Classifications

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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
• • 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
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—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
  • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—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
  • C07D405/02—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 two hetero rings
  • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • 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
  • C07D409/02—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
  • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • 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
  • C07D409/02—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

Definitions

• This invention relates generally to novel 5- substituted-indeno [1, 2-c]pyrazol-4-ones which are useful as cyclin dependent kinase (cdk) inhibitors, pharmaceutical compositions comprising the same, methods for using the same for treating proliferative diseases, and intermediates and processes for making the same.
• cdk cyclin dependent kinase
• kinase catalytic subunit
• cyclin regulatory subunit
• Each transition of the cell cycle is regulated by a particular cdk complex: Gl/S by cdk2 /cyclin E, cdk4/cyclin Dl and cdk6/cyclinD2 ; S/G2 by cdk2/cyclin A and cdkl/cyclin A; G2/M by cdkl/B.
• the coordinated activity of these kinases guides the individual cells through the replication process and ensures the vitality of each subsequent generation (Sherr, Cell 73:1059- 1065, 1993; Draetta, Trends Biochem. Sci. 15:378-382, 1990) An increasing body of evidence has shown a link between tumor development and cdk related malfunctions.
• inhibitors include pl6 IN ⁇ 4 (an inhibitor of cdk4/Dl), p21 CIP1 (a general cdk inhibitor), and p27 KIP1 (a specific cdk2/E inhibitor) .
• pl6 IN ⁇ 4 an inhibitor of cdk4/Dl
• p21 CIP1 a general cdk inhibitor
• p27 KIP1 a specific cdk2/E inhibitor
• the present invention describes a novel class of indeno [1, 2-c]pyrazol-4-ones or pharmaceutically acceptable salt forms thereof that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk 1-7 and their regulatory subunits know as cyclins A-H.
• the present invention is also directed to a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof .
• a novel method of treating cancer or other proliferative diseases which comprises administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents is also described herein.
• the present invention also describes compounds of formula (I) :
• Ri, R2 and X are defined below or pharmaceutically acceptable salts thereof as cyclin dependent kinase inhibitors .
• the invention pertains to novel cyclin dependent kinase inhibitors (cdks) and specifically, but not exclusively, as inhibitors of cdk/cyclin complexes.
• the inhibitors of this invention are indeno [1, 2-c]pyrazol-4-one analogs. Certain analogs were selective for their activity against cdks and their cyclin bound complexes and were less active against other known serine/threonine kinases such as Protein Kinase A (PKA) and Protein Kinase C (PKC) . In addition, these inhibitors were less active against tyrosine kinases such as c-Abl.
• the inhibitors of this invention are capable of inhibiting the cell-cycle machinery and consequently would be useful in modulating cell-cycle progression, which would ultimately control cell growth and differentiation.
• Such compounds would be useful for treating subjects having disorders associated with excessive cell proliferation, such as the treatment of cancer, psoriasis, immunological disorders involving unwanted leukocyte proliferation, in the treatment of restinosis and other smooth muscle cell disorders, and the like.
• the present invention in a first embodiment, describes a novel compound of formula (I) :
• X is selected from the group: 0, S, and NR;
• R is selected from the group: H, Ci-4 alkyl, and NR ⁇ R ⁇ a.
• R 1 is selected from the group: H, Ci-io alkyl substituted
• R2 is selected from the group: H, Ci-io alkyl substituted
• R is selected from the group: H, halo, -CN, NO2 , C ⁇ _4
• (CF2)m F3 C3-10 carbocycle substituted with 0-5 R 6 , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from 0, N, and S, substituted with
• R ⁇ is independently at each occurrence selected from the group: H, -CN, C ⁇ _4 alkyl, C ⁇ _4 haloalkyl, NR 3 R 3a , NR 3 C(0)OR 3 , NR 3 C(0)R 3 , OR 3 , COR 3 , CO2R 3 , CONR 3 R 3a , NHC(0)NR 3 R 3a , NHC(S)NR 3 R 3a , S ⁇ 2NR 3 R 3a , S ⁇ 2R 3b , C3-10 carbocycle substituted with 0-5 R a , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected
• R 3 3 provided that at least one R is present and that this R is selected from the group: Ci-4 alkyl substituted with 1-
• R is independently at each occurrence selected from the group: halo, -CN , N 3 , NO2 / C1-4 alkyl, C1-4
• NR 3 R 3a 0, OR 3 , COR 3 , CO2R 3 , CONR 3 R 3a , NHC(0)NR 3 R 3a , NHC (S)NR 3 R 3a , NR 3 C(0)OR 3 , NR 3 C(0)R 3 , S ⁇ 2NR 3 R 3a , S ⁇ 2 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from 0, N, and S;
• R is independently at each occurrence selected from the group: halo, -CN, NO2 , C1-4 alkyl, C1-4 haloalkyl,
• NR 3 R 3a NR 3 C(0)OR 3 , NR 3 C(0)R 3 , OR 3 , COR 3 , C02R 3 , CONR 3 R 3a , NHC(0)NR 3 R 3a , NHC (S) NR 3 R 3a , S02NR 3 R 3 , and S02R 3b ;
• R is independently at each occurrence selected from the group: halo, -CN, N ⁇ 2 C1-4 alkyl, C1-4 haloalkyl,
• NR 3 R 3a , NR 5 NR 5 R 5a , NR 3 C(0)OR 3 , ,NR 3 C(0)R 3 , 0, OR 3 , COR 3 , C02R 3 , CONR 3 R 3a , NHC(0)NR 3 R 3a , NHC (S)NR 3 R 3 , S ⁇ 2NR 3 R 3a , S ⁇ 2R 3b , C3-10 carbocycle substituted with
• R 3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl ;
• R 3 and R 3a together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring containing an additional 0-1 N,
• R is selected from the group: H, C1-4 alkyl, phenyl, and benzyl ;
• R 3c is independently at each occurrence selected from the group: halo, -CN , N 3 , NO2 / C1-4 alkyl, C1-4
• NHC(0)NR 3 R 3b NHC(S)NR 3 R 3 , NR 3 C(0)OR 3 , NR 3 C(0)R 3 , S02NR 3 R 3 , S ⁇ 2R 3b , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from 0, N, and S;
• R 5 is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;
• R 5a is independently selected from the group: H, C ⁇ _4 alkyl, phenyl and benzyl;
• R 5b is independently selected from the group: H, C ⁇ _4 alkyl, phenyl and benzyl;
• R is independently at each occurrence selected from the group: halo, -CN, O2 , C ⁇ _4 alkyl, C1-4 haloalkyl,
• NR 5 R 5 , NR 5 NR 5 R 5a , NR 5 C(0)OR 5 , NR 5 C(0)R 5 , 0, OR 5 , COR 5 , C02R 5 , CONR 5 R 5 , NHC(0)NR 5 R 5a , NHC (S) NR 5 R 5a , S ⁇ 2NR 5 R 5a ,
• n is selected from 0, 1, 2, and 3.
• the compounds of formula (I) are selected from:
• Another embodiment of the present invention is a pharmaceutical composition
• a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) .
• Another embodiment of the present invention is a method of treating cancer and proliferative diseases comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically effective salt form thereof.
• the compounds of the present invention may contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art h ⁇ w to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
• alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms .
• alkyl include, but are not limited to, methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
• alkyl moieties having one or more hydrogen substituents replaced by, but not limited to halogen, hydroxyl, carbonyl, alkoxy, ester, ether, cyano, phosphoryl, amino, imino, amido, sulfhydryl, alkythio, thioester, sulfonyl, nitro, heterocyclo, aryl or heteroaryl . It will also be " understood by those skilled in the- art that the substituted moieties themselves can be substituted as well when appropriate.
• halo or halogen as used herein refer to fluoro, chloro, bromo and iodo.
• aryl is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as, but not limited to phenyl, indanyl or naphthyl.
• cycloalkyl and “bicycloalkyl” are intended to mean any stable ring system, which may be saturated or partially unsaturated.
• Examples of such include, but are not limited to; cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo [2.2.2]nonane, adamantly, or tetrahydronaphthyl (tetralin) .
• carrier or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocycl/ic or bicyclic or 7- to 13-membered bicyclic or tricyclic, (any of which may be saturated, partially unsaturated, or aromatic.
• carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, ; [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0]bicyclodecane (decalin) , [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) .
• heterocycle or “heterocyclic system” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic' rings is fused to a benzene ring.
• the nitrogen and sulfur heteroatoms may optionally be oxidized.
• the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
• heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1.
• aromatic heterocyclic system is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
• heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5, 2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-1, 2 , 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinol,
• Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non- toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference .
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic, response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
• Prodrugs are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (i.e., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same, and compositions containing the same. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
• Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfydryl group, respectively.
• Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
• Substituted is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group (s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
• anti cancer or "anti- proliferative" agent includes, but is not limited to, altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide,
• Another method for preparing the triketones 6 of Scheme 2 employs the condensation of a 1,3-diketone 6a with 3- nitrophthalic anhydride as described in Rotberg and Oshkaya, Zh. Organ. Khim. 8:84-87, 1972; Zh. Organ. Khi . 9:2548- 2550, 1973, the contents of " which are hereby incorporated herein by reference.
• the 1, 3-diketones when not commercially available can be readily prepared by one skilled in the art by the acetylation or trifluoroacetylation of the requisite methyl ketone, R 1 C0CH 3 .
• Reduction of the nitro derivative 6b to the aniline 6c can be accomplished in a variety of ways including catalyic hydrogenation, treatment with zinc or iron under acidic conditions, or treatment with other reducing agents such as sodium dithionite or stannous chloride. Subsequently the aniline 6c can be converted to the indeno [1, 2-c]pyrazol-4- ones of this invention by acylation followed by treatment with hydrazine as described previously in Scheme 2.
• Step 1 Synthesis of 2 from dimethyl 3-nitrophthalate.
• the solution was filtered (Celite) , the filtrate collected and the solvent removed at reduced pressure.
• the residue was dissolved in acetic anhydride (20 mL) treated with pyridine (0.05mL) and heated to 80 °C for 1 min. The reaction was cooled and stirred at 25°C for 2 h.
• Step 1 Synthesis of 13 from 12.
• a suspension of 12 (1.0 g, 3.0 mmol) in MeOH (10 mL) was treated with cone. HCI (1 mL) and heated to reflux. After 2 h, the reaction was cooled and the product was collected as a greenish solid (0.7 g, 81%).
• Example V Preparation of 3- (4-methoxyphenyl) -5- (ethylamido) indeno [1, 2- c]pyrazol-4-one Prepared in a similar fashion as described for example II using propionyl chloride as the starting material, mp 287 °C; CIMS m/e calc'd for C20HI8N3O3: 348.1348, found: 348.1313.
• Example X Preparation of 3- (4-methoxyphenyl) -5- ( (4- chlorophenyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example II using 4-chlorophenylacetyl chloride as the starting material, mp 238 °C; CIMS m/e calc'd for C25H19N3O3CI : 444.1115, found: 444.1110.
• Example XIII Preparation of 3- (4-methoxyphenyl) -5- ( (3 , 4- dimethoxyphenyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example II using 3 , 4-dimethoxyphenylacetyl chloride as the starting material, mp >300 °C; CIMS m/e calc'd for C27H24N3O5: 470.1716, found: 470.1731.
• Example XIV Preparation of 3- (4-methoxyphenyl) -5- ( (2, 5- dimethoxyphenyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example II using 2 , 5-dimethoxyphenylacetyl chloride as the starting material, mp 226 °C; CIMS m/e calc'd for C27H24N3O5: 470.1716, found: 470.1739.
• Example XV Preparation of 3- (2-methoxyphenyl) -5- (acetamido) indeno [1, 2- c]pyrazol-4-one Prepared in a similar fashion as described for example I using 2-methoxyacetophenone as the- starting material, mp ⁇ 276 °C; CIMS m/e calc'd for C19H16N3O3 : 334.1192, found: 334.1169.
• Example XVI Preparation of 3- (3 , 4-dimethoxyphenyl) -5- (acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example I using 3 , 4-dimethoxyacetophenone as the starting material, mp >300 °C; CIMS m/e calc'd for C20HI8N3O4: 364.1297, found: 364.1288.
• Example XIX Preparation of 3- (4-methoxyphenyl) -5- ( (2- methoxyphenyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XVII using the acid chloride of 2-methoxyphenylacetic acid as the starting material, mp 255 °C; CIMS m/e calc'd for C26H22N3O4: 440.1610, found: 440.1622.
• Example XXII Preparation of 3- (4-methoxyphenyl) -5- ( (2- chlorophenyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XVII using the acid chloride of 2-chlorophenylacetic acid as the starting material, mp 300 °C; CIMS m/e calc'd for C25H19N3O3CI: 444.1115, found: 444.1111.
• Example XXVII Preparation of 3- (4-methoxyphenyl) -5- (4- methylpiperazinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using 4-methylpiperizine as the starting material, mp >300 °C; CIMS m/e calc'd for C24H26N5O3: 432.2036, found: 432.2030.
• Example XXVIII Preparation of 3- (4-methoxyphenyl) -5- (4- (2- hydroxyethyl)piperazinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using 4-hydroxyethylpiperizine as the starting material, mp >300 °C; CIMS m/e calc'd for C25H28N5O4: 462.2141, found: 462.2128.
• Example XXX Preparation of 3- (4-methoxyphenyl) -5- (4- aminomethylpiperidinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using 4-aminomethylpiperidine as the starting material, mp >300 °C; CIMS m/e calc'd for C25H28 5O3 : 446.2192, found: 446.2166.
• Example XXXIX Preparation of 3- (4-methoxyphenyl) -5- ( (4-N,N- dimethylaminomethylcarbonylaminophenyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII and XXXII using chloroacetyl chloride and dimethyl amine as the starting materias. mp >300 °C; CIMS m/e calc'd for C29H28N5O4: 510.2141, found: 510.2121.
• Example XLI Preparation of 3- (4-methoxyphenyl) -5- ( (4- aminophenyl) acetamido) ⁇ ndeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXVII using the acid chloride of 4-azidophenylacetic acid as the starting material, mp 283°C; CIMS m/e calc'd for C25H21N4O3: 425.1614, found: 42,5.1643.
• Example XLIV Preparation of 3- (4-methoxyphenyl) -5- (4- aminobenzylcarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XLII using 4-aminobenzyl amine as the starting material. ( mp >300 °C; CIMS m/e calc'd for C25H22N5O3: 440.1723, found: 440.1700.
• Example L Preparation of 3- (4-pyridyl) -5- (formamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XLVII using 4-acetylpyridine as the starting material, mp >300 °C; CIMS m/e calc'd for C16H11N4O2 : 291.0882, found: 291.0882.
• Example LV Preparation of 3- (4-N,N-dimethylaminophenyl) -5- (morpholinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and morpholine as the starting materials, mp >300 °C; CIMS iii/e calc'd for C24H26N5O3: 432.2036, found: 432.2020.
• Example LXIII Preparation of 3- (4-methoxyphenyl) -5- carbamoylaminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XLII using concentrated ammonium hydroxide as the starting material, mp >300 °C; CIMS m/e calc'd for C18H15 4O3 : 335.1144, found: 335.1113.
• Example LXV Preparation of 3- (4--methoxyphenyl) -5- (methylcarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XLII using methylamine as the starting material, mp >300 °C; CIMS m/e calc'd for C19H17N4O3 : 349.1300, found: 349.1311.
• Example LXVIII Preparation of 3- (4-methoxyphenyl) -5- (4- methylpiperazinylcarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XLII using (4-amino)methylpiperazine as the starting material, mp >300 °C; CIMS m/e calc'd for C23H25N6O3 : 433.1987, found: 433.1999.
• Example LXIX Preparation of 3- (4-methoxyphenyl) -5- (4- uridomethylpiperadinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using example XXX as the starting material, mp >300 °C; CIMS m/e calc'd for C26H29N6O4: 489.2250, found: 489.2209.
• Example LXX Preparation of 3- (4-methoxyphenyl) -5- (4- (2- pyridyl)piperazinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using 4- (2-pyridyl)piperazine as the starting material, mp >300 °C; CIMS m/e calc'd for C28H27N6O3: 495.2144, found: 495.2111.
• Example LXXI Preparation of 3- (4-methoxyphenyl) -5- (4- (2- pyridyl)piperazinylacetamido) indeno [1, 2-c]pyrazol-4-one
• Example LXXIII Preparation of 3- (4-methoxyphenyl) -5- (4- hydroxypiperadinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using 4-hydroxypiperadine as the starting material, mp >300 °C; CIMS m/e calc'd for C24H25N4O4: 433.1875, found: 433.1844.
• Example LXXVII Preparation of 3- (4-methoxyphenyl) -5- (4- aminopiperadinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using 4-aminopiperadine as the starting material, mp >300 °C; CIMS m/e calc'd for C24H26N5O5: 464.1933, found: 46411975.
• Example LXXX Preparation of 3- (4- (dimethylamino) phenyl) -5- ( (4-hydroxy-l- piperidinyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for examples II and XXIII employing the product of example LIV and 4- hydroxypiperidine as the starting materials, mp 267 °C; ESI- MS m/e calc'd for C25H28N5O3: 446.2192, found: 446.2206.
• Example LXXXI Preparation of 3- (4- (4-morpholinyl)phenyl) -5- (4- morpholinyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and morpholine as the starting materials, mp 258 °C; ESI-MS m/e calc'd for C26H28N5O4: 474.2141, found: 474.2151.
• Example LXXXIV Preparation of 3- (4- (4-morpholinyl) phenyl) -5- ( (4-amino methyl-1-piperidinyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for examples II and XXIII employing the product of example LVIII and 4- (aminomethyl) piperidine as the starting materials, mp 240 °C; ESI-MS m/e calc'd for C28H33N6O3 : 501.2614, found: 501.2619.
• Example LXXXV Preparation of 3- (4- (dimethylamino) phenyl) -5- ( ( ( (4-methyl-l- piperazinyl) amino) carbonyl) amino) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for examples I, XXVII, and XLII employing the 4- (dimethylamino) acetophenone and l-amino-4-methylpiperazine as the starting materials, mp >300 °C; ESI-MS m/e calc'd for C24H28 7O2: 446.2304, found: 446.2310.
• Step 1 Synthesis of 26 from 3-nitrophthalic anhydride.
• a solution of 3-nitrophthalic anhydride (9.7 g, 50 mmol) and 1, 1, 1-trifluoro-5-methyl-2 , 4-hexanedione (9.1 g, 50 mmol) in acetic anhydride (28.3 mL, 300 mmol) was treated with triethylamine (13.95 mL, 100 mmol) and stirred at 25 °C for 4 h.
• the solution was diluted with 1 N HCI (200 mL) and the precipate collected and washed with water (200 mL) and hexane (400 mL) to give the product as a yellow solid (11.1 g, 85%).
• mp 127-129 °C; CIMS (M+H) calc'd for C13H12NO5 : 262.0715, found: 262.0694.
• Step 4 Synthesis of 29 from 28.
• a solution of 28 (240 mg, 0.88 mmol) in BuOH (5 mL) was treated with hydrazine hydrate (0.055 mL, 1.76 mmol) and p- TsOH (8.4 mg, 0.044 mmol).
• the reaction was heated to reflux and stirred for 4 h.
• the reaction was cooled to 25 °C and the solvent removed at reduced pressure. Recrystalization with i-propyl alcohol gave the product collected as an off- white solid (173 mg, 73%). mp >250 °C;
• ESIMS (M+H) calc'd for C15H16N3O2: 270.1242, found: 270.1258.
• Example XC Preparation of 3- (3-methyl-2-thienyl) -5- ( cetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using the 3-methyl-2-thienyl analog of 26 as the starting material, mp 275 °C; ESIMS (M+H) calc'd for C17H14N3O2S: 324.0811, found: 324.0807.
• Example XCIV Preparation of 3- (c-propyl) -5- (carbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using ammonia and the c-propyl analog of 15 as the starting materials, mp 252-253 °C; ESIMS (M-H) calc'd for C14H11N4O2: 267.0881, found: 267.0884.
• Example XCVIII Preparation of 3- (5-methyl-2-thienyl) -5- (carbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using ammonia and the 5-methyl-2 -thienyl analog of 15 as the starting materials, mp >280 °C; ESIMS (M+H) calc'd for C16H13N4O2S: 325.0759, found: 325.0761.
• Example CVI Preparation of 3- (c-hexyl) -5- (N,N- dimethylaminocarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using.1, 1-dimethylhydrazine and the c-hexyl analog of 15 as the starting materials, mp 229-231 °C; ESIMS (M+H) calc'd for C19H24N5O2 354.1929, found: 354.1932.
• Example CVII Preparation of 3- (2-thienyl) -5- (N,N- dimethylaminocarbamoyl ) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using 1, 1-dimethylhydrazine and the 2-thienyl analog of 15 as the starting materials, mp 279 °C; ESIMS (M+H) calc'd for C17H16 5O2S: 354.1024, found: 354.1025.
• Example CIX Preparation of 3- (5-methyl-2-thienyl) -5- (N,N- dimethylaminocarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using 1, 1-dimethylhydrazine and the 5-methyl-2- thienyl analog of 15 as the starting materials, mp >280 °C; ESIMS (M+H) calc'd for C18H18N5O2S: 368.1181, found: 368.1171.
• Example CXIII Preparation of 3- (2 , 5-dimethyl-3-thienyl) -5- (N,N- dimethylaminocarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using 1, 1-dimethylhydrazine and the 2 , 5-dimethyl-3- thienyl analog of 15 as the starting materials, mp 252 °C; ESIMS (M+H) calc'd for C19H20N5O2S: 382.1338, found: 382.1357.
• Example CXV Preparation of 3- (i-propyl) -5- (4- carbamoylpiperidinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using isonipecotamide and the i-propyl analog of 14 as the starting materials, mp 224-225 °C; ESIMS (M+H) calc'd for C21H26N5O3: 396.2035, found: 396.2036.
• Example CXVI Preparation of 3- (c-hexyl) -5- (4- carbamoylpiperidinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using isonipecotamide and the c-hexyl analog of 14 as the starting materials, mp 228-229 °C; ESIMS (M+H) calc'd for C24H30N5O3: 436.2348, found: 436.2345.
• Example CXVII Preparation of 3- (ethyl) -5- (4- aminomethylpiperidinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using 4- (aminomethyl)piperidine and the ethyl analog of 14 as the starting materials, mp 174-176 °C; ESIMS (M+H) calc'd for C20H26N5O2: 368.2086, found: 368.2078.
• Example CXX Preparation of 3- (c-hexyl) -5- (4- aminomethylpiperidinylacetamido) indeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example XXIII using 4- (aminomethyl) piperidine and the c-hexyl analog of 14 as the starting materials, mp 196-198 °C; ESIMS (M+H) calc'd for C24H32N5O2: 422.2555, found: 422.2540.
• Example CXXI Preparation of 3- (i-propyl) -5- (4- methylpiperazinylcarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using l-amino-4-methylpiperazine and the i-propyl analog of 15 as the starting materials, mp 231-233 °C; ESIMS (M+H) calc'd for C19H25N6O2 : 369.2038, found: 369.2039.
• Example CXXVIII Preparation of 3- (5-chloro-3-thienyl) -5- (morpholinylcarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI using 4-aminomorpholine and the 5-chloro-3 -thienyl analog of 15 as the starting materials, mp 259 °C; ESIMS (M+H) calc'd for C19H17N5O3SCI : 430.0741, found: 430.0757.
• Example CXXXI Preparation of 3- (5-carboxyl-2-thienyl) -5- (morpholinylcarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one Prepared in a similar fashion as described for example LXXXVI (HYDROLYSIS OF PREVIOUS ESTER) . mp 273 °C; ESIMS (M+H) calc'd for C20HI8N5O5S: 440.1028, found: 440.1026.
• Example CXXXII Preparation of 3- (5-benzylcarboxamido-2-thienyl) -5- (morpholinylcarbamoyl) aminoindeno [1, 2-c]pyrazol-4-one
• a solution of benzylamine (0.01 mL, 0.09 mmol) in DMF (1 mL) was treated with acid CXXXI (40 mg, 0.09 mmol) and stirred at 25 °C.
• the reaction was treated with TBTU (29 mg, 0.09 mmol) and stirred at 25 °C for 30 min.
• Triethylamine (0.01 mL, 0.09 mmol) was added and the reaction stirred at 25 °C for 12 h.
• Example CXXXVI Preparation of 3- (5- (2- (N,N-dimethylamino) ethyl) carboxamido- 2-thienyl) -5- (morpholinylcarbamoyl) aminoindeno [1, 2- c]pyrazol-4-one Prepared in a similar fashion as described for example CXXXII using N,N-dimethylethylenediamine as the starting material, mp 190 °C; ESIMS (M+H) calc'd for C24H28N7O4S: 510.1923, found: 510.1922.
• Example CLIV Preparation of 3- (4- (1-piperazinyl) phenyl) -5- ( (4-amino methyl-1-piperidinyl) acetamido) indeno [1, 2-c]pyrazol-4-one Prepared employing 2- (4- (4-t-butoxycarbonyl-l- piperazinyl) benzoyl) -4-amino-l, 3-indanedione obtained in example CXLVII as the starting material.
• Boisclair, M. Burton, C.R.; Cox, S.; Czerniak, P.M.;
• Example CLXXII The product prepared in Example CLXXII (0.03 g, 0.072 mmol) in anhydrous DMSO (2 mL) is treated with 4- aminomorpholine (0.0084g, 0.082 mmol) and 4- dimethylaminopyridine (0.005 g, 0.04 mmol) and heated to 80 °C for 3h. The solvent is removed under reduced pressure and the residue triturated with ethanol to give a dark solid. The solid is collected and washed with ethanol (5 mL) to give a tricarbonyl urea (0.03 g, 100%).
• the tricarbonyl urea intermediate (0.03 g, 0.078 mmol) is treated with hydrazine hydrate (0.1 L, 3.21 mmol) and' p-toluenesulfonic acid / monohydrate (0.01 g, 0.05 mmol) in refluxing ethanol (4 mL) for a period of 3 h.
• the reaction mixture is cooled to room temperature, the solid collected, washed with cold ethanol (2 2 mL) , and air dried to, give the product as a yellowish solid (0.012 g, 41.3%).
• Example CLXXII The product prepared in Example CLXXII (0.03 g, 0.072 mmol) in anhydrous DMSO (2 mL) is treated with excess ammonium hydroxide solution and 4-dimethylaminopyridine (0.005 g, 0.04 mmol) and is heated to 80 °C for 3h. The solvent is removed under reduced pressure and the residue triturated with ethanol to give a dark solid. The solid is collected and washed with ethanol (5 mL) to give urea (0.03 g, 100%).
• the tricarbonyl urea intermediate (0.03 g, 0.078 mmol) is treated with hydrazine hydrate (0.1 mL, 3.21 mmol) and p-toluenesulfonic acid monohydrate (0.01 g, 0.05 mmol) in refluxing ethanol (4 mL) for a period of 3 h.
• the reaction mixture is cooled to room temperature, the solid collected, washed with cold ethanol (2 x 2 mL) , and air dried to give the product as a yellowish solid (0.018 g, 62.4%).
• Example CLXXII The product prepared in Example CLXXII (0.03 g, 0.072 mmol) in anhydrous DMSO (2 mL) is treated with 1,2- diaminocyclohexane (O.Olg, 0.082 mmol) and 4- dimethylaminopyridine (0.005 g, 0.04 mmol) and heated to 80 °C for 3h. The solvent is removed under reduced pressure and the residue triturated with ethanol to give a dark solid. The solid is collected and washed with ethanol (5 mL) to give a tricarbonyl urea (0.03 g, 100%).
• 1,2- diaminocyclohexane O.Olg, 0.082 mmol
• 4- dimethylaminopyridine 0.005 g, 0.04 mmol
• the tricarbonyl urea intermediate (0.03 g, 0.078 mmol) is treated with hydrazine hydrate (0.1 mL, 3.21 mmol) and p-toluenesulfonic acid monohydrate (0.01 g, 0.05 mmol) in refluxing ethanol (4 mL) for a period of 3 h.
• the reaction mixture is cooled to room temperature, the solid collected, washed with cold ethanol (2 x 2 mL) , and air dried to give the product as a yellowish solid (0.01 g, 30.6%).
• Example CLXXVI A suspension of the product prepared in Example CLXXVI (0.2 g, 0.7 mmol) in dioxane (10 mL) was treated with aqueous saturated NaHC0 3 (3 mL) and chloroacetyl chloride (3 mL, 0.21 mmol). The reaction was heated to 50°C and stirred for 2 h. The reaction is then cooled, poured into water (20 mL) , extracted with EtOAc (100 mL) , the organic layer separated, dried (MgS0 4 ) and the solvent removed at reduced pressure. The residue is recrystallized from EtOH to give the product as a yellow solid (0.09 g, 35%) .
• the cdk/cyclini lysate is combined in a microtitre-type plate along with a kinase compatible buffer, ⁇ >-labeled ATP at a concentration of 50 mM, a GST-Rb fusion protein and the test compound at varying concentrations.
• the kinase reaction is allowed to proceeded with the radiolabled ATP, then effectively stopped by the addition of a large excess of EDTA and unlabeled ATP.
• the GST-Rb labeled protein is sequestered on a GSH-Sepharose bead suspension, washed, resuspended in scintillant, and the 2 activity detected in a scintillation counter.
• the compound concentration which inhibits 50% of the kinase activity was calculated for each compound. A compound was considered active if its IC50 was found to be less than 1 ⁇ M.
• HCT116 cells are cultured in the presence of test compounds at increasing concentrations.
• groups of cells are fixed with trichloroacetic acid and stained with sulforhodamine B (SRB) . Unbound dye was removed by washing and protein-bound dye was extracted for determination of optical density.
• SRB sulforhodamine B

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