiments, R» is selected from C_6-8 aryl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-Ci-4 alkyl, halosubstituted-C^ alkoxy, C_5-8 heteroaryl-Co^ alkyl, or C_3-6 heterocycloalkyl-C_0-4 alkyl; and the said heteroaryl and

heterocycloalkyl substituents of R4 are optionally substituted with Q_-4 alkyl or the N-oxide derivatives. In some embodiments, R4 is selected from C_6-8 aryl optionally substituted with 1 to 2 groups independently selected from halogen, halosubstituted-C_1-4 alkyl, halosubstituted-C alkoxy.

In some embodiments, R4 is phenyl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-C_1-6 alkyl, halosubstituted-Ci- alkoxy, Cs-io heteroaryl-Co^ alkyl, or C_3-8 heterocycloalkyl-Co^ alkyl; and the said heteroaryl and heterocycloalkyl substituents of R4 are optionally substituted with Q_-6 alkyl or the N-oxide derivatives.

In some embodiments, at least one of R₅ and Re are independently selected from hydrogen or C alkyl.

In some embodiments, R₅ and Re are both hydrogens.

In some embodiments, R₅ and R₆, together with the phenyl ring to which R₅ and Re are attached, form quinolinyl or naphthalenyl.

In some embodiments, Rj, R₃, R₅ and Re are independently selected from the group consisting of hydrogen, halogen, or lower alkyl; and R4 is phenyl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-C_1-6 alkyl, halosubstituted-Ci_-6 alkoxy, C5.10 heteroaryl-Co-4alkyl, or C_3-8 heterocycloalkyl-Co-4 alkyl.

In some embodiments, Rj, R₃, R₅ and Re are all hydrogens; and R4 is phenyl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-Ci-6 alkyl, halosubstituted-Ci_-6 alkoxy, C_5-io heteroaryl-C_0-4alkyl, or C_3-8 heterocycloalkyl-C_0-4 alkyl.

In some embodiments, at least one compound selected from:

l-(4-(6-(N-(2-(piperidin-l-yl)ethyl)aminocarbonyl)-lH-indazol-4-yl)phenyl)-3-(3-(trifluoro- methoxy)phenyl)urea

1 -(4-(6-(N-(2-(piperazin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro- methoxy)phenyl)urea

1 -(4-(6-(N-(2-(pyrrolidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3-(3-(trifluoro- methoxy)phenyl)urea

1 -(4-(6-(N-(2-(2-methoxyethoxy)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

1 -(4-(6-(N-((2-methoxyethoxy)methyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3-(3-(trifluoro methoxy)phenyl)urea

1 -(4-(6-(N-(2-(piperidin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro- methoxy)phenyl)urea

1 -(4-(6-(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro- methoxy)phenyl)urea

1 -(4-(6-(N-(2-(pyrrolidin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro- methoxy)phenyl)urea

l-(4-(6-(N-(2-(2-methoxyethoxy)ethyl)amm^

methoxy)phenyl)urea

1 -(4-(6-(N-((2-methoxyethoxy)methyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

1 -(4-(6-(2-(piperidin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea

1 -(4-(6-(2-(piperazin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea

1 -(4-(6-(2-(pyrrolidin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3-(3-(trifluoromethoxy) phenyl)urea

l-(4-(6-(2-(2-methoxyethoxy)ethoxy)-lH-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea

1 -(4-(6-(2-(piperidin- 1 -yl)ethylamino)- lH-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea

1 -(4-(6-(2-(piperazin- 1 -yl)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea

1 -(4-(6-(2-(pyrrolidin- 1 -yl)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea

1 -(4-(6-(2-(2-methoxyethoxy)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea W

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)- H-pyrrolo[2,3-c]pyridin-l -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(piperazin-l-yl)ethyl)aminoca^ H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(Tvi-(2-(pyrrolidin-l-yl)ethyl)ami

H-pyrrolo [2 ,3 -c] pyridin- 1 -yl)pheny l)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-( -(2-(2-methoxyethoxy)ethyl)aminocarbonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)ur

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-((2-methoxyethoxy)methyl)aminocarbonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)

l-(4-chloro-3-(trifluoromethyl)phen^

pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(pyiTolidin- 1 -yl)ethyl)aminosulfonyl)- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-( 1 -(2-methoxyethoxy):

aminosulfonyl)- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3 -(4-(3 -(4-(piperidin- 1 -yl)butyl)- 1 H-pyrrolo[2,3 - c] pyridin- 1 -y l)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 - (4-(3 -(4-(piperazin- 1 -yl)butyl)- 1 H-pyrrolo[2,3 - cjpyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(pyrrolidin- 1 -yl)butyl)-l H-pyrrolo[2,3- cjpyridin- 1 -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(2-methoxyethoxy)butyl)-lH-pyrrolo[2,3- c]pyridin- 1 -yl)phenyl)urea

l-(4-cUoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(2-(2-methoxyethoxy)ethyl)-lH-pyrrolo[2,3- cjpyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)-

1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l^

lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(pyrrolidin- 1 -yl)ethyl)aminocarbonyl) lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(2-methoxyethoxy)ethyl)aminocarbonyl)- 1 H-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-((2-methoxyethoxy)methyl)aminocarbonyl)- 1 H-pyrrolo [3 ,2-c] pyridin-3 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(piperidin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo [3 ,2-c]pyridin-3 -yl)pheny l)ure

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)ure

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l -(N-(2-(pyrrolidin- 1 -yl)ethyl)aminosulfonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-( -(2-(2-niethoxyethoxy)ethyl)aminosulfonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-((2-methoxyethoxy)methyl)aminosulfonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3-(4-( 1 -(3 -(piperidin- 1 -yl)propoxy)- 1 H-pyrrolo[3 ,2- c]pyridin-3 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(3 -(piperazin- 1 -yl)propoxy)- 1 H-pyrrolo [3 ,2- c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(3 -(pyrrolidin- 1 -yl)propoxy)- 1 H-pyrrolo [3 ,2- c]pyridin-3 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3 -(4-( 1 -(2-(2-methoxyethoxy)ethoxy)- 1 H-pyrrolo [3 ,2- c]pyridin-3 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(2-(2-methoxyethoxy)ethyl)- 1 H-pyrrolo[3 ,2- c]pyridin-3 -yl)phenyl)urea.

In a second aspect, the present invention provides a pharmaceutical composition which contains at least one compound of Formulas I, II and III, or a N-oxide derivative, individual isomers or mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

In some embodiments, the said pharmaceutical composition also combines with one or more additional compound.

In a third aspect, the present invention provides the use of the said pharmaceutical composition, in the manufacture of a medicament for treating a disease in which the kinase activity of Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, Abl, Abl-T315I, FGFRl, FGFR3, Aurora- A, Axl, BMX, CHK2, cSRC, Fes, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, PKA, SAPK2a, ROCK-II, Ros, Rskl , SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or TrkB contributes to the pathology and/or symptomology of the disease.

In a fourth aspect, the present invention provides a method for treating a disease in which inhibition of kinase activity, particularly Flt3, PDGFRa, PDGFR , c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, Abl, Bcr-Abl, Aurora- A, Axl, BMX, CHK2, cSRC, Fes, FGFRl, FGFR3, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2a,

SAPK2ss, SAPK3 SAPK4, Syk, Tie2, TrkA and/or TrkB activity, can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formulas I, II and III, or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.

In a fifth aspect, the present invention provides the compound of formulas I, II and III, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in which kinase activity, particularly Flt3, PDGFRoc, PDGFRp, c-KIT, VEGFR1 , VEGFR2,

VEGFR3, c-RAF, Abl, Bcr-Abl, Aurora- A, Axl, BMX, CHK2, cSRC, Fes, FGFR1, FGFR3, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2a, SAPK2ss, SAPK3 SAPK4, Syk, Tie2, TrkA and/or TrkB activity, contributes to the pathology and/or symptomology of the disease.

In a sixth aspect, the present invention provides a process for preparing compounds of

Formulas I, II and III, and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.

Definitions

"Alkyl" refers to a saturated, branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-l-yl, propan-2-yl, and cyclopropan-l-yl, butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l -yl, 2-methyl-propan-2- yl, cyclobutan-l-yl, tert-butyl, and the like. In certain embodiments, an alkyl group comprises from 1 to 20 carbon atoms. As used herein the term "lower alkyl" refers to an alkyl group comprising from 1 to 6 carbon atoms.

"Alkenyl" refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z- or E- forms (or cis or trans conformation) about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop- 1 -en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-1 -en-l-yl; cycloprop-2-en-l-yl; butenyls such as but- 1 -en-l-yl, but-l-en-2-yl, 2-methyl-prop-l -en-l-yl, but-2- en-l-yl, but-2-en-2-yl, buta- 1,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl;and the like. In certain embodiments, an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms, i.e. "lower alkenyl." "Alkynyl" refers to an unsaturated branched or straight-chain having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2- pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. In certain embodiments, an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms ( i.e. "lower alkynyl").

"Alkoxy" refers to a radical -OR where R represents an alkyl. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like.

"Alkoxycarbonyl" refers to a radical -C(0)-OR where R represents an alkyl as defined herein. "Aryl" means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms. For example, aryl may be phenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group.

"Heteroaryl" is as defined for aryl above where one or more of the ring members is a heteroatom. For example heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.

"Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated. For example, C3.i₀

cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

"Heterocycloalkyl" means cycloalkyl, as defined in this application, provided that one or more of the ring carbons indicated, are replaced by a moiety selected from -0-, -N=, -NR-, -C(O)-, -S-, - S(O) - or -S(0)₂-, wherein R is hydrogen, Ci^alkyl or a nitrogen protecting group. For example, C_3-8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8- aza-spiro[4.5]dec-8-yletc.

"Halogen" (or halo) preferably represents chloro or fluoro, but may also be bromo or iodo.

"Kinase Panel" is a list of kinases comprising Abl(human), Abl(T3 151), JAK2, JAK3, ALK, JNK 1 al , ALK4, KDR, Aurora- A, Lck, Blk, MAPK1, Bmx, MAPUPK2, BRK, MEK1,

CaMKII(rat), Met, CDKl/cyclinB, p70S6K7 CHK2, PAK2, CK1 , PDGFRa, CK2, PDK1, c-kit, Pim-2, c-RAF, PKA(h), CSK, PKBa, cSrc, PKCa, DYRK2, Plk3, EGFR, ROCK-I, Fes, Ron,

FGFR3, Ros, Flt3, SAPK2a, Fms, SGK, Fyn, SIK, GSK3/3, Syk, IGF-IR, Tie-2, IKWJ, TrKB, IR, WNK3, IRAK4,ZAP-70, ITK, AMPK(rat), LIMK1, RsU, Axl, LKB1, SAPK2P, BrSK2, Lyn (h), SAP 3, BT , MAP AP- 3, SAP 4, CaM IV, MARK1, Snk, CD 2/cyclinAa MINK, SRPK1, CDK3/cyclinE, MKK4(m), TAK1, CDK51p25, MKK6(h), TBK1, CDK61cyclinD3, MLCK, TrkA, CDK7icyclin WM AT 1 , MRCKJ3, TSSK1, CHK, es, CK1 d, MST2, ZIPK, c-Kit (D816V), MUSK, DAPK2, NEK2, DDR2, NEK6, DMPK, PAK4, DRAK1 , PAR-lBa, EphAl, PDGFRP, EphA2, Pim- 1, EphA5, PKBP, EphB2, PKCPI, EphB4, PKCG, FGFRI, PKCq, FGFR2, PKCB, FGFR4, PKD2, Fgr, PKG1P, Fltl, PRK2, Hck, PYK2, HIPK2, Ret, IKKa, RIPK2, IRR, ROCK-II(human), JNK2a2, Rse, JN'K3, Rskl(h), PI3 Ky, PI3 KG andP13-KP. Compounds of the invention are screened against the kinase panel (wild type and/or mutation thereof) and inhibit the activity of at least one of said panel members.

"Mutant forms of BCR-Abl" means single or multiple amino acid changes from the wild-type sequence. Mutations in BCR-ABL act by disrupting critical contact points between protein and inhibitor (for example, Gleevec, and the like), more often, by inducing a transition from the inactive to the active state, i.e. to a conformation to which BCR-ABL and Gleevec is unable to bind. From analyses of clinical samples, the repertoire of mutations found in association with the resistant phenotype has been increasing slowly but inexorably over time. Mutations seem to cluster in four main regions. One group of mutations (G250E, Q252R, Y253F/H, E255WV) includes amino acids that form the phosphate-binding loop for ATP (also known as the P-loop). A second group (V289A, F31 1 L, T3151 , F317L) can be found in the Gleevec binding site and interacts directly with the inhibitor via hydrogen bonds or Van der Waals' interactions. The third group of mutations (M351T, E355G) clusters in close proximity to the catalytic domain. The fourth group of mutations (H396R1P) is located in the activation loop, whose conformation is the molecular switch controlling kinase activation or inactivation. BCR-ABL point mutations associated with Gleevec resistance detected in CML and ALL patients include: M224V, L248V, G250E, G250R, Q252R, Q252H, Y253H, Y253F, E255K, E255V, D276G, T277A, V289A, F3 1 1L, T3151, T3 15N, F317L, M343T, M3 15T, E355G, F359V, F359A, V3791, F382L, L387M, L387F, H396P, H396R, A397P, S417Y, E459K, and F486S (Amino acid positions, indicated by the single letter code, are those for the GenBank sequence, accession number AAB60394, and correspond to ABL type la; Martinelli et al.,

Haematologica/The Hematology Journal, 2005, April; 90-4). Unless otherwise stated for this invention, Bcr/Abl refers to wild-type and mutant forms of the enzyme. "Treat", "treating" and "treatment" refer to a method of alleviating or abating a disease and/or its attendant symptoms.

"Pharmaceutically acceptable" refers to generally recognized for use in animals, and more particularly in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (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, N-methylglucamine, dicyclohexylamine, and the like.

In another aspect, the present invention is directed to a pharmaceutical composition, comprising : at least one of the above compound and a pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to any of a diluent, adjuvant, excipient or carrier with which at least one compound of the present disclosure is administered.

"Therapeutically effective amount" refers to the amount of a compound that, when

administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The

"therapeutically effective amount" can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements.

As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

Compounds of Formula I, II, and III include, but are not limited to optical isomers of compounds of Formula I, II, and III, racemates, and other mixtures thereof. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, compounds of Formula I, II, and III include Z- and E- forms (or cis- and trans- forms) of compounds with double bonds. Where compounds of Formula I, II, and III exist in various tautomeric forms, chemical entities of the present invention include all tautomeric forms of the compound.

Compounds of the present disclosure include, but are not limited to compounds of Fomula I, II, and III, and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms

(including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of

pharmaceutically acceptable salts. As used henceforth, the term "compound" encompasses not only the compound itself, but also a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, and mixtures of any of the foregoing. As noted above, prodrugs also fall within the scope of chemical entities, for example, ester or amide derivatives of the compounds of Formula I, II, and III. The term "prodrugs" includes any compounds that become compounds of Formula I, II, and III when administered to a patient, e.g., upon metabolic processing of the prodrug. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate and like derivatives of functional groups (such as alcohol oramine groups) in the compounds of Formula I, II, and III.

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C 1.3 alkyl" is specifically intended to individually disclosed methyl, ethyl, and C₃ alkyl (including n- propryl and isopropyl).

The term "n-membered" where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.

The present invention provides compounds, compositions and methods for the treatment of kinase related disease, particularly Flt3, PDGFRa, PDGFRp, c-KIT, VEGFRl, VEGFR2, VEGFR3, c-RAF, Abl, Bcr-Abl, Aurora- A, Axl, BMX, CHK2, cSRC, Fes, FGFR1, FGFR3, IKKa, IR, J K2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2a, SAPK2ss, SAPK3 SAPK4, Syk, Tie2, TrkA and/or TrkB kinase related diseases. For example, leukemia and other proliferation disorders related to BCR-Abl can be treated through the inhibition of wild type and mutant forms of Bcr-Abl.

In one embodiment, with reference to compounds of Formulas I, II and III, R₅ and ¾ are both hydrogen.

In another embodiment, R₅ and R6, together with the phenyl ring to which R₅ and R6 are attached, form quinolinyl or naphthalenyl.

In another embodiment, Ri and R₃ is selected from phenyl optionally substituted with 1 to 3 gruops independently selected from chloro, fluoro, trifiuoro-methyl, methoxy, trifluoro-methoxy, imidazolyl or piperazinyl; wherein said imidazolyl or piperazinyl substituents of Ri and R₃ are optionally substituted with methyl and ethyl.

Preferred compounds of the invention are selected from: 1 -(4-(6-(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3-(3-(trifluoro methoxy)phenyl)urea

1 -(4-(6-(N-(2-(piperazin- 1 -yl)ethyl)aminocarbonyl)-lH-indazol-4-yl)phenyl)-3-(3-(trifluoro methoxy)phenyl)urea

1 -(4-(6-(N-(2-(pyrrolidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

l-(4-(6-(N-(2-(2-methoxyethoxy)ethyl)aminocarbonyl)-lH-indazol-4-yl)phenyl)-3-(3-(triflu^ methoxy)phenyl)urea

1 -(4-(6-(N-((2-methoxyethoxy)methyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

l-(4-(6-( -(2-^iperidin-l-yl)ethyl)aminosulfonyl)-lH-indazol-4-yl)phenyl)-3-(3-(trifluoro methoxy)phenyl)urea

1 -(4-(6-(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3-(3 -(trifluoro methoxy)phenyl)urea

1 -(4-(6-(N-(2-(pyrrolidin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3-(3-(trifluoro methoxy)phenyl)Urea

l-(4-(6-(N-(2-(2-methoxyethoxy)ethyl)aminosulfonyl)-lH-indazol-4-yl)phenyl)-3-(3-(trifluoro methoxy)phenyl)urea

l-(4-(6-(K-((2-methoxyethoxy)methyl)aminosulfonyl)-lH-indazol-4-yl)phenyl)-3-(3-(tri methoxy)phenyl)urea

1 -(4-(6-(2-(piperidin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3-(3-(trifluoromethoxy) phenyl) urea

1 -(4-(6-(2-(piperazin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl) urea

1 -(4-(6-(2-(pyrrolidin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl) urea

1 -(4-(6-(2-(2-methoxyethoxy)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl) urea

l-(4-(6-(2-^iperidin-l-yl)ethylamino)-lH-indazol-4-yl)phenyl)-3-(3-(trifluoromethoxy) phenyl) urea 1 -(4-(6-(2-(piperazin- 1 -yl)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea

l-(4-(6-(2-( yirolidin-l-yl)ethylamm^^

phenyl)urea

l-(4-(6-(2-(2-methoxyethoxy)ethylamino)-lH-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(piperazin- 1 -yl)ethyl)aminocarbonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3-(4-(3 -(N -(2-(pyrrolidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-^

1 H-pyrrolo [2 , 3 -c]pyridin- 1 -y l)pheny l)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-((2-methoxyethoxy)methyl)aminocarbonyl)-

1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(piperidin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(pyrrolidin- 1 -yl)ethyl)aminosulfonyl)- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(l-(2-methoxyethoxy)methyl)aminosulfo^ - 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(4-(piperidin- 1 -yl)butyl)- 1 H-pyrrolo [2,3 -c] pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(4-(piperazin- 1 -yl)butyl)- 1 H-pyrrolo [2,3 -c] pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(4-(pyrrolidin- 1 -yl)butyl)- 1 H-pyrrolo[2,3 -c] pyridin- l-yl)phenyl)urea l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(2-methoxyethoxy)butyl)-lH-pyrrolo[2,3-c] pyridin-1 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(2-(2-methoxyethoxy)ethyl)- 1 H-pyrrolo[2,3-c] pyridin- 1 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(l -(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(piperazin- 1 -yl)ethyl)aminocarbonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3- 1 H-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(TSr-(2-(2-methoxyethoxy)ethyl)aminocarbonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -( -((2-methoxyethoxy)methyl)aminocarbonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(piperidin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo [3 ,2-c]pyridin-3 -y l)pheny l)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-(2-(pyrrolidin-l-yl)ethyl)aminosulfonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(2-methoxyethoxy)ethyl)aminosulfonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-( 1 -(N-((2-methoxyethoxy)methyl)aminosulfonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(3-(piperidin-l-yl)propoxy)-lH-pyrrolo[3,2- c]pyridin-3-yl)phenyl)urea

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(3 -(piperazin- 1 -yl)propoxy)- 1 H-pyrrolo[3 ,2- c]pyridin-3 -yl)phenyl)urea

1 -(4-chloro-3-(trifluoromethy l)phenyl)-3 -(4-( 1 -(3 -(pyrrolidin- 1 -yl)propoxy)- 1 H-pyrrolo [3 ,2- c]pyridin-3-yl)phenyl)urea 1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(2-(2-methoxyethoxy)ethoxy)- 1 H-pyrrolo[3 ,2- c]pyridin-3 -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(2-(2-methoxyethoxy)ethyl)-lH-pyrrolo[3,2- c]pyridin-3 -yl)phenyl)urea.

Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims.

Further preferred compounds of the invention are detailed in the Examples, infra.

Administration and Pharmaceutical Compositions

In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 300mg active ingredient.

Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in fiee form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose andlor glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The

compositions may be sterilized andlor contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). For example, synergistic effects can occur with other immunomodulatory or anti-inflammatory substances, for example when used in combination with cyclosporin, rapamycin, or ascomycin, or

immunosuppressant analogues thereof, for example cyclosporine A (CsA), cyclosporin G, FK-506, rapamycin, or compounds, corticosteroids, cyclophosphamide, azathioprine,

methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate mofetil, 1 5- deoxyspergualin, immunosuppressant antibodies, especially monoclonal antibodies for leukocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, or other immunomodulatory compounds, such as CTLA41g. Where the compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth. The invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.

The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formulas I, II and III, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formulas I, II and III, and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the

administration of 3 or more active ingredients.

Modes for Carrying out the Invention

The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.

Detailed examples of the synthesis of a compound of Formulas I, II and III can be found in the Examples, infra.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.

Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared from N-oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.

Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.

Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography, or preferably, by separation/ resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not - result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds fiom their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.

In summary, the compounds of Formula I, II and III can be made by a process, which involves:

(a) that of reaction schemes widely used by medicinal chemists, or that of reaction schemes as shown in the examples, infra; and

(b) optionally converting a compound of the invention into a pharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention to a non-salt form;

(d) optionally converting an unoxidized form of a compound of the invention into a

pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form;

(f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of the invention to its non- derivatized form.

Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and that other well known methods can similarly be used. Examples

The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds of Formulas I, II and III according to the invention.

Example 1

Synthesis of 1 -(4-(6-(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -

(trifluoromethoxy)phenyl)urea

DBDMH(14.3g, 0.05mol) was added to the solution of compound 1(18. lg, O.lmol) in concentrated H₂SO₄(100ml) in portions. The reaction mixture was stirred at rt for 16h., and then poured into the ice (400g) while stirring for another 20min. Product 2 was collected by filtration and drying (22.1 g, 85%) as solid. Thiolyl chloride (7.2g, 0.06mol) was added into methanol(50ml) drop-wisely at -5°C, and then followed by the addition of 3-bromo-4-methyl-5-nitrobenzoic acid(13g, 0.05mol). The reaction mixture was stirred for 30min at rt, and then refluxed for 2h. The mixtuer was evaporated at reduced pressure and the residue was purified by column chromatograph to give the product 3 (1 1.2g, 82%).

To a mixture of 3(5.1 g,0.02mol) in 100 ml THF was added 10 mL acetic acid and 5.6g Fe. The reaction mixture was stirred and refluxed for 10 hours. After cooled down to room temperature the mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layers was dried over Na2S04. Drying agent was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was treated with 100 ml acetic acid and sodium nitrite (1.52g,0.022mol) while stirring, and then refluxed for 10 hours. The reaction mixture was concentrated under reduced pressure to yield a residue which was diluted with water and extracted with ethyl acetate. The ethyl acetate layers was concentrated under reduced pressure, and the residue was purified by flash column chromatography to give 4 (3.1g, 61%)

A mixture of 4(3.1g,0.012mol) in 50 ml EtOH was treated with LiOH (0.43g,0.018mol)in 10ml water. The reaction mixture was stirred for 20 h at room temperature and then mixture was concentrated under reduced pressure. The residue was diluted with water and PH was adjusted to 4 by the addition of IN HC1. The precipitates was collected by filtration and dried over vacuum to give 5 (2.32g, 80%)

A mixture of 5 (1.21g 0.005mol),CDI(0.82g 0.005mol), 2-(piperidin-l-yl)ethanamine (0.83g 0.005mol ) and DIPEA (0.65g 0.005mol) was dissolved in 20ml DMF and then stirred for 2 h at room temperature . The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography to give 6 (1.05g)

In the nitrogen atmosphere, 6 (0.35 lg), 4-aminophenylboronic acid (0.21g), Sodium

carbonate0.32g and Pd(PPh₃)₄ 1 15.6mg in DME/H₂0 (4: 1 ) 8ml was stirred at 95^°C for 16h. After cooled down to room temperature the reaction mixture was extracted with ethyl acetate 3 X 25ml. All the organic extracts was combined, washed with saturated salt and dried over Na₂S0₄. The drying agent was removed by filtration. The filtrates was concentrated by evaporation to give the compound 7,which was further purified by flash column.

7 (0.363g) in the THF was treated with phenyl 3-(trifluoromethoxy)phenylcarbamate 0.297g. The mixture was stirred at 25 ^°C for lh and then was concentrated by evaporation. The W residue was treated in dichloromethane. The compound 8 was collected by filtration (0.45g, 80%), with the LC-MS [M+H]⁺ m/z 567.5.

Example 2

Synthesis of 1 -(4-(6-(N-(2-(piperazin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 - (3 -(trifluoromethoxy)pheny l)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 568.6.

Example 3

Synthesis of 1 -(4-(6-(N-(2-(pyrrolidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 - (3 -(trifluoromethoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 553.4.

Example 4

Synthesis of 1 -(4-(6-(N-(2-(2-methoxyethoxy)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)- 3 -(3 -(trifluoromethoxy)phenyl)urea.

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 558.3.

Example 5

Synthesis of 1 -(4-(6-(N-((2-methoxyethoxy)methyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)- 3 -(3 -(trifluoromethoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 544.6.

Example 6

Synthesis of 1 -(4-(6-(N-(2-(piperidin- 1 -yl)ethyl)aminosulfonyl)- lH-indazol-4-yl)phenyl)-3-(3- (trifluoromethoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 603.4. Example 7

Synthesis of 1 -(4-(6-(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3- (trifluoromethoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 604.5.

Example 8

Synthesis of 1 -(4-(6-(N-(2-(pyrrolidin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 - (3 -(trifIuoromethoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 589.4.

Example 9

Synthesis of 1 -(4-(6-(N-(2-(2-methoxyethoxy)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)- 3 -(3 -(trifluoromethoxy)phenyl)urea

Arrive at the title compound 8, with the LC-MS [M+H]⁺ m/z 594.4.

Example 10

Synthesis of 1 -(4-(6-(N-((2-methoxyethoxy)methy l)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 - (3 -(trifluoromethoxy)pheny l)ure

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 580.3. Example 11

Synthesis of 1 -(4-(6-(2-(piperidin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 540.4.

Example 12

Synthesis of 1 -(4-(6-(2-(piperazin- 1 -yl)ethoxy)-l H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 541.3.

Example 13

Synthesis of 1 -(4-(6-(2-(pyrrolidin-l -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 526.6. Example 14

Synthesis of l-(4-(6-(2-(2-methoxyethoxy)ethoxy)-lH-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 531.4.

Example 15

Synthesis of 1 -(4-(6-(2-(piperidin- 1 -yl)ethylamino)-l H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 539.5.

Example 16

Synthesis of 1 -(4-(6-(2-(piperazin- 1 -yl)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoro methoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 540.5. Example 17

Synthesis of 1 -(4-(6-(2-(pyrrolidin- 1 -yl)ethylamino)- 1 H-indazol-4-yl)phenyl)-3-(3-(trifluoro methoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 525.4.

Example 18

Synthesis of 1 -(4-(6-(2-(2-methoxyethoxy)ethylamino)- 1 H-indazol-4-yl)phenyl)-3-(3-(trifluoro methoxy)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 530.5.

Example 19

Synthesis of 1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(piperidin- 1 -yl)ethyl) aminocarbonyl)- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 585.9.

Example 20

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3- N-(2-(piperazin-l-yl)ethyl) aminocarbonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 587.0.

Example 21

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(pyrrolidin-l -yl)ethyl) aminocarbonyl)- 1 H-pyrrolo [2,3 -cjpyridin- 1 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 572.1.

Example 22

Synthesis of 1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(2-methoxyethoxy)ethyl) aminocarbonyl)- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 576.9.

Example 23

Synthesis of 1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-((2-methoxyethoxy)methyl) aminocarbonyl)-lH-pyrrolo[2,3-c]pyridin-l-yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 562.7.

Example 24

Synthesis of 1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(piperidin- 1 -yl)ethyl) aminosulfonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 622.0.

Example 25

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(piperazin-l-yl)ethyl) aminosulfonyl)- 1 H-pyrrolo[2,3-c]pyridin-l -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 623.1.

Example 26

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(Tvr-(2-(pyrrolidin-l-yl)ethyl) aminosulfonyl)- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 608.0.

Example 27

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(l-(2-methoxyethoxy) methyl) aminosulfonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 598.9.

Example 28 Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(piperidin-l-yl)butyl)-lH- pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)ure

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 571.1.

Example 29

Synthesis of 1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(piperazin- 1 -yl)butyl)- 1 H- pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)ure

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 571.9.

Example 30

Synthesis of 1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3-(4-(3-(4-(pyrrolidin- 1 -yl)butyl)- 1 H- pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 557.1.

Example 31

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(2-methoxyethoxy)butyl)-lH- pyrrolo[2,3-c]pyridin-l-yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 561.9.

Example 32

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(2-(2-methoxyethoxy)ethyl)-lH- pyrrolo[2,3-c]pyridin-l-yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 533.8.

Example 33

Synthesis of 1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(piperidin- 1 -yl)ethyl) aminocarbonyl)- 1 H-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

Arrive at the title compound 7, with the LC-MS [M+H]⁺ m/z 585.8.

Example 34

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-(2-(piperazin-l-yl)ethyl) aminocarbonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 586.9.

Example 35

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-(2-(pyrrolidin-l-yl)ethyl) aminocarbonyl)- 1 H-pyrrolo[3 ,2-c]pyridin-3 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 571.8.

Example 36

Synthesis of 1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l -(N-(2-(2-methoxyethoxy)ethyl) aminocarbonyl)- 1 H-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

Example 37

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-((2-methoxyethoxy)methyl) aminocarbonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 562.8.

Example 38

Synthesis of 1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l -(N-(2-(piperidin- 1 -yl)ethyl) aminosulfonyl)-lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

Example 39

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-(2-(piperazin-l-yl)ethyl) aminosulfonyl)- 1 H-pyrrolo[3 ,2-c]pyridin-3 -yl)phenyl)urea

Example 40

Synthesis of 1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(N-(2-(pyrrolidin- 1 -yl)ethyl) aminosulfonyl)-lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 607.9.

Example 41

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-(2-(2-methoxyethoxy)ethyl) aminosulfonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 612.9.

Example 42

Synthesis of 1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l -(N-((2-methoxyethoxy)methyl) aminosulfonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 599.0.

Example 43

Synthesis of 1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(3 -(piperidin- 1 -yl)propoxy)- 1 H- pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)ure

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 572.8.

Example 44

Synthesis of 1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(3 -(piperazin- 1 -yl)propoxy)- 1 H- pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 574.0.

Example 45

Synthesis of 1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l -(3-(pyrrolidin- 1 -yl)propoxy)- 1 H- pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)ure

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 558.9.

Example 46

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(2-(2-methoxyethoxy)ethoxy)-lH- pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

Similar procedure to the previous example was followed to arrive at the title compound, with the LC-MS [M+H]⁺ m/z 549.8.

Example 47

Synthesis of l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(2-(2-methoxyethoxy)ethyl)-lH- pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea

The compounds listed in Table 1 below were synthesized according to the general methods shown above.

Table 1

Table 1, continued

Table 1, continued

Table 1, continued

Table 1, continued

Table 1, continued

Assays

Upstate KinaseprofilerTM- Radio-enzymatic filter binding assay

Compounds of the invention are assessed for their ability to inhibit individual members of the kinase panel. The compounds are tested in duplicates at a final concentration of 0.5 uM following this generic protocol. Note that the kinase buffer composition and the substrates vary for the different kinases included in the "Upstate KinaseProfiler™ panel". Kinase buffer (2.5 uL, lOx - containing MnC12 when required), active kinase (0.00 1-0.0 1 Units; 2.5 uL), specific or Poly(Glu4- Tyr) peptide (5-500 uM or .01 mg/ml) in kinase buffer and kinase buffer (50 uM; 5 uL) are mixed in an eppendorf on ice. A Mg/ATP mix (10 uL; 67.5 (or 33.75) mM MgC12, 450 (or 225) uM ATP and 1 uCi/ul [γ- ³²P] (3000 Ci/mmol)) is added and the reaction is incubated at about 30°C for about lOminutes. The reaction mixture is spotted (20 uL) onto a 2cm x 2cm P81 (phosphocellulose, for positively charged peptide substrates) or Whatman No. 1 (for Poly (Glu4-Tye) peptide substrate) paper square. The assay squares are washed 4 times, for 5 minutes each, with 0.75% phosphoric acid and washed once with acetone for 5 minutes. The assay squares are transferred to a scintillation vial, 5 ml scintillation cocktail are added and P incorporation (cpm) to the peptide substrate is quantified with a Beckman scintillation counter. Percentage inhibition is calculated for each reaction.

Compounds of Formulas I, II and III in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. For example, compounds of Formulas I, II and III, at a concentration of 0.5 uM, preferably show a percentage inhibition of greater than 50%, preferably greater than about 70%, against Flt3, PDGFRoc, PDGFRp, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, Abl, AM-T315I, FGFR1 and FGFR3 kinases.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

The inhibition values for certain example compounds of invention in the Enzyme Assays are provided in Table 2 as follows. Table 2

Claims

THE CLAIMS

1. At least one compound of Formula I, II, or III:

I II III

wherein:

R₂ is selected from the group consisting of R₇, OR₇, NR₇R₈, S(0)_qR₇, S0₂NR₇R8, NR₇S0₂R₈, C(0)R₇, C(0)OR₇, C(0)NR₇R₈, NR₇C(0)R₈, or NR₇C(0)OR₈; the said q is independently selected from 0, 1, or 2; the said R₇ and Rs are independently selected from the group consisting of:

(a) C_1-6 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with 5-8 membered heterocycloalkyl having 1 -4 heteroatoms selected from the group consisting of O, N and S, and is optionally substituted with halogen up to per-halo;

(b) C_1-6 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo;

(c) C_1-10 linear, branched, or cyclic polyether chain, and is optionally substituted with halogen up to per-halo;

(e) CMO linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo;

Ri and R₃ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, arylalkenyl, alkynyl, aryl, arylalkyl, arylalkynyl, aryloxyalkyl, alkoxycarbonylalkynyl, aryloxyalkynyl, arylsulfanylalkyl, arylsulfanylalkynyl, arylsulfonyloxyalkenyl, carboxy, carboxyalkenyl, carboxyalkyl, cycloalkyl, carboxyalkynyl, cyano, cyanoalkenyl, cyanoalkyl, cyanoalkynyl, cycloalkylalkoxyalkynyl, halogen, heteroarylalkenyl, heteroarylalkyl, heteroarylalkynyl, heteroarylcarbonyl, heteroarylcarbonylalkenyl, heteroarylcarbonylalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkyl, heterocyclylalkynyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylakenyl, cycloalkylalkenyl, cycloalkylalkynyl, formylalkenyl, formylalkyl, haloalkyl, heteroaryl, heterocyclylcarbonylalkyl , heterocyclyloxyalkenyl, hydroxyalkenyl, hydroxyalkyl, hydroxyalkynyl, NR_aRb, (NR_aR_b)alkenyl, (NR_aR_b)alkyl, (NR_aR_b )alkynyl, (NR_aR_b)carbonyl, (NR_aR_b)carbonylalkenyl, (NR_aR_b)carbonylalkyl, (NR_aR_b)carbonylalkynyl, nitro, nitroalkenyl, nitroalkyl, or Nitroalkynyl; and

The said R_a and R_b are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, aryl, alkylcarbonyl, alkylsulfanylalkyl, alkylsulfonyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylsulfonyl, hydroxyalkoxyalkyl, hydroxyalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, heteroaryl, heteroarylalkyl, (NRcR_d)alkylcarbonyl,

(NRcR_d)carbonyl, (NR_cR_<i)alkyl, or (NRcR_d)carbonylalkyl; wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkoxycarbonylalkyl, the arylalkyl, the arylcarbonyl, and the

arylsulfonyl, the cycloalkyl, the cycloalkyl part of the cycloalkylalkyl, the heteroaryl, the heteroaryl part of the heteroarylalkyl, and the heteroarylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, allcoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, halo, haloalkoxy, haloalkyl, hydroxy, nitro, NRcR_d, (NRcR_d)alkyl, (NRcR_d)alkylcarbonyl, (NRcR_d)carbonyl, (NRcR_d)carbonylalkyl, oxo, or spiroheterocyclyl, wherein the aryl and the aryl part of the arylalkyl can be substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, nitro, or oxo; and

The said Rc and R_d are independently selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, carboxyalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, hydroxyalkoxyalkyl, hydroxyalkyl, or (NReRf)alkyl; wherein the said aryl, heteroaryl, and

heterocyclyl can be optionally substituted with one, two, three, four, or five substituents

independently selected from the group consisting of alkenyl, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, or nitro; and The said R_« and R_f are independently selected from the group consisting of hydrogen or alkyl;

The said R4 is selected from C_6-10 aryl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-Ci_-6 alkyl, halosubstituted-Ci_-6 alkoxy, Cs-io heteroaryl-Co^ alkyl, or C_3-g heterocycloalkyl-C_0-4 alkyl; and the said heteroaryl and heterocycloalkyl substituents of R4 are optionally substituted with Ci_-6 alkyl or the N-oxide derivatives;

R₅ and R^ are independently selected from hydrogen or Ci_-6 alkyl; or

R₅ and R^, together with the phenyl ring to which R₅ and R^ are attached form a C_6-10 aryl or C_5- 10 heteroaryl.

2. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, X is N.

3. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Y is N.

4. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R₂ is selected from the group consisting of R₇, OR₇, NR₇R₈, S0₂NR₇Rg, C(0)R₇, C(0)OR₇, C(0)NR₇R₈, NR₇C(0)R₈, or NR₇C(0)OR₈.

5. At least one compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, at least one of R₇ and R₈ are independently selected from the group consisting of:

(a) C_1-5 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with 5-8 membered heterocycloalkyl having 1 -3 heteroatoms selected from the group consisting of O or N, and is optionally substituted with halogen up to per-halo;

(b) Ci_-5 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo;

(c) Ci-g linear, branched, or cyclic polyether chain, and is optionally substituted with halogen up to per-halo;

(d) Ci-8 linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with 5-8 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of O or N, and is optionally substituted with halogen up to per-halo; or

6. At least one compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein, at least one of R₇ and Rg are independently selected from the group consisting of: (a) C_1-6 linear, branched, or cyclic polyether chain, and is optionally substituted with halogen up to per-halo;

(b) C_1-6 linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with 5-8 membered heterocycloalkyl having 1-2 heteroatoms selected from the group consisting of O or N, and is optionally substituted with halogen up to per-halo; or

(c) C_1-6 linear, branched, or cyclic polyether chain, wherein the said polyether chain is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo.

7. At least one compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein, at least one of R₇ and R₈ are independently selected from C_1-4 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with 5-8 membered heterocycloalkyl having 1-2 heteroatoms selected from the group consisting of O or N, and is optionally substituted with halogen up to per-halo.

8. At least one compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein, at least one of R₇ and R₈ are independently selected from Ci_-4 linear, branched, or cyclic alkyl, wherein the said alkyl is further substituted with amide or sulfonamide, and is optionally substituted with halogen up to per-halo.

9. At least one compound according to any one of claim 6-8 or a pharmaceutically acceptable salt thereof, wherein, Ri, R₃, R₅ and R$ are independently selected from the group consisting of hydrogen, halogen, or lower alkyl; and R₄ is phenyl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-Ci_-6 alkyl, halosubstituted-Ci_-6 alkoxy, C_5-10 heteroaryl-Co^alkyl, or C_3-8 heterocycloalkyl-C_0-4 alkyl.

10. At least one compound according to any one of claim 6-8 or a pharmaceutically acceptable salt thereof, wherein, Rj, R₃, R₅ and R₆ are all hydrogens; and R is phenyl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-C_1- alkyl, halosubstituted- C_1-6 alkoxy.

1 1. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, at least one of R_\ and R₃ are independently selected from the group consisting of hydrogen, holagen, or alkyl.

12. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, at least one of Ri and R₃ are independently selected from the group consisting of holagen or Ci_-6 alkyl.

13. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, at least one of Ri and R₃ are independently selected from the group consisting of hydrogen or holagen.

14. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R_\ and R₃ are both hydrogens.

15. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from Ce-io aryl optionally substituted with 1 to 2 groups independently selected from halogen, halosubstituted-C_1-4 alkyl, halosubstituted-C_1-4 alkoxy, C_5-8 heteroaryl-Co-4 alkyl, or C_3-6 heterocycloalkyl-C_0-4 alkyl; and the said heteroaryl and heterocycloalkyl substituents of R4 are optionally substituted with alkyl or the N-oxide derivatives.

16. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from C _-8 aryl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-Ci-4 alkyl, halosubstituted-C_1-4 alkoxy, C_5-8 heteroaryl-C_0-4 alkyl, or C_3-6 heterocycloalkyl-C_0-4 alkyl; and the said heteroaryl and heterocycloalkyl substituents of i are optionally substituted with Ο alkyl or the N-oxide derivatives.

17. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from C _-8 aryl optionally substituted with 1 to 2 groups independently selected from halogen, halosubstituted-C M alkyl, halosubstituted-C alkoxy.

18. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R4 is phenyl optionally substituted with 1 to 3 groups independently selected from halogen, halosubstituted-Ci_-6 alkyl, halosubstituted-C_1-6 alkoxy, Cs-io heteroaryl-Co^ alkyl, or C_3-8

heterocycloalkyl-C_0-4 alkyl; and the said heteroaryl and heterocycloalkyl substituents of R4 are optionally substituted with C|_-6 alkyl or the N-oxide derivatives.

19. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, at least one of R5 and R6 are independently selected from hydrogen or C alkyl.

20. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R₅ and R^ are both hydrogens.

21. At least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R₅ and R6, together with the phenyl ring to which R₅ and R$ are attached, form quinolinyl or naphthalenyl.

22. At least one compound according to claim 1 selected from: 1 -(4-(6-(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 - (trifluoromethoxy)phenyl)urea;

1 -(4-(6-(N-(2-(piperazin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3-(3- (trifluoromethoxy)phenyl)urea;

1 -(4-(6-(N-(2-(pyrrolidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -

(trifluoromethoxy )phenyl)urea;

l-(4-(6-( -(2-(2-methoxyethoxy)ethyl)aminocarbonyl)-lH-indazol-4-yl)phenyl)-3-(3- (trifluoromethoxy)phenyl)urea;

1 -(4-(6-(N-((2-methoxyethoxy)methyl)aminocarbonyl)- 1 H-indazol-4-yl)phenyl)-3-(3- (trifluoromethoxy )phenyl)urea;

1 -(4-(6-(N-(2-(piperidin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 - (trifluoromethoxy )phenyl)urea;

1 -(4-(6-(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 - (trifluoromethoxy)phenyl)urea;

1 -(4-(6-(N-(2-(pyrrolidin- 1 -yl)ethyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3 -(3 -

(trifluoromethoxy)phenyl)urea;

l-(4-(6-( I-(2-(2-methoxyethoxy)ethyl)aminosulfonyl)-lH-indazol-4-yl)phenyl)-3-(3- (trifluoromethoxy)phenyl)urea;

1 -(4-(6-(N-((2-methoxyethoxy)methyl)aminosulfonyl)- 1 H-indazol-4-yl)phenyl)-3-(3- (trifluoromethoxy)phenyl)urea;

1 -(4-(6-(2-(piperidin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea;

1 -(4-(6-(2-(piperazin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea;

1 -(4-(6-(2-(pyrrolidin- 1 -yl)ethoxy)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea;

l-(4-(6-(2-(2-methoxyethoxy)ethoxy)-lH-indazol-4-yl)phenyl)-3-(3-(trifluoromethoxy) phenyl)urea;

1 -(4-(6-(2-(piperidin- 1 -yl)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea; 1 -(4-(6-(2-(piperazin- 1 -yl)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea;

1 -(4-(6-(2-(pyrrolidin- 1 -yl)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3-(trifluoromethoxy) phenyl)urea;

1 -(4-(6-(2-(2-methoxyethoxy)ethylamino)- 1 H-indazol-4-yl)phenyl)-3 -(3 -(trifluoromethoxy) phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(piperazin- 1 -yl)ethyl)aminocarbonyl)- 1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(pyrrolidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(2-methoxyethoxy)ethyl)aminocarbo 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea;

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-( -((2-methoxyethoxy)methyl)ami

lH-pyrrolo[2,3-c]pyridin-l-yl)phenyl)urea;

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(piperidin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo[2,3-c]pyridin-l-yl)phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-(3 -(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo [2,3 -c]pyridin- 1 -y l)phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)^^

1 H-pyrrolo [2,3 -c]pyridin- 1 -yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-^

— 1 H-pyrrolo[2,3-c]pyridin- 1 -yl)phenyl)urea;

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(piperidin- 1 -yl)butyl)- 1 H-pyrrolo [2,3- c]pyridin- 1 -yl)phenyl)urea;

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3 -(4-(3 -(4-(piperazin- 1 -yl)butyl)- 1 H-pyrrolo [2,3 - cjpyridin- 1 -yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(pyrrolidin-l-yl)butyl)-l H-pyrrolo [2,3- c] pyridin- 1 -yl)phenyl)urea; 1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 4-(3 -(4-(2-methoxyethoxy)butyl)- 1 H-pyrrolo [2,3 - cjpyridin- 1 -yl)phenyl)urea

l-(4-chloro-3-(trifluoromethyl)phenyl)-3 4-(3-(2-(2-methoxyethoxy)ethyl)-lH-pyrrolo[2,3- cjpyridin- 1 -yl)phenyl)urea;

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3 4-( 1 -(N-(2-(piperidin- 1 -yl)ethyl)aminocarbonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 4-( 1 -(N-(2-(piperazin- 1 -yl)ethyl)aminocarbonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 4-( 1 -(N-(2-(pyrrolidin- 1 -yl)ethyl)aminocarbonyl)- 1 H-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3 4-( 1 -(N-(2-(2-methoxyethoxy)ethyl)aminocarbonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3- 4-( 1 -(N-((2-methoxyethoxy)methyl)aminocarbonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea;

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3- 4-( 1 -(N-(2-(piperidin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3- 4-( 1 -(N-(2-(piperazin- 1 -yl)ethyl)aminosulfonyl)- 1 H- pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3- 4-( 1 -(N-(2-(pyrrolidin- 1 -yl)ethyl)aminosulfonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3- 4-( 1 -(N-(2-(2-methoxyethoxy)ethyl)aminosulfonyl)- 1 H-pyrrolo [3 ,2-c]pyridin-3 -yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3- 4-( 1 -(N-((2-methoxyethoxy)methyl)aminosulfonyl)- lH-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea;

1 -(4-chloro-3-(trifluoromethyl)phenyl)-3- 4-( 1 -(3 -(piperidin- 1 -yl)propoxy)- 1 H-pyrrolo [3 ,2- c]pyridin-3 -yl)phenyl)urea;

l-(4-chloro-3-(trifluoromethyl)phenyl)-3- 4-( 1 -(3 -(piperazin- 1 -yl)propoxy)- 1 H-pyrrolo [3,2- c]pyridin-3-yl)phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 - 4-( 1 -(3 -(pyrrolidin- 1 -yl)propoxy)- 1 H-pyrrolo [3 ,2- c]pyridin-3-yl)phenyl)urea; 1 -(4-cUoro-3-(trifluoromethyl)phenyl)-3 -(4-( 1 -(2-(2-methoxyethoxy)ethoxy)- 1 H-pyrrolo [3 ,2- c] pyridin-3 -yl)phenyl)urea;

1 -(4-chloro-3 -(trifluoromethyl)phenyl)-3 -(4-( 1 -(2-(2-methoxyethoxy)ethyl)- 1 H-pyrrolo [3 ,2- c]pyridin-3 -yl)phenyl)urea.

23. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claim 1-22 or pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

24. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claim 1-22 or pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient, with at least one additional compound.

25. Use of at least one pharmaceutical composition according to claim 23 or 24, in the manufacture of a medicament for treating a disease in which the kinase activity of Flt3, PDGFR, c- KIT, RET, Tie2, VEGFRl, VEGFR2, VEGFR3, c-RAF, Abl, Abl-T315I, FGFRl and/or FGFR3 contributes to the pathology and/or symptomology of the disease.

26. Use of at least one pharmaceutical composition according to claim 23 or 24, in the manufacture of a medicament for treating a disease in which the kinase activity of Aurora- A, Axl, BMX, CHK2, cSRC, Fes, IKKa, IR, J K2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, PKA, SAPK2a, ROCK-II, Ros, Rskl, SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or TrkB contributes to the pathology and/or symptomology of the disease.

27. A method for treating a disease in which inhibition of kinase activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which the method comprises administering a therapeutically effective amount of at least one compound according to any one of Claims 1 -22 or pharmaceutically acceptable salt thereof.

28. The method according to claim 27 in which the kinase is selected from Flt3, PDGFR, c-

KIT, RET, Tie2, VEGFRl, VEGFR2, VEGFR3, c-RAF, Abl, Abl-T315I, FGFRl or FGFR3.

29. The method according to claim 27 in which the kinase is selected from Aurora- A, Axl, BMX, CHK2, cSRC, Fes, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, PKA, SAPK2a, ROCK-II, Ros, Rskl, SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or TrkB.

30. Use of at least one compound according to any one of claims 1-22 or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in which the kinase activity of Flt3, PDGFR, c-KIT, RET, Tie2, VEGFR1, VEGFR2, VEGFR3, c-RAF, Abl, AM-T315I, FGFRl and/or FGFR3 contributes to the pathology and/or symptomology of the disease.

31. Use of at least one compound according to any one of claims 1-22 or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in which the kinase activity of Aurora- A, Axl, BMX, CHK2, cSRC, Fes, IKKa, IR, J K2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, PKA, SAPK2a, ROCK-II, Ros, Rskl, SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or TrkB contributes to the pathology and/or symptomology of the disease.