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(12) United States Patent (10) Patent No.: US 7,338,957 B2 Ding Et Al

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(12) United States Patent (10) Patent No.: US 7,338,957 B2 Ding Et Al US007338957B2 (12) United States Patent (10) Patent No.: US 7,338,957 B2 Ding et al. (45) Date of Patent: Mar. 4, 2008 (54) COMPOUNDS AND COMPOSITIONS AS (58) Field of Classification Search ................ 544/280; PROTEIN KNASE INHIBITORS 51.4/265.1 See application file for complete search history. (75) Inventors: Qiang Ding, San Diego, CA (US); (56) References Cited Nathanael Schiander Gray, San Diego, CA (US); Bing Li, San Diego, OTHER PUBLICATIONS CA (US); Yi Liu, San Diego, CA (US); West, Anthony R., Solid State Chemistry and its Applications, Tetsuo Uno, San Diego, CA (US) Wiley, New York, 1988, pp. 358 & 365.* Vippagunta et al., Advanced Drug Delivery Reviews 48: 3-26, (73) Assignee: IRM LLC, Hamilton (BM) 2001.* Cecil Textbook of Medicine, edited by Bennet, J.C., and Plum F. *) Notice: Subject to anyy disclaimer, the term of this 20th edition,vol. 1, 1004-1010, 1996.* Mass, R. D., Int. J. Radiation Oncology Bio. Phys.vol. 58(3): patent is extended or adjusted under 35 932-940, 2004.* U.S.C. 154(b) by 393 days. Fabbro et al. Pharmacology & therapeutics 93, 79-98, 2002.* Vlahovic G. et al. Activation of Tyrosine Kinases in Cancer, (21) Appl. No.: 10/927,992 Oncologist. 2003, vol. 8, No. 6, pp. 531-538. * cited by examiner (22) Filed: Aug. 26, 2004 Primary Examiner Venkataraman Balasubram (74) Attorney, Agent, or Firm Emily Tongco Wu: Institute of the Novartis Research Foundation (65) Prior Publication Data US 2005/O159391 A1 Jul. 21, 2005 (57) ABSTRACT The invention provides a novel class of compounds, phar Related U.S. Application Data maceutical compositions comprising Such compounds and (60) Provisional application No. 60/498.532, filed on Aug. methods of using such compounds to treat or prevent 28, 2003. diseases or disorders associated with abnormal or deregu lated kinase activity, particularly diseases or disorders that (51) Int. Cl. involve abnormal activation of the Abl, BCR-Abl, Bmx, CO7D 487/04 (2006.01) CSK, TrkB, FGFR3, Fes, Lck, B-RAF C-RAF, MKK6, A 6LX 3/59 (2006.01) SAPK2C. and SAPK2|B kinases. A6IP35/00 (2006.01) (52) U.S. Cl. .................................... 514/265.1: 544/280 8 Claims, No Drawings US 7,338,957 B2 1. 2 COMPOUNDS AND COMPOSITIONS AS hydrogen and Calkyl, R, is selected from Coaryl, PROTEIN KNASE INHIBITORS Csoheteroaryl, C-cycloalkyl and C-sheterocycloalkyl, or R and R, together with the nitrogen to which both R and CROSS-REFERENCE TO RELATED R, are attached form C-sheterocycloalkyl or Csohet APPLICATIONS eroaryl; wherein any aryl, heteroaryl, cycloalkyl or hetero cycloalkyl of R, or of the combination of R and R, can be This application claims the benefit of priority under 35 optionally substituted with 1 to 3 radicals selected from halo, U.S.C. S 119(e) to U.S. Provisional Patent Application No. cyano, nitro, Calkyl, C2-alkenyl, C2-galkynyl, halo-Sub 60/498.532, filed Aug. 28, 2003. The disclosure of the stituted-Calkyl, Calkoxy, halo-substituted-Calkoxy, priority application is incorporated herein by reference in its 10 —XNRRs, XC(O)NR'Rs, XC(O)NRXORs, XS entirety and for all purposes. (O)NRRs —XS(O)o-Rs, —XNRS(O)o-Rs. —XNRC(O)Rs, XNRSRs, XP(O)NR'Rs, XCR BACKGROUND OF THE INVENTION (ORs)Rs —XOC(O)Rs —XORs and —XOR; wherein X is a bond or C-alkylene, Rs is independently selected from 1. Field of the Invention 15 hydrogen and Calkyl, R is selected from Coaryl and The invention provides a novel class of compounds, Cs-oheteroaryl; pharmaceutical compositions comprising such compounds and methods of using Such compounds to treat or prevent R is selected from hydrogen and Calkyl; diseases or disorders associated with abnormal or deregu R is selected from hydrogen, hydroxy, Calkyl, Calk lated kinase activity, particularly diseases or disorders that enyl, C2-alkynyl, Calkoxy, mercapto, halo, nitro and involve abnormal activation of the Abl, BCR-Abl, Bmx, cyano; CSK, TrkB, FGFR3, Fes, Lck, B-RAF, C-RAF, MKK6, n is 0, 1 or 2: SAPK2C. and SAPK2B kinases. R is selected from hydrogen, halo, hydroxy, cyano, nitro, 2. Background Calkyl, halo-substituted-Calkyl, Calkoxy, halo-Sub The protein kinases represent a large family of proteins, 25 stituted-Calkoxy and —XRo, wherein X is a bond or which play a central role in the regulation of a wide variety Coalkylene, Rio is selected from Co-oaryl, Csohet of cellular processes and maintaining control over cellular eroaryl, C-acycloalkyl and C-sheterocycloalkyl, wherein function. A partial, non-limiting, list of these kinases any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of Rio is include: receptor tyrosine kinases Such as the nerve growth optionally substituted with a radical selected from halo, factor receptor, trkB, and the fibroblast growth factor recep 30 hydroxy, cyano, nitro, Calkyl, halo-substituted-Calkyl, tor, FGFR3; non-receptor tyrosine kinases such Abl and the Calkoxy and halo-substituted-Calkoxy; fusion kinase BCR-Abl, Lck, Csk, Fes, Bmx and c-src; and m is 1, 2 or 3; and wherein the phenyl rings A and B can serine/threonine kinases such as c-RAF, Sgk, MAP kinases independently have up to four —C= groups replaced by (e.g., MKK4, MKK6, etc.), SAPK2C. and SAPK2B. Aber —N=; and the N-oxide derivatives, prodrug derivatives, rant kinase activity has been observed in many disease states 35 protected derivatives, individual isomers and mixture of including benign and malignant proliferative disorders as isomers thereof, and the pharmaceutically acceptable salts well as diseases resulting from inappropriate activation of and Solvates (e.g. hydrates) of Such compounds. the immune and nervous systems. In a second aspect, the present invention provides a The novel compounds of this invention inhibit the activity pharmaceutical composition which contains a compound of of one or more protein kinases and are, therefore, expected 40 Formula I or a N-oxide derivative, individual isomers and to be useful in the treatment of kinase-associated diseases. mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipi SUMMARY OF THE INVENTION entS. In a third aspect, the present invention provides a method In one aspect, the present invention provides compounds 45 of treating a disease in an animal, including human, in which of Formula I: inhibition of kinase activity, particularly the Abl, BCR-Abl, Bmx, CSK, TrkB, FGFR3, Fes, Lck, B-RAF, C-RAF, MKK6. SAPK2C. and/or SAPK2B activity, can prevent, R inhibit or ameliorate the pathology and/or symptomology of 50 the diseases, which method comprises administering to the C N (R3)n animal a therapeutically effective amount of a compound of e Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable S.-->{ X), N salt thereof. Y, 55 /n 1s B --R) In a fourth aspect, the present invention provides the use O 21 of a compound of Formula I in the manufacture of a R medicament for treating a disease in an animal in which kinase activity, particularly the Abl, BCR-Abl, Bmx, CSK, in which: 60 TrkB, FGFR3, Fes, Lck, B-RAF, C-RAF, MKK6, SAPK2O. W is selected from CH and N: and/or SAPK2B activity, contributes to the pathology and/or Y is selected from C, S and S(O); symptomology of the disease. Z is a divalent radical selected from Y(O)NRs and In a fifth aspect, the present invention provides a process - NRY(O) ; wherein Y is selected from C, S and S(O); for preparing compounds of Formula I and the N-oxide and Rs is selected from hydrogen and C-alkyl: 65 derivatives, prodrug derivatives, protected derivatives, indi R is selected from hydrogen, halo, hydroxy Calkyl, vidual isomers and mixture of isomers thereof, and the Calkoxy and —NRR, wherein R is selected from pharmaceutically acceptable salts thereof. US 7,338,957 B2 3 4 DETAILED DESCRIPTION OF THE Coheteroaryl; or R and R, together with the nitrogen to INVENTION which both R and R, are attached form C-sheterocy cloalkyl; wherein any aryl, heteroaryl or heterocycloalkyl of Definitions R, or of the combination of R and R, can be optionally “Alkyl as a group and as a structural element of other substituted with 1 to 3 radicals selected from halo, cyano, groups, for example halo-substituted-alkyl and alkoxy, can Calkyl, Calkenyl, halo-substituted-Calkyl, halo-Sub be either straight-chained or branched. C-alkoxy includes, stituted-Calkoxy, XNRRs, XC(O)NR'Rs, XC(O) methoxy, ethoxy, and the like. Halo-substituted alkyl NRXORs —XS(O)NRRs —XSRs —XNRS(O)Rs. includes trifluoromethyl, pentafluoroethyl, and the like. —XNRC(O)Rs —XOC(O)Rs, XORs and XORs: Unless otherwise defined, “alkyl can be optionally inter 10 wherein X is a bond or Calkylene, Rs is hydrogen or rupted by —O— or optionally substituted by —OH. C-calkyl, Ro is Co-oaryl; "Aryl means a monocyclic or fused bicyclic aromatic In a further embodiment, R is selected from hydrogen ring assembly containing six to ten ring carbon atoms. For and Calkyl; R is Calkyl; n is 1; and R is selected from example, aryl may be phenyl or naphthyl, preferably phenyl. halo, halo-substituted-Calkyl and —XR, wherein X is a 15 bond or Calkylene, Ro is selected from Csoheteroaryl "Arylene' means a divalent radical derived from an aryl and C-sheterocycloalkyl, wherein any heteroaryl or hetero group. “Heteroaryl is as defined for aryl where one or more cycloalkyl of Rio is optionally Substituted with Calkyl; of the ring members are a heteroatom. For example het and m is 1, 2 or 3. eroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, In another embodiment, Z is a divalent radical selected quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl.
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