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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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  • C07D495/04—Ortho-condensed systems

Definitions

• Akt and PDKl are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al (2002) Nature Rev. Cancer 2:489; Phillips et al (1998) Cancer 83:41).
• PI3 kinase/ Akt/PTEN pathway is an attractive target for cancer drug development since such agents would be expected to inhibit proliferation, reverse the repression of apoptosis and surmount resistance to cytotoxic agents in cancer cells.
• PI3 kinase inhibitors have been reported (Yaguchi et al (2006) Jour, of the Nat. Cancer Inst.
• Monocyclic heteroaryl radicals include, but are not limited to: 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyridazinyl, 4-pyridazinyl, 5- pyridazinyl, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 2-oxazolyl, A- oxazolyl, 5-oxazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 3-triazolyl, 1-triazolyl, 5- tetrazolyl, 1-tetrazolyl, and 2-tetrazoly
• a "chemotherapeutic agent” is a chemical compound useful in the treatment of cancer.
• chemotherapeutic agents include erlotinib (T ARCEV A®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATEN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), sora
• the prodrugs of this invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, ⁇ -lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs, optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine and other 5-fluorouridine prodrugs which can be converted into the more active cytotoxic free drug.
• cytotoxic drugs that can be derivatized into a prodrug form for use in this invention include, but are not limited to, compounds of the invention and chemotherapeutic agents such as described above.
• a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the PB kinase inhibitors disclosed herein and, optionally, a chemotherapeutic agent) to a mammal.
• a drug such as the PB kinase inhibitors disclosed herein and, optionally, a chemotherapeutic agent
• the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
• the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
• Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
• the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulf
• an inorganic acid such as hydrochloric acid
• Y is O, S, or NR 12 ;
• the compounds of the invention exclude 6-((4- methylsulfonylpiperazin-l-yl)methyl)-4-morpholino-2-(pyrimidin-5-yl)thieno[2,3- d]pyrimidine; 2-( 1 H-imidazol- 1 -yl)-6-((4-methylsulfonylpiperazin- 1 -yl)methyl)-4- morpholinothieno[3,2-d]pyrimidine; 5-(6-((4-methylpiperazin-l-yl)methyl)-4- morpholinothieno[3,2-d]pyrimidin-2-yl)pyridin-3-ol; 6-((4-methylpiperazin-l-yl)methyl)-4- morpholino-2-( 1 H-pyrazol-4-yl)thieno [3 ,2-d]pyrimidine; 6-((4-methylsulfonylpiperazin- 1 - yl)methyl)-4-morpholino-2-( 1
• the Formula Ia-d compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
• isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• Compounds of Formula Ia-d may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds.
• Libraries of compounds of Formula Ia-d may be prepared by a combinatorial 'split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
• a compound library comprising at least 2 compounds, or pharmaceutically acceptable salts thereof.
• the palladium catalyst may be any that is typically used for Suzuki-type cross-couplings, such as PdCl 2 (PPh 3 ) 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf)-DCM, Pd 2 (dba) 3 /Pt-Bu) 3 (Owens et al (2003) Bioorganic & Med. Chem. Letters 13:4143-4145; Molander et al (2002) Organic Letters 4(l l):1867-1870; US 6448433). [00135] METHODS OF SEPARATION
• a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ - (trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165), of the racemic mixture, and analyzing the 1 H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers.
• chiral esters such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ - (trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165), of the racemic mixture, and analyzing the 1 H NMR spectrum for the presence of the two at
• ADME properties were measured for certain exemplary compounds by assays including: Caco-2 Permeability (Example 349), Hepatocyte Clearance (Example 350), Cytochrome P450 Inhibition (Example 351), Cytochrome P450 Induction (Example 352), Plasma Protein Binding (Example 353), and hERG channel blockage (Example 354).
• Exemplary Formula Ia-d compounds No. 101 -318 in Table 1 and No. 319-429 in Table 2 which were made according to the methods of this invention, have the following structures and their corresponding names (ChemDraw Ultra, Version 9.0.1, CambridgeSoft Corp., Cambridge MA) in Tables 1 and 2.
• Diseases and conditions treatable according to the methods of this invention include, but are not limited to, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone- related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, and CNS disorders in a patient.
• CML chronic myelogenous leukemia
• the formulations may be prepared using conventional dissolution and mixing procedures.
• the bulk drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above.
• the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
• the formulations include those suitable for the administration routes detailed herein.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
• the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w.
• the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
• the active ingredients may be formulated in a cream with an oil-in- water cream base.
• Aqueous suspensions of Formula Ia-d compounds contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbit
• the in vivo metabolic products of Formulas Ia-d described herein include metabolites of compounds of Formulas Ia-d, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
• Metabolite products typically are identified by preparing a radiolabeled (e.g.,
• metabolites In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art.
• the metabolite products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
• a free carboxyl group of a compound of Formula Ia-d can be derivatized as an amide or alkyl ester.
• compounds of this invention comprising free hydroxy groups may be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Advanced Drug Delivery Reviews, (1996) 19:115.
• Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
• More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1 -methyl- 1 -((C i-C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N-(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C ]-C 6 )al
• the kit may further comprise directions for the administration of the compound of Formula Ia-d and, if present, the second pharmaceutical formulation.
• the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.
• Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and were used without further purification unless otherwise indicated.
• the reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
• Column chromatography was conducted on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or on a silica SEP PAK® cartridge (Waters). 1 H NMR spectra were recorded on a Varian instrument operating at 400 MHz.
• Example 35 5-(7-methyl-6-((4-(methylsulfonyl)pi ⁇ eridin-l- yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyridin-2-amine 118
• 2-Chloro-6-(4-methanesulfonyl-piperidin- 1 -ylmethyl)-4-morpholin-4-yl- thieno[3,2-d]pyrimidine (Example 34) was reacted with 2-amino-pyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 118.
• Example 43 4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperazine- 1 -carboxamide 126
• Reaction between 2-chloro-7-methyl-4-morpholin-4-yl-thieno [3 ,2- d]pyrimidine-6-carbaldehyde and piperazine-1-carboxylic acid dimethylamide (Example 26) using General Procedure B-3 yielded 4-(2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2- d]pyrimidin-6-ylmethyl)-piperazine-l-carboxylic acid dimethylamide.
• Procedure B-3 yielded 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)- piperazin- 1 -yl] -N-methyl-isobutyramide .
• Example 90 2-(4-((2-(2-aminopyrimidin-5-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-l-yl)-N,2-dimethylpropanamide
• Example 92 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperazine- 1 -carboxamide 175
• Example 94 N,2-dimethyl-2-(4-((2-(6-methylpyridin-3-yl)-4- morpholinothieno [3 ,2-d]pyrimidin-6-yl)methyl)piperazin- 1 -yl)propanamide 177 [00455] 2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)- piperazin-l-yl]-N-methyl-isobutyramide (Example 88) was reacted with 2-methyl-5-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridine via General Procedure A.
• Procedure D-2 (720 mg) was reacted with Boc-piperazine via General Procedure B-4 to generate tert-butyl 4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazine- 1-carboxylate.
• Tert-butyl 4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6- yl)methyl)piperazine-l-carboxylate (1.1 g) was converted via General Procedure D to the HCl salt of 2-chloro-4-morpholino-6-((piperazin-l-yl)methyl)thieno[2,3-d]pyrimidine.
• Example 108 5-(7-methyl-4-morpholino-6-((4-N- methylsulfonylpiperazin-l-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine 191
• 2-Chloro-6-((4-methylsulfonylpiperazin-l-yl)methyl)-4- morpholinothieno[3,2-d]pyrimidine from Example 133 (2.24 mmol) was reacted using General Procedure A: Suzuki Coupling which was worked up by filtering off precipitate, dissolving it in IM HCl, basification of the resulting aqueous layer with NaHCO 3 , extraction with EtOAc and DCM, drying over MgSO 4, and concentrating in vacuo to give 191 in 88% yield (no further purification necessary).
• Example 3 (200 mg) was used according to General Procedure B-3 with (S)-4-N-trityl-2- methyl-piperazine.
• the crude product was then dissolved in 10 mL of methanol and reacted with 0.5 mL of concentrated HCl for several hours before basifying with NaOH and extracting into EtOAc. After evaporation the crude reaction mixture containing 200 mg of 2- chloro-6-(((S)-2-methylpiperazin- 1 -yl)methyl-4-morpholinothieno [3 ,2-d]pyrimidine was reacted with lactic acid via General Procedure B-2.
• Example 114 5-(6-((l-methylpiperidin-4-ylamino)N- methylaminomethyl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyridin-2-amine 197 [00502] N-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N, 1 - dimethylpiperidin-4-amine following Example 115 (0.23 mmol) was reacted using General
• Example 118 (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin- 1 -yl)-2-hydroxypropan- 1 -one 201
• 2-Chloro-7-methyl-4-mo ⁇ holinothieno[3,2-d]pyrimidine-6-carbaldehyde (495 mg) was reacted with Boc-piperazine via General Procedure B-3 to give tert-butyl 4-((2- chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-l-carboxylate.
• Example 132 N-(5 -(4-morpholino-6-((4-N-methylsulfonylpiperazin- 1 - yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)acetamide 215
• Compound 221 from Example 138 (1.0 eq) was treated with 60 eq of acetyl chloride in pyridine (-0.1M) at 80 °C. The reaction was stirred until complete. Water/methanol (1:1) were added and the mixture was concentrated to yield the crude intermediate. This intermediate was purified by reverse phase HPLC to yield 13 mg of 215.
• Example 134 7-methyl-4-morpholino-6-((4-N- methylsulfonylpiperazin-l-yl)methyl)-2-(pyridin-3-yl)thieno[3,2-d]pyrimidine 217
• 2-Chloro-6-((4-methylsulfonylpiperazin- 1 -yl)methyl)-4- morpholinothieno[3,2-d]pyrimidine from Example 133 (0.24 mmol) was reacted using General Procedure A: Suzuki Coupling to give 217 (TFA salt) in 25% yield after reverse- phase HPLC purification. MS (Ql) 489 (M)+.
• Example 140 N-(5-(4-morpholino-6-((4-N-methylsulfonylpiperazin-l- yl)methyl)furo[3,2-d]pyrimidin-2-yl)pyridin-2-yl)acetamide 223
• Example 141 4-morpholino-6-((4-N-methylsulfonylpiperazin-l- yl)methyl)-2-(pyridin-3-yl)furo[3,2-d]pyrimidine 224
• Example 143 (5-(4-morpholino-6-((4-N-methylsulfonylpiperazin-l- yl)methyl)thieno[3,2-d]pyrimidin-2-yl)furan-2-yl)methanol 226

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