WO2008144253A1

WO2008144253A1 - Protein kinase inhibitors and methods for using thereof

Info

Publication number: WO2008144253A1
Application number: PCT/US2008/063187
Authority: WO
Inventors: Pingda Ren; Xia Wang; Songchun Jiang; Advait Nagle; Barun Okram; Yun He; Yongping Xie; Xing Wang; Shenlin Huang; Xiaodong Wang; Yi Liu; Pamela A. Albaugh; Nathanael S. Gray; Guobao Zhang
Original assignee: Irm Llc
Priority date: 2007-05-14
Filing date: 2008-05-09
Publication date: 2008-11-27

Abstract

The invention provides compounds of formula (l) and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, and methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of AIk, AbI, Aurora-A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, CSK, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRalpha, PDGFRbeta, PKCalpha, SAPK2alpha, Src, SIK, Syk, Tie2 and TrkB kinases.

Description

PROTEIN KINASE INHIBITORS AND METHODS FOR USING THEREOF

Cross-Reference to Related Applications

[0001] This application claims the benefit of U.S. provisional application serial number 60/917,758, filed May 14, 2007, which is incorporated herein by reference in its entirety.

Technical Field

[0002] The invention relates to protein kinase inhibitors, and methods of using such compounds.

Background Art

[0003] 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 (PDGFR), the nerve growth factor receptor, TrkB, Met, and the fibroblast growth factor receptor, FGFR-3 ; non-receptor tyrosine kinases such AbI and the fusion kinase Bcr-Abl, Lck, Csk, Fes, Bmx and Src; and serine/threonine kinases such as B-Raf, C-Raf, Sgk, MAP kinases (e.g., MKK4, MKK6, etc.) and SAPK2α, SAPK2β and SAPK3. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders, as well as diseases resulting from inappropriate activation of the immune and nervous systems.

Disclosure of the Invention

[0004] The invention provides compounds and pharmaceutical compositions thereof, which may be useful as protein kinase inhibitors.

[0005] In one aspect, the invention provides compounds having Formula (1): P A T E N T

GNF Docket No.: P1267PC10

or pharmaceutically acceptable salts thereof, wherein: X¹ and X² are independently CR or N; X³ is CH or N, or C if attached to L¹ or R⁴; Y is a 5-7 membered aryl or heteroaryl containing N, O or S; L¹ and L² are independently NRCO or CONR; R and R¹ are independently H or Ci_₆ alkyl; R² is halo, or an optionally halogenated Ci_₆ alkyl; R³ is halo, an optionally halogenated Ci_₆ alkyl, (CR₂)_qR⁸ or O(CR₂)_qR⁹; R⁴ is H, halo, NR⁶R⁷, NR⁵(CR₂)_PNR⁶R⁷, NR⁵CONR⁶R⁷ or NR⁵CO₂R⁶; R⁵ is H or Ci_6 alkyl;

R⁶ and R⁷ are independently H, an optionally halogenated Ci_₆ alkyl, C₂_₆ alkenyl or C₂_₆ alkynyl; Ci_₆ alkanol, (CR₂)_q-R⁸ or (CR₂)_pO(CR₂)_qR⁹; or R⁶ and R⁷ together with N in NR⁶R⁷ may form an optionally substituted ring;

R and R are independently an optionally substituted C₃_₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl; or R⁹ is H; m is 1-4; and n, p and q are independently 0-4.

[0006] In the above Formula (1), Y may be phenyl, thienyl, pyridyl, pyrazolyl or isoxazolyl. In some examples, R² is Ci_₆ alkyl. In other examples, R³ is halo, an optionally halogenated Ci_₆ alkyl, (CR₂)_qR⁸ or O(CR₂)_qR⁹; and R⁸ and R⁹ are independently an optionally substituted piperidinyl, morpholinyl, imidazolyl or piperazinyl.

[0007] In one embodiment, the invention provides compounds of Formula (2): P A T E N T

GNF Docket No.: P1267PC10

wherein R¹⁰ is halo, an optionally halogenated Ci_₆ alkyl, or OCi_₆ alkyl; R¹¹ is halo, Ci_₆ alkyl, (CR₂)_qR⁸ or O(CR₂)_qR⁹; and

R⁸ and R⁹ are independently an optionally substituted C₃_₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl; or R⁹ is H; and k is 0-2.

[0008] In the above Formula (2), R¹⁰ may be CF₃. In some examples, k is 0 or k is 1 and R¹¹ is halo, Ci_6 alkyl, (CR₂)_qR⁸, O(CR₂)_qR⁹; and R⁸ and R⁹ are independently an optionally substituted piperidinyl, morpholinyl, imidazolyl or piperazinyl.

[0009] In the above Formula (1) and (2), X¹ and X² may each be CH; or one of X¹ or X² is N, and the other is CH.

[0010] In the above Formula (1) and (2), R⁴ may be H, halo, NR⁵(CR₂)_PNR⁶R⁷ or NR⁶R⁷;

R⁶ and R⁷ are independently H, Ci_₆ alkyl, Ci_₆ alkanol, or (CR₂)_qR⁸; or R⁶ and R⁷ together with N in NR⁶R⁷ form an optionally substituted morpholinyl, piperidinyl or pyrrolidinyl; and

R⁸ is an optionally substituted C₃-₇ cycloalkyl, pyridyl, phenyl, morpholinyl, furanyl, naphthalenyl, piperazinyl, pyrimidinyl, imidazolyl, triazolyl, isothiazolyl, isoxazolyl, pyrazolyl or pyrazinyl.

[0011] In certain embodiments, a compound of Formula (1) is selected from: N-(3-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-4-carboxamide, N-(3- (3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-4-carboxamide, N-(2-methyl- 5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-4-carboxamide, N-(2- methyl-5-(3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-4-carboxamide, N-(5-(4-((4-ethylpiperazin-l-yl)methyl)-3- (trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridine-4-carboxamide, N-(2-methyl-5-(4-(morpholinomethyl)-3-(trifluoromethyl)phenylcarbamoyl)phenyl)-lH- pyrrolo[2,3-b]pyridine-4-carboxamide, N-(2-methyl-5-(4-(piperazin-l-ylmethyl)-3- (trifluoromethyl)phenylcarbamoyl)phenyl)-lH-pyrrolo[2,3-b]pyridine-4-carboxamide, N-(2- P A T E N T

GNF Docket No.: P1267PC10 methyl-5-(4-(morpholinomethyl)-3-(trifluoromethyl)phenylcarbamoyl)phenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(4-methyl-lH-imidazol-l-yl)-5- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(4-((4- ethylpiperazin-l-y^methy^-S-Ctrifluoromethy^phenylcarbamoy^^-methylpheny^-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(4-methyl-lH-imidazol-l-yl)-5- (trifluoromethyl)phenylcarbamoyl)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2- methyl-5-(4-((4-methylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenylcarbamoyl)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(4-(morpholinomethyl)-3- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(l-tert- butyl-5-methyl-lH-pyrazole-3-carboxamido)-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide, N-(2-methyl-5-(3-(4-methylpiperazin-l-yl)-5-

(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(3-(4- ethylpiperazin-l-yl)-5-(trifluoromethyl)benzamido)-2-methylphenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, N-(5-(3-(4-(2-hydroxyethyl)piperazin-l-yl)-5- (trifluoromethyl)benzamido)-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5- (5-tert-butylthiophene-2-carboxamido)-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide, N-(2-methyl-5-(3-(l-methylpiperidin-4-yloxy)-5- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(3-(4-hydroxypiperidin-l-yl)-5-(trifluoromethyl)benzamido)-2-methylphenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(3-(4-ethylpiperazin-l-yl)-5- (trifluoromethyl)benzamido) -2-methylphenyl) -4- (methylamino) - 1 H-pyrrolo [2,3 -b]pyridine- 5 - carboxamide, N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(4-methyl-lH-imidazol-l-yl)-5- (trifluoromethyl)benzamido)phenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide, N-(5-(3-(4-ethylpiperazin-l-yl)-5-(trifluoromethyl)benzamido)-2-methylphenyl)- 4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(5-tert-butylthiophene-2- carboxamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)-4- (methylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(l-tert-butyl-5-methyl-lH- pyrazole-3-carboxamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide, N-(2-methyl-5-(3-methylbenzamido)phenyl)-4-(methylamino)-lH-pyrrolo[2,3- P A T E N T

GNF Docket No.: P1267PC10 b]pyridine-5-carboxamide, N-(5-(3-methoxybenzamido)-2-methylphenyl)-4-(methylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(2-tert-butylisonicotinamido)-2-methylphenyl)-4- (methylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(4-fluoro-3- (trifluoromethyl)benzamido) -2-methylphenyl) -4- (methylamino) - 1 H-pyrrolo [2,3 -b]pyridine- 5 - carboxamide, N-(5-(4-chloro-3-(trifluoromethyl)benzamido)-2-methylphenyl)-4-(methylamino)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(3-fluoro-5-(trifluoromethyl)benzamido)-2- methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(5-(3- chlorobenzamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide, N-(5-(3-bromobenzamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, 3-tert-butyl-N-(4-methyl-3-(4-(methylamino)-lH-pyrrolo[2,3- b]pyridine-5-carboxamido)phenyl)isoxazole-5-carboxamide, N-(2-methyl-5-(2-methyl-3- (trifluoromethyl)benzamido)phenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide, 4-(isobutylamino)-N-(2-methyl-5-(2-methyl-3- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, 3-tert-butyl-N-(3-(4-(isobutylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamido)-4- methylphenyl)isoxazole-5-carboxamide, 4-(2-(dimethylamino)ethylamino)-N-(5-(4-((4- ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, 4-(2-(dimethylamino)ethylamino)-N-(2-methyl-5-(3-(piperidin-4- yloxy)-5-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(2-methyl-3-(trifluoromethyl)benzamido)phenyl)-4-(2-morpholinoethylamino)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(piperidin-4-yloxy)-5- (trifluoromethyl)benzamido)phenyl)-4-(2-morpholinoethylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide, 4-(ethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, 4-(2-(dimethylamino)ethylamino)-N-(2-methyl-5-(3- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5- (3-(trifluoromethyl)benzamido)phenyl)-4-(2-morpholinoethylamino)-lH-pyrrolo[2,3-b]pyridine- 5 -carboxamide, 4-((dimethylamino)methylamino)-N-(2-methyl-5-(3-

(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5- (3-(trifluoromethyl)benzamido)phenyl)-4-(2-(4-methylpiperazin-l-yl)ethylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, 4-(3-(dimethylamino)propylamino)-N-(2-methyl-5-(3- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, 4-(3- aminopropylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3- P A T E N T

GNF Docket No.: P1267PC10 b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(2- (piperidin- 1 -yl)ethylamino) - 1 H-pyrrolo [2,3 -b]pyridine-5 -carboxamide , N- (2-methyl- 5 - (3 - (trifluoromethyl)benzamido)phenyl)-4-(4-methylpiperazin-l-ylamino)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, 4-(cyclopropylamino)-N-(2-methyl-5-(3- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, 4-(ethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, 4-(diethylamino)-N-(2-methyl-5-(3- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(2-(pyrrolidin-l-yl)ethylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)- 4-(piperazin-l-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3- (trifluoromethyl)benzamido)phenyl)-4-morpholino-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-((tetrahydrofuran-2-yl)methylamino)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide, 4-(dimethylamino)-N-(2-methyl-5-(3- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, 4-(2- hydroxyethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(2-(pyridin- 3-yl)ethylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5-(3- (trifluoromethyl)benzamido)phenyl)-4- (pyridin- 3 -ylmethylamino) - 1 H-pyrrolo [2,3 -b]pyridine- 5 - carboxamide, 4-(butylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, 4-(benzylamino)-N-(2-methyl-5-(3- (trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-methyl-5- (3-(trifluoromethyl)benzamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide, N-(5-(4- ((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)-7H- pyrrolo[2,3-d]pyrimidine-4-carboxamide, N-(2-methyl-5-(3-

(trifluoromethyl)benzamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide, N-(2-methyl- 5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxamide, N-(5-(4- ((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)-lH- pyrazolo[3,4-b]pyridine-5-carboxamide, 7-chloro-3-(methoxymethyl)-2-methyl-N-(2-methyl-5- (3-(trifluoromethyl)phenylcarbamoyl)phenyl)-3H-imidazo[4,5-b]pyridine-6-carboxamide, and 7- chloro-3-(methoxymethyl)-2-methyl-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-3H- imidazo[4,5-b]pyridine-6-carboxamide. P A T E N T

GNF Docket No.: P1267PC10

[0012] In another aspect, the present invention provides pharmaceutical compositions comprising a compound having Formula (1) or (2), and a pharmaceutically acceptable excipient.

[0013] In yet another aspect, the invention provides methods for inhibiting a kinase, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of Formula (1) or Formula (3),

or pharmaceutically acceptable salts or pharmaceutical compositions thereof, wherein:

X¹ and X² are independently CR or N;

X³ is CH or N, or C if attached to L¹ or R⁴;

Y is a 5-7 membered aryl or heteroaryl containing N, O or S;

L¹ and L² are independently NRCO or CONR;

R and R¹ are independently H or C_1-6 alkyl;

R² is halo, or an optionally halogenated Ci_₆ alkyl;

R³ is halo, an optionally halogenated Ci_₆ alkyl, (CR₂)_qR⁸ or O(CR₂)_qR⁹;

R⁴ is H, halo, NR⁶R⁷, NR⁵(CR₂)_PNR⁶R⁷, NR⁵CONR⁶R⁷ or NR⁵CO₂R⁶;

R⁵ is Ci_₆ alkyl;

R⁶ and R⁷ are independently H, an optionally halogenated C_1-6 alkyl, C₂_6 alkenyl or C₂_6 alkynyl; Ci_₆ alkanol, (CR₂)_q-R⁸ or (CR₂)_pO(CR₂)_qR⁹; or R⁶ and R⁷ together with N in NR⁶R⁷ may form an optionally substituted ring;

R⁸ and R⁹ are independently an optionally substituted C₃-₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl; or R⁹ is H;

R¹² is halo, an optionally halogenated Ci_₆ alkyl, OCi_₆ alkyl, NR⁶R⁷, NR⁵(CR₂)_PNR⁶R⁷, NR⁵CONR⁶R⁷ or NR⁵CO₂R⁶; P A T E N T

GNF Docket No.: P1267PC10 m and o are independently 1-4; and n, p and q are independently 0-4; thereby inhibiting said kinase.

[0014] In the above Formula (1), (2) and (3), suitable substituents will be known to those of ordinary skill in the art, including but not limited to halo, optionally halogenated C_1-6 alkyl, C₂_₆ alkenyl, C_2-6 alkynyl, cyano, nitro or (CR₂)_PR¹³; wherein R¹³ is O(CR₂)_qR¹⁴, S(CR₂)_qR¹⁴, (CR₂)_qCOi_₂R¹⁴, CONR¹⁴(CR₂)_PR¹⁴, SO₂NR¹⁴(CR₂)_PR¹⁴ or NR¹⁴(CR₂)_qR¹⁴ or R¹⁴; R¹⁴ is H, optionally halogenated C_1-6 alkyl, or an optionally substituted C₃-₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl.

[0015] The invention also provides methods for modulating a protein kinase, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound having Formula (1), (2) or (3), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby modulating said protein kinase.

[0016] Examples of protein kinases which may be modulated using the compounds of the invention include but are not limited to AIk, AbI, Aurora-A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), Src, SIK, Syk, Tie2 and TrkB kinases. More particularly, the compounds of Formula (1), (2) or (3) may be used for inhibiting B-Raf, Bcr-Abl or Lck or a combination thereof.

[0017] In yet another aspect, the invention provides methods for ameliorating a condition mediated by a protein kinase, such as a B-Raf, Bcr-Abl or Lck-mediated condition, comprising administering to a system or subject in need of such treatment an effective amount of a compound having Formula (1), (2) or (3) or pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition. For example, the compounds of the invention, optionally in combination with a chemotherapeutic agent, may be used to treat a cell proliferative disorder, including but not limited to, melanoma, leukemia, chronic myelogenous leukemia, lymphoma, osteosarcoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor. The compounds of the invention may also be used to treat an autoimmune disorder, including but not limited to systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, or multiple scleriosis. P A T E N T

GNF Docket No.: P1267PC10

[0018] In the above methods for using the compounds of the invention, a compound having Formula (1), (2) or (3) may be administered to a system comprising cells or tissues. In other embodiments, a compound having Formula (1), (2) or (3) may be administered to a human or animal subject.

[0019] The invention also provides for the use of a compound of Formula (1), (2) or (3), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for treating a condition mediated by a protein kinase.

[0020] The invention also provides for the use of a compound of Formula (1), (2) or (3), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, in the manufacture of a medicament for treating a condition mediated by a protein kinase.

[0021] In the above uses the protein kinases include, but are not limited to, AIk, AbI, Aurora- A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), Src, SIK, Syk, Tie2 and TrkB kinases. More particularly, the protein kinasesare B-Raf, Bcr-Abl or Lck or a combination thereof.

[0022] In the above uses the condition is a cell proliferative disorder or an autoimmune disorder. The cell proliferative disorder include, but are not limited to, melanoma, leukemia, chronic myelogenous leukemia, lymphoma, osteosarcoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor. The autoimmune disorder include, but are not limited to, systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, or multiple sclerosis.

Definitions

[0023] "Alkyl" refers to a moiety and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, and may be straight-chained or branched. An optionally substituted alkyl, alkenyl or alkynyl as used herein may be optionally halogenated (e.g., CF₃), or may have one or more carbons that is substituted or replaced with a heteroatom, such as NR, O or S (e.g., -OCH₂CH₂O-, alkylthiol, thioalkoxy, alkylamine, etc).

[0024] "Aryl" refers to a monocyclic or fused bicyclic aromatic ring containing carbon atoms. For example, aryl may be phenyl or naphthyl. "Arylene" means a divalent radical derived from an aryl group.

[0025] "Heteroaryl" as used herein is as defined for aryl above, where one or more of the ring members are a heteroatom. Examples of heteroaryls include but are not limited to pyridyl, P A T E N T

GNF Docket No.: P1267PC10 indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzoimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.

[0026] A "carbocyclic ring" as used herein refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring containing carbon atoms, which may optionally be substituted, for example, with =0. Examples of carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.

[0027] A "heterocyclic ring" as used herein is as defined for a carbocyclic ring above, wherein one or more ring carbons is a heteroatom. For example, a heterocyclic ring may contain N, O, S, -N=, -S-, -S(O), -S(O)₂-, or -NR- wherein R may be hydrogen, Ci^alkyl or a protecting group. Examples of heterocyclic rings include but are not limited to morpholino, pyrrolidinyl, pyrrolidin-2-one, piperazinyl, piperidinyl, piperidinone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.

[0028] The terms "co- administration" or "combined administration" or the like as used 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.

[0029] The term "pharmaceutical combination" as used herein refers to a product obtained from mixing or combining active ingredients, 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 Formula (1) 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 Formula (1) 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 active ingredients in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0030] The term "therapeutically effective amount" means the amount of the subject compound that will elicit a biological or medical response in a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0031] The term "administration" or "administering" of the subject compound means providing a compound of the invention and prodrugs thereof to a subject in need of treatment. P A T E N T

GNF Docket No.: P1267PC10

[0032] "Kinase Panel" is a list of kinases including but not limited to AbI, Abl(T315I), JAK2, JAK3, ALK, JNKl αl, ALK4, KDR, Aurora-A, Lck, BIk, MAPKl, Bmx, MAPKAP-K2, BRK, MEKl, CaMKII, Met, CDKl/cyclinB, p70S6K, CHK2, PAK2, CKl, PDGFRα, CK2, PDKl, c- Kit, Pim-2, C-Raf, PKA, CSK, PKBα, Src, PKCα, DYRK2, Plk3, EGFR, ROCK-I, Fes, Ron, FGFR-3, Ros, Flt3, SAPK2α, Fms, SGK, Fyn, SIK, GSK3β, Syk, IGFR, Tie-2, IKKβ, TrkB, IR, WNK3, IRAK4, ZAP-70, ITK, AMPK, LIMKl, Rsk2, AxI, LKBl, SAPK2β, BrSK2, Lyn, SAPK3, BTK, MAPKAP-K3, SAPK4, CaMKIV, MARKl, Snk, CDK2/cyclinA, MINK, SRPKl, CDK3/cyclinE, MKK4, TAKl, CDK5/p25, MKK6, TBKl, CDK6/cyclinD3, MLCK, TrkA, CDK7/cyclinH/MATl, MRCKβ, TSSKl, CHKl, MSKl, Yes, CKId, MST2, ZIPK, c-Kit (D816V), MuSK, DAPK2, NEK2, DDR2, NEK6, DMPK, PAK4, DRAKl, PAR-lBα, EphAl, PDGFRβ, EphA2, Rm-I, EphA5, PKB β, EphB2, PKCβl, EphB4, PKCδ, FGFRl, PKCη, FGFR2, PKCΘ, FGFR4, PKD2, Fgr, PKGlβ, Fltl, PRK2, Hck, PYK2, HIPK2, Ret, IKKα, RIPK2, IRR, ROCK-II, JNK2α2, Rse, JNK3, Rskl(h), PI3 Kγ, PI3 Kδ and PI3-Kβ.

Modes of Carrying Out the Invention

[0033] The present invention provides compounds and pharmaceutical compositions thereof, which may be useful as protein kinase inhibitors.

[0034] In one aspect, the invention provides compounds having Formula (1):

or pharmaceutically acceptable salts thereof, wherein:

X¹ and X² are independently CR or N;

X³ is CH or N, or C if attached to L¹ or R⁴;

Y is a 5-7 membered aryl or heteroaryl containing N, O or S;

L¹ and L² are independently NRCO or CONR;

R and R¹ are independently H or Ci_₆ alkyl;

R² is halo, or an optionally halogenated C_1-6 alkyl;

R⁴ is H, halo, NR⁶R⁷, NR⁵(CR₂)_PNR⁶R⁷, NR⁵CONR⁶R⁷ or NR⁵CO₂R⁶; P A T E N T

GNF Docket No.: P1267PC10

R⁵ is d_₆ alkyl;

R⁶ and R⁷ are independently H, an optionally halogenated Ci_₆ alkyl, C₂-₆ alkenyl or C₂-₆ alkynyl; Ci_₆ alkanol, (CR₂)_q-R⁸ or (CR₂)_p0(CR₂)_qR⁹; or R⁶ and R⁷ together with N in NR⁶R⁷ may form an optionally substituted ring;

R⁸ and R⁹ are independently an optionally substituted C₃-₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl; or R⁹ is H; m is 1-4; and n, p and q are independently 0-4.

[0035] In one embodiment, the invention provides compounds of Formula (2):

R⁸ and R⁹ are independently an optionally substituted C₃-₇ cycloalkyl, 5-7 membered aryl, heterocyclic or heteroaryl; or R⁹ is H; and k is 0-2.

[0036] In some embodiments, the invention further provides compounds having Formula (1) and (2), wherein L¹ and L² may be C(=S)-NR, NR-C(=S), C(=NR)-NR or NR-C(=NR).

[0037] In another aspect, the invention provides methods for inhibiting a kinase, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of Formula (1) or Formula (3),

P A T E N T

GNF Docket No.: P1267PC10

X¹ and X² are independently CR or N;

X³ is CH or N, or C if attached to L¹ or R⁴;

Y is a 5-7 membered aryl or heteroaryl containing N, O or S;

L¹ and L² are independently NRCO or CONR;

R and R¹ are independently H or C_1-6 alkyl;

R² is halo, or an optionally halogenated C]_₆ alkyl;

R³ is halo, an optionally halogenated C_1-6 alkyl, (CR₂)_qR⁸ or O(CR₂)_qR⁹;

R⁵ is Ci_₆ alkyl;

R¹² is halo, an optionally halogenated Ci_₆ alkyl, OCi_₆ alkyl, NR⁶R⁷, NR⁵(CR₂)_PNR⁶R⁷, NR⁵CONR⁶R⁷ or NR⁵CO₂R⁶; m and 0 are independently 1-4; and n, p and q are independently 0-4; thereby inhibiting said kinase.

[0038] The present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof. An isotopic variation of a P A T E N T

GNF Docket No.: P1267PC10 compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸0, ³⁵S, ¹⁸F, ³⁶Cl and ¹²³I. Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples, ³H and ¹⁴C isotopes may be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as ²H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

[0039] Compounds having Formula (1), (2) and (3) may be useful as protein kinase inhibitors. For example, compounds having Formula (1), (2) or (3), and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, may be used for the treatment of a kinase-mediated condition or disease, such as diseases mediated by AIk, AbI, Aurora- A, B- Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), Src, SIK, Syk, Tie2 and TrkB kinases, or a combination thereof.

[0040] The compounds of the invention may also be used in combination with a second therapeutic agent, for ameliorating a condition mediated by a protein kinase, such as a B-Raf, Bcr-Abl or Lck-mediated condition. For example, the compounds of the invention may be used in combination with a chemotherapeutic agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.

[0041] Examples of chemotherapeutic agents which may be used in the compositions and methods of the invention include but are not limited to anthracyclines, alkylating agents (e.g., mitomycin C), alkyl sulfonates, aziridines, ethylenimines, methylmelamines, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, folic acid analogs (e.g., dihydrofolate reductase inhibitors such as methotrexate), purine analogs, pyrimidine analogs, enzymes, podophyllotoxins, P A T E N T

GNF Docket No.: P1267PC10 platinum-containing agents, interferons, and interleukins. Particular examples of known chemotherapeutic agents which may be used in the compositions and methods of the invention include, but are not limited to, busulfan, improsulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, aclacinomycins, actinomycin F(I), anthramycin, azaserine, bleomycin, cactinomycin, carubicin, carzinophilin, chromomycin, dactinomycin, daunorubicin, daunomycin, 6-diazo-5-oxo-l-norleucine, doxorubicin, epirubicin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, fluorouracil, tegafur, L-asparaginase, pulmozyme, aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, carboplatin, cisplatin, defofamide, demecolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, etoposide, flutamide, gallium nitrate, hydroxyurea, interferon-alpha, interferon-beta, interferon-gamma, interleukin-2, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, sizofiran, spirogermanium, paclitaxel, tamoxifen, teniposide, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, urethane, vinblastine, vincristine, and vindesine.

Pharmacology and Utility

[0042] Compounds of the invention are screened against the kinase panel (wild type and/or mutation thereof) and may modulate the activity of at least one panel kinase panel member. As such, compounds of the invention may be useful for treating diseases or disorders in which kinases contribute to the pathology and/or symptomology of the disease. Examples of kinases that may be inhibited by the compounds and compositions described herein and against which the methods described herein may be useful include, but are not limited to AIk, AbI, Aurora-A, B- Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, c-SRC, EphBl, EphB2, EphB4, P A T E N T

GNF Docket No.: P1267PC10

FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), Src, SIK, Syk, Tie2 and TrkB kinases, and mutant forms thereof.

[0043] The Ras-Raf- MEK-ERK signaling pathway mediates cellular response to growth signals. Ras is mutated to an oncogenic form in approximately 15% of human cancer. The Raf family belongs to the serine/threonine protein kinase and it includes three members, A-Raf, B-Raf and C-Raf (or Raf-1). The focus on Raf being a drug target has centered on the relationship of Raf as a downstream effector of Ras. However, B-Raf may have a prominent role in the formation of certain tumors with no requirement for an activated Ras allele (Nature 417:949-954 (2002). In particular, B-Raf mutations have been detected in a large percentage of malignant melanomas. Existing medical treatments for melanoma are limited in their effectiveness, especially for late stage melanomas. The compounds of the present invention also inhibit cellular processes involving B-Raf kinase, providing a new therapeutic opportunity for treatment of human cancers, such as melanoma.

[0044] Certain abnormal proliferative conditions are believed to be associated with Raf expression and are, therefore, believed to be responsive to inhibition of Raf expression. Abnormally high levels of expression of the Raf protein are also implicated in transformation and abnormal cell proliferation. These abnormal proliferative conditions are also believed to be responsive to inhibition of Raf expression. For example, expression of the c-Raf protein is believed to play a role in abnormal cell proliferation since it has been reported that 60% of all lung carcinoma cell lines express unusually high levels of c-Raf mRNA and protein. Further examples of abnormal proliferative conditions are hyper-proliferative disorders such as cancers, tumors, hyperplasia, pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis and smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty. The cellular signaling pathway of which Raf is a part has also been implicated in inflammatory disorders characterized by T-cell proliferation (T-cell activation and growth), such as tissue graft rejection, endotoxin shock, and glomerular nephritis, for example.

[0045] The compounds of the present invention may also inhibit cellular processes involving c-Raf kinase. c-Raf is activated by the Ras oncogene, which is mutated in a wide number of human cancers. Therefore inhibition of the kinase activity of c-Raf may provide a way to prevent Ras mediated tumor growth [Campbell, S. L., Oncogene, 17, 1395 (1998)].

[0046] The Src family of kinases is implicated in cancer, immune system dysfunction and bone remodeling diseases. Members of the Src family include the following eight kinases in P A T E N T

GNF Docket No.: P1267PC10 mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, and BIk. For general reviews, see Thomas and Brugge, Annu. Rev. Cell Dev. Biol. (1997) 13, 513; Lawrence and Niu, Pharmacol. Ther. (1998) 77, 81; Tatosyan and Mizenina, Biochemistry (Moscow) (2000) 65, 49; Boschelli et al., Drugs of the Future 2000, 25(7), 717.

[0047] Fyn encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth.

[0048] Lck plays a role in T-cell signaling. Mice that lack the Lck gene have a poor ability to develop thymocytes. The function of Lck as a positive activator of T-cell signaling suggests that Lck inhibitors may be useful for treating autoimmune disease such as rheumatoid arthritis. Molina et al., Nature, 357, 161 (1992). Hck, Fgr and Lyn have been identified as important mediators of integrin signaling in myeloid leukocytes. Lowell et al., J. Leukoc. Diol., 65, 313 (1999). Inhibition of these kinase mediators may therefore be useful for treating inflammation. Boschelli et al., Drugs of the Future 2000, 25(7), 717.

[0049] Lyn, a member of the Src family, plays a role in the regulation of B -cell immune responses. Lyn-deficient mice display disrupted B-cell function, leading to autoimmunity and defective mast cell degranulation. Studies have also suggested that Lyn is a negative regulator of apoptosis in various cell systems. In leukemic cells, Lyn is constitutively activated, and the inhibition of Lyn expression reversed proliferation. In addition, Lyn has been shown to be expressed in colon and PC cells, and that overexpression of a dominant active Lyn in colon cancer cell lines induced chemoresistance. (Goldenberg-Furmanov et al., Cancer Res. 64:1058-1066 (2004)).

[0050] The kinase, c-Src transmits oncogenic signals of many receptors. For example, over- expression of EGFR or HER2/neu in tumors leads to the constitutive activation of c-Src, which is characteristic for the malignant cell but absent from the normal cell. On the other hand, mice deficient in the expression of c-Src exhibit an osteopetrotic phenotype, indicating a key participation of c-Src in osteoclast function and a possible involvement in related disorders. c-Src tyrosine kinase (CSK) influences the metastatic potential of cancer cells, particularly colon cancer.

[0051] c-Kit has a substantial homology to the PDGF receptor and to the CSF-I receptor (c- Fms). Investigations on various erythroid and myeloid cell lines indicate an expression of the c- Kit gene in early stages of differentiation (Andre et al., Oncogene 4 (1989), 1047-1049). Certain tumors such as glioblastoma cells likewise exhibit a pronounced expression of the c-Kit gene. P A T E N T

GNF Docket No.: P1267PC10

[0052] Eph receptors, which include EphA and EphB subfamily, consist of the largest group of receptor tyrosine kinases. EphB was found to be overexpressed in several tumors including ovarian tumors, liver tumors, kidney tumors as well as melanomas. Downregulation of EphB signaling has shown to inhibit tumor growth and metastasis. Therefore, EphB may be an important target for anti-tumorigenic therapies. (Clevers et al., Cancer Res. 66:2-5 (2006); Heroult et al., Experimental Cell Res. 312: 642-650 (2006); and Batlle et al., Nature 435:1126- 1130 (2005)).

[0053] Kinase insert domain-containing receptor (referred to as "KDR" hereinafter) [WO 92/14748; Proc. Natl. Acad. Sci. USA, 88: 9026 (1991)]; Biochem. Biophys. Res. Comm., 187: 1579 (1992); WO 94/11499) and Fms-like tyrosine kinase (referred to as "Fltl" hereinafter) [Oncogene, 5: 519 (1990); Science, 255: 989 (1992)] belong to the receptor type tyrosine kinase family. It has been reported that VEGF specifically binds to Fit- 1 and KDR at Kd values of 20 pM and 75 pM and that Fltl and KDR are expressed in vascular endothelial cells in a specific manner [Proc. Natl. Acad. Sci. USA, 90: 7533 (1993); Proc. Natl. Acad. Sci. USA, 90: 8915 (1993)]. With regard to FIt-I in various diseases, it has been reported that, in comparison with vascular endothelial cells in normal tissues, expression of FIt-I mRNA increases in tumor vascular endothelial cells of human glioblastoma tissues [Nature, 359: 845 (1992)] and tumor vascular endothelial cells of human digestive organ cancer tissues [Cancer Research, 53: 4727 (1993)]. Additionally, it has been reported that expression of FIt-I mRNA is observed by in situ hybridization in vascular endothelial cells of joints of patients with rheumatoid arthritis [J. Experimental Medicine, 180: 341 (1994)]. Studies also suggest that FIt-I plays an important role in tumor angiogenesis.

[0054] Flt3 is a member of the type III receptor tyrosine kinase (RTK) family. Flt3 (Fms-like tyrosine kinase) is also known as Flk-2 (fetal liver kinase T). Aberrant expression of the Flt3 gene has been documented in both adult and childhood leukemias including acute myeloid leukemia (AML), AML with trilineage myelodysplasia (AML/TMDS), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). In approximately 25% of AML, the leukemia cells express a constitutively active form of auto-phosphorylated (p) FLT3 tyrosine kinase on the cell surface. The activity of p-FLT3 confers growth and survival advantage on the leukemic cells. Inhibition of p-FLT3 kinase activity induces apoptosis (programmed cell death) of the leukemic cells. P A T E N T

GNF Docket No.: P1267PC10

[0055] Abelson tyrosine kinase (i.e. AbI, c-Abl) is involved in the regulation of the cell cycle, in the cellular response to geno toxic stress, and in the transmission of information about the cellular environment through integrin signaling. The AbI protein appears to serve a complex role as a cellular module that integrates signals from various extracellular and intracellular sources and that influences decisions in regard to cell cycle and apoptosis. Abelson tyrosine kinase includes sub-types derivatives such as the chimeric fusion (oncoprotein) Bcr-Abl with deregulated tyrosine kinase activity or the v-Abl. Bcr-Abl is important in the pathogenesis of 95% of chronic myelogenous leukemia (CML) and 10% of acute lymphocytic leukemia.

[0056] Compounds of the present invention may inhibit AbI kinase, for example, v-Abl kinase. The compounds of the present invention may also inhibit wild-type Bcr-Abl kinase and mutations of Bcr-Abl kinase, and thus may be suitable for the treatment of Bcr-Abl-positive cancer and tumor diseases, such as leukemias (e.g., chronic myeloid leukemia and acute lymphoblastic leukemia) and other proliferation disorders related to Bcr-Abl. Compounds of the present invention may also be effective against leukemic stem cells, and may be potentially useful for the purification of these cells in vitro after removal of said cells (for example, bone marrow removal), and reimplantation of the cells once they have been cleared of cancer cells (for example, reimplantation of purified bone marrow cells).

[0057] Anaplastic lymphoma kinase (ALK), a member of the insulin receptor superfamily of receptor tyrosine kinases, has been implicated in oncogenesis in hematopoietic and non- hematopoietic tumors. The aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas; and ALK fusion proteins have occurred in anaplastic large cell lymphoma. The study of ALK fusion proteins has also raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies. (Pulford et al., Cell. MoI. Life Sci. 61:2939-2953 (2004)).

[0058] Aurora-A, a serine/threonine mitotic kinase, has been reported to be overexpressed in various human cancers, and its overexpression induces aneuploidy, centrosome amplification and tumorigenic transformation in cultured human and rodent cells. (Zhang et al., Oncogene 23:8720-30 (2004)).

[0059] Bmx/Etk non-receptor tyrosine protein kinase has been implicated in endothelial cell migration and tube formation in vitro. Bmx in endothelium and bone marrow has also been reported to play an important role in arteriogenesis and angiogenesis in vivo, suggesting that Bmx P A T E N T

GNF Docket No.: P1267PC10 may be a novel target for the treatment of vascular diseases such as coronary artery disease and peripheral arterial disease. (He et al., J. Clin. Invest. 116:2344-2355 (2006)).

[0060] Bruton's tyrosine kinase (BTK) gene encodes a cytoplasmic tyrosine kinase that plays an essential role in mediating BCR signaling, (de Weers et al., J. Biol. Chem. 269:23857-23860 (1994); Kurosaki et al., Immunity. 12:1-5 (2000)). Defects in the BTK gene cause Agammaglobulinemia, an X- linked immunodeficiency characterized by failure to produce mature B lymphocyte cells and associated with a failure of Ig heavy chain rearrangement.

[0061] Breast tumor kinase (Brk) is a soluble protein-tyrosine kinase overexpressed in the majority of breast cancers and also in normal skin and gut epithelium, but not in normal breast epithelial cells. (Zhang et al., J Biol. Chem. 280:1982-1991 (2005)).

[0062] The Janus kinases (JAK) are a family of tyrosine kinases consisting of JAKl, JAK2, JAK3 and TYK2. The JAKs play an important role in cytokine signaling. The down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematologic malignancies such as leukemias and lymphomas.

[0063] An important factor in the tumor angiogenesis is vascular endothelium growth factor(VEGF). VEGF can promote and maintain the establishment of tumor vascular system, and can also promote the tumor growth directly. VEGF can induce the mitogenesis and chemotaxis of vascular endothelial cell(VEC) and tumor cell (TC). Almost all types of TC and tumor VEC can secret VEGF, but the expression of VEGF in the normal tissue is very low. In the four VEGF receptors, KDR is the main receptor which gives play to VEGF functions. KDR is highly expressed on the TC and tumor VEC while lowly expressed on the normal tissues. (Ren et al., World J. Gastroentrol. 8:596-601 (2002)).

[0064] Mitogen- activated protein kinases (MAPKs) are members of conserved signal transduction pathways that activate transcription factors, translation factors and other target molecules in response to a variety of extracellular signals. MAPKs are activated by phosphorylation at a dual phosphorylation motif having the sequence Thr-X-Tyr by mitogen- activated protein kinase kinases (MKKs). In higher eukaryotes, the physiological role of MAPK signaling has been correlated with cellular events such as proliferation, oncogenesis, development and differentiation. Accordingly, the ability to regulate signal transduction via these pathways P A T E N T

GNF Docket No.: P1267PC10

(particularly via MKK4 and MKK6) could lead to the development of treatments and preventive therapies for human diseases associated with MAPK signaling, such as inflammatory diseases, autoimmune diseases and cancer.

[0065] Multiple forms of p38 MAPK (α, β, γ, δ), each encoded by a separate gene, form part of a kinase cascade involved in the response of cells to a variety of stimuli, including osmotic stress, UV light and cytokine mediated events. These four isoforms of p38 are thought to regulate different aspects of intracellular signaling. Its activation is part of a cascade of signaling events that lead to the synthesis and production of pro-inflammatory cytokines like TNFα. P38 functions by phosphorylating downstream substrates that include other kinases and transcription factors. Agents that inhibit p38 kinase have been shown to block the production of cytokines, including but not limited to TNFα, IL-6, IL-8 and IL-lβ. Peripheral blood monocytes (PBMCs) have been shown to express and secrete pro-inflammatory cytokines when stimulated with lipopoly saccharide (LPS) in vitro. P38 inhibitors efficiently block this effect when PBMCs are pretreated with such compounds prior to stimulation with LPS. P38 inhibitors are efficacious in animal models of inflammatory disease. The destructive effects of many disease states are caused by the over production of pro-inflammatory cytokines. The ability of p38 inhibitors to regulate this overproduction makes them useful as disease modifying agents.

[0066] Molecules that block p38's function have been shown to be effective in inhibiting bone resorption, inflammation, and other immune and inflammation-based pathologies. Thus, a safe and effective p38 inhibitor would provide a means to treat debilitating diseases that can be regulated by modulation of p38 signaling like. Therefore, compounds of the invention that inhibit p38 activity are useful for the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, autoimmune diseases, and for the treatment of other cytokine mediated diseases.

[0067] PDGF (Platelet-derived Growth Factor) is a commonly occurring growth factor, which plays an important role both in normal growth and also in pathological cell proliferation, such as is seen in carcinogenesis and in diseases of the smooth-muscle cells of blood vessels, for example in atherosclerosis and thrombosis. Compounds of the invention may inhibit PDGF receptor (PDGFR) activity, and may therefore be suitable for the treatment of tumor diseases, such as gliomas, sarcomas, prostate tumors, and tumors of the colon, breast, and ovary.

[0068] Compounds of the present invention, may be used not only as a tumor-inhibiting substance, for example in small cell lung cancer, but also as an agent to treat non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma and fibrosis. P A T E N T

GNF Docket No.: P1267PC10

Compounds of the present invention may also be useful for the protection of stem cells, for example to combat the hemotoxic effect of chemotherapeutic agents, such as 5-fluoruracil, and in asthma. Compounds of the invention may especially be used for the treatment of diseases, which respond to an inhibition of the PDGF receptor kinase.

[0069] Compounds of the present invention may exhibit useful effects in the treatment of disorders arising as a result of transplantation, for example, allogenic transplantation, especially tissue rejection, such as obliterative bronchiolitis (OB), i.e. a chronic rejection of allogenic lung transplants. In contrast to patients without OB, those with OB often show an elevated PDGF concentration in bronchoalveolar lavage fluids.

[0070] Compounds of the present invention may also be effective against diseases associated with vascular smooth-muscle cell migration and proliferation (where PDGF and PDGFR often also play a role), such as restenosis and atherosclerosis. These effects and the consequences thereof for the proliferation or migration of vascular smooth-muscle cells in vitro and in vivo may be demonstrated by administration of the compounds of the present invention, and also by investigating its effect on the thickening of the vascular intima following mechanical injury in vivo.

[0071] Protein kinase C (PKC) functions in processes relevant to carcinogenesis, tumor cell metastasis, and apoptosis. PKCα is associated with a diverse range of cancers, and is previously shown to be overexpressed in three out of four antiestrogen resistant breast cancer cell lines. (Frankel et al., Breast Cancer Res Treat. 2006 Oct. 24 (ePub)).

[0072] The stress activated protein kinases (SAPKs) are a family of protein kinases that represent the penultimate step in signal transduction pathways that result in activation of the c-Jun transcription factor and expression of genes regulated by c-Jun. In particular, c-Jun is involved in the transcription of genes that encode proteins involved in the repair of DNA that is damaged due to genotoxic insults. Therefore, agents that inhibit SAPK activity in a cell prevent DNA repair and sensitize the cell to agents that induce DNA damage or inhibit DNA synthesis and induce apoptosis of a cell or that inhibit cell proliferation.

[0073] The region encompassing the SNFlLK locus (also known as SIK) has been implicated in congenital heart defects often observed in patients with Down syndrome. Snf Ilk is also expressed in skeletal muscle progenitor cells of the somite beginning at 9.5 dpc, suggesting a more general role for snf Ilk in the earliest stages of muscle growth and/or differentiation. (Genomics 83:1105-15 (2004)). P A T E N T

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[0074] Syk is a tyrosine kinase that plays an important role in mast cell degranulation and eosinophil activation. Accordingly, Syk kinase is implicated in various allergic disorders, in particular asthma. It has been shown that Syk binds to the phosphorylated gamma chain of the FcεRl receptor via N-terminal SH₂ domains, and is important for downstream signaling.

[0075] An inhibition of tumor growth and vascularization, and a decrease in lung metastases during adenoviral infections or during injections of the extracellular domain of Tie-2 (Tek)have been shown in breast tumor and melanoma xenograft models. Lin et al., J. Clin. Invest. 100, 8: 2072-2078 (1997) and P. Lin, PNAS 95, 8829-8834, (1998). Tie2 inhibitors can be used in situations where neovascularization takes place inappropriately (i.e. in diabetic retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma, chronic neovascularization due to macular degeneration, rheumatoid arthritis, infantile haemangioma and cancers).

[0076] The Trk family of neurotrophin receptors (TrkA, TrkB, TrkC) promotes the survival, growth and differentiation of the neuronal and non-neuronal tissues. The TrkB protein is expressed in neuroendocrine-type cells in the small intestine and colon, in the alpha cells of the pancreas, in the monocytes and macrophages of the lymph nodes and of the spleen, and in the granular layers of the epidermis (Shibayama and Koizumi, 1996). Expression of the TrkB protein has been associated with an unfavorable progression of Wilms tumors and of neuroblastomas. Moreover, TrkB is expressed in cancerous prostate cells but not in normal cells. The signaling pathway downstream of the Trk receptors involves the cascade of MAPK activation through the She, activated Ras, ERK-I and ERK-2 genes, and the PLC-gamma transduction pathway (Sugimoto et al., Jpn J. Cancer Res. 2001 Feb; 92(2): 152-60).

[0077] The class III receptor tyrosine kinases (RTKs), which include c-FMS, c-KIT, FLT3, platelet-derived growth factor receptor α(PDGFRα) and /^PDGFR/)), have been reported to be associated with the pathogenesis of an increasing number of malignancies. (Blume-Jensen et al., Nature 411:355-565 (2001); Scheijin et al., Oncogene 21:3314-3333 (2002)).

[0078] In accordance with the foregoing, the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount of a compound of Formula (1), (2) or (3) or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. (See, "Administration and Pharmaceutical Compositions," infra) P A T E N T

GNF Docket No.: P1267PC10

Administration and Pharmaceutical Compositions

[0079] 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 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, 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 50 mg active ingredient.

[0080] Compounds of the invention may be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally in the form of tablets or capsules; 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.

[0081] Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may 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 and/or glycine; and/or b) lubricants, e.g., silica, talcum, stearic acid or its magnesium or calcium salt and/or polyethyleneglycol. Tablets may further comprise c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; and 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.

[0082] The compositions may be sterilized and/or 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 P A T E N T

GNF Docket No.: P1267PC10 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, may be aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0083] Compounds of the invention may 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 cyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or comparable compounds, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate mofetil, 15-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.

[0084] 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.

Processes for Making Compounds of the Invention

[0085] General procedures for preparing compounds of the invention are described in the Examples, infra. In the reactions described, reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, may be protected to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice (see e.g., T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991). P A T E N T

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[0086] A compound of the invention may 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 may 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 may be prepared using salts of the starting materials or intermediates.

[0087] The free acid or free base forms of the compounds of the invention may 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 may 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 may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0088] Compounds of the invention in unoxidized form may 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 8O⁰C.

[0089] Prodrug derivatives of the compounds of the invention may be prepared by methods known to those of ordinary skill in the art (See e.g., Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs may 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).

[0090] Compounds of the present invention may be conveniently prepared or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

[0091] Compounds of the invention may 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. Resolution of enantiomers may be carried out using covalent diastereomeric derivatives of the compounds of the invention, or by using dissociable complexes (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting P A T E N T

GNF Docket No.: P1267PC10 points, boiling points, solubility, reactivity, etc.), and may be readily separated by taking advantage of these dissimilarities. The diastereomers may be separated by chromatography, or 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 from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.

[0092] In summary, compounds having Formula (1), (2) or (3) may be made by a process as described in the Examples; and

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

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

(c) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;

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

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

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

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

[0093] Insofar as the production of the starting materials is not particularly described, the compounds are known or may 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.

[0094] The following examples are offered to illustrate but not to limit the invention. P A T E N T

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Example 1 lH-pyrrolor2,3-blpyridine-4-carboxylic acid r3-(3-trifluoromethyl-benzoylamino)-phenyll- amide

lH-Pyrrolor2,3-fclpyridine-4-carboxylic acid

[0095] To a solution of 4-bromo-lH-pyrrolo[2,3-£]pyridine (490 mg, 2.49 mmol) in dry TΗF (15 mL) at -78 ⁰C is added n-BuLi (1.6 M in hexanes) in 10 min. After stirring 45 min at that temperature, crushed dry ice is added. The cold bath is removed and the reaction is allowed to warm up to rt. The solvent is evaporated, and the light yellow solid is dissolved in water (20 mL) and extracted with EtOAc (2x25 mL). The aqueous is acidified with IN HCl to pΗ = 4; and the white precipitate is collected by filtration, washed with water, and dried in vacuo. MS m/z 163.3 (M + 1).

lH-Pyrrolor2,3-^lpyridine-4-carboxylic acid r3-(3-trifluoromethyl-benzoylamino)- phenyll -amide

[0096] To a solution of lH-pyrrolo[2,3-&]pyridine-4-carboxylic acid (59mg, 0.364 mmol) and ΗATU (274 mg, 0.721 mmol) in dry DMF (3 mL) is added DIEA (189 μL, 1.09 mmol). After stirring at rt for 10 min, 1/6 portion of the reaction is added to a vial containing N-(3-amino- phenyl)-3-trifluoromethyl-benzamide (25 mg, 0.089 mmol). After stirring for 2.5 h, sodium hydroxide solution (IN, 0.1 mL) is added and reaction is stirred at 60 ⁰C for 4 hr. An additional 0.25 mL INNaOH is added, and the reaction mixture is stirred for 30 min. The reaction is neutralized with IN HCl (0.35 mL), and purified by ΗPLC to give an off-white powder as trifluoroacetic acid salt. ¹H ΝMR 400 MHz (DMSO-J₆) δ 11.89 (s, IH), 10.50 (s, IH), 10.45 (s, P A T E N T

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IH), 8.32 (m, 2H), 8.26 (s, IH), 8.23(d, J = 8.0 Hz, IH), 7.91(d, J = 7.6Hz, IH), 7.73 (t, J = 8.0 Hz, IH), 7.57 (t, J = 6.8 Hz, IH), 7.51(m, IH), 7.47-7.43 (m, 2H), 7.30(t, J = 8.0, IH), 6.71 (dd, J = 2.0, 3.2 Hz, IH); MS m/z 425.2 (M + 1).

[0097] Table 1 describes representative compounds obtained by the above procedure.

Table 1

PATENT

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P A T E N T

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Example 2 lH-Pyrrolor2,3-blpyridine-5-carboxylic acid r2-methyl-5-(4-morpholin-4-ylmethyl-3- trifluoromethyl-phenylcarbamovD-phenyll-amide

1) HATU/DIEA

4-Chloro- 1-triisopropylsilanyl- lH-pyrrolor2,3-frlpyridine

TI

[0098] To a solution of 4-chloro-lH-pyrrolo[2,3-£]pyridine (3.21 g, 21 mmol) in TΗF (60 mL), cooled at -78 ⁰C, is slowly added n-BuLi (1.6 M in hexane, 13.8 mL, 22 mmol). After stirring for 30 minutes, TIPSOTf (5.77 mL, 21.4 mmol) is added. The mixture is allowed to rise to room temperature and quenched with water. The mixture is partitioned between hexanes (200 mL) and brine. The organic extracts are washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluting with hexanes) to afford the title compound. ¹H NMR 600 MHz (acetone-J₆) δ 8.19 (d, IH, J = 5.4 Hz), 7.57 (J, IH, J = 3.0 Hz), 7.18 (J, IH, J = 5.4 Hz), 6.69 (d, IH, J = 3.0 Hz), 1.92 (sept, 3H, J = 7.2 Hz ), 1.12 (J, 18H, J = 7.2 Hz); MS m/z 309.2 (M + 1). P A T E N T

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4-Chloro- 1-triisopropylsilanyl- lH-pyrrolor2,3-£lpyridine-5-carboxyric acid

[0099] To a solution of 4-chloro- 1-triisopropylsilanyl- lH-pyrrolo[2,3-&]pyridine (3.18g, 10.3 mmol) in TΗF (30 mL) at -78 ⁰C is added sec-BuLi (1.4M, 13.2 mL). After stirring for 45 min., dry ice is added to the reaction. The cold bath is removed and the reaction is stirred for two hours. The reaction is quenched with IN HCl (20 mL, pΗ = 2), extracted with EtOAc, washed with brine, dried over Na₂SO₄ and evaporated.

1-Triisopropylsilanyl- lH-pyrrolor2,3-^lpyridine-5-carboxylic acid

[0010O] A suspension of 4-chloro- 1-triisopropylsilanyl- lH-pyrrolo[2,3-&]pyridine (355 mg, 1 mmol), triethylamine (0.4 mL) and Pd catalyst (10% on wet carbon, 50 mg) in EtOH (20 mL) is stirred under hydrogen atmosphere (1 atm). After 14 hr., additional 60 mg Pd catalyst is added and the reaction continued for additional 29 hr. The reaction mixture is filtered through a pad of celite. The filtrate is evaporated. Water (10 mL) is added and the reaction is acidified to pΗ = 4 with 1NΗC1. The aqueous is extracted with EtOAc (2x50 mL). EtOAc is washed with brine (10 mL), dried over MgSO₄, and evaporated to give a white solid. MS m/z 319.2 (M + 1).

lH-Pyrrolor2,3-£1pyridine-5-carboxyric acid r2-methyl-5-(4-morpholin-4-ylmethyl-3- trifluoromethyl-phenylcarbamovD-phenyll-amide

[0010I] To a solution of l-triisopropylsilanyl-lH-pyrrolo[2,3-&]pyridine-5-carboxylic acid (21 mg, 0.066 mmol) and ΗATU (24 mg, 63 mmol) in anhydrous DMF (0.5 mL) is added DIEA (34 μL, 0.196 mmol). After stirring at rt for two min., the aniline 3-amino-4-methyl-N-(4-morpholin- P A T E N T

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4-ylmethyl-3-trifluoromethyl-phenyl)-benzamide (24 mg, 0.061 mmol) is added. The reaction is stirred at rt for one week. NaOH solution (IN, 0.1 mL) is added and the reaction is stirred at 50 ⁰C for 30 min. The reaction is purified by HPLC to afford the product as a white powder. MS m/z 538.2 (M + 1).

[00102] Table 2 describes representative compounds obtained by the above procedure.

Table 2

PATENT

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Example 3 lH-pyrrolor2,3-blpyridine-5-carboxylic acid r2-methyl-5-(4-morpholin-4-ylmethyl-3- trifluoromethyl-benzoylamino)-phenyll-amide

P A T E N T

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H₉N

BocHN

(3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl ester

[00103] To the solution of 4-Me-3-nitroaniline (3.02 g, 20 mmol) in THF (25 ml) is added di- tert-butyl dicarbonate (5.16 g, 1.2 eq.). The reaction is refluxed for 8 hours, and 1.0 g of άi-tert- butyl dicarbonate is added and reaction is further refluxed for 4 hours. The reaction mixture is concentrated under reduced pressure and purified by flash chromatography.

[00104] Into a solution of (4-methyl-3-nitro-phenyl)-carbamic acid tert-butyl ester (1.0 g, 3.96 mmol, 1.0 eq.) in MeOH (25 ml) is added Pd-C (0.1 g, 10 wt %). The suspension is stirred under hydrogen atmosphere in a Parr shaker (60 psi) for 24 hours. The reaction mixture is then filtered over celite and the filtrate is concentrated under reduced pressure to give the desired product. IH P A T E N T

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NMR δ 7.19 (s, IH), 6.93 (s, IH), 6.87 (d, IH, J = 8.0 Hz), 6.52 (d, IH, J =8.0 Hz), 6.32 (s, IH). MS m/z 223.1(M + 1).

{3-r(4-Chloro-lH-pyrrolor2,3-^lpyridine-5-carbonyl)-aminol-4-methyl-phenyll- carbamic acid tert-butyl ester

[00105] To a solution of 4-chloro-l-triisopropylsilanyl-lH-pyrrolo[2,3-&]pyridine-5- carboxylic acid (355 mg, 1.006 mmol) in CH₂Cl₂ (10 niL) at 0 ⁰C is added oxalyl chloride (2M in CH₂Cl₂, 1 mL, 2 mmol) and DMF (50 μL). The ice bath is removed after addition. After stirring at rt for Ih, the solvent is removed to give a white residue.

[0100] To a suspension of acyl chloride in CH₂Cl₂ (20 mL) at 0 ⁰C is added (3-amino-4- methyl-phenyl)-carbamic acid tert-butyl ester (232 mg, 1.04 mmol), followed by slow addition of DIEA (1.05 mL). The yellow solution is warmed up slowly and stirred at rt overnight. EtOAc (100 mL) and water (20 mL) are added. The aqueous layer is separated. EtOAc is washed with brine (10 mL), dried over MgSO₄, and evaporated to give a light amber colored residue.

[0101] The above crude is dissolved in methanol (20 mL). NaOH solution (IN, 1.0 mL) is added. After stirring at rt for 4 h, EtOAc (100 mL) and water (10 mL) are added. The aqueous layer is separated; and EtOAc is dried over MgSO₄, and evaporated to give a white solid. The solid is suspended in methanol (10 mL) and stirred for several hours. The suspension is filtered to give an off white solid product. MS m/z 401.1 (M + 1).

lH-Pyrrolor2,3-£1pyridine-5-carboxyric acid (5-amino-2-methyl-phenyl)-amide

[0102] A suspension of {3-[(4-chloro-lH-pyrrolo[2,3-&]pyridine-5-carbonyl)-amino]-4- methyl-phenyl}-carbamic acid tert-butyl ester (520 mg, 1.30 mmol) and Pd/C (10% wet, 280 mg) in EtOΗ/TΗF (3:1) is stirred under 1 atm H₂ atmosphere overnight. The reaction is filtered P A T E N T

GNF Docket No.: P1267PC10 through celite, washed with EtOH/THF (3:1), and concentrated. The crude is purified by column chromatography (SiO₂, EtOAc:hexanes/20-100%) to give the product. MS m/z 267.1 (M + 1).

[0103] To a solution of the above product in MeOH (20 niL) and THF (20 niL) is added IN HCl (10 mL). The reaction is stirred at 60 ⁰C for 4 hours, then 50 ⁰C overnight. The solvent is evaporated. The residue is basified with saturated Νa₂Cθ₃, and extracted with EtOAc (2x50 mL). The EtOAc is dried, evaporated and the crude is purified by column chromatography to give the desired product.

lH-Pyrrolor2,3-frlpyridine-5-carboxyric acid r2-methyl-5-(4-morpholin-4-ylmethyl-3- trifluoromethyl-benzoylamino)-phenvH-amide

[0104] To a solution of 4-morpholin-4-ylmethyl-3-trifluoromethyl-benzoic acid (17 mg, 0.052 mmol) and HATU (19 mg, 0.050 mmol) in anhydrous DMF (0.5 mL) is added DIEA (45 μL, 0.26 mmol) at rt. The reaction is stirred for two min, then a solution of iH-pyrrolo[2,3- &]pyridine-5-carboxylic acid (5-amino-2-methyl-phenyl)-amide (12.5 mg, 0.047 mmol) in 0.5 mL DMF is added. After stirring at rt overnight, the reaction is purified by ΗPLC to give an off-white solid as TFA salt. MS m/z 538.2 (M + 1).

[0105] Table 3 describes representative compounds obtained by the above procedure.

Table 3

PATENT

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Example 4 -methylamino-lH-pyrrolor2,3-blpyridine-5-carboxylic acid { 5-r3-(4-ethyl-piperazin-l-yl)-5- trifluoromethyl-benzoylaminol-2-methyl-phenyll -amide

P A T E N T

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4-Methylamino- lH-pyrrolor2,3-£lpyridine-5-carboxyric acid (5-amino-2-methyl- phenvD-amide

[0106] To a solution of the {3-[(4-chloro-lH-pyrrolo[2,3-&]pyridine-5-carbonyl)-amino]-4- methyl-phenyl}-carbamic acid tert-butyl ester (173 mg, 0.43 mmol) in 2-methoxy-ethanol (2 mL) is added methylamine (40% in water, 2mL). The reaction is heated in a microwave reactor for 30 min at 130 ⁰C, and evaporated to give a white solid. MS m/z 396.2 (M + 1).

[0107] To a suspension of the above crude in CH₂Cl₂ (10 mL) is slowly added TFA (2 mL). After stirring at rt for one hr. the solvent is evaporated. The residue is dissolved in water (10 mL), and basified with IN NaOH. The off-white product is collected by filtration. MS m/z 296.1 (M + 1).

4-Methylamino- lH-pyrrolor2,3-£lpyridine-5-carboxyric acid { 5-r3-(4-ethyl-piperazin- 1- yl)-5-trifluoromethyl-benzoylaminol-2-methyl-phenyl| -amide

[0108] The title compound is prepared from 4-methylamino-lH-pyrrolo[2,3-&]pyridine-5- carboxylic acid (5-amino-2-methyl-phenyl)-amide and 3-(4-ethyl-piperazin-l-yl)-5- trifluoromethyl-benzoic acid in a manner similar to that of Example 3 for 1H-Pyrrolo[2,3- &]pyridine-5-carboxylic acid [2-methyl-5-(4-morpholin-4-ylmethyl-3-trifluoromethyl- benzoylamino)-phenyl]-amide.

[0109] Table 4 describes representative compounds obtained by the above procedure. PATENT

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Table 4

PATENT

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PATENT

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δ 1)

PATENT

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PATENT

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P A T E N T

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Example 5

4-(ethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolor2,3- bl pyridine-5 -c arboxamide

[0110] Tert-butyl-3-(4-chloro-lH-pyrrolo[2,3-b]pyridine-5-carboxamido)-4- methylphenylcarbamate (1) is suspended in CH₂Cl₂ (20.0 mL), and TFA (10.0 mL) is added slowly to the solution. After stirring at rt for 6 hours, the solvent is removed to offer crude salt, which is neutralized by saturated Na₂CC^ solution, and then extracted with ethyl acetate. The organic layer is washed with brine and dried over Na₂SO₄, filtered and concentrated. N-(5-amino- 2-methylphenyl)-4-chloro-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (2) is obtained as a crude product, and used without purification.

[0111] Intermediate 2 is dissolved in DMF (5.OmL), to which is added 3- (trifluoromethyl)benzoic acid (166 mg, 0.875 mmol), HATU (332 mg, 0.875 mmol) and DIEA (113 mg, 0.875 mmol). After the mixture is stirred 5 h, the solution is diluted with ethyl acetate (150 mL), washed with Na₂CC^ solution and water, dried, and evaporated to offer crude 4-chloro- N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (3), which is used without purification. To the mixture of EtOH/EtNH₂ (3:1, 2mL), intermediate 3 (15 mg, 0.0317 mmol) is added and heated at 100⁰C for 14 h. The solvent is removed and product purified by LC-MS preparation to give the desired product 4.

[0112] Table 5 describes representative compounds obtained by the above procedure using intermediate 3 as starting material. PATENT

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Table 5

PATENT

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PATENT

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PATENT

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(s,

PATENT

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P A T E N T

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Example 6

7H-pyrrolor2,3-dlpyrimidine-4-carboxylic acid r2-methyl-5-(3-trifluoromethyl- phenylcarbamovD-phenyll-amide

7H-Pyrrolor2,3-<ilpyrimidine-4-carbonitrile

[0113] To a solution of 6-Cl-7-deazapurine (0.3 g, 1.96 mmol) in DMSO (6.0 niL) is added KCN (0.64 g, 5.0 eq.). The reaction is heated to 15O⁰C for a period of 8 h. The mixture is partitioned between ethyl acetate (20 mL) and water. The organic extracts are washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluting with hexanes/ ethyl acetate) to afford the title compound. MS m/z 145.1 (M + I)-

7-(Toluene-4-sulfonyl)-7H-pyrrolor2,3-dlpyrimidine-4-carbonitrile

[0114] Into a solution of 7H-Pyrrolo[2,3-<f|pyrimidine-4-carbonitrile (0.15 g, 1.04 mmol, 1.0 eq.) in dichloromethane (3.0 ml) is added triethylamine (0.15 ml, 1.1 eq.) and a catalytic amount P A T E N T

GNF Docket No.: P1267PC10 of 4-dimethylamino pyridine. Tosyl chloride (0.204 g, 1.03 eq.) is added in portions into the reaction mixture, which is further equilibrated for 60 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, dried over Na₂SO₄, filtered and concentrated to afford the title product. The title compound is used in the next step without further purification.

7-(Toluene-4-sulfonyl)-7H-pyrrolor2,3-Jlpyrimidine-4-carboxylic acid

[0115] 7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-J]pyrimidine-4-carbonitrile (100 mg, 0.33 mmol) is dissolved in 10 ml of 12 N HCl. The mixture is heated at 100 ⁰C for 1.5 h. The reaction is evaporated, the residue is washed with H₂O, and dried to give the title compound as a grey solid. MS m/z 318.1 (M + 1).

7-(Toluene-4-sulfonyl)-7H-pyrrolor2,3-<ilpyrimidine-4-carboxylic acid r2-methyl-5-(3- trifluoromethyl-phenylcarbamovD-phenvH-amide

[0116] 7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-J]pyrimidine-4-carboxylic acid (0.05 g, 0.15 mmol) dissolved in dichloromethane is treated with oxalyl chloride (0.157 ml; 2.0 M in CH₂Cl₂). The reaction is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to yield crude acid chloride.

[0117] The crude acid chloride is added dropwise to a mixture of 3-amino-4-methyl-N-(3- trifluoromethyl-phenyl)-benzamide (0.046 g, 1.0 eq.) and DIEA (0.135 ml, 5.0 eq.) in dichloromethane. The reaction is stirred at ambient temperature for 15 minutes. The reaction mixture is then partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic extracts are P A T E N T

GNF Docket No.: P1267PC10 washed with water, dried over Na₂SO₄, filtered and concentrated to afford the title product. The title compound is used in the next step without further purification. MS m/z 594.1 (M + 1).

7H-Pyrrolor2,3-Jlpyrimidine-4-carboxylic acid r2-methyl-5-(3-trifluoromethyl- phenylcarbamovD-phenyll-amide

[0118] The tosylated amide [(7-(Toluene-4-sulfonyl)-7Η-pyrrolo[2,3-d]pyrimidine-4- carboxylic acid [2-methyl-5-(3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide) (0.1 g, 0.168 mmol, 1.0 eq.) is dissolved in THF (2 ml), and Na-Hg (0.077 g, 2.0 eq based on Na) is added followed by addition of trifluoroethanol (24.7 uL, 4.0 mmol, 2.0 eq.) The reaction is stirred for 15 minutes after which reaction mixture is decanted to remove mercury salts, and the supernatant liquid is concentrated under reduced pressure. The crude product is purified by preparative HPLC. ¹H NMR 400 MHz (DMSO-J₆) δ 10.54(s, IH), 10.44 (s, IH), 8.92 (s, IH), 8.42(m, IH), 8.30 (m, 2H), 7. 98 (d, IH, J = 8.4), 7.82 (m, 2H), 7.65 (m, IH), 7.29 (d, IH, J =8.8 Hz), 7.12 (m, IH), 2.35 (s, 3H,). MS m/z 440.1(M + 1).

[0119] Table 6 describes representative compounds obtained by the above procedure.

Table 6

PATENT

GNF Docket No.: P1267PC10

Example 7 lH-PyrazolorSΛ-blpyridine-S-carboxylic acid r2-methyl-5-(3-trifluoromethyl-benzoylamino)- phenyll- amide

NC

d-C/H2/Et3N/EtOH

P A T E N T

GNF Docket No.: P1267PC10

2-1 ri-(4-Methoxy-benzyl)-lH-pyrrol-2-ylaminol-methylene|-malonic acid diethyl ester

[0120] Acrylonitrile (7.5 g, 141 mmol) is dissolved in THF (75 mL) and cooled at 0⁰C, and hydrazine monohydrate (7.41g, 148 mmol) is added at the same temperature. The reaction mixture is brought to room temperature and stirred for 2 h. p-Anisaldehyde (20.1 g, 148 mmol) is added drop-wise and stirred at room temperature for 1O h. The above reaction mixture is concentrated to give a red oil, followed by drop- wise addition of n-BuONa in 80 mL n-BuOH at 0⁰C. The reaction mixture is brought to room temperature, then heated at 120 ⁰C for 3.5 h. After cooling, the reaction mixture is poured onto 300 mL of cold water and extracted with 2 X 200 mL of Et₂O. The ether layer is collected and washed with 3 X 100 mL of IN HCl. The combined acidic layer is collected and neutralized with 50 % NaOH. The mixture is again extracted with 200 mL Of Et₂O, washed with water, dried over Na₂SO₄, and concentrated to give l-(4-Methoxy- benzyl)-lH-pyrazol-2-ylamine as red oil. MS m/z 204.1 (M + 1). A mixture of l-(4-methoxy- benzyl)-lH-pyrazol-2-ylamine (1 g, 5.0 mmol) and diethylethoxymethylene- malonate (1 mL, 5.0 mmol) is heated at 120⁰C for 5 h, cooled and isolated by silica gel column chromatography. MS m/z 374.2 (M + 1).

4-Chloro-l-(4-methoxy-benzyl)-lH-pyrazolor3,4-^lpyridine-5-carboxylic acid ethyl ester

[0121] 2-{[l-(4-Methoxy-benzyl)-lΗ-pyrrol-2-ylamino]-methylene}-malonic acid diethyl ester (1.5 g, 4.0 mmol) is irradiated by MW at 200 ⁰C for 45 min. When 20 mL of Et₂O is added, the cyclized compound 4-hydroxy-l-(4-methoxy-benzyl)-lH-pyrazolo[3,4-&]pyridine-5- carboxylic acid ethyl ester is crystallized out as a white crystal. ¹H NMR 400 MHz φMSO-dβ) δ 12.10 (s, IH), 10.32(s, IH), 8.81 (s, IH), 8.31(s, IH), 7.21 (d, IH, J = 8.8 Hz), 6.86 (d, IH, J = 8.8), 4.39 (m, 2H), 4.26 (m, 2H), 3.72 (s, 3H), 1.35 (t, 3H, J = 7.2 Hz). MS m/z 328.2 (M + 1). The above compound is heated with POCI₃ (2 mL) in a sealed tube at 80° C for 10 h. The reaction P A T E N T

GNF Docket No.: P1267PC10 mixture is cooled and poured onto 10 mL of ice. The solid appeared, collected by filtration and washed with 2X5 mL of water to give the title compound as white solid. MS m/z 346.2 (M + 1).

l-(4-Methoxy-benzyl)-lH-pyrazolor3,4-£lpyridine-5-carboxylic acid ethyl ester

[0122] 4-Chloro-l-(4-methoxy-benzyl)-lΗ-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (150 mg, 0.43 mmol) is suspended in ethanol. Et₃N (100 uL) is added and followed by the addition of Pd-C (450 mg, wt. 5%). The reaction mixture is stirred at room temperature under H₂ balloon for 6 h. It is then filtered, washed (EtOH) and concentrated to give crude dechlorinated compound as white solid. MS m/z 312.1 (M + 1).

1 -(4-Methoxy-benzyl)- 1 H-pyrazolo [3 ,4-fclpyridine-5 -carboxylic acid

[0123] l-(4-Methoxy-benzyl)-lH-pyrazolo[3,4-&]pyridine-5-carboxylic acid ethyl ester (100 mg, 0.31 mmol) is dissolved in 10 ml of TΗF:Η₂O (2:1) and LiOH (37 mg, 1.55 mmol) is added. The mixture is heated at 9O⁰C for 5h. THF is evaporated, and the reaction mixture is neutralized with IN HCl. The residue is collected by filtration, washed with H₂O and dried to give the title compound as a white solid. MS m/z 284.1 (M + 1).

l-(4-Methoxy-benzyl)-lH-pyrazolor3,4-£1pyridine-5-carboxyric acid [2-methyl-5-(3- trifluoromethyl-benzoylamino)-phenvH-amide

P A T E N T

GNF Docket No.: P1267PC10

[0124] To a solution of l-(4-Methoxy-benzyl)-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide (40 mg, 0.13 mmol) in DMF is added DIEA (300 uL, 0.19 mmol) and HATU (74 mg, 0.14 mmol). The reaction mixture is stirred for 20 min at room temperature. N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl- benzamide (40 mg, 0.14 mmol) is then added and stirred for another couple of hours. The solvent is removed by rotary evaporation. The crude product is purified by reverse phase HPLC to give the title compound as white solid. MS m/z 560.1 (M + 1).

lH-Pyrazolor3,4-fclpyridine-5-carboxyric acid r2-methyl-5-(3-trifluoromethyl- benzoylamino)-phenyll -amide

[0125] The above PMB protected compound is deprotected by heating in TFA (100 uL) at 70 ⁰C for 4 h. The crude product is purified by reverse phase ΗPLC to give the title compound as white solid. ¹H NMR 400 MHz (DMSO-J₆) δ 10.51 (s, IH), 10.13 (s, IH), 9.11 (d, IH, J = 2 Hz), 8.87 (J, 1 H, J = 2 Hz), 8.35 (5,1 H), 8.32 (s, IH), 8.28 (d, IH, J = 7.6 Hz), 7.97 (d, IH, J = 7.6 Hz), 7.90 (d, IH, J = 2 Hz), 7.79 (t, IH, J = 8Hz), 7.63 (dd, IH, J = 8 Hz, 2 Hz), 7.29 (d, IH, J = 8.4 Hz), 2.27 (5, 3H) MS m/z 440.1 (M + 1).

[0126] Table 7 describes representative compounds obtained by the above procedure.

PATENT

GNF Docket No.: P1267PC10

Table 7

P A T E N T

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Example 8

7-chloro-3-(methoxymethyl)-2-methyl-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-

3H-imidazor4,5-blpyridine-6-carboxamide (16) and 7-chloro-3-(methoxymethyl)-2-methyl-N-

(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)-3H-imidazor4,5-blpyridine-6- carboxamide (18) OH Sn(II)CI₂, HCI heat EtOH, 75⁰C

[0127] Intermediates 6 and 7 are prepared following reported synthetic procedures. (Synthetic Communication, 27(5), 861-870, 1997; Cai et al., J. Med. Chem. 40: 3679-3686 (1997)). Intermediate 7 (2.31 g, 13.31 mmol) is suspended in EtOH (20.OmL), to which is added a solution of SnCl₂ (6.31 g, 33.27 mmol) in HCl (con. 6.0 mL), and the reaction mixture is heated at 75°C for half h. The solution is diluted with ethyl acetate (250 mL), washed with K₂CO₃ solution and brine, dried and evaporated to give crude 4-chloropyridine-2,3-diamine (8), which is P A T E N T

GNF Docket No.: P1267PC10 used without purification. ¹H NMR 400 MHz (CDCl₃) δ 7.26 (d, J= 5.4 Hz, IH), 6.55 (d, J= 5.4 Hz, IH), 5.86 (s, 2H), 4.97 (s, 2H); MS m/z 144.00 (M + 1).

[0128] Intermediate 8 (700mg, 4.876 mmol), polyphosphoric acid (5 g) and HOAc (442 mg, 7.31 mmol) are heated at 150⁰C for one hour. The reaction is dissolved in water, then NaOH is added until the pH is adjusted to pH=13. The solution is extracted with ethyl acetate (2x150 mL), washed with K₂CO₃ solution and brine, dried, and evaporated to give crude 7-chloro-2-methyl- 3H-imidazo[4,5-b]pyridine (9), which is used without purification. ¹H NMR 400 MHz (CDCl₃) δ 8.14 (s, IH), 6.55 (m, 2H), 2.69 (s, 3H); MS m/z 168.00 (M + 1).

[0129] To a solution of 7-chloro-2-methyl-3H-imidazo[4,5-b]pyridine (9) (665 mg, 3.97 mmol) in DMF (15 mL) is added Cs₂CO₃ (2.58 g, 7.94 mmol) and MOMCl (415 mg, 5.153 mmol), and the reaction mixture is stirred at 50⁰C for 2 h. The solution is diluted with ethyl acetate (200 mL), washed with K₂CO₃ solution and brine, dried, and evaporated to offer crude 7- chloro-3-(methoxymethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (10), which is purified by flash chromatography (EtOAc/Hexane, 1:1). ¹H NMR 400 MHz (CDC13) δ 8.14 (d, J= 5.2 Hz, IH), 7.18 (d, J= 5.2 Hz, IH), 5.55 (s, 2H), 3.27 (s, 3H), 2.67 (s, 3H); MS m/z 212.00 (M + 1).

[0130] To a solution of 7-chloro-3-methoxymethyl-2-methyl-3H-imidazo[4,5-b]pyridine (10) (500 mg, 2.36 mmol) in HOAc/H₂O (1: 1, 10 mL) is added Br₂ (378 mg, 2.36 mmol) dropwise, and the reaction mixture is stirred at rt for two days. The solution is diluted with ethyl acetate (200 mL), washed with K₂CO₃ solution and brine, dried, and evaporated to offer crude 6- bromo-7-chloro-3-methoxymethyl-2-methyl-3H-imidazo[4,5-b]pyridine (11), which is purified by flash chromatography (EtOAc/Hexane, 1:1). ¹H NMR 400 MHz (CDC13) δ 8.43 (s, IH), 5.59 (s, 2H), 3.33 (s, 3H), 2.73 (s, 3H); MS m/z 289.90 (M + 1).

[0131] To a solution of 6-bromo-7-chloro-3-methoxymethyl-2-methyl-3H-imidazo[4,5- b]pyridine (11) (150 mg, 0.516 mmol) in DMF (6 mL), is added tributyl-vinyl-stannane (196.45 mg, 0.62 mmol), LiCl (65.6 mg, 1.55 mmol) and PdCl₂(PPh₃)₂ (36.2mg, 0.052mmol). The mixture is purged with N₂ and heated to 140⁰C for 10 min under microwave condition. The reaction is diluted with ethyl acetate (100 mL), washed with sat. NaHCO₃ solution and brine, dried, and evaporated to offer crude 7-chloro-3-methoxymethyl-2-methyl-6-vinyl-3H- imidazo[4,5-b]pyridine (12), which is purified by flash chromatography (EtOAc/Hexane, 4:6). ¹H NMR 400 MHz (CDC13) δ 8.42 (s, IH), 7.08 (q, IH), 5.77 (d, IH), 5.53 (s, 2H), 5.40 (d, IH), 3.27 (s, 3H), 2.65 (s, 3H); MS m/z 238.00 (M + 1). P A T E N T

GNF Docket No.: P1267PC10

[0132] Ozonolysis is carried out to the solution of 7-chloro-3-methoxymethyl-2-methyl-6- vinyl-3H-imidazo[4,5-b]pyridine (12) (2.6 g, 10.93 mmol) in DCM/MeOH (4:1, 10 niL). The solution is diluted with ethyl acetate (200 mL), washed with K₂CO₃ solution and brine, dried, and evaporated to offer crude 7-chloro-3-methoxymethyl-2-methyl-3H-imidazo[4,5-b]pyridine-6- carbaldehyde (13), which is purified by the flash chromatography (EtOAc/Hexane, 1:1). ¹H NMR 400 MHz (CDC13) δ 10.57 (s, IH), 8.85(s, IH), 5.64 (s, 2H), 3.35 (s, 3H), 2.76 (s, 3H); MS m/z 239.90 (M + 1).

[0133] 7-Chloro-3-(methoxymethyl)-2-methyl-3H-imidazo[4,5-b]pyridine-6-carbaldehyde

(13) (3.0 g, 16.6 mmol) is stirred in a mixture of t-BuOH/THF (12 mL, 1: 1), to which is added 2- methyl-2-butene (2.0 ml, 18.8 mmol). Phosphate (1.7 g, 12.5 mmol) is stirred in water (4.0 mL) until it is dissolved, then added to above mixture. Finally, solid NaClO₂ (80 %, 1.22 g, 10.8 mmol) is added, and the mixture is stirred overnight. The organic layer is extracted with ethyl acetate, and the combined organic layers are dried and evaporated to offer crude 7-chloro-3- (methoxymethyl)-2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (14). MS m/z 256.00 (M + 1).

[0134] 7-Chloro-3-(methoxymethyl)-2-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid

(14) (50 mg, 0.196 mmol) is dissolved in DMF (2.5 mL), followed by addition of intermediate 15 (57.5 mg, 0.196 mmol), HATU (74.4 mg, 0.196 mmol) and DIEA (25.3 mg, 0.196 mmol). After the reaction mixture is stirred for 3 h, the solution is diluted with ethyl acetate (100 mL), washed with Na₂CO₃ solution and water, dried, and evaporated to offer crude 7-chloro-3- (methoxymethyl)-2-methyl-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-3H- imidazo[4,5-b]pyridine-6-carboxamide (16), which is purified by the flash chromatography. ¹H NMR 400 MHz (CD₃OD) δ 8.49 (s, IH), 8.17 (s, IH), 8.11(d, J= 58.0 Hz, IH), 7.86 (d, J= 2.0 Hz, IH), 7.79 (d, J= 8.0 Hz, IH), 7.64 (t, J= 5.6 Hz, IH), 7.50 (dd, J= 2.0 Hz, J= 8.0 Hz, IH), 7.22 (d, J= 8.0 Hz, IH), 5.63 (s, 2H), 3.27 (s, 3H), 2.66 (s, 3H), 2.29 (s, 3H); MS m/z 532.10 (M + 1).

[0135] 7-chloro-3-(methoxymethyl)-2-methyl-N-(2-methyl-5-(3-(trifluoromethyl)phenyl- carbamoyl)phenyl)-3H-imidazo[4,5-b]pyridine-6-carboxamide (18) is prepared with the same procedure, and characterized by NMR and MS. P A T E N T

GNF Docket No.: P1267PC10

Example 9 2,6-dichloro-3,5-dimethoxy-N-(lH-pyrrolor2,3-blpyridin-5-yl)benzamide

Benzyl lH-pyrrolor2,3-blpyridin-5-ylcarbamate

[0136] A mixture of l-(tert-butyldimethylsilyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1.65g, 6 mmol), DPPA (1.66 g, 7.6 mmol), triethylamine (1.8 ml, 12 mmol) and benzyl alcohol (3 ml, 30 mmol) in 20 ml toluene is heated to 110 ⁰C for 4 hours. The reaction mixture is cooled down to room temperature and the solvent is removed by rotary evaporation. The residue is reconstituted in 200 ml ethyl acetate and washed with saturated sodium bicarbonate (3x) and brine (Ix). The organic phase is dried over sodium sulfate and dried by rotary evaporation to give the title compound as light yellowish oil. MS m/z 268.1 (M + 1).

lH-pyrrolor2,3-blpyridin-5-amine

[0137] To a solution of benzyl lH-pyrrolo[2,3-b]pyridin-5-ylcarbamate (1.38 g, 5.2 mmol) in 80 ml ethanol is added 150 mg Pd(OH)₂. The mixture is stirred at room temperature for 6 hours with a hydrogen balloon attached. The reaction mixture is flushed with nitrogen and P A T E N T

GNF Docket No.: P1267PC10 filtered through a celite pad to remove the Pd(OH)₂. The filtrate is evaporated and dried to give the title compound as light brown oil. MS m/z 134.1 (M + 1).

2,6-dichloro-3,5-dimethoxy-N-(lH-pyrrolor2,3-blpyridin-5-yl)benzamide

[0138] A mixture of lH-pyrrolo[2,3-b]pyridin-5-amine (28 mg, 0.2 mmol), 2,6-dichloro-3,5- dimethoxybenzoic acid (50 mg, 0.2 mmol), HATU (76 mg, 0.2 mmol), DIEA (77 mg, 0.6 mmol) in 1 ml DMF is stirred for 2 hours at room temperature. The reaction mixture is neutralized with acetic acid and purified by reverse phase HPLC to give the title compound as light gray solid. ¹H NMR 600 MHz (DMSO-J₆) δ 11.61 (s, IH), 10.61 (s, IH), 8.30 (d, 1 H, J = 2.0 Hz), 8.27 (d, 1 H, J = 2.0 Hz), 7.43 (U H, J = 2.8 Hz), 6.95(5, IH), 6.41 (m, IH), 3.90 (s, 6H); MS m/z 366.1 (M + 1).

[0139] Table 8 describes representative compounds obtained by the above procedure.

Table 8

P A T E N T

GNF Docket No.: P1267PC10

Assays

[0140] Compounds of the present invention may be assayed to measure their capacity to inhibit a kinase panel, including but not limited to AIk, AbI, Aurora-A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), Src, SIK, Syk, Tie2 and TrkB kinases.

B-Raf (Enzymatic assay)

[0141] Compounds of the invention may be tested for their ability to inhibit the activity of b- Raf. The assay is carried out in 384-well MaxiSorp plates (NUNC) with black walls and clear bottom. The substrate, IκBα is diluted in DPBS (1:750) and 15 μl is added to each well. The plates are incubated at 4 ⁰C overnight and washed 3 times with TBST (25 mM Tris, pH 8.0, 150 P A T E N T

GNF Docket No.: P1267PC10 mM NaCl and 0.05% Tween-20) using the EMBLA plate washer. Plates are blocked by Superblock (15 μl/well) for 3 hours at room temperature, washed 3 times with TBST and pat- dried. Assay buffer containing 20 μM ATP (10 μl) is added to each well followed by 100 nl or 500 nl of compound. B-Raf is diluted in the assay buffer (1 μl into 25 μl) and 10 μl of diluted b- Raf is added to each well (0.4 μg/well). The plates are incubated at room temperature for 2.5 hours. The kinase reaction is stopped by washing the plates 6 times with TBST. Phosph- IκBα (Ser32/36) antibody is diluted in Superblock (1:10,000) and 15 μl is added to each well. The plates are incubated at 4 ⁰C overnight and washed 6 times with TBST. AP-conjugated goat- anti-mouse IgG is diluted in Superblock (1: 1,500) and 15 μl is added to each well. Plates are incubated at room temperature for 1 hour and washed 6 times with TBST. 15 μl of fluorescent Attophos AP substrate (Promega) is added to each well and plates are incubated at room temperature for 15 minutes. Plates are read on Acquest or Analyst GT using a Fluorescence Intensity Program (Excitation 455 nm, Emission 580 nm).

B-Raf (Cellular Assay)

[0142] Compounds of the invention are tested in A375 cells for their ability to inhibit phosphorylation of MEK. A375 cell line (ATCC) is derived from a human melanoma patient and has a V599E mutation on the B-Raf gene. The levels of phosphorylated MEK are elevated due to the mutation of B-Raf. Sub-confluent to confluent A375 cells are incubated with compounds for 2 hours at 37⁰C in serum free medium. Cells are then washed once with cold PBS and lysed with the lysis buffer containing 1% Triton XlOO. After centrifugation, the supernatants are subjected to SDS-PAGE, and then transferred to nitrocellulose membranes. The membranes are then subjected to western blotting with anti-phospho-MEK antibody (ser217/221) (Cell Signaling). The amount of phosphorylated MEK is monitored by the density of phospho-MEK bands on the nitrocellulose membranes.

Inhibition of cellular Bcr-Abl dependent proliferation (High Throughput method) [0143] The murine cell line 32D hemopoietic progenitor cell line may be transformed with Bcr-Abl cDNA (32D-p210). These cells are maintained in RPMI/10% fetal calf serum (RPMI/FCS) supplemented with penicillin 50 μg/mL, streptomycin 50 μg/mL and L-glutamine 200 mM. Untransformed 32D cells are similarly maintained with the addition of 15% of WEHI conditioned medium as a source of IL3. P A T E N T

GNF Docket No.: P1267PC10

[0144] 50 μl of a 32D or 32D-p210 cells suspension are plated in Greiner 384 well microplates (black) at a density of 5000 cells per well. 50 nl of test compound (1 mM in DMSO stock solution) is added to each well (STI571 is included as a positive control). The cells are incubated for 72 hours at 37 °C, 5% CO₂. 10 μl of a 60% Alamar Blue solution (Tek diagnostics) is added to each well and the cells are incubated for an additional 24 hours. The fluorescence intensity (Excitation at 530 nm, Emission at 580 nm) is quantified using the Acquest™ system (Molecular Devices).

Inhibition of cellular Bcr-Abl dependent proliferation

[0145] 32D-p210 cells are plated into 96 well TC plates at a density of 15,000 cells per well. 50 μL of two fold serial dilutions of the test compound (C_max is 40 μM) are added to each well (STI571 is included as a positive control). After incubating the cells for 48 hours at 37 °C, 5% CO₂, 15 μL of MTT (Promega) is added to each well and the cells are incubated for an additional 5 hours. The optical density at 570 nm is quantified spectrophotometrically and IC₅₀ values, the concentration of compound required for 50% inhibition, determined from a dose response curve.

Effect on cell cycle distribution

[0146] 32D and 32D-p210 cells are plated into 6 well TC plates at 2.5xlO⁶ cells per well in 5 ml of medium and test compound at 1 or 10 μM is added (STI571 is included as a control). The cells are then incubated for 24 or 48 hours at 37 °C, 5% CO₂. 2 ml of cell suspension is washed with PBS, fixed in 70% EtOH for 1 hour and treated with PBS/EDTA/RNase A for 30 minutes. Propidium iodide (Cf=IO μg/ml) is added and the fluorescence intensity is quantified by flow cytometry on the FACScalibur™ system (BD Biosciences). In some embodiments, test compounds of the present invention may demonstrate an apoptotic effect on the 32D-p210 cells but not induce apoptosis in the 32D parental cells.

Effect on Cellular Bcr-Abl Autophosphorylation

[0147] Bcr-Abl autophosphorylation is quantified with capture Elisa using a c-Abl specific capture antibody and an antiphosphotyrosine antibody. 32D-p210 cells are plated in 96 well TC plates at 2xlO⁵ cells per well in 50 μL of medium. 50 μL of two fold serial dilutions of test compounds (C_max is 10 μM) are added to each well (STI571 is included as a positive control). The cells are incubated for 90 minutes at 37 °C, 5% CO₂. The cells are then treated for 1 hour on P A T E N T

GNF Docket No.: P1267PC10 ice with 150 μL of lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA and 1% NP-40) containing protease and phosphatase inhibitors. 50 μL of cell lysate is added to 96 well optiplates previously coated with anti-Abl specific antibody and blocked. The plates are incubated for 4 hours at 4 °C. After washing with TBS-Tween 20 buffer, 50 μL of alkaline -phosphatase conjugated anti-phosphotyrosine antibody is added and the plate is further incubated overnight at 4 °C. After washing with TBS-Tween 20 buffer, 90 μL of a luminescent substrate are added and the luminescence is quantified using the Acquest™ system (Molecular Devices). In some embodiments, test compounds of the invention may inhibit the proliferation of the Bcr-Abl expressing cells, inhibiting the cellular Bcr-Abl autophosphorylation in a dose-dependent manner.

Effect on proliferation of cells expressing mutant forms of Bcr-Abl

[0148] Compounds of the invention may be tested for their antiproliferative effect on Ba/F3 cells expressing either wild type or the mutant forms of Bcr-Abl (G250E, E255V, T315I, F317L, M351T) that confers resistance or diminished sensitivity to STI571. The antiproliferative effect of these compounds on the mutant-Bcr-Abl expressing cells and on the non transformed cells may be tested at 10, 3.3, 1.1 and 0.37 μM as described above (in media lacking IL3). The IC₅₀ values of the compounds lacking toxicity on the untransformed cells are determined from the dose response curves obtained as described above.

FGFR-3 (Enzymatic Assay)

[0149] Kinase activity assay with purified FGFR-3 (Upstate) is carried out in a final volume of 10 μL containing 0.25 μg/mL of enzyme in kinase buffer (30 mM Tris-HCl pH7.5, 15 mM MgCl₂, 4.5 mM MnCl₂, 15 μM Na₃VO₄ and 50 μg/mL BSA), and substrates (5 μg/mL biotin- poly-EY(Glu, Tyr) (CIS-US, Inc.) and 3μM ATP). Two solutions are made: the first solution of 5 μl contains the FGFR-3 enzyme in kinase buffer was first dispensed into 384-well format ProxiPlate® (Perkin- Elmer) followed by adding 50 nL of compounds dissolved in DMSO, then 5 μl of second solution contains the substrate (poly-EY) and ATP in kinase buffer was added to each wells. The reactions are incubated at room temperature for one hour, stopped by adding 10 μL of HTRF detection mixture, which contains 30 mM Tris-HCl pH 7.5, 0.5 M KF, 50 mM ETDA, 0.2 mg/mL BSA, 15 μg/mL streptavidin-XL665 (CIS-US, Inc.) and 150 ng/mL cryptate conjugated anti-phosphotyrosine antibody (CIS-US, Inc.). After one hour of room temperature P A T E N T

GNF Docket No.: P1267PC10 incubation to allow for streptavidin-biotin interaction, time resolved florescent signals are read on Analyst GT (Molecular Devices Corp.)- IC₅₀ values are calculated by linear regression analysis of the percentage inhibition of each compound at 12 concentrations (1:3 dilution from 50 μM to 0.28 nM). In this assay, compounds of the invention have an IC₅₀ in the range of 10 nM to 2 μM.

FGFR-3 (Cellular Assay)

[0150] Compounds of the invention are tested for their ability to inhibit transformed Ba/F3- TEL-FGFR3 cells proliferation, which is dependent on FGFR-3 cellular kinase activity. Ba/F3- TEL-FGFR3 are cultured up to 800,000 cells/mL in suspension, with RPMI 1640 supplemented with 10% fetal bovine serum as the culture medium. Cells are dispensed into 384-well format plate at 5000 cell/well in 50 μL culture medium. Compounds of the invention are dissolved and diluted in dimethylsulfoxide (DMSO). Twelve points 1:3 serial dilutions are made into DMSO to create concentrations gradient ranging typically from 10 mM to 0.05 μM. Cells are added with 50 nL of diluted compounds and incubated for 48 hours in cell culture incubator. AlamarBlue® (TREK Diagnostic Systems), which can be used to monitor the reducing environment created by proliferating cells, are added to cells at a final concentration of 10%. After additional four hours of incubation in a 37 ⁰C cell culture incubator, fluorescence signals from reduced AlamarBlue® (Excitation at 530 nm, Emission at 580 nm) are quantified on Analyst GT (Molecular Devices Corp.). IC₅₀ values are calculated by linear regression analysis of the percentage inhibition of each compound at 12 concentrations.

FLT3 and PDGFRβ

[0151] The effects of compounds of the invention on the cellular activity of FLT3 and PDGFRβ may be conducted following identical methods as described above for FGFR3 cellular activity, using Ba/F3-FLT3-ITD and Ba/F3-Tel-PDGFRβ.

[0152] Compounds of the invention may be tested for their ability to inhibit transformed Ba/F3-FLT3-ITD or Ba/F3-Tel-PDGFRβ cells proliferation, which is dependent on FLT3 or PDGFRβ cellular kinase activity. Ba/F3-FLT3-ITD or Ba/F3-Tel-PDGFRβ are cultured up to 800,000 cells/mL in suspension, with RPMI 1640 supplemented with 10% fetal bovine serum as the culture medium. Cells are dispensed into 384-well format plate at 5000 cell/well in 50 μL culture medium. Compounds of the invention are dissolved and diluted in dimethylsulfoxide (DMSO). Twelve points 1:3 serial dilutions are made into DMSO to create concentrations gradient ranging typically from 10 mM to 0.05 μM. Cells are added with 50 nL of diluted P A T E N T

GNF Docket No.: P1267PC10 compounds and incubated for 48 hours in cell culture incubator. AlamarBlue® (TREK Diagnostic Systems), which can be used to monitor the reducing environment created by proliferating cells, are added to cells at final concentration of 10%. After additional four hours of incubation in a 37 ⁰C cell culture incubator, fluorescence signals from reduced AlamarBlue® (Excitation at 530 nm, Emission at 580 nm) are quantified on Analyst GT (Molecular Devices Corp.). IC₅₀ values are calculated by linear regression analysis of the percentage inhibition of each compound at 12 concentrations.

c-Kit

[0153] Compounds of the invention may be tested for inhibition of SCF dependent proliferation using Mo7e cells which endogenously express c-Kit in a 96-well format. Briefly, two-fold serially diluted test compounds (C_max = 10 μM) are evaluated for their antiproliferative activity on Mo7e cells stimulated with human recombinant SCF. After 48 hour incubation at 37 ⁰C, cell viability is measured by using a MTT colorimetric assay from Promega.

Upstate KinaseProfiler™ - Radio-enzymatic filter binding assay

[0154] Compounds of the invention may be assessed for their ability to inhibit individual members of a panel of kinases (a partial, non- limiting list of kinases includes: AIk, AbI, Aurora- A, B-Raf, Bcr-Abl, BRK, BIk, Bmx, c-Kit, c-Raf, cSRC, CSK, EphB, FLTl, Fms, Fyn, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), SIK, Src, Syk, Tie2 and TrkB kinases). The compounds are tested in duplicates at a final concentration of 10 μM following this generic protocol, using varying kinase buffer composition and substrates for the different kinases included in the "Upstate KinaseProfiler™ panel. Kinase buffer (2.5 μL, 10x - containing MnCl₂ when required), active kinase (0.001-0.01 Units; 2.5 μL), specific or Poly(Glu4-Tyr) peptide (5-500 μM or .01 mg/ml) in kinase buffer and kinase buffer (50 μM; 5 μL) are mixed in an eppendorf on ice. A Mg/ATP mix (10 μL; 67.5 (or 33.75) mM MgCl₂, 450 (or 225) μM ATP and 1 μCi/μl [γ-³²P]-ATP (3000Ci/mmol)) is added and the reaction is incubated at about 30 ⁰C for about 10 minutes. The reaction mixture is spotted (20 μL) onto a 2cm x 2cm P81 (phosphocellulose, for positively charged peptide substrates) or Whatman No. 1 (for Poly (Glu4-Tyr) 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 ³²P P A T E N T

GNF Docket No.: P1267PC10 incorporation (cpm) to the peptide substrate is quantified with a Beckman scintillation counter. Percentage inhibition is calculated for each reaction.

[0155] Compounds of Formula (1), (2) or (3) in free form or in pharmaceutically acceptable salt form, may exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. The IC₅₀ value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50 % lower than that obtained using the control without inhibitor. In general, compounds of the invention have IC₅₀ values from 1 nM to 10 μM against one or more of the following kinases: AIk, AbI, Aurora- A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), Src, SIK, Syk, Tie2 and TrkB kinases.

[0156] In some examples, compounds of the invention have IC₅₀ values from 0.01 μM to 5 μM. In other examples, compounds of the invention have IC₅₀ values from 0.01 μM to 1 μM, or more particularly from 1 nM to 1 μM. In yet other examples, compounds of the invention have IC₅₀ values of less than 1 nM or more than 10 μM.

[0157] Compounds of Formula (1), (2) or (3) may exhibit a percentage inhibition of greater than 50%, or in other embodiments, may exhibit a percentage inhibition greater than about 70%, against one or more of the following kinases at 10 μM: AIk, AbI, Aurora-A, B-Raf, C-Raf, Bcr- Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), Src, SIK, Syk, Tie2 and TrkB kinases.

[0158] 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.

Claims

P A T E N TGNF Docket No.: P1267PC10Claims

1. A compound of Formula ( 1) :

or pharmaceutically acceptable salts thereof, wherein:

X¹ and X² are independently CR or N;

X³ is CH or N, or C if attached to L¹ or R⁴;

Y is a 5-7 membered aryl or heteroaryl containing N, O or S;

L¹ and L² are independently NRCO or CONR;

R and R¹ are independently H or Ci_₆ alkyl;

R is halo, or an optionally halogenated Ci_₆ alkyl;

R⁵ is Ci_₆ alkyl;

R⁶ and R⁷ are independently H, an optionally halogenated C]_₆ alkyl, C₂-₆ alkenyl or C₂_₆ alkynyl; Ci_-6 alkanol, (CR₂)_q-R⁸ or (CR₂)_pO(CR₂)_qR⁹; or R⁶ and R⁷ together with N in NR⁶R⁷ may form an optionally substituted ring;

2. The compound of claim 1, wherein X¹ and X² are each CH; or one of X¹ or X² is N, and the other is CH.

3. The compound of claim 1, wherein Y is phenyl, thienyl, pyridyl, pyrazolyl or isoxazolyl. P A T E N T

GNF Docket No.: P1267PC10

4. The compound of claim 1, wherein R is C]_₆ alkyl.

5. The compound of claim 1, wherein R³ is halo, an optionally halogenated Ci_₆ alkyl, (CR₂)_qR⁸ or O(CR₂)_qR⁹; and

R⁸ and R⁹ are independently an optionally substituted piperidinyl, morpholinyl, imidazolyl or piperazinyl.

6. The compound of claim 1 , wherein R⁴ is H, halo, NR⁵(CR₂)_PNR⁶R⁷ or NR⁶R⁷; R⁶ and R⁷ are independently H, Ci_₆ alkyl, Ci_₆ alkanol, or (CR₂)_qR⁸; or R⁶ and R⁷ together with N in NR R⁷ form an optionally substituted morpholinyl, piperidinyl or pyrrolidinyl; and

R⁸ is an optionally substituted C₃_₇ cycloalkyl, pyridyl, phenyl, morpholinyl, furanyl, naphthalenyl, piperazinyl, pyrimidinyl, imidazolyl, triazolyl, isothiazolyl, isoxazolyl, pyrazolyl or pyrazinyl.

7. The compound of claim 1, wherein said compound is of Formula (2):

8. The compound of claim 7, wherein X¹ and X² are each CH; or one of X¹ or X² is N, and the other is CH.

9. The compound of claim 7, wherein R¹⁰ is CF₃. P A T E N T

GNF Docket No.: P1267PC10

10. The compound of claim 7, wherein k is 0, or k is 1 and R¹¹ is halo, C]_₆ alkyl, (CR₂)_qR⁸, O(CR₂)_qR⁹; and R⁸ and R⁹ are independently an optionally substituted piperidinyl, morpholinyl, imidazolyl or piperazinyl.

11. The compound of claim 7, wherein R⁴ is H, halo, NR⁵(CR₂)_PNR⁶R⁷ or NR⁶R⁷; R⁶ and R⁷ are independently H, Ci_₆ alkyl, Ci_₆ alkanol, or (CR₂)_qR⁸; or R⁶ and R⁷ together with N in NR⁶R⁷ form an optionally substituted morpholinyl, piperidinyl or pyrrolidinyl; and

12. The compound of claim 1, selected from:

N-(3-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-4-carboxamide, N-(3-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-4-carboxamide, N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-4- carboxamide,

N-(2-methyl-5-(3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-4-carboxamide,

N-(5-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)- lH-pyrrolo[2,3-b]pyridine-4-carboxamide,

N-(2-methyl-5-(4-(morpholinomethyl)-3-(trifluoromethyl)phenylcarbamoyl)phenyl)-lH- pyrrolo[2,3-b]pyridine-4-carboxamide,

N-(2-methyl-5-(4-(piperazin-l-ylmethyl)-3-(trifluoromethyl)phenylcarbamoyl)phenyl)-lH- pyrrolo[2,3-b]pyridine-4-carboxamide,

N-(2-methyl-5-(4-(morpholinomethyl)-3-(trifluoromethyl)phenylcarbamoyl)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N- (2-methy 1-5 - (3 -(trifluoromethyl)benzamido)phenyl) - 1 H-pyrrolo [2,3 -b]pyridine- 5 - carboxamide,

N-(2-methyl-5-(3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide, P A T E N T

GNF Docket No.: P1267PC10

N-(5-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenylcarbamoyl)phenyl)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(4-((4-methylpiperazin-l-yl)methyl)-3-

(trifluoromethyl)phenylcarbamoyl)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(4-(morpholinomethyl)-3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide,

N-(5-(l-tert-butyl-5-methyl-lH-pyrazole-3-carboxamido)-2-methylphenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(4-methylpiperazin-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(5-(3-(4-ethylpiperazin-l-yl)-5-(trifluoromethyl)benzamido)-2-methylphenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(5-(3-(4-(2-hydroxyethyl)piperazin-l-yl)-5-(trifluoromethyl)benzamido)-2-methylphenyl)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(5-(5-tert-butylthiophene-2-carboxamido)-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide,

N-(2-methyl-5-(3-(l-methylpiperidin-4-yloxy)-5-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(5-(3-(4-hydroxypiperidin-l-yl)-5-(trifluoromethyl)benzamido)-2-methylphenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(5-(3-(4-ethylpiperazin-l-yl)-5-(trifluoromethyl)benzamido)-2-methylphenyl)-4-

(methylamino) - 1 H-pyrrolo [2,3 -b]pyridine- 5 -carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)benzamido)phenyl)-4-

(methylamino) - 1 H-pyrrolo [2,3 -b]pyridine- 5 -carboxamide,

N-(5-(5-tert-butylthiophene-2-carboxamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, P A T E N T

GNF Docket No.: P1267PC10

N-(5-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)-4-

(methylamino) - 1 H-pyrrolo [2,3 -b]pyridine- 5 -carboxamide,

N-(5-(l-tert-butyl-5-methyl-lH-pyrazole-3-carboxamido)-2-methylphenyl)-4-(methylamino)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-methylbenzamido)phenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide,

N-(5-(3-methoxybenzamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide,

N-(5-(2-tert-butylisonicotinamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide,

N-(5-(4-fluoro-3-(trifluoromethyl)benzamido)-2-methylphenyl)-4-(methylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(5-(4-chloro-3-(trifluoromethyl)benzamido)-2-methylphenyl)-4-(methylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(5-(3-fluoro-5-(trifluoromethyl)benzamido)-2-methylphenyl)-4-(methylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(5-(3-chlorobenzamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide,

N-(5-(3-bromobenzamido)-2-methylphenyl)-4-(methylamino)-lH-pyrrolo[2,3-b]pyridine-5- carboxamide,

3 -tert-butyl-N- (4-methyl- 3 - (4- (methylamino) - 1 H-pyrrolo [2,3 -b]pyridine-5 - carboxamido)phenyl)isoxazole-5-carboxamide,

N-(2-methyl-5-(2-methyl-3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

4-(isobutylamino)-N-(2-methyl-5-(2-methyl-3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

3-tert-butyl-N-(3-(4-(isobutylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamido)-4- methylphenyl)isoxazole-5-carboxamide,

4-(2-(dimethylamino)ethylamino)-N-(5-(4-((4-ethylpiperazin-l-yl)methyl)-3-

(trifluoromethyl)benzamido)-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

4-(2-(dimethylamino)ethylamino)-N-(2-methyl-5-(3-(piperidin-4-yloxy)-5-

(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide, P A T E N T

GNF Docket No.: P1267PC10

N-(2-methyl-5-(2-methyl-3-(trifluoromethyl)benzamido)phenyl)-4-(2-morpholinoethylamino)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(piperidin-4-yloxy)-5-(trifluoromethyl)benzamido)phenyl)-4-(2- morpholinoethylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

4-(ethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide,

4-(2-(dimethylamino)ethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(2-morpholinoethylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

4-((dimethylamino)methylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(2-(4-methylpiperazin-l- yl)ethylamino)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

4-(3-(dimethylamino)propylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

4-(3-aminopropylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(2-(piperidin-l-yl)ethylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(4-methylpiperazin-l-ylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

4-(cyclopropylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyπOlo[2,3- b]pyridine-5-carboxamide,

4-(diethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(2-(pyrrolidin-l-yl)ethylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(piperazin-l-yl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide, P A T E N T

GNF Docket No.: P1267PC10

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-morpholino-lH-pyrrolo[2,3- b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-((tetrahydrofuran-2-yl)methylamino)- lH-pyrrolo[2,3-b]pyridine-5-carboxamide,

4-(dimethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxamide,

4-(2-hydroxyethylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(2-(pyridin-3-yl)ethylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(pyridin-3-ylmethylamino)-lH- pyrrolo[2,3-b]pyridine-5-carboxamide,

4-(butylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyπOlo[2,3- b]pyridine-5-carboxamide,

4-(benzylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyπOlo[2,3- b]pyridine-5-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4- carboxamide,

N-(5-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)-

7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide,

N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxamide,

N-(5-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenylcarbamoyl)-2-methylphenyl)- lH-pyrazolo[3,4-b]pyridine-5-carboxamide,

7-chloro-3-(methoxymethyl)-2-methyl-N-(2-methyl-5-(3-

(trifluoromethyl)phenylcarbamoyl)phenyl)-3H-imidazo[4,5-b]pyridine-6-carboxamide, and

3H-imidazo[4,5-b]pyridine-6-carboxamide.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. P A T E N T

GNF Docket No.: P1267PC10

14. A method for inhibiting a kinase, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of Formula (1) or Formula (3),

X¹ and X² are independently CR or N;

X³ is CH or N, or C if attached to L¹ or R⁴;

Y is a 5-7 membered aryl or heteroaryl containing N, O or S;

L¹ and L² are independently NRCO or CONR;

R and R¹ are independently H or C_1-6 alkyl;

R² is halo, or an optionally halogenated C_1-6 alkyl;

R⁵ is Ci_₆ alkyl;

R⁶ and R⁷ are independently H, an optionally halogenated Ci_₆ alkyl, C₂-₆ alkenyl or C₂_₆ alkynyl; Ci_-6 alkanol, (CR₂)_q-R⁸ or (CR₂)_pO(CR₂)_qR⁹; or R⁶ and R⁷ together with N in NR⁶R⁷ may form an optionally substituted ring;

15. The method of claim 14, wherein said kinase is AIk, AbI, Aurora-A, B-Raf, C- Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, p38 (p38 MAP kinase, SAPK2α), Src, SIK, Syk, Tie2 and TrkB kinases, or a combination thereof.

16. The method of claim 14, wherein said kinase is B-Raf, Bcr-Abl, Lck or a combination thereof.

17. The method of claim 14, comprising administering said compound to a cell or tissue system; or to a human or animal subject.

18. A method for treating a B-Raf, a Bcr-Abl, or a Lck-mediated condition, comprising administering to a system or subject in need of such treatment an effective amount of a compound of Formula (1) or Formula (3),

or pharmaceutically acceptable salts or pharmaceutical compositions thereof, wherein: X¹ and X² are independently CR or N; X³ is CH or N, or C if attached to L¹ or R⁴; P A T E N T

GNF Docket No.: P1267PC10

Y is a 5-7 membered aryl or heteroaryl containing N, O or S; L¹ and L² are independently NRCO or CONR; R and R¹ are independently H or C_1-6 alkyl;

R ^2 i •s halo, or an optionally halogenated Ci_₆ alkyl;

R⁵ is Ci_₆ alkyl;

R¹² is halo, an optionally halogenated Ci_₆ alkyl, OCi_₆ alkyl, NR⁶R⁷, NR⁵(CR₂)_PNR⁶R⁷, NR⁵CONR⁶R⁷ or NR⁵CO₂R⁶; m and 0 are independently 1-4; and n, p and q are independently 0-4; thereby treating said condition.

19. The method of claim 18, comprising administering said compound to a cell or tissue system; or to a human or animal subject.

20. The method of claim 18, wherein said condition is a cell proliferative disorder or an autoimmune disorder.

21. The method of claim 20, wherein said cell proliferative disorder is melanoma, leukemia, chronic myelogenous leukemia, lymphoma, osteosarcoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.

22. The method of claim 20, wherein said autoimmune disorder is systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, or multiple sclerosis. P A T E N T

GNF Docket No.: P1267PC10

23. A use of a compound of any one of claims 1-12, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for treating a B-Raf, a Bcr-Abl, or a Lck-mediated condition.

24. A use of a compound of any one of claims 1-12, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the manufacture of a medicament for treating a B-Raf, Bcr-Abl, or Lck-mediated condition.

25. The use of claim 23 or 24, wherein said condition is a cell proliferative disorder or an autoimmune disorder.

26. The use of claim 25, wherein said cell proliferative disorder is melanoma, leukemia, chronic myelogenous leukemia, lymphoma, osteosarcoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.

27. The use of claim 25, wherein said autoimmune disorder is systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, or multiple sclerosis.