US20080269267A1 - Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases - Google Patents

Kinase inhibitors useful for the treatment of myleoprolific diseases and other proliferative diseases Download PDF

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US20080269267A1
US20080269267A1 US12/105,302 US10530208A US2008269267A1 US 20080269267 A1 US20080269267 A1 US 20080269267A1 US 10530208 A US10530208 A US 10530208A US 2008269267 A1 US2008269267 A1 US 2008269267A1
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c6alkyl
pyrazol
phenyl
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yloxy
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Daniel L. Flynn
Peter A. Petillo
Michael D. Kaufman
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Deciphera Pharmaceuticals LLC
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of C-Abl c-Kit, the HER family, FGFR, VEGFR, PDGFR, Flt-3, the Raf kinase family and disease causing polymorphs thereof.
  • kinases which have been shown to cause or contribute to the pathogensis of these diseases include C-Abl kinase and the oncogenic fusion protein bcr-Abl kinase; c-Kit kinase.
  • FGFR PDGF receptor kinase
  • VEGF receptor kinases Flt-3 kinase, the HER family and the Raf kinase family.
  • C-Abl kinase is an important non-receptor tyrosine kinase involved in cell signal transduction. This ubiquitously expressed kinase—upon activation by upstream signaling factors including growth factors, oxidative stress, integrin stimulation, and ionizing radiation—localizes to the cell plasma membrane, the cell nucleus, and other cellular compartments including the actin cytoskeleton (Van Etten, Trends Cell Biol . (1999) 9: 179). There are two normal isoforms of Abl kinase: Abl-1A and Abl-1B.
  • the N-terminal half of c-Abl kinase is important for autoinhibition of the kinase domain catalytic activity (Pluk et al, Cell (2002) 108: 247). Details of the mechanistic aspects of this autoinhibition have recently been disclosed (Nagar et al, Cell (2003) 112: 859).
  • the N-terminal myristolyl amino acid residue of Abl-1B has been shown to intramolecularly occupy a hydrophobic pocket formed from alpha-helices in the C-lobe of the kinase domain.
  • Such intramolecular binding induces a novel binding area for intramolecular docking of the SH2 domain and the SH3 domain onto the kinase domain, thereby distorting and inhibiting the catalytic activity of the kinase.
  • an intricate intramolecular negative regulation of the kinase activity is brought about by these N-terminal regions of c-Abl kinase.
  • An aberrant dysregulated form of c-Abl is formed from a chromosomal translocation event, referred to as the Philadelphia chromosome (P. C. Nowell et al, Science (1960) 132: 1497; J. D. Rowley, Nature (1973) 243: 290).
  • This abnormal chromosomal translocation leads aberrant gene fusion between the Abl kinase gene and the breakpoint cluster region (BCR) gene, thus encoding an aberrant protein called bcr-Abl (G. Q. Daley et al, Science (1990) 247: 824; M. L. Gishizky et al, Proc. Natl. Acad. Sci. USA (1993) 90: 3755; S. Li et al, J. Exp. Med . (1999) 189: 1399).
  • the bcr-Abl fusion protein does not include the regulatory myristolylation site (B.
  • CML chronic myeloid leukemia
  • CML is a malignancy of pluripotent hematopoietic stem cells.
  • the p210 form of bcr-Abl is seen in 95% of patients with CML, and in 20% of patients with acute lymphocytic leukemia and is exemplified by sequences such as e14a2 and e13a2.
  • the corresponding p190 form, exemplified by the sequence e1a2 has also been identified.
  • a p185 form has also been disclosed and has been linked to being causative of up to 10% of patients with acute lymphocytic leukemia.
  • C-KIT (Kit, CD117, stem cell factor receptor) is a 145 kDa transmembrane tyrosine kinase protein that acts as a type-III receptor (Pereira et al. J Carcin . (2005), 4: 19).
  • the c-KIT proto-oncogene located on chromosome 4q11-21, encodes the c-KIT receptor, whose ligand is the stem cell factor (SCF, steel factor, kit ligand, mast cell growth factor, Morstyn G. et al. Oncology (1994) 51(2):205, Yarden Y, et al. Embo J (1987) 6(11):3341).
  • the receptor has tyrosine-protein kinase activity and binding of the ligands leads to the autophosphorylation of KIT and its association with substrates such as phosphatidylinositol 3-kinase (Pi3K).
  • Tyrosine phosphorylation by protein tyrosine kinases is of particular importance in cellular signalling and can mediate signals for major cellular processes, such as proliferation, differentiation, apoptosis, attachment, and migration.
  • Defects in KIT are a cause of piebaldism, an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.
  • Gain-of-function mutations of the c-KIT gene and the expression of phosphorylated KIT are found in most gastrointestinal stromal tumors and mastocytosis. Further, almost all gonadal seminomas/dysgerminomas exhibit KIT membranous staining, and several reports have clarified that some (10-25%) have a c-KIT gene mutation (Sakuma, Y. et al. Cancer Sci (2004) 95:9, 716). KIT defects have also been associated with testicular tumors including germ cell tumors (GCT) and testicular germ cell tumors (TGCT).
  • GCT germ cell tumors
  • TGCT testicular germ cell tumors
  • c-kit expression has been studied in hematologic and solid tumours, such as acute leukemias (Cortes J. et al. Cancer (2003) 97(11):2760) and gastrointestinal stromal tumors (GIST, Fletcher C. D. et al. Hum Pathol (2002) 33(5):459).
  • the clinical importance of c-kit expression in malignant tumors relies on studies with Gleevece (imatinib mesylate, ST1571, Novartis Pharma AG Basel, Switzerland) that specifically inhibits tyrosine kinase receptors (Lefevre G. et al. J Biol Chem (2004) 279(30):31769).
  • c-MET is a unique receptor tyrosine kinase (RTK) located on chromosome 7p and activated via its natural ligand hepatocyte growth factor.
  • RTK receptor tyrosine kinase
  • c-MET is found mutated in a variety of solid tumors (Ma P. C. et al, Cancer Metastasis (2003) 22:309). Mutations in the tyrosine kinase domain are associated with hereditary papillary renal cell carcinomas (Schmidt L et al. Nat. Genet . (1997)16:68; Schmidt L, et al.
  • the TPR-MET oncogene is a transforming variant of the c-MET RTK and was initially identified after treatment of a human osteogenic sarcoma cell line transformed by the chemical carcinogen N-methyl-N-nitro-N-nitrosoguanidine (Park M. et al. Cell (1986) 45:895).
  • the TPR-MET fusion oncoprotein is the result of a chromosomal translocation, placing the TPR3 locus on chromosome 1 upstream of a portion of the c-MAET gene on chromosome 7 encoding only for the cytoplasmic region.
  • Studies suggest that TPR-MET is detectable in experimental cancers (e.g. Yu J. et al. Cancer (2000) 88:1801).
  • TPR-MET acts to activated wild-type c-MET RTK and can activate crucial cellular growth pathways, including the Ras pathway (Aklilu F. et al. Am J Physiol (1996) 271:E277) and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway (Ponzetto C. et al. Mol Cell Biol (1993) 13:4600).
  • TPR-MET is ligand independent, lacks the CBL binding site in the juxtamembrane region in c-MET, and is mainly cytoplasmic.
  • c-Met immunohistochemical expression seems to be associated with abnormal ⁇ -catenin expression, and provides good prognostic and predictive factors in breast cancer patients.
  • kinases are regulated by a common activation/deactivation mechanism wherein a specific activation loop sequence of the kinase protein binds into a specific pocket on the same protein which is referred to as the switch control pocket.
  • a specific activation loop sequence of the kinase protein binds into a specific pocket on the same protein which is referred to as the switch control pocket.
  • Such binding occurs when specific amino acid residues of the activation loop are modified for example by phosphorylation, oxidation, or nitrosylation.
  • the binding of the activation loop into the switch pocket results in a conformational change of the protein into its active form (Huse, M. and Kuriyan, J. Cell (109) 275)
  • Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary tumor sites, mycloproliferative diseases, leukemias, papillary thyroid carcinoma, non small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, rheumatoid arthritis, asthma, chronic obstructive pulmonary disorder, mastocyclosis, mast cell leukemia, a disease caused by c-Abl kinase, oncogenic forms thereof aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by a laf kinase, oncogenic forms thereof, aberrant
  • Cycloalkyl refers to monocyclic saturated carbon rings taken from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl and cyclooctanyl;
  • Aryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized n electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring; preferred aryl rings are taken from phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl;
  • Heteroaryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring; heteroaryl rings are taken from, but not limited to, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, be
  • Heterocyclyl refers to monocyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms; heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetraliydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholiniyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homo
  • Poly-aryl refers to two or more monocyclic or fused aryl bicyclic ring systems characterized by delocalized ⁇ electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring wherein the rings contained therein are optionally linked together;
  • Poly-heteroaryl refers to two or more monocyclic or fused bicyclic systems characterized by delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring wherein the rings contained therein are optionally linked together, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heteroaryl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;
  • Poly-heterocyclyl refers to two or more monocyclic or fused bicyclic ring systems containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms wherein the rings contained therein are optionally linked, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heterocyclyl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;
  • Alkyl refers to straight or branched chain C1-C6alkyls
  • Halogen refers to fluorine, chlorine, bromine, and iodine
  • Alkoxy refers to —O-(alkyl) wherein alkyl is defined as above;
  • Alkoxylalkyl refers to -(alkyl)-O-(alkyl) wherein alkyl is defined as above;
  • Alkoxyl carbonyl refers to —C(O)O-(alkyl) wherein alkyl is defined as above;
  • CarboxylC1-C 6 alkyl refers to —(C 1 -C 6 alkyl)CO 2 H wherein alkyl is defined as above;
  • Substituted in connection with a moiety refers to the fact that a further substituent may be attached to the moiety to any acceptable location on the moiety.
  • salts embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric and
  • Suitable pharmaceutically-acceptable salts of free acid-containing compounds of Formula I include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Preferred organic salts can be made from primary amines, secondary amines, tertiary amines and quaternary ammonium salts, including in part, tromethamine, diethylamine, tetra-N-methylammonium, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • prodrug refers to derivatives of active compounds which revert in vivo into the active form.
  • a carboxylic acid form of an active drug may be esterified to create a prodrug, and the ester is subsequently converted in vivo to revert to the carboxylic acid form. See Ettmayer et. al, J. Med. Chew (2004) 47: 2393 and Lorenzi et. al, J Pharm. Exp. Therapeutics (2005) 883 for reviews.
  • Structural, chemical and stereochemical definitions are broadly taken from IUPAC recommendations, and more specifically from Glossary of Terms used in Physical Organic Chemistry (IUPAC Recommendations 1994) as summarized by P. Müller, Pure Appl. Chem., 66, 1077-1184 (1994) and Basic Terminology of Stereochemistry (IUPAC Recommendations 1996) as summarized by G. P. Moss Pure and Applied Chemistry, 68. 2193-2222 (1996). Specific definitions are as follows:
  • Atropisomers are defined as a subclass of conformers which can be isolated as separate chemical species and which arise from restricted rotation about a single bond.
  • Enantiomers are defined as one of a pair of molecular entities which are mirror images of each other and non-superimposable.
  • Diastereomers or diastereoisomers are defined as stereoisomers other than enantiomers. Diastereomers or diastereoisomers are stereoisomers not related as mirror images.
  • Diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents.
  • Tautomerism is defined as isomerism of the general form
  • Tautomers are defined as isomers that arise from tautomerism, independent of whether the isomers are isolable.
  • the invention includes compounds of the formula Ia:
  • Q1 and Q2 are each individually and independently selected from the group consisting of N and CH and wherein at least one of Q1 and Q2 is N; and wherein the ring containing Q1 and Q2 may be optionally substituted with one or more R20 moieties; each D is individually taken from the group consisting of C, CH, C—R20, N-Z3, N, O and S, such that the resultant ring is taken from the group consisting of pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxazolyl, and thiadiazolyl; wherein E is selected from the group consisting of phenyl, pyridyl, and pyrimidinyl; when Q1 and Q2 are both N, the A ring is selected from the group consisting of cyclopentyl, cyclohexyl, G1, G2, and G3; when only one of Q1 and Q2 is N, the A ring is selected from the group consisting of cyclopent
  • G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl-4-yl, isoxazolyl-5-yl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl
  • G2 is a fused bicyclic heteroaryl taken from the group consisting of indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimida
  • G2 or G3 has one or more substitutable nitrogen atoms, each respective nitrogen atom may be optionally substituted with a Z4 substituent; each Z1 is independently and individually selected from the group consisting of C1-6alkyl, branched C3-C7alkyl, C3-C8cycloalkyl, halogen, fluoroC1-C 6 alkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, C1-C6alkoxy, fluoroC1-C6alkoxy wherein the alkyl moiety can be partially or fully fluorinated, —(CH 2 ) n OH, oxo.
  • each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, phenyl, G1, and G3; each R7 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl-, dihydroxyC2-C6alkyl-, C1-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl, branched hydroxyC2-C6alkyl-, branched C1-C6alkoxyC2-C6alkyl-, branched dihydroxyC2-C6alkyl-, —(CH 2 ) q R5, —(CH 1 ) n C(O)R5, —
  • A is selected from the group consisting of any possible isomer of phenyl, pyridine and pyrimidine.
  • the invention includes methods of modulating kinase activity of a variety of kinases, e.g. C-Abl kinase, ber-Abl kinase, VEGFR-2 kinase mutants, c-Met, the HER family of kinases, FGFR, Flt-3, c-Kit, PDGFR ⁇ , PDGFR ⁇ and the Raf family of kinases.
  • the kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing.
  • the method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections section 1.
  • the kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation.
  • the kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, inhibition of phosphorylation, oxidation or nitrosylation of said kinase by another enzyme, enhancement of dephosphorylation, reduction or denitrosylation of said kinase by another enzyme, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
  • the methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases or diseases characterized by angiogenesis.
  • These methods comprise administering to such individuals compounds of the invention, and especially those of section 1, said diseases including, but not limited to, solid tumors, malignant melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, diabetic retinopathy and age-related macular degeneration and hyperosinophilic syndrome,
  • compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stabilizers.
  • ureas of general formula 1 can be readily prepared by the union of amines of general formula 2 with isocyanates 3 or isocyanate surrogates 4 (trichloroethyl carbamates) or 5 (isopropenyl carbamates).
  • Preferred conditions for the preparation of compounds of general formula 1 involve heating a solution of 4 or 5 with 2 in the presence of a tertiary base such as diisopropylethylamine, triethylamine or N-methylpyrrolidine in a solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or 1,4-dioxane at a temperature between 50 and 100° C. for a period of time ranging from 1 hour to 2 days.
  • a tertiary base such as diisopropylethylamine, triethylamine or N-methylpyrrolidine
  • a solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or 1,
  • isocyanates 3 can be prepared from amines A-NH 2 6 with phosgene, or a phosgene equivalent such as diphosgene, triphosgene, or N,N-dicarbonylimidazole.
  • Trichloroethyl carbamates 4 and isopropenyl carbamates 5 are readily prepared from amines A-NH 2 (6) by acylation with trichloroethyl chloroformate or isopropenyl chloroformate by standard conditions familiar to those skilled in the art.
  • Preferred conditions for the preparation of 4 and 5 include treatment of compound 6 with the appropriate chloroformate in the presence of pyridine in an aprotic solvent such as dichloromethane or in the presence of aqueous hydroxide or carbonate in a biphasic aqueous/ethyl acetate solvent system.
  • compounds of formula 1 can also be prepared from carboxylic acids 7 by the intermediacy of in-situ generated acyl azides (Curtius rearrangement) as indicated in Scheme 3.
  • Preferred conditions for Scheme 3 include the mixing of acid 7 with amine 2 and diphenylphosphoryl azide in a solvent such as 1,4-dioxane or dimethylformamide in the presence of base, such as triethylamine, and raising the temperature of the reaction to about 80-120° C. to affect the Curtius rearrangement.
  • A1-substituted, pyrazole amines 10 are available by the condensation of hydrazines 8 and beta-keto nitriles 9. Preferred conditions for this transformation are by heating in ethanolic HCl. Hydrazines 8 are in turn available by the diazotization of amines 11 followed by reduction or, alternately from the hydrolysis of hydrazones 13 obtained by the palladium mediated coupling of benzophenone hydrazone with compounds of formula A1-X 12, wherein X represents a halogen or triflate moiety.
  • A1-substituted pyrazoles Another preferred method for constructing A1-substituted pyrazoles is illustrated by the general preparation of pyrazole acid 16 (Scheme 5), an aspect of A-CO 2 H 7 (Scheme 3). As indicated in Scheme 5, the union of a pyrazole 5-carboxylic ester 14 with A1-X 12, wherein X represents a halide, triflate, or boronic acid suitable for direct transition metal-catalyzed couplings with pyrazoles 14, provides A1-substituted pyrazole esters 15.
  • the esters 15 in turn can be converted to acids 16 using conditions familiar to those skilled in the art.
  • the X-groups on the reactants 12 and 21 or 22 are moieties that undergo transition metal catalyzed cross coupling reactions, such as halides or triflates and boronic acids or esters, stannanes, silanes, organozincs or other organometallic moieties known by those skilled in the art to be suitable substrates for such processes.
  • the X-groups in Scheme 7 are complementary moieties for cross coupling processes such that when A1-X 12 is a halide or triflate, A-X 21 or A-X 22 will be a complementary organometallic, such as a stannane or the like or a boronic acid or ester Likewise, if A1-X 12 is an organometallic reagent or a boronic acid or ester, A-X will be a halide or triflate.
  • the Y group of 21 might also be a protected amino group such as N-Boc or a surrogate amino group such as nitro that would give rise to compounds of formula 23 after acidic hydrolysis or reduction respectively.
  • the Y group of 22 might also be an ester which could be hydrolyzed to an acid of formula 24 by standard synthetic methods.
  • Scheme 7 A non limiting example of Scheme 7 is illustrated by the preparation of compound 28, an example of general intermediate A-CO 2 H 7, above.
  • iodoester 25 can be combined with phenylboronic acid 26 in the presence of a palladium catalyst to provide compound 27.
  • Saponification of ester 27 provides acid 28 an example of general intermediate A-CO 2 H 7, above.
  • Isocyanates 29 can be prepared from general amines 2 by standard synthetic methods. Suitable methods for example, include reaction of 2 with phosgene, or a phosgene equivalent such as diphosgene, triphosgene, or N,N-dicarbonylimidazole. In addition to the methods above for converting amines 2 into isocynates 299 the isocyanates 29 can also be prepared in situ by the Curtius rearrangement and variants thereof.
  • acids 30 can be converted to compounds of formula 1 either with or without isolation of 29.
  • Preferred conditions for the direct conversion of acids 30 to compounds of formula 1 involve the mixing of acid 30, amine A-NH, 6, diphenylphosphoryl azide and a suitable base, for example diisopropylethylamine, in an aprotic solvent, for example dioxane. Heating said mixture to a temperature of between 80 and 120° C. provides the compounds of formula 1.
  • compounds of formula 1 can also be prepared from amines 2 by first preparing stable isocyanate equivalents, such as carbamates (Scheme 10).
  • carbamates include trichloroethyl carbamates (31) and isopropenyl carbamates (32) which are readily prepared from amine 2 by acylation with trichloroethyl chloroformate or isopropenyl chloroformate respectively using standard conditions familiar to those skilled in the art.
  • Further reaction of carbamates 31 or 32 with amines A-NH 2 6 provides compounds of formula 1.
  • certain carbamates can also be prepared from acids 30 by Curtius rearrangement and trapping with an alcoholic co-solvent. For example, treatment of acids 30 (Scheme 9) with diphenylphosphoryl azide and trichloroethanol at elevated temperature provide carbamates of formula 31.
  • Amines 2 useful for the invention can be synthesized according to methods commonly known to those skilled in the art.
  • Amines of general formula 2 contain three rings and can be prepared by the stepwise union of three monocyclic subunits as illustrated in the following non-limiting Schemes.
  • Scheme 11 illustrates one mode of assembly in which an E-containing subunit 33 is combined with the central six-membered-ring-containing subunit 34 to provide the bicyclic intermediate 35.
  • the “M” moiety of 33 represents a hydrogen atom of a heteroatom on the X2 linker that participates in a nucleophilic aromatic substitution reaction with monocycle 34.
  • M may also represent a suitable counterion (for example potassium, sodium, lithium, or cesium) within an alkoxide, sulfide or amide moiety.
  • the “M” group can represent a metallic species (for example, copper, boron, tin, zirconium, aluminum, magnesium, lithium, silicon, etc.) on a carbon atom of the X2 moiety that can undergo a transition-metal-mediated coupling with monocycle 34.
  • the “Y” group of monocyclic species 33 is an amine or an amine surrogate, such as an amine masked by a protecting group (“P” in formula 36), a nitro group, or a carboxy acid or ester that can be used to prepare an amine via known rearrangement.
  • suitable protecting groups “P” include but are not limited to tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and acetamide.
  • the products of Scheme 11 will be amine surrogates such as 36 or 37 that can be converted to amine 2 by a deprotection, reduction or rearrangement (for example, Curtius rearrangement) familiar to those skilled in the art.
  • the “LG” of monocycle 34 represents a moiety that can either be directly displaced in a nucleophilic substitution reaction (with or without additional activation) or can participate in a transition-mediated union with fragment 33.
  • the W group of monocycle 34 or bicycle 35 represents a moiety that allows the attachment of a 5-membered heterocycle.
  • the “W” group represents a halogen atom that will participate in a transition-metal-mediated coupling with a pre-formed heterocyclic reagent (for example a boronic acid or ester, or heteroaryl stannane) to give rise to amine 2.
  • the “W” group of 34 and 35 represents a functional group that can be converted to a five-membered heterocycle by an annulation reaction.
  • annulation reaction Non-limiting examples of such processes would include the conversion of a cyano, formyl, carboxy, acetyl, or alkynyl moiety into a five-membered heterocycle.
  • annulations may in fact be reaction sequences and that the reaction arrows in Scheme 11 may represent either a single reaction or a reaction sequence.
  • the “W” group of 35 may represent a leaving group (halogen or triflate) that can be displaced by a nucleophilic nitrogen atom of a pyrazole or triazole ring.
  • Scheme 12 illustrates the preparation of pyrazole 42) an example of general amine 2.
  • Scheme 12 commercially available 3-fluoro-4-aminophenol is reacted with potassium tert-butoxide and 2,4-dichloropyridine 39 to provide chloropyridine 40.
  • the preferred solvent for this transformation is dimethylacetamide at a temperature between 80 and 100° C.
  • a palladium catalyst preferably palladium tetrakis(triphenylphosphine
  • Scheme 13 illustrates the preparation of amine 48, also an example of general amine 2.
  • the chloropyridine 43 is representative of general intermediate 34 (Scheme 11) wherein the “W” group of 34 is a tert-butoxycarbonyl moiety.
  • the union of chloropyridine 43 with phenol 38 provides ether 44, an example of general intermediate 35 (Scheme 11).
  • Introduction of a benzylcarbamate (Cbz) protecting group provides compound 45.
  • the ester of 45 can be reduced using diisobutylaluminum hydride to provide aldehyde 46, also an example of general intermediate 35 (Scheme 11).
  • Isoxazole 47 is an example of general intermediate 36 (wherein the “Y” group is —NH-Cbz). Hydrogenation of 47 provides amine 48, an example of general amine 2.
  • Scheme 14 illustrates another general method of preparing amines 2 by first attaching the 5-membered heterocycle to the central 6-membered ring (34).
  • the “LG” of monocycle 34 represents a moiety that can either be directly displaced in a nucleophilic substitution reaction (with or without additional activation) or can participate in a transition-mediated union with fragment 33.
  • the “W” group of monocycle 34 represents a moiety that allows the attachment of a 5-membered heterocycle.
  • the “W” group represents a halogen atom that will participate in a transition-metal-mediated coupling with a pre-formed heterocyclic reagent (for example, a boronic acid or ester, or heteroaryl stannane) to give rise to amine 2.
  • a pre-formed heterocyclic reagent for example, a boronic acid or ester, or heteroaryl stannane
  • the “W” group of 34 represents a functional group that can be converted to a five-membered heterocycle by an annulation reaction. After conversion of 34 to 49, the “LG” moiety can be replaced with an “X2” linkage to the E-sub-unit to provide the tricylic amine 2, as described above in Scheme 11.
  • amines 2 may be accessed directly from the union of 49 and 33 or may arise indirectly via the intermediacy of 36 or 37, as described previously.
  • Scheme 14 A specific example of Scheme 14 is illustrated by the preparation of amine 55 in Scheme 15.
  • commercially available pyrimidine 50 an example of general intermediate 34 undergoes a palladium-catalyzed coupling with the commercially available pyrazole boronate 51 to provide the bicycle 52 an example of general intermediate 49.
  • Oxidation of the sulfide moiety of 52 (The “LG” group of general intermediate 42) with m-chloroperbenzoic acid further activates this moiety toward nucleophilic displacement and gives rise to intermediate 53.
  • Treatment of sulfone 53 with phenol 54 in the presence of a base provides tricylic amine 55, an example of general amine 2.
  • Preferred bases for the later transformation include potassium carbonate and potassium tert-butoxide in polar aprotic solvents such as dimethylformamide or dimethylacetamide.
  • isoxazoles 63 and 65 can be obtained by the palladium-catalyzed reaction of 40 with 4-isoxazoleboronic acid pinacol ester 62 (commercially available, Frontier Scientific) or tributylstannane 64 (see: Sakamoto, et al. Tetrahedron, 1991, 5111).
  • amines of general formula 2 containing an isothiazole ring can also be prepared by the methods described above.
  • Scheme 17 shows a non-limiting example wherein a palladium-catalyzed Stille reaction of trimethylstannane 66 (see: Wentland, et al. J. Med. Chem., 1993, 1580) with 40 can provide isothiazole 67.
  • palladium-catalyzed Suzuki-cross coupling between 40 and the boronate ester 68 gives rise to isothiazole amine 69.
  • Scheme 18 illustrates non-limiting examples of Scheme 11 wherein the “W” group is a leaving group for nucleophilic aromatic substitution.
  • some amines of general formula 2 in which the 5-membered heterocycle is a nitrogen-linked pyrazole (73)) or triazole (74-77) can be prepared from general intermediate 40 by reaction with pyrazole (70) or triazoles (71 and 72).
  • Preferred conditions for such transformations include the use of polar aprotic solvents such as 1-methyl-2-pyrrolidinone, dimethylacetamide, or dimethylsulfoxide in the presence of non-nucleophilic bases such as potassium carbonate, sodium hydride, 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU), and the like.
  • Preferred temperatures for such transformations are from ambient temperature up to about 250° C. and may optionally include the use of microwave irradiation or sonication.
  • Scheme 19 illustrates the preparation of amine 79, a non-limiting example of a general amine of formula 2 bearing a C-linked 1,2,3-triazole.
  • Conversion of chloropyridine 40 into alkyne 78 can be accomplished by Sonogashira cross-coupling with trimethylsilylacetylene, followed by aqueous hydrolysis of the trimethylsilyl group.
  • Reaction of alkyne 78 with trimethylsilyl azide at elevated temperature affords the triazole 79 after aqueous work-up (see for example, Kallander, et. al, J. Med. Chem. 2005, 5644, and references therein).
  • 1,3-Difluoro-2-methyl-4-nitro-benzene (16 g, 0.092 mol), benzyl alcohol (10 g, 0.092 mol) and K 2 CO 3 (25.3 g, 0.18 mol), were combined in DMF (300 mL) and heated to 100° C. overnight. The mixture was poured into water and extracted with ethyl acetate (3 ⁇ 200 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), concentrated in vacuo and purified by silica gel chromatography to give 1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 33% yield).
  • 1,2,3-Trifluoro-4-nitro-benzene (30 g, 0.17 mol), benzyl alcohol (18.4 g, 0.17 mol) and K 2 CO 3 (35 g, 0.25 mol) were combined in DMF (300 mL) and were stirred at RT for 8 h. Water (300 mL) was added, and the mixture was extracted with EtOAc (3 ⁇ 500 mL). The combined organic layers were washed with brine, dried (MgSO 4 ), concentrated in vacuo and purified by column chromatography on silica gel to give 1-benzyloxy-2,3-difluoro-4-nitro-benzene (16 g, 36% yield).
  • 1 HNMR 400 MHz, DMSO-d 6 ): ⁇ 8.06 (m, 1H), 7.49-7.30 (m, 6H), 5.37 (s, 2H).
  • Example A2 To a biphasic mixture of Example A2 (1.5 g, 4.96 mmol) in ethyl acetate (20 ml) and water (20.00 ml) was added NaHCO 3 (1.3 g, 15 mmol) and isopropenyl chloroformate (0.6 mL). The reaction was stirred at RT for 1 hour. The organic layer was separated and washed with brine, dried and evaporated to provide prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate which was used for the next reaction (0.92 g, 48% yield). MS (ESI) m/z: 387.1 (M+H + ).
  • Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a ⁇ 10° C. solution of 2-chloro-4-fluorophenol (100 g, 0.68 mol) and sodium hydroxide (32.8 g, 0.82 mol) in water (550 mL).
  • Phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 3-t-butyl-1-phenyl-1H-pyrazol-5-amine. See WO 2006/071940.
  • the reaction is treated with additional isopropyliodide (1.5 mL) and stirred at 80° C. overnight.
  • the reaction is treated with additional isopropyliodide (1.5 mL) and stirred at 80° C. overnight.
  • the reaction is cooled to RT and filtered free of insolubles.
  • Example B1 (0.0898 g, 0.30 mmol), THE (1.0 mL), Example A1 (0.0853 g, 0.30 mmol) and 1-methylpyrrolidine (0.00312 mL) were combined and the resultant product purified via column chromatography to yield 1-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.125 g, 79% yield) as a white foam.
  • Example B2 (0.060 g, 0.24 mmol) and Example A1 (0.200 g, 0.71 mmol) were combined and the resultant product purified via column chromatography to yield 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.077 g, 61% yield) as a white solid.
  • Example B3 100 mg, 0.370 mmol
  • Example A9 100 mg, 0.370 mmol
  • DPPA 117 mg, 0.426 mmol
  • triethylamine 66 mg, 0.648 mmol
  • Example A1 150 mg, 0.563 mmol
  • DPPA 178 mg, 0.648 mmol
  • Example B4 A solution of Example B4 (249 mg, 1.02 mmol) in THF (2 mL) was cooled to ⁇ 78° C. and treated with a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF) (2.12 mL, 2.12 mmol). The resultant solution was stirred 20 min at ⁇ 78° C. Isopropenyl chloroformate (0.12 mL, 1.11 mmol) was added rapidly and the reaction was stirred 10 min at ⁇ 78° C. and quenched by addition of 2 M aq HCl (1.2 mL, 2.4 mmol). The mixture was warmed to RT and partitioned between EtOAc and water.
  • reaction mixture was purified by silica gel chromatography and recrystallization (acetone-acetonitrile) to provide 1-(1-(3-cyano-4-fluorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (49 mg, 30% yield).
  • Example B5 (0.100 g, 0.371 mmol), TEA (0.259 mL, 1.857 mmol), DPPA (0.10 mL, 0.464 mmol) and Example A1 (0.211 g, 0.743 mmol) were combined and was purified by chromatography to afford 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.116 g, 57% yield) as a white foam.
  • Example B6 (1.50 g, 5.22 mmol) was converted to ethyl 3-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)benzoate (2.79 g, 116% yield) as a thick oil.
  • Example B7 (0.31 g, 1.079 mmol) was converted to ethyl 4-(3-tert-butyl-5-((prop-1-en-2-yloxy)carbonyl)-1H-pyrazol-1-yl)benzoate (0.35 g, 87% yield) as an off-white solid.
  • Example B8 (0.250 g, 1.18 mmol) was converted to prop-1-en-2-yl 1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-ylcarbamate and purified via recrystallization (hexanes) to isolate a colorless semi-solid (0.350 g, 100% yield)
  • Example B9 60 mg, 0.23 mmol
  • Example A1 67 mg, 0.23 mmol
  • DPPA 57 ⁇ L, 0.23 mmol
  • 36 ⁇ L, 0.23 mmol 36 ⁇ L, 0.23 mmol
  • Example B10 To a solution of Example B10 (0.15 g, 0.624 mmol) in CH 2 Cl 2 (10 mL) were added pyridine (0.102 ml, 1.248 mmol) and 2,2,2-trichloroethyl carbonochloridate (0.103 ml, 0.749 mmol) at 0° C. After stirring for 2 h at RT, 2M HCl was added, the organic layer was separated and aqueous layer was extracted with CH 2 Cl 2 (1 ⁇ 20 mL). The combined organics were washed with brine, dried (Na 2 SO 4 ) and concentrated to afford a white foam.
  • Example A1 (0.177 g, 0.624 mmol), DIPEA (0.081 g, 0.624 mmol) and DMSO (2 mL) and the mixture was heated to 65° C. for 5 h. Water (40 mL) was added and product was extracted with EtOAc (2 ⁇ 35 ml).
  • Prop-1-en-2-yl 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (63 mg, 0.20 mmol), prepared from Example B11 according to General Method D, Example A2 (57 mg, 0.19 mmol) and N-methylpyrrolidine (1.627 mg, 0.019 mmol) were combined in THF (0.4 mL) and heated to 55° C. overnight.
  • reaction mixture was purified by chromatography to provide 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (58 mg, 55% yield.
  • reaction mixture was purified by chromatography to provide 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (77 mg, 62% yield).
  • Example B12 75 mg, 0.352 mmol
  • triethylamine 41 mg, 0.405 mmol
  • Example A1 100 mg, 0.352 mmol
  • DPPA 111 mg, 0.405 mmol
  • Example B8 To a solution of Example B8 (0.300 g, 1.413 mmol) and Troc-Cl (0.233 ml, 1.696 mmol) in EtOAc (7 ml) at 0° C. was added 3M NaOH (0.707 ml, 2.120 mmol). The reaction was stirred at 0° C. for 30 min and then at RT for 2 h. The reaction was treated with satd. NaHCO 3 (2-3 ml) and more Troc-Cl (0.1 ml) and stirred at RT.
  • Example B13 (0.301 g, 1.161 mmol) was converted to ethyl 4-(3-ethyl-5-((prop-1-en-2-yloxy)carbonyl)-1H-pyrazol-1-yl)benzoate (0.4 g, 100%) as a thick residue.
  • Example B14 (79 mg, 0.210 mmol), DIEA (81 mg, 0.629 mmol) and Example A1 (60 mg, 0.210 mmol) in DMSO (2 mL) was warmed to 80° C. overnight and then 110° C. overnight. The reaction was cooled to RT, diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine (30 mL), dried (Na 2 SO 4 ), concentrated in vacuo and purified by column chromatography (ethyl acetate/hexane-methanol/ethyl acetate) to give an impure foam (21 mg).
  • This foam was purified by reverse phase chromatography (acetonitrile/water/0.1% TFA), lyophilized, and dissolved a mixture of water (5 mL), saturated sodium bicarbonate (5 mL) and ethyl acetate (15 mL). The organic phase was separated, washed with brine (10 mL), dried (Na 2 SO 4 ), concentrated in vacuo, dissolved in acetonitrile/water and lyophilized to afford 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-5-phenyl-1H-pyrazol-4-yl)urea (11 mg, 10% yield).
  • Example B15 200 mg, 0.531 mmol
  • DIEA 206 mg, 1.593 mmol
  • Example A1 151 mg, 0.531 mmol
  • column chromatography ethyl acetate/hexane
  • reverse phase chromatography acetonitrile/water/0.1% TFA
  • Example B16 (261 mg. 0.720 mmol), DIEA (372 mg, 2.88 mmol) and Example A1 (205 mg, 0.720 mmol) in DMSO (5 mL) was warmed to 75° C. and stirred overnight. The mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with brine (30 mL), dried (Na 2 SO 4 ), concentrated in vacuo and purified by column chromatography (methanol/dichloromethane) to give a film.
  • DIEA 356 mg, 2.76 mmol
  • Example A1 196 mg, 0.689 mmol
  • DMSO DMSO
  • the temperature was increased to 100° C. and stirring continued overnight.
  • the mixture was cooled to RT and diluted with ethyl acetate (25 mL) and water (25 mL).
  • the organic phase was washed with brine (20 mL), dried (Na 2 SO 4 ), concentrated in vacuo and purified by column chromatography (methanol/dichloromethane) to give a film.
  • Example B18 To a stirring solution of Example B18 (0.09 g, 0.363 mmol) and TEA (0.076 mL, 0.544 mmol) in dioxane (3.0 mL) was added DPPA (0.117 mL, 0.544 mmol). After stirring for 0.5 h at RT, Example A1 (0.103 g, 0.363 mmol) was added and the reaction was heated at 100° C. for 3 h. Water (15 mL) was added to reaction mixture and the resulting precipitate was collected by filtration.
  • Example A8 (0.083 g, 0.21 mmol) and Example B19 (0.04 g 0.21 mmol) in presence of N-methylpyrrolidine (cat amount) were combined to afford 1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea as white solid (0.059 g, 53% yield).
  • Example B3 (0.085 g, 0.31 mmol), Example A10 (0.075 g, 0.26 mmol) in presence of triethylamine (0.08 g, 0.79 mmol) and DPPA (0.14 g, 0.52 mmol) were combined to afford 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea as a white solid (0.099 g, 68% yield).
  • Abl kinase Activity of Abl kinase (SEQ ID NO:1) was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A 340nm ) was continuously monitored spectrophometrically. The reaction mixture (100 ⁇ l) contained Abl kinase (1 nM. Abl from deCode Genetics), peptide substrate (EAIYAAPFAKKK.
  • reaction rate was calculated using the 1.0 to 2.0 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC 50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
  • T315I Abl kinase (SEQ ID NO:2) was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A 340nm ) was continuously monitored spectrophometrically. The reaction mixture (100 ⁇ l) contained Abl kinase (4.4 nM.
  • M315I Abl from deCode Genetics peptide substrate (EAIYAAPFAKKK, 0.2 mM), MgCl 2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Test compounds were incubated with T315I Abl (SEQ ID NO:2) and other reaction reagents at 30° C. for 1 h before ATP (500 ⁇ M) was added to start the reaction.
  • the absorption at 340 nm was monitored continuously for 2 hours at 30° C. on Polarstar Optima plate reader (BMG).
  • the reaction rate was calculated using the 1.0 to 2.0 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound).
  • IC 50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
  • c-Kit kinase Activity of c-Kit kinase (SEQ ID NO:9) was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340 nm) was continuously monitored spectrophometrically.
  • the reaction mixture (1001) contained c-Kit (cKIT residues T544-V976, from ProQinase, 5.4 nM), polyE4Y (1 mg/ml), MgCl2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Test compounds were incubated with C-Met (SEQ ID NO:9) and other reaction reagents at 22° C. for ⁇ 2 min before ATP (200 ⁇ M) was added to start the reaction.
  • C-Met SEQ ID NO:9
  • the absorption at 340 nm was monitored continuously for 0.5 hours at 30° C. on Polarstar Optima plate reader (BMG).
  • the reaction rate was calculated using the 0 to 0.5 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound).
  • IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
  • C-Met kinase (SEQ ID NO:10) was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340 nm) was continuously monitored spectrophometrically.
  • the reaction mixture (100 ⁇ l) contained C-Met (c-Met residues; 956-1390, from Invitrogen, catalogue #PV3143, 6 nM), polyE4Y (1 mg/ml), MgCl2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris buffer containing 0.25 mM DTT, 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Test compounds were incubated with C-Met (SEQ ID NO:10) and other reaction reagents at 22° C.
  • ATP 100 ⁇ M
  • the absorption at 340 n was monitored continuously for 2 hours at 30° C. on Polarstar Optima plate reader (BMG).
  • BMG Polarstar Optima plate reader
  • the reaction rate was calculated using the 1.0 to 2.0 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound).
  • IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
  • B-Raf(V600E) kinase SEQ ID NO:11
  • the activity of B-Raf(V600E) kinase was determined by following the formation of ADP from the reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942).
  • the oxidation of NADH was continuously monitored spectrophotometrically.
  • the reaction mixture (100 ⁇ l) contained B-Raf(V600E) kinase (0.34 nM nominal concentration, SEQ ID NO:11), unphosphorylated, full-length MEK1 (42 nM, SEQ ID NO:12), MgCl 2 (13 mM), pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1 mM), and NADH (0.28 mM), in 60 mM Tris buffer, containing 0.13% octyl-glucoside and 3.5% DMSO concentration at pH 7.5. The test compounds were incubated with the reaction mixture at 30° C. for 1 h.
  • the reaction was initiated by adding ATP (0.2 mM, final concentration). The absorption at 340 nm was continuously monitored for 3 h at 30° C. on a Polarstar Optima plate reader (BMG). The reaction rate was calculated using the 0.5 h to 1.5 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC 50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
  • BRaf V600E kinase (SEQ ID NO:11) MDRGSHHHHHHGSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFG TVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGY STKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHA KSIIHRDLKSNNIFLHEDLTVKIGDFGLATEKSRWSGSHQFEQLSGSILW MAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMV GRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLAR SLPKIHR MEK1 kinase (SEQ ID NO:12) MELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQ IIRELQVLHECNSP
  • BaF3 cells Parental or transfected with the following: wild type p210 BCR-Abl and T315I p210 BCR-Abl was obtained from Professor Richard Van Etten (New England Medical Center, Boston, Mass.). Briefly, cells were grown in RPMI 1640 supplemented with 10% characterized fetal bovine serum (HyClone, Logan, Utah) at 37 degrees Celsius, 5% CO 2 , 95% humidity. Cells were allowed to expand until reaching 80% saturation at which point they were subcultured or harvested for assay use.
  • test compound was dispensed into a 96 well black clear bottom plate (Corning, Corning, N.Y.). For each cell line, three thousand cells were added per well in complete growth medium. Plates were incubated for 72 hours at 37 degrees Celsius, 5% CO 2 , 95% humidity. At the end of the incubation period Cell Titer Blue (Promega, Madison, Wis.) was added to each well and an additional 4.5 hour incubation at 37 degrees Celsius, 5% CO 2 , 95% humidity was performed. Plates were then read on a BMG Fluostar Optima (BMG, Durham, N.C.) using an excitation of 544 nM and an emission of 612 nM. Data was analyzed using Prism software (Graphpad, San Diego, Calif.) to calculate IC50's.

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