Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the present invention comprises a novel class of thieno[2,3-d
• the present invention also comprises methods of treating a subject by administering a therapeutically effective amount of a compound of Formula I to the subject. In general, these compounds, in whole or in part, inhibit ADP- mediated platelet aggregation.
• the present invention further comprises methods for making the' compounds of Formula I and corresponding intermediates.
• Thrombosis is a pathological process in which a platelet aggregate and/or a fibrin clot occludes a blood vessel.
• Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery.
• Venous thrombosis may cause edema and inflammation in the tissue drained by the vein.
• Compounds that inhibit platelet function can be administered to a patient to decrease the risk of occlusive arterial events in patients suffering from or susceptible to atherosclerotic cardiovascular, cerebrovascular and peripheral arterial diseases.
• cycloxygenase inhibitors such as aspirin (see Awtry, E.H. et al., Circulation, 2000, Vol. 101 , pg. 1206); (2) glycoprotein llb-llla antagonists, such as tirofiban (see Scarborough, R. M. et al., Journal of Medicinal Chemistry, 2000, Vol. 43, pg. 3453); and (3) P2Y12 receptor antagonists (also known as ADP receptor antagonists), such as the thienopyridine compounds ticlopidine and clopidogrel (see Quinn, MJ.
• the invention comprises a class of compounds (including the pharmaceutically acceptable salts of the compounds) having the structure of Formula I:
• the invention comprises a pharmaceutical composition comprising a compound having the structure of Formula I.
• the invention comprises methods of treating a condition in a subject by administering to a subject a therapeutically effective amount of a compound having the structure of Formula I.
• the conditions that can be treated in accordance with the present invention include, but are not limited to, atherosclerotic cardiovascular diseases, cerebrovascular diseases and peripheral arterial diseases. Other conditions that can be treated in accordance with the present invention include hypertension and angiogenesis.
• the invention comprises methods for inhibiting platelet aggregation in a subject by administering to the subject a compound having a structure of Formula I. In another embodiment, the invention comprises methods of making compounds having the structure of Formula I.
• the invention comprises intermediates useful in the synthesis of compounds having the structure of Formula I.
• alkyl refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substitue ⁇ t containing only carbon and hydrogen) containing in one embodiment, from about one to about twentycarbon atoms; in another embodiment fro ⁇ r about one to about twelve carbon atoms; in another embodiment, from about one to about ten carbon atoms; in another embodiment, from about one to about six carbon atoms; and in another embodiment, from about one to about four carbon atoms.
• substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like.
• alkenyl refers to a linear or branched-chain hydrocarbyl substituent containing one or more double bonds and from about two to about twenty carbon atoms; in another embodiment, from about two to about twelve carbon atoms; in another embodiment, from about two to about six carbon atoms; and in another embodiment, from about two to about four carbon atoms.
• alkenyl include ethenyl (also known as vinyl), ally], propenyl (including 1-propenyl and 2-propenyl) and butenyl (including 1-butenyl, 2-butenyl and 3-butenyl).
• alkenyl embraces substituents having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
• alkynyl refers to linear or branched-chain hydrocarbyl substituents containing one or more triple bonds and from about two to about twenty carbon atoms; in another embodiment, from about two to about twelve carbon atoms; in another embodiment, from about two to about six carbon atoms; and in another embodiment, from about two to about four carbon atoms.
• alkynyl substituents include ethynyl, propynyl (including 1-propynyl and 2-propynyl) and butynyl (including 1-butynyl, 2-butynyl and 3-butynyl).
• benzyl means a methyl radical substituted with phenyl, i.e., the following structure:
• carbocyclyl refers to a saturated cyclic (i.e., “cycloalkyl”), partially saturated cyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., “aryl”) hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms” are the atoms bound together to form the ring or rings of a cyclic substituent).
• a carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms.
• Examples of such single-ring carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
• a carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”), fluorenyl, and decalinyl.
• cycloalkyl refers to a saturated carbocyclic substituent having three to about fourteen carbon atoms. In another embodiment, a cycloalkyl substituent has three to about eight carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkylalkyl” refers to alkyl substituted with cycloalkyl. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
• cycloalkenyl refers ⁇ to a partially unsaturated carbocyclyl substituent.
• examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
• aryl refers to a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
• aryl refers to aromatic substituents such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
• arylalkyl means alkyl substituted with aryl.
• the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -Cy-,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
• CrC ⁇ -alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C 3 -C 6 -cycloalkyl means a saturated carbocyclyl containing from 3 to 6 carbon ring atoms.
• hydrogen means a hydrogen substituent, and may be depicted as -H.
• hydroxy indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents.
• Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phenol.
• phenol refers to a hydroxy substituent bonded to a benzene ring.
• hydroxyalkyl refers to an alkyl substituent wherein at least one hydrogen substituent is replaced with a hydroxy substituent.
• Examples of hydroxyalkyl substituents include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
• nitro means -NO 2 .
• carbonyl means-C(O)-, which also may be depicted as:
• amino refers to -NH 2 .
• alkylamino refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom.
• alkylamino substituents include monoalkylamino such as methylamino (exemplified by the formula -NH(CH 3 )), which may also
• dialkylamino such as dimethylamino, (exemplified by the formula -N((CH 3 ) 2 ), which may also be
• aminocarbonyl mean s -C(O)-NH 2 , which also may be depicted as:.
• halogen refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I).
• the halogen is chlorine.
• the halogen is a fluorine.
• halo indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents.
• haloalkyl means an alkyl substituent wherein at least one hydrogen substituent is replaced with a halogen substituent. Where there are more than one hydrogens replaced with halogens, the halogens may be the identical or different.
• haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl.
• haloalkoxy means an alkoxy substituent wherein at least one hydrogen substituent is replaced by a halogen substituent.
• haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 2,2,2-trifluoroethoxy. It should be recognized that if a substituent is substituted by more than one halogen substituent, those halogen substituents may be identical or different (unless otherwise stated).
• the prefix "perhalo" indicates that each hydrogen substituent on the substituent to which the prefix is attached is replaced with an independently selected halogen substituent. If all the halogen substituents are identical, the prefix may identify the halogen substituent. Thus, for example, the term “perfluoro” means that every hydrogen substituent on the substituent to which the prefix is attached is substituted with a fluorine substituent. To illustrate, the term “perfluoroalkyl” means an alkyl substituent wherein a fluorine substituent is in the place of each hydrogen substituent.
• perfluoroalkyl substituents examples include trifluoromethyl (-CF 3 ), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl.
• perfluoroalkoxy means an alkoxy substituent wherein each hydrogen substituent is replaced with a fluorine substituent.
• perfluoroalkoxy substituents include trifluoromethoxy (-0-CF 3 ), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy.
• oxy means an ether substituent, and may be depicted as -O-.
• alkoxy refers to-an-alkyHinked to an oxygen (sometimes referred to as an oxygen bridge), which may also be represented as -O-R, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
• alkylthio means -S-alkyl.
• methylthio is -S-CH 3 .
• alkylthio include ethylthio, propylthio, butylthio, and hexylthio.
• alkylcarbonyl means -C(O)-alkyl.
• ethylcarbonyl may be depicted
• alkylcarbonyl examples include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, and hexylcarbonyl.
• aminoalkylcarbonyl means -C(O)-alkyl-NH 2 .
• aminomethylcarbonyl aminomethylcarbonyl
• alkoxycarbonyl means -C(O)-O-alkyl.
• ethoxycarbonyl may be
• alkoxycarbonyl examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl.
• the carbon atom of the carbonyl is attached to a carbon atom of a second alkyl, the resulting functional group is an ester.
• carbocyclylcarbonyl means -C(O)-carbocyclyl.
• phenylcarbonyl may be
• heterocyclylcarbonyl alone or in combination with another term(s), means -C(O)-heterocyclyl.
• carbocyclylalkylcarbonyl means -C(O)-alkyl-carbocyclyl.
• phenylethylcarbonyl may be depicted as: . Similarly, the term
• heterocyclylalkylcarbonyl alone or in combination with another term(s), means -C(O)-alkyl-heterocyclyl.
• carbocyclyloxycarbonyl means -C(O)-O-carbocyclyl.
• phenyloxycarbonyl may be depicted as:
• carbocyclylalkoxycarbonyl means -C(O)-O-alkyl-carbocyclyl.
• phenylethoxycarbonyl may be depicted as:
• thio and thia mean a divalent sulfur atom and such a substituent may be depicted as -S-.
• a thioether is represented as "alkyl-thio-alkyP or, alternatively, alkyl-S-alkyl.
• thiol means a sulfhydryl substituent, and may be depicted as -SH.
• alkyl-sulfonyl-alkyl means alkyl-S(O) 2 -alkyl.
• alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
• aminosulfonyl means -S(O) 2 -NH 2 , which also may be depicted as:
• alkylsulfinyl or “sulfoxido” means -S(O)-, which also may be depicted as : 7
• alkylsulfinylalkyl or “alkylsulfoxidoalkyl” means alkyl-S(O)-alkyl.
• alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.
• heterocyclyP means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
• heteroatom i.e., oxygen, nitrogen, or sulfur
• a heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
• single-ring heterocyclyls include furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazo
• a heterocyclyl alternatively may be 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (Ae., nitrogen, oxygen, or sulfur).
• 2-fused-ring heterocyclyls include, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyrany
• fused-ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as “isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (including quinolinyl (also known as “1 -benzazinyl”) or isoquinolinyl (also known as "2-benzazinyl”)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as “1 ,2-benzodiazinyl”) or quinazolinyl (also known as “1 ,3-benzodiazinyl”)), benzopyranyl (including “chromanyl” or “isochromanyl) or
• 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as quinolinyl, isoquinoiinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl
• heterocyclylalkyl means alkyl substituted with a heterocyclyl.
• heterocycloalkyl means a fully saturated heterocyclyl
• a substituent is "substitutable” if it comprises at least one carbon, sulfur, oxygen or nitrogen atom that is bonded to one or more hydrogen atoms.
• hydrogen, halogen, and cyano do not fall within this definition.
• a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon or nitrogen of the substituent.
• a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent.
• monofluoroalkyl is alkyl substituted with a fluoro substituent
• difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there are more than one substitutions on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated).
• substituent may be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon
• One exemplary substituent may be depicted as -NR'R," wherein R' and R" together with the nitrogen atom to which they are attached, may form a heterocyclic ring.
• the heterocyclic ring formed from R' and R" together with the nitrogen atom to which they are attached may be partially or fully saturated.
• the heterocyclic ring consists of 3 to 7 atoms.
• the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl.
• a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include: (1) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and/or (3) substitutable substituents that are substituted by one or more of the optional substituents. If a substituent is described as being optionally substituted with up to a particular number of non- hydrogen substituents, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
• any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions.
• tetrazolyl which has only one substitutable position
• an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen substituents, then the nitrogen will be optionally substituted with up to 2 non-hydrogen substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be optionally substituted with up to only 1 non-hydrogen substituent if the amino nitrogen is a secondary nitrogen.
• alkylcycloalkyl contains two moieties: alkyl and cycloalkyl.
• the C 1 -C 6 - prefix on CrC 6 -aikylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C 1 -C 6 - prefix does not describe the cycloalkyl moiety.
• the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents.
• halogen substitution may alternatively or additionally occur on the alkyl moiety, the substituent would instead be described as "halogen-substituted alkoxyaikyl” rather than “haloalkoxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl moiety, the substituent would instead be described as "alkoxyhaloalkyl.”
• substituent may also be be depicted as .
• substituent trifluoromethylaminocarbonyl the carbonyl moiety is attached to the remainder of the molecule
• the present invention comprises, in part, a novel class of thieno[2,3-d]pyrimidine compounds.
• the present invention is directed, in part, to a class of compounds and pharmaceutically acceptable salts of the compounds or tautomers are disclosed, wherein the compounds have the structure of Formula I:
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
• R 2 is selected from the group consisting of -C(O)R 2a , -C(S)R Za , -C(O)OR 2a , -C(O)NR 2a R 2b , -C(S)NR 2a R 2b , -R 2c1 and -R 2c2 wherein: R 2a and R 2b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R 2a and R 2b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently
• X 4 is selected from the group consisting of -C(O)-, -C(S)-, -S(O)- and -S(O) 2 -;
• R 4 is selected from the group consisting of -CN, -R 4a , -0R 4a , -C(0)R 4a , -0C(0)R 4a , -
• R 4h and R 4 ' are independently selected from the group consisting of hydrogen, alkyl, • haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
• R 5 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, heterocyclyl, and -0R 5a ;
• R 5a is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl; wherein the R 5 and R 5a alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, haloalkyl, and hydroxyalkyl;
• X 6 represents a bond or is -C(O)-; wherein: when X 6 is -C(O)-, R 6 is selected from the group consisting of halogen, -CN, -NO 2 , -R 6a ,
• R 6 is selected from the group consisting of halogen, -
• R 6o and R 6d are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, carboxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl.
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen.
• a 1 , A 2 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen and A 3 is methyl.
• a 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen and A 1 is methyl.
• R 5 is selected from the group consisting of hydrogen, halogen, alkyl, and -0R 5a , wherein the R 5 alkyl substituent may be optionally substituted as provided in other embodiments herein, and R 5a is defined as provided in other embodiments herein.
• R 5 is selected from the group consisting of hydrogen, halogen, and alkyl, wherein the R 5 alkyl substituent may be optionally substituted as above.
• R 5 is selected from the group consisting of hydrogen, halogen and methyl.
• R 5 is hydrogen.
• R 6 is selected from the group consisting of halogen, -R 6a and -0R 6a , wherein R 6a is defined as provided in other embodiments herein.
• R 6 is halogen.
• R 6 is fluorine.
• R 6 is chlorine.
• R 6 is bromine.
• X 6 represents a bond and R 6 is -R 6a , wherein R 6a is defined as provided in other embodiments herein.
• X 6 is -C(O)- and R 6 is - 0R 6a , wherein R 6a is defined as provided in claim 1.
• R 6 is selected from the group consisting of -R 6a and -0R 6a
• R 6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heterocyclyl, wherein the R 6a alkyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein.
• R 6 is selected from the group consisting of -R 6a and -0R 6a
• R 6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R 6a alkyl and aryl substituents may be optionally substituted as provided in other embodiments herein.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is hydrogen and alkyl, wherein the R 6a alkyl substituent may be optionally substituted as provided in other embodiments herein.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is hydrogen.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl and phenyl.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is selected from the group consisting of methyl, ethyl, propyl, butyl, and pentyl.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is unsubstituted alkyl.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R 6a substituent is substituted with one or more halogen substituents.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R 6a substituent is substituted with one or more fluorine substituents.
• X 6 represents a bond, R 6 is -R 6a ; and R 6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R 6a substituent is substituted with one or more chlorine substituents.
• X 6 represents a bond
• R 6 is -R 6a
• R 6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R 6a substituent is substituted with one or more bromine substituents.
• X 4 is -C(O)-.
• R 4 is selected from the group consisting of -R 4a , -OR 4a , and -NR 4a R 4b ; and R 4a and R 4b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, wherein the R 4a and R 4b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein.
• R 4 is selected from the group consisting of -R 4a , -OR 4a , and -NR 4a R 4b ;
• R 4a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R 4a alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein;
• R 4b is selected from the group consisting of hydrogen and alkyl, wherein the R 4b alkyl substituent may be optionally substituted as provided in other embodiments herein.
• R 4 is -R 4a ; and R 4a is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, wherein the R 4a alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein.
• R 4 is -R 4a ; and R 4a is selected from the group consisting of phenyl, oxadiazolyl, thiazolyl, pyridinyl, cyclopropyl, methyl, ethyl and fluorenyl; wherein the R 4a substituents may be optionally substituted as provided in other embodiments herein.
• R 4 is -OR 4a ; and R 4a is selected from the group consisting of methyl and ethyl, wherein the R 4a substituents may be optionally substituted as provided in other embodiments herein.
• R 4 is -NR 4a R 4b ; and R 4a is selected from the group consisting of methyl and R 4b is hydrogen, wherein the R 4a methyl may be optionally substituted as provided in other embodiments herein.
• R 4 is -R 4a ; and R 4a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R 4a substituent is substituted with one or more halogen substituents.
• R 4 is -R 4a ; and R 4a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R 4a substituent is substituted with one or more fluorine substituents.
• R 4 is -R 4a ; and R 4a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R 4a substituent is substituted with one or more chlorine substituents.
• R 4 is -R 4a ; and R 4a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R 4a substituent is substituted with one or more bromine substituents.
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen;
• R 2 is selected from the group consisting of -R 2c1 and -R 2 ° 2 ;
• X 4 is -C(O)-;
• R 4 is selected from the group consisting of -R 4a , -OR 4a , and -NR 4a R 4b ;
• R 4a and R 4b are independently selected from the group consisting of hydrogen, alky], cycloalkyl, aryl, and heterocyclyl, wherein the R 4a and R 4b alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein;
• R 5 is selected from the group consisting of hydrogen, halogen, alkyl, and -OR 5a , wherein the R 5 alkyl substituent may be optionally substituted as provided in other embodiments herein
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen;
• R 2 is selected from the group consisting of -R 2c1 and -R 2c2 ;
• X 4 is -C(O)-;
• R 4 is selected from the group consisting of -R 4a , -OR 4a , and -NR 4a R 4b ;
• R 4a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R 4a alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein;
• R 4b is selected from the group consisting of hydrogen and alkyl, wherein the R 4b alkyl substituent may be optionally substituted as provided in other embodiments herein;
• R 5 is selected from the group consisting of hydrogen, halogen,
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen;
• R 2 is selected from the group consisting of -R 2c1 and -R 2c2 ;
• X 4 is -C(O)-;
• R 4 is - R 4a ;
• R 4a is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R 4a alkyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein;
• R 5 is hydrogen;
• R 6 is selected from the group consisting of -R 6a and -OR 6a ; and
• R 6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R 6a alkyl and aryl substituents may be optionally substituted as provided in other embodiments herein.
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen;
• R 2 is selected from the group consisting of -R 2c1 and -R 2c2 ;
• X 4 is -C(O)-;
• R 4 is - OR 4a ;
• R 4a is alkyl, wherein the R 4a alkyl substituent may be optionally substituted as provided in other embodiments herein;
• R 5 is hydrogen;
• R 6 is selected from the group consisting of -R 6a and -OR 6a ; and
• R 6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R 6a alkyl and aryl substituents may be optionally substituted as provided in other embodiments herein.
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen;
• R 2 is selected from the group consisting of -R 2c1 and -R 2c2 ;
• X 4 is -C(O)-;
• R 4 is - NR 4a R 4b ;
• R 4a is alkyl and R 4b is hydrogen, wherein the R 4a alkyl substituent may be optionally substituted as provided in other embodiments herein;
• R 5 is hydrogen;
• R 6 is selected from the group consisting of -R 6a and -OR 6a ; and
• R 6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R 6a alkyl and aryl substituents may be optionally substituted as provided in other embodiments herein.
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen;
• R 2 is selected from the group consisting of -R 2c1 and -R 202 ;
• X 4 is -C(O)-;
• R 4 is - R 4a ;
• R 4a is selected from the group consisting of phenyl, oxadiazolyl, thiazolyl, pyridinyl, cyclopropyi, methyl, ethyl and fluorenyl, wherein the R 4a substituents may be optionally substituted as provided in other embodiments herein;
• R 5 is hydrogen;
• X 6 represents a bond;
• R 6 is -R 6a ; and
• R 6a is alkyl, wherein the R 6a alkyl substituent may be optionally substituted as provided in other embodiments herein.
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen;
• R 2 is selected from the group consisting of -R 2c1 and -R 202 ;
• X 4 is -C(O)-;
• R 4 is - OR 4a ;
• R 4a is selected from the group consisting of methyl and ethyl, wherein the R 4a alkyl substituents may be optionally substituted as provided in other embodiments herein;
• R 5 is hydrogen;
• X 6 represents a bond;
• R 6 is -R 6a ; and
• R 6a is alkyl, wherein the R 6a alkyl substituent may be optionally substituted as provided in other embodiments herein.
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 and A 8 are each hydrogen;
• R 2 is selected from the group consisting of -R 2c1 and -R 2c2 ;
• X 4 is -C(O)-;
• R 4 is - NR 4a R 4b ;
• R 4a is selected from the group consisting of methyl, wherein the R 4a methyl may be optionally substituted as provided in other embodiments herein;
• R 4b is hydrogen;
• R 5 is hydrogen;
• X 6 represents a bond;
• R 6 is -R 6a ; and
• R 6a is alkyl, wherein the R 6a aikyl substituent may be optionally substituted as provided in other embodiments herein.
• X 6 represents a bond;
• R 6 is -R 6a ; and
• R 6a is unsubstituted alkyl.
• the compound of Formula (I) has one of the structures shown in Table B below:
• R 2 , R 2b , R 2c1 , R 2c2 , R 4 , and R 6 are as defined in any of the embodiments described in this application.
• the compound of Formula (I) has one of the structures shown in Table B; and R 6 is -R 6a , wherein R 6a is selected from the group consisting of alkyl and phenyl.
• the compound of Formula (I) has one of the structures shown in Table B; and R 6 is -R 6a , wherein R 6a is unsubstituted alkyl.
• Formula (II) has one of the structures shown in Table B; and R 6 is -R 6a , wherein R 6a is selected from the group consisting of methyl, ethyl, propyl and isopropyl.
• Another class of compounds of specific interest includes compounds, and pharmaceutically acceptable salts of the compounds, wherein the compounds have the structure of Formula II:
• R is selected from the group consisting of -R ,2c1 and -R ,2c2 , wherein:
• R 2g , R 2h and R 2 ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R 2Ql R 2h and R 2 ' alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen and R 2m ;
• r is 1 or 2;
• R 4i and R 4k are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylaikyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocycloxyalkyl, aryloxyaryl, heterocycloxyheterocyclyl, aryloxyheterocyclyl, heterocycloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxyalkyl, aryl
• R 4 ' and R 4 " 1 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
• R 5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy and haloalkoxy;
• X 6 represents a bond or is -C(O)-; wherein:
• R 6 is selected from the group consisting of -R 6a and -0R 6a ;
• R 6 is selected from the group consisting of halogen, -R 6a and -0R 6a ;
• R 5 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl; and R 6 is selected from the group consisting of -R 6a and -0R 6a , wherein R 6a is defined as above.
• R 5 is selected from the group consisting of hydrogen and alkyl;
• R 6 is selected from the group consisting of -R 6a and -OR 6a ;
• R 6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl, wherein the R 6a alkyl, cycloalkyl and aryl substituents may be optionally substituted as above.
• R 5 is hydrogen; X 6 represents a bond; and R 6 is -R 6a , wherein R 6a is defined as provided in other embodiments herein.
• R 6a is alkyl, wherein the R 6a alkyl substituent may be optionally substituted as provided in other embodiments herein.
• R 6a is unsubstituted alkyl.
• R 4 is -NR 4) R 4k , wherein the R 4i and R 4k substituents may be optionally substituted as provided in other embodiments herein.
• R 4 is -NR 4i R 4k , wherein R 4 ' and R 4k are independently selected from the group consisting of hydrogen, alkyl and aryl, and wherein the R 4 ' and R 4k alkyl and aryl may be optionally substituted as provided in other embodiments herein.
• R 4 ' and R 4k are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, phenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylpropyl, and phenylbutyl, wherein the R 4i and R 4k methyl, ethyl, propyl, butyl, phenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylpropyl, and phenylbutyl may be optionally substituted as provided in other embodiments herein.
• R 4 is -NR 4 'R 4k , wherein R 4 ' and R 4k are independently selected from the group consisting of hydrogen, phenylmethyl and phenylphenyl, and wherein the R 4 ' and R 4k phenylmethyl and phenylphenyl may be optionally substituted as provided in other embodiments herein.
• R 4 is -R 4 Or -OR 4 '; wherein R 4i is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocyclyloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl; and wherein the R 4 ' substituents may be optionally substituted as provided in other embodiments herein.
• R 4 is -R 4 ' or -OR 4 '; wherein R 4 Ms alkyl; and wherein the R 4 ' substituent is further substituted with one or more halogen substituents.
• R 4 is -R 4 ' or -OR 4 '; wherein R 4i is alkyl; and wherein the R 4i substituent is further substituted with one or more chlorine substituents.
• R 4 is -R 4 ' or -OR 4 '; wherein R 4i is alkyl; and wherein the R 41 substituent is further substituted with one or more fluorine substituents.
• R 4 is -R 4 ' or -OR 4 '; wherein R 41 is alkyl; and wherein the R 41 substituent is further substituted with one or more haloalkyl substituents.
• R 4 is -R 4i or -OR 4 '; wherein R 4 ' is alkyl; and wherein the R 4 ' substituent is further substituted with one or more fluoroalkyl substituents.
• R 4 is -R 41 or -OR 4 '; wherein R 41 is alkyl; and wherein the R 4) substituent is further substituted with one or more chloroalkyl substituents:
• R 4 is -R 4i or -OR 4 '; wherein R 4 ' is alkyl; and wherein the R 4) substituent is further substituted with one or more trifluoroalkyl substituents.
• R 4 is -R 4 ' or -OR 4j ; wherein R 4 ' is alkyl; and wherein the R 4 ' substituent is further substituted with one or more trifluoromethyl substituents.
• R 4 is -R 4i or -OR 4) ; wherein R 41 is selected from the group consisting of (CrC 6 )-alkyl, (C 3 -Ci 0 )-aryl, (C 3 -C 14 )-heterocyclyl, (C 3 -C 10 )" aryl -(CrC 6 )-alkyl, (C 3 -C 14 )-heterocyclyl-(C 1 -C 6 )-alkyl, (C 3 -C 10 )-aryl-(C 3 -C 6 )-cycloalkyl, (C 3 -C 6 )- cycloalkyl-(C 3 -C 10 )-aryl, (C 3 -C 10 )-aryl-(C 3 -C 14 )-heterocyclyl, (C 3 -C 10 )-aryl-O-(C 3 -Ci 0
• R 4 is -R 4j or -OR 4i ; wherein R 4i is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, naphthyl, anthracenyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, furanyl, dioxolanyl, imidazolidinyl, imidazolynyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, oxazolyl, isoxazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,4-oxadiazolyl, thiophenyl, thiazolyl, thiadiazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyrazinyl, pyrimidin
• R 4 is -R 4 ' or -OR 4 '; wherein R 4 ' is selected from the group consisting of phenylphenyl, phenylnaphthyl, phenylanthracenyl, naphthylphenyl, naphthylnaphthyl, naphthylanthracenyl, anthracenylphenyl, anthracenylnaphthyl and anthracenylanthracenyl; and wherein the R 4 ' substituents may be optionally substituted as provided in other embodiments herein.
• R 4 is -R 4 ' or -OR 4 '; wherein R 4 ' is selected from the group consisting of phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, anthracenylmethyl, anthracenylethyl, anthracenylpropyl, anthracenylbutyl, phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl, naphthylcyclopentyl, naphthylcyclohexyl, anthracenylcyclopropyl, anthracenylcyclobutyl,
• R 4 is -R 4i or -OR 4 '; wherein R 4 ' is selected from the group consisting of phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, phenyloxybutyl, naphthyloxyn ⁇ ethyl, naphthyloxyethyl, " naphthyloxypropyl, naphthyloxybutyl, anthracenyloxymethyl, anthracenyloxyethyl, anthracenyloxypropyl, anthracenyloxybutyl, " methoxyphenyl, ethoxyphenyl, propoxyphene, butoxyphenyl, methoxynaphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, phenyloxyphenyl, phenyloxynaphthyl, phenyloxynaph
• R 4 is -R 4 ' or -OR 4i ; wherein R 4 ' is selected from the group consisting of phenylcarbonylphenyl, phenylcarbonylnaphthyl, phenylcarbonylanthracenyl, naphthylcarbonylphenyl, naphthylcarbonylnaphthyl, naphthylcarbonylanthracenyl, anthracenylcarbonylphenyl, anthracenylcarbonylnaphthyl, anthracenylcarbonylanthracenyl, phenylcarbonylaminomethyl, phenylcarbonylaminoethyl, phenylcarbonylaminopropyl, phenylcarbonylaminobutyl, naphthylcarbonylaminomethyl, naphthylcarbonylaminoethyl, naphthylcarbonyla
• R 4 is -R 4 ' or -OR 4i ; wherein R 4 ' is selected from the group consisting of pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylbutyl, pyrrolinylmethyl, pyrrolinylethyl, pyrrolinylpropyl, pyrrolinylbutyl, pyrrolylmethyl, pyrrolylethyl, pyrrolylpropyl, pyrrolylbutyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrofuranylpropyi, tetrahydrofuranylbutyl, furanylmethyl, furanylethyl, furanylpropyl, furanylbutyl, dioxolanylmethyl, dioxolanylethyl, dioxolanylethyl, dio
• R 4 is -R 4i or -OR 4 '; wherein R 4) is selected from the group consisting of phenylpyrrolidinyl, naphthylpyrrolidinyl, anthracenylpyrrolidinyl, phenylpyrrolinyl, naphthylpyrrolinyl, anthracenylpyrrolinyl, phenylpyrrolyl, naphthylpyrrolyl, anthracenylpyrrolyl, phenyltetrahydrofuranyl, naphthyltetrahydrofuranyl, anthracenyltetrahydrofuranyl, phenylfuranyl, naphthylfuranyl, anthracenylfuranyl, phenyldioxolanyl, naphthyldioxolanyl, anthracenyldioxolanyl, phenylim
• R 4 is -R 4i or -OR 4i ; wherein R 4i is selected from the group consisting of pyrrolidinyloxyphenyl, pyrrolidinyloxynaphthyl, " pyrrolidinyloxyanthracenyl; pyrrolinyloxyphenyl, pyrrolinyloxynaphthyl, pyrrolinyloxyanthracenyl, pyrrolyloxyphenyl, pyrrolyloxynaphthyl, pyrrolyloxya ⁇ thracenyl, tetrahydrofuranyloxyphenyl, tetrahydrofuranyloxynaphthyl, tetrahydrofuranyloxyanthracenyl, furanyloxyphenyl, furanyloxynaphthyl, furanyloxyanthracenyl, dioxolanyloxyphenyl,
• R 4 is -R 41 or -OR 4 '; wherein R 4 ' is selected from the group consisting of pyrrolidinylphenyl, pyrrolidinylnaphthyl, pyrrolidinylanthracenyl, pyrrolinylphenyl, pyrrolinylnaphthyl, pyrrolinylanthracenyl, pyrrolylphenyl, pyrrolylnaphthyl, pyrrolylanthracenyl, tetrahydrofuranylphenyl, tetrahydrofuranylnaphthyl, tetrahydrofuranylanthracenyl, furanylphenyl, furanylnaphthyl, furanylanthracenyl, dioxolanylphenyl, dioxolanylnaphthyl, dioxolanylphenyl, dioxolanyln
• R 4 is -R 4i or -OR 4 '; wherein R 4i is selected from the group consisting of butyl, phenyl, fluorenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylphenylmethyl, diphenylethyl, phenyloxymethyl, phenyloxyethyl, phenyioxyphenyl, naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl, phenylcarbonylaminoethyl, phenylcarbonyl(phenyl)aminoethyl, thiophenylmethyl, phenyl-1 ,2,3- oxadiazolyl, phenyl-1 ,3,4-oxadiazolyl, 1 ,3,4-oxadiazolylphenyl, thiazolylphenyl, phenyl, phenyl-1 ,2,3
• R 4 is selected from the group consisting of -R 4i , -OR 4 ' and -NR 4 'R 4k ; wherein R 4i and R 4k are independently selected from the groups shown in Table C below:
• R 4i and R 4k substituents shown in Table C may be optionally substituted as provided in other embodiments herein.
• the compound of Formula (II) has one of the structures shown in Table D below:
• R 2c1 , R 2c2 , R 4 , and R 6 are as defined in any of the embodiments described in this application.
• the compound of Formula (II) has one of the structures shown in Table D and R 6 is -R 6a , wherein R 6a is selected from the group consisting of hydrogen, halogen, alkyl, phenyl and haloalkyl; wherein the alkyl or phenyl substituent may be optionally substituted as provided in other embodiments herein.
• the compound of Formula (II) has one of the structures shown in Table D and R 6 is -R 6a , wherein R 6a is selected from the group consisting of alkyl and phenyl.
• the compound of Formula (II) has one of the structures shown in Table D; and R 6 is -R 6a , wherein R 6a is unsubstituted alkyl.
• the compound of Formula (II) has one of the structures shown in Table D; and R 6 is -R 6a , wherein R 6a is selected from the group consisting of methyl, ethyl, propyl and isopropyl.
• the compound of Formula (II) has one of the structures shown in Table D;
• R 4 is selected from the group consisting of -R 4i , -OR 4 ' and -NR 4i R 4k , wherein R 4J and R 4k are independently selected from the groups shown in Table D; and wherein the R 4 ' and R 4k substituents may be optionally substituted as provided in other embodiments herein; and
• R 6 is - R 6a , wherein R 6a is selected from the group consisting of alkyl and phenyl.
• the compound of Formula (II) has one of the structures shown in Table D; R 4 is -R 4j , wherein R 4i is selected from the groups shown in Table D and wherein the R 41 substituent may be optionally substituted as provided in other embodiments herein; and R 6 is - R 6a , wherein R 6a is unsubstituted alkyl.
• the compound of Formula (II) has one of the structures shown in Table D;
• R 2d R 2e and R 2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R 2c1 , R 2d , R 2e and R 2f substituents may be optionally substituted as provided in other embodiments herein.
• n is 1 or 2; and R 2d , R 2 ⁇ and R 2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; and wherein the R 2c1 , R 2d , R 2e and R 2f substituents may be optionally substituted as provided in other embodiments herein.
• R 2 is -R 2c1 ; -R 2c1 is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, carboxyalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, oxoalkyl, alkylaminocarbonylalkyl, hydroxyalkoxyalkyl, aminocarbonylalkoxyalkyl and alkylcarbonylalkyl; wherein the R 2c1 hydroxyalkyl, alkoxyalkyl, carboxyalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, oxoalkyl, alkylaminocarbonylalkyl, hydroxyalkoxyalkyl, aminocarbonylalkoxyalkyl and alkylcarbonylalkyl substituents may be optionally substituted with one or more substituents
• R 2 is -R 2c1 ; -R 2c1 is selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, ethoxymethyl, propoxym ethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, butoxypropyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, aminoalkyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, alkylaminoalkyl, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminomethylaminoethyl, dimethyl
• R 2 is -R 2c1 ; -R 2c1 is selected from the group consisting of pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinylbutyl, pyrrolinylmethyl, pyrrolinylethyl, pyrrolinylpropyl, pyrrolinylbutyl, pyrrolylmethyl, pyrrolylethyl, pyrrolylpropyl, pyrrolylbutyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrofuranylpropyl, tetrahydrofuranylbutyl, furanylmethyl, furanylethyl, furanylpropyl, furanylbutyl, dioxolanylmethyl, dioxolanylethyl, dioxolanylprop
• R 2 is -R 2G1 ;
• R 2 is -R 2c1 ; -R 2c1 is selected from the group consisting of hydroxypropyl, hydroxybutyl, ethoxyethyl, carboxyethyl, aminoethyl, dimethylaminoethyl, aminocarbonylmethyl, oxoethyl, tetrahydrofuranylmethyl, oxetanylmethyl, oxiranylmethyl.piperazinylethyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl and dioxanylmethyl; wherein the R 2c1 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of methyl, hydroxy, methoxy and ethoxy.
• R 2 is -R 2c1 ; -R 2c1 is Ci-C 6 -alkyl; wherein the R 2c1 Ci-C 6 -alkyl is substituted with at least one hydroxyl substituent.
• R 2 is -R 2c1 ; -R 2c1 is Ci-C 6 -alkyl; wherein the R 2c1 CrC 6 -alkyl is substituted'with at least two hydroxyl substituents.
• R 2 is -R 2c1 ; -R 2c1 is d-C 6 -alkyl; wherein the R 2c1 CrC 6 -alkyl is substituted with one hydroxyl substituent.
• R 2 is -R 2c1 ; -R 2c1 is CrC 6 -alkyl; wherein the R 2c1 C r C 6 -alkyl is substituted with two hydroxyl substituents.
• R 2 is -R 2c1 ; -R 201 is Ci-C 6 -alkyl; wherein the R 2c1 Ci-C 6 -alkyl is substituted with at least one hydroxyl substituent;
• R 4 is selected from the group consisting of -R 4i , -OR 4 ' and -NR 4) R 4k , wherein R 4 ' and R 4k are independently selected from the groups shown in Table C and wherein the R 4 ' and R 4k substituents may be optionally substituted as provided in other embodiments herein; and
• R 6 is -R 6a , wherein R 6a is selected from the group consisting of alkyl and phenyl.
• R 2 is -R 2c1 ; -R 2c1 is CrC 6 -alkyl; wherein the R 2c1 Ci-C 6 -alkyl is substituted with at least one hydroxyl substituent; R 4 is -R 4 ', wherein R 4 ' is selected from the groups shown in Table C and wherein the R 4) substituent may be optionally substituted as provided in other embodiments herein; and R 6 is -R 6a , wherein R 6a is unsubstituted alkyl.
• R 2 is -R 2c1 ; -R 2c1 is Ci-C 6 -alkyl; wherein the R 2c1 CrCe-alkyl is substituted with at least one hydroxyl substituent;
• R 2 is -R 2c1 ; -R 2c1 is Ci-C 6 -alkyl; wherein the R 2c1 Ci-C 6 -alkyl is substituted with at least two hydroxyl substituents;
• R 4 is selected from the group consisting of -R 4 ', -OR 4) and -NR 4) R 4k , wherein R 4 ' and R 4k are independently selected from the groups shown in Table C and wherein the R 4 ' and R 4k substituents may be optionally substituted as provided in other embodiments herein; and
• R 6 is -R 6a , wherein R 6a is selected from the group consisting of alkyl and phenyl.
• R 2 is -R 2c1 ; -R 2c1 is Ci-C 6 -alkyl; wherein the R 2c1 C r C 6 -alkyl is substituted with at least two hydroxyl substituents; R 4 is -R 4i , wherein R 4 ' is selected from the groups shown in Table C and wherein the R 4) substituent may be optionally substituted as provided in other embodiments herein; and R 6 is -R 6a , wherein R 6a is unsubstituted alkyl.
• R 2 is -R 2c1 ; -R 2c1 is d-C 6 -alkyl; wherein the R 2c1 C r C 6 -alkyl is substituted with at least two hydroxyl substituents;
• R 2 is -R 2c1 ; -R 2c1 is C r C 6 -alkyl; wherein the R 2c1 CrC 6 -alkyl is substituted with one hydroxyl substituent;
• R 4 is selected from the group consisting of -R 4j , -OR 4 ' and -NR 4i R 4k , wherein R 4i and R 4k are independently selected from the groups shown in Table C and wherein the R 4 ' and R 4k substituents may be optionally substituted as provided in other embodiments herein; and R 6 is -R 6a , wherein R 6a is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and phenyl.
• R 2 is -R 2c1 ; -R 2c1 is C r C 6 -alkyl; wherein the R 2c1 Ci-C 6 -alkyl is substituted with one hydroxyl substituent; R 4 is -R 4i , wherein R 4 ' is selected from the groups shown in Table C and wherein the R 4 ' substituent.may be optionally substituted as provided in other embodiments herein; and R 6 is -R 6a , wherein R 6a is unsubstituted alkyl.
• R 2 is -R 2c1 ; -R 2c1 is C r C 6 -alkyl; wherein the R 2c1 CrC 6 -alkyl is substituted with one hydroxyl substituent;
• R 2 is -R 2c1 ; -R 2c1 is CrC ⁇ -alkyl; wherein the R 2c1 CrC ⁇ -alkyl is substituted with two hydroxyl substituents;
• R 4 is selected from the group consisting of -R 4i , -OR 4J and -NR 4i R 4 ⁇ wherein R 4 ' and R 4k are independently selected from the . groups shown in Table C and wherein the R 4 ' and R 4k substituents may be optionally substituted as provided in other embodiments herein; and
• R 6 is -R 6a , wherein R 6a is selected from the group consisting of alkyl and phenyl.
• R 2 is -R 2c1 ; -R 2c1 is CrC 6 -alkyl; wherein the R 2c1 Ci-C 6 -alkyl is substituted with two hydroxyl substituents; R 4 is -R 4 ', wherein R 4i is selected from the groups shown in Table C and wherein the R 4 ' substituent may be optionally substituted as provided in other embodiments herein; and R 6 is -R 6a , wherein R 6a is unsubstituted alkyl.
• R 2 is -R 2c1 ; -R 2c1 is Ci-C 6 -alkyl; wherein the R 2c1 CrC 6 -alkyl is substituted with two hydroxyl substituents;
• n is 1 or 2; and R 2d , R 2e and R 2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R 2c2 , R 2d , R 2e and R 2f substituents may be optionally substituted as provided in other embodiments herein.
• R 2 is -R 202 ;
• R 2d and R 2e are independently selected from the group consisting of hydrogen and alkyl; wherein the R 2c2 , R 2d and R 2e substituents may be optionally substituted with one or more -OR 29 ;
• R 2 is -R 2c2 ; and -R 2c2 is selected from the group consisting of pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, furanyl, dioxolanyl, imidazolidinyl, imidazolynyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, oxazolyl, isoxazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,4-oxadiazolyl, oxadiazolyl, oxetanyl, oxiranyl, thiophenyl, thiazolyl, thiadiazolyl, , triazolyl, piperidinyl, pyridinyl, piperazinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
• R 2 is -R 2c2 ; and -R 202 Is tetrahydrofuranyl; wherein the R 2c2 tetrahydrofuranyl may be optionally substituted with one or more substituents independently selected from the group consisting of methyl', hydroxy, methoxy and ethoxy.
• Another class of compounds of specific interest includes compounds, and pharmaceutically acceptable salts of the compounds, wherein the compounds have the structure of Formula III:
• R 2 is selected from the group consisting of hydroxyalkyl, oxoalkyl, aminoalkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylaminoalkyl, aminocarbonyialkyl, alkylcarbonylalkyl, alkylaminocarbonylalkyl, and aminocarbonylcycloalkyl; wherein the R 2 substituent may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, carboxy, alkyl, hydroxyalkyl, aminoalkyl, alkoxy, and aminocarbonyl; and
• R 6 is alkyl
• R 2 is selected from the group consisting of hydroxyalkyl, oxoalkyl, aminoalkyl, carboxyalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylaminoalkyl and aminocarbonyialkyl, wherein the R 2 substituent-may be optionally substituted with one or more substituents independently selected from the group consisting of hyd.roxy, oxo, carboxy, alkyl, hydroxyalkyl, aminoalkyl, alkoxy, and aminocarbonyl;
• R 4 is -R 4J ;
• R 4J is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyary
• R 2 is hydroxyalkyl, wherein the R 2 hydroxyalkyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, carboxy, alkyl, hydroxyalkyl, aminoalkyl, alkoxy, and aminocarbonyl;
• R 4 is -R 41 ;
• R 2 is heterocyclylalkyl, wherein the R 2 heterocyclylalkyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, carboxy, alkyl, hydroxyalkyl, aminoalkyl, alkoxy, and aminocarbonyl;
• R 2 is selected from the group consisting of hydroxypropyl, hydroxybutyl, ethoxyethyl, carboxyethyl, aminoethyl, dimethylaminoethyl, aminocarbonylmethyl, oxoethyl, tetrahydrofuranylmethyl, oxetanylmethyl, oxiranylmethyl.piperazinylethyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, dioxanylmethyl and tetrahydrofuranyl, wherein the R 2 substituent may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, carboxy, alkyl, hydroxyalkyl, aminoalkyl, alkoxy, and aminocarbonyl; R 4 is -R 4i ; R 4i is selected from the group consisting of butyl, phenyl, fluor
• R 2 is selected from the group consisting of hydroxypropyl, hydroxybutyl, ethoxyethyl, carboxyethyl, aminoethyl, dimethylaminoethyl, aminocarbonylmethyl, oxoethyl, tetrahydrofuranylmethyl, oxetanylmethyl, oxiranylmethyl.piperazinylethyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, dioxanylmethyl and tetrahydrofuranyl, wherein the R 2 substituent may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, methyl methoxy and ethoxy; R 4 is -R 4 '; R 4 ' is selected from the group consisting of butyl, phenyl, fluorenyl, phenylphenyl, phenylmethyl, pheny
• compound of Formula (II) is selected from the group consisting of: tert-butyl 4-[2-(2,2-diethoxyethoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate;
• compound of Formula (II) is selected from the group consisting of: (2R)-3-( ⁇ 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-isopropylthieno[2,3-d]pyrimidin-2- yl ⁇ oxy)propane-1 ,2-diol;
• the compound of Formula (II) is selected from the group consisting of: piperazine, 1-[2-(3-amino-2-hydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl]-4-(t1 ,1'- biphenyl]-4-ylcarbonyl)-; piperazine, 1 -[2-(3-amino-2-hydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl]-4-([1 ,1 '- biphenyl]-3-ylcarbonyl)-; piperazine, 1-[2-(3-amino-2-hydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl]-4-(phenylacetyl)-; acetic acid, [[4-[4-([1 ,1'-biphenyl]-3-ylcarbonyl)-1-piperazinyl]-6
• compound of Formula (II) is selected from the group consisting of: piperazine, 1-[6-ethyl-2-[2-hydroxy-1-(hydroxymethyl)ethoxy]thieno[2,3-d]pyrimidin-4-yl]-4-
• the compound of Formula (II) is selected from the group consisting of: piperazine, 1 -([1 , 1 '-biphenylH-ylcarbonylH-t ⁇ -ethyl ⁇ -K ⁇ -oxo-S-pyrrolidiny ⁇ oxyfthienop.S- d]pyrimidin-4-yl]-; piperazine, 1-([1 ,1 '-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-(3-pyrrolidinyloxy)thieno[2,3-d]pyrimidin-
• compound of Formula (II) is selected from the group consisting of: 2- ⁇ [(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy ⁇ -6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-
• the compound may exist in the form of optical isomers (enantiomers).
• the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of Formulae (I) through (III).
• the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds.
• geometric isomers may arise.
• the present invention comprises the tautomeric forms of compounds of Formulae (I) through (III).
• tautomeric isomerism 'tautomerism'
• This can take the form of proton tautomerism in compounds of formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
• the various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound.
• the compounds of this invention may be used in the form of salts derived from inorganic or organic acids.
• a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
• a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
• a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context)
• the salt preferably is pharmaceutically acceptable.
• pharmaceutically acceptable salt refers to a salt prepared by combining a compound of Formulae (I) - (III) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
• Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
• salts of the compounds of this invention are non-toxic “pharmaceutically acceptable salts.”
• Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
• Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
• inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids
• organic acids such as ace
• Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
• examples of suitable addition salts formed include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsyate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihidrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
• representative salts include benzenesulfonate, hydrobromide and hydrochloride.
• suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
• base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
• Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
• secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
• Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (CrC 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
• hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
• the compounds of the invention may exist in both unsolvated and solvated forms.
• the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
• the term 'hydrate' is employed when said solvent is water.
• complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
• complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts.
• the resulting complexes may be ionised, partially ionised, or non- ionised.
• Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of any of Formulae (I) through (III) with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in “Design of Prodrugs” by H Bundgaard (Elseview, 1985).
• the present invention further comprises methods for treating a condition in a subject having or susceptible to having such a condition, by administering to the subject a therapeutically-effective amount of one or more compounds of Formulae (I) through (III) as described above.
• the treatment is preventative treatment.
• the treatment is palliative treatment.
• the treatment is restorative treatment.
• the conditions that can be treated in accordance with the present invention include platelet aggregation mediated conditions such as atherosclerotic cardiovascular conditions, cerebrovascular conditions and peripheral arterial conditions, particularly those related to thrombosis.
• platelet aggregation mediation conditions may be treated.
• the compounds of the invention can be used to treat acute coronary syndrome.
• Acute coronary syndrome includes, but is not limited to, angina (such as unstable angina) and myocardial infarction (such as non-ST-segment elevation myocardial infarction, non- Q-wave myocardial infarction and Q-wave myocardial infarction).
• the compounds of the invention can be used to treat stroke (such as thrombotic stroke, ischemic stroke, embolic stroke and transient ischemic attack).
• stroke such as thrombotic stroke, ischemic stroke, embolic stroke and transient ischemic attack.
• the ⁇ compounds ⁇ of the invention can be used to treat a subject who has suffered from at least one event selected from the group consisting of myocardial infarction and stroke.
• the compounds of the present invention can be used to treat thrombotic and restenotic complications or treat reocclusion following invasive procedures including, but not limited to, angioplasty, percutaneous coronary intervention, carotid endarterectomy, coronary arterial bypass graft ("CABG") surgery, vascular graft surgery, stent placements, lower limb arterial graft, prosthetic heart valve placement, hemodialysis and insertion of endovascular devices and prostheses.
• CABG coronary arterial bypass graft
• the compounds of the present invention can be used to treat hypertension.
• the compounds of the present invention can be used to treat angiogenesis.
• a compound described in this specification is administered in an amount effective to inhibit ADP mediated platelet aggregation.
• the compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
• Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
• the compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. . In another embodiment, the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
• Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
• Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
• the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
• the compounds of the invention can also be administered intranasally or by inhalation.
• the compounds of the invention may be administered rectally or vaginally.
• the compounds of the invention may also be administered directly to the eye or ear.
• the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular " compound employed. " Thus the-dosage regimen may vary widely.
• Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions.
• the total daily dose of a compound of Formulae (I) through (III) is typically from about 0.01 to about 100 mg/kg.
• total daily dose of the compound of Formulae (I) through (III) is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of Formulae (I) through (III) per kg body weight).
• dosing is from 0.01 to 10 mg/kg/day.
• dosing is from 0.1 to 1.0 mg/kg/day.
• Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose.
• the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
• compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1mg to about 100 mg of active ingredient.
• doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
• Suitable subjects to be treated according to the present invention include mammalian subjects.
• Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero.
• humans are suitable subjects; Human subjects may be of either gender and at any stage of development.
• the present invention comprises methods for the preparation of a pharmaceutical composition, (or "medicament) comprising the compounds of Formulae (I) through (III) in combination with one or more pharmaceutically-acceptable carriers and/or other active ingredients for use in treating a platelet aggregation mediated condition.
• the invention comprises the use of one or more compounds of Formulae (I) through (III) in the preparation of a medicament for the treatment of acute coronary syndrome. In another embodiment, the invention comprises the use of one or more compounds of Formulae (I) through (III) in the preparation of a medicament for the reduction of atherosclerotic events. In another embodiment, the invention comprises the use of one or more compounds of Formulae (I) through (III) in the preparation of a medicament for the treatment of thrombosis.
• the invention comprises the use of one or more compounds of Formulae (I) through (III) in the preparation of a medicament to be co-administered before, during or after revascularization procedures, including, but not limited to, lower limb arterial graft, carotid — endarterectomyr coronary artery bypass ' surgery, atrial fibrillation, prosthetic heart valve placement, hemodialysis and placement of mechanical devices.
• compositions for the treatment of the conditions referred to above, the compounds of Formulae (I) through (III) can be administered as compound perse.
• pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
• the present invention comprises pharmaceutical compositions.
• Such pharmaceutical compositions comprise compounds of Formulae (I) through (III) presented with a pharmaceutically-acceptable carrier.
• the carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds.
• Compounds of Formulae (I) through (III) may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
• the active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
• the active compounds and compositions may be administered orally, rectally, parenterally, or topically.
• Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention.
• the oral administration may be in a powder or granule form.
• the oral dose form is sub-lingual, such as, for example, a lozenge.
• the compounds of Formulae (I) through (III) are ordinarily combined with one or more adjuvants.
• Such capsules or tablets may contain a controlled-release formulation.
• the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.
• oral administration may be in a liquid dose form.
• Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).
• Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
• the present invention comprises a parenteral dose form.
• Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal ⁇ , intramuscular injections, intrasternal injections, and infusion.
• injectable preparations e.g., sterile injectable aqueous or oleaginous suspensions
• the present invention comprises a topical dose form.
• Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration ⁇
• Compositions-for topical administration also include,-for example, topical gels, sprays, ointments, and creams.
• a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
• Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
• Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
• Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
• Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in suitable carrier.
• a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
• Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
• a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
• a preservative such as benzalkonium chloride.
• Such formulations may also be delivered by iontophoresis.
• the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
• Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
• the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
• the present invention comprises a rectal dose form.
• rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
• Other carrier materials and modes of administration known in the pharmaceutical art may also be used.
• Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks.
• the compounds of the present invention can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states.
• the compound(s) of the present invention and other therapeutic agent(s) may be may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
• the administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
• the two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
• compounds of Formulae (I) through (III) may be co-administered with an oral antiplatelet agent, including, but not limited to, aspirin, dipyridamole, cilostazol and anegrilide hydrochloride.
• compounds of Formulae (I) through (III) may be co- administered with aspirin.
• compounds of Formulae (I) through (III) may be co-administered with a glycoprotein llb/llla inhibitor, including, but not limited to, abciximab, eptifibatide and tirofiban.
• compounds of Formulae (I) through (III) may be co-administered with eptifibatide.
• compounds of Formulae (I) through (III) may be co-administered with a heparin or heparinoid, including, but not limited to, heparin sodium, enoxaparin sodium, dalteparin sodium, ardeparin sodium, nadroparin calcium, reviparin sodium, tinzaparin sodium and fondaparinux sodium.
• compounds of Formulae (I) through (III) may be co-administered with a direct thrombin inhibitor, including, but not limited to, danaparoid, hirudin, bivalirudin and lepirudin.
• compounds of Formulae (I) through (III) may be co-administered with an anti-coagulant including, but not limited to, warfarin, warfarin sodium, 4-hydroxycoumarin, dicoumarol, phenprocoumon, anisindione, acenocoumerol and phenindione.
• compounds of Formulae (I) through (lll)- may be co-administered with warfarin sodium.
• compounds of Formulae (I) through (III) may be co-administered with an oral factor Xa inhibitor including, but not limited to, ximelagatran, melagatran, dabigatran etexilate and argatroban.
• compounds of Formulae (I) through (III) may be coadministered with ximelagatran.
• compounds of Formulae (I) through (111) may be co-administered with a fibrinolytic including, but not limited to, streptokinase, urokinase, tissue plasminogen activator, tenecteplase, reteplase,reteplase and aminocaproic acid.
• compounds of Formulae (I) through (III) may be co-administered with an investigational compound useful in treating platelet aggregation including, but not limited to, BAY 59-7939, YM-60828, M-55532, M-55190, JTV-803 and DX-9065a.
• kits that are suitable for use in performing the methods of treatment or prevention described above.
• the kit contains a first dosage form comprising one or more of the compounds of the present invention and a container for the dosage, in quantities sufficient to carry out the methods of the present invention.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and an oral antiplatelet agent, including, but not limited to, aspirin, dipyridamole, cilostazol and anegrilide hydrochloride.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and aspirin.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and a glycoprotein llb/llla inhibitor, including, but not limited to,- abciximab, eptifibatide and tirofiban.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and eptifibatide.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and a heparin or heparinoid, including, but not limited to, heparin sodium, enoxaparin sodium, dalteparin sodium, ardeparin sodium, nadroparin calcium, reviparin sodium, tinzaparin sodium and fondaparinux sodium.
• a heparin or heparinoid including, but not limited to, heparin sodium, enoxaparin sodium, dalteparin sodium, ardeparin sodium, nadroparin calcium, reviparin sodium, tinzaparin sodium and fondaparinux sodium.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and a direct thrombin inhibitor, including, but not limited to, danaparoid, hirudin, bivalirudin and lepirudin.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and an anti-coagulant including, but not limited to, warfarin, warfarin sodium, 4-hydroxycoumarin, dicoumarol, phenprocoumon, anisindione, acenocoumerol and phenindione.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and warfarin sodium.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and an oral factor Xa inhibitor including, but not limited to, ximelagatran, melagatran, dabigatran etexilate and argatroban.
• the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and ximelagatran.
• kit of the present invention comprises one or more compounds of
• Formulae (I) through (III) and a fibrinolytic including, but not limited to, streptokinase, urokinase, tissue plasminogen activator, tenecteplase, reteplase,reteplase and aminocaproic acid.
• kit of the present invention comprises one or more compounds of
• Formulae (I) through (III) and an investigational compound useful in treating platelet aggregation including, but not limited to, BAY 59-7939, YM-60828, M-55532, M-55190, JTV-803 and DX-
• the invention relates to the novel intermediates useful for preparing the thieno[2,3-d
• the starting materials used herein are commercially available or may prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley- Interscience)).
• the compounds of the present invention may be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes are presented for purposes of illustration and are not intended to be limiting.
• Scheme A Thienopyrimidines may be prepared by various methods— One-method for the preparation of thienopyrimidine 7 is depicted in Scheme A.
• Commercially available aldehyde/ketone 1 and esters 2 are combined in the presence of sulfur to give thiophene 3 using the general method of Tinney et al. (J. Med. Chem. (1981) 24, 878-882).
• Thiophene 3 is then treated with potassium cyanate or urea in the presence of water and an acid such as acetic acid to give dione 4.
• Dione 4 is then treated with a chloride source such as phosphorous oxychloride, thionyl chloride, or phosphorous pentachloride with or without the presence of a tertiary amine or concentrated HCI and with or without added inert solvent such as dimethylformamide at temperatures ranging from 75 0 C to 175 0 C, optionally with an excess of phosphorous oxychloride in a sealed vessel at 130-175 0 C, to give dichloropyrimidine 5.
• a chloride source such as phosphorous oxychloride, thionyl chloride, or phosphorous pentachloride
• inert solvent such as dimethylformamide
• Dichloropyrimidine 5 is then treated with piperazine 6 (see Scheme B) in the presence of a base such as trialkylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, and other bases well known to those versed in the art and in the presence of a solvent such as THF, acetonitrile, dichloromethane, dialkyl ether, toluene, DMF, N-methyl pyrrolidinone and the like at temperatures ranging from room temperature to the reflux temperature of the solvent to give thienopyrimidine 7.
• a base such as trialkylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, and other bases well known to those versed in the art and in the presence of a solvent such as THF, acetonitrile, dichloromethane, dialkyl ether, toluene, DMF, N-methyl pyrrolidinone and the like
• a solvent such as THF, acetonitrile, dichlorome
• Scheme B depicts the preparation of intermediate 6.
• Protected piperazine 8 is commercially available or can be prepared by (1) attaching a suitable protecting group including, but not limited to, Boc, Cbz, Fmoc and benzyl, to one of the nitrogen ring atoms of the piperazine and (2) reacting with alkylOCOCI or (alkylOCO) 2 O).
• Suitable coupling agents include, but are not limited to, DCC, EDC, DEPC, HATU, HBTU and CDI.
• a base including, but not limited to, a trialkylamine, pyridine, or an alkaline earth metal carbonate and in the presence of inert solvents such as THF, dichloromethane, acetonitrile, toluene, dialkyl ether, DMF, N-methylpyrrolidinone, dimethylacetamide and the like at temperatures
• Bisamide 10 is converted to piperazine 6 using methods well know to those versed in the art, many of which are discussed by Greene and Wuts in Protective Groups in Organic Synthesis, Third Ed., Wiley- Interscience, pp. 502-550.
• the protecting group of bisamide 10 is a benzyl group
• removal of the benzyl group to give intermediate 6 is accomplished using standard methods known in the art (e.g., those discussed by Greene and Wuts in Protective Groups in Organic Synthesis, Third Ed., Wiley-lnterscience, pp. 502-550).
• Scheme C The order of addition of various functionalities to the thienopyrimidine can be changed to take advantage of commercially available materials or in order to avoid reactivities at other parts of the molecule.
• An alternative method for the preparation of thienopyrmidine 7 using an order of addition differing from that of Scheme A is shown in Scheme C.
• Dichioropyrimidine 5 (Scheme A) is aminated with 8 (Scheme B) in inert solvents at temperatures ranging from room temperature to the boiling point of the solvent to give pyrimidine 11.
• the amination may be done using excess 8 or in the presence of a base, including but not limited to, a trialkylamine, pyridine, or an alkaline earth metal carbonate.
• pyrimidine- piperazine 12 Removal of the protecting group to give pyrimidine- piperazine 12 is achieved using standard deprotection method, such as those discussed by Greene and Wuts in Protective Groups in Organic Synthesis, Third Ed., Wiley-lnterscience, pp. 502-550.
• a base preferably a trialkylamine, pyridine, or an alkaline earth metal carbonate
• inert solvents including, but not limited to, THF, dichloromethane, acetonitrile, toluene, dialkyl ether, DMF, N-methylpyrrolidinone and the like at temperatures ranging between ice/water temperature to the reflux temperature of the solvent.
• Suitable strong include, but are not limited to, alkali metal hydrides (such as sodium hydride).
• the addition of the strong base to reagent 13, or addition of reagent 13 to strong base is done at temperatures ranging from -30 °C to room temperature.
• the addition of the strong base to reagent 13, or addition of reagent 13 to strong base is done at a temperature from 0 °C to room temperature.
• reagent 13 can be protected first (i.e. R 2 is in a protected form) namely reagent 13A, to give substituted thienopyrimidine 14A, wherein the protecting group may be removed at a later stage to give substituted thienopyrimidine 14.
• Reagent 13A is commercially available or may be prepared by methods well known to those versed in the art.
• R 7 is desired to be an alkyl diol
• the diol of H-Y-R 2 may be protected using methods known in the art. Methods for the synthesis and removal diol protecting groups are discussed by Greene and Wuts in "Protective Groups in Organic Synthesis," Third Ed., Wiley- Interscience, pp. 201-245.
• R 2 in 14A may be an alkyl aldehyde or alkyl ketone in its protected form.
• Many protected aldehydes and ketones 13A are commercially available.
• Conventional procedures for the synthesis and removal of aldehyde and ketone protecting groups are known in the art (e.g. the procedures discussed by Greene and Wuts in "Protective Groups in Organic Synthesis," Third Ed., Wiley-lnterscience, pp. 201-245.) After removal of the aldehyde or ketone protecting group to give substituted thienopyrimidine 14B, the aldehyde or ketone may be further manipulated.
• substituted thienopyrimidine 14 where R 2 contains a carboxylic acid.
• treatment of an aldehyde or ketone with an amine in the presence of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, tri(trifluoroacetoxy)borohydride, or hydrogen gas and a metal catalyst give substituted thienopyrimidine 14 where R 2 contains an amino group.
• R 4 is phenyl or heteroaryl substituted with Br, I, Cl, and O-triflate
• additional manipulations of R 4 may be carried out using standard methods known in the art.
• aryl- or heteroaryl-boronic acids or esters may be reacted, in the presence of a metal catalyst, with substituted thienopyrimidine 14A to give biaryl substituted thienopyrimidine 14C.
• aryl or heteroaryl boronic acid or heteroaryl or aryl boronic acid ester such as [(aryl or heteroaryl)-B(OH)2] or [(aryl or heteroaryl)- B(OR a )(OR b ) (where R a and R b are each C-] -Cg alkyl, or when taken together, R a and R b are C2-C12 alkylene)] in the presence of a metal catalyst with or without a base in an inert solvent yields biaryl substituted thienopyrimidine 14C.
• an aryl or heteroaryl boronic acid or heteroaryl or aryl boronic acid ester such as [(aryl or heteroaryl)-B(OH)2] or [(aryl or heteroaryl)- B(OR a )(OR b ) (where R a and R b are each C-] -Cg alkyl, or when taken together, R a and R b are C
• Metal catalysts in these transformations include, but are not limited to, salts or phosphine complexes of Cu, Pd, or Ni (for example, Cu(OAc)2, PdCl2(PPh3)2, NiCl2(PPh3)2)- Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydrides, alkali metal dialkylamides, alkali metal bis(trialkylsilyl)amides, trialkyl amines or aromatic amines.
• the alkali metal hydride is sodium hydride.
• the alkali metal alkoxide is sodium methoxide.
• the alkali metal alkoxide is sodium ethoxide.
• the alkali metal dialkylamide is lithium diisopropylamide.
• the alkali metal bis(trialkylsilyl)amide is sodium bis(trimethylsilyl)amide.
• the trialkyl amine is diisopropylethylamine.
• the trialkylamine is triethylamine.
• the aromatic amine is pyridine.
• Inert solvents may include, but are not limited to, acetonitrile, dialkyl ethers, cyclic ethers, N,N- dialkylacetamides (dimethylacetamide), N,N-dialkylformamides, dialkylsulfoxides, aromatic hydrocarbons or haloalkanes.
• the dialkyl ether is diethyl ether.
• the cyclic ether is tetrahydrofuran.
• the cyclic ether is 1 ,4-dioxane.
• the N,N-dialkylacetamide is dimethylacetamide.
• the N, N- dialkylformamide is dimethylformamide.
• dialkylsulfoxide is dimethylsulfoxide.
• aromatic hydrocarbon is benzene.
• aromatic hydrocarbon is toluene.
• haloalkane is methylene chloride.
• Exemplary reaction temperatures range from room temperature up to the boiling point of the solvent employed.
• Non-commercially available boronic acids or boronic acid esters may be obtained from the corresponding optionally substituted aryl halide as described in Tetrahedron, 50, 979-988 (1994).
• Tetrahedron, 50, 979-988 (1994) one may convert the R 4 substituent to the corresponding boronic acid or boronic acid ester (OH)2B- or
• Scheme E The order of addition of various functionalities of the thienopyrimidine can be changed in the preparation of substituted thienopyrimidine 14 in order to take advantage of commercially available materials or in order to avoid reactivities at other parts of the molecule.
• Another method for the preparation of substituted thienopyrimidine 14 is shown in Scheme E, where piperazinyl pyrimidine 11 is combined with reagent 13 where H-OR ⁇ is commercially available or may be prepared by methods well-known to those versed in the art, to give di- substituted thienopyrimidine 15.
• Reagent 13 is first treated with a strong base and is then added to piperazinyl pyrimidine 11.
• piperazinyl pyrimidine 11 may be added to reagent 13 after the addition of strong base.
• reagent 13 is first treated with a strong base to form an anion.
• Suitable strong bases include an alkali metal hydride.
• the strong base is sodium hydride.
• the addition of the strong base to reagent 13, or addition of reagent 13 to strong base is done at temperatures ranging from -30 0 C to room temperature.
• the addition of strong base to reagent 13, or addition of reagent 13 to strong base is done at 0 °C to room — temperature.
• Disubstituted thienopyrmidine 15 is then combined with a reagent-suitable for the removal of the protecting group to give amine 16.
• Suitable means for removal of the protecting ⁇ group depends on the nature of the group;
• the protecting group Boc is removed by dissolving disubstituted thienopyrimidine in a trifluoroacetic acid/dichloromethane mixture.
• Annother method for removing the protecting group Boc is the addition of hydrogen chloride gas dissolved in an alcohol or ether such as methanol or dioxane.
• the solvents are removed under reduced pressure to give the corresponding amine as the corresponding salt, i.e. trifluoroacetic acid or hydrogen chloride salt.
• the amine can be purified further, for example by recrystallization or other standard techniques known in the art. Further, if the non-salt form is desired that also can be obtained by means known to those skilled in the art, such as for example, preparing the free base amine via treatment of the salt with mild basic conditions. Additional deprotection conditions and deprotection conditions for other protecting groups can be found in T.W. Green and P.G.M. Wuts in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1999, pp. 502-550.
• a base including, but not limited to, a trialkylamine, pyridine, or an alkaline earth metal carbonate
• inert solvents such as THF, dichloromethane, acetonitrile, toluene, dialkyl ether, DMF, N-methylpyrrolidinone and the like at temperatures ranging between ice/water temperature to the reflux temperature of the solvent.
• the protecting group of 11 may be removed to give 12 as described in Scheme C.
• Pyrimidine-piperazine 12 may then be reacted with 13 in the same manner as described for the conversion of 7 to 14 in Scheme D to give 16.
• pyrimidine-piperazine 12 may be reacted with a protected form of 13, namely 13A, to give 17.
• Addition of R 4 C(O)X (9) to 17 gives 14A, which then may be further manipulated as described for Scheme D.
• amine 17 may be converted to 16 by methods described for the conversion of 14A to 14 in Scheme D.
• Example 2 The diol of Example 2 (4.0 g,) was placed into a pressure vessel with phosphorus oxychloride (35 ml_). The mixture was heated to 150 0 C for 1.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was twice azeotroped with toluene (50 mL) to remove any residual phosphorus oxychloride under reduced pressure. The residue was partitioned between saturated sodium bicarbonate and dichloromethane. The resulting layers were separated and decolorizing carbon (1 g) was added to organic layer.
• Methyl cyanoacetate (15.0 g) and elemental sulfur (4.85 g) were suspended in DMF (30 mL) followed by addition of triethylamine (22 mL). Phenyl acetaldehyde (33.8 mL) was added such that the temperature was maintained at 50 0 C. The mixture was stirred for an additional 20 min at 50 °C followed by stirring at room temperature overnight. The mixture was poured into water (100 mL) and the aqueous solution was extracted with ethyl acetate (3 x 80 mL). The organic layers were washed with brine, separated, dried over MgSO 4 , filtered and concentrated.
• 6-Phenylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (Example 8, 1.2 g) and POCI 3 (IO mL) were placed in a thick-walled glass sealed tube and heated to 150 0 C for 2 hours. The mixture was cooled to room temperature and the POCI 3 was evaporated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined and dried over MgSO 4 , filtered, and concentrated. The crude residue was triturated with acetonitrile and the resulting solid was collected to give 0.71 g of the title compound.
• 1 H NMR 400 MHz, CDCI 3
• Example 11 To a mixture of the pyrimidine dihydrochloride salt of Example 11 (1.02 g) in DMF (5.0 mL) was added diisopropylethylamine (2.0 mL) and 4-biphenyl carbonyl chloride (0.63 g). The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in ethyl acetate, adsorbed to silica gel and placed on top of a Vz inch silica gel plug in a 60 mL sintered glass funnel.
• 6-Methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (Example 10, 2.0 g) and POCI 3 were heated together in a sealed tube at 150 0 C for 3 hours. The mixture was then cooled and concentrated under reduced pressure and the residue was partitioned between dichlorom ethane and aqueous saturated sodium bicarbonate. The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was triturated with diethyl ether containing a small amount of acetonitrile and the resulting solid was collected and dried under reduced pressure to give the title compound (1.75 g). MS (ESI+) m/z219.05 (M+H) + .
• 6-Propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 17, 2.0 g) and POCI 3 were heated in a sealed tube for 1.5 hours at 150 0 C. The mixture was then allowed to cool to room temperature and concentrated. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was dried over MgSO 4 , filtered and " concentrated under reduced pressure to give 1.1 g of the title compound. " MS (ESI+) for C 9 H 8 CI 2 N 2 S m/z 247.09 (M+H) + .
• HCI HCI gas was bubbled through methanol (75 mL) for 10 minutes, then cooled to room temperature.
• the carboxylate of Example 20 (1.34 g) was then added. The mixture was stirred at room temperature for 2 hours. The solvents were removed under reduced pressure and the residue dried under high vacuum for 48 hours. Ethyl acetate was added to residue and refluxed for 1 hour. The resulting solids were collected via filtration and dried under reduced pressure to give 0.93 g of the title compound.
• Example 25 To a mixture of the pyrimidine of Example 25 (0.123 g) in THF (4.0 ml_) in a round bottomed flask was added diisopropylethylamine (0.088 g), 3-biphenyl carboxylic acid (0.071 g), and HATU (0.136 g). The mixture was stirred at room temperature for 20 hours at which time the mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated.
• Example 28 To a mixture of the pyrimidine of Example 28 (0.15 g) in NMP (3.0 mL) was added 5M K 3 PO 4 (1.0 mL), trans-dichloro-bis triphenylphosphine palladium Il (0.019 g) and 4-carboxyphenyl boronic acid (0.049 g). The mixture was heated at 90 °C overnight then cooled to room temperature. The mixture was then partitioned between 1 N HCI and ethyl acetate. The layers were separated and the organic layer washed three times with 1N HCI, dried over anhydrous magnesium sulfate and concentrated.
• Example 30 To a mixture of the pyrimidine of Example 30 (0.43 g) in DMF (5 mL) was added diisopropylethylamine (0.284 g), 3-biphenyl carboxylic acid (0.218 g), and HATU (0.418 g). The mixture was stirred at room temperature for 18 hours at which time the mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated.
• Example 23 To a mixture of the pyrimidine of Example 23 (0.202 g) in DMF (5 mL) was added diisopropylethylamine (0.194 g), trans-2-phenyl-i-cyclopropyl carboxylic acid (0.123 g), and HATU (0.285 g). The mixture was stirred at room temperature for 4 days. The mixture was partitioned between brine and ethyl acetate.
• Example 39 The dione of Example 39 (2.6 g) was placed into a pressure vessel with phosphorus oxychloride (15 mL). The mixture was heated at 200 0 C for 2.3 hours and then cooled to room temperature and concentrated under reduced pressure. Residual phosphorus oxychloride was azeotroped . twice with toluene (30 mL) under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The resulting layers were separated and the organic layer was filtered through anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 1.06 g of the title compound: MS (ESI+) for C 6 H 2 N 2 CI 2 S m/z205.0 (M+H) + . 1 H NMR (400 MHz, CDCI 3 ) ⁇ 7.42 (d,1 H), 7.61 (d,1 H).
• 2,4-Dichloro-6-phenylthieno[2,3-d]pyrimidine (Example 9, 0.69 g) was dissolved in a mixture of THF/DMF (20 mL/3 mL). Diisopropylethylamine (0.42 g) and 1-(1 ,1'-biphenyl-4- ylcarbonyl)piperazine (0.98 g) were added. The mixture was stirred overnight at room temperature. The mixture was partitioned between ethyl acetate and brine. The organic layer was separated and washed four times with brine then separated, dried over MgSO 4 , filtered and concentrated. The resulting residue was stirred with hot acetonitrile containing a few drops of methanol.
• 2,4-Dichloro-6-methylthieno[2,3-d]pyrimidine (Example 16, 0.80 g) was dissolved in a mixture of THF/DMF (10 mL/6 mL) followed by addition of 1-(1 ,1'-biphenyl-4-ylcarbonyl)piperazine (1.45 g, 3.65 mmol) and diisopropylethylamine (0.61 g, 4.7 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and brine. The organic layer was separated and washed additional four times with brine. The organic layer was dried over MgSO 4 , filtered and concentrated.
• 2,4-Dichloro-6-propylthieno[2,3-d]pyrimidine (Example 18, 0.68 g) was dissolved in a mixture of THF/DMF (5 ml_/2 mL) followed by addition of 1-(1 ,1'-biphenyl-4-ylcarbonyl)piperazine (1.1 g) and DIEA (0.46 g). The mixture was stirred overnight at room temperature and then partitioned between ethyl acetate and brine. The ethyl acetate layer was washed an additional four times with brine. The organic layer was dried over MgSO 4 , filtered and concentrated.
• tert-Butyl (3R)-3-methylpiperazine-1 -carboxylate (332 mg) and 1 ,1'-biphenyl-4-carbonyl chloride (300 mg) were placed in a flask with 2.5 ml. of NMP and DIEA (0.5 ml_). The mixture was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by silica gel chromatography, eluting with 30:70 ethyl acetate-hexanes, to give 0.387 g of the title compound.
• tert-Butyl (3S)-3-methylpiperazine-1 -carboxylate (332 mg) and 1 ,1'-biphenyl-4-carbonyl chloride (300 mg) were placed in a flask with 2.5 mL of NMP and DIEA (0.5 mL). The mixture was stirred at room temperature overnight and then was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by silica gel chromatography, eluting with 30/70 ethyl acetate/hexanes, to give 0.466 g of the title compound.
• Example 49 The carboxylate of Example 49 was placed in a flask and cooled to 0 0 C (ice bath). 4N HCI in dioxane (2 ml_) was added. The mixture was stirred and gradually warmed to room temperature. After 90 minutes the mixture was diluted with ether. The resulting precipitate was collected, washed with ether, and dried to give 0.197g of the title compound. MS (ESI+) for Ci 8 H 20 N 2 O m/z 281.1627 (MH-H) + .
• Example 50 The carboxylate of Example 50 was placed in a flask and cooled to 0 0 C (ice bath). 4N HCI in dioxane (2 ml_) was added. The reaction was stirred and gradually warmed to room temperature. After 90 minutes the mixture was diluted with ether. The resulting precipitate was collected, washed with ether, and dried to give 0.212 g of the title compound.
• 2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine (Example 3, 125.8 mg) was dissolved in NMP (2.5mL). To this was added (2R)-1-(1 ,1'-biphenyl-4-ylcarbonyl)-2-methylpiperazine (170 mg) followed by DIEA (0.19 mL). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO 4 , filtered, and concentrated.
• 2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine (Example 3, 0.126 g) was dissolved in NMP (2.5mL). To this was added (2S)-1 -(1 ,1 '-biphenyl-4-ylcarbonyl)-2-methylpiperazine (170 mg) followed by DIEA (0.19 ml_). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO 4 , filtered, and concentrated.
• 2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine (Example 3, 0.300 g) and tert-butyl (3R)-3- methylpiperazine-1-carboxylate (0.307 g) were dissolved in NMP (2.5 mL) followed by addition of DIEA (0.5mL). The mixture was heated to 80 C C and stirred at this temperature overnight. The mixture was then cooled to room temperature and diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO 4 , filtered and concentrated.
• 2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine (Example 3, 0.300 g) and tert-butyl (3S)-3- methylpiperazine-1 -carboxylate (0.307 g) were dissolved in NMP (2.5 mL) followed by addition of DIEA (0.5mL). The mixture was heated to 80 0 C and stirred at this temperature overnight. The mixture was then cooled to room temperature and diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO 4 , filtered and concentrated.
• EXAMPLE 64 4-[(2S)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1 -yl]-2- ⁇ [(4S)-2,2-dimethyl-1 ,3-dioxolan- 4-yl]methoxy ⁇ -6-ethylthieno[2,3-d]pyrimidine
• Example 12 To the carboxylate of Example 12 (1.22 g) in dichloromethane (10 mL) was added HCI/MeOH (50 mL, prepared by the addition of 1.25 g of acetyl chloride to 50 mL of MeOH). The mixture was stirred at room temperature overnight, after which an additional 5 equivalents of HCI/MeOH (prepared as above) was added. After stirring for 4.5 hours, the mixture was concentrated to near dryness and diethyl ether was added. The resulting solid was collected and dried to give 1.08 g of the hydrochloride salt of Example 23.
• Example 24 To a mixture of the pyrimidine of Example 24 (0.116 g) in THF (3 mL) were added diisopropylethylamine (0.098 g), and 4-biphenyl carbonyl chloride (0.082 g). The mixture was stirred at room temperature for 3.5 hours. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated.
• HCI gas was bubbled through methanol (50 mL) for 1 minute then cooled to room temperature.
• the pyrimidine of Example 26 (0.15 g) was added. The mixture was stirred at room temperature for 15 minutes. The solvents were removed under reduced pressure and the residue was partitioned between saturated sodium bicarbonate and ethyl acetate.
• Example 33 To a mixture of the propanal of Example 33 (0.168 g) in methylene chloride (5 mL) was added m- chloroperoxybenzoic acid (0.078 g). The mixture was stirred at room temperature for 4 hours then chromatographed on silica gel (100 mL) using 2% methanol and 0.1% glacial acetic acid in hexanes to give 0.0708 g of the title compound: MS (ESI+) for C 28 H 28 N 4 O 4 S m/z 517.25 (MH-H) + .
• Example 35 To a mixture of the cyclopropane of Example 35 (0.197 g) in methanol (4 mL) was added 4N HCI in dioxane (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate.
• the mixture was then partitioned between saturated sodium bicarbonate and ethyl acetate.
• the layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated.
• the residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent.
• the residue was dissolved in methanol (2.0 mL) and 4N HCI in dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours, at which time the mixture was partitioned between saturated sodium bicarbonate and ethyl acetate.
• Example 36 To a mixture of the pyrimidine of Example 36 (0.1 g) and NMP (2 ml_) in a 2 dram screw capped vial was added 3,4-difluorophenyl boronic acid (0.056 g), 5M K 3 PO 4 (0.5 ml_), palladium Il acetate (0.004 g) and, tri-o-tolyl phosphine (0.011 g).
• the vial was placed into a Lab-Line MAX Q2000 orbital shaker at 80 0 C overnight. The mixture was partitioned between brine and ethyl acetate, the layers were separated and the organic layer washed three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
• Example 36 To a mixture of the pyrimidine of Example 36 (0.1 g) and NMP (2 mL) in a 2 dram screw capped vial was added 4-trifluoromethyl phenyl boronic acid (0.068 g), 5M K 3 PO 4 (1.0 mL), palladium Il acetate (0.004 g) and, tri-o-tolyl phosphine (0.011 g).
• the vial was placed into a Lab-Line MAX Q2000 orbital shaker at 80 0 C overnight. The mixture was partitioned between brine and ethyl acetate, the layers were separated and the organic layer washed three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated.
• Example 37 Sodium hydride 60% in mineral oil (0.026 g) was placed into a round bottom flask, washed with hexanes and chilled in an ice/acetone bath. NMP (1 mL) was added and the mixture stirred for 15 minutes. (2,2-Dimethyl-1 ,3-dioxan-5-yl)methanol (Example 37, 0.095 g) was added and the mixture stirred for 30 minutes. The pyrimidine of Example 13 (0.15 g) was dissolved in NMP (2.0 mL) and added drop-wise to the chilled mixture. Once the addition was complete the mixture was removed from the ice/acetone bath and stirred at room temperature for 18 hours.
• the mixture was then partitioned between saturated sodium bicarbonate and ethyl acetate.
• the layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated.
• the residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent.
• the residue was dissolved in methanol (2.0 mL) and 4N HCI in dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour, at which time the mixture was partitioned between saturated sodium bicarbonate and ethyl acetate.
• Example 25 To a mixture of the pyrimidine of Example 25 (0.15 g) in NMP (3 mL) was added diisopropylethylamine (0.109 g), phenoxy acetic acid(0.064 g), and HATU (0.16 g). The mixture was stirred at room temperature for 4 hours. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed three times with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent. Fractions containing product were combined and concentrated.
• Example 36 To a mixture of the pyrimidine of Example 36 (0.1 g) in NMP (1 mL) was added tri-o- tolylphosphine (0.011 g), palladium (II) acetate (0.004 g), 5M K 3 PO 4 (1 mL), and pyrimidine-5- boronic acid (0.044 g). The mixture was placed in a 20 mL screw cap vial and place in a Lab- Line MAX Q2000 orbital shaker at 80 0 C overnight. The mixture was removed from heat and cooled to room temperature. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated.
• Example 36 To a mixture of the pyrimidine of Example 36 (0.105 g) in NMP (2 mL) was added tri-o- tolylphosphine (0.011 g), palladium (II) acetate (0.004 g), 5M K 3 PO 4 (1 mL), and 3,5- difluorophenyl boronic acid (0.059 g). The mixture was placed in a 20 mL screw cap vial and place in a Lab-Line MAX Q2000 orbital shaker at 80 0 C overnight. The mixture was removed from heat and cooled to room temperature. The mixture was partitioned between brine and ethyl acetate.
• Example 25 To a mixture of the pyrimidine of Example 25 (0.159 g) in NMP (.15 mL) was added diisopropylethylamine (0.109 g), 3,4-difluorophenyl acetic acid (0.077 g), and HATU (0.171 g). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent.
• the mixture was then partitioned between saturated sodium bicarbonate and ethyl acetate.
• the layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated.
• the residue was chromatographed on silica gel (100 mL) using ethyl acetate.
• the resulting residue was dissolved in methanol (5 mL) to which was added 4N HCI in dioxane (0.5 mL).
• the mixture was placed in a 4 0 C refrigerator for 18 hours.
• the mixture was partitioned between saturated sodium bicarbonate and ethyl acetate.

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