WO2003030909A1 - 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer - Google Patents

2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer Download PDF

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WO2003030909A1
WO2003030909A1 PCT/US2002/030616 US0230616W WO03030909A1 WO 2003030909 A1 WO2003030909 A1 WO 2003030909A1 US 0230616 W US0230616 W US 0230616W WO 03030909 A1 WO03030909 A1 WO 03030909A1
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formula
group
compound
optionally substituted
hydrogen
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PCT/US2002/030616
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French (fr)
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Dhanapalan Nagarathnam
Chunguang Wang
Yuanwei Chen
Lin Yi
Jianqing Chen
Olaf Weber
Stephen Boyer
Roger B. Clark
Barton Phillips
Jennifer Burke
Gaetan Ladouceur
Cheng Bi
Michael J. Burke
James Cook
Sharad K. Verma
Jianmei Fan
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Bayer Pharmaceuticals Corporation
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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 certain multi-ring compounds, particularly to compounds that are useful as inhibitors of kinases such as, but not limited to, serine/threonine kinases.
  • the present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, as well as methods of using the compounds in inhibiting the kinases and treating patients suffering from diseases caused by various altered kinases.
  • the invention also relates to a method of producing the compounds of the present invention.
  • the present invention relates to intermediates used to prepare the compounds of the present invention.
  • serine/threonine protein kinases are involved in cellular signaling mechanisms that regulate gene expression and cell proliferation (Su and Karin, Curr. Opinion. Immunol. (1996), 8:402; Kolch, Biochem. J. (2000) 351:289).
  • Some serine/threonine kinases, such as cyclin dependent kinases (CDK) are necessary to progress from one step in the cell cycle to the next (Meyerson et al., EMBO J. (1992) 11 :2909). They are active when specifically bound to other cell cycle proteins (cyclin family). Changes in their activities or in the activities of their activators or inhibitors are common in cancerous cells (Motokura and Arnold, Biochim. Biophys.
  • Apoptosis is an intrinsic process present in all cells that can be regulated by extrinsic factors such as hormones, growth factors, cell surface receptors or cellular stress.
  • extrinsic factors such as hormones, growth factors, cell surface receptors or cellular stress.
  • the actions of both pro- and anti-apoptotic factors are often affected by modulation of the phosphorylation state of key elements of the apoptotic process.
  • Evidence has been accumulated that serine/threonine kinases are also involved directly in the regulation of the apoptotic cascade (Cross et al., Experimental Cell Research (2000) 256:34).
  • Viruses are by definition unable to replicate on their own but must enter a host cell in order to use the host cell's macromolecular machinery to replicate (Knipe in: Fields et al., Virology. Third Edition (Lippincott-Raven, 1996), p. 273. Inhibition of protein kinases has also shown encouraging results in controlling viral infections such as infections with human cytomegaloviruses (Bresnahan et al.,
  • the present invention relates to certain multi-ring compounds represented by the Formula (I):
  • each R 5 is independently an optionally substituted -Y (n) -mono-ring group or an optionally substituted -Y ( n ) -multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n is 0 or 1 , and -Y- is selected from the group consisting of straight- or branched-chain C 2-3 -alky
  • each R 6 is independently hydrogen or alkyl
  • each R 8 and R 9 is independently hydrogen, optionally substituted C ⁇ -5 - alkyl, optionally substituted aryl, or optionally substituted arylalkyl, wherein said substitution is selected from the group consisting of optionally substituted alkyl, wherein said substitution on said alkyl is selected from the group consisting of fluoro and dialkylamino; and pharmaceutically acceptable salts and prodrugs thereof.
  • each X individually is -NR 1 R 6 , -NR 4 R 5 , or R 4 , with the proviso that at least one X is -NR 1 R 6 ; each R 1 is independently an optionally substituted moiety selected from the group consisting of indazolyl, quinolinyl, benzothiazolyl, benzotriazolyl, or benzoxazolyl, wherein said substitution is selected from the group consisting of hydrogen, methyl, and ethyl; R 2 is halo or optionally substituted alkyl, wherein said substitution is selected from the group consisting of fluoro, -COOR 8 , -COOR 9 , and -CONR 8 R 9 ; R 3 is hydrogen or methyl; each R 4 is hydrogen, methyl, phenyl, aryl, benzothiophenyl, pyridyl, indolyl, naphthalenyl, biphenyl, in
  • the present invention also relates to compounds of Formula (1-1)
  • each R 1 is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazolyl, 6-(1- methyl)indazolyl, 5-(1-ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3- quinolyl, or 3-isoquinolyl;
  • R 2 is hydrogen, fluoro, bromo, chloro, methyl, or trifluoromethyl;
  • R 3 is hydrogen or methyl, and pharmaceutically acceptable salts and prodrugs thereof.
  • the present invention also relates to compounds of Formula (I-2)
  • each R 1 is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazolyl, 6-(1- methyl)indazolyl, 5-(1-ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3- quinolyl, or 3-isoquinolyl;
  • R 2 is hydrogen, fluoro, bromo, chloro, methyl, or trifluoromethyl;
  • R 3 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • the present invention also relates to compounds of Formula (I-3)
  • R 1 is 5-quinolyl or 6-quinolyl;
  • R 2 is fluoro or trifluoromethyl; and
  • R 4 is optionally substituted phenyl or pyridyl, wherein said substitution is selected from the group consisting of halo, amino, hydroxy, acetyl, alkyl, alkoxy, alkenyl, hydroxyalkyl, dialkylamino, and phenyl; and pharmaceutically acceptable salts and prodrugs thereof.
  • the present invention also relates to the compounds of Formula (1-4)
  • R 1 is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazoIyI, 6-(1- methyl)indazolyl, 5-(1-ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3- quinolyl, or 3-isoquinolyl;
  • R 2 is hydrogen, fluoro, chloro, bromo, methyl, or trifluoromethyl;
  • R 3 is hydrogen or methyl;
  • R 4 is hydrogen or methyl
  • R 5 is an optionally substituted -Y(n)-moiety, wherein n is 0 or 1 , Y is selected from the group consisting of straight- or branched-chain
  • C 2 _ 3 -alkylenyl, -N CH, and -N-CHCH 3 , and said moiety is selected from the group consisting of cycloalkyl, phenyl, naphthyl, pyridyl, thienyl, furyl, quinolinyl, benzothiophenyl, benzothiazolyl, indol-3-yl, and quinoline-4-thio, said substitution being selected from the group consisting of methyl, ethyl, fluoro, bromo, chloro, trifluoromethyl, methoxyl, methylenedioxyl, sulfonamidyl, morpholinyl, and - pyrazinyl; and and pharmaceutically acceptable salts and prodrugs thereof.
  • the present invention also relates to compounds of Formula (I-5)
  • R >1 is 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5-benzothiazolyl, 6- quinolinyl, 5-(1-methyl)indazolyl, 6-(1-methyl)indazolyl, 5-(1- ethyi)indazolyl, 6-(1-ethyl)-indazolyI, 3-quinolyl, or 3-isoquinolyl;
  • R 2 is hydrogen, fluoro, methyl, bromo, chloro, trifluoromethyl, -C0 2 CH 3 ,
  • R 3 is hydrogen or methyl
  • Another aspect of the present invention relates to pharmaceutical composition containing at least one of the compounds of the present invention.
  • the present invention also relates to a method for inhibiting kinases such as serine/threonine kinases in a warm-blooded animal in need thereof by administering at least one of the compounds of the present invention in an amount sufficient to inhibit said kinases.
  • kinases such as serine/threonine kinases
  • the present invention also relates to a method for treating a CDK- dependent disorder or disease in a warm-blooded animal in need of same, by administering to said animal at least one of the compounds of the present invention in an amount sufficient to inhibit CDK.
  • the present invention further relates to a method for inhibiting cellular proliferation in a warm-blooded animal in need thereof by administering to said animal at least one of the compounds of the present invention in an amount sufficient to inhibit said proliferation.
  • the present invention also relates to methods of treating a warm-blooded animal suffering from cancer or neoplastic disease by administering to said warmblooded animal an effective amount of at least one of the compounds of the present invention.
  • a still further aspect of the present invention relates to a method for modulating apoptosis in a warm-blooded animal in need thereof by administering at least one of the compounds of the present invention in an amount sufficient to modulate apoptosis.
  • the present invention relates to intermediates used to prepare the above compounds of the present invention. Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein are shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
  • alkyl when used alone or as part of another term, refers to straight- or branched-chain optionally substituted hydrocarbon groups containing 1 to 6 carbon atoms; or optionally substituted cycloalkyl groups.
  • suitable straight-chain alkyl groups include methyl, ethyl and propyl.
  • Examples of branched-chain alkyl groups include isopropyl and t-butyl.
  • the preferred alkyl group is methyl.
  • the cycloalkyl groups typically contain 3-6 atoms in the ring and can include up to 2 heteroatoms such as N, S and O, and can include unsaturation in the ring.
  • Typical cycloalkyl groups and cycloalkyl groups containing hetero atoms in the ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 2-pyrrolinyl, imidazolidinyl, 2- imidazolinyl, pyrazolidinyl, 3-pyrazolyl, piperidinyl, piperazinyl and morpholinyl.
  • alkenyl refers to straight- or branched-chain optionally substituted hydrocarbon groups containing 2 to 6 carbon atoms comprising one carbon-carbon double bond. Examples of suitable alkenyl groups are methenyl and ethenyl.
  • alkoxy refers to straight- or branched-chain optionally substituted Ci-C 6 -alkyl-0-, wherein “alkyl” is as defined above.
  • dialkylamino refers to a nitrogen atom substituted with two alkyl groups, each alkyl being independently as defined above.
  • Suitable halo groups are chloro, bromo and fluoro.
  • An example of a fluoro substituted alkyl is trifluoromethyl.
  • at least one of R 2 or R 3 is alkyl substituted with either halo or halo-substituted alkyl , and most preferably one of R 5 or R 3 is alkyl substituted with either halo or halo-substituted alkyl and the other of R 5 or R 6 is hydrogen.
  • hydroxyalkyl refers to an alkyl as defined above substituted with at least one hydroxy group.
  • fused bicyclic unsaturated ring groups are 2-quinolinyl, 3- quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 1 -isoquinolinyl, 3-isoquinolinyl, 6- isoquinolinyl, 7-isoquinolinyl, 3-cinnolyl, 6-cinnolyl, 7-cinnoIyl, 2-quinazoIinyl, 4- quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 2-quinoxalinyI, 5-quinoxalinyl, 6- quinoxalinyl, 1-phthalazinyl, 6-phthalazinyl, 1 ,5-naphthyridin-2-yl, 1 ,5-naphthyridin- 3-yl, 1 ,6-naphthyridin-3-yl, 1 ,6-naphthyl
  • Substitutions for each of the fused ring groups are selected from the group consisting of -NR 8 R 9 , -OR 8 , fluoro, methenyl and ethenyl.
  • mono- and multi-ring groups include aryl and bicyclic fused aryl-cycloalkyl groups.
  • the aryl groups include an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently, directly or via a linker, e.g. methylene, O, S, N, -NR 8" S0 2 -, -COR 8 , -NR 8 CO- , and -S0 2 -NR 8 .
  • the rings may each contain from zero to four heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized.
  • aryl groups include phenyl, 1 -naphthyl, 2-naphthyl, biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyr
  • -NR 8 S0 2 R 9 , -S0 2 R 8 , -S0 2 NR 8 R 9 , -NR 8 CONR 9 , -SR 8 , -NR 8 S0 2 , -OR 8 NR 8 R 9 , -N CR 8 , and optionally substituted alkyl wherein said substitutions on said alkyl are selected from the group consisting of -NR 8 R 9 , -OR 8 , fluoro, methenyl, and ethenyl.
  • the "bicyclic fused aryl-cycloalkyl" groups are those groups in which an aryl ring (or rings) is fused to a cycloalkyl group (including cycloheteroalkyl groups).
  • the group can be attached to the remainder of the molecule through either an available valence on the aryl portion of the group, or an available valence on the cycloalkyl portion of the group.
  • Examples of such bicyclic fused aryl-cycloalkyl groups are indanyl, benzotetrahydrofuranyl, benzotetrahydropyranyl and 1 ,2,3,4- tetrahydronaphthyl.
  • a substituted moiety When a substituted moiety is employed, it can be substituted at one or more positions with at least one of the above disclosed groups up to the number of available positions, but typically contain 1-3 substitutions, when substituted. When more than one substitution is present, the same or different substitution groups can be employed.
  • Pharmaceutically acceptable salts of the compounds of the above formulae include those derived from pharmaceutically acceptable, inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic and benzenesulfonic acids.
  • Salts derived from appropriate bases include alkali such as sodium and ammonia or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the compounds of the formula (I) may be administered in the form of a pro- drug which is broken down in the human or animal body to give a compound of the formula (I).
  • pro-drugs include in vivo hydrolysable esters of a compound of the formula (I).
  • An in vivo hydrolyzable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include C 1-6 - alkoxymethyl esters, for example methoxymethyl; C ⁇ -6 -a!kanoyloxymethy!
  • esters for example pivaloyloxymethyl; phthalidyl esters; C 3 - 8 -cycloalkoxycarbonyloxy, C- ⁇ - 6 -alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1 ,3-dioxolen-2- onylmethyl esters, for example 5-methyl-1 ,3-dioxolen-2-onylmethyl; and C-i -6 - alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolyzable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ - acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ - acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy- methoxy.
  • a selection of in vivo hydrolyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)- ⁇ /-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring.
  • Some compounds of the formula (I) may have chiral centers and/or geometric isomeric centers (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess cyclin-dependent kinase (CDK) inhibitory activity.
  • CDK cyclin-dependent kinase
  • the invention relates to any and all tautomeric forms of the compounds of the formula (I) that possess CDK inhibitory activity.
  • the compounds of the present invention can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, e.g. intravenously, subcutaneously, intramuscularly, intraperitoneally, and locally (intratumorally) in sterile liquid dosage forms.
  • the active ingredient can also be administered intranasally (nose drops) or by inhalation of drug powder mist.
  • Other dosage forms are potentially possible such as administration transdermally, via patch mechanism or ointment.
  • Formulations suitable for oral administration can comprise of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard-or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.
  • Tablet forms can include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • Immediate release tablets/capsules solid oral dosage forms are made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the compounds of the present invention alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • the compounds of the present invention can be administered in the form of nose drops, or metered dose and a nasal or buccal inhaler.
  • the drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol such as poly (ethyleneglycol) 400, glycerol ketals, such as 2,2-dimethyl-1 ,3-dioxolane-4- methanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or any acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulos, or emulsifying agents and other
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isosteric acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include: (a) cationic detergents such as, dimethyldialkylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, alkyl, aryl, and olefin sulfonates, alkyl, olefin, either, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, alkyl ⁇ -aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the pharmaceutically acceptable carriers described herein for example, vehicles, adjuvants, excipients, or diluents, are well-known to those who are skilled in the art.
  • the pharmaceutically acceptable carrier is chemically inert to the active compounds and has no detrimental side effects or toxicity under the conditions of use.
  • the pharmaceutically acceptable carriers can include polymers and polymer matrices.
  • Pharmaceutically acceptable excipients are also well-known to those who are skilled in the art. The choice of excipient will be determined in part by the particular compound, as well as the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following methods and excipients are merely exemplary and are in no way limiting.
  • Suitable carriers and excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field, incorporated by reference.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B.
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the animal over a reasonable time frame.
  • dosage will depend upon a variety of factors including a condition of the animal, the body weight of the animal, as well as the severity and stage of the cancer.
  • a suitable dose is that which will result in a concentration of the active agent in a patient which is known to effect the desired response.
  • the preferred dosage is the amount which results in maximum inhibition of cancer, without unmanageable side effects.
  • the dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
  • the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect.
  • a daily dosage of active ingredient can be expected to be about 0.001 to 1000 milligrams (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg.
  • Dosage forms contain from about 1 mg to about 500 mg of active ingredient per unit.
  • the active ingredient will ordinarily be present in any amount of about 0.5-95% weight based on the total weight of the composition.
  • a 5,6-disubstituted uracil (II) may be converted to a 2,4- dichloro-5,6-disubstituted pyrimidine intermediate of formula (III). This key intermediate is allowed to react with heating up to 120°C, as shown in Reaction
  • Ar aryl or heteroaryl
  • Intermediate (III) may react under a Suzuki-type coupling conditions (a palladium catalyst, and a base such as Na 2 C0 3 ) with a boronic acid of type R 4 B(OH) 2 to give a chloropyrimidine of formula (Vlb).
  • This formula (Vlb) compound may undergo reaction with an amine of type R 1 R 6 NH, as previously described in Reaction Scheme 1, to give the compounds of the invention of formula (If).
  • the compound of formula (IV), as previously described in Reaction Scheme 1 may be allowed to react with a boronic acid of type R 4 B(OH) 2 under the Suzuki-type coupling conditions described above to give the compound of the invention of formula (Ig).
  • Another type of compound of the invention, formula (Ih), is prepared as shown in Reaction Scheme 3.
  • a ketone of formula (VII) (wherein R" is methyl, methoxy, -0-CH 2 -O-, fluoro, CN, or N0 2 ) reacts with DMF- dimethylacetal of formula (VIII) in a refluxing solvent such as toluene to give an enaminone intermediate of formula (IX).
  • a guanidine of formula (XII) is also prepared from an amine of formula (XI) and the reagent of formula (X) by heating the two together in a higher boiling solvent such as toluene/acetic acid mixtures. Reaction of the enaminone (IX) with the guanidine (XII) in a protic solvent such as methanol and a base such as sodium methoxide gives the compound of the invention of formula (Ih).
  • Ketones of formula (VII) that are not commercially available may be conveniently prepared by the method illustrated in Reaction Scheme 4.
  • An aryl or heteroaryl bromide of formula (XIII) may be converted to an aryllithium intermediate by halogen-metal exchange with butyllithium; reaction of the intermediate with an amide such as the compound of formula (XIV) provides the corresponding ketone of formula (XV).
  • Additional compounds of formula (I) may be prepared from other formula (I) compounds by elaboration of functional groups present. Such elaboration includes, but is not limited to, hydrolysis, reduction, oxidation, alkylation, acylation, esterification, amidation and dehydration reactions. Such transformations may in some instances require the use of protecting groups by the methods disclosed in T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis (Wiley,
  • Method 1 Eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.02% TFA. Elution conditions consisted of a flow rate of 1.0 mL/min with an initial hold at 10% B for 0.5 min, followed by gradient elution from 10% B to 95% B over 3.5 min, followed by a final hold at 95% B for 0.5 min. Total run time was 6.5 min.
  • Celite ® diatomaceous earth filter agent ® Celite Corp.
  • the enamine was prepared according to the process of Example 22 using ethyl 4-methoxybenzoyl acetate to afford the desired product as an orange oil which was used without further purification; MS (ES) 278.0 (M+H) + .
  • Example 34 Preparation of ⁇ /-r4-(3-chloro-4-fluorophenv ⁇ -5-fluoro-2-pyrimidinvn-6- guinolinamine
  • Step 1 To a solution of 2, 4-dichloro-5-fluoropyrimidine (500 mg, 3.0 mmol) in degassed DME/H 2 0 (9.3 mL/1.8 mL) was added 4-carbobutoxyphenyl boronic acid (244 mg, 1.1 equiv), followed by PdCI 2 (dppf) (49 mg, 0.060 mmol). The reaction was stirred at rt overnight. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (95:5 hexanes/ EtOAc) to afford the desired product which was verified by 1 H NMR and LC-MS and used directly in the next step. Step 2. In a 8 mL vial were placed butyl 4-[5-fluoro-2-(6-quinolinylamino)-
  • the compound was prepared analogously to that described in Example 35, Step 1.
  • the crude product was purified by preparative HPLC (C 18 ODS, 10-90% CH 3 CN/H 2 0, 0.1%TFA) and dried in vacuo at 50 °C to afford the desired product as a white solid (30 mg, 0.078 mmol; 11% yield); mp 155-157 °C; MS (ES) 387.4 (M+H) + .
  • Example 39 Preparation of 1-(1 ,3-benzodioxol-5-yl)-2-fluoroethanone
  • the reaction mixture was diluted with EtOAc (25 mL) and H 2 0 (25 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3 X 10 mL) and the combined organic layers were washed with brine, dried (Na 2 S0 4 ), and concentrated in vacuo. The crude solid was recrystallized from hot EtOH to afford 387 mg (24%) of the desired product as off-white needles.
  • Step 1 2,4-Dichloro-5-fluoropyrimidine (1 equiv) was allowed to react with 4-acetylphenylboronic acid (1.2 equiv), in the presence of PdCI 2 dppf (0.06 equiv) and sodium carbonate (1.5-2 equiv), in DME and water (4:1 v/v) at rt to 60 °C for 2-6 h.
  • the reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (EtOAc-hexane).
  • Step 2 The intermediate from Step 1 was treated with 6-aminoquinoline (2 equiv) in n-BuOH and 2N HCI (1 :1 v/v) at 120 °C for 2-6 days. The solvents were removed by evaporation. The residue was purified by silica gel column (EtOAc- Hexane or MeOH-CH 2 CI 2 ) to give a pure solid product.
  • LC-MS RT 2.04 min; [M+H] + 359.
  • Step 1 5-Fluoro-2,4-dichloropyrimidine (1 equiv) was allowed to react with phenylboronic acid (1.2 equiv) in the presence of PdCI 2 dppf (0.02 equiv) and sodium bicarbonate (3 equiv), in DME and water (4:1 v/v) at 70 °C overnight. The reaction mixture was evaporated to dryness and the residue was purified by Biotage (15% EtOAc/Hexanes) to give the desired product (80% purity) that was used directly in the next step. Step 2.
  • Step 1 The intermediate obtained in Step 1 was treated with 6- aminoquinoline (2 equiv) in n-BuOH/1N HCI (1/1) at 120 °C, or in 1 N HCI at 100 °C for 10 days. It was cooled and neutralized with 2N Na 2 C0 3 , and extracted with n-BuOH. The organic layer was collected, and dried. The resulting crude product was purified by preparative TLC (60% EtOAc / hexanes). LC-MS: RT 2.08 min;
  • Step 1 To a solution of 2,4-dichloro-5-fluoropyrimidine (500 mg, 3.0 mmol) in degassed DME/H 2 0 (9.3 mL/1.8 mL) was added 3-trifluoromethyl phenylboronic acid (627 mg, 3.3 mmol), followed by PdCI 2 (dppf) (49 mg, 0.060 mmol). The reaction was stirred at rt overnight. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (95:5 hexanes/EtOAc) to afford the desired product. The product was verified by 1 H NMR and LC/MS.
  • Step 2 To a solution of 2-chloro-5-fluoro-4-(3-trifluoromethyl phenyl)pyrimidine obtained in Step 1 (100 mg, 0.36 mmol) in n-BuOH (2 mL) were added an 6-amino quinoline (1 equiv) and 1 N HCI (1 mL). The mixture was shaken at 125 °C over 4 days. The mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C ⁇ ODS, 10-90% CH 3 CN/H 2 0, 0.1%TFA) and dried in vacuo at 45 °C to afford the desired product in 12-17% yield. The product was verified by 1 H NMR and
  • Elk-1 Assay The following assay measures the inhibitory activity of the compounds on
  • Elk-1 transactivated luciferase expression is a gene regulatory protein that is activated by MAP kinases (mitogen activated protein kinases).
  • MAP kinases mitogen activated protein kinases
  • epidermal growth factor (EGF) stimulates Elk-1 transactivation of luciferase expression through phosphorylation of the Gal4 (a yeast gene activator protein)-Elk-1 fusion protein (Hexdall and Zheng, 2001 , Boulikas 1995).
  • EGF epidermal growth factor
  • 1 luc cells are plated at 2 x 10 4 cells per well in 96-well plates in complete medium (DMEM, 10% FBS, 20 mM HEPES, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, 250 ⁇ g/ml G418 (geneticin) and 100 ⁇ g/ml hygromycin B; all reagents Gibco BRL).
  • DMEM 10% FBS
  • 20 mM HEPES 100 U/mL penicillin
  • 100 ⁇ g/mL streptomycin 250 ⁇ g/ml G418 (geneticin) and 100 ⁇ g/ml hygromycin B; all reagents Gibco BRL
  • the cells are incubated at 37 °C in 5% C0 2 in a humidified incubator overnight.
  • the cells are washed and subsequently incubated in serum-free medium containing 1 % fatty acid free bovine serum albumin (BSA) for an additional 24 hours.
  • BSA bovine serum
  • Test compounds are added in serum-free medium and the plates are incubated for 45 min followed by addition of 100 ng/ml recombinant EGF or 50 ng/ml PMA (phorbol 12-myristate 13-acetate, Sigma). After a 5 h incubation period, luciferase activity is quantified in a Wallace Luminometer.
  • HCT 116 human colorectal carcinoma cells (ATCC CCL247) were cultured in standard growth medium (DMEM, 10% FBS, 10 mM HEPES, 2 mM glutamine,
  • MTS assay e.g. Promega CellTiter 96 Aqueous One Solution Cell Proliferation Assay #G3581. Briefly, the MTS assay is a colorimetric method for determining the number of viable cells in the proliferation assay.
  • the MTS (3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)2-(4-sulfophenyl)-2H- tetrazolium) reagent is bioreduced by cells into a colored formazan product that is soluble in tissue cultured medium.
  • the quantity of formazan product as measured by the amount of 490 nm absorbance is directly proportional to the number of living cells in culture.
  • Test compounds were dissolved in 100% DMSO (dimethylsulfoxide) to prepare 10 mM stocks. Stocks were further diluted 1 :250 in growth medium to yield working stocks of 40 ⁇ M test compound in 0.4% DMSO.
  • Test compounds were serially diluted in a 6 point dose response from 10 ⁇ M to 0.033 ⁇ M in growth medium containing 0.4% DMSO to maintain constant DMSO concentrations for all wells.
  • One hundred microliters of diluted test compound were added to each culture well to give a final volume of 200 ⁇ L).
  • the treated cells were incubated for 72h at 37 °C. After the completion of the 72h incubation, 40 ⁇ L of MTS reagent is added to each well. The plates were incubated for 30min at 37°C and read at 490 nm.
  • the IC 50 values were determined with a least squares analysis program using compound concentration versus percent inhibition.
  • % Inhibition [1-(T 72h test-T 0 h)/(T 72 h ctrl-T 0h )] x 100 where
  • T 72h test LDH activity at 72 h in presence of test compound
  • T 7 2h Ctrl LDH activity at 72 h in absence of test compound
  • HCT116 or H460 (ATCC #HTB177) cells are mixed with an agar-medium 1 x DMEM (DMEM powder, Gibco) + 1x FBS at a ratio 3:2; i.e. 3 mL agar (SeaPlaque agarose, FMC Corporation) + 2 mL cells.
  • the initial cell concentration is 5000 cells/mL (resulting in 100 cells/well).
  • 50 ⁇ L is plated as a bottom layer agar mix consisting of 6.3 mL 4x agar, 6.3 mL 2x DMEM, and 12.5 mL 1x DMEM + 2x FBS for a 0.6% f.c.
  • a suitable assay for determining apoptosis is as follows. H460 human lung cancer cells are plated in six well plates (Costar 3506) at 250,000 cells per well in standard medium (DMEM, 10% FBS, 10 mM HEPES, 2 mM glutamine, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin) and incubated over night at 37 °C in 5% C0 2 in a humidified incubator. The cells are treated with various concentrations of the test compounds for 24 h. Cells are harvested and fixed with 1 % paraformaldehyde on ice for 15 min.
  • DMEM 10% FBS
  • 10 mM HEPES 2 mM glutamine
  • penicillin 100 ⁇ g/mL streptomycin
  • the cells are rinsed and put in ice cold ethanol (80%) overnight at -20 °C.
  • Apoptosis is detected using a TUNEL assay (Pharmingen, APO-BRDU kit) as described by the manufacturer. Briefly, cells are incubated with DNA labeling solution for 1 h at 37 °C, washed and subsequently incubated with propidium iodide. In a dark room, the cells are Rnase treated. Samples were analyzed using a FACS Calibur (Becton Dickinson) using CellQuest software. Using this assay, a representative compound of the present invention induced apoptosis.
  • Inhibition of tumor growth in vivo is readily determined via the following assay: HCT 116, H460, or A549 cells are cultured as described above. The cells are harvested by trypsinization, washed, counted, adjusted to 2.5x10 7 cells/mL with ice cold phosphate-buffered saline (PBS), and subsequently stored on ice until transplantation. Xenograft experiments are conducted using eight-to-ten week-old female NCr nude mice (Taconic Labs) with an average body mass of about 20-25g. All the procedures are performed using sterile technique and in accordance with IACUC guidelines.
  • various dosages e.g. 0.75, 1.5, 3, 10, 30, and 100 mg/kg
  • schedules e.g. twice a day (bid) for 14 days, once a day for fourteen consecutive days, or every other day for seven treatments in total.
  • a suitable vehicle for oral administration is Cremophor, ethanol and 0.9% saline (12.5:12.5:75). Tumor measurements are performed twice per week. Tumor weights are calculated as described above. Student's T - test is used to verify the significance of the activity compared to untreated (vehicle only) controls. Animals are sacrificed after treatment and plasma was harvested for pharmacokinetic analyses. Tumors undergo further subsequent analyses, e.g. histology.
  • Example 59 demonstrated antitumor activity in this assay using HCT 116 and H460 cells.
  • Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows:
  • a large number of unit hard shell capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
  • the capsules are washed and dried.
  • the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium sterate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended ' for immediate release, without the need of water.

Abstract

A coumpound of the formula (I) wherein each X is independently NR1R6, NR4R5, or R4, with the proviso that at least one X must be NR1R6; each R1 is independently an optionally substituted fused bicyclic unsaturated ring containing 9 or 10 atoms optionally containing 1-4 heteroatoms selected from the group consisting of N, S and O, and the variables R2-6 are as defined in claim 1, are claimed. These compounds are kinase inhibitors useful in the treatment of cancer and viral infections.

Description

2- AND 4-AMINOPYRIMIDINES N-SUBSTITUTED BY A BICYCLIC RING FOR USE AS KINASE INHIBITORS IN THE TREATMENT OF CANCER
BACKGROUND Technical Field
The present invention relates to certain multi-ring compounds, particularly to compounds that are useful as inhibitors of kinases such as, but not limited to, serine/threonine kinases. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, as well as methods of using the compounds in inhibiting the kinases and treating patients suffering from diseases caused by various altered kinases. The invention also relates to a method of producing the compounds of the present invention. In addition, the present invention relates to intermediates used to prepare the compounds of the present invention.
Background of the Invention At the present time, many cancer treatments use components that interfere with cell division by unspecific mechanisms such as inhibition of DNA synthesis. Although toxic in general, these compounds have a toxic effect on the rapidly growing tumor cells that can provide an effective cancer treatment. However, anti- cancer compounds that act by mechanisms more specific to cancer cells rather than inhibiting DNA synthesis have the potential to display enhanced specificity to cancer cells.
For example, serine/threonine protein kinases are involved in cellular signaling mechanisms that regulate gene expression and cell proliferation (Su and Karin, Curr. Opinion. Immunol. (1996), 8:402; Kolch, Biochem. J. (2000) 351:289). Some serine/threonine kinases, such as cyclin dependent kinases (CDK), are necessary to progress from one step in the cell cycle to the next (Meyerson et al., EMBO J. (1992) 11 :2909). They are active when specifically bound to other cell cycle proteins (cyclin family). Changes in their activities or in the activities of their activators or inhibitors are common in cancerous cells (Motokura and Arnold, Biochim. Biophys. Acta (1993) 1155:63). The frequent deregulation of kinase activities in cancer and the discovery of natural inhibitors of cyclin dependent kinases have stimulated the active search for chemical inhibitors of CDK proteins (Vesely et al., Eur. J. Biochem. (1994) 224771). Apoptosis, the programmed cell death, plays an important role in the embryogenesis, regulation of the immune cell populations and probably aging. Failures in apoptotic signal transduction pathways lead to a variety of diseases including tumors (Hug, Biol. Chem. (1997) 378:1412). It is widely recognized that the induction of apoptosis holds promise as a treatment strategy for cancer. In fact, a number of chemotherapeutic agents have already been identified that induce apoptosis in cancer cells in vitro (Arends and Wyllie, Int. Rev. Exp. Pathol. (1991) 32:223 and Mesner et al., Adv. Pharmacol. (1997) 41 :461).
Apoptosis is an intrinsic process present in all cells that can be regulated by extrinsic factors such as hormones, growth factors, cell surface receptors or cellular stress. The actions of both pro- and anti-apoptotic factors are often affected by modulation of the phosphorylation state of key elements of the apoptotic process. Evidence has been accumulated that serine/threonine kinases are also involved directly in the regulation of the apoptotic cascade (Cross et al., Experimental Cell Research (2000) 256:34). Because apoptosis is regulated, biochemical alterations that make cells more or less susceptible to apoptosis might affect their sensitivity to a broad range of anti-neoplastic agents (Kaufmann and Eamshaw, Experimental Cell Research (2000) 256:42). Therefore, new drugs that sensitize tumor cells for apoptosis or induce apoptosis by interfering with key regulators of the apoptotic process such as serine/threonine kinases would be of great benefit for future cancer treatment strategies.
Viruses are by definition unable to replicate on their own but must enter a host cell in order to use the host cell's macromolecular machinery to replicate (Knipe in: Fields et al., Virology. Third Edition (Lippincott-Raven, 1996), p. 273. Inhibition of protein kinases has also shown encouraging results in controlling viral infections such as infections with human cytomegaloviruses (Bresnahan et al.,
Virology (1997) 231 :239).
Therefore, controlled inhibition of serine-threonine kinase activities are useful in controlling and treating diseases such as cancer and viral infections. Accordingly, it is desirable to develop inhibitors of kinases including serine/threonine kinases.
SUMMARY OF THE INVENTION The present invention relates to certain multi-ring compounds represented by the Formula (I):
Figure imgf000005_0001
(I) wherein each X is independently NR1R6, NR4R5, or R4, with the proviso that at least one X must be NR1R6; each R1 is independently an optionally substituted fused bicyclic unsaturated ring containing 9 or 10 atoms and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein said substitution on said ring is selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -NO2, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9, -N=CR8, optionally substituted alkyl, and optionally substituted alkenyl wherein the substitution on said alkyl and alkenyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; R2 is hydrogen, halo, optionally substituted alkyl, or an optionally substituted -Y(n)-mono-ring group or -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N,
S, and O; wherein said substitution on said ring group is selected from the group consisting of halo, -COOR8, -COR8, -OR8, -C=0, -N02, -CONR8R9, and optionally substituted alkyl, wherein said substitution on each of said alkyls is independently selected from the group consisting of -NR8R9, -OR8, and fluoro;
R3 is hydrogen, alkyl, or halo; each R4 is independently an optionally substituted -Y(n)-mono-ring group or optionally substituted -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n is 0 or 1, and -Y- is selected from the group consisting of straight- or branched-chain C2-C3-alkylenyl and -C(CN)-; wherein R4 can also be hydrogen or alkyl when R5 is present; and wherein said substitution on said ring group is selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8,
-S02NR8R9, -NR8CONR9, -SR8, -NR8SOz, -OR8NR8R9 -N=CR8, and optionally substituted alkyl, wherein said substitution on said alkyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; with the proviso that the multi-ring group cannot be benzimidazolyl; each R5 is independently an optionally substituted -Y(n)-mono-ring group or an optionally substituted -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n is 0 or 1 , and -Y- is selected from the group consisting of straight- or branched-chain C2-3-alkylenyl, -N=CH, and -N=CHCH3; and wherein said substitution on said ring group is selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02,
-OR8NR8R9, -N=CR8, and optionally substituted alkyl wherein said substitution on said alkyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; with the proviso that the multi-ring group cannot be benzimidazolyl; each R6 is independently hydrogen or alkyl; each R8 and R9 is independently hydrogen, optionally substituted Cι-5- alkyl, optionally substituted aryl, or optionally substituted arylalkyl, wherein said substitution is selected from the group consisting of optionally substituted alkyl, wherein said substitution on said alkyl is selected from the group consisting of fluoro and dialkylamino; and pharmaceutically acceptable salts and prodrugs thereof.
The present invention also relates to compounds of Formula (I) wherein: each X individually is -NR1R6, -NR4R5, or R4, with the proviso that at least one X is -NR1R6; each R1 is independently an optionally substituted moiety selected from the group consisting of indazolyl, quinolinyl, benzothiazolyl, benzotriazolyl, or benzoxazolyl, wherein said substitution is selected from the group consisting of hydrogen, methyl, and ethyl; R2 is halo or optionally substituted alkyl, wherein said substitution is selected from the group consisting of fluoro, -COOR8, -COOR9, and -CONR8R9; R3 is hydrogen or methyl; each R4 is hydrogen, methyl, phenyl, aryl, benzothiophenyl, pyridyl, indolyl, naphthalenyl, biphenyl, indanyl, indenyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzotriazolyl, cyclohexanyl, cyclopentanyl, cyclobutanyl, or multiple rings which are linked covalently, either directly or via a linker, wherein said linker is selected from the group consisting of methylene, O, S, N, -R8-S02, -S02-NR8, -NR8CO- and
-CONR8; each R5 is independently an optionally substituted -Y(n)-mono-ring group or an optionally substituted -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n is 0 or 1 , and -Y- is selected from the group consisting of straight- or branched-chain C2-3-alkylenyl, -N=CH, and -N=CHCH3; and wherein said substitution is selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9,
-CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9, -N=CR8, and optionally substituted alkyl, wherein said substitution on said alkyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; with the proviso that the multi-ring group cannot be benzimidazolyl; each R6 is independently hydrogen or alkyl; each R8 and R9 is independently hydrogen, optionally substituted Chalky!, optionally substituted aryl, and optionally substituted arylalkyl, wherein said substitution is selected from the group consisting of optionally substituted alkyl; wherein said substitution on said alkyl is selected from the group consisting of fluoro and dialkylamino; and pharmaceutically acceptable salts and prodrugs thereof.
The present invention also relates to compounds of Formula (1-1)
Figure imgf000008_0001
(1-1) wherein each R1 is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazolyl, 6-(1- methyl)indazolyl, 5-(1-ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3- quinolyl, or 3-isoquinolyl; R2 is hydrogen, fluoro, bromo, chloro, methyl, or trifluoromethyl; and
R3 is hydrogen or methyl, and pharmaceutically acceptable salts and prodrugs thereof.
The present invention also relates to compounds of Formula (I-2)
Figure imgf000008_0002
(I-2) wherein: each R1 is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazolyl, 6-(1- methyl)indazolyl, 5-(1-ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3- quinolyl, or 3-isoquinolyl; R2 is hydrogen, fluoro, bromo, chloro, methyl, or trifluoromethyl;
R3 is hydrogen or methyl; R4 is hydrogen or methyl; and
R5 is an optionally substituted moiety selected from the group consisting of phenyl, pyridyl, thiophene, furan, -Y(n)-mono-ring group or -Y(n)-multi- ring group, said ring group in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n is 0 or 1 , and -Y- is selected from the group consisting of straight or branched-chain C2-3-alkenyl, -N=CH, and -N=CHCH3; and wherein said substitution is selected from the group consisting of halo, -COOR8, -COR8, -CN,
-OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9 -N=CR8, and optionally substituted alkyl wherein said substitution on said alkyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; with the proviso that the multi-ring group cannot be benzimidazolyl; and pharmaceutically acceptable salts and prodrugs thereof.
The present invention also relates to compounds of Formula (I-3)
Figure imgf000009_0001
(I-3) wherein:
R1 is 5-quinolyl or 6-quinolyl; R2 is fluoro or trifluoromethyl; and R4 is optionally substituted phenyl or pyridyl, wherein said substitution is selected from the group consisting of halo, amino, hydroxy, acetyl, alkyl, alkoxy, alkenyl, hydroxyalkyl, dialkylamino, and phenyl; and pharmaceutically acceptable salts and prodrugs thereof.
The present invention also relates to the compounds of Formula (1-4)
Figure imgf000010_0001
H
(I-4) wherein: R1 is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazoIyI, 6-(1- methyl)indazolyl, 5-(1-ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3- quinolyl, or 3-isoquinolyl; R2 is hydrogen, fluoro, chloro, bromo, methyl, or trifluoromethyl; R3 is hydrogen or methyl;
R4 is hydrogen or methyl; and
R5 is an optionally substituted -Y(n)-moiety, wherein n is 0 or 1 , Y is selected from the group consisting of straight- or branched-chain
C2_3-alkylenyl, -N=CH, and -N-CHCH3, and said moiety is selected from the group consisting of cycloalkyl, phenyl, naphthyl, pyridyl, thienyl, furyl, quinolinyl, benzothiophenyl, benzothiazolyl, indol-3-yl, and quinoline-4-thio, said substitution being selected from the group consisting of methyl, ethyl, fluoro, bromo, chloro, trifluoromethyl, methoxyl, methylenedioxyl, sulfonamidyl, morpholinyl, and - pyrazinyl; and and pharmaceutically acceptable salts and prodrugs thereof.
The present invention also relates to compounds of Formula (I-5)
Figure imgf000011_0001
H
(I-5) wherein:
R >1 is 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5-benzothiazolyl, 6- quinolinyl, 5-(1-methyl)indazolyl, 6-(1-methyl)indazolyl, 5-(1- ethyi)indazolyl, 6-(1-ethyl)-indazolyI, 3-quinolyl, or 3-isoquinolyl; R2 is hydrogen, fluoro, methyl, bromo, chloro, trifluoromethyl, -C02CH3,
-C02H, and -CO-morpholinyl; R3 is hydrogen or methyl; and R4 is an optionally substituted -Y(n)-mo no-ring group or optionally substituted -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n = 0 or 1 , -Y- is -C(CN)-; and wherein said ring group is selected from the group consisting of optionally substituted phenyl or pyridyl, wherein said substitution on said rings is selected from the group consisting of halo, amino, hydroxy, acetyl, alkyl, alkoxy, alkenyl, hydroxyalkyl, dialkylamino, and phenyl; and pharmaceutically acceptable salts and prodrugs thereof.
Another aspect of the present invention relates to pharmaceutical composition containing at least one of the compounds of the present invention.
The present invention also relates to a method for inhibiting kinases such as serine/threonine kinases in a warm-blooded animal in need thereof by administering at least one of the compounds of the present invention in an amount sufficient to inhibit said kinases.
The present invention also relates to a method for treating a CDK- dependent disorder or disease in a warm-blooded animal in need of same, by administering to said animal at least one of the compounds of the present invention in an amount sufficient to inhibit CDK. The present invention further relates to a method for inhibiting cellular proliferation in a warm-blooded animal in need thereof by administering to said animal at least one of the compounds of the present invention in an amount sufficient to inhibit said proliferation. The present invention also relates to methods of treating a warm-blooded animal suffering from cancer or neoplastic disease by administering to said warmblooded animal an effective amount of at least one of the compounds of the present invention.
A still further aspect of the present invention relates to a method for modulating apoptosis in a warm-blooded animal in need thereof by administering at least one of the compounds of the present invention in an amount sufficient to modulate apoptosis.
In addition, the present invention relates to intermediates used to prepare the above compounds of the present invention. Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein are shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
DETAILED DESCRIPTION OF THE INVENTION
Except as expressly stated otherwise, the term "alkyl", when used alone or as part of another term, refers to straight- or branched-chain optionally substituted hydrocarbon groups containing 1 to 6 carbon atoms; or optionally substituted cycloalkyl groups. Examples of suitable straight-chain alkyl groups include methyl, ethyl and propyl. Examples of branched-chain alkyl groups include isopropyl and t-butyl. The preferred alkyl group is methyl. The cycloalkyl groups typically contain 3-6 atoms in the ring and can include up to 2 heteroatoms such as N, S and O, and can include unsaturation in the ring. Typical cycloalkyl groups and cycloalkyl groups containing hetero atoms in the ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, 2-pyrrolinyl, imidazolidinyl, 2- imidazolinyl, pyrazolidinyl, 3-pyrazolyl, piperidinyl, piperazinyl and morpholinyl.
The term "alkenyl" refers to straight- or branched-chain optionally substituted hydrocarbon groups containing 2 to 6 carbon atoms comprising one carbon-carbon double bond. Examples of suitable alkenyl groups are methenyl and ethenyl.
The term "alkoxy" refers to straight- or branched-chain optionally substituted Ci-C6-alkyl-0-, wherein "alkyl" is as defined above.
The term "dialkylamino" refers to a nitrogen atom substituted with two alkyl groups, each alkyl being independently as defined above.
Substitutions for each of the alkyl, alkenyl, alkoxy, and dialkylamino groups are selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9, -N=CR8, and optionally substituted alkyl wherein said substitutions on said alkyl are selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl. Examples of suitable halo groups are chloro, bromo and fluoro. An example of a fluoro substituted alkyl is trifluoromethyl. Preferably at least one of R2 or R3 is alkyl substituted with either halo or halo-substituted alkyl , and most preferably one of R5 or R3 is alkyl substituted with either halo or halo-substituted alkyl and the other of R5 or R6 is hydrogen.
The term "hydroxyalkyl" refers to an alkyl as defined above substituted with at least one hydroxy group.
Examples of fused bicyclic unsaturated ring groups are 2-quinolinyl, 3- quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 1 -isoquinolinyl, 3-isoquinolinyl, 6- isoquinolinyl, 7-isoquinolinyl, 3-cinnolyl, 6-cinnolyl, 7-cinnoIyl, 2-quinazoIinyl, 4- quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 2-quinoxalinyI, 5-quinoxalinyl, 6- quinoxalinyl, 1-phthalazinyl, 6-phthalazinyl, 1 ,5-naphthyridin-2-yl, 1 ,5-naphthyridin- 3-yl, 1 ,6-naphthyridin-3-yl, 1 ,6-naphthyridin-7-yl, 1 ,7-naphthyridin-3-yl, 1 ,7- naphthyridin-6-yl, 1 ,8-naphthyridin-3-yl, 2,6-naphthyridin-6-yl, 2,7-naphthyridin-3- yl, indolyl, 1 -/-indazolyl, benzothiazolyl, benzotriazolyl, purinyl and pteridinyl. Substitutions for each of the fused ring groups are selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl and ethenyl. Examples of mono- and multi-ring groups include aryl and bicyclic fused aryl-cycloalkyl groups. The aryl groups include an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently, directly or via a linker, e.g. methylene, O, S, N, -NR8"S02-, -COR8, -NR8CO- , and -S02-NR8. The rings may each contain from zero to four heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. Non- limiting examples of aryl groups include phenyl, 1 -naphthyl, 2-naphthyl, biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substitutions for each of the above noted aryl systems include halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9,
-NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9, -N=CR8, and optionally substituted alkyl wherein said substitutions on said alkyl are selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl. The "bicyclic fused aryl-cycloalkyl" groups are those groups in which an aryl ring (or rings) is fused to a cycloalkyl group (including cycloheteroalkyl groups). The group can be attached to the remainder of the molecule through either an available valence on the aryl portion of the group, or an available valence on the cycloalkyl portion of the group. Examples of such bicyclic fused aryl-cycloalkyl groups are indanyl, benzotetrahydrofuranyl, benzotetrahydropyranyl and 1 ,2,3,4- tetrahydronaphthyl. Substitutions for each of the above noted groups include halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9, -N=CR8, and optionally substituted alkyl wherein said substitutions on said alkyl are selected from the group consisting of -NR8R9, OR8, fluoro, methenyl, and ethenyl.
When a substituted moiety is employed, it can be substituted at one or more positions with at least one of the above disclosed groups up to the number of available positions, but typically contain 1-3 substitutions, when substituted. When more than one substitution is present, the same or different substitution groups can be employed.
Pharmaceutically acceptable salts of the compounds of the above formulae include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic and benzenesulfonic acids.
Salts derived from appropriate bases include alkali such as sodium and ammonia or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. The compounds of the formula (I) may be administered in the form of a pro- drug which is broken down in the human or animal body to give a compound of the formula (I). Examples of pro-drugs include in vivo hydrolysable esters of a compound of the formula (I).
An in vivo hydrolyzable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include C1-6- alkoxymethyl esters, for example methoxymethyl; Cι-6-a!kanoyloxymethy! esters, for example pivaloyloxymethyl; phthalidyl esters; C3-8-cycloalkoxycarbonyloxy, C-ι-6-alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1 ,3-dioxolen-2- onylmethyl esters, for example 5-methyl-1 ,3-dioxolen-2-onylmethyl; and C-i-6- alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolyzable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α- acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy- methoxy. A selection of in vivo hydrolyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-Λ/-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring.
Some compounds of the formula (I) may have chiral centers and/or geometric isomeric centers (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess cyclin-dependent kinase (CDK) inhibitory activity.
The invention relates to any and all tautomeric forms of the compounds of the formula (I) that possess CDK inhibitory activity.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess CDK inhibitory activity.
The compounds of the present invention can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, e.g. intravenously, subcutaneously, intramuscularly, intraperitoneally, and locally (intratumorally) in sterile liquid dosage forms. The active ingredient can also be administered intranasally (nose drops) or by inhalation of drug powder mist. Other dosage forms are potentially possible such as administration transdermally, via patch mechanism or ointment.
Formulations suitable for oral administration can comprise of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard-or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
Immediate release tablets/capsules solid oral dosage forms are made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water. The compounds of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
Moreover, the compounds of the present invention can be administered in the form of nose drops, or metered dose and a nasal or buccal inhaler. The drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol.
The foregoing description of the invention illustrates and describes the present invention.
Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol such as poly (ethyleneglycol) 400, glycerol ketals, such as 2,2-dimethyl-1 ,3-dioxolane-4- methanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or any acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulos, or emulsifying agents and other pharmaceutical adjuvants.
Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isosteric acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include: (a) cationic detergents such as, dimethyldialkylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, alkyl, aryl, and olefin sulfonates, alkyl, olefin, either, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, alkyl β-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof. The parenteral formulations typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
Additionally, formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well-known to those who are skilled in the art. Typically, the pharmaceutically acceptable carrier is chemically inert to the active compounds and has no detrimental side effects or toxicity under the conditions of use. The pharmaceutically acceptable carriers can include polymers and polymer matrices. Pharmaceutically acceptable excipients are also well-known to those who are skilled in the art. The choice of excipient will be determined in part by the particular compound, as well as the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following methods and excipients are merely exemplary and are in no way limiting. The pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredients and do not cause adverse side-effects. Suitable carriers and excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field, incorporated by reference. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., 622-630 (1986). The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including a condition of the animal, the body weight of the animal, as well as the severity and stage of the cancer. A suitable dose is that which will result in a concentration of the active agent in a patient which is known to effect the desired response. The preferred dosage is the amount which results in maximum inhibition of cancer, without unmanageable side effects. The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. A daily dosage of active ingredient can be expected to be about 0.001 to 1000 milligrams (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg.
Dosage forms (compositions suitable for administration) contain from about 1 mg to about 500 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in any amount of about 0.5-95% weight based on the total weight of the composition.
General Preparative Methods Compounds of formula (I) may be prepared as illustrated in the General Reaction Schemes shown below. In the structures shown below, R1, R2, R3, R4, R5, and R6 are independently selected and have the definitions as described above.
Reaction Scheme 1
Figure imgf000022_0001
(lc)
Specifically, a 5,6-disubstituted uracil (II) may be converted to a 2,4- dichloro-5,6-disubstituted pyrimidine intermediate of formula (III). This key intermediate is allowed to react with heating up to 120°C, as shown in Reaction
Scheme 1 , with amines of type R1R6NH in a protic solvent such as n-butanol, for 1 to 3 days, with the optional presence of an acid such as aqueous HCI, or a base such as Na2C03, to provide compounds of the invention of the type depicted as formula (la). Compounds of the invention of formula (lb) and (lc) may be prepared by conducting similar reactions in a stepwise manner. For example, the first step is conducted in base to give either the compound of formula (IV) or formula (V), depending on the amine of type selected (R1R6NH or R4R5NH) as co-reactant. Subsequent reaction of (IV) or (V) with a second amine of type R4R5NH or R1R6NH, with heating and acid catalysis, provides the compounds of formula (lb) or (lc), respectively. Intermediate (V) is reacted with hydrazine followed by reaction with appropriate aryl aldehyde to compounds of the formula -(1d). Reaction Scheme 2
Figure imgf000023_0001
R1R6NH R1R6NH base H+
Figure imgf000023_0002
(if)
R4B(OH)2
PdCI2dppf base
Ar = aryl or heteroaryl
Figure imgf000023_0003
(ig)
Compounds of the invention of formula (le), (If) and (Ig) are also prepared from the intermediate of formula (III) as shown in Reaction Scheme 2. For example, reaction of (III) with a nitrile, represented by ArCH2CN, where Ar is a aryl or heteroaryl radical, in the presence of a strong base such as NaH, provides the chloropyrimidine of formula (Via); reaction of (Via) with an amine of type R1R6NH, as previously described in Reaction Scheme 1 , gives the compound of the invention of formula (le).
Intermediate (III) may react under a Suzuki-type coupling conditions (a palladium catalyst, and a base such as Na2C03) with a boronic acid of type R4B(OH)2 to give a chloropyrimidine of formula (Vlb). This formula (Vlb) compound may undergo reaction with an amine of type R1R6NH, as previously described in Reaction Scheme 1, to give the compounds of the invention of formula (If).
The compound of formula (IV), as previously described in Reaction Scheme 1 , may be allowed to react with a boronic acid of type R4B(OH)2 under the Suzuki-type coupling conditions described above to give the compound of the invention of formula (Ig).
Reaction Scheme 3
Figure imgf000024_0001
(X) (XI) (XII)
Figure imgf000024_0002
(Ih)
Another type of compound of the invention, formula (Ih), is prepared as shown in Reaction Scheme 3. In this scheme, a ketone of formula (VII) (wherein R" is methyl, methoxy, -0-CH2-O-, fluoro, CN, or N02) reacts with DMF- dimethylacetal of formula (VIII) in a refluxing solvent such as toluene to give an enaminone intermediate of formula (IX). A guanidine of formula (XII) is also prepared from an amine of formula (XI) and the reagent of formula (X) by heating the two together in a higher boiling solvent such as toluene/acetic acid mixtures. Reaction of the enaminone (IX) with the guanidine (XII) in a protic solvent such as methanol and a base such as sodium methoxide gives the compound of the invention of formula (Ih).
Reaction Scheme 4
Figure imgf000025_0001
Ketones of formula (VII) that are not commercially available may be conveniently prepared by the method illustrated in Reaction Scheme 4. An aryl or heteroaryl bromide of formula (XIII) may be converted to an aryllithium intermediate by halogen-metal exchange with butyllithium; reaction of the intermediate with an amide such as the compound of formula (XIV) provides the corresponding ketone of formula (XV). Additional compounds of formula (I) may be prepared from other formula (I) compounds by elaboration of functional groups present. Such elaboration includes, but is not limited to, hydrolysis, reduction, oxidation, alkylation, acylation, esterification, amidation and dehydration reactions. Such transformations may in some instances require the use of protecting groups by the methods disclosed in T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis (Wiley,
New York, 1999), incorporated herein by reference. Such methods would be initiated after synthesis of the desired compound or at another place in the synthetic route that would be readily apparent to one skilled in the art. Experimental Examples
The following specific preparative examples are included as illustrations of preparation of specific compounds of the invention, and are not to be construed as limiting the scope of the invention in any way.
LC-MS instrumentation:
(a) a Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2 x 23mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD (Evaporative Light Scattering Detector) data was also acquired as an analog channel.
(b) a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm,
120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source.
HPLC conditions:
Method 1. Eluents were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in acetonitrile with 0.02% TFA. Elution conditions consisted of a flow rate of 1.0 mL/min with an initial hold at 10% B for 0.5 min, followed by gradient elution from 10% B to 95% B over 3.5 min, followed by a final hold at 95% B for 0.5 min. Total run time was 6.5 min.
Method 2. Eluents as above; elution at a flow rate of 1.5 mL/min with an initial hold at 10% B for 0.5 min, followed by gradient elution from 10% B to 90% B over 3.5 min, followed by a final hold at 90% B for 0.5 min. Total run time was 4.8 min.
Abbreviations and Acronyms
When the following abbreviations are used herein, they have the following meaning: Ac20 acetic anhydride anhy anhydrous
BOC te/f-butoxycarbonyl t?-BuOH π-butanol f-BuOH ferf-butanol f-BuOK potassium ferf-butoxide
GDI carbonyl diimidazole
CD3OD methanol-c/4
Celite® diatomaceous earth filter agent, ®Celite Corp.
CI-MS chemical ionization mass spectroscopy cone concentrated
DCC dicyclohexylcarbodiimide
DCM dichloromethane
DEAD diethyl azodicarboxylate dec decomposition
DIA diisopropyl amine
DIBAL diisobutylaluminum hydroxide
DMAP 4-(Λ/,Λ/-dimethylamino)pyidine
DME dimethoxyethane
DMF Λ/,Λ/-dimethylformamide
DMSO dimethylsulfoxide
EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
ELSD evaporative light scattering detector
ES-MS electrospray mass spectroscopy
EtOAc ethyl acetate
EtOH ethanol (100%)
EtSH ethanethiol
Et20 diethyl ether
Et3N triethylamine
GC-MS gas chromatography-mass spectroscopy h hour
HPLC high performance liquid chromatography I PA isopropylamine
LAH lithium aluminum hydride
LC-MS liquid chromatography-mass spectroscopy
LDA lithium diisopropylamide m/z mass-to-charge ratio
MeCN acetonitrile
NBS N- bromosuccinimide
NMM 4-methylmorpholine
PdCI2dppf [1 ,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll)
Pd(OAc)2 palladium acetate
P(0)CI3 phosphorous oxychloride
PS-DIEA Polystyrene-bound diisopropylethylamine
Rf retention factor (TLC)
RT retention time (HPLC)
It room temperature
TEA triethylamine
THF tetrahydrofuran
TFA trifluoroacetic acid
TFFH Fluoro-Λ/,/V,/V',Λ/'-tetramethylformamidiniunr hexafluorophosphate
TLC thin layer chromatography
TMAD /V,/V,/V',ΛT-tetramethylethylenediamine
Preparation of 2.4-dichloro-5-substituted pyrimidine starting materials:
Preparation of 2,4-dichloro-5-(trifluoromethyl yrimidine
Figure imgf000028_0001
POCI3 (25 mL) was mixed with DMF (0.5 mL). After the mixture cooled to room temperature, 5-trifluoromethyl uracil was added and the resulted mixture was heated to 110°C overnight. The reaction mixture was then cooled to room temperature again and added slowly to ice water. The aqueous solution was then extracted by dichloromethane. The extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was purified by preparative TLC (20% EtOAc in methylene chloride) to give 585 mg of the object compound. Using this procedure and the appropriately substituted uracils as starting materials, 2,4-dichloro-5-fluoropyrimidine, 2,4-dichloro-5-bromopyrimidine and 2,4-dichIoro-5-methylpyrimidine were similarly prepared.
Example 1 Preparation of /V-(6-quinolinvπ-/V- 2-(6-quinolinylaminoV5-(trifluoromethvπ-4- pyrimidinvπamine
Figure imgf000029_0001
To an 8-mL vial was added 6-aminoquinoline (1.67 mmol), 2,4-dichloro-5- trifluoromethylpyrimidine (0.67 mmol), butanol (5 mL) and Na2Cθ3 (2 equiv). The mixture was heated to 120°C for 3 days, followed by evaporation to dryness. The residue was then dissolved in DMF and separated by preparative TLC (5% methanol in dichloromethane). LC-MS:RT 2.07; [M+H]+ 433.
Example 2 Preparation of A/-(1-methyl-1H-indazol-6-yl)-Λ/-(5-methyl-2-r(1-methyl-1H-indazol-
6-vDamino1-4-pyrimidinyl)amine
Figure imgf000030_0001
To an 8-mL vial was added (1-methyl-indazole-6-amine, 0.245 g, 1.67 mmol), 2,4-dichloro-5-trifluoromethylpyrimidine (0.11 g, 0.67 mmol), n-butanol (5 mL) and HCI (0.1 N, cat. amount). The mixture was heated to 120 °C for 3 days, followed by evaporation to dryness. The residue was then dissolved in DMF and separated by preparative TLC (5% methanol in dichloromethane). LC-MS: RT 1.64 min; [M + H]+ 388.
Example 3 Preparation of /V-r5-fluoro-2-(1ry-indazol-6-ylamino)-4-pyrimidinyll-/V-(1H-indazol-
Figure imgf000030_0002
A mixture of 2, 4-dichloro~5-fluoro-pyrimidine (16.6 mg, 0.1 mmol) and 6- aminoindazole (39.9 mg, 0.3 mmol) in n-BuOH (2-3 mL) was heated at 120 °C with shaking for 48 h. The mixture was cooled to room temperature and purified by prep-TLC. LC-MS: RT 1.73 min; [M+H]+ 361.
Example 4 Preparation of Λ/-(1 H-indazol-6-yl)-Λ/-r2-(1 f7-indazol-6-ylamino)-5-methyl-4- pyrimidinyllamine
Figure imgf000031_0001
A mixture of 2,4-dichloro-5-methylpyrimidine (2.50 g, 9.6 mmol), 6- aminoindazole (3.2 g, 24.1 mmol) and catalytic amount of 1 N HCI in n-BuOH was heated to 110°C for 24 h. The solvent was removed by evaporation under reduced pressure. The crude product was purified by silica gel column (gradient, ethyl acetate/hexane, 50/50 to 90/10) to afford the object compound (2.95 g, 67%) as an off-white powder. HPLC/MS: (M+H)+ 357.48 m/z. Retention time (HPLC/MS) = 1.98 min. 1H NMR (DMSO-d6): 512.86 (1H, s); 12.61 (1H, s); 9.14 (1H, s); 8.43 (1 H, s); 8.11 (1 H, s); 7.99 (2H, d); 7.86(2H, s); 7.70 (1 H, d); 7.51(2H, m); 7.37 (1H, d); 2.15 (3H, s).
Example 5 Preparation of Λ/-r5-chloro-2-(1 -/-indazol-5-ylamino)-4-pyrimidinyll-/V-(1/- -indazol-
5-yl)amine
Figure imgf000031_0002
A mixture of 2,4,5-trichloro-pyrimidine (200 mg, 1.09 mmol), 5- aminoindazole (363 mg, 2.72 mmol) and catalytic amount of 1 N HCI was heated to 120 °C for 24 h. The solvent was removed by evaporation under reduced pressure. The crude product was purified by silica gel column (gradient, ethyl acetate/hexane, 50/50 to 8/20) to afford the target compound) (102mg, 25%) as yellow powder. HPLC/MS: (M+H)+ 377 m/z. Retention time (HPLC/MS) = 1.86 min. Example 6 Preparation of /V-(2.5-dichloro-4-pyrimidinv0-1H-indazol-6-amine intermediate:
Figure imgf000032_0001
In a 250 mL round bottom flask was placed 2,4,5-trichloropyrimidine (5.0 g, 27.2 mmol), sodium carbonate (17.3 g, 163.2 mmol) and 6-aminoindazole (3.63 g,
27.2 mmol) in 136 mL of ethanol. The reaction mixture was stirred at room temperature overnight. An insoluble white solid was filtered, suspended in water (50 mL), stirred at room temperature for 1-2 h and then filtered, washed with acetonitrile and dried in an oven to provide 6.41 g of the desired compound. An additional 0.5 g was recovered from the filtrate. Total yield was 90.7%.
GC/MS 280.2 (M+1) RT = 2.38 min; 1H-NMR (DMSO- 6) δ 13.061 (s, 1 H); 9.578 (s, 1 H); 8.382 (s, 1 H); 8.020 (s, 1H); 7.850 (s, 1 H); 7.705-7.735 (d, 1 H); 7.267- 7.302 (d, 1 H).
Example 7
Preparation of A/-(5-chloro-2-r(3-chlorophenyl)amino1-4-pyrimidinyl)-/V-(1 H-indazol-
Figure imgf000032_0002
In a 8 mL vial were placed Λ/-(2,5-dichloro-4-pyrimidinyl)-1H-indazol-6- amine from Example 6 (64.4 mg, 0.23 mmol), 3-chloroaniline (58.7 mg, 0.46 mmol) and 1 mL of 1 N HCI solution. The vial was capped under argon and shaken at 100 °C overnight. Upon cooling, white solid crystallized out of solution and was simply removed by filtration. The crude white solid was dissolved in methanol, absorbed on silica gel, dried, and chromatographed with CH2CI2/methanol (100/2) to provide 44 mg of a white solid target compound (51.5 %). GC/MS 371.3 (M+1) RT = 2.73 min; 1H-NMR (DMSO- 6) δ 12.962 (s, 1 H) 9.531 (s, 1 H); 9.075 (s, 1 H); 8.262 (s, 1 H); 8.003 (s, 1 H); 7.706-7.765 (m, 2H) 7.646 (s, 1H); 7.468-7.488 (d, 1 H); 7.309-7.349 (d, 1 H); 7.012-7.071 (t, 1 H) 6.813-6.853.(d, 1 H).
Example 8 Preparation of Λ/-f5-fluoro-2-(3-quinolinylamino)-4-pyrimidinyll-Λ/-(6- guinolinvDamine
Figure imgf000033_0001
In a 15 mL round bottom flask were placed Λ/-(2-chloro-5-fluoro-4- pyrimidinyl)-6-quinolinamine (63.2 mg, 0.23 mmol, obtained by the method of Example 6), 3-aminoquinoline (66.3 mg, 0.46 mmol), 1.5 mL of 1 -butanol and 0.5 mL of 1 N HCI solution. The mixture was heated at 128-130 °C overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in methanol, absorbed on silica gel, dried and chromatographed with CH2CI2/methanol (100/5) to provide 36.7 mg of a white solid of the target product (44%). GC/MS 383.4 (M+1) RT = 1.89 min; 1H-NMR (DMSO-c/6) δ 9.821 .(s, 2H); 9.012 (s, 1H); 8.805 (s, 1H); 8.635 (s, 1H); 8.504 (s, 1H); 8.278 (s, 1H); 8.052- 8.146 (m, 2H); 7.976-8.014 (d, 1 H); 7.864-7.920 (d,1 H); 7.373-7.525 (m, 4H).
Example 9 Preparation of /V-(5-fluoro-2-hvdrazino-4-pyrimidinyl)-6-guinolinamine intermediate
Figure imgf000033_0002
H In a 25 mL round bottom flask was placed 2,4-dichloro-5-fluoropyrimidine
(1.0 g, 6.0 mmol, 1 equiv) and 6-aminoquinoline (0.95 g, 6.6 mmol, 1.1 equiv) in 10 mL of THF. To this was added K2C03 (0.83 g, 6.0 mmol, 1 equiv) and 2 mL of H20. This was heated to 60 °C overnight at which point TLC revealed no remaining starting material. The volatiles were removed under reduced pressure and the residue allowed to stir in 50 mL of H20. The remaining solids were filtered to provide 1.84 g of Λ/-(2-chloro-5-fluoro-4-pyrimidinyl)-6-quinolinamine as a white solid. 1H-NMR (300 MHz, DMSO- 6) δ 7.50 (dd, 1 H), 8.02 (m, 2H), 8.27 (d, 1 H), 8.30 (m, 1 H), 8.40 (d, 1 H), 8.81 (dd, 1H), 10.30 (s, 1 H); LC/MS/+esi 275.4 [M+H]+.
In a 50 mL round-bottomed flask was placed 1.0 g (3.6 mmol) of Λ/-(2- chloro-5-fluoro-4-pyrimidinyl)-6-quinolinamine in 18 mL of EtOH. To this was added 0.73 g (14.5 mmol, 4 equiv) of hydrazine monohydrate and the reaction was allowed to reflux overnight. The reaction was allowed to cool to room temperature and 20 mL of H2O was added, resulting in a white precipitate. This was filtered to yield 0.78 g of the desired pure compound as a white solid. 1H- NMR (300 MHz, DMSO-ofe) δ 3.85 (br s, 2H), 7.08 (dd, 1 H), 7.52 (m, 2H), 7.66 (m,
2H), 7.91 (d, 1 H), 8.35 (m, 1 H), 8.47 (d, 1 H), 9.16 (s, 1 H); LC/MS/+esi 271.5 [M+H]+.
Example 10 Preparation of derivatives of benzaldehvde |"5-fluoro-4-(6-quinolinylamino)-2- pyrimidinyllhydrazone
Figure imgf000034_0001
In a 8 mL amber vial was placed Λ/-(5-fluoro-2-hydrazino-4-pyrimidinyl)6- quinolinamine prepared according to Example 9 (50 mg, 0.19 mmol) in 2 mL of anhydrous EtOH. To this was added 0.20 mmol (1.1 equiv) acetophenone, and the vial was capped under argon and shaken on a reflux block for 0.5 h. This resulted in precipitate formation. The solids were filtered and rinsed with EtOH to provide the pure desired product in 70-80% yield. LC-MS: RT: 2.19 min. Example 11 Preparation of /V-(5-bromo-2-chloro-4-pyrimidinylV6-quinolinamine intermediate
Figure imgf000035_0001
To 2,4-dichloro-5-bromopyrimidine (10 g, 44 mmol) in ethanol (100 mL) was added 6-aminoquinoline (6.33 g, 44 mmol) and sodium carbonate (28 g, 0.26 mol) at room temperature. The reaction was stirred for 18 h and then quenched with water (100 mL). Diethyl ether (300 mL) was added to the mixture resulting in the formation of a precipitate. The solids were filtered then washed with water (50 mL) and diethyl ether (200 mL). The tan powder was dried to yield 12.5 g of the target compound (37 mmol, 85%). The product was taken directly to the next step.
Example 12 Preparation of Λ/-{5-bromo-2-f(2-fluorophenyl)amino1-4-pyrimidinyl)-Λ/-(6- guinolinvPamine:
Figure imgf000035_0002
To Λ/-(5-bromo-2-chloro-4-pyrimidinyl)-6-quinolinamine obtained according to the method of Example 11 (100 mg, 0.30 mmol) in butanol (2 mL) was added 2- fluoroaniline (80 mg, 0.31 mmol), followed by 1 N HCI (2 mL). The reaction was heated to 115 °C for 26 h. The reaction was cooled to room temperature and then concentrated to yield the crude product. The product was chromatographed with 20% ethyl acetate in hexane yielding the target compound as a tan powder (65 mg, 52%). Rf = 0.61 (CH2CI2/MeOH = 95/5). 1H NMR (DMSO-d6) δ 9.42-9.45 (2H, m), ), 9.09-9.12 (1 H, m), 8.73-8.78 (1H, m), 8.63 (1 H, s), 8.21-8.38 (3H, m), 7.94-7.98 (1 H, dd, J = 1.2, 2.7Hz), 7.55-7.62 (1H, m), 6.97-7.21 (3H, m). Example 13 Preparation of the mixture of two intermediate isomers: 2-chloro-Λ/-(4- methoxyphenvπ-5-(trifluoromethvπ-4-pyrimidinamine (A) and 4-chloro-/V-(4-methoxyphenyl)-5-(trifluoromethyl)-2-pyrimidinamine (B)
Figure imgf000036_0001
(A) (B)
A suspension of 2,4-dichloro-5-trifluoromethylpyrimidine (3.90 mmol, 1 equiv), 4-methoxyaniline (3.90 mmol, 1 equiv), and sodium carbonate (16.6 mmol, 6 equiv) in 10 mL of ethanol was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and water. The layers were separated, and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography (20% ethyl acetate in hexane) which gave a mixture of (A) and (B). Total yield 95 %.
Example 14
Preparation of the mixture of two isomers: /V-(4-methoxyphenyl)-Λ/-r2-(6- guinolinylamino)-5-(trifluoromethvπ-4-pyrimidinyl1amine (C) and A/-(4- methoxyphenyl)-/V-f4-(6-guinolinylamino)-5-(trifluoromethvπ-2-pyrimidinyl1amine
(D)
Figure imgf000036_0002
(C) (D)
A suspension of isomeric mixture of (A) and (B) obtained according to Example 13 (0.33 mmol, 1 equiv) and 6-aminoquinoline (0.66 mmol, 2 equiv) in 2.7 mL of butanol and 1.3 mL of 1N HCI was shaken at 120 °C overnight. The reaction was concentrated, and the isomers (C) and (D) were separated by HPLC purification on a funnel and washed with cold EtOH and dried in vacuo.
Example 15
Preparation of N-(5-fluoro-2-r(3-fluorophenyl)amino1-4-pyrimidinyl)-N-(6- quinolinvDamine
Figure imgf000037_0001
Λ/-(2-Chloro-5-fluoro-4-pyrimidinyl)-6-quinolinamine, (1 equiv) obtained by the method of Example 6 from 2,4-dichloro-5-fluoropyrimidine and 6- quinolinamine, and 3-fluoroaniline (2 equiv) were suspended in n-BuOH and heated at 120 °C overnight for 2 days. The pure product was obtained by column
Chromatography. LC-MS: RT 1.64 min; [M+H]+ 350.
Example 16
Preparation of 4-{2-r(5-bromo-2-chloro-4-pyrimidinyl)amino1ethyl)- benzenesulfonamide intermediate
Figure imgf000037_0002
A solution of 4-(2-aminoethyl)benzenesulfonamide (1.7 g, 8.5 mmol), 5- bromo-2,4-dichloropyrimidine (1.8 g, 7.9 mmol), and sodium carbonate in ethanol was stirred at rt overnight. LC-MS showed the major peak as the desired product.
The solvent was removed in vacuo. The residue was added to water, and extracted with ethyl acetate several times. The organic layer was dried over magnesium sulfate and filtered. The solution was evaporated until a small amount of solid precipitated out. After standing at rt for several h, more solid crystallized out. LC-MS shows two regioisomers. The material was then recrystallized from ethyl acetate to give the desired regioisomer (1.2 g, 31 %).
Example 17 Preparation of 3-[5-fluoro-4-(6-guinolinylamino)-2-pyrimidinyllbenzaldehvde
Figure imgf000038_0001
Λ/-(2-Chloro-5-fluoro-4-pyrimidinyl)-6-quinolinamine (1 equiv), obtained from 5-fluoro-2, 4-dichloro-pyrimidine and 6-quinolinamine by the method of Example 6, was treated with 3-formylphenylboronic acid (1.2 equiv) in the presence of PdCI2dppf (0.06 equiv) and Na2C03 (2 equiv), in ethylene glycol ether and water (4:1 v/v) at 60 °C for 2-6 h. The reaction mixture was evaporated to dryness. The residue was purified by silica gel chromatography (EtOAc-Hexane) to give the pure product. LCMS: RT 1.93 min; [M+H]+345.
Example 18
Preparation of 4-(2-{r5-bromo-2-(1 -/-indol-5-ylamino)-4-pyrimidinyl1amino} ethvDbenzenesulfonamide
Figure imgf000038_0002
A solution of 4-{2-[(5-bromo-2-chloro-4-pyrimidinyl)amino]ethyI- benzenesulfonamide (50 mg, 0.13 mmol), 1H-indazol-5-amine, and a catalytic amount of hydrochloride acid in 1-butanol (3 mL) was heated at 115 °C overnight. Some yellow solid precipitated out. The solution was filtered. The filtrate was washed with a small amount of methanol and ethyl acetate to give a yellow solid (42.3 mg, 68.0%). Example 19 Preparation of 2-chloro-4-Λ-(4-morpholinophenyl)-6-methylpyrimidine
Figure imgf000039_0001
To a solution of 4-morpholinoaniline (0.535 g, 3.00 mmol) in ethanol (20 mL) was added 2,4-dichloro-6-methylpyrimidine (0.978 g, 6.00 mmol) and Na2C03
(1.59 g, 15 mmol). After mixing at room temperature for 72 h, the reaction was concentrated in vacuo. The solids were washed with hexanes (3 x 10 mL) and water (10 mL), filtered, and dried under high vacuum to afford the title compound (0.894 g, 97% crude yield) as a slightly purple solid. HPLC/MS: (M+H)+ 305.28 m/z. Retention time (HPLC/MS) = 0.37 min.
Example 20 Preparation of 2-/V-5'-aminoindazole-4-(4-morpholinophenyl)-6-methylpyrimidine
Figure imgf000039_0002
To a solution of 2-chloro-4-Λ/-(4-morpholinophenyl)-6-methylpyrimidine obtained according to the process of Example 19 0.305 g, 1.00 mmol) in n-butanol (10 mL) was added 5-aminoindazole (0.266 g, 2.00 mmol) and HCI (4.0M in 1 ,4- dioxane, 50 μL, 0.20 mmol). The mixture was heated to 115 °C for 16 h. Upon cooling to room temperature, the precipitate was filtered and recrystallized from EtOH. This afforded 0.1495 g (37% yield) of the title compound as an off-white solid. 1H NMR (DMSO-c 6): δ 9.06 (s, 1H), 8.99 (s, 1H), 8.27 (s, 1H), 7.88 (s, 1 H), 7.4-7.6 (m, 4H), 6.91 (d, 2H, J=9.2Hz), 5.97 (s, 1H), 3.77 (m, 4H), 3.08 (m, 4H), 2.19 (s, 3H). HPLC/MS: (M+H)+ 402.22 m/z. Retention time (HPLC/MS) = 1.13 min.
Example 21 Preparation of 2-chloro-5-fluoro-A/-(4-methoχyphenvπ-4-Pyrimidinamine intermediate
Figure imgf000040_0001
A suspension of 2,4-dichloro-5-fluoropyrimidine (8.98 mmol, 1 equiv), 4- methoxyaniline (8.98 mmol, 1 equiv), and sodium carbonate (53.9 mmol, 6 equiv) in 10 mL of ethanol was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and water. The layers were separated, and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting residue was used without further purification. Total yield was 88%.
Example 22 Preparation of (2E)-3-(dimethylamino)-1 -[3-(trifluoromethyl)phenyll-2-propen-1 - one intermediate
Figure imgf000040_0002
A suspension of 3'-(trifluoromethyl)acetophenone (6.0 g, 31.9 mmol) and
/V,/V-dimethylformamide dimethyl acetal (3.8 g, 31.9 mmol) in toluene (35 mL) was heated at reflux overnight. The yellow solution was cooled to room temperature and concentrated under reduced pressure. The crude material was coated on silica and purified by column chromatography (100% CH2CI2) to afford the desired product as a yellow solid (6.1 g; 25.1 mmol; 79% yield); 1H NMR (DMSO-dg) 8.19
(d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 12 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 5.89 (d, J = 11.7 Hz, 1 H), 3.15 (s, 3H), 2.94 (s, 3H); ES MS (M+H)+= 244.1.
Example 23 Preparation of ethyl (2Z)-3-(dimethylamino)-2-(4-methoxybenzovD-2-propenoate intermediate
Figure imgf000041_0001
The enamine was prepared according to the process of Example 22 using ethyl 4-methoxybenzoyl acetate to afford the desired product as an orange oil which was used without further purification; MS (ES) 278.0 (M+H)+.
Example 24 Preparation of methyl 2-(1H-indazol-5-ylamino)-4-(4-methoxyphenyl)-5- pyrimidinecarboxylate
Figure imgf000041_0002
A mixture of ethyl (2Z)-3-(dimethylamino)-2-(4-methoxybenzoyI)-2- propenoate obtained according to the process of Example 23 ( 500 mg, 1.8 mmol), Λ/-(1H-indazol-5-yl)ethanimidamide diacetate obtained by reaction of indazole-5-amine (1 equiv) and 1 H-pyrazole-1-carboxamidine hydrochloride. (532 mg, 1.8 mmol), and 0.5 M sodium methoxide in MeOH (10.8 mL) in MeOH (7.2 mL) were heated at reflux overnight. The reaction was cooled to rt and quenched with H20 (2 mL). The mixture was made neutral with the addition of 1N HCI and extracted with EtOAc (3 x 50 mL). The combined organics were dried (MgS04), filtered, and concentrated under reduced pressure. The crude product was recrystallized from MeOH and dried in vacuo at 45°C to afford the desired product as a tan solid (147 mg, 0.39 mmol; 22% yield); mp 218-221 °C; TLC (DCM/MeOH, 95:5): Rf = 0.39.
Example 25 Preparation of Λ/-f4-(4-methoxyphenyl)-5-(4-morpholinylcarbonvπ-2-pyrimidinyl1-
1 H-indazol-5-amine
Figure imgf000042_0001
To a solution of morpholine (116 mg, 1.3 mmol) in toluene (5 mL) was added 2M trimethylaluminum in toluene (670 μL), dropwise. The mixture was stirred until gas evolution ceased (approximately 45 min). The preformed aluminum amide was then added dropwise to a suspension of methyl 2-(1H- indazol-5-yIamino)-4-(4-methoxyphenyl)-5-pyrimidinecarboxylate obtained according to the process of Example 24 (100 mg, 0.27 mmol) in toluene (5 mL). The reaction was allowed to stir at reflux for 2 h. The heat was removed and the reaction was allowed to stir at rt overnight. The mixture was then heated at reflux for an additional 6 h. The mixture was cooled to rt and was quenched with the addition of 1 N HCI (2 mL). The heterogeneous mixture was filtered through Extrelut and the filtering aid was washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 ODS, 10-90% CH3CN/H20, 0.1% TFA) and dried in vacuo at 50°C to afford the desired product as a tan solid (61 mg, 0.14 mmol; 53% yield); mp152-154 °C; MS (ES) 431.3 (M+H)+. Example 26 Preparation of 2-chloro-4-(5-chloro-2-thienv0-5-fluoropyrimidine intermediate
Figure imgf000043_0001
A mixture of 2,4-dichloro-5-fluoropyrimidine (0.834 g, 5.00 mmol) and NaHC03 (1.26 g, 15.0 mmol) in 1 ,2-dimethoxyethane:water (4:1 , 15 mL) was degassed with Argon for 30 min at room temperature. This solution was slowly heated to reflux, and 5-chloro-2-thiophene boronic acid (0.812 g, 5.0 mmol, Lancaster) and tetrakis(triphenylphospine)-palladium(0) (0.578 g, 5.00 mmol) were added. After 16 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. 20 mL of H20 was added and the crude product was extracted with ethyl acetate (3 x 40 mL). The combined organics were dried over Na2S04 and concentrated in vacuo. The product was purified by silica gel column chromatography (1% ethyl acetate/hexanes to 10% ethyl acetate/hexanes gradient) to afford 0.025 g (2%) of the title compound as a slightly green solid. LC-MS: (M+H)+ 247.9 m/z. Retention time (LC-MS): 3.22 min.
Example 27 Preparation of Λ/-r4-(5-chloro-2-thienyl)-5-fluoro-2-pyrimidinyl1-1 H-indazol-5-amine
Figure imgf000043_0002
5-Aminoindazole (0.020 g, 0.20 mmol) was added to a mixture of 5-chloro-
2-(2-chloro-5-fluoropyrimidin-4-yl)thiophene (0.025 g, 0.10 mmol) in n-butanol (1 mL). Catalytic HCI (0.002 mL) was added, and the reaction mixture was heated to 115 °C. After 16 h the solvent was removed in vacuo, and the product was purified by preparative HPLC (10% acetonitrile, 90% water, 0.1% TFA to 90% acetonitrile, 10% water, 0.1% TFA gradient) to afford 0.0036 g of A (10%) as a brownish solid. LC/MS: (M+H)+ 345.1 m/z. Retention time (LC-MS): 2.96 min. 1H NMR (DMSO-de) δ 9.74 (s, 1 H), 8.62 (d, 1H, J = 3.2 Hz), 8.16-8.17 (m, 1 H), 8.03 (s, 1 H), 7.74-7.75 (dd, 1 H, J = 1.4 Hz, J = 2.8 Hz), 7.55-7.58 (dd, 1 H, J = 2.0 Hz, J = 9.2 Hz), 7.49 (d, 1 H, J = 9.2 Hz), 7.32 (d, 1 H, J = 4.0 Hz).
Example 28 Preparation of 2-fluoro-/V-methoxy-Λ/-methylacetamide intermediate
O
^N^F
I To a stirred -10°C solution of Λ/,0-dimethylhydroxylamine hydrochloride
(18.4 g, 189 mmol) in dichloromethane (175 mL) was added 2.0M trimethyl aluminum (94.5 mL, 189 mmol) dropwise via an addition funnel. This was slowly warmed to rt and stirred for 1h. This solution was then added dropwise to a -10 °C solution of ethyl fluoroacetate (10.0 g, 94.3 mmol) in dichloromethane (100 mL). This was warmed to rt and stirred for 18 h. 1 M Rochelle's salt (50 mL) was added slowly and this was stirred for 1 h. The reaction mixture was then diluted with H2O and the layers were separated. The aqueous layer was extracted with dichloromethane (3 X 25 mL). The organic layers were combined, washed with brine, dried (Na2S04), and concentrated in vacuo to afford 8.70 g (76%) of the desired product as a dark oil that was used without further purification.
Example 29 Preparation of 2-fluoro-1-(4-methoxyphenvDethanone intermediate
Figure imgf000044_0001
To a -78 °C solution of bromoanisole (2.7 mmol, 1.3 equiv) in 15 mL of
THF was added 1.6 M n-BuLi (5.4 mmol, 2.6 equiv). This was stirred for 15 min and then added to a solution of 2-fluoro-/V-methoxy-/V-methylacetamide obtained according to the process of Example 28 (2.07 mmol, 1.0 equiv) in 15 mL of THF. The reaction was maintained at -78 °C for 45 min and then 5 mL of 1M HCI was added. The reaction was diluted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, and reduced. The residue was purified by flash column chromatography (5% ethyl acetate in hexanes) to yield the desired product as a pure oil that solidified upon standing. Total yield 21%.
Example 30 Preparation of /V-(4-benzylphenvh-Λ/-r5-fluoro-2-(6-guinolinylamino)-4- pyrimidinvnamine
Figure imgf000045_0001
Λ/-(4-Benzylphenyl)-2-chloro-5-fluoro-4-pyrimidinamine, obtained from 5- fluoro-2,4-dichloropyrimidine and 4-benzylaniline using the method of Example 21 , (1 equiv) was treated with 6-aminoquinoline (2 equiv), and suspended in 1 N HCI. The mixture was heated at 100 °C for 7 days. Upon cooling to rt, the solution was neutralized with 2N Na2Cθ3 and extracted with n-BuOH. The organic layer was collected, and dried. The resulting crude product was purified by preparative TLC
(60% EtOAc / Hexanes). LCMS: RT 2.18 min; [M+H]+ 422.
Example 31 Preparation of (2Z)-3-(dimethylamino)-2-fluoro-1 -(4-methoxyphenyl)-2-propen-1 - one intermediate
Figure imgf000045_0002
A solution of 2-fluoro-1-(4-methoxyphenyl)ethanone obtained according to the process of Example 29 (7.1 mmol, 1 equiv) and Λ/,/V-dimethylformamide dimethyl acetal (28.4 mmol, 4 equiv) was heated at 120 °C for 2 h. The reaction was diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layers were separated, dried over sodium sulfate, filtered, and reduced.
The residue was purified by flash column chromatography (75% ethyl acetate in hexanes) to yield the desired product as a pure oil that solidified upon standing. Total yield 85.4%.
This intermediate was converted to the product of Example 375 using the procedure for Example 41.
Example 32 Preparation of (,2-chloro-5-fluoro-4-pyrimidinyl)(4-methoxyphenyl)acetonitrile
Figure imgf000046_0001
A solution of p-methoxyphenylacetonitrile (381 μL, 2.7 mmol) in 4 mL of DMF at -15 °C was treated with sodium hydride (60% dispersion in mineral oil,
102 mg, 2.7 mmol) and allowed to react for 15 min. The suspension was then treated with 5-fluoro-2,4-dichloropyrimidine (296 mg, 1.78 mmol) and allowed to stir for 1.5 h at -15 °C and an additional 0.5 h at rt. The reaction was quenched with isopropanol and saturated ammonium chloride. Purification with silica gel chromatography gave a single regioisomer as a faintly yellow oil (346 mg, 70%).
Example 33 Preparation of r5-fluoro-2-(1 H-indazol-5-ylamino')-4-pyrimidinyll(4-methoxy- phenvDacetonitrile
Figure imgf000046_0002
The compound was prepared by a method similar to that described for Example 18, using (2-chloro-5-fluoro-4-pyrimidinyl)(4-methoxyphenyl)acetonitrile, obtained according to Example 32, as the chloride. Example 34 Preparation of Λ/-r4-(3-chloro-4-fluorophenvπ-5-fluoro-2-pyrimidinvn-6- guinolinamine
Figure imgf000047_0001
In a 15 mL flask were placed 2-chloro-4-(3-chloro-4-fluorophenyl)-5- fluoropyrimidine (130.0 mg, 0.5 mmol), 6-aminoquinoIine (144.2 mg, 1.0 mmol), 3.4 mL of 1-butanol and 1.1 mL of 1 N HCI solution. The mixture was heated at 128-130 °C for 2 days. The reaction mixture was evaporated to dryness and the residue was dissolved in methanol, absorbed on silica gel, dried and chromatographed with CH2CI2/methanoi = 100/3 to provide a mixture of the desired compound with trace impurities. This mixture was purified again by Prep.TLC with CH2CI2/methanol (100/3) to give 9.3 mg of a yellow solid (5.1%). GC/MS 369.4 (M+1) RT = 2.65 min; 1H-NMR (DMSO-d6) δ 10.28 (s, 1 H); 8.787 (s, 1H); 8.744 (s, 1 H); 8.528 (s, 1H); 8.290-8.311 (d, 1H); 8.203-8.247 (d, 1H); 8.074-
8.139 (m, 1H); 7.944 (s, 2H); 7.642-7.707 (t, 1 H); 7.447-7.491 (m, 1 H).
Example 35 Preparation of 4-f5-fluoro-2-(6-guinolinylamino)-4-pyrimidinvnbenzoic acid
Figure imgf000047_0002
Step 1. To a solution of 2, 4-dichloro-5-fluoropyrimidine (500 mg, 3.0 mmol) in degassed DME/H20 (9.3 mL/1.8 mL) was added 4-carbobutoxyphenyl boronic acid (244 mg, 1.1 equiv), followed by PdCI2(dppf) (49 mg, 0.060 mmol). The reaction was stirred at rt overnight. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (95:5 hexanes/ EtOAc) to afford the desired product which was verified by 1H NMR and LC-MS and used directly in the next step. Step 2. In a 8 mL vial were placed butyl 4-[5-fluoro-2-(6-quinolinylamino)-
4-pyrimidinyljbenzoate obtained in Step 1 (6.3 mg, 0.015 mmol), methanol (0.75 mL) and 0.09 mL of 1 N NaOH solution. The vial was shaken at 60 °C overnight. Upon cooling, the reaction mixture was acidified with 1N HCI to pH 1-2 and evaporated to dryness. To this residue was added water and the resulting precipitated solid was filtered, washed with water and methanol, and dried in an oven to provide 4.3 mg of an off-white solid (79.6%). GC/MS 361.3 (M+1) RT = 2.00 min; 1H-NMR (DMSO-of6) 510.415. (s, 1 H); 8.755-8.845 (m, 2H); 8.653 (s, 1H); 8.443-8.496 (d, 1H); 8.164-8.234 (m, 4H); 8.007-8.059 (m, 2H); 7.571-7.606 (m, 1 H).
Example 36
Preparation of 2-(1H-indazol-5-ylamino)-4-(4-methoxyphenyl)-5- pyrimidinecarboxylic acid
Figure imgf000048_0001
A solution of methyl 2-(1H-indazol-5-ylamino)-4-(4-methoxyphenyl)-5- pyrimidinecarboxylate (50 mg, 0.13 mmol) and 1 N NaOH (0.13 mL) in MeOH/H20/THF (2 mL/0.13 mL/0.13 mL) was stirred at 50 °C overnight. The reaction was cooled to room temperature and the mixture was concentrated under reduced pressure. The residue was dissolved in H20 and the pH was adjusted to 6 with the addition of 1 N HCI. The resulting solid was collected by filtration and was dried in vacuo at 45 °C to afford the desired product (42 mg, 0.12 mmol; 87% yield); mp = 269-272 °C, MS (ES) 362.3 (M+H)+; TLC (DCM/MeOH, 90:10): Rf = 0.40. Example 37 Preparation of methyl 4-(4-methoxyphenylV2-(6-quinolinylamino)-5- pyrimidinecarboxylate
Figure imgf000049_0001
The compound was prepared analogously to that described in Example 35, Step 1. The crude product was purified by preparative HPLC (C18 ODS, 10-90% CH3CN/H20, 0.1%TFA) and dried in vacuo at 50 °C to afford the desired product as a white solid (30 mg, 0.078 mmol; 11% yield); mp 155-157 °C; MS (ES) 387.4 (M+H)+.
Example 38 Preparation of 4-(4-methoxyphenv0-2-(6-guinolinylamino)-5-pyrimidinecarboxylic acid
Figure imgf000049_0002
The product was prepared according to the process described for Example 36 using methyl 4-(4-methoxyphenyl)-2-(6-quinolinylamino)-5- pyrimidinecarboxylate obtained according to the process of Example 37. The product was triturated with CH3CN and collected by filtration to afford the desired product as a yellow solid (21 mg, 0.056 mmol; 89% yield); mp = 216-220 °C; MS (ES) 373.4 (M+H)+. Example 39 Preparation of 1-(1 ,3-benzodioxol-5-yl)-2-fluoroethanone
Figure imgf000050_0001
To a stirred -78 °C solution of 4-bromo-1 , 2-(methylenedioxy) benzene (1.29 mL, 10.7 mmol) in THF (25 mL) was added 1.6M n-BuLi (13.4 mL) dropwise via syringe. This was stirred for 0.5 h then added dropwise to a stirred -78 °C solution of 2-fluoro-Λ/-methoxy-Λ/-methylacetamide obtained according to the process of Example 23 (1.00 g, 8.26 mmol) in THF (25 mL). The reaction was stirred for 1 h and then acidified to pH 2 with 1 N HCI. The reaction mixture was diluted with EtOAc (25 mL) and H20 (25 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3 X 10 mL) and the combined organic layers were washed with brine, dried (Na2S04), and concentrated in vacuo. The crude solid was recrystallized from hot EtOH to afford 387 mg (24%) of the desired product as off-white needles.
Example 40 Preparation of (2Z)-1-(1 ,3-benzodioxol-5-yl)-3-(dimethylamino)-2-fluoro-2-propen-
1-one
Figure imgf000050_0002
To a stirred solution of 1-(1,3-benzodioxol-5-yI)-2-fluoroethanone obtained according to the process of Example 39 (300 mg, 1.65 mmol) in DMF (20 mL) was added Bredereck's reagent (0.476 mL, 2.31 mmol). This was warmed to 120 °C and stirred for 20 h. The reaction mixture was cooled to rt and then diluted with EtOAc (10 mL) and H20 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 X 5 mL). The combined organic layers were washed with H20 (3 X 5 mL), dried (Na2S04), and concentrated in vacuo. The crude product was purified via flash chromatography eluting with EtOAc/ H20 (80:20) to afford 169 mg (43%) of desired product as a brown solid. Example 41 Preparation of Λ/-C1.3-benzodioxol-5-vπ-/V-r5-fluoro-2-(3-guinolinylamino)-4- pyrimidinyllamine
Figure imgf000051_0001
To a suspension of (2Z)-1-(1 ,3-benzodioxol-5-yl)-3-(dimethylamino)-2- fluoro-2-propen-1-one obtained according to the process of Example 40 (51.0 mg, 0.215 mmol) and /V-(3-quinolinyl)guanidine (64.0 mg, 0.215 mmol) in MeOH (2 mL) was added 0.5M NaOMe (1.29 mL, 0.645 mmol). This was heated to 70 °C and shaken for 36 h. Complete consumption of starting material was not obtained, but the reaction mixtures were concentrated in vacuo and purified via prep HPLC (RT 2.10 min, 10-90% CH3CN/H20 over 3.5 min) to afford 1.7 mg (1 %) of the desired product as an off-white solid. ESIMS m/z 361.4 (MH+).
Example 42 Preparation of 4-(1 ,3-benzodioxol-5-yl)-2-chloro-5-fluoropyrimidine intermediate
Figure imgf000051_0002
To a stirred solution of 1 ,3-benzodioxol-5-ylboronic acid (300 mg, 1.81 mmol), 2,4-dichloro-5-fluoro-pyrimidine (332 mg, 2.00 mmol) and sodium carbonate (384 mg, 3.62 mmol) in DME (10 mL) and H20 (2 mL) was added PdC (dppf) (30.0 mg, 0.04 mmol). After 0.5 h a precipitate began to form, and after 2 h the reaction was complete. The crude mixture was concentrated in vacuo and redissolved in H20. The resulting solid was filtered and dried to afford 443 mg (97%) of the desired product as a tan solid, mp 134-136 °C. Example 43 Preparation of N-\Λ-(λ ,3-benzodioxol-5-vπ-5-fluoro-2-pyrimidinyll-1-methyl-1H- indazol-6-amine
Figure imgf000052_0001
To a suspension of 4-(1 ,3-benzodioxol-5-yl)-2-chloro-5-fluoropyrimidine obtained according to the process of Example 42 (75.0 mg, 0.297 mmol), and 5- amino-2-methylindazole in n-butanol (2 mL) was added 1 N HCI (1 mL). This was warmed to 120 °C~and shaken for 120 h. The crude reaction mixture was concentrated in vacuo and purified by prep HPLC (RT 2.89 min, 30-70% CH3CN/H2O over 3.5 min) to afford 2.2 mg (2%) of the desired product as a tan solid, mp 218-219 °C. ESIMS m/z 364.4 (MH+).
Example 44 Preparation of 2-chloro-5-fluoro-4-(2-methoxyphenyl)pyrimidine intermediate
Figure imgf000052_0002
A suspension of 2,4-dichloro-5-fluoropyrimidine (3 mmol, 1 equiv) and PdCI2dppf (0.06 mmol, 0.02 equiv) in 9 mL of deoxygenated DME was stirred for 5 min. 2-Methoxyphenylboronic acid (3.6 mmol, 1.2 equiv), sodium carbonate (6 mmol, 2 equiv), and 2 mL water were then added. The vial was capped under argon and shaken overnight. The reaction was diluted with ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (8% ethyl acetate in hexanes) to yield the desired product as a white solid. Total yield 45%.
Example 45 Preparation of Λ/-r5-fluoro-4-(2-methoxyphenvπ-2-pyrimidinyll-1 -methyl-1 H- indazol-6-amine
Figure imgf000053_0001
A suspension of 2-chloro-5-fluoro-4-(2-methoxyphenyl)pyrimidine according to the process of Example 44 (0.5 mmol, 1 equiv) and 1-methyl-6-amino-indazole (1 mmol, 2 equiv) in 2 mL of n-butanol and 1 mL of 1 N HCI was shaken at 120 °C for 3 days. The reaction was concentrated and the resulting residue purified by HPLC. Fractions were combined, acetonitrile removed, and the resulting aqueous layer treated with saturated sodium bicarbonate solution to give a precipitate. This was filtered and dried in a vacuum oven overnight to yield the target compound as a pure compound. Total yield was 25%
Example 46 Preparation of /V-(5-bromo-2-[(1-ethyl-1/- -indazol-5-vπamino1-4-pyrimidinyll-Λ/-(1- ethyl-1 H-indazol-5-yl)amine
Figure imgf000053_0002
A solution of 5-bromo-2,4-dichloropyrimidine (100 mg, 0.20 mmol), 1-ethyl- 1H-indazol-5-amine, and catalytic amount of hydrochloric acid in 1-butanol (3 mL) was heated at 115 °C overnight. Some yellow solid precipitated out. The solution was filtered. The filtrate was washed with a little bit of methanol and ethyl acetate to give a yellow solid (86.6 mg, 71.0%). Example 47 Preparation of 1 -(4-r5-fluoro-2-(6-guinolinylamino)-4-pyrimidinvnphenyl}ethanone
Figure imgf000054_0001
Step 1 : 2,4-Dichloro-5-fluoropyrimidine (1 equiv) was allowed to react with 4-acetylphenylboronic acid (1.2 equiv), in the presence of PdCI2dppf (0.06 equiv) and sodium carbonate (1.5-2 equiv), in DME and water (4:1 v/v) at rt to 60 °C for 2-6 h. The reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (EtOAc-hexane).
Step 2: The intermediate from Step 1 was treated with 6-aminoquinoline (2 equiv) in n-BuOH and 2N HCI (1 :1 v/v) at 120 °C for 2-6 days. The solvents were removed by evaporation. The residue was purified by silica gel column (EtOAc- Hexane or MeOH-CH2CI2) to give a pure solid product. LC-MS: RT 2.04 min; [M+H]+ 359.
Example 48 Preparation of /V-(5-fluoro-4-phenyl-2-pyrimidinyl)-6-guinolinamine
Figure imgf000054_0002
Step 1. 5-Fluoro-2,4-dichloropyrimidine (1 equiv) was allowed to react with phenylboronic acid (1.2 equiv) in the presence of PdCI2dppf (0.02 equiv) and sodium bicarbonate (3 equiv), in DME and water (4:1 v/v) at 70 °C overnight. The reaction mixture was evaporated to dryness and the residue was purified by Biotage (15% EtOAc/Hexanes) to give the desired product (80% purity) that was used directly in the next step. Step 2. The intermediate obtained in Step 1 was treated with 6- aminoquinoline (2 equiv) in n-BuOH/1N HCI (1/1) at 120 °C, or in 1 N HCI at 100 °C for 10 days. It was cooled and neutralized with 2N Na2C03, and extracted with n-BuOH. The organic layer was collected, and dried. The resulting crude product was purified by preparative TLC (60% EtOAc / hexanes). LC-MS: RT 2.08 min;
[M+H]+ 317.
Example 49 Preparation of A/-(5-fluoro-4-r3-(trifluoromethyl)phenyl1-2-pyrimidinyl -6- guinolinamine
Figure imgf000055_0001
Step 1. To a solution of 2,4-dichloro-5-fluoropyrimidine (500 mg, 3.0 mmol) in degassed DME/H20 (9.3 mL/1.8 mL) was added 3-trifluoromethyl phenylboronic acid (627 mg, 3.3 mmol), followed by PdCI2(dppf) (49 mg, 0.060 mmol). The reaction was stirred at rt overnight. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (95:5 hexanes/EtOAc) to afford the desired product. The product was verified by 1H NMR and LC/MS.
Step 2. To a solution of 2-chloro-5-fluoro-4-(3-trifluoromethyl phenyl)pyrimidine obtained in Step 1 (100 mg, 0.36 mmol) in n-BuOH (2 mL) were added an 6-amino quinoline (1 equiv) and 1 N HCI (1 mL). The mixture was shaken at 125 °C over 4 days. The mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Cιβ ODS, 10-90% CH3CN/H20, 0.1%TFA) and dried in vacuo at 45 °C to afford the desired product in 12-17% yield. The product was verified by 1H NMR and
LC/MS: RT 2.73 min; [M+H]+ 385.
Using methods analogous to the above described procedures, other examples of the invention were prepared and are listed in Tables 1-5 below: Tablel
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000057_0001
Figure imgf000058_0002
Table 2
Figure imgf000058_0001
Figure imgf000058_0003
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Table 3
Figure imgf000065_0001
Figure imgf000066_0001
Table 4
Figure imgf000066_0002
Figure imgf000066_0003
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0002
Table 5
Figure imgf000082_0001
Figure imgf000082_0003
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
85
Figure imgf000087_0001
84
Figure imgf000088_0001
Figure imgf000089_0001
Biological tests
Elk-1 Assay: The following assay measures the inhibitory activity of the compounds on
Elk-1 transactivated luciferase expression. Elk-1 is a gene regulatory protein that is activated by MAP kinases (mitogen activated protein kinases). In this assay, epidermal growth factor (EGF) stimulates Elk-1 transactivation of luciferase expression through phosphorylation of the Gal4 (a yeast gene activator protein)-Elk-1 fusion protein (Hexdall and Zheng, 2001 , Boulikas 1995). Hela Elk-
1 luc cells are plated at 2 x 104 cells per well in 96-well plates in complete medium (DMEM, 10% FBS, 20 mM HEPES, 100 U/mL penicillin, 100 μg/mL streptomycin, 250 μg/ml G418 (geneticin) and 100 μg/ml hygromycin B; all reagents Gibco BRL). The cells are incubated at 37 °C in 5% C02 in a humidified incubator overnight. The cells are washed and subsequently incubated in serum-free medium containing 1 % fatty acid free bovine serum albumin (BSA) for an additional 24 hours. Test compounds are added in serum-free medium and the plates are incubated for 45 min followed by addition of 100 ng/ml recombinant EGF or 50 ng/ml PMA (phorbol 12-myristate 13-acetate, Sigma). After a 5 h incubation period, luciferase activity is quantified in a Wallace Luminometer.
In vitro Proliferation Inhibition Assay:
HCT 116 human colorectal carcinoma cells (ATCC CCL247) were cultured in standard growth medium (DMEM, 10% FBS, 10 mM HEPES, 2 mM glutamine,
100 U/mL penicillin, 100 μg/mL streptomycin) at 37 °C in 5% C02 in a humidified incubator. Cells were detached using trypsin and plated at a density of 3000 cells per well in 100 μL growth medium in a 96 well culture dish. Twenty-four hours after plating, compounds were added and the cell number is quantified 72 h after treatment using a MTS assay (e.g. Promega CellTiter 96 Aqueous One Solution Cell Proliferation Assay #G3581. Briefly, the MTS assay is a colorimetric method for determining the number of viable cells in the proliferation assay. The MTS (3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)2-(4-sulfophenyl)-2H- tetrazolium) reagent is bioreduced by cells into a colored formazan product that is soluble in tissue cultured medium. The quantity of formazan product as measured by the amount of 490 nm absorbance is directly proportional to the number of living cells in culture.) Test compounds were dissolved in 100% DMSO (dimethylsulfoxide) to prepare 10 mM stocks. Stocks were further diluted 1 :250 in growth medium to yield working stocks of 40 μM test compound in 0.4% DMSO. Test compounds were serially diluted in a 6 point dose response from 10 μM to 0.033 μM in growth medium containing 0.4% DMSO to maintain constant DMSO concentrations for all wells. One hundred microliters of diluted test compound were added to each culture well to give a final volume of 200 μL). The treated cells were incubated for 72h at 37 °C. After the completion of the 72h incubation, 40 μL of MTS reagent is added to each well. The plates were incubated for 30min at 37°C and read at 490 nm. In addition, the IC50 values were determined with a least squares analysis program using compound concentration versus percent inhibition. % Inhibition = [1-(T72h test-T0h)/(T72h ctrl-T0h)] x 100 where
T72h test = LDH activity at 72 h in presence of test compound T72h Ctrl = LDH activity at 72 h in absence of test compound
Toh = LDH activity at Time Zero
Representative results are shown in Table 8 below:
Table 8.
Figure imgf000090_0001
A suitable assay for assessing inhibition of colony formation is as follows. HCT116 or H460 (ATCC #HTB177) cells are mixed with an agar-medium 1 x DMEM (DMEM powder, Gibco) + 1x FBS at a ratio 3:2; i.e. 3 mL agar (SeaPlaque agarose, FMC Corporation) + 2 mL cells. The initial cell concentration is 5000 cells/mL (resulting in 100 cells/well). 50 μL is plated as a bottom layer agar mix consisting of 6.3 mL 4x agar, 6.3 mL 2x DMEM, and 12.5 mL 1x DMEM + 2x FBS for a 0.6% f.c. 50 mL of regular growth medium (DMEM, 10% FBS, 10 mM HEPES, 2 mM glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin) and incubated at 37 °C in 5% C02 in a humidified incubator overnight. The compound (10mM stock in 100% DMSO) is added in serial dilutions ranging from 10 μM to 33nM the next day and the plates are incubated for another 7 days 37 °C in 5% C02 in a humidified incubator. MTS (Promega) analysis is performed essentially as described by the manufacturer. Briefly, 40 μL MTS are added to each well and the plates were incubated for 2 h at 37°C in 5% C02 in a humidified incubator, shaken for 1 min at room temperature, and read at 490 nm.
Detection of Apoptosis: A suitable assay for determining apoptosis is as follows. H460 human lung cancer cells are plated in six well plates (Costar 3506) at 250,000 cells per well in standard medium (DMEM, 10% FBS, 10 mM HEPES, 2 mM glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin) and incubated over night at 37 °C in 5% C02 in a humidified incubator. The cells are treated with various concentrations of the test compounds for 24 h. Cells are harvested and fixed with 1 % paraformaldehyde on ice for 15 min. Subsequently, the cells are rinsed and put in ice cold ethanol (80%) overnight at -20 °C. Apoptosis is detected using a TUNEL assay (Pharmingen, APO-BRDU kit) as described by the manufacturer. Briefly, cells are incubated with DNA labeling solution for 1 h at 37 °C, washed and subsequently incubated with propidium iodide. In a dark room, the cells are Rnase treated. Samples were analyzed using a FACS Calibur (Becton Dickinson) using CellQuest software. Using this assay, a representative compound of the present invention induced apoptosis.
In vivo Tumor Growth Inhibition Assay: Inhibition of tumor growth in vivo is readily determined via the following assay: HCT 116, H460, or A549 cells are cultured as described above. The cells are harvested by trypsinization, washed, counted, adjusted to 2.5x107 cells/mL with ice cold phosphate-buffered saline (PBS), and subsequently stored on ice until transplantation. Xenograft experiments are conducted using eight-to-ten week-old female NCr nude mice (Taconic Labs) with an average body mass of about 20-25g. All the procedures are performed using sterile technique and in accordance with IACUC guidelines. Approximately 5 x 106 cells in a total volume of 0.2 mL PBS are injected subcutaneously in the flank region. Tumor measurements are performed one week after transplantation. Tumor weights are calculated using the formula (a x b x b)/2. Thereafter the mice are randomized and divided into several groups that reflect different dosages or schedules, respectively (n=10 mice/group). The test compounds are administered starting with day 8 after transplantation at various dosages (e.g. 0.75, 1.5, 3, 10, 30, and 100 mg/kg) and different schedules (e.g. twice a day (bid) for 14 days, once a day for fourteen consecutive days, or every other day for seven treatments in total). A suitable vehicle for oral administration is Cremophor, ethanol and 0.9% saline (12.5:12.5:75). Tumor measurements are performed twice per week. Tumor weights are calculated as described above. Student's T - test is used to verify the significance of the activity compared to untreated (vehicle only) controls. Animals are sacrificed after treatment and plasma was harvested for pharmacokinetic analyses. Tumors undergo further subsequent analyses, e.g. histology.
Representative compound of Example 59 demonstrated antitumor activity in this assay using HCT 116 and H460 cells. Pharmaceutical Compositions:
Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows:
Hard shell capsules:
A large number of unit hard shell capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules:
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium sterate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules:
These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended 'for immediate release, without the need of water.
Additionally, the disclosure shows and describes only the preferred embodiments of the invention but, as mentioned above, it is to be understood that the invention is capable of use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the inventive concept as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described hereinabove are further intended to explain best modes known of practicing the invention and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with the various modifications required by the particular applications or uses of the invention. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended that the appended claims be construed to include alternative embodiments.

Claims

What is claimed is:
1. A compound of the formula:
Figure imgf000095_0001
(I) wherein each X is independently NR1R6, NR4R5, or R4, with the proviso that at least one X must be NR1R6; each R1 is independently an optionally substituted fused bicyclic unsaturated ring containing 9 or 10 atoms and optionally containing
1-4 heteroatoms selected from the group consisting of N, S, and O; wherein said substitution on said ring is selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9, -N=CR8, optionally substituted alkyl, and optionally substituted alkenyl wherein the substitution on said alkyl and alkenyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; R2 is hydrogen, halo, optionally substituted alkyl, or an optionally substituted -Y(n)-mono-ring group or -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein said substitution on said ring group is selected from the group consisting of halo, -COOR8, -COR8, -OR8, -C=0, -N02, -CONR8R9, and optionally substituted alkyl, wherein said substitution on each of said alkyls is independently selected from the group consisting of -NR8R9, -OR8, and fluoro; R3 is hydrogen, alkyl, or halo; each R4 is independently an optionally substituted -Y(n)-mono-ring group or optionally substituted -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n is 0 or 1 , and Y is selected from the group consisting of straight- or branched-chain C2-3-alkylenyl and -C(CN)-; wherein R4 can also be hydrogen or alkyl when R5 is present; and wherein said substitution on said ring group is selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9,
-CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9 -N=CR8, and optionally substituted alkyl wherein said substitution on said alkyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; with the proviso that the multi-ring group cannot be benzimidazolyl; each R5 is independently an optionally substituted -Y(n)-mono-ring group or an optionally substituted -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N,
S, and O; wherein n is 0 or 1 , and -Y- is selected from the group consisting of straight- or branched-chain C2-3-alkylenyl, -N=CH, and -N=CHCH3; and wherein said substitution on said ring group is selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9,
-NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9, -N=CR8, and optionally substituted alkyl wherein said substitution on said alkyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; with the proviso that the multi-ring group cannot be benzimidazolyl; each R6 is independently hydrogen or alkyl; each R8 and R9 is independently hydrogen, optionally substituted C1-C5 alkyl, optionally substituted aryl, or optionally substituted arylalkyl, wherein said substitution is selected from the group consisting of optionally substituted alkyl wherein said substitution on said alkyl is selected from the group consisting of fluoro and dialkylamino; and pharmaceutically acceptable salts and prodrugs thereof. ompound according to claim 1 wherein: each X individually is -NR1R6, -NR4R5, or R4, with the proviso that at least one X is -NR1R6; each R1 is independently an optionally substituted moiety selected from the group consisting of indazolyl, quinolinyl, benzothiazolyl, benzotriazolyl, or benzoxazolyl, wherein said substitution is selected from the group consisting of hydrogen, methyl, and ethyl; R2 is halo or optionally substituted alkyl, wherein said substitution is selected from the group consisting of fluoro, -COOR8, -COOR9, and -CONR8R9;
R3 is hydrogen or methyl; each R4 is hydrogen, methyl, phenyl, aryl, benzothiophenyl, pyridinyl, indolyl, naphthalenyl, biphenyl, indanyl, indenyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzotriazolyl, cyclohexanyl, cyclopentanyl, cyclobutanyl, or multiple rings which are linked covalently, either directly or via a linker, wherein said linker is selected from the group consisting of methylene, O, S, N, -R8-S02,
-S02-NR8, -NR8CO- and -CONR8; each R5 is independently an optionally substituted -Y(n)-mono-ring group or an optionally substituted -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n is 0 or 1 , and -Y- is selected from the group consisting of straight- or branched-chain C2-3-alkylerιyl, -N=CH, and - N=CHCH3; and wherein said substitution is selected from the group consisting of halo, -COOR8, -COR8, -CN, -OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9, -N=CR8, and optionally substituted alkyl wherein said substitution on said alkyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; with the proviso that the multi-ring group cannot be benzimidazolyl; each R6 is independently hydrogen or alkyl; each R8 and R9 is independently hydrogen, optionally substituted Crs-alkyl, optionally substituted aryl, and optionally substituted arylalkyl, wherein said substitution is selected from the group consisting of optionally substituted alkyl wherein said substitution on said alkyl is selected from the group consisting of fluoro and dialkylamino; and pharmaceutically acceptable salts and prodrugs thereof.
3. A compound according to claim 1 of the formula
Figure imgf000098_0001
(1-1 ) wherein each R1 is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazolyl, 6-(1- methyl)indazolyl, 5-(1-ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3- quinolyl, or 3-isoquinolyl;
R2 is hydrogen, fluoro, bromo, chloro, methyl, or trifluoromethyl; and
R3 is hydrogen or methyl; and pharmaceutically acceptable salts thereof.
4. A compound according to claim 1 of the formula:
Figure imgf000098_0002
(I-2) wherein: each R is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazolyl, 6-(1-methyI)indazolyI, 5-
(l-ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3-quinolyl, or 3-isoquinolyl; R2 is hydrogen, fluoro, bromo, chloro, methyl, or trifluoromethyl; R3 is hydrogen or methyl; R4 is hydrogen or methyl; and
R5 is an optionally substituted moiety selected from the group consisting of phenyl, pyridyl, thiophene, furan, -Y(n)-mono-ring group or -Y(n)-multi- ring group, said ring group in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n is 0 or 1 , and -Y- is selected from the group consisting of straight or branched-chain C2-3-alkylenyl, -N=CH, and -N=CHCH3; and wherein said substitution is selected from the group consisting of halo, -COOR8, -COR8, -CN,
-OR8, -C=0, -N02, -NR8R9, -CONR8R9, -NR8COR9, -NR8COOR9, -NR8S02R9, -S02R8, -S02NR8R9, -NR8CONR9, -SR8, -NR8S02, -OR8NR8R9 -N=CR8, and optionally substituted alkyl wherein said substitution on said alkyl is selected from the group consisting of -NR8R9, -OR8, fluoro, methenyl, and ethenyl; with the proviso that the multi-ring group cannot be benzimidazolyl; and pharmaceutically acceptable salts and prodrugs thereof.
5. A compound according to claim 1 of the formula:
. 1
HN' RXX XX4
(1-3) wherein:
R1 is 5-quinolyl or 6-quinolyl; R2 is fluoro or trifluoromethyl; and
R4 is optionally substituted phenyl or pyridyl, wherein said substitution is selected from the group consisting of halo, amino, hydroxy, acetyl, alkyl, alkoxy, alkenyl, hydroxyalkyl, dialkylamino, and phenyl, and pharmaceutically acceptable salts and prodrugs thereof.
6. A compound according to claim 1 of the formula
Figure imgf000100_0001
(I-4) wherein:
R1 is independently 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5- benzothiazolyl, 6-quinolinyl, 5-(1-methyl)indazolyl, 6-(1- methyl)indazolyl, 5-(1-ethyl)indazoIyl, 6-(1-ethyl)-indazolyl, 3- quinolyl, or 3-isoquinolyl;
R2 is hydrogen, fluoro, chloro, bromo, methyl, or trifluoromethyl;
R3 is hydrogen or methyl; R4 is hydrogen or methyl; and
R5 is an optionally substituted -Y(n)-moiety, wherein n is 0 or 1 , Y is selected from the group consisting of straight- or branched-chain
C2.3-alkylenyl, -N=CH, and -N-CHCH3, and said moiety is selected from the group consisting of cycloalkyl, phenyl, napthyl, pyridyl, thienyl, furyl, quinolinyl, benzothiophenyl, benzothiazolyl, indol-3-yl, and quinoline-4-thio, said substitution being selected from the group consisting of methyl, ethyl, fluoro, bromo, chloro, trifluoromethyl, methoxyl, methylenedioxyl, sulfonamidyl, morpholinyl, and -O- pyrazinyl; and pharmaceutically acceptable salts and prodrugs thereof.
7. A compound according to claim 1 of the formula
R4
R 1 2 \ 1
Ti
R3 / VX H R1
(I-5) wherein:
R1 is 5-indazolyl, 6-indazolyl, 5-benzotriazolyl, 5-benzothiazolyl, 6- quinolinyl, 5~(1-methyl)indazolyl, 6-(1-methyl)indazolyl, 5-(1- ethyl)indazolyl, 6-(1-ethyl)-indazolyl, 3-quinolyl, or 3-isoquinolyl; R2 is hydrogen, fluoro, methyl, bromo, chloro, trifluoromethyl, -C02CH3,
-C02H, and -CO-morpholinyl; R3 is hydrogen or methyl; and
R4 is an optionally substituted -Y(n)-mono-ring group or optionally substituted -Y(n)-multi-ring group, said ring groups in each case containing 4-18 atoms in the ring and optionally containing 1-4 heteroatoms selected from the group consisting of N, S, and O; wherein n = 0 or 1 , -Y- is -C(CN)-, and wherein said ring group is selected from the group consisting of optionally substituted phenyl or pyridyl, wherein said substitution is selected from the group consisting of halo, amino, hydroxy, acetyl, -alkyl, alkoxy, alkenyl, hydroxyalkyl, dialkylamino, and phenyl; and pharmaceutically acceptable salts and prodrugs thereof.
8. A compound according to claim 1 selected from the group consisting of the compounds of Examples 1 - 375.
9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable adjuvant, buffer, or carrier.
10. A method for inhibiting kinases in a warm-blooded animal in need thereof by administering at least one of the compounds of the present invention in an amount sufficient to inhibit said kinase.
11. The present invention also relates to a method for treating a CDK-dependent disorder or disease in a warm-blooded animal in need of same, by administering to said animal at least one of the compounds of the present invention in an amount sufficient to inhibit CDK.
12. A method for inhibiting cellular proliferation in a warm-blooded animal in need thereof by administering to said animal at least one of the compounds of the present invention in an amount sufficient to inhibit said proliferation.
13. A method of inhibiting proliferative disorders in warm-blooded animals, comprising administering to said animal a compound of claim 1 in an amount sufficient to inhibit
14. A method of treating a warm-blooded animal suffering from cancer or neoplastic disease by administering to said warm-blooded animal an effective amount of at least one of the compounds of the present invention.
15. A method of treating a warm-blooded animal suffering from viral infection by administering to said warm-blooded animal an effective amount of at least one of the compounds of the present invention.
16. A method for modulating apoptosis in a warm-blooded animal in need thereof by administering at least one of the compounds of the present invention in an amount sufficient to modulate apoptosis.
17. A process for making compounds of the formula (la):
Figure imgf000102_0001
(la)
said process comprising reacting a compound of the formula (III):
Figure imgf000102_0002
(III)
with an amine of the formula R1R6NH in a protic solvent to yield the compound of formula (la); wherein R6 is hydrogen and R1, R2, and R3 are as defined in claim 3.
18. The process of claim 17 wherein said reaction is carried out in the presence of an acid.
19. The process of claim 17 wherein said reaction is carried out in the presence of a base.
20. A process for making a compound of the formula (lb):
Figure imgf000103_0001
(lb)
said process comprising reacting a compound of the formula (III)
Figure imgf000103_0002
(III)
with an amine of the formula R1R6NH in a base to yield a compound of the formula (IV)
Figure imgf000103_0003
(IV)
followed by reaction of the compound of formula (IV) with HNR4R5 to yield a compound of the formula (lb), wherein R6 is hydrogen and R1, R2, R3, R4, and R5 are as defined in claim 4.
21. A process for making a compound of the formula (lc)
Figure imgf000104_0001
(lc)
said process comprising reacting a compound of the formula (III)
Figure imgf000104_0002
(III)
with an amine of the formula R4R5NH in the presence of base to give the compound of the formula (V)
Figure imgf000104_0003
(V)
followed by reaction with a compound of formula (V) with HNR1R6 in acid to yield the compound of formula (lc), wherein R6 is hydrogen and R1, R2, R3, R4, and R5 are as defined in claim 6.
22. A process for making a compound of the formula (Id):
Figure imgf000104_0004
said process comprising reacting a compound of the formula (III)
Figure imgf000105_0001
(III)
with an amine of the formula R4R5NH in base to give the compound of the formula (V):
Figure imgf000105_0002
(V)
followed by reaction of the compound of formula (V) with hydrazine, followed by reaction with ArCHO to yield the compound of formula (Id), wherein R2, R3, R4, and R5are as defined in claim 1.
23. A process for making a compound of formula (le):
Figure imgf000105_0003
(le)
said process comprising reacting a compound of formula (III)
Figure imgf000105_0004
(III)
with a nitrile, represented by ArCH2CN, where Ar is an aryl or heteroaryl radical, in the presence of a strong base, to provide the chloropyrimidine of formula (Via):
Figure imgf000106_0001
followed by reaction of the compound of formula (Via) with an amine of formula R1R6NH to yield the compound of formula (le), wherein R6 is hydrogen and R1, R2, and R3 are as defined in claim 7.
24. A process for making a compound of formula (If):
Figure imgf000106_0002
(if)
said process comprising reacting a compound of formula (III):
Figure imgf000106_0003
(III)
with a boronic acid of formula R4B(OH)2 in the presence of a palladium catalyst and a base to give a chloropyrimidine of formula (Vlb)
Figure imgf000106_0004
followed by reaction of the compound of formula (Vlb) with an amine of the formula R1R6NH, to yield compounds of formula (If), wherein R6 is hydrogen and R1, R2, R3, and R4 are as defined in claim 7.
25. A process for making a compound of formula (Ig)
Figure imgf000107_0001
(ig)
said process comprising reacting a compound of the formula (III)
Figure imgf000107_0002
(III)
with a compound of the formula R1R6NH in a base to give the compound of formula (IV)
Figure imgf000107_0003
followed by reaction of the compound of formula (IV) with a boronic acid of formula R4B(OH)2 in the presence of a palladium catalyst and a base to yield the compound of formula (Ig), wherein R6 is hydrogen and R1, R2, R3, and R4 are as defined in claim 5.
26. A process for making compounds of the formula (Ih)
Figure imgf000108_0001
(Ih)
said process comprising the steps of
(a) reacting a compound of formula (VII)
Figure imgf000108_0002
with DMF-dimethylacetal of formula (VIII)
Figure imgf000108_0003
(VIII)
in a refluxing solvent to give an enaminone intermediate of formula (IX)
Figure imgf000108_0004
(IX)
(b) reacting a compound of formula (X)
Figure imgf000109_0001
(X)
with an amine of the formula R1NH2 with heating in a higher boiling solvent to give the compound of formula (XII)
NH
R1NH NH2
(XII)
(c) reacting the enaminone of formula (IX)
Figure imgf000109_0002
(IX)
with the guanidine of formula (XII) in a protic solvent and a base to yield the compound of formula (Ih), wherein R" is methyl, methoxy, -0-CH2-, fluoro, CN, or N02, and R1 and R2 are as defined in claim 1.
27. A process for making a compound of formula (XV)
Ar'
(XV) said process comprising reacting an aryl or heteroaryl bromide of the formula ArBr with butyllithium to form the aryllithium compound of the formula ArLi, followed be reaction of the compound of formula ArLi with a compound of the formula (XIV)
Figure imgf000110_0001
to yield the compound of formula (XV).
PCT/US2002/030616 2001-09-25 2002-09-25 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer WO2003030909A1 (en)

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