EP1844052A1 - Thieno[2,3-d]pyrimidine compounds as inhibitors of adp-mediated platelets aggregation - Google Patents

Thieno[2,3-d]pyrimidine compounds as inhibitors of adp-mediated platelets aggregation

Info

Publication number
EP1844052A1
EP1844052A1 EP06710294A EP06710294A EP1844052A1 EP 1844052 A1 EP1844052 A1 EP 1844052A1 EP 06710294 A EP06710294 A EP 06710294A EP 06710294 A EP06710294 A EP 06710294A EP 1844052 A1 EP1844052 A1 EP 1844052A1
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
aryl
heterocyclyl
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06710294A
Other languages
German (de)
French (fr)
Inventor
Michael Dalton Pfizer Global R & D ENNIS
Steven Wade Pfizer Global R & D KORTUM
Hayat Pfizer Global R & D RAHMAN
Barbara Ann Pfizer Global R & D SCHWEITZER
Ruth Elizabeth Pfizer Global R & D TENBRINK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co LLC
Original Assignee
Pharmacia and Upjohn Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia and Upjohn Co LLC filed Critical Pharmacia and Upjohn Co LLC
Publication of EP1844052A1 publication Critical patent/EP1844052A1/en
Withdrawn legal-status Critical Current

Links

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.

Abstract

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I): wherein A1, A2, A3, A4, A5, A6, A7, A8, X4, X6, R2, R4, R5, and R6 are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

Description

THIENO [2 , 3-D] PYRIMIDINE COMPOUNDS AS INHIBITORS OF ADP-MEDIATED PLATELETS AGGREGATION
CROSS REFERENCE TO OTHER APPLICATIONS
This application claims priority to U.S. Provisional application number 60/647,340, filed January 26, 2005 and U.S. Provisional application number 60/659,337, filed March 7, 2005.
FIELD OF THE INVENTION
The present invention comprises a novel class of thieno[2,3-d|pyrimidine compounds having the structure of Formula I (including tautomers and salts of those compounds) and pharmaceutical compositions comprising a compound of Formula I. 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.
BACKGROUND OF THE INVENTION
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. Commercially available drugs that inhibit platelet function typically fall within one of three classes of drugs that antagonize different molecular targets: (1) 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. et al., Circulation, 1999, Vol.100, pg.1667. There are several disadvantages associated with use of the P2Y12 receptor antagonists ticlopidine and clopidogrel. First, although both compounds selectively inhibit platelet aggregation by blocking the P2Y12 receptor, such inhibition is irreversible and increases the bleeding risk to the patient. Second, both ticlopidine and clopidogrel each have a relatively slow onset of action. Both compounds apparently are prodrugs that first must be metabolized by the liver into the corresponding active metabolites. Third, a number of patients are resistant to treatment with clopidogrel. Such resistance may result, in whole or in part, from drug-drug interactions between clopidogrel and other drugs commonly administered to atherosclerotic patients. Fourth, both ticlopidine and clopidogrel have been associated with side-effects such as thrombocytopenia in some patients (see Bennett, CL. et al., New England Journal of Medicine, 2000, Vol. 342, pg. 1773). Other compounds have been reported in the literature as useful for the treatment of cardiovascular events such as thrombosis:
US2003/0153566 A1 (published August 14, 2003)describes a class of piperazine compounds as
ADP receptor antagonists. WIPO Int'l Publ. No. WO99/05144 A1 (published February 4, 1999) describes a class of triazolo[4,5-d]pyrimidine compounds as P2T antagonists.
WIPO Int'l Publ. No. WO99/36425 A1 (published July 22, 1999) describes a class of tricyclic compounds as ADP receptor antagonists.
WIPO Int'l Publ. No. WO01/57037 A1 (published August 9, 2001) describes a class of compounds including sulfonylureas as ADP receptor antagonists.
US 5,057,517 (granted October 15, 1991) describes a class of heteroaromatic compounds including 6-piperazinopurines as antidiabetic agents.
US 4,459,296 (granted July 10, 1984) describes a class of N-(benzimidazolyl, indolyl, purinyl or benzotriazolyl)-piperazine compounds as antihypertensive agents. Humphries et al. describe several purine compounds as selective ADP receptor antagonists in an animal thrombosis model. Trends in Pharmacological Sciences, 1995, Vol. 16, pg. 179. These compounds are further described in Ingall, A.H et al., Journal of Medicinal Chemistry, 1999, Vol.
42, pg. 213.
Accordingly, a need still exists for new drug therapies for the treatment of subjects suffering from or susceptible to a platelet aggregation mediated condition. In particular, a need still exists for new P2Y12 antagonists having one or more improved properties (such as safety profile, efficacy, or physical properties) relative to currently available P2Y12 antagonists.
SUMMARY OF THE INVENTION In one embodiment, the invention comprises a class of compounds (including the pharmaceutically acceptable salts of the compounds) having the structure of Formula I:
Formula I wherein A1, A2, A3, A4, A5, A6, A7, A8, X4, X6, R2, R4, R5, and R6 are as defined in the detailed description of the invention.
In another embodiment, the invention comprises a pharmaceutical composition comprising a compound having the structure of Formula I.
In another embodiment, 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.
In another embodiment, 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.
In another embodiment, the invention comprises intermediates useful in the synthesis of compounds having the structure of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
This detailed description of embodiments is intended only to acquaint others skilled in the art with Applicants' inventions, its principles, and its practical application so that others skilled in the art may adapt and apply the inventions in their numerous forms, as they may be best suited to the requirements of a particular use. These inventions, therefore, are not limited to the embodiments described in this specification, and may be variously modified.
A. Abbreviations and Definitions
TABLE A - Abbreviations
The term "alkyl" refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substitueπt containing only carbon and hydrogen) containing in one embodiment, from about one to about twentycarbon atoms; in another embodiment froπr 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. Examples of such 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.
-The term "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. Examples of 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). The term "alkenyl" embraces substituents having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.
The term "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. Examples of alkynyl substituents include ethynyl, propynyl (including 1-propynyl and 2-propynyl) and butynyl (including 1-butynyl, 2-butynyl and 3-butynyl). The term "benzyl" means a methyl radical substituted with phenyl, i.e., the following structure:
The term "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.
The term "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.
The term "cycloalkenyl" refers~to a partially unsaturated carbocyclyl substituent. Examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
The term "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. The term "aryl" refers to aromatic substituents such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
The term "arylalkyl" means alkyl substituted with aryl.
In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix "Cx-Cy-," wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example,
"CrCβ-alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C3-C6-cycloalkyl means a saturated carbocyclyl containing from 3 to 6 carbon ring atoms.
The term "hydrogen" means a hydrogen substituent, and may be depicted as -H.
The term "hydroxy" refers to -OH. When used in combination with another term(s), the prefix
"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.
The term "phenol" refers to a hydroxy substituent bonded to a benzene ring.
The term "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.
The term "nitro" means -NO2.
N
C
The term "cyano" (also referred to as "nitrile") -CN, which also may be depicted: ^^Arυ
The term "carbonyl" means-C(O)-, which also may be depicted as:
The term "amino" refers to -NH2.
The term "alkylamino" refers to an amino group, wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom. Examples of alkylamino substituents include monoalkylamino such as methylamino (exemplified by the formula -NH(CH3)), which may also
be depicted: and dialkylamino such as dimethylamino, (exemplified by the formula -N((CH3)2), which may also be
The term "aminocarbonyl" mean s -C(O)-NH2, which also may be depicted as:.
The term "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). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is a fluorine.
The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen substituents. For example, 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. Examples of haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl. Illustrating further, "haloalkoxy" means an alkoxy substituent wherein at least one hydrogen substituent is replaced by a halogen substituent. Examples of 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. Examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl. To illustrate further, the term "perfluoroalkoxy" means an alkoxy substituent wherein each hydrogen substituent is replaced with a fluorine substituent. Examples of perfluoroalkoxy substituents include trifluoromethoxy (-0-CF3), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy. The term "oxo" refers to =0. The term "oxy" means an ether substituent, and may be depicted as -O-. The term "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.
The term "alkylthio" means -S-alkyl. For example, "methylthio" is -S-CH3. Other examples of alkylthio include ethylthio, propylthio, butylthio, and hexylthio.
The term "alkylcarbonyl" means -C(O)-alkyl. For example, "ethylcarbonyl" may be depicted
as: . Examples of other alkylcarbonyl include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, and hexylcarbonyl.
The term "aminoalkylcarbonyl" means -C(O)-alkyl-NH2. For example, "aminomethylcarbonyl"
may be depicted as:
The term "alkoxycarbonyl" means -C(O)-O-alkyl. For example, "ethoxycarbonyl" may be
depicted as: . Examples of other alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl. In another embodiment, where the carbon atom of the carbonyl is attached to a carbon atom of a second alkyl, the resulting functional group is an ester. The term "carbocyclylcarbonyl" means -C(O)-carbocyclyl. For example, "phenylcarbonyl" may be
depicted as: . Similarly, the term "heterocyclylcarbonyl," alone or in combination with another term(s), means -C(O)-heterocyclyl.
The term "carbocyclylalkylcarbonyl" means -C(O)-alkyl-carbocyclyl. For example,
"phenylethylcarbonyl" may be depicted as: . Similarly, the term
"heterocyclylalkylcarbonyl," alone or in combination with another term(s), means -C(O)-alkyl-heterocyclyl. The term "carbocyclyloxycarbonyl," means -C(O)-O-carbocyclyl. For example,
"phenyloxycarbonyl" may be depicted as:
The term "carbocyclylalkoxycarbonyl" means -C(O)-O-alkyl-carbocyclyl. For example,
"phenylethoxycarbonyl" may be depicted as:
The terms "thio" and "thia" mean a divalent sulfur atom and such a substituent may be depicted as -S-. For example, a thioether is represented as "alkyl-thio-alkyP or, alternatively, alkyl-S-alkyl.
The term "thiol" means a sulfhydryl substituent, and may be depicted as -SH.
The term "thione" refers to =S.
The term "sulfonyl" means -S(O)2-, which also may be depicted as: . Thus, for example, "alkyl-sulfonyl-alkyl" means alkyl-S(O)2-alkyl. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
The term "aminosulfonyl" means -S(O)2-NH2, which also may be depicted as:
The term "sulfinyl" or "sulfoxido" means -S(O)-, which also may be depicted as : 7 Thus, for example, "alkylsulfinylalkyl" or "alkylsulfoxidoalkyl" means alkyl-S(O)-alkyl. Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl. The term "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.
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. Examples of 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, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (Including oxadiazolyl, 1 ,2,4-oxadiazolyl (also known as "azoximyl"), 1 ,2,5-oxadiazolyl (also known as "furazanyl"), or 1 ,3,4-oxadiazolyl), oxatriazolyl (including 1 ,2,3,4-oxatriazolyl or 1 ,2,3,5-oxatriazolyl), dioxazolyl (including 1 ,2,3-dioxazolyl, 1 ,2,4-dioxazolyl, 1 ,3,2-dioxazolyl, or 1 ,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1 ,2-pyranyl or 1 ,4-pyranyl), dihydropyranyl, pyridinyl (also known as "azinyl"), piperidinyl, diazinyl (including pyridazinyl (also known as "1 ,2-diazinyl"), pyrimidinyl (also known as "1 ,3-diazinyl" or "pyrimidyl"), or pyrazinyl (also known as "1 ,4-diazinyl")), piperazinyl, triazinyl (including s-triazinyl (also known as "1 ,3,5-triazinyl"), as-triazinyl (also known 1 ,2,4-triazinyl), and v-triazinyl (also known as "1 ,2,3-triazinyl")), oxazinyl (including 1 ,2,3-oxazinyl, 1 ,3,2-oxazinyl, 1 ,3,6-oxazinyl (also known as "pentoxazolyl"), 1 ,2,6-oxazinyl, or 1 ,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl.'isoxazolidinyl, oxathiazinyl (including 1 ,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1 ,4,2-oxadiazinyl or 1 ,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.
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). Examples of 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, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl. Other examples of 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"), benzothiopyranyl (also known as "thiochromanyl"), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl," "thionaphthenyl," or "benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl," "isothionaphthenyl," or "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1 ,3,2-benzoxazinyl , 1 ,4,2-benzoxazinyl , 2,3,1 -benzoxazinyl , or 3,1 ,4-benzoxazinyl ), benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl), tetrahydroisoquinolinyl , carbazolyl, xanthenyl, and acridinyl. The term "heteroaryl" means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include
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.
The term "heterocyclylalkyl" means alkyl substituted with a heterocyclyl.
The term "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. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition.
If a substituent is described as being "substituted," a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon or nitrogen of the substituent. Thus, for example, 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. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and 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).
If a substituent is described as being "optionally substituted," the 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
(to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen 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 nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent.
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. In one embodiment, the heterocyclic ring consists of 3 to 7 atoms. In another embodiment, the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl.
This specification uses the terms "substituent," "radical," and "group" interchangeably.
If 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. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then 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. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen substituent. To illustrate further, if 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.
A prefix attached to a multi-moiety substituent only applies to the first moiety. To illustrate, the term "alkylcycloalkyl" contains two moieties: alkyl and cycloalkyl. Thus, the C1-C6- prefix on CrC6-aikylcycloalkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the C1-C6- prefix does not describe the cycloalkyl moiety. To illustrate further, the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkyl substituent is substituted with one or more halogen substituents. If 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."
When a substituent is comprised of multiple moieties, unless otherwise indicated, it is the intention for the final moiety to serve as the point of attachment to the remainder of the molecule. For example, in a substituent A-B-C, moiety C is attached to the remainder of the molecule. In a substituent A-B-C-D, moiety D is attached to the remainder of the molecule. Similarly, in a substituent aminocarbonylmethyl, the methyl moiety is attached to the remainder of the molecule,
where the substituent may also be be depicted as . In a substituent trifluoromethylaminocarbonyl, the carbonyl moiety is attached to the remainder of the molecule,
where the substituent may also be depicted as F F
If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s). B. Compounds
The present invention comprises, in part, a novel class of thieno[2,3-d]pyrimidine compounds.
These compounds are useful as inhibitors of platelet mediated aggregation.
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:
Formula I wherein:
A1, A2, A3, A4, A5, A6, A7 and A8 are independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
R2 is selected from the group consisting of -C(O)R2a, -C(S)RZa, -C(O)OR2a, -C(O)NR2aR2b, -C(S)NR2aR2b, -R2c1 and -R2c2 wherein: R2a and R2b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2a and R2b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently
2d ,2d selected from the group consisting of halogen, -CN, =0, =S, -SR , -NO2, -R , -C(O)R -,2d
-C(S)R2d,
-C(O)OR2d , -C(S)OR2d , -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2θ, -OR2d, -OC(O)R2d, -0C(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2β, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2θ, -NR2dC(O)NR2eR2f, -S(O)nR2 -S(O)2NR2dR2e, and -SC(O)R2d;
-,2c1
R is Ci-C6-alkyl, wherein the R Ci-C6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -Cl, -Br, -I, -CN, =0, =S, -SR2d, -NO2, -C(0)R2d, -C(S)R2d, -C(O)OR2d , -C(S)OR2d , -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -0R2d, -OC(O)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f,- -S(O)nR2d, -S(O)2NR2dR2Θ, and -SC(O)R2d; wherein the alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents of the R2c1 C1- C6-alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R29, -
SR29,
-C(O)R29, -C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR29R2h, -C(O)OC(O)R29, -C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R29, -OC(O)OR29, -OC(O)NR29R2h, -OC(S)NR29R2h, -NR2gR2h, -NR2gC(O)R2h, -NR29C(S)R2h, -NR29C(O)OR2h, -NR29C(S)OR211, -NR2gS(O)2R2h, -NR29C(O)NR2hR2i, -S(O)PR29, -S(O)2NR2gR2h, and -SC(O)R29; R2c2 is selected from the group consisting of C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein the R202 C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halogen, -CN, =0, =S, -SR2d, -NO2, -C(0)R2d, -C(S)R2d, -C(0)0R2d , -
C(S)0R2d ,
-C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -0R2d, -0C(0)R2d, -OC(S)R2d, -0C(0)0R2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2θ, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)0R26, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d, -S(O)2NR2dR2e, and -SC(O)R2d; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents of the
R2c2 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R2g, - SR29, -C(O)R29,
-C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29, - C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR29, -OC(O)NR2gR2h, -OC(S)NR2gR2h, - NR2gR2h, -NR29C(O)R2h, -NR29C(S)R2h, -NR29C(O)OR2h, -NR29C(S)OR2h, -NR29S(O)2R2h, -NR2gC(O)NR2hR2i, -S(O)PR29, -S(O)2NR2gR2h, and -SC(O)R29; n is 1 or 2;
R2d, R2e and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2d, R2e and R2f 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, -CN, =0, =S, -NO2, -R2g, -SR2g, -C(O)R29, -C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29, -C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR2g, -OC(O)NR2gR2h, -OC(S)NR2gR2h, -NR2gR2h, -NR2gC(O)R2h, -NR2gC(S)R2h, -NR2gC(O)OR2h, -NR2gC(S)OR2h, -NR2gS(O)2R2h, -NR2gC(O)NR2hR21, -S(O)pR2g, -S(O)2NR2gR2h, and -SC(O)R29; p" is 1 or 2; R2g, R2h and R2' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R29' R2h and R2' 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 R2m;
R2m is selected from the group consisting of -CN, -NO2, -NH2, =0, =S, -SR2n, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C(O)R2", -C(S)R2", -C(O)OR2" , -C(S)OR2"
-C(O)SR2", -C(O)NR2nR20, -C(S)NR20R20, -OR2", -OC(O)R2", -OC(S)R2", -OC(O)OR2", -OC(O)NR2"R20, -OC(S)NR2"R20, -NR2nR2°, -NR2nC(O)R2°, -NR2nC(S)R2°, -NR20C(O)OR20, -NR2"C(S)OR20, -NR20S(O)2R20, -NR2nC(O)NR2oR2p, -S(O)qR2", -S(O)2NR2"R2°, and -SC(O)R2"; q is 1 or 2;
R2" R20 and R2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2m, R2", R20 and R2p alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -NO2, =0, =S, -SR2q, -R2q, -C(0)R2q, -C(S)R20, -C(O)OR20 , -C(S)0R2q , -C(0)SR2q, -C(O)NR2qR2r, -C(S)NR2qR2r, -C(0)0C(0)R2q, -C(0)SC(0)R2q, -OR2q, -0C(0)R2r, -OC(S)R2q,-OC(O)OR2q,-OC(O)NR2qR2r, -OC(S)NR2qR2r, -NR2qR2r, -NR2qC(O)R2r, -NR2qC(S)R2r, -NR2qC(O)OR2r, -NR2qC(S)OR2r, -NR2qS(O)2R2r, -NR2qC(O)NR2rR2s, -S(O)rR2q, -S(O)2N R2qR2r, and -SC(O)R2q; r is 1 or 2; R2q, R2r and R2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2q> R2r and R2s 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, hydroxy, -CN, =0, =S, -SH, -NO2, amino, alkyl, haloalkyl, carboxy, alkoxy, alkylamino and alkoxycarbonyl;
X4 is selected from the group consisting of -C(O)-, -C(S)-, -S(O)- and -S(O)2-;
R4 is selected from the group consisting of -CN, -R4a, -0R4a, -C(0)R4a, -0C(0)R4a, -
NR4aR4b, -NR4aC(O)R4b, -NR4aS(O)2R4b, -SR4a, and -SC(0)R4a; wherein:
R4a and R4b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R4a and R4b 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, haloalkyl, hydroxyalkyl, =0, =S, -CN, - NO2, -R4d, -OR40, -C(0)R4d, -C(O)OR40, -C(O)NR4dR4e, -OC(O)R40, -OC(O)NR4oR4e, - NR4dR4e, -NR4dC(O)R4β, -NR4dS(O)2R4e, -S(O)bR4d, -SC(O)R4d, and -SC(O)NR4dR4e; b is 0, 1 or 2;
R4dand R4e are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R4d and R4e 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, haloalkyl, =0, =S, -CN, -NO2, -R4V-
C(0)R4f, -C(O)OR4',
-C(O)NR4fR4g, -0R4f, -OC(O)R4', -OC(O)NR4fR4g, -NR4fR4g, -NR4fC(O)R4g, -NR4fS(O)2R49, -S(O)cR4f, -S(O)2NR4fR43, -SC(O)R4', and -SC(O)NR4fR4g; c is 0, 1 or 2;
R4' and R4g are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; the R4' and R4g alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, =0, =S, -CN, -NO2, -SR4h, -R4h, -C(O)R4h, -C(O)OR4h, -
C(O)NR4hR4i,
-0R4h, -OC(O)R41, -OC(O)NR4hR4i, -NR4hR4i, -NR4hC(O)R4i, -NR4hS(O)2R4i, -S(O)dR4h, -S(O)2NR4hR4i, -SC(0)R4h, and -SC(O)NR4hR41; d is 1 or 2;
R4hand R4' are independently selected from the group consisting of hydrogen, alkyl, • haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
R5 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, heterocyclyl, and -0R5a; R5a is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl; wherein the R5 and R5a 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;
X6 represents a bond or is -C(O)-; wherein: when X6 is -C(O)-, R6 is selected from the group consisting of halogen, -CN, -NO2, -R6a,
-0R6a, -OC(O)R63, -OC(O)NR6aR6b, -NR6aR6b, -NR6aC(O)R6b, -NR6aS(O)2R6b, -SR6a, -
SC(O)R68, and -SC(O)NR6aR6b; and when X6 represents a bond, R6 is selected from the group consisting of halogen, -
CN, -NO2, -R6a, -SR6a, -0R6a, -S(O)xR63, -S(O)2N R6aR6b, -OC(O)R63, -S(O)xOR63, - S(O)xOC(O)R63,
-OC(O)NR6aR6b, -NR63R6", -NR6aC(O)R6b, -NR6aS(O)2R6b, -SR6a, -SC(O)R63, and -SC(O)NR6aR6b; x is 1 or 2;
R6a and R6b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; ' wherein the R6a and R6b alkyl, alkenyl,"alkyήyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -SR6c, -R60, -C(O)R6c, -C(O)OR60, -C(O)NR60R6d, -C(O)SR60, -OR60, -OC(O)R60, -OC(0)NR6oR6d, -NR6oR6d, -NR6oC(O)R6d, -NR60S(O)2R6d, -S(O)vR6c, -S(O)2NR6cR6d, -SC(O)R60, and -SC(O)NR6cR6d; v is 1 or 2; and
R6oand R6d are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, carboxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl.
In one embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen. In another embodiment, A1, A2, A4, A5, A6, A7 and A8 are each hydrogen and A3 is methyl. In still another embodiment, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen and A1 is methyl. In another embodiment of the compounds of Formula (I), R5 is selected from the group consisting of hydrogen, halogen, alkyl, and -0R5a, wherein the R5 alkyl substituent may be optionally substituted as provided in other embodiments herein, and R5a is defined as provided in other embodiments herein. In another embodiment, R5 is selected from the group consisting of hydrogen, halogen, and alkyl, wherein the R5 alkyl substituent may be optionally substituted as above. In still another embodiment, R5 is selected from the group consisting of hydrogen, halogen and methyl. In still another embodiment, R5 is hydrogen.
In another embodiment of the compounds of Formula (I), R6 is selected from the group consisting of halogen, -R6a and -0R6a, wherein R6a is defined as provided in other embodiments herein. In one embodiment, R6 is halogen. In another embodiment, R6 is fluorine. In another embodiment, R6 is chlorine. In another embodiment, R6 is bromine.
In still another embodiment, X6 represents a bond and R6 is -R6a, wherein R6a is defined as provided in other embodiments herein. In still another embodiment, X6 is -C(O)- and R6 is - 0R6a, wherein R6a is defined as provided in claim 1. In still another embodiment, R6 is selected from the group consisting of -R6a and -0R6a, and R6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heterocyclyl, wherein the R6a alkyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein. In still another embodiment, R6 is selected from the group consisting of -R6a and -0R6a, and R6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R6a alkyl and aryl substituents may be optionally substituted as provided in other embodiments herein. In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is hydrogen and alkyl, wherein the R6a alkyl substituent may be optionally substituted as provided in other embodiments herein. In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is hydrogen. In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl and phenyl. In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl. In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is selected from the group consisting of methyl, ethyl, propyl, butyl, and pentyl. In another embodiment, X6 represents a bond, R6 is -R6a; and R6a is unsubstituted alkyl. In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R6a substituent is substituted with one or more halogen substituents. In still another embodiment, X6 represents a bond, R6 is -R6a; and R6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R6a substituent is substituted with one or more fluorine substituents. In another embodiment, X6 represents a bond, R6 is -R6a; and R6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R6a substituent is substituted with one or more chlorine substituents. In another embodiment, X6 represents a bond, R6 is -R6a; and R6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R6a substituent is substituted with one or more bromine substituents. In another embodiment of the compounds of Formula (I), X4 is -C(O)-.
In another embodiment of the compounds of Formula (I), R4 is selected from the group consisting of -R4a, -OR4a, and -NR4aR4b; and R4a and R4b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, wherein the R4a and R4b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein. In another embodiment, R4 is selected from the group consisting of -R4a, -OR4a, and -NR4aR4b; R4a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R4a alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein; and R4b is selected from the group consisting of hydrogen and alkyl, wherein the R4b alkyl substituent may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), R4 is -R4a; and R4a is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, wherein the R4a alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein. In another embodiment, R4 is -R4a; and R4a is selected from the group consisting of phenyl, oxadiazolyl, thiazolyl, pyridinyl, cyclopropyl, methyl, ethyl and fluorenyl; wherein the R4a substituents may be optionally substituted as provided in other embodiments herein. In still another embodiment, R4 is -OR4a; and R4a is selected from the group consisting of methyl and ethyl, wherein the R4a substituents may be optionally substituted as provided in other embodiments herein. In still another embodiment, R4 is -NR4aR4b; and R4a is selected from the group consisting of methyl and R4b is hydrogen, wherein the R4a methyl may be optionally substituted as provided in other embodiments herein.
In still another embodiment, R4 is -R4a; and R4a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R4a substituent is substituted with one or more halogen substituents. In still another embodiment, R4 is -R4a; and R4a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R4a substituent is substituted with one or more fluorine substituents. In another embodiment, R4 is -R4a; and R4a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R4a substituent is substituted with one or more chlorine substituents. In another embodiment, R4 is -R4a; and R4a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein said R4a substituent is substituted with one or more bromine substituents. In another embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R2°2; X4 is -C(O)-; R4 is selected from the group consisting of -R4a, -OR4a, and -NR4aR4b; R4a and R4b are independently selected from the group consisting of hydrogen, alky], cycloalkyl, aryl, and heterocyclyl, wherein the R4a and R4b alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein; R5 is selected from the group consisting of hydrogen, halogen, alkyl, and -OR5a, wherein the R5 alkyl substituent may be optionally substituted as provided in other embodiments herein, and R5a is defined as provided in other embodiments herein; and R6 is selected from the group consisting of -R6a and -OR6a, wherein R6a is defined as provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R2c2; X4 is -C(O)-; R4 is selected from the group consisting of -R4a, -OR4a, and -NR4aR4b; R4a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R4a alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein; R4b is selected from the group consisting of hydrogen and alkyl, wherein the R4b alkyl substituent may be optionally substituted as provided in other embodiments herein; R5 is selected from the group consisting of hydrogen, halogen, and alkyl, wherein the R5 alkyl substituent may be optionally substituted as provided in other embodiments herein; R6 is selected from the group consisting of -R6a and -OR6a; and R6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heterocyclyl, wherein the R6a alkyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R2c2; X4 is -C(O)-; R4 is - R4a; R4a is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R4a alkyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted as provided in other embodiments herein; R5 is hydrogen; R6 is selected from the group consisting of -R6a and -OR6a; and R6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R6a alkyl and aryl substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R2c2; X4 is -C(O)-; R4 is - OR4a; R4a is alkyl, wherein the R4a alkyl substituent may be optionally substituted as provided in other embodiments herein; R5 is hydrogen; R6 is selected from the group consisting of -R6a and -OR6a; and R6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R6a alkyl and aryl substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R2c2; X4 is -C(O)-; R4 is - NR4aR4b; R4a is alkyl and R4b is hydrogen, wherein the R4a alkyl substituent may be optionally substituted as provided in other embodiments herein; R5 is hydrogen; R6 is selected from the group consisting of -R6a and -OR6a; and R6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R6a alkyl and aryl substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R202; X4 is -C(O)-; R4 is - R4a; R4a is selected from the group consisting of phenyl, oxadiazolyl, thiazolyl, pyridinyl, cyclopropyi, methyl, ethyl and fluorenyl, wherein the R4a substituents may be optionally substituted as provided in other embodiments herein; R5 is hydrogen; X6 represents a bond; R6 is -R6a; and R6a is alkyl, wherein the R6a alkyl substituent may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R202; X4 is -C(O)-; R4 is - OR4a; R4a is selected from the group consisting of methyl and ethyl, wherein the R4a alkyl substituents may be optionally substituted as provided in other embodiments herein; R5 is hydrogen; X6 represents a bond; R6 is -R6a; and R6a is alkyl, wherein the R6a alkyl substituent may be optionally substituted as provided in other embodiments herein. In another embodiment of the compounds of Formula (I), A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R2c2; X4 is -C(O)-; R4 is - NR4aR4b; R4a is selected from the group consisting of methyl, wherein the R4a methyl may be optionally substituted as provided in other embodiments herein; R4b is hydrogen; R5 is hydrogen; X6 represents a bond; R6 is -R6a; and R6a is alkyl, wherein the R6a aikyl substituent may be optionally substituted as provided in other embodiments herein. In another embodiment of the compounds of Formula (I), X6 represents a bond; R6 is -R6a; and R6a is unsubstituted alkyl.
In another embodiment, the compound of Formula (I) has one of the structures shown in Table B below:
TABLE B - Formulae
wherein R2, R2b, R2c1, R2c2, R4, and R6 are as defined in any of the embodiments described in this application.
In another embodiment, the compound of Formula (I) has one of the structures shown in Table B; and R6 is -R6a, wherein R6a is selected from the group consisting of alkyl and phenyl. In still another embodiment, the compound of Formula (I) has one of the structures shown in Table B; and R6 is -R6a, wherein R6a is unsubstituted alkyl. In still another embodiment, the compound of
Formula (II) has one of the structures shown in Table B; and R6 is -R6a, wherein R6a 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:
wherein:
R is selected from the group consisting of -R ,2c1 and -R ,2c2 , wherein:
,2c1
R is Ci-C6-alkyl, wherein the R CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -Cl, -Br, -I, -CN, =0, =S, -SR ι2d , -NO2,
-)2d ,2d -,2d ,2d 2d 32dD2e
-C(O)R"0, -C(S)R'0, -C(O)OR"0 , -C(S)OFT , -C(O)SR*0, -C(O)NR -,2^do2e6, -C(S)NRΛFT, -OR"0, - 0C(0)R2d, -OC(S)R20, -OC(O)OR20, -OC(O)NR2aR2e, -OC(S)NR2dR2e, -NR20R26, -NR20C(O)R26, -NR20C(S)R26, -NR20C(O)OR26, -NR20C(S)OR26,
-NR20S(O)2R26, -NR20C(O)NR26R2', -S(O)nR20, -S(O)2NR20R28, and -SC(O)R20; wherein the alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents of the R2c1 C1- C6-alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R29, -SR29, -C(O)R29, -C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR29R2h,
-C(S)NR29R2h, -C(O)OC(O)R29, -C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R29, -OC(O)OR29, -OC(O)NR29R211, -OC(S)NR29R211, -NR29R2h, -NR29C(O)R211, -NR29C(S)R2h, -NR2gC(O)OR2h, -NR29C(S)OR211, -NR29S(O)2R211, -NR2gC(O)NR2hR2i, -S(O)pR2g, -S(O)2NR29R2*1, and -SC(O)R29;
R2c2 is selected from the group consisting of C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein the R2c2 C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryi and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halogen, -CN, =0, =S, -SR2d, -NO2, -C(O)R20, -C(S)R20, -C(O)OR20 , - C(S)OR20 , -C(O)SR20, -C(O)NR20R26, -C(S)NR20R28, -0R2d, -OC(O)R20, -OC(S)R20, -OC(O)OR20,
-OC(O)NR20R28, -OC(S)NR20R28, -NR2dR2e, -NR20C(O)R26, -NR20C(S)R28, -NR20C(O)OR26, -NR20C(S)OR28, -NR20S(O)2R26, -NR20C(O)NR28R2', -S(O)nR20, -S(O)2NR20R26, and -SC(O)R20; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents of the R2c2 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R2g, - SR29, -C(O)R29, -C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29, - C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR29, -OC(O)NR2gR2h, -OC(S)NR2gR2h, - NR2gR2h, -NR2gC(O)R2h, -NR2gC(S)R2h, -NR2gC(O)OR2h, -NR2gC(S)OR2h, -NR2gS(O)2R2h, -NR29C(O)NR211R21, -S(O)pR2g, -S(O)2NR29R2h, and -SC(O)R29; n is 1 or 2; R2d, R2e and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2d, R2e and R2f 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, -CN, =0, =S, -NO2, -R2g, -SR2g, -C(O)R29, -C(S)R29,
-C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29, -C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR29, -OC(O)NR2gR2h, -OC(S)NR2gR2h, - NR29R2h, -NR29G(O)R211, -NR2gC(S)R2h, -NR29C(O)OR2h, -NR2gC(S)OR2h, -NR29S(O)2R211, -NRZgC(O)NR2hR2i, -S(O)pR29, -S(O)2NR29R2h, and -SC(O)R29; p is 1 or 2;
R2g, R2h and R2' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2Ql R2h and R2' 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 R2m;
R2m is selected from the group consisting of -CN, -NO2, -NH2, =0, =S, -SR2n, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C(O)R2", -C(S)R2n, -C(O)OR2" , -C(S)OR2" , -C(O)SR2", -C(O)NR2nR20, -C(S)NR2nR2°, -OR2", -OC(O)R2", -OC(S)R2", -OC(O)OR2", -OC(O)NR2"R20, -OC(S)NR2"R2°, -NR2nR2°, -NR2nC(O)R2°, -NR20C(S)R20, -NR2"C(O)OR20, -NR2nC(S)OR20, -NR20S(O)2R20, -NR2"C(O)NR2oR2p, -S(O)qR2n, -S(O)2NR20R20, and -SC(O)R2"; q is 1 or 2;
R2", R20 and R2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2m, R2n, R20 and R2p alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -NO2, =0, =S, -SR2q, -R2q, -C(0)R2q, -C(S)R2q,
-C(0)0R2q , -C(S)OR2q , -C(0)SR2q, -C(O)NR2qR2r, -C(S)NR2qR2r, -0R2q, -OC(O)R2r, -OC(S)R2q,-OC(O)OR2q,-OC(O)NR2qR2r, -OC(S)NR2qR2r, -NR2qR2r, -NR2qC(O)R2r, -NR2qC(S)R2r, -NR2qC(O)OR2r, -NR2qC(S)OR2r, -NR2qS(O)2R2r, -NR2qC(O)NR2rR2s, -S(O)rR2q,
-S(O)2NR2qR2r, and -SC(O)R2q; r is 1 or 2;
R2q, R2r and R2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;wherein the R2q" R2r and R2s 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, hydroxy, -CN, =0, =S, -SH, -NO2, amino, alkyl, haloalkyl, carboxy, alkoxy, alkylamino and alkoxycarbonyl; R4 is selected from the group consisting of -R4i, -OR41, and -NR4iR4k, wherein:
R4i and R4k 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, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonyl(aryl)aminoalkyl, and heterocyclylcarbonyl(aryl)aminoalkyl; wherein the R4' and R4k substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyalkyl, =0, =S,
-CN, -NO2, -R41, -SR41, -OR41, -C(O)R41, -C(O)OR41, -C(O)NR4lR4m, -OC(O)R41, -ONR41R4"1,
-NR4lR4m, -NR41C(O)R4"1, -NR41S(O)2R4"1, -S(O)bR41, -SC(O)R41 and -SC(O)NR41R4"1; b is 1 or 2;
R4' and R4"1 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy and haloalkoxy; X6 represents a bond or is -C(O)-; wherein:
(a) when X6 is -C(O)-, R6 is selected from the group consisting of -R6a and -0R6a;
(b) when X6 represents a bond, R6 is selected from the group consisting of halogen, -R6a and -0R6a;
R6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; wherein: the R6a alkyl, cycloalkyl and aryl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, =0, =S, -CN, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl and heterocyclyl. In another embodiment of the compounds of Formula (II), R5 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl; and R6 is selected from the group consisting of -R6a and -0R6a, wherein R6a is defined as above. In still another embodiment, R5 is selected from the group consisting of hydrogen and alkyl; R6 is selected from the group consisting of -R6a and -OR6a; and R6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl, wherein the R6a alkyl, cycloalkyl and aryl substituents may be optionally substituted as above. In still another embodiment, R5 is hydrogen; X6 represents a bond; and R6 is -R6a, wherein R6a is defined as provided in other embodiments herein. In still another embodiment, R6a is alkyl, wherein the R6a alkyl substituent may be optionally substituted as provided in other embodiments herein. In still another embodiment, R6a is unsubstituted alkyl. In another embodiment of the compounds of Formula (II), R4 is -NR4)R4k, wherein the R4i and R4k substituents may be optionally substituted as provided in other embodiments herein. In still another embodiment, R4 is -NR4iR4k, wherein R4' and R4k are independently selected from the group consisting of hydrogen, alkyl and aryl, and wherein the R4' and R4k alkyl and aryl may be optionally substituted as provided in other embodiments herein. In still another embodiment, R4' and R4k are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, phenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylpropyl, and phenylbutyl, wherein the R4i and R4k methyl, ethyl, propyl, butyl, phenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylpropyl, and phenylbutyl may be optionally substituted as provided in other embodiments herein. In still another embodiment, R4 is -NR4'R4k, wherein R4' and R4k are independently selected from the group consisting of hydrogen, phenylmethyl and phenylphenyl, and wherein the R4' and R4k phenylmethyl and phenylphenyl may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4Or -OR4'; wherein R4i 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 R4' substituents may be optionally substituted as provided in other embodiments herein.
In still another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4'; wherein R4Ms alkyl; and wherein the R4' substituent is further substituted with one or more halogen substituents. In still another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4'; wherein R4i is alkyl; and wherein the R4i substituent is further substituted with one or more chlorine substituents. In still another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4'; wherein R4i is alkyl; and wherein the R41 substituent is further substituted with one or more fluorine substituents.
In still another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4'; wherein R41 is alkyl; and wherein the R41 substituent is further substituted with one or more haloalkyl substituents. In still another embodiment of the compounds of Formula (II), R4 is -R4i or -OR4'; wherein R4' is alkyl; and wherein the R4' substituent is further substituted with one or more fluoroalkyl substituents. In still another embodiment of the compounds of Formula (II), R4 is -R41 or -OR4'; wherein R41 is alkyl; and wherein the R4) substituent is further substituted with one or more chloroalkyl substituents: In still another embodiment of the compounds of Formula (II), R4 is -R4i or -OR4'; wherein R4' is alkyl; and wherein the R4) substituent is further substituted with one or more trifluoroalkyl substituents. In still another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4j; wherein R4' is alkyl; and wherein the R4' substituent is further substituted with one or more trifluoromethyl substituents.
In another embodiment of the compounds of Formula (II), R4 is -R4i or -OR4); wherein R41 is selected from the group consisting of (CrC6)-alkyl, (C3-Ci0)-aryl, (C3-C14)-heterocyclyl, (C3-C10)" aryl -(CrC6)-alkyl, (C3-C14)-heterocyclyl-(C1-C6)-alkyl, (C3-C10)-aryl-(C3-C6)-cycloalkyl, (C3-C6)- cycloalkyl-(C3-C10)-aryl, (C3-C10)-aryl-(C3-C14)-heterocyclyl, (C3-C10)-aryl-O-(C3-Ci0)-aryl, (C3-C10)- aryl-(C3-C10)-aryl, (C3-C14)-heterocyclyl-O-(C3-C10)-aryl, (C3-C10)-aryl-C(O)-(C3-C10)-aryl, (C3-C10)- aryl-O-(CrC6)-alkyl, and (C3-C10)-aryl-C(O)-amino-(C1-C6)-alkyl; and wherein the R4' substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of Formula (II), R4 is -R4j or -OR4i; wherein R4i 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, pyrimidinyl, pyridazinyl, triazinyl, morpholinyl, dioxanyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, thiomorpholinyl, indolyl, dihydrobenzofuranyl, quinolinyl and fluorenyl; and wherein the R4i substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4'; wherein R4' is selected from the group consisting of phenylphenyl, phenylnaphthyl, phenylanthracenyl, naphthylphenyl, naphthylnaphthyl, naphthylanthracenyl, anthracenylphenyl, anthracenylnaphthyl and anthracenylanthracenyl; and wherein the R4' substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4'; wherein R4' 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, anthracenylcyclopentyl, anthracenylcyclohexyl, cyclopropylphenyl, cyclopropylnaphthyl, cyclopropylanthracenyl, cyclobutylphenyl, cyclobutylnaphthyl, cyclobutylanthracenyl, cyclopentylphenyl, cyclopentylnaphthyl, cyclopentylanthracenyl, cyclohexylphenyl, cyclohexylnaphthyl, cyclohexylanthracenyl, phenylphenylmethyl, phenylphenylethyl, phenylphenylpropyl, phenylphenylbutyl, diphenylmethyl, diphenylethyl, diphenylpropyl and diphenylbutyl; and wherein the R4' substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compounds of Formula (II), R4 is -R4i or -OR4'; wherein R4' is selected from the group consisting of phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, phenyloxybutyl, naphthyloxynτethyl, naphthyloxyethyl,"naphthyloxypropyl, naphthyloxybutyl, anthracenyloxymethyl, anthracenyloxyethyl, anthracenyloxypropyl, anthracenyloxybutyl, " methoxyphenyl, ethoxyphenyl, propoxyphene, butoxyphenyl, methoxynaphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, phenyloxyphenyl, phenyloxynaphthyl, phenyloxyanthracenyl, naphthyloxyphenyl, naphthyloxynaphthyl, naphthyloxyanthracenyl, anthracenyloxyphenyl, anthracenyloxynaphthyl and anthracenyloxyanthracenyl; and wherein the R41 substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4i; wherein R4' is selected from the group consisting of phenylcarbonylphenyl, phenylcarbonylnaphthyl, phenylcarbonylanthracenyl, naphthylcarbonylphenyl, naphthylcarbonylnaphthyl, naphthylcarbonylanthracenyl, anthracenylcarbonylphenyl, anthracenylcarbonylnaphthyl, anthracenylcarbonylanthracenyl, phenylcarbonylaminomethyl, phenylcarbonylaminoethyl, phenylcarbonylaminopropyl, phenylcarbonylaminobutyl, naphthylcarbonylaminomethyl, naphthylcarbonylaminoethyl, naphthylcarbonylaminopropyl, naphthylcarbonylaaminobutyl, anthracenylcarbonylaminomethyl, anthracenylcarbonylaminoethyl, anthracenylcarbonylaminopropyl, anthracenylcarbonylaminobutyi, phenylcarbonyl.(phenyl)aminomethyl, phenylcarbonyl(phenyl)aminoethyl, phenylcarbonyl(phenyl)aminopropyl and phenylcarbonyl(phenyl)aminobutyl; and wherein the R4' substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compounds of Formula (II), R4 is -R4' or -OR4i; wherein R4' 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, dioxolanylpropyl, dioxolanylbutyl, imidazolidinylmethyl, imidazolidinylethyl, imidazolidinylpropyl, imidazolidinylbutyl, imidazolynylmethyl, imidazolynylethyl, imidazolynylpropyl, imidazolynylbutyl, imidazolylmethyl, imidazolylethyl, imidazolylpropyl, imidazolylbutyl, pyrazolidinylmethyl, pyrazolidinylethyl, pyrazolidinylpropyl, pyrazolidinylbutyl, pyrazolinylmethyl, pyrazolinylethyl, pyrazolinylpropyl, pyrazolinylbutyl, pyrazolylmethyl, pyrazolylethyl, pyrazolylpropyl, pyrazolylbutyl, oxazolylmethyl, oxazolylethyl, oxazolylpropyl, oxazolylbutyl, isoxazolylmethyl, isoxazolylethyl, isoxazolylpropyl, isoxazolylbutyl, 1 ,2,3-oxadiazolylmethyl, 1 ,2,3-oxadiazolylethyl, 1 ,2,3-oxadiazolylpropyl, 1 ,2,3- oxadiazolylbutyl, 1 ,3,4-oxadiazolylmethyl, 1 ,3,4-oxadiazolylethyl, 1 ,3,4-oxadiazolylpropyl, 1 ,3,4- oxadiazolylbutyl, thiophenylmethyl, thiophenylethyl, thiophenylpropyl, thiophenylbutyl, thiazolylmethyl, thiazolylethyl, thiazolylpropyl, thiazolylbutyl, thiadiazolylmethyl, thiadiazolylethyl, thiadiazolylpropyl, thiadiazolylbutyl, triazolylmethyl, triazolylethyl, triazolylpropyl, triazolylbutyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl, piperidinylbutyl, pyridinylmethyl, pyridinylethyl, pyridinylpropyl, pyridinylbutyl, piperazinylmethyl, piperazinylethyl, piperazinylpropyl, piperazinylbutyl, pyrazinylmethyl, pyrazinylethyl, pyrazinylpropyl, pyrazinylbutyl, pyrim id inyl methyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, pyridazinylm ethyl, pyridazinylethyl, pyridazinylpropyl, pyridazinylbutyl, triazinylmethyl, triazinylethyl, triazinylpropyl, triazinylbutyl, morpholinylmethyl, morpholinylethyl, fnorpholinylprόpyl, morpholinylbutyl, dioxanylmethyl, dioxanylethyl, dioxanylpropyl, dioxanylbutyl, tetrahydro-2H-pyranylmethyl, tetrahydro-2H-pyranylethyl, tetrahydro-2H-pyranylpropyl, tetrahydro-2H-pyranylbutyl, 21-l-pyranylmethyl, 2H-pyranylethyl, 2H-pyranylpropyl, 2H- pyranylbutyl, 4H-pyranylmethyl, 4H-pyranylethyl, 41-l-pyranylpropyl, 4H-pyranylbutyl, thiomorpholinylmethyl, thiomorpholinylethyl, thiomorpholinylpropyl, thiomorpholinylbutyl, quinolinylmethyl, quinolinylethyl, quinolinylpropyl, quinolinylbutyl, fluorenylmethyl, fluorenylethyl, fluorenylpropyl and fluorenylbutyl; and wherein the R4' substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R4i or -OR4'; wherein R4) 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, phenylimidazolidinyl, naphthylimidazolidinyl, anthracenylimidazolidinyl, phenylimidazolynyl, naphthylimidazolynyl, anthracenylimidazolynyl, phenylimidazolyl, naphthylimidazolyl, anthracenylimidazolyl, phenylpyrazolidinyl, naphthylpyrazolidinyl, anthracenylpyrazolidinyl, phenylpyrazolinyl, naphthylpyrazolinyl, anthracenylpyrazolinyl, phenylpyrazolyl, naphthylpyrazolyl, anthracenylpyrazolyl, phenyloxazolyl, naphthyloxazolyl, anthracenyloxazolyl, phenylisoxazolyl, naphthylisoxazolyl, anthracenylisoxazolyl, phenyl-1 ,2,3-oxadiazolyl, naphthyl-1 ,2,3-oxadiazolyl, anthracenyl-1 ,2,3-oxadiazolyl, phenyl-1 ,3,4-oxadiazolyl, naphthyl-1 ,3,4-oxadiazolyl, anthracenyl- 1 ,3,4-oxadiazolyl, phenylthiophenyl, naphthylthiophenyl, anthracenylthiophenyl, phenylthiazolyl, naphthylthiazolyl, anthracenylthiazolyl, phenylthiadiazolyl, naphthylthiadiazolyl, anthracenylthiadiazolyl, phenyltriazolyl, naphthyltriazolyl, anthracenyltriazolyl, phenylpiperidinyl, naphthylpiperidinyl, anthracenylpiperidinyl, phenylpyridinyl, naphthylpyridinyl, anthracenylpyridinyl, phenylpiperazinyl, naphthylpiperazinyl, anthracenylpiperazinyl, phenylpyrazinyl, naphthylpyrazinyl, anthracenylpyrazinyl, phenylpyrimidinyl, naphthylpyrimidinyl, anthracenylpyrimidinyl, phenylpyridazinyl, naphthylpyridazinyl, anthracenylpyridazinyl, phenyltriazinyl, naphthyltriazinyl, anthracenyltriazinyl, phenylmorpholinyl, naphthylmorpholinyl, anthracenylmorpholinyl, phenyldioxanyl, naphthyldioxanyl, anthracenyldioxanyl, phenyltetrahydro-2H-pyranyl, naphthyltetrahydro-2H-pyranyl, anthracenyltetrahydro-2H-pyranyl, phenyl-2H-pyranyl, naphthyl-2H-pyranyl, anthracenyl-2H-pyranyl, phenyl-4H-pyranyl, naphthyl- 4H-pyranyl, anthracenyl-4H-pyranyl, phenylthiomorpholinyl, naphthylthiomorpholinyl, anthracenylthiomorpholinyl, phenylquinolinyl, naphthylquinolinyl, anthracenylquinolinyl, phenyifluorenyl, naphthylfluorenyl and anthracenylfluorenyl; and wherein the R4) substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compounds of Formula (II), R4 is -R4i or -OR4i; wherein R4i is selected from the group consisting of pyrrolidinyloxyphenyl, pyrrolidinyloxynaphthyl, "pyrrolidinyloxyanthracenyl; pyrrolinyloxyphenyl, pyrrolinyloxynaphthyl, pyrrolinyloxyanthracenyl, pyrrolyloxyphenyl, pyrrolyloxynaphthyl, pyrrolyloxyaπthracenyl, tetrahydrofuranyloxyphenyl, tetrahydrofuranyloxynaphthyl, tetrahydrofuranyloxyanthracenyl, furanyloxyphenyl, furanyloxynaphthyl, furanyloxyanthracenyl, dioxolanyloxyphenyl, dioxolanyloxynaphthyl, dioxolanyloxyanthracenyl, imidazolidinyloxyphenyl, imidazolidinyloxynaphthyl.imidazolidinyloxyanthracenyl, imidazolynyloxyphenyl, imidazolynyloxynaphthyl, imidazolynyloxyanthracenyl, imidazolyloxyphenyl, imidazolyloxynaphthyl, imidazolyloxyanthracenyl, pyrazolidinyloxyphenyl, pyrazolidinyloxynaphthyl, pyrazolidinyloxyanthracenyl, pyrazolinyloxyphenyl, pyrazolinyloxynaphthyl, pyrazolinyloxyanthracenyl, pyrazolyloxyphenyl, pyrazolyloxynaphthyl, pyrazolyloxyanthracenyl, oxazolyloxyphenyl, oxazolyloxynaphthyl, oxazolyloxyanthracenyl, isoxazolyloxyphenyl, isoxazolyloxynaphthyl, isoxazolyloxyanthracenyl, 1 ,2,3- oxadiazolyloxyphenyl, 1 ,2,3-oxadiazolyloxynaphthyl, 1 ,2,3-oxadiazolyloxyanthracenyl, 1 ,3,4- oxadiazolyloxyphenyl, 1 ,3,4-oxadiazolyloxynaphthyl, 1 ,3,4-oxadiazolyloxyanthracenyl, thiophenyloxyphenyl, thiophenyloxynaphthyl, thiophenyloxyanthracenyl, thiazolyloxyphenyl, thiazolyloxynaphthyl, thiazolyloxyanthracenyl, thiadiazolyloxyphenyl, thiadiazolyloxynaphthyl, thiadiazolyloxyanthracenyl, triazolyloxyphenyl, triazolyloxynaphthyl, triazolyloxyanthracenyl, piperidinyloxyphenyl, piperidinyloxynaphthyl, piperidinyloxyanthracenyl, pyridinyloxyphenyl, pyridinyloxynaphthyl, pyridinyloxyanthracenyl, piperazinyloxyphenyl, piperazinyloxynaphthyl, piperazinyloxyanthracenyl, pyrazinyloxyphenyl, pyrazinyloxynaphthyl, pyrazinyloxyanthracenyl, pyrimidinyloxyphenyl, pyrimidinyloxynaphthyl, pyrimidinyloxyanthracenyl, pyridazinyloxyphenyl, pyridazinyloxynaphthyl, pyridazinyloxyanthracenyl, triazinyloxyphenyl, triazinyloxynaphthyl, triazinyloxyanthracenyl, morpholinyloxyphenyl, morpholinyloxynaphthyl, morpholinyloxyanthracenyl, dioxanyloxyphenyl, dioxanyloxynaphthyl, dioxanyloxyanthracenyl, tetrahydro-2H-pyranyloxyphenyl, tetrahydro-2H-pyranyloxynaphthyl, tetrahydro-2H- pyranyloxyanthracenyl, 2H-pyranyloxy phenyl, 2H-pyranyloxy naphthyl, 2H-pyranyloxy anthracenyl, 4H-pyranyloxyphenyl, 4H-pyranyloxynaphthyl, 4H-pyranyloxyanthracenyl, thiomorpholinyloxyphenyl, thiomorpholinyloxynaphthyl, thiomorpholinyloxyanthracenyl, quinolinyloxyphenyl, quinolinyloxynaphthyl, quinolinyloxyanthracenyl, fluorenyloxyphenyl, fluorenyloxynaphthyl and fluorenyloxyanthracenyl; and wherein the R4' substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compounds of Formula (II), R4 is -R41 or -OR4'; wherein R4' is selected from the group consisting of pyrrolidinylphenyl, pyrrolidinylnaphthyl, pyrrolidinylanthracenyl, pyrrolinylphenyl, pyrrolinylnaphthyl, pyrrolinylanthracenyl, pyrrolylphenyl, pyrrolylnaphthyl, pyrrolylanthracenyl, tetrahydrofuranylphenyl, tetrahydrofuranylnaphthyl, tetrahydrofuranylanthracenyl, furanylphenyl, furanylnaphthyl, furanylanthracenyl, dioxolanylphenyl, dioxolanylnaphthyl, dioxolanylanthracenyl, imidazolidinylphenyl, imidazolidinylnaphthyl, imidazolidinylanthracenyl, imidazolynylphenyl, imidazolynylnaphthyl, imidazolynylanthracenyl, imidazolylphenyl, imidazolylnaphthyl, imidazolylanthracenyl, pyrazolidinylphenyl, pyrazolidinylnaphthyl, pyrazolidinylanthracenyl, pyrazolinylphenyl, "pyrazolinylnaphthyl, pyrazolinylanthracenyl, pyrazolylphenyl, pyrazolylnaphthyl, pyrazolylanthracenyl, oxazolylphenyl, oxazolylnaphthyl, oxazolylanthracenyl, isoxazolylphenyl, isoxazolylnaphthyl, isoxazόlylanthracenyl, 1 ,2,3-oxadiazolylphenyl,1 ,2,3-oxadiazolylnaphthyl, 1 ,2,3-oxadiazolylanthracenyl, 1 ,3,4-oxadiazolylphenyl, 1 ,3,4-oxadiazolylnaphthyl, 1 ,3,4- oxadiazolylanthracenyl, thiophenylphenyl, thiophenylnaphthyl, thiophenylanthracenyl, thiazolylphenyl, thiazolylnaphthyl, thiazolylanthracenyl, thiadiazolylphenyl, thiadiazolylnaphthyl, thiadiazolylanthracenyl, triazolylphenyl, triazolylnaphthyl, triazolylanthracenyl, piperidinylphenyl, piperidinylnaphthyl, piperidinylanthracenyl, pyridinylphenyl, pyridinylnaphthyl, pyridinylanthracenyl, piperazinylphenyl, piperazinylnaphthyl, piperazinylanthraceπyl, pyrazinylphenyl, pyrazinylnaphthyl, pyrazinylanthracenyl, pyrimidinylphenyl, pyrimidinylnaphthyl, pyrimidinylanthracenyl, pyridazinylphenyl, pyridazinylnaphthyl, pyridazinylanthracenyl, triazinylphenyl, triazinylnaphthyl, triazinylanthraceπyl, morpholinylphenyl, morpholinylnaphthyl, morpholinylanthracenyl, dioxanylphenyl, dioxanylnaphthyl, dioxanylanthracenyl, tetrahydro-2H- pyranylphenyl, tetrahydro-2H-pyranylnaphthyl, tetrahydro-2H-pyranylanthracenyl, 2H-pyranyl phenyl, 2H-pyranyl naphthyl, 2H-pyranyl anthraceπyl, 4H-pyranylphenyl, 4H-pyranylnaphthyl, 4H- pyranylanthracenyl, thiomorpholinylphenyl, thiomorpholinylnaphthyl, thiomorphόlinylanthracenyl, quinolinylphenyl, quinolinylnaphthyl, quinolinylanthracenyl, fluorenylphenyl, fluorenylnaphthyl and fluorenylanthracenyl; and wherein the R4i substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compounds of Formula (II), R4 is -R4i or -OR4'; wherein R4i 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, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, pyridinylphenyl and pyrimidinylphenyl; and wherein the R4' substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compounds of Formula (II), R4 is selected from the group consisting of -R4i, -OR4' and -NR4'R4k; wherein R4i and R4k are independently selected from the groups shown in Table C below:
TABLE C - Formulae
wherein the R4i and R4k substituents shown in Table C may be optionally substituted as provided in other embodiments herein. In one illustrative embodiment, the R41 and R4k substituents shown in Table C each may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl.
In another embodiment, the compound of Formula (II) has one of the structures shown in Table D below:
TABLE D - Formulae
wherein R2c1, R2c2, R4, and R6 are as defined in any of the embodiments described in this application.
In another embodiment, the compound of Formula (II) has one of the structures shown in Table D and R6 is -R6a, wherein R6a 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. In still another embodiment, the compound of Formula (II) has one of the structures shown in Table D and R6 is -R6a, wherein R6a is selected from the group consisting of alkyl and phenyl. In still another embodiment, the compound of Formula (II) has one of the structures shown in Table D; and R6 is -R6a, wherein R6a is unsubstituted alkyl. In still another embodiment, the compound of Formula (II) has one of the structures shown in Table D; and R6 is -R6a, wherein R6a is selected from the group consisting of methyl, ethyl, propyl and isopropyl.
In another embodiment, the compound of Formula (II) has one of the structures shown in Table D; R4 is selected from the group consisting of -R4i, -OR4' and -NR4iR4k, wherein R4J and R4k are independently selected from the groups shown in Table D; and wherein the R4' and R4k substituents may be optionally substituted as provided in other embodiments herein; and R6 is - R6a, wherein R6a is selected from the group consisting of alkyl and phenyl. In another embodiment, the compound of Formula (II) has one of the structures shown in Table D; R4 is -R4j, wherein R4i is selected from the groups shown in Table D and wherein the R41 substituent may be optionally substituted as provided in other embodiments herein; and R6 is - R6a, wherein R6a is unsubstituted alkyl.
In another embodiment, the compound of Formula (II) has one of the structures shown in Table D; R4 is -R4i, wherein R4' is selected from the groups shown in Table D and wherein the R4' substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl; and R6 is -R6a, wherein R6a is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl and fluoromethyl. In another embodiment, the compound of Formula (II), R2 is -R2c1; -R2c1 is C1-C6-SIkVl, wherein the R2c1 CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -Cl, -Br, -I, - CN, =0, =S, -SR2d, -NO2, -C(O)R2d, -C(S)R2d, -C(O)OR2d ,
-C(S)OR2d , -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -OR2d, -OC(O)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d,
-S(O)2N R2dR2e, and -SC(O)R2d; n is 1 or 2; and R2d, R2e and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2c1, R2d, R2e and R2f substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl, wherein the R2c1 CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -Cl, -Br, -I, - CN, =0, =S, -SR2d, -NO2, -C(O)R2d, -C(S)R2d, -C(0)0R2d , -C(S)OR2d , -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -OR2d, -OC(O)R2d, -OC(S)R2d, - OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)N R2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -
NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d, -S(O)2NR2dR26, and -SC(O)R2d; n is 1 or 2; and R2d, R2β and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; and wherein the R2c1, R2d, R2e and R2f substituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl, wherein the R2c1 CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of heterocyclyl, =0, -C(O)OR ,2d -C(O)NR2dR2e, -OR2d, -OC(O)R2d and -NR2dR2e; and R2d and R2e are independently selected from the group consisting of hydrogen, alkyl and heterocyclyl; and wherein the R2c1, R2d and R2e substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is d-C6-alkyl, wherein the R2c1 CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of heterocyclyl, =0, -C(O)OR2d ,
-C(O)NR2dR2e, -OR2d, -OC(O)R2d and -NR2dR2e; R2d and R2e are independently selected from the group consisting of hydrogen, alkyl and heterocyclyl; wherein the R2c1, R2d and R2e substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, =0, -R2g, -C(O)OR29 , C(O)NR2gR2h, -OR29 and -NR29R2h; and R2g and R2h are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl, wherein the R29 and R2h 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, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl, wherein the R2c1 CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of heterocyclyl, =0, -C(O)OR2d ,-C(O)NR2dR2e, -0R2d, - 0C(0)R2d and -NR2dR2e; R2d and R2e are independently selected from the group consisting of hydrogen, alkyl and heterocyclyl; wherein the R2c1, R2d and R2e substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, =0, -R2g, -C(O)OR29 , C(O)NR29R211, -OR29 and -NR2gR2h; and R29 and R2h are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; and -R2c1 is d-Cβ-alkyl, wherein the R201 CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of heterocyclyl, =0, -C(0)0R2d , -C(O)NR2dR2e, -0R2d, -0C(0)R2d and -NR2dR2e; R2d and R2e are independently selected from the group consisting of hydrogen, alkyl and heterocyclyl, arid wherein the R2G1 , R2d and R2θ substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, =0, -R2g, -C(O)OR29 , -C(O)NR2gR2h, -OR29 and -NR2gR2h; and R2g and R2h are independently selected from the group consisting of hydrogen and alkyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, carboxyalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, oxoalkyl, alkylaminocarbonylalkyl, hydroxyalkoxyalkyl, aminocarbonylalkoxyalkyl and alkylcarbonylalkyl; wherein the R2c1 hydroxyalkyl, alkoxyalkyl, carboxyalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, oxoalkyl, alkylaminocarbonylalkyl, hydroxyalkoxyalkyl, aminocarbonylalkoxyalkyl and alkylcarbonylalkyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =O, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, carboxyalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl and oxoalkyl; wherein the R2c1 hydroxyalkyl, alkoxyalkyl, carboxyalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl and oxoalkyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 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, dimethylaminopropyl, dimethylaminobutyl, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, propylaminomethyl, propylaminoethyl, propylaminopropyl, propylaminobutyl, dipropylaminomethyl, dipropylaminoethyl, dipropylaminopropyl, dipropylaminobutyl, butylaminomethyl, butylaminoethyl, butylaminopropyl, butylaminobutyl, dibutylaminomethyl, dibutylaminoethyl, dibutylaminopropyl, dibutylaminobutyl, methylethylaminomethyl, methylpropylaminomethyl, methylbutylaminomethyl, methylethylaminoethyl, methylpropylaminoethyl, methylbutylaminoethyl, methylethylaminopropyl, methylpropylaminopropyl, methylbutylaminopropyl, methylethylaminobutyl, methylpropylaminobutyl, methylbutylaminobutyl, ethylpropylaminomethyl, ethylbutylaminomethyl, propylbutylaminomethyl, ethylpropylaminoethyl, ethylbutylaminoethyl, propylbutylaminoethyl, ethylpropylaminopropyl, ethylbutylaminopropyl, propylbutylaminopropyl, ethylpropylaminobutyl, ethylbutylaminobutyl, propylbutylaminobutyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylbutyl, oxomethyl, oxoethyl, oxopropyl and oxobutyl; wherein the R2c1 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 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, dioxolanylpropyl, dioxolanylbutyl, imidazolidinylmethyl, imidazolidinylethyl, imidazolidinylpropyl, imidazolidinylbutyl, imidazolynylmethyl, imidazolynylethyl, imidazolynylpropyl, imidazolynylbutyl, imidazolylmethyl, imidazolylethyl, imidazolylpropyl, imidazolylbutyl, pyrazolidinylmethyl, pyrazolidinylethyl, pyrazolidinylpropyl, pyrazolidinylbutyl, pyrazolinylmethyl, pyrazolinylethyl, pyrazolinylpropyl, pyrazolinylbutyl, pyrazolylmethyl, pyrazolylethyl, pyrazolylpropyl, pyrazolylbutyl, oxazolylmethyl, oxazolylethyl, oxazolylpropyl, oxazolylbutyl, isoxazolylmethyl, isoxazolylethyl, isoxazolylpropyl, isoxazolylbutyl, 1 ,2,3-oxadiazolylmethyl, 1 ,2,3-oxadiazolylethyl, 1 ,2,3-oxadiazolylpropyl, 1 ,2,3- oxadiazolylbutyl, 1 ,3,4-oxadiazolylmethyl, 1 ,3,4-oxadiazolylethyl, 1 ,3,4-oxadiazolylpropyl, 1 ,3,4- oxadiazolylbutyl, oxetanylmethyl, oxetanylethyl, oxetanylpropyl, oxetanylbutyl, oxiranylmethyl, oxiranylethyl, oxiranylpropyl, oxiranylbutyl, thiophenylmethyl, thiophenylethyl, thiophenylpropyl, thiophenylbutyl, thiazolylmethyl, thiazolylethyl, thiazolylpropyl, thiazolylbutyl, thiadiazolylmethyl, thiadiazolylethyl, thiadiazolylpropyl, thiadiazolylbutyl, triazolylmethyl, triazolylethyl, triazolylpropyl, triazolylbutyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl, piperidinylbutyl, pyridinylmethyl, pyridinylethyl, pyridinylpropyl, pyridinylbutyl, piperazinylmethyl, piperazinylethyl, piperazinylpropyl, piperazinylbutyl, pyrazinylmethyl, pyrazinylethyl, pyrazinylpropyl, pyrazinylbutyl, pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, pyridazinylmethyl, pyridazinylethyl, pyridazinylpropyl, pyridazinylbutyl, triazinylmethyl, triazinylethyl, triazinylpropyl, triazinylbutyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, morpholinylbutyl, dioxanylmethyl, dioxanylethyl, dioxanylpropyl, dioxanylbutyl, tetrahydro-2H-pyranylmethyl, tetrahydro-2H-pyranylethyl, tetrahydro-2H-pyranylpropyl, tetrahydro-2H-pyranylbutyl, 2H-pyranylmethyl, 2H-pyranylethyl, 2H-pyranylpropyl, 2H- pyranylbutyl, 4H-pyranylmethyl, 4H-pyranylethyl, 4H-pyranyipropyl, 4H-pyranylbutyl, thiomorpholinylmethyl, thiomorpholinylethyl, thiomorpholinylpropyl, thiomorpholinylbutyl, quinolinylmethyl, quinolinylethyl, quinolinylpropyl, quinolinylbutyl, fluorenylmethyl, fluorenylethyl, fluorenylpropyl and fluorenylbutyl; wherein the R2c1 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl.
In another embodiment of the compound of Formula (II), R2 is -R2G1 ; -R2c1 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 R2c1 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 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 R2c1 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of methyl, hydroxy, methoxy and ethoxy.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is Ci-C6-alkyl; wherein the R2c1 Ci-C6-alkyl is substituted with at least one hydroxyl substituent. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is Ci-C6-alkyl; wherein the R2c1 CrC6-alkyl is substituted'with at least two hydroxyl substituents. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is d-C6-alkyl; wherein the R2c1 CrC6-alkyl is substituted with one hydroxyl substituent. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl; wherein the R2c1 CrC6-alkyl is substituted with two hydroxyl substituents.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R201 is Ci-C6-alkyl; wherein the R2c1 Ci-C6-alkyl is substituted with at least one hydroxyl substituent; R4 is selected from the group consisting of -R4i, -OR4' and -NR4)R4k, wherein R4' and R4k are independently selected from the groups shown in Table C and wherein the R4' and R4k substituents may be optionally substituted as provided in other embodiments herein; and R6 is -R6a, wherein R6a is selected from the group consisting of alkyl and phenyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl; wherein the R2c1 Ci-C6-alkyl is substituted with at least one hydroxyl substituent; R4 is -R4', wherein R4' is selected from the groups shown in Table C and wherein the R4) substituent may be optionally substituted as provided in other embodiments herein; and R6 is -R6a, wherein R6a is unsubstituted alkyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is Ci-C6-alkyl; wherein the R2c1 CrCe-alkyl is substituted with at least one hydroxyl substituent; R4 is -R4', wherein R4j is selected from the groups shown in Table C and wherein the R4' substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =O, -CN, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl; and R6 is -R6a, wherein R6a is selected from the group consisting of methyl, ethyl, propyl and isopropyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is Ci-C6-alkyl; wherein the R2c1 Ci-C6-alkyl is substituted with at least two hydroxyl substituents; R4 is selected from the group consisting of -R4', -OR4) and -NR4)R4k, wherein R4' and R4k are independently selected from the groups shown in Table C and wherein the R4' and R4k substituents may be optionally substituted as provided in other embodiments herein; and R6 is -R6a, wherein R6a is selected from the group consisting of alkyl and phenyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is Ci-C6-alkyl; wherein the R2c1 CrC6-alkyl is substituted with at least two hydroxyl substituents; R4 is -R4i, wherein R4' is selected from the groups shown in Table C and wherein the R4) substituent may be optionally substituted as provided in other embodiments herein; and R6 is -R6a, wherein R6a is unsubstituted alkyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is d-C6-alkyl; wherein the R2c1 CrC6-alkyl is substituted with at least two hydroxyl substituents; R4 is -R4i, wherein R4' is selected from the groups shown in Table C and wherein the R4' substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl; and R6 is -R6a, wherein R6a is selected from the group consisting of methyl, ethyl, propyl and isopropyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl; wherein the R2c1 CrC6-alkyl is substituted with one hydroxyl substituent; R4 is selected from the group consisting of -R4j, -OR4' and -NR4iR4k, wherein R4i and R4k are independently selected from the groups shown in Table C and wherein the R4' and R4k substituents may be optionally substituted as provided in other embodiments herein; and R6 is -R6a, wherein R6a is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and phenyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl; wherein the R2c1 Ci-C6-alkyl is substituted with one hydroxyl substituent; R4 is -R4i, wherein R4' is selected from the groups shown in Table C and wherein the R4' substituent.may be optionally substituted as provided in other embodiments herein; and R6 is -R6a, wherein R6a is unsubstituted alkyl. In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl; wherein the R2c1 CrC6-alkyl is substituted with one hydroxyl substituent; R4 is -R4i, wherein R4' is selected from the groups shown in Table C and wherein the R4' substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN1 -CI, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl; and R6 is -R6a, wherein R6a is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl and fluoromethyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrCε-alkyl; wherein the R2c1 CrCβ-alkyl is substituted with two hydroxyl substituents; R4 is selected from the group consisting of -R4i, -OR4J and -NR4iR4\ wherein R4' and R4k are independently selected from the . groups shown in Table C and wherein the R4' and R4k substituents may be optionally substituted as provided in other embodiments herein; and R6 is -R6a, wherein R6a is selected from the group consisting of alkyl and phenyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is CrC6-alkyl; wherein the R2c1 Ci-C6-alkyl is substituted with two hydroxyl substituents; R4 is -R4', wherein R4i is selected from the groups shown in Table C and wherein the R4' substituent may be optionally substituted as provided in other embodiments herein; and R6 is -R6a, wherein R6a is unsubstituted alkyl.
In another embodiment of the compound of Formula (II), R2 is -R2c1; -R2c1 is Ci-C6-alkyl; wherein the R2c1 CrC6-alkyl is substituted with two hydroxyl substituents; R4 is -R4', wherein R4i is selected from the groups shown in Table C and wherein the R4j substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl; and R6 is -R6a, wherein R6a is selected from the group consisting of methyl, ethyl, propyl and isopropyl.
In another embodiment of the compound of Formula (II), R is -R , -R is selected from the group consisting of C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein the R2c2C7-C2o-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halogen, -CN, =0, =S, -SR2d, -NO2, -C(O)R2d, -C(S)R2d, -C(O)OR2d , -C(S)OR2d , -C(O)SR2d, -C(O)NR2dR2e,
-C(S)NR2dR2e, -0R2d, -OC(O)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(0)nR2d, -S(O)2N R2dR2e, and -SC(O)R2d; n is 1 or 2; and R2d, R2e and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2c2, R2d, R2e and R2f sωbstituents may be optionally substituted as provided in other embodiments herein.
In another embodiment of the compound of Formula (11), R2 is -R2c2; -R2c2 is selected from the group consisting of C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein the R2c2 C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halogen, -CN, =0, =S, -SR2d, -NO2, -C(O)R2d, -C(S)R2d, -C(O)OR2d , -C(S)OR2d , -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -0R2d, -0C(0)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)N R2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2θ, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e,
-NR2dC(O)NR2eR2f, -S(0)nR2d, -S(O)2N R2dR2e, and -SC(0)R2d; n is 1 or 2; and R2d, R2e and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2c2, R2d, R2e and R2f substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compound of Formula (II), R2 is -R2c2; -R2c2 is selected from the group consisting of cycloalkyl and heterocyclyl, wherein the R202 cycloalkyl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -C(O)OR2d , -C(O)NR2dR2e and -0R2d; and R2d and R2e are independently selected from the group consisting of hydrogen and alkyl; wherein the R2c2, R2d and R2β substituents may be optionally substituted as provided in other embodiments herein. In another embodiment of the compound of Formula (II), R2 is -R202; -R202 is selected from the group consisting of cycloalkyl and heterocyclyl, wherein the R2c2 cycloalkyl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -C(O)OR2d , -C(O)NR2dR2e and -0R2d; R2d and R2e are independently selected from the group consisting of hydrogen and alkyl; wherein the R2c2, R2d and R2e substituents may be optionally substituted with one or more -OR29; and R2g is hydrogen or alkyl, wherein the R29 alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl. In another embodiment of the compound of Formula (II), R2 is -R2c2; -R2c2 is selected from the group consisting of cycloalkyl and heterocyclyl, wherein the R2c2cycloalkyl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -C(O)OR2d , -C(O)NR2dR2B and -0R2d; R2d and R2e are independently selected from the group consisting of hydrogen and alkyl; wherein the R2°2, R2d and R2e substituents may be optionally substituted with one or more -OR2g; and R29 is hydrogen or alkyl, wherein the R29 alkyl substituent may be optionally substituted with one or more hydroxy substituents.
In another embodiment of the compound of Formula (II), R2 is -R2c2; and -R2c2 is selected from the group consisting of heterocyclyl, hydroxyheterocyclyl, cycloalkyl, carboxycycloakyl, aminocarbonylcycloalkyl and oxoheterocyclyl; wherein the R202 heterocyclyl, hydroxyheterocyclyl, cycloalkyl, carboxycycloakyl, aminocarbonylcycloalkyl and oxoheterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloaikyl, carboxy, alkoxy and alkoxycarbonyl. In another embodiment of the compound of Formula (II), R2 is -R2c2; and -R2c2 is heterocyclyl; wherein the R2c2 heterocyclyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl. In another embodiment of the compound of Formula (II), R2 is -R2c2; and -R2c2 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, , triazinyl, morpholinyl, dioxalanyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, thiomorpholinyl, quinolinyl and fluorenyl; wherein the R2c2 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, -CN, =0, =S, -SH, -NO2, alkyl, haloalkyl, carboxy, alkoxy and alkoxycarbonyl. In another embodiment of the compound of Formula (II), R2 is -R2c2; and -R202Is tetrahydrofuranyl; wherein the R2c2 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:
Formula III
wherein:
R2 is selected from the group consisting of hydroxyalkyl, oxoalkyl, aminoalkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylaminoalkyl, aminocarbonyialkyl, alkylcarbonylalkyl, alkylaminocarbonylalkyl, and aminocarbonylcycloalkyl; wherein the R2 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
R4 is -R4i or -OR4i; wherein R4j is selected from the group consisting of alkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl; wherein the R4i and R4k substituents each may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; and
R6 is alkyl.
In another embodiment of Formula (II), R2 is selected from the group consisting of hydroxyalkyl, oxoalkyl, aminoalkyl, carboxyalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylaminoalkyl and aminocarbonyialkyl, wherein the R2 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; R4 is -R4J; R4J is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl, wherein the R41 substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; and R6 is alkyl.
In another embodiment of the compound of Formula (II), R2 is hydroxyalkyl, wherein the R2 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; R4 is -R41; R4' is selected from the group consisting of alkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl, wherein the R4' substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; and R6 is selected from the group consisting of hydrogen, halogen, alkyl and haloalkyl. In another embodiment of the compound of Formula (II), R2 is heterocyclylalkyl, wherein the R2 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; R4 is -R4), R4' is selected from the group consisting of alkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl, wherein the R4i substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; and R6 is hydrogen, halogen, alkyl and haloalkyl. In another embodiment of the compound of Formula (II), R2 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 R2 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; R4 is -R4i; R4i is selected from the group consisting of butyl, phenyl, fluorenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylphenylmethyl, diphenylethyl, phenyloxymethyl, phenyloxyethyl, phenyloxyphenyl, naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl, phenylcarbonylaminoethyl, phenylcarbonyl(phenyl)aminoethyl, thiophenylmethyl, phenyl-1 ,2,3-oxadiazolyl, phenyl-1 ,3,4- oxadiazolyl, 1 ,3,4-oxadiazolylphenyl, thiazolylphenyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, pyridinylphenyl and pyrimidinylphenyl, wherein the R4i substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; and R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl and trifluoromethylmethyl. In another embodiment of the compound of Formula (II), R2 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 R2 substituent may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, methyl methoxy and ethoxy; R4 is -R4'; R4' is selected from the group consisting of butyl, phenyl, fluorenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylphenylmethyl, diphenylethyl, phenyloxymethyl, phenyloxyethyl, phenyloxyphenyl, naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl, phenylcarbonylaminoethyl, phenylcarbonyl(phenyl)aminoethyl, thiophenylmethyl, phenyl-1 ,2,3-oxadiazolyl, phenyl-1 ,3,4-oxadiazolyl, 1 ,3,4-oxadiazolylphenyl, thiazolylphenyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, pyridinylphenyl and pyrimidinylphenyl, wherein the R4) substituent may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluorom ethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl, and aminocarbonyl; and R6 is ethyl.
In another embodiment of the 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;
4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-(2,2-diethoxyethoxy)-6-ethylthieno[2,3- d]pyrimidine;
4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-
6-ethylthieno[2,3-d]pyrimidine;
4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-
6-ethylthieno[2,3-d]pyrimidine; (2R)-3-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yljoxy) propane- 1 ,2-diol;
(2S)-3-({4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)acetιc acid;
({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)acetaldehyde;
N-[2-({4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)ethyl]-N,N-dimethylamine; 3-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthienot2,3-d]pyrimidin-4-yl)piperazin-1- yl]carbonyl}benzonitrile;
(2R)-3-[(6-ethyl-4-{4-[(5-phenyl-1 ,3,4-oxadiazol-2-yl)carbonyl]piperazin-1-yl}thieηo[2,3- d]pyrimidin-2-yl)oxy]propane-1 ,2-diol;
(2R)-3-[(6-ethyl-4-{4-[(2-phenyl-1 ,3-thiazol-4-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol; 4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-i-y|]-2-(2-ethoxyethoxy)-6-ethylthieno[2,3-d]pyrimidine;
2-({4-t4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)acetamide;
(2R)-3-({4-[4-(1 ,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-y|]-6-ethyl-2-(tetrahydrofuran-2-ylmethoxy)thieno[2,3- d]pyrimidine;
(2R)-3-({4-[4-(3-bromobenzoy!)piperazin-1-y|]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)propane-1 ,2- diol; (2S)-4-({4-[4-(1 ,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)butane-1 ,2-diol;
3l-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazin-1- yl]carbonyl}-1 , 1 '-biphenyl-4-carboxylic acid; and
2-({4-[4-(1 ,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)ethanamine;
In another embodiment of the compound of Formula (II) is selected from the group consisting of:
3-({4-[4-(1 ,1 '-biphenyl-3-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)propanoic acid;
(2R)-3-[(6-iethyl-4-{4-[(4-phenylpyridin-2-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol;
(2R)-3-({6-ethyl-4-[4-(3-pyridin-3-ylbenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
(2R)-3-[(6-ethyl-4-{4-[(3'-fluoro-1 ,1 '-biphenyl-3-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol; (2R)-3-({6-ethyl-4-[4-(3-pyrimidin-5-ylbenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
(2R)-3-[(4-{44(3',4'-difluoro-1 ,1l-biphenyl-3-yl)carbonyl]piperazin-1-yl}-6-ethylthieno[2,3- d]pyrimidin-2-yl)oxy]propane-1 ,2-diol;
(2R)-3-[(6-ethyl-4-{4-[(4'-methyl-1 , 1 '-biphenyl-3-yl)carbonyl]piperazin-1 -yl}thieno[2,3-d]pyrimidin- . 2-yl)oxy]propane-1 ,2-diol;
(2R)-3-[(6-ethyl-4-{4-[3-(6-methoxypyridin-3-yl)benzoyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol;
3'-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazin-1- yl]carbonyl}-1 ,1 '-biphenyl-3-carbonitrile; 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethyl-2-(2-morpholin-4-ylethoxy)thieno[2,3- djpyrimidine;
(2R)-3-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-
1 ,2-diol;
4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(2-piperazin-1-ylethoxy)thieno[2,3- djpyrimidine; (2S)-4-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)pipera2in-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)butane-1 ,2-diol;
4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(morpholin-2-ylmethoxy)thienot2,3- d]pyrimidine; 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethyl-2-(3-morpholin-4-ylpropoxy)thieno[2,3- d]pyrimidine;
2-({4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)ethanamine;
(2R)-3-[(6-ethyl-4-{4-[(2-phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol;
(2R)-3-({6-ethyl-4-[4-(phenylacetyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-1 ,2- diol;
3-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)propan-
1-ol; and (2R)-3-({4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-phenylthieno[2,3-d]pyrimidin-2- yljoxy) propane- 1 ,2-diol.
In another embodiment of the compound of Formula (II) is selected from the group consisting of:
4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethyl-2-[(3-methyloxetan-3- yl)methoxy]thieno[2,3-d]pyrimidine; 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethyl-2-(tetrahydrofuran-3-yloxy)thieno[2,3- djpyrimidine;
4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-[(2R)-oxiran-2-ylmethoxy]thieno[2,3- d]pyrimidine;
(2R)-3-({4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-methylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
(2R)-4-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy) butane- 1 ,2-diol;
(2R)-3-[(4-{4-[(3',4'-dif luoro-1 , 1 '-biphenyl-4-yl)carbonyl]piperazin-1 -yl}-6-ethylthieno[2,3- d]pyrimidin-2-yl)oxy]propane-1 ,2-diol; (2R)-3-[(6-ethyl-4-{4-[4-(6-methoxypyridin-3-yl)benzoyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol;
(2R)-3-{[6-ethyl-4-(4-{[4'-(trif luoromethyl)-1 , 1 '-biphenyl-4-yl]carbonyl}piperazin-1 -yl)thieno[2,3- d]pyrimidin-2-yl]oxy}propane-1 ,2-diol;
(2R)-3-({6-ethyl-4-[4-(4-pyridin-3-ylbenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
2-[({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)methyl]propane-1 ,3-diol;
(2R)-3-({6-ethyl-4-[4-(phenoxyacetyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-1 ,2- diol; (2R)-3-({6-ethyl-4-[4-(3-phenoxypropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-
1 ,2-diol;
4-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)pipera2in-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)-2- methylbutan-2-ol; (2R)-3-({6-ethyl-4-[4-(4-pyrimidin-5-ylben2oyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
(2R)-3-[(4-{4-[(3',5'-difluoro-1 ,1'-biphenyl-4-yl)carbonyl]piperazin-1-yl}-6-ethylthieno[2,3- d]pyrimidin-2-yl)oxy]propane-1 ,2-diol;
(2R)-3-[(4-{4-[(3,4-difluorophenyl)acetyl]piperazin-1-yl}-6-ethylthieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol;
(2S)-5-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)pentane-1 ,2-diol;
4-[4-(1,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-
6-propylthieno[2,3-d]pyrimidine; 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-
6-isopropylthieno[2,3-d]pyrimidine; and
(2R)-3-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-propylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol.
In another embodiment of the 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;
N-1 ,1 '-biphenyl-4-yl-4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4- yl)piperazine-1 -carboxamide;
N-(3-(4-(2-((R)-2,3-dihydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-3- oxopropyl)-N-phenylbenzamide;
N-(3-(4-(2-(((S)-2,2-dimethyl-1 ,3-dioxolan-4-yl)methoxy)-6-ethylthieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl)-3-oxopropyl)-N-phenylbenzamide;
(3-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazin-1- yl]carbonyl}phenyl)(phenyl)methanone; (3-{[4-(2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methanone;
2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(thien-2-ylacetyl)piperazin-1- yl]thieno[2,3-d]pyrim idine;
(2R)-3-({6-ethyl-4-[4-(thien-2-ylacetyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-1 ,2- diol;
2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3-phenoxybenzoyl)piperazin-1- yl]thieno[2,3-d]pyrimidine;
2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-4-[4-(3,3-diphenylpropanoyl)piperazin-1-yl]-6- ethylthieno[2,3-d]pyrim idine; 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(1- phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine;
3-{[4-(2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-y|]methoxy}-6-ethyithienot2,3-d]pyrimidin-4- yl)piperazin-1-yl]carbonyl}-9H-fluoren-9-one; 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(2-naphthyloxy)acetyl]piperazin-1- yl}thieno[2,3-d]pyrimidine;
2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(4'-ethy!-1 ,1 '-biphenyl-4- yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine;
(2R)-3-({4-[(3R)-4-(1 ,1 '-biphenyl-4-ylcarbonyl)-3-methy!piperazin-1 -yl]-6-ethylthieno[2,3- d]pyrimidin-2-yl}oxy)propane-1 ,2-diol;
(2R)-3-({4-[(3S)-4-(1 ,1 '-biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-6-ethylthieno[2,3- d]pyrimidin-2-yl}oxy)propane-1 ,2-diol;
(2R)-3-({4-[(2R)-4-(1 , 1 '-biphenyl-4-ylcarbonyl)-2-methylpiperazin-1 -yl]-6-ethylthieno[2,3- d]pyrimidin-2-yl}oxy)propane-1 ,2-diol; (2R)-3-({4-[(2S)-4-(1 ,1 '-biphenyl-4-ylcarbonyl)-2-methylpiperazin-1 -yl]-6-ethylthieno[2,3- d]pyrimidin-2-yl}oxy)propane-1 ,2-diol;
4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yϊ]methoxy}-
6-phenylthieno[2,3-d]pyrimidine;
4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-methylthieno[2,3-d]pyrimidine; and
4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)-N-(3- methoxybenzyl)piperazine-1-carboxamide.
In another embodiment of 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-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-; acetic acid, [[6-ethyl-4-[4-(phenylacetyl)-1 -piperazinyl]thieno[2,3-d]pyrimidin-2-yl]oxy]-; acetam ide, 2-[[4-[4-([1 , 1 '-biphenyl]-3-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3-d]pyrim idin-2- yl]oxy]-; acetam ide, 2-[[6-ethyl-4-[4-(phenylacetyl)-1-piperazinyl]thieno[2,3-d]pyrimidin-2-yl]oxy]-; acetamide, 2-[[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-methylthieno[2,3-d]pyrimidin-2- yl]oxy]-; acetic acid, [[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-methylthieno[2,3-d]pyrimidin-2- yl]oxy]-; acetamide, 2-[[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-N-methyl-; acetamide, 2-[[4-[4-([1 ,1 '-biphenyl]-3-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-N-methyl-; acetamide, 2-[[6-ethyl-4-t4-(phenylacetyl)-1-piperazinyl]thienot2,3-d]pyrimidin-2-yl]oxy]-N-methyl-
propanoic acid, 3-[[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-
2-yl]oxy]-; propanamide, 3-[[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-; propanamide, 3-[[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyi]-6-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-N-methyl-; propanamide, 3-[f4-[4-([1 ,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-N,N-dimethyl-; piperazine, 1-[2-(3-aminopropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl]-4-([1 ,1'-biphenyl]-4- ylcarbonyl)-; piperazine, 1-([1 ,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[3-(methylamino)propoxy]thienot2,3- d]pyrimidin-4-yl]-; piperazine, 1 -([1 ,1 '-biphenylJ^-ylcarbonyO^-Iβ-ethyl^-^^methylaminoJethoxylthieno^.S- d]pyrimidin-4-yl]-; and piperazine, 1 -([1 , 1 '-biphenyl]-3-ylcarbonyl)-4-[6-ethyl-2-[2-hydroxy-1 - (hydroxymethyl)ethoxyJthieno[2,3-d]pyrimidin-4-yl]-.
In another embodiment of the 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-
(phenylacetyl)-; propanoic acid, 2-[[4-[4-([1 , 1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3-d]pyrim idin- 2-yl]oxy]-2-methyl-; propanoic acid, 2-[[4-[4-([1 ,1'-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-
2-yl]oxy]-3-hydroxy-; propanamide, 2-[[4-[4-([1,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-2-methyl-; propanamide, 2-[[4-[4-([1 ,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-3-hydroxy-N-methyl-; propanamide, 2-[[4-[4-([1 ,1'-biphenyl]-4-ylcarbonyl)-1-piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2- yl]oxy]-3-hydroxy-; cyclopropanecarboxylic acid, 1-[[4-[4-([1 ,1'-biphenyl]-4-ylcarbonyl)-1- piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2-yl]oxy]-; cyclopropanecarboxamide, 1 -[[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3- djpyrim idin-2-yl]oxy]-; piperazine, 1 -([1 ,1 '-biphenyl^-ylcarbonyl^-fδ-ethyl^-Ktetrahydro^-hydroxy-S- furanyl)oxy]thieno[2,3-d]pyrimidin-4-yl]-; piperazine, 1-([1 ,1'-biphenyl]-4-ylcarbonyl)-4-[2-[[(1 R,2R,3R)-2,3-dihydroxycyclopentyl]oxy]-6- ethylthieno[2,3-d]pyrimidin-4-yl]-; piperazine, 1 -([1 ,1 '-biphenylj-ΦylcarbonyO^-^-^.S-dihydroxycyclopentylJoxyj-e-ethylthienop.a- d]pyrim idin-4-yl]-; piperaziheI 1-(f1,1l-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[[(1 R,2R,3R,4S)-2,3I4- trihydroxycyclopentyl]oxy]thieno[2,3-d]pyrim idin-4-yl]-; 1 -piperazinecarboxaldehyde, 4-[6-ethyl-2-[(2,3,4-trihydroxycyclopentyl)oxy]thieno[2,3- djpyrim idin-4-yl]-; piperazine, 1 -([1 , 1 '-biphenyl]-4-ylcarbonyl)-4-[2-[[(1 R,2R,3S,4S)-2,3-dihydroxy-4-(2- hydroxyethoxy)cyclopentyl]oxy]-6-ethylthieno[2,3-d]pyrimidin-4-yl]-; piperazine, 1 -([1 ,1 '-biphenyl]-4-ylcarbonyl)-4-[2-[[2,3-dihydroxy-4-(2- hydroxyethoxy)cyclopentyl]oxy]-6-ethylthieno[2,3-d]pyrimidin-4-yl]-; cyclopentanecarboxamide, 4-
[[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2-yl]oxy]-2,3- ■ dihydroxy-, (1S,2R,3R,4R)-; cyclopentanecarboxamide, 4-[[4-[4-([1 ,1'-biphenyl]-4-ylcarbonyl)-1- piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2-yl]oxy]-2,3-dihydroxy-; piperazine, 1-([1,1'-biphenyl]-
4-ylcarbonyl)-4-[6-ethyl-2-[2-(2-hydroxyethoxy)ethoxy]thieno[2,3-d]pyrimidin-4-yl]-; acetic acid, [2- [[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3-d]pyrimidin-2-yl]oxy]ethoxy]-; and acetamide, 2-[2-[[4-[4-([1 ,1 '-biphenyl]-4-ylcarbonyl)-1 -piperazinyl]-6-ethylthieno[2,3- d]pyrim idin-2-yl]oxy]ethoxy]-.
In another embodiment of the compound of Formula (II) is selected from the group consisting of: piperazine, 1 -([1 , 1 '-biphenylH-ylcarbonylH-tθ-ethyl^-Kδ-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-
4-yl]-; piperazine, 1 -([1 ,1 '-biphenyl]-4-ylcarbonyl)-4-t6-ethyl-2-[(2-oxo-3-pyrrolidinyl)oxy]thieno[2,3- d]pyrimidin-4-yl]-; piperazine, 1 -([1 , 1 '-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-(4-piperidinyloxy)thieno[2,3-d]pyrimidin-4- yi]-; piperazine, 1 -([1 ,1 '-biphenylJ^-ylcarbonyO^-fβ-ethyl^-f^etrahydro^H-pyran^-yOoxyJthieno^.S- d]pyrimidin-4-yl]-; piperazine, 1 -([1 , 1 '-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[[(2S,3R)-2,3,4- trihydroxybutyl]oxy]thieno[2,3-d]pyrimidin-4-yl]-; piperazine, 1 -([1 , 1 '-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-f[(2S,3S)-2,3,4- trihydroxybutyl]oxy]thieno[2,3-d]pyrimidin-4-yl]-; piperazine, 1 -([1 , 1 '-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-[[(2R,3R)-2,3,4- trihydroxybutyl]oxy]thieno[2,3-d]pyrimidin-4-yl]-; piperazine, 1 -([1,1 '-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-t[(2R, 3S)-2,3,4- trihydroxybutyl]oxy]thieno[2,3-d]pyrim idin-4-yl]-; piperazine, 1 -([1 ,1 '-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-(3-oxobutoxy)thieno[2,3-d]pyrimidin-4-yl]-; and piperazine, 1-([1,1'-biphenyl]-4-ylcarbonyl)-4-[6-ethyl-2-(2-oxopropoxy)thieno[2,3-d]pyrimidin-4- yl]-. In another embodiment of the~compound of Formula~(ll) is selected from the group consisting of:
(2S)-3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-~diόl;~
(2S)-3-({6-(1 ,1-difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
(2R)-3-({6-(1 ,1 -difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
2-({6-(1 ,1-difluoroethyl)-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)ethylamine; (2S)-3-({6-(2,2,2-trifluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-
2-yl}oxy)propane-1 ,2-diol;
(2R)-3-({6-(2,2,2-trifluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-
2-yl}oxy)propane-1 ,2-diol;
(2S)-3-({6-(trifluoromethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
(2R)-3-({6-(trifluoromethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propan-1- ol; 2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)ethanol;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)ethylamine;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-
1 ,3-diol; ({e-ethyl^-^^S.S.S-trifluoropropanoyOpiperazin-i-yllthieno^.S-dlpyrimidin^-ylJoxyJacetic acid;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)acetamide;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-N- methylacetamide;
N-(tert-butyl)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)acetamide;
1-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)acetone;
4-({6-ethyl-4-f4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)butan-2- one;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thienot2,3-d]pyrimidin-2-yl}oxy)propanoic acid; and
3-({6-ethyl-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propanam ide.
In another embodiment of the compound of Formula (II) is selected from the group consisting of:
6-ethyl-2-(1 H-tetrazol-5-ylmethoxy)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3- djpyrimidine; (4R)-4-[({6-ethyl-4-[4-(3;3,3-trifluoropropanoyl)piperazin-r-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)m ethyl] isoxazo! id in-3-one;
(4S)-4-[({6-ethyl-4-[4-(3,3,3-trif luoropropanoyl)piperazin-1 -yl]th ieno[2,3-d]pyrim idin-2- yl}oxy)methyl]isoxazolidin-3-one; (3S)-3-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)methyl]dihydrofuran-2(3H)-one;
(3R)-3-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)methyl]dihydrofuran-2(3H)-one;
(4R)-4-({6-ethyl-4-[4-(3)3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)isoxazolidin-3-one;
(4S)-4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)isoxazolidin-3-one;
4-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)methyl]isoxazol-3(2H)-one; (2S)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-3- hydroxypropanoic acid;
(2R)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-3- hydroxypropanoic acid;
(2S)-2-({6-ethyl-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-3- hydroxypropanamide;
(2R)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-3- hydroxypropanamide;
(2S)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thienot2,3-d]pyrimidin-2- yl}oxy)propanamide; (2R)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propanamide;
(2S)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propanoic acid;
(2R)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propanoic acid;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)ethanesulfonamide; and
6-ethyl-2-[2-(methylsulfonyl)ethoxy]-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3- d]pyrimidine. In another embodiment of the compound of Formula (II) is selected from the group consisting of:
(2S)-3-({6-(1 ,1-difluoroethyl)-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
(2R)-3-({6-(1 ,1-difluoroethyl)-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol; 2-({6-(1 ,1-difluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)ethylamine;
(2S)-3-({6-(2,2,2-trifluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-
2-yl}oxy)propane-1 ,2-diol; (2R)-3-({6-(2,2,2-trifluoroethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-
2-yl}oxy)propane-1 ,2-diol;
(2S)-3-({6-(trifluoromethyl)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
(2R)-3-({6-(trifluoromethyl)-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propan-1- ol;
2-({6-ethyl-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thienot2,3-d]pyrimidin-2-yl}oxy)ethanol;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)ethylamine;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-
1 ,3-diol;
^^^(^-^-(S.S.S-trifluoropropanoyOpiperazin-i-yllthieno^.S^pyrimidin^-ylJoxyJacetic acid;
2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)acetamide; 2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrinnidin-2-yl}oxy)-N- methylacetamide;
N-(tert-butyl)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)acetamide;
1-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)acetone; 4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1ryl]thieno[2,3-d]pyrimidin-2-yl}oxy)butan-2- one;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propanoic acid;
3-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propanamide; and
6-ethyl-2-(1 H-tetrazol-5-ylmethoxy)-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3- d]pyrimidine.
In another embodiment of the compound of Formula (II) is selected from the group consisting of:
(4R)-4-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)methyl]isoxazolidin-3-one;
(4S)-4-[({6-ethyl-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)methyl]isoxazolidin-3-one;
(3S)-3-[({6-ethyl-4-t4-(3)3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)methyl]dihydrofuran-2(3H)-one; -(3R)-3-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-cl]pyrimidin-2- yl}oxy)methyl]dihydrofuran-2(3H)-one;
(4R)-4-({6-ethyl-4-t4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)isoxazolidin-3-one; (4S)-4-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)isoxazolidin-3-one;
4-[({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)methyl]isoxazol-3(2H)-one;
(2S)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-3- hydroxypropanoic acid;
(2R)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thienot2,3-d]pyrimidin-2-yl}oxy)-3- hydroxypropanoic acid;
(2S)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-3- hydroxypropanamide; (2R)-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)-3- hydroxypropanamide;
(2S)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propanamide;
(2R)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1 -yl]thienot2,3-d]pyrimidin-2- yl}oxy)propanamide;
(2S)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propanoic acid;
(2R)-3-amino-2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propanoic acid; 2-({6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)ethanesulfonamide; and
6-ethyl-2-[2-(methylsulfonyl)ethoxy]-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3- d]pyrimidine.
In another embodiment of the 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-
1-yl]thieno[2,3-d]pyrimidine and
(2R)-3-({6-Ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol.
C. Isomers
When an asymmetric center is present in a compound of Formulae (I) through (III) the compound may exist in the form of optical isomers (enantiomers). In one embodiment, the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of Formulae (I) through (III). In another embodiment, for compounds of Formulae (I) through (III) that contain more than one asymmetric center, the present invention comprises diastereomeric forms (individual diastereomers and mixtures thereof) of compounds. When a compound of Formulae (I) through (III) contains an alkenyl group or moiety, geometric isomers may arise.
D. Tautomeric Forms
The present invention comprises the tautomeric forms of compounds of Formulae (I) through (III). Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. 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.
E. Salts
The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, 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. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
Where 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. The term "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. For use in medicine, the 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. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. "Specific examples of suitable^organicacidsiπclαde'acetatertrifluoroacetaterfoTmate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.
In another embodiment, 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. In another embodiment, representative salts include benzenesulfonate, hydrobromide and hydrochloride. Furthermore, where the compounds of the invention carry an acidic moiety, 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. In another embodiment, 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. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (CrC6) 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. In one embodiment, 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. Included within the scope of the invention are 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. Also included are 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. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).
F. Prodrugs Also within the scope of the present invention are so-called "prodrugs" of the compounds of
Formulae (I) through (III).- Thus, certain derivatives of compounds of any of Formulae (I) through (III) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of any of Formulae (I) through (III) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs may be found in "Pro-drugs as Novel
Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). 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).
G. Methods of Treatment
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. In one embodiment, the treatment is preventative treatment. In another embodiment, the treatment is palliative treatment. In another embodiment, the treatment is restorative treatment.
1. Conditions
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. In another embodiment, platelet aggregation mediation conditions may be treated. In one embodiment, 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). In another embodiment, the compounds of the invention can be used to treat stroke (such as thrombotic stroke, ischemic stroke, embolic stroke and transient ischemic attack). "Irranother embodiment, 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.
In another embodiment, 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. In another embodiment, the compounds of the present invention, can be used to treat hypertension.
In another embodiment, the compounds of the present invention can be used to treat angiogenesis.
2. Administration and Dosing
Typically, 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.
In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, 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. In one embodiment, the total daily dose of a compound of Formulae (I) through (III) (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, 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). In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment, 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. In many instances, 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.
For oral administration, the 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. ' Intravenously, 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. In one embodiment, humans are suitable subjects; Human subjects may be of either gender and at any stage of development.
H. .. Use in the Preparation of a Medicament
In one embodiment, 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.
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 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. In another embodiment, 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.
I. Pharmaceutical Compositions For the treatment of the conditions referred to above, the compounds of Formulae (I) through (III) can be administered as compound perse. Alternatively, pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound. In another embodiment, 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, for example, 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. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, 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. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings. In another embodiment, 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.
In another embodiment, 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) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. In another embodiment, 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. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. 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. Such formulations may also be delivered by iontophoresis.
For intranasal administration or administration by inhalation, 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. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
In another embodiment, the present invention comprises a rectal dose form. Such 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. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.
J. Co-administration 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. The phrases "concurrent administration," "co-administration," "simultaneous administration," and "administered simultaneously" mean that the compounds are administered in combination. In one embodiment, 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. In still another embodiment, compounds of Formulae (I) through (III) may be co- administered with aspirin.
In another embodiment, 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. In still another embodiment, compounds of Formulae (I) through (III) may be co-administered with eptifibatide. In another embodiment, 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. In another embodiment, 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.
In another embodiment, 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. In still another embodiment, compounds of Formulae (I) through (lll)-may be co-administered with warfarin sodium.
In another embodiment, 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. In still another embodiment, compounds of Formulae (I) through (III) may be coadministered with ximelagatran.
In another embodiment, 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, alteplase and aminocaproic acid. In another embodiment, 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.
K. Kjts The present invention further comprises kits that are suitable for use in performing the methods of treatment or prevention described above. In one embodiment, 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. In another embodiment, 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. In still another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and aspirin. In another embodiment, 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. In still another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and eptifibatide. In another embodiment, 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.
In another embodiment, 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. In another embodiment, 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. In still another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and warfarin sodium. In another embodiment, 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. In still another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (III) and ximelagatran.
In another embodiment, the 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, alteplase and aminocaproic acid.
In another embodiment, the 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-
9065a.
L. Intermediates
In another embodiment, the invention relates to the novel intermediates useful for preparing the thieno[2,3-d|pyrimidine compounds of Formulas (I)-(III).
M. General Synthetic Schemes
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
•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 0C to 175 0C, optionally with an excess of phosphorous oxychloride in a sealed vessel at 130-175 0C, to give dichloropyrimidine 5. 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.
Scheme B
Scheme B. 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)2O). Protected piperazine 8 is then acylated using acyl reagent 9, where acyl reagent 9 is used in its acid form (X = OH) in the presence of a coupling agent. Suitable coupling agents include, but are not limited to, DCC, EDC, DEPC, HATU, HBTU and CDI. In an alternative preparation of intermediate 6, acyl reagent 9 is used in the form of an acid halide (X = Cl, Br, F) or anhydride (X = O(COR4))in the presence of 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 ranging between ice/water temperature to the reflux temperature of the solvent, to give bisamide 10. 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. When the protecting group of bisamide 10 is a benzyl group, then 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
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. 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. Thienopyrimidine 7 is obtained upon combining acyl reagent 9 (X = OH) with pyrimidine-piperazine 11 using coupling reagents, many of which are well known to those versed in the art and include but are not limited to DCC, EDC, DEPC, HATU, HBTU and CDI. Alternatively, 9 is used in the form of an acid halide X = Cl, Br, F) or anhydride (X = 0(COR4)) in the presence of a base, preferably a trialkylamine, pyridine, or an alkaline earth metal carbonate and in the presence of 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.
Scheme D
14C 14A 14B
Scheme D. Elaboration of thienopyrimidine 7 to substituted thienopyrimidine 14 is accomplished by treating thienopyrimidine 7 with H-OR2 (13), and where H-OR2 is commercially available or may be prepared by methods well-known to those versed in the art. Regaent 13 is combined with thienopyrimidine 7 in the presence of a base and an inert solvent. Reagent 13 may be treated with a strong base and is then added to thienopyrimdine 7. Alternatively, thienopyrimidine 7 may be added to reagent 13 after the addition of strong base. Whichever the order of addition, in one example, reagent 13 is first treated with a strong base to form an anion. Suitable strong include, but are not limited to, alkali metal hydrides (such as sodium hydride). In one embodiment, 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. In another embodiment, 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. To reduce undesired reactions, reagent 13 can be protected first (i.e. R2 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. For example, when R7 is desired to be an alkyl diol, the diol of H-Y-R2 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.
Alternatively, R2 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. For example, treatment of an aldehyde with an oxidizing agent such as 3- chloroperoxbenzoic acid and the like gives substituted thienopyrimidine 14 where R2 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 R2 contains an amino group.
When R4 is phenyl or heteroaryl substituted with Br, I, Cl, and O-triflate, then additional manipulations of R4 may be carried out using standard methods known in the art. For example, aryl- or heteroaryl-boronic acids or esters, many of which are commercially available, may be reacted, in the presence of a metal catalyst, with substituted thienopyrimidine 14A to give biaryl substituted thienopyrimidine 14C. Thus, treatment with 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(ORa)(ORb) (where Ra and Rb are each C-] -Cg alkyl, or when taken together, Ra and Rb 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. 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. In one embodiment, the alkali metal hydride is sodium hydride. In another embodiment, the alkali metal alkoxide is sodium methoxide. In another embodiment, the alkali metal alkoxide is sodium ethoxide. In another embodiment, the alkali metal dialkylamide is lithium diisopropylamide. In another embodiment, the alkali metal bis(trialkylsilyl)amide is sodium bis(trimethylsilyl)amide. In another embodiment, the trialkyl amine is diisopropylethylamine. In another embodiment, the trialkylamine is triethylamine. In another embodiment, 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. In one embodiment, the dialkyl ether is diethyl ether. In another embodiment, the cyclic ether is tetrahydrofuran. In another embodiment, the cyclic ether is 1 ,4-dioxane. In another embodiment the N,N-dialkylacetamide is dimethylacetamide. In another embodiment, the N, N- dialkylformamide is dimethylformamide. In another embodiment, the dialkylsulfoxide is dimethylsulfoxide. In another embodiment, the aromatic hydrocarbon is benzene. In another embodiment, the aromatic hydrocarbon is toluene. In another embodiment, the 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). Alternatively, as described in Tetrahedron, 50, 979-988 (1994), one may convert the R4 substituent to the corresponding boronic acid or boronic acid ester (OH)2B- or
(ORa)(ORb)B- and obtain the same products set forth above by treating with a suitable aryl or heteroaryl halide or triflate. The protecting group on R'2 of 14C is then removed using conditions discussed above to give 14.
Scheme E
12 12
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. Alternatively, piperazinyl pyrimidine 11 may be added to reagent 13 after the addition of strong base. Whichever the order of addition, in one embodiment, reagent 13 is first treated with a strong base to form an anion. Suitable strong bases include an alkali metal hydride. In another embodiment, the strong base is sodium hydride. In one embodiment, the addition of the strong base to reagent 13, or addition of reagent 13 to strong base, is done at temperatures ranging from -30 0C to room temperature. In another embodiment, 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; For example, in one embodiment, 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. When complete, the solvents are removed under reduced pressure to give the corresponding amine as the corresponding salt, i.e. trifluoroacetic acid or hydrogen chloride salt. If desired, 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. Thienopyrimidine 14 is obtained upon combining acyl reagent 9 (X = OH) with amine 16 using coupling reagents, many of which are well known to those versed in the art and include but are not limited to DCC, EDC, DEPC, HATU, HBTU and CDI. In another embodiment, 9 is used in the form of an acid halide (X = Cl, Br, F) or anhydride (X = 0(COR4)) in the presence of 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 and the like at temperatures ranging between ice/water temperature to the reflux temperature of the solvent.
Depending upon the nature of the various substituents, it may be desirable to change the order of addition of the substituents. For example, 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. Alternatively, pyrimidine-piperazine 12 may be reacted with a protected form of 13, namely 13A, to give 17. Addition of R4C(O)X (9) to 17 gives 14A, which then may be further manipulated as described for Scheme D. Alternatively, amine 17 may be converted to 16 by methods described for the conversion of 14A to 14 in Scheme D.
N. Working Examples
The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art.
EXAMPLE 1 Methyl 2-amino-5-ethylthiophene-3-carboxylate
To a mixture of sulfur (6.4 g) in DMF (25 ml.) were added methyl cyanoacetate (19.8 g) and triethylamine (15 ml_) under nitrogen. The mixture was stirred for 10 minutes at which time butyraldehyde (18 mL) was added drop-wise at a sufficient rate to maintain a temperature of 50 0C. The mixture was then stirred at room temperature for 20 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. The residue was chromatographed on silica gel (150 mL) using 10% ethyl acetate in hexanes to give a yellow solid. The solid was slurried in hexanes and collected and dried under reduced pressure to give 25.74 g of the title compound. MS (ESI+) for C8H11NO2S m/∑ 186.0598 (M+H)+. 1H NMR (300 MHz, CDCI3) δ 1.22 (t, 3 H), 2.6 (q, 2 H), 3.79 (s, 3 H), 5.79 (s, 2 H), 6.62 (s, 1 H).
EXAMPLE 2
6-Ethyl-4a, 7a-dihydrothieno[2,3-d] pyrimidine-2, 4-diol
To a mixture of the carboxylate of Example 1 (25.2 g) in glacial acetic acid (450 mL) and water (45 mL) was added drop-wise a solution of potassium cyanate (30.9 g) in water (150 mL). The mixture exothermed to 33°C and some gas was evolved. A white precipitate formed during addition. The mixture was stirred at room temperature for 20 hours. Ice water (300 mL) was added to the mixture and the solids were collected by filtration and washed with water (200 mL). The solids were transferred to a round bottom flask to which was added 6% aqueous sodium hydroxide (500 mL). The mixture was refluxed for 2 hours and then cooled to room temperature. The temperature was further lowered to 5 0C in an ice bath. The pH was adjusted to approximately 6 with concentrated hydrochloric acid. The resulting solids were collected, washed with water and dried under reduced pressure to give 16.39 g of the title compound. The material was subsequently azeotroped using THF/toluene to remove any residual water: MS (ESI+) for C8H8N2O2S m/z 197.0 (MH-H)+; 1H NMR (300 MHz, DMSO-c/6) δ 1.24 (t, 3 H), 2.74 (q, 2 H), 6.85 (s, 1 H), 11.1 (s, 1 H), 11.8 (s, 1 H).
EXAMPLE 3
2,4-Dichloro-6-ethylthieno[2,3-d]pyrimidine
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 0C 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. Organic layer was filtered through anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 3.96 g of the title compound: MS (ESI+) for C8H6CI2N2S m/z 233.0 (M+H)+; 1H NMR (300 MHz, CDCI3) δ 1.4 (t, 3 H), 3.0 (q, 2 H), 7.1 (s, 1 H).
EXAMPLE 4 Tert-butyl 4-(phenylacetyl)piperazine-1 -carboxylate
To a mixture of Boc-piperazine (4.2 g) in dry THF (30 mL) in a round bottom flask in an ice bath was added triethylamine (3.14 mL). Phenyl acetyl chloride (2.9 mL) was added drop wise keeping temperature below 15 °C. Once addition was complete removed the mixture from the ice bath and allowed to stir at room temperature for 2 hours. The solvents were removed under reduced pressure and the residue partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed with brine. The organic layer was then dried over anhydrous magnesium sulfate and concentrated. Hexanes were added to the resulting solids and collected via filtration to give 6.24 g of the title compound. MS (ESI+) for C17H24N2O3 m/z 327.0 (M+H+Na)+; 1H NMR (300 MHz, CDCI3) δ 1.44 (s, 9 H), 3.2 (m, 2 H), 3.4 (m, 4 H), 3.6 (m, 2 H), 7.25 (m, 3 H), 7.33 (m, 2 H).
EXAMPLE 5 1 -(Phenylacetyl)piperazine
To a mixture of the carboxylate of Example 4 (6.0 g) in dichloromethane (5 mL) was added trifluoroacetic acid (5.0 mL). The mixture was stirred at room temperature for 8 hours. The solvents were removed under reduced pressure and the residue partitioned between saturated sodium bicarbonate and dichloromethane. The layers were separated and the aqueous layer extracted with dichloromethane. The combined dichloromethane extracts were dried using anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 ml_) using 8% methanol in dichloromethane with 0.1% ammonium hydroxide to give 2.01 g of the title compound: 1H NMR (300 MHz, CDCI3) δ 1.75 (s, 1 H), 2.66 (t, 2 H)1 2.8 (t, 2 H), 3.4 (t, 2 H), 3.6 (t, 2 H)1 3.7 (s, 2 H), 7.2 (m, 3 H), 7.3 (m, 2 H).
EXAMPLE 6 2-Chloro-6-ethyl-4-[4-(phenylacetyl)piperazin-1-yl]thieno[2,3-d]pyrimidine
To a mixture of the pyrimidine of Example 3 (1.53 g) in dry THF (60 ml_) was added diisopropylethylamine (4.6 mL) and 1-(phenylacetyl)piperazine (1.35 g; EXA 5). The mixture was stirred at room temperature for 2.5 hours, at which time the mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using 2% methanol in dichloromethane to give 2.28 g of the title compound: MS (ESI+) for C20H2ICIN4OS m/z 401.0 (M+H)+; 1H NMR (300 MHz, CDCI3) δ 1.35 (t, 3 H), 2.85 (q, 2 H), 3.63 (m, 2 H), 3.74 (m, 2 H), 3.80 (s, 2 H), 3.85 (m, 2 H), 3.89 (m, 2 H), 6.9 (s, 1 H), 7.27 (m, 3 H), 7.34 (m, 2 H).
EXAMPLE 7
Methyl 2-amino-5-phenylthiophene-3-carboxylate
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 0C. 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 MgSO4, filtered and concentrated. The residue was triturated with diethyl ether containing a few drops of acetonitrile and the resulting solid was collected to give the title compound (20.8 g). 1H NMR (400 MHz, CDCI3) δ 7.41-7.43 (m, 2H), 7.29-7.34 (m, 2H), 7.22 (s, 1 H), 7.18-7.21 (m, 1 H). EXAMPLE 8 6-Phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
Methyl 2-amino-5-phenylthiophene-3-carboxylate (Example 7, 3.0 g) and urea (6.8 g) were combined in a thick-walled glass sealed tube and heated to 200 0C for 2 hours. The mixture was then cooled to room temperature and DMF (45 ml.) was added and the mixture refluxed for one hour. Ice water (120 ml_) was added and the resulting precipitate was collected and dried under reduced pressure to give 1.6 g of the title compound, which was used in the next step without further purification. LCMS (ESI+) for C12H8N2O2S m/z 245.11 (M+H)+.
EXAMPLE 9
2,4-Dichloro-6-phenylthieno[2,3-d]pyrimidine
6-Phenylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (Example 8, 1.2 g) and POCI3(IO mL) were placed in a thick-walled glass sealed tube and heated to 150 0C for 2 hours. The mixture was cooled to room temperature and the POCI3 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 MgSO4, 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. 1H NMR (400 MHz, CDCI3) δ 7.72-7.69 (m, 2H), 7.55 (s, 1 H), 7.50-7.44 (m, 3H).
EXAMPLE 10 6-Methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione
2-Amino-5-methyl-thiophene-3-carboxylic acid (4.0 g) and urea (8.4 g) were placed in a sealed tube and heated to 200 0C for 2 hours. The mixture was cooled to room temperature and DMF was added (50 mL) and the mixture was refluxed for 1 hour. After cooling to room temperature, ice water was added to the mixture. The resulting solid was collected and dried under reduced pressure to give 2.47 g of the title compound, which was used in the next step without further purification. MS (ESI+) for C7H6N2O2S m/z 183.1 (M+H)+. EXAMPLE 11 2-Chloro-6-ethyl-4-piperazin-1 -ylthieno[2,3-d]pyrimidine dihydrochloride
HCI gas was bubbled through dry 1,4-dioxane (400 mL) for 15 minutes. The mixture was cooled to room temperature and added to the carboxylate of Example 12 (22.1 g) in dry 1,4-dioxane. The mixture was stirred at room temperature overnight. 1 ,4-Dioxane was removed under reduced pressure and dichloromethane was added. The resulting solids were collected via filtration to give 19.22 g of the title compound: 1H NMR (300 MHz, DMSO-ofe) δ 1.28 (t, 3 H), 2.90 (q, 2 H), 3.23 (m, 4 H), 4.05 (m, 4 H), 7.39 (s, 1 H), 9.47 (s, 2 H).
EXAMPLE 12 tert-Butyl 4-(2-chloro-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazine-1 -carboxylate
To a mixture of the pyrimidine of Example 3 (10.38 g) in dry THF (300 mL) was added diisopropylethylamine (19.4 mL) and Boc-piperazine (9.9 g). The mixture was stirred at room temperature 6 hours at which time the solvents were removed under reduced pressure and the residue partitioned between brine and dichloromethane. The layers were separated and the organic layer washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness to give 15.35 g of the title compound. 1H NMR (300 MHz, CDCI3) δ 1.36 (t, 3 H), 1.49 (s, 9 H)1 2.89 (q, 2 H), 3.62 (m, 4 H), 3.91 (m, 4 H)1 6.95 (s, 1 H).
EXAMPLE 13 4-[4-(1 , 1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-chloro-6-ethylthieno[2,3-d]pyrim idine
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. The silica gel plug was eluted with dichloromethane to remove impurities. The silica gel plug was then washed with ethyl acetate. The ethyl acetate filtrates were concentrated to give 0.966 g of the title compound. MS (ESI+) for C25H23CIN4OS m/z 465.14 (M+H)+; 1H NMR (300 MHz, CDCI3) δ 1.36 (t, 3 H), 2.9 (q, 2 H), 3.98 (m, 8 H), 6.95 (s, 1 H), 7.37-7.68 (m, 9 H).
EXAMPLE 14 tert-Butyl 4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazine-1 -carboxylate
To a mixture of Boc-piperazine (5.0 g) in THF (100 mL) was added 4-biphenyl carbonyl chloride (3.9 g) and diisoprqpylethylamine (6.0 g). The mixture was stirred at room temperature overnight. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 6.0 g of the title compound. 1H NMR (400 MHz, CDCI3) δ 1.47 (s, 9 H), 3.4- 3.8 (m, 8 H), 7.39 (m, 1 H), 7.43-7.48 (m, 4 H), 7.57-7.64 (m, 4 H).
EXAMPLE 15
1-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazine hydrochloride
HCI
HCI gas was bubbled through methanol (100 mL) for 20 minutes then cooled to room temperature. The carboxylate of Example 14 was added(6.0 g). The mixture was stirred at room temperature for 20 hours. The solvents were removed under reduced pressure and hexanes added to the residue. The resulting solids were collected via filtration to give 4.8 g of the title compound. 1H NMR (400 MHz, DMSO-Cf6) δ 3.14 (m, 4 H), 4.14 (m, 4 H), 7.36 (m, 1 H), 7.45 (m, 2 H), 7.54 (m, 2 H), 7.68 (d, 2 H), 7.73 (d, 2 H), 9.64 (s, 1 H).
EXAMPLE 16 2,4-Dichloro-6-methylthieno[2,3-d]pyrimidine
6-Methylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione (Example 10, 2.0 g) and POCI3 were heated together in a sealed tube at 150 0C 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 MgSO4, 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)+.
EXAMPLE 17
6-Propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione
2-amino-5-propylthiophene-3-carboxylate (8.1 g) and urea (15.0 g) were heated together in a sealed tube to 200 0C for 3 hours and then stirred at room temperature overnight. The resulting mixture was poured into ice water (250 mL) and the resulting solid was collected. The solid was washed with diethyl ether and dried under reduced pressure to give 3.1 g of the title compound. MS (ESI+) m/z 219.05 (M+H)+.
EXAMPLE 18 2,4-Dichloro-6-propylthieno[2,3-d]pyrimidine
6-Propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 17, 2.0 g) and POCI3 were heated in a sealed tube for 1.5 hours at 150 0C. 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 MgSO4, filtered and " "concentrated under reduced pressure to give 1.1 g of the title compound." MS (ESI+) for C9H8CI2N2S m/z 247.09 (M+H)+.
EXAMPLE 19 4-[4-(1 ,1 '-biphenyl-3-ylcarbonyl)piperazin-1 -yl]-2-chloro-6-ethylthieno[2,3-d]pyrimidine
To biphenyl-3-carboxylic acid (0.489 g) in dichloromethane (10 ml.) was added 1 ,1'- carbonyldiimidazole. The mixture was stirred for 45 min, at which time a slurry of 2-chloro-6- ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine dihydrochloride (0.750 g) and triethylamine (0.33 mL) in dichloromethane (15 mL) and DMF (1 mL) was added. The mixture was stirred overnight and then partitioned between dichloromethane, aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crystallization from dichloromethane and hexane gave 0.914 g of the title compound. MS [m+H] 463.27; 1H NMR (400 MHz, CDCI3) δ 1.34 (3H), 2.88 (2H), 3.6-4.1 (8 H), 6.93 (1 H), 7.36-7.53 (5H), 7.58 (2H), 7.67 (2H).
EXAMPLE 20
Tert-butyl 4-(2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidin-4- yl)piperazine-1 -carboxylate
Sodium hydride 60% in mineral oil (0.16 g) was placed into a round bottom flask, washed with hexanes and chilled in an ice/acetone bath. NMP (10 mL) was added and the mixture stirred for 5 minutes. (S)-(+)-2,2-Dimethyl-1 ,3-dioxolane-4-methanol (0.502 g) was added and the mixture stirred for 15 minutes. The carboxylate of Example 12 (1.46 g) was dissolved in NMP (15 mL) and added drop-wise to the chilled mixture. Once the addition was complete removed from the ice/acetone bath and stirred at room temperature for 30 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- hexanes (20/80) to give 1.346 g of the title compound. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 1.38 (s, 3 H), 1.46 (s, 3 H), 1.48 (s, 6 H), 1.58 (s, 3 H), 2.84 (q, 2 H), 3.58 (m, 4 H), 3.84 (m, 4 H), 3.92 (m, 1 H), 4.15 (m, 1 H), 4.31 (m, 1 H), 4.45-4.55 (m, 2 H), 6.86 (s, 1 H).
EXAMPLE 21
6-lsopropylthieno[2,3-d]pyrimidine-2,4(1 H,3H)-dione
Methyl 2-amino-5-isopropylthiophene-3-carboxylate (8.0 g) and urea (14.4 g) were heated together in a sealed tube to 200 0C for 3 hours and then cooled to room temperature and stirred overnight. The mixture was poured into ice cold water (25OmL) and the resulting solid was collected, washed with diethyl ether and dried under reduced pressure to give 7.9 g of the title compound. MS (ESkJ fOr C9H10N2O2S m/z 212.19 (M+H)+.
EXAMPLE 22 (2R)-3-[(6-Ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidin-2-yl)oxy]propane-1 ,2-diol hydrochloride
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. 1H NMR (400 MHz, DMSO-Of6) δ 1.25 (t,.3 H), 2.82 (q, 2 H), 3.20 (m, 4 H), 3.6 (m, 2 H), 3.77 (m, 1 H), 4.03 (m, 4 H), 4.15 (m, 1 H), 4.3 (m, 1 H), 7.24 (s, 1 H), 9.54 (s, 1 H).
EXAMPLE 23 2-Chloro-6-ethyl-4-piperazin-1-y!thieno[2,3-d]pyrimidine
HCI gas was bubbled through a solution of the carboxylate of Example 12 (6.36 g) dissolved in methanol (100 mL) for 1 minute. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 3.65 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.34 (t, 3 H), 2.87 (q, 2 H), 3.05 (m, 4 H), 3.96 (m, 4 H), 6.93 (s, 1 H).
EXAMPLE 24
2-(2-Ethoxyethoxy)-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine
Sodium hydride 60% in mineral oil (0.024 g) was placed into a round bottom flask, washed with hexanes and chilled in an ice/acetone bath. NMP (1.0 mL) was added and the mixture stirred for 5 minutes. 2-Ethoxyethanol (0.05 g) was added and the mixture stirred for 5 minutes. The mixture was removed from the ice/ acetone bath for 30 minutes then placed back in ice bath. The pyrimidine of Example 23 (0.15 g) was dissolved in NMP (1 mL) and added drop-wise to the chilled mixture. Once the addition was complete 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 to dryness to give 0.116 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.21 (t, 3 H), 1.32 (t, 3 H), 2.3 (m, 1 H), 2.36 (m, 1 H), 2.83 (m, 2 H), 3.00 (m, 4 H), 3.37 (m, 1 H), 3.58 (q, 2 H), 3.78-3.83 (m, 4 H), 4.48 (m, 1 H), 6.86 (s, 1 H).
EXAMPLE 25 2-{t(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine
Sodium hydride 60% in mineral oil (0.042 g) was placed into a round bottom flask, washed with hexanes and chilled in an ice/acetone bath. NMP (1.0 ml.) was added and the mixture stirred for 5 minutes. (S)-(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol (0.14 g) was added and the mixture stirred for 5 minutes. The mixture was removed from the ice/ acetone bath for 30 minutes then placed back in ice bath. The pyrimidine of Example 23 (0.15 g) was dissolved in NMP (1 ml.) and added drop-wise to the chilled mixture. Once the addition was complete removed from the ice/acetone bath and stirred at room temperature for 4 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 to dryness to give 0.1234 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 1.37 (s, 3 H), 1.46 (s, 3 H), 2.84 (q, 2 H), 2.99 (m, 4 H), 3.83 (m, 4 H), 3.91 (m, 1 H), 4.15 (m, 1 H), 4.28 (m, 1 H), 4.44-4.53 (m, 2 H), 6.87 (s, 1 H).
EXAMPLE 26
4-[4-(1 ,1 '-biphenyl-3-ylcarbonyl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-ethylthieno[2,3-d]pyrimidine
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. The residue was chromatographed on silica gel using acetone:hexanes (20:80) as eluent to give 0.15 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 1.37 (s, 3 H), 1.45 (s, 3 H), 2.84 (q, 2 H), 3.6-4.0 (m, 9 H)1 4.14 (m, 1 H), 4.29 (m, 1 H), 4.42-4.52 (m, 2 H), 6.85 (s, 1 H), 7.38-7.53 (m, 5 H), 7.6 (d, 2 H), 7.66 (m, 2 H).
EXAMPLE 27 2,4-Dichloro-6-isopropylthieno[2,3-d]pyrimidine
6-lsopropylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 21 , 2.1 g) and POCI3 were heated together in a sealed tube to 15O0C for 1.5 hours. The mixture was cooled to room temperature and stirred overnight. The mixture was concentrated and the residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 1.0 g of the title compound. MS (ESI+) for C9H8CI2N2S m/z 247.01 (M+H)+.
EXAMPLE 28 4-[4-(3-Bromobenzoyl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6- ethylthieno[2,3-d]pyrim idine
To a mixture of the pyrimidine of Example 25 (2.5 g) in THF (50.0 mL) and NMP (25 mL) in a round bottom flask were added diisopropylethylamine (1.8 g), 3-bromobenzoic acid (1.35 g), and HATU (2.54 g). The mixture was stirred at room temperature for 4 hours at which time the mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed four times with brine, dried over anhydrous magnesium sulfate and concentrated to dryness to give 2.8 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.34 (t, 3 H), 1.37 (s, 3 H), 1.45 (s, 3 H), 2.85 (q, 2 H), 3.6 (m, 2 H), 3.8-4.0 (m, 7 H), 4.12 (m, 1 H), 4.31 (m, 1 H), 4.42-4.52 (m, 2 H), 6.85 (s, 1 H), 7.28-7.37 (m, 2 H), 7.59 (m, 2 H).
EXAMPLE 29 2-{2-[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]ethoxy}-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine
Sodium hydride 60% in mineral oil (0.057 g) was placed into a round bottom flask, washed with hexanes and chilled in an ice/acetone bath. NMP (1.5 ml.) was added and the mixture stirred for 15 minutes. (S)-(+)-4-(2-Hydroxyethyl)-2,2-dimethyl-1 ,3-dioxolane (0.205 g) was added and the mixture stirred for 30 minutes. The pyrimidine of Example 23 (0.2 g) was dissolved in NMP (2.5 mL) and added drop-wise to the chilled mixture. Once the addition was complete, the flask was removed from the ice/acetone bath and the mixture stirred at room temperature for 3 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 to dryness to give 0.222 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.32 (m, 6 H), 1.41 (s, 3 H), 2.07 (m, 2 H), 3.00 (m, 4 H), 3.61 (m, 1 H), 3.83 (m, 4 H), 4.11 (m, 1 H), 4.33 (m, 1 H), 4.44 (m, 1 H), 6.86 (s, 1 H).
EXAMPLE 30 2-(3,3-Diethoxypropoxy)-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine
Sodium hydride 60% in mineral oil (0.084 g) was placed into a round bottom flask, washed with hexanes and chilled in an ice/acetone bath. NMP (1.0 mL) was added and the mixture stirred for 15 minutes. 3,3-Diethoxy-1 -propanol (0.33 g) was added and the mixture stirred for 30 minutes. 2-Chloro-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine (Example 23, 0.3 g) was dissolved in NMP (1.5 mL) and added drop-wise to the chilled mixture. Once the addition was complete removed from the ice/acetone bath and stirred at room temperature for 3 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 to dryness to give 0.435 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.22 (m, 6 H), 1.34 (t, 3 H), 1.89 (m, 1 H), 2.12 (m, 1 H), 2.84 (m, 2 H), 3.0 (m, 4 H), 3.39 (m, 1 H), 3.53 (m, 2 H), 3.84 (m, 4 H), 4.4 (m, 1 H), 4.6-4.8 (m, 1 H), 6.86 (m, 1 H).
EXAMPLE 31 3'-{[4-(2-{[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidirι-4- yl)piperazin-1-yl]carbonyl}-1 ,1 '-biphenyl-4-carboxylic acid
To a mixture of the pyrimidine of Example 28 (0.15 g) in NMP (3.0 mL) was added 5M K3PO4 (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. The residue was chromatographed on silica gel (75 mL) using 5% methanol in methylene chloride with 0.5% glacial acetic acid to give 0.0868 g of the title compound: MS (ESI+) for C32H34N4O6S m/z 603.35 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 1.37 (s, 3 H), 1.45 (s, 3 H), 2.84 (q, 2 H), 3.67 (m, 2 H), 3.8-4.0 (m, 7 H), 4.14 (m, 1 H), 4.31 (m, 1 H), 4.4-4.6 (m, 2 H), 6.85 (s, 1 H), 7.16 (m, 1 H), 7.46 (m, 1 H), 7.71 (m, 1 H), 7.71 (d, 2 H), 8.18 (d, 2 H).
EXAMPLE 32
4-[4-(1 ,1'-Biphenyl-3-ylcarbonyl)piperazin-1-yl]-2-(3,3-diethoxypropoxy)-6-ethylthieno[2,3- d]pyrimidine
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. The residue was chromatographed on silica gel (100 ml_) using 20% ethyl acetate in hexanes to give 0.380 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.19 (t, 6 H), 1.32 (t, 3 H), 2.08 (m, 2 H), 2.83 (q, 2 H), 3.48 (m, 2 H), 3.66 (m, 2 H), 3.8-4.0 (m, 8 H), 4.4 (m, 2 H), 4.46 (m, 1 H), 6.84 (s, 1 H), 7.38-7.49 (m, 5 H), 7.58 (d, 2 H), 7.66 (m, 2 H).
EXAMPLE 33
3-({4-[4-(1 ,1 '-Biphenyl-3-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)propanal
To a mixture of the pyrimidine of Example 32 (0.36 g) in methylene chloride (4 ml_) was added p- toluenesufonic acid (0.131 g). The mixture was stirred at room temperature for 6 hours. The mixture was washed twice with brine, dried over anhydrous magnesium sulfate and chromatographed on silica gel (75 ml_) using 2% methanol in methylene chloride to give 0.168 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.84 (q, 2 H)1 2.92 (m, 2 H),
3.67 (m, 2 H), 3.8-4.0 (m, 6 H), 4.68 (m, 2 H), 6.85 (s, 1 H), 7.36-7.53 (m, 5 H), 7.6 (d, 2 H), 7.66 (m, 2 H), 9.88 (s, 1 H).
EXAMPLE 34 Trans-2-chloro-6-ethyl-4-{4-[(2-phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine
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. The layers were separated and the organic layer washed six times with brine, dried over anhydrous magnesium sulfate and concentrated to give 0.27 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.34 (m, 4 H)1 1.72 (m, 1 H), 1.98 (m, 1 H), 2.52 (m, 1 H), 2.88 (q, 2 H), 3.85 (m, 4 H), 3.97 (m, 4 H), 6.95 (s, 1 H), 7.13 (m, 2 H), 7.2- 7.31 (m, 3 H).
EXAMPLE 35
Trans-2-{[(4S)-2,2-dim ethyl-1 ,3-dioxolan-4-yl]m ethoxy}-6-ethyl-4-{4-[(2- phenylcyclopropyl)carbonyl]piperazin-1-yl}thienot2,3-d]pyrimidine
Sodium hydride 60% in mineral oil (0.028 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 was stirred for 15 minutes. (S)-(+)-2,2-Dimethyl-1 ,3-dioxolane-4-methanol (0.093 g) was added and the mixture stirred for 30 minutes. The pyrimidine of Example 34 (0.15 g) was dissolved in NMP (2.0 mL) and added drop-wise to the chilled mixture. Once the addition was complete removed from the ice/acetone bath and stirred at room temperature for 3 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 dissolved in ethyl acetate and passed through a Vz inch silica gel plug in a 30 m L scintered glass funnel. The filtrates were concentrated to dryness to give 0.177 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.34 (t, 3 H), 1.37 (s, 3 H), 1.44 (m, 3 H), 1.7-1.81 (m, 1 H), 2.0 (m, 1 H), 2.3-2.55 (m, 1 H), 2.84 (m, 3 H), 3.3-3.8 (m, 1 H), 3.7- 4.0 (m, 9 H), 4.0-4.2 (m, 1 H), 4.2-4.35 (m, 1 H), 4.4-4.58 (m, 1 H), 6.87 (s, 1 H)1 7.13 (d, 1 H), 7.2-7.35 (m, 4 H).
EXAMPLE 36 4-[4-(4-Bromobenzoyl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6- ethylthieno[2,3-d]pyrim idine
To a mixture of the pyrimidine of Example 25 (1.08 g) in NMP (5 ml_) in a round bottom flask was added diisopropylethylamine (0.039 g), 4-bromobenzoic acid (0.603 g), and HATU (1.14 g). The mixture was stirred at room temperature overnight at which time the mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent to give 0.9 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.25 (t, 3 H), 1.37 (s, 3 H), 1.45 (s, 3 H), 2.84 (q, 2 H), 3.6 (m, 2 H), 3.8-4.0 (m, 7 H), 4.14 (m, 1 H), 4.29 (m, 1 H)1 4.46 (m, 1 H), 4.5 (m, 1 H), 6.84 (s, 1 H), 7.32 (d, 2 H), 7.58 (d, 2 H).
EXAMPLE 37 (2,2-Dimethyl-1 ,3-dioxan-5-yl)methanol
To a mixture of 2-(hydroxymethylpropane-1 ,3-diol (0.953 g) in THF (5 mL) was added 2,2- dimethoxypropane (1.28 mL) and p-toluenesulfonic acid monohydrate (0.053 g). The mixture was stirred at room temperature for 18 hours. Triethyl amine (0.028 g) was added and the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (100 mL) using 10% methanol in methylene chloride as eluent to give 0.963 g of the title compound: 1H NMR (CDCI3) δ 1.39 (s, 3 H), 1.44 (s, 3 H), 1.57 (m, 1 H), 1.83 (m, 1 H), 3.75 (m, 4 H), 4.01 (dd, 2 H).
EXAMPLE 38 N-Benzoyl-N-phenyl-beta-alanine
A mixture of aniline (0.858 g, 9.22 mmol), 3-chloropropionic acid (1.00 g, 9.22 mmol), triethylamine (1.86 g, 18.4 mmol), sodium iodide (0.05 g), and THF (10 mL) was stirred at reflux for 2 days, at which time it was cooled. Benzoyl chloride (1.42 g, 10.1 mmol) and additional triethylamine (1.41 mL) and THF (3 mL) were added. The mixture was stirred for 3 hours, at which time it was partitioned between ethyl acetate and 1 N HCI. The organic layer was dried over magnesium sulfate and the crude product was chromatographed on silica gel using methanokdichloromethane (5:95) with 0.005% acetic acid added to give 0.47 g of the title compound. MS [m+H] 270.2; 1H NMR (400 MHz, CDCI3) δ 2.76 (2H), 4.23 (2H), 7.0-7.3 (10H). EXAMPLE 39
Thieno[2,3-d]pyrimidine-2,4(1 H, 3H)-dione
Methyl 2-amino thiophene-3-carboxylate (1.0 g) and urea (2.2 g) were heated in sealed tube for 3.5 hours at 200 0C and then cooled to room temperature. DMF (20 mL) was added and the mixture was refluxed for 1 hour. Ice water (50 ml) was added and the solid thus precipitated was collected and dried to give 0.5 g of the title compound after 1 hour. The compound was used in the next step without further purification. MS (ESI+) for C6H4O2N2S m/z (M+H)+ 169.05.
EXAMPLE 40
2,4-Dichlorothieno[2,3-d]pyrimidine
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 0C 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 C6H2N2CI2S m/z205.0 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.42 (d,1 H), 7.61 (d,1 H).
EXAMPLE 41 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl) piperazin-1 -yl]-2-chlorothieno[2,3d]pyrimidine
To a mixture of 2,4-dichlorothieno[2,3-d]pyrimidine (Example 40, 0.4 g) in THF/DMF (20/8 mL) was added diisopropylethylamine (0.44mL) and (1,1'-biphenyl-4-yl)piperazine trifluoroacetate (0.780 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. "The resulting crude mixture was stirred in hot MeOH to remove impurities and the remaining solid was collected and dried to give 0.34 g of the title compound: MS (ESI+) for C23H19CIN4O1S1 m/z 435.25 (M+H)+.1H NMR (400 MHz, CDCI3). δ 3.6 to 4.2 (m, 8H) 7.3 to 7.67 (m.11 H). To a mixture of the pyrimidine of Example 40 (0.4 g) in THF/DMF (20/8 ml_) was added diisopropylethylamine (0.44 ml_) and the TFA salt of Example 15 (0.780 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was stirred in hot methanol to remove impurities and the remaining solid was collected and dried to give 0.34 g of the title compound: MS (ESI+) for C23H19CIN4OS m/z 435.25 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 3.6-4.2 (m, 8H) 7.3-7.67 (m, 11H).
EXAMPLE 42
4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4- yl]methoxy}thieno[2,3-d]pyrimidine
Sodium hydride (0.277 g, 60% in hexane) was washed with hexane. The flask was cooled in an ice bath and then NMP (2 mL) and (S)-(+)-2,2-dimethyl-1 ,3-dioxolane-4-methanol (0.9 ml_) were added to the flask. The solution was slowly allowed to warm to room temperature and stirred for an additional 30 min. The mixture was cooled to 0 0C and a solution of the pyrimidine of Example 41 (1.5 g) in NMP (10 mL) was added slowly. The mixture was stirred at room temperature for 3 h and then diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate and concentrated to give the title compound (2.3 g). The compound was used in the next step without further purification. MS (ESI+) for C23H30N4O4S1 m/z 531.36 (M+H)+.
EXAMPLE 43 4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-chloro-6-phenylthieno[2,3-d]pyrimidine
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 MgSO4, filtered and concentrated. The resulting residue was stirred with hot acetonitrile containing a few drops of methanol. The resulting solid was collected and dried under reduced pressure to give 0.99 g of the title compound. MS (ESI+) m/z 511.27 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.37-7.67 (m, 15H), 3.6-4.2 (m, 8H).
EXAMPLE 44 4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-chloro-6-methylthieno[2,3-d]pyrimidine
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 MgSO4, filtered and concentrated. The resulting residue was stirred in hot acetonitrile with a few drops of methanol. The resulting solid was collected and dried under reduced pressure to give 1.41 g of the title compound. MS (ESI+) for C24H21CIN4OS1 m/z 449.242 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.66 to 7.36 (m, 9H), 6.93 (s, 1H), 3.95 (br s, 8H), 2.54 (s, 3H).
EXAMPLE 45 Methyl 2-am ino-δ-propylthiophene-3-carboxylate
To a mixture of sulfur (5.5 g) in DMF (30 ml.) was added methyl cyanoacetate (17.0 g) and triethylamine (24 ml.,) under nitrogen. The mixture was stirred for 10 minutes at which time valeraldehyde (29.55 g) was added dropwise at a sufficient rate to maintain a temperature of 50 0C. The mixture was then stirred at room temperature for 20 hours. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed with brine three times, dried over anhydrous magnesium sulfate and concentrated. The residue was dried on vacuum line. Crude residue was purified on silica gel using hexanes and ethyl acetate (95:5) to give 33.0 g of the title compound. MS (ESI+) m/z200.16 (M+H)+. 1H NMR (CDCI3) δ 6.60 (s, 1 H), 3.77 (s, 3H), 2.53 (t, 3H), 1.59 (t, 3H), 0.93 (t, 3H).
EXAMPLE 46 Methyl 2-amino-5-isopropylthiophene-3-carboxylate
To a mixture of sulfur (5.5 g) in DMF (30 ml_) was added methyl cyanoacetate (17.0 g) and triethylamine (24 mL,) under nitrogen. The mixture was stirred for 10 minutes at which time isovaleraldehyde (29.55 g) was added dropwise at a sufficient rate to maintain a temperature of 50 0C. The mixture was then stirred at room temperature for 20 hours. The mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed with brine three times, dried over anhydrous magnesium sulfate and concentrated. The residue was dried on vacuum line. The crude residue was purified on silica gel using hexanes and ethyl acetate (95:5) to give 29.1 g of the title compound. MS (ESI+) 200.01 (M+H)+. 1H NMR (400 MHz, CDCI3) 86.61 (s, 1 H), 3.77 (s, 3H), 2.91 (s, 1 H), 1.22 (d, 6H).
EXAMPLE 47
4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-chloro-6-propylthieno[2,3-d]pyrimidine
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 MgSO4, filtered and concentrated. The resulting residue was treated with acetonitrile containing a few drops of methanol and the resulting solid was collected and dried under reduced pressure to give 0.85 g of the title compound. MS (ESI+) m/z 477.22 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.66-7.38 (m, 9H), 6.93 (s, 1 H), 3.96 (br s, 8H), 2.82 (t, 2H), 1.74 (m, 2H), 1.00 (t, 3H).
EXAMPLE 48 4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-isopropylthieno[2,3-d]pyrimidine
2,4-Dichloro-6-isopropylthieno[2,3-d]pyrimidine (Example 27, 1.0 g) was dissolved in a mixture of THF/DMF (5 mL/2 mL) followed by addition of 1-(1 ,1'-biphenyl-4-ylcarbonyl)piperazine (1.6 g, 4.0 mmol) and DIEA (0.68 g). The mixture was stirred overnight at room temperature and then was partitioned between ethyl acetate and brine. The ethyl acetate layer was then washed an additional four times with brine. The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was treated with acetonitrile containing a few drops of methanol and the resulting solid was collected and dried under vacuum to give 1.26 g of the title compound. MS (ESI+) m/z 477.029 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.66 to 7.36 (m, 9H), 6.92 (s, 1 H), 3.77 (br s, 8H), 3.18 (m, 1H), 1.40 (d, 6H). EXAMPLE 49 tert-Butyl (3R)-4-(1 ,1 '-biphenyl-4-ylcarbonyl)-3-methylpiperazine-1 -carboxylate
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 MgSO4, 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. MS (ESI+) for C23H28N2O3 m/z 381.2192 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.61 (d, 2H), 7.56-7.58 (m, 2H), 7.42-7.46 (m, 4H), 7.34-7.38 (m, 1 H), 3.88- 4.13 (m, 4H), 2.84-3.21 (m, 3H), 1.45 (s, 9H), 1.26 (d, 3H).
EXAMPLE 50 tert-Butyl (3S)-4-(1 ,1 '-biphenyl-4-ylcarbonyl)-3-methylpiperazine-1 -carboxylate
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 MgSO4, 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. MS (ESI+) for C23H28N2O3 m/z (M+H)+ 381.41. 1H NMR (400 MHz, CDCI3) δ 7.61 (d, 2H), 7.56-7.58 (m, 2H), 7.44 (t, 4H), 7.25-7.39 (m, 1 H), 3.88-4.13 (m, 4H), 2.84- 3.20 (m, 3H), 1.45 (s, 9H), 1.25 (d, 3H).
EXAMPLE 51
(2R)-1 -(1 ,1 '-Biphenyl-4-ylcarbonyl)-2-methylpiperazine hydrochloride
The carboxylate of Example 49 was placed in a flask and cooled to 0 0C (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 Ci8H20N2O m/z 281.1627 (MH-H)+. 1H NMR (400 MHz, CD3OD) δ 7.73-7.76 (m, 2H), 7.63-7.66 (m, 2H), 7.53-7.56 (m, 2H), 7.44-7.48 (m, 2H), 7.36-7.40 (m, 1H), 4.73 (br s, 1H), 4.23 (br s, 1H), 3.45-3.53 (m, 1H), 3.33-3.39 (m, 3H), 3.15-3.22 (m, 1H), 1.44 (d, 3H).
EXAMPLE 52 (2S)-1-(1 ,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazine hydrochloride
The carboxylate of Example 50 was placed in a flask and cooled to 0 0C (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. 1H NMR (400 MHz, CD3OD) δ 7.74-7.76 (m, 2H), 7.63-7.66 (m, 2H), HRMS (ESI+) for C18H20N2O m/z (M+H)+ 281.16047.53-7.56 (m, 2H), 7.44-7.48 (m, 2H), 7.36-7.40 (m, 1 H), 4.73 (br s, 1 H), 7.24 (br s, 1 H), 3.46-3.53 (m, 1 H), 3.29-3.39 (m, 3H), 3.15-3.22 (m, 1H), 1.44 (d, 3H).
EXAMPLE 53
4-[(3R)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1 -yl]-2-chloro-6-ethylthieno[2,3- d]pyrimidine
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 MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30:70 ethyl acetate/hexanes) to give 0.234 g of the title compound. MS (ESI+) for C26H25CIN4OS m/z 477.14 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.62-7.65 (m, 2H), 7.57-7.59 (m, 2H)1 7.43-7.49 (m, 4H), 7.24-7.39 (m, 1H), 6.92 (s, 1H), 4.30-4.51 (m, 4H), 3.31-3.56 (m, 3H), 2.87 (q, 2H), 1.31-1.35 (m, 6H).
EXAMPLE 54 4-[(3S)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1 -yl]-2-chloro-6-ethylthieno[2,3- djpyrimidine
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 MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30:70 ethyl acetate:hexanes) to give 0.203 g of the title compound. MS (ESI+) for C26H25CIN4OS m/z 477.1484 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.62-7.65 (m, 2H), 7.56-7.59 (m, 2H), 7.44-7.49 (m, 4H), 7.24-7.39 (m, 1 H), 6.92 (s, 1 H), 4.30-4.51 (m, 4H), 3.31-3.57 (m, 3H), 2.87 (q, 2H), 1.32-1.35 (m, 6H).
EXAMPLE 55
4-[(3R)-4-(1,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan- 4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine
(2,2-Dimethyl-1 ,3-dioxolan-4-yl)methanol (133 mg) was placed in a flask along with 2.5 mL of NMP. The mixture was cooled to 0 0C and NaH (0.024 g of 60% dispersion in oil) was added. After stirring for 15 minutes at 0 0C, the pyrimidine of Example 53 was added as a solution in NMP (2 mL). The mixture was allowed to warm to room temperature and was stirred for an additional 90 minutes. The mixture was then diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (35:65 ethyl acetate/hexanes) to give 0.129 g of the title compound. MS (ESI+) for C32H36N4O4S m/z 573.2578 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.62-7.64 (m, 2H), 7.57-7.59 (m, 2H), 7.43-7.48 (m, 4H), 7.35-7.39 (m, 1H), 6.84 (s, 1 H), 4.11- 4.52 (m, 8H), 3.88-3.92 (m, 1 H), 3.49 (br s, 2H), 3.24-3.31 (m, 1 H), 2.83 (q, 2H), 1.58 (s, 3H), 1.29-1.44 (m, 9H).
EXAMPLE 56
4-[(3S)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan- 4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine
(2,2-Dimethyl-1 ,3-dioxolan-4-yl)methanol (133 mg) was placed in flask along with 2.5 ml_ of NMP. The solution was cooled to 0 0C and NaH (0.024 g of 60% dispersion in oil) was added. After stirring for 15 min at 0 0C, the pyrimidine of Example 54 (0.160 g) was added as a solution in NMP (2 ml_). The mixture was allowed to warm to room temperature and was stirred for an additional 90 min, after which the mixture was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (35:65 ethyl acetate/hexanes) to give 0.137 g of the title compound. MS (ESI+) for C32H36N4O4S m/z 573.2532 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.62-7.65 (m, 2H), 7.58-7.60 (m, 2H), 7.43-7.48 (m, 4H), 7.35-7.39 (m, 1 H), 6.84 (s, 1H), 4.25- 4.52 (m, 6H), 4.11-4.15 (m, 2H), 3.88-3.92 (m, 1H), 3.49 (br s, 2H), 3.24-3.31 (m, 1 H), 2.83 (q, 2H), 1.44 (s, 3H), 1.36 (s, 3H), 1.29-1.36 (m, 6H).
EXAMPLE 57 tert-Butyl (3R)-4-(2-chloro-6-ethylthieno[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
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 CC 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 MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (20/80 ethyl acetate/hexanes) to give 0.420 g of the title compound. MS (ESI+) for C18H25CIN4O2S m/z397.1438 (M+H)+. 1H NMR (300 MHz, CDCI3) δ 6.89 (s, 1 H), 4.77 (br s, 1 H), 4.37 (d, 1 H), 3.87-4.12 (m, 2H), 3.47 (t, 1 H), 3.06-3.24 (m, 2H)1 2.86 (q, 2H), 1.47 (s, 9H), 1.33 (t, 6H).
EXAMPLE 58 tert-Butyl (3S)-4-(2-chloro-6-ethylthienot2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
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 0C 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 MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (20:80 ethyl acetate:hexanes) to give 0.409 g of the title compound. MS (ESI+) for C18H25CIN4O2S m/z397.1423 (M+H)+. 1H NMR ( 400 MHz, CDCI3) δ 6.90 (s, 1 H), 4.78 (br s, 1 H), 4.37 (d, 1 H), 3.89-4.14 (m, 2H), 3.47 (t, 1 H), 3.02-3.23 (m, 2H), 2.87 (q, 2H), 1.47 (s, 9H), 1.33 (t, 6H).
EXAMPLE 59 2-Chloro-6-ethyl-4-[(2R)-2-methylpiperazin-1 -yl]thieno[2,3-d]pyrimidine hydrochloride
To tert-butyl (3R)-4-(2-chloro-6-ethylthieno[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1 - carboxylate (Example 57, 0.350 g) was added 4N HCI in dioxane (2 mL) at 0 0C. The mixture was allowed to warm to room temperature and stir for 90 min. The mixture was then diluted with diethyl ether and the resulting solid was collected, washed with diethyl ether, and dried under reduced pressure to give 0.245 g of the title compound. MS (ESI+) for C13H17CIN4S m/z 297.0900 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.23 (s, 1H), 5.09-5.15 (m, 1 H), 4.69-4.73 (m, 1 H), 3.64-3.72 (m, 1 H), 3.48-3.52 (m, 1H)1 3.41 (d, 2H), 3.23-3.30 (m, 1 H), 2.93-2.99 (m, 2H), 1.52 (d, 3H), 1.36 (t, 3H).
EXAMPLE 60
2-Chloro-6-ethyl-4-((S)-2-methylpiperazin-1-yl)thieno[2,3-φyrimidine
To tert-butyl (3S)-4-(2-chloro-6-ethylthieno[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1 -carboxylate (Example 58, 0.350 g) was added 4N HCI in dioxane (2 ml_) at 0 0C. The mixture was allowed to warm to room temperature and stir for 90 min, at which time the mixture was diluted with diethyl ether and the resulting solid was collected, washed with diethyl ether, and dried under reduced pressure to give 0.241 g of the title compound. MS (ESI+) for C13H17CIN4S m/z297.0896 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.24 (s, 1 H), 5.11-5.14 (m, 1 H), 4.69-4.73 (m, 1 H), 3.64- 3.72 (m, 1 H), 3.48-3.51 (m, 1H), 3.41 (d, 2H), 3.23-3.30 (m, 1 H), 2.96 (q, 2H), 1.52 (d, 3H), 1.36 (t, 3H).
EXAMPLE 61 4-[(2R)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1 -yl]-2-chloro-6-ethylthieno[2,3- d]pyrimidine
2-Chloro-6-ethyl-4-[(2R)-2-methylpiperazin-1-yl]thieno[2,3-d]pyrimidine (Example 59, 0.210 g) was dissolved in NMP (4 mL) and 1 ,1'-biphenyl-4-carbonyl chloride (204 mg, 0.94 mmol) was added followed by DIEA (0.23 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated and the resulting residue was purified by silica gel chromatography, eluting with 30/70 ethyl acetate/hexanes, to give 0.211 g of the title compound. MS (ESI+) for C26H25CIN4OS m/z 477.1497 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.63-7.65 (m, 2H), 7.57-7.60 (m, 2H), 7.50 (d, 2H), 7.43-7.47 (m, 2H), 7.36-7.40 (m, 1H), 6.90 (s, 1H), 4.44- 4.86 (m, 3H), 3.1-4.0 (m, 4H), 2.87 (q, 2H), 1.31-1.61 (m, 6H).
EXAMPLE 62 4-[(2S)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1 -yl]-2-chloro-6-ethylthieno[2,3- d]pyrimidine
2-Chloro-6-ethyl-4-[(2S)-2-methylpiperazin-1-yl]thieno[2,3-φyrimidine (Example 60, 0.210 g) was dissolved in NMP (4 mL) and 1 ,1'-biphenyl-4-carbonyl chloride (204 mg, 0.94 mmol) was added followed by DIEA (0.23 mL). The mixture was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate and washed with brine and the ethyl acetate layer was dried over MgSO4, filtered and concentrated. The resulting residue was chromatographed on silica gel (30/70 ethyl acetate/hexanes) to give 0.165 g of the title compound. MS (ESI+) for C26H25CIN4OS m/2477.1501 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.63-7.65 (m, 2H), 7.57-7.61 (m, 2H), 7.51 (d, 2H), 7.45-7.48 (m, 2H), 7.36-7.40 (m, 1 H), 6.90 (s, 1 H), 4.44-4.85 (m, 3H), 3.0- 4.0 (m, 4H), 2.87 (q, 2H), 1.1.31-1.61 (m, 6H).
EXAMPLE 63
4-[(2R)-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
((S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl)methanol (0.133 g) was placed in flask along with 2.5 mL of NMP. The mixture was cooled to 0 0C and NaH (0.024 g of 60% dispersion in oil) was added. After stirring for 15 min at 0 0C, 4-[(2R)-4-(1 ,1'-biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-2- chloro-6-ethylthieno[2,3-d]pyrimidine (Example 61 , 0.160 g) was added as a mixture in NMP (2 mL). The mixture was allowed to warnTto room temperature and was stirred for an additional 90 min. The mixture was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated. Silica gel chromatography (40/60 ethyl acetate/hexanes) gave 0.098 g of the title compound. MS (ESI+) for C32H36N4O4S m/z 573.2523 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.64 (d, 2H), 7.59 (d, 2H), 7.50 (d, 2H), 7.45 (t, 2H), 7.35- 7.39 (m, 1H), 6.83 (s, 1H), 4.40-4.82 (m, 5H), 4.24-4.29 (m, 1H), 4.11-4.15 (m, 1H), 3.88-3.91 (m, 1H), 3.20-3.70 (m, 4H), 2.82 (q, 2H), 1.43 (s, 3H), 1.35 (s, 3H), 1.29-1.36 (m, 6H).
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
((S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl)methanol (0.133 g) was placed in flask along with 2.5 mL of NMP. The mixture was cooled to 0 0C and NaH (0.024 mg of 60% dispersion in oil) was added. After stirring for 15 min at 0 0C, 4-[(2S)-4-(1 ,1'-biphenyl-4-ylcarbonyl)-2-methylpiperazin-1-yl]-2- chloro-6-ethylthieno[2,3-d]pyrimidine (Example 62, 0.120 g) was added as a mixture in NMP (2 mL). The mixture was allowed to warm to room temperature and was stirred for an additional 90 min. The mixture was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated. Silica gel chromatography (40/60 ethyl acetate/hexanes) gave 0.079 g of the title compound. MS (ESI+) for C32H36N4O4S m/z 573.2538 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.64 (d, 2H), 7.58-7.60 (m, 2H), 7.50 (d, 2H), 7.43-7.47 (m, 2H), 7.36-7.39 (m, 1H), 6.83 (s, 1 H), 4.40-4.57 (m, 5H), 4.25-4.29 (m, 1 H), 4.11-4.15 (m, 1H), 3.87-3.91 (m, 1 H), 3.20-3.80 (m, 4H), 2.82 (q, 2H), 1.55 (s, 3H), 1.36-1.43 (m, 6H), 1.31 (t, 3H).
EXAMPLE 65
4- bonyl)piperazin-1 -yl]-2-chloro-6-ethylthieno[2,3-d]pyrimidine
H
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. To biphenyl-3-carboxylic acid (0.49 g) in dichloromethane (10 mL) was added 1 ,1'-carbonyldiimidazole (0.40 g). The mixture was stirred for 45 min, after which a slurry prepared from the hydrochloride salt of Example 23 (0.75 g), triethylamine (0.33 mL), dichloromethane (15 mL), and DMF (1 mL) was added. The mixture was stirred at room temperature overnight, after which it was partitioned between dichloromethane and saturated aq. sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. Crystallization from dichloromethane-hexane gave 0.91 g of the title compound. MS [m+H] 463.3; 1H NMR (400 MHz, CDCI3) δ 1.34 (3H), 2.88 (2H), 3.6-4.1 (8H), 6.93 (1 H), 7.36-7.53 (5H), 7.58-7.69 (4H).
EXAMPLE 66 (2R)-3-[(6-Ethyl-4-{4-[(5-phenyl-1 ,3,4-oxadiazol-2-yl)carbonyl]piperazin-1 -yl}thieno[2,3- d]pyrimidin-2-yl)oxy]propane-1 ,2-diol
To a mixture of the diol hydrochloride salt of Example 22 (0.103 g) in THF (3.0 mL) were added diisopropylethylamine (0.087 g) and 5-phenyl-1 ,3,4-oxadiazole-2-carbonyl chloride (0.057 g). The mixture was stirred at room temperature for 18 hours. The solvents were removed under reduced pressure and the residue chromatographed on silica gel (100 mL) using 5% methanol in ethyl acetate to give 0.0238 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.35 (t, 3 H), 2.87 (q, 2 H), 3.73 (m, 2 H), 4.0-4.13 (m, 6 H), 4.46 (m, 2 H), 4.50 (m, 2 H), 6.91 (s, 1 H), 7.52- 7.60 (m, 3 H), 8.16 (d, 2 H).
EXAMPLE 67
(2R)-3-[(6-Ethyl-4-{4-[(2-phenyl-1 ,3-thiazol-4-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
To a mixture of the diol hydrochloride salt of Example 22 (0.1 g) in THF (5 ml_) and NMP (2 mL) was added diisopropylethylamine (0.116 g), HATU (0.114 g), and 2-phenyl-1,3-thiazole-4- carboxylic acid (0.055 g). The mixture was stirred at room temperature for 18 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. The residue was chromatographed on silica gel (100 mL) using 5% methanol in ethyl acetate to give 0.0446 g of the title compound: MS (ESI+) for C25H27N5O4S2 m/z 526.18 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.34 (t, 3 H), 2.85 (q, 2 H), 3.67-3.77 (m, 2 H), 3.98-4.1 (m, 6 H), 4.29 (m, 2 H), 4.51 (m, 2 H), 6.92 (s, 1 H), 7.47 (m, 3 H), 7.95 (m, 2 H), 8.03 (s, 1 H).
EXAMPLE 68 4-t4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-(2-ethoxyethoxy)-6-ethylthieno[2,3-d]pyrimidine
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. The residue was chromatographed on silica gel (100 mL) using ethyl acetate-hexanes (30/70) to give 0.0603 g of the title compound: MS (ESI+) for C29H32N4O3S m/z 517.37 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.21 (t, 3 H), 1.32 (t, 3 H), 2.84 (q, 2 H), 3.58 (q, 2 H), 3.6-4.0 (m, 10 H), 4.49 (m, 2 H), 6.85 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.52 (d, 2 H), 7.60 (d, 2 H), 7.65 (d, 2 H). EXAMPLE 69
(2R)-3-({4-[4-(1 ,1 '-Biphenyl-3-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol
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. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0868 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.84 (q, 2 H), 3.6-3.8 (m, 3 H), 3.94 (m, 6 H), 4.08 (m, 1 H), 4.48 (m, 2 H)1 6.87 (s, 1 H), 7.36-7.53 (m, 5 H), 7.59 (d, 2 H), 7.66 (m, 2 H).
EXAMPLE 70
(2R)-3-({4-[4-(3-Bromobenzoyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)propane-1 ,2- diol
HCI gas was bubbled through methanol (15 mL) for 1 minute then cooled to room temperature and added to the pyrimidine of Example 28 (0.4 g). The mixture was stirred at room temperature for 2.5 hours. The solvents were removed under reduced pressure and the residue was triturated in ethyl acetate. The resulting solids were collected via filtration to give 0.298 g of the title compound: MS (ESI+) for C22H25BrN4O4S m/z 523.17 (M+H)+. 1H NMR (400 MHz, DMSO- d6) δ 1.13 (t, 3 H), 2.8 (q, 2 H), 3.4-4.0 (m, 11 H), 4.14 (m, 1 H), 4.30 (m, 1 H), 7.24 (s, 1 H), 7.45 (m, 2 H), 7.65 (m, 2 H). EXAMPLE 71
(2S)-4-({4-[4-(1 ,1'-Biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)butane-1 ,2-diol
To a mixture of 2-{2-[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]ethoxy}-6-ethyl-4-piperazin-1- ■ ylthieno[2,3-d]pyrimidine (Example 29, 0.222 g) in NMP (5 mL) were added 3-biphenyl carboxylic acid (0.112 g), HATU (0.215 g), and diisopropylethylamine (0.155 g). The mixture was stirred at room temperature for 2.5 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. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent. The residue was dissolved in HCI/methanol (10 mL) and stirred at room temperature for 2 hours. The solvents were removed under reduced pressure and the residue dried under reduced pressure to give 0.1136 g of the title compound: MS (ESI+) for C29H32N4O4S m/z 533.31 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.23 (t, 3 H), 1.8 (m, 1 H), 1.9 (m, 1 H), 2.76 (q, 2 H), 3.4-3.6 (m, 2 H), 3.8-4.4 (m, 9 H), 4.6 (m, 2 H), 6.99 (s, 1 H), 7.3 (m, 1 H), 7.4 (m, 4 H), 7.38 (d, 2 H), 7.54 (d, 1 H), 7.66 (s, 1 H).
EXAMPLE 72
3-{[4-(2-{t(2R)-2,3-Dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yi)piperazin-1- yl]carbonyl}benzonitrile
To a mixture of the diol hydrochloride salt of Example 22 (0.1 g) in NMP (5 mL) was added diisopropylethylamine (0.076 g), HATU (0.102 g), and 3-cyanobenzoic acid (0.04 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. The residue was chromatographed on silica gel (100 mL) using 10% ethyl acetate in hexanes to give 0.0386 g of the title compound: MS. (ESI+) for C23H25N5O4S m/z 468.31 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.85 (q, 2 H), 3.6-4.0 (m, 10 H), 4.08 (m, 1 H), 4.48 (m, 2 H), 6.86 (s, 1 H), 7.58 (t, 1 H), 7.69 (d, 1 H)1 7.75 (m, 2 H).
EXAMPLE 73 3'-{[4-(2-{[(2R)-2,3-Dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazin-1- yl]carbonyl}-1 , 1 '-biphenyl-4-carboxylic acid
To a mixture of the carboxylic acid of Example 31 (0.0868 g) in dioxane (4.0 mL) and water (0.7 ml_) was added 4N HCI in dioxane (1 mL). The mixture was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure. Toluene (10 mL) was added then removed under reduced pressure three times. The solids were triturated in diethyl ether and filtered to give 0.0675 g of the title compound: MS (ESI+) for C29H30N4O6S m/z 563.35 (M+H)+. 1H NMR (400 MHz, DMSO-Of6) δ 1.23 (t, 3 H), 2.8 (q, 2 H), 3.4 (m, 2 H), 3.58 (m, 2 H), 3.77 (m, 2 H), 3.89 (m, 2 H), 4.0 (m, 2 H), 4.3 (m, 2 H), 7.24 (s, 1 H), 7.4-7.6 (m, 4 H), 7.83 (d, 2 H), 8.0 (d, 2 H).
EXAMPLE 74
3-({4-[4-(1 ,1'-Biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)propanoic acid
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 C28H28N4O4S m/z 517.25 (MH-H)+. 1H NMR (400 MHz, CDCI3) δ 1.31 (t, 3 H), 2.87 (m, 4 H), 3.67 (m, 2 H)1 3.8-4.0 (m, 6 H), 4.61 (m, 2 H), 6.84 (s, 1 H), 7.37-7.52 (m, 5 H), 7.58 (d, 2 H), 7.67 (m, 2 H). EXAMPLE 75
(2R)-3-({6-Ethyl-4-[4-(3-pyridin-3-ylbenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimiclin-2- yl}oxy)propane-1 ,2-dioI
To a mixture of the pyrimidine of Example 28 (0.1 g) and NMP (2 ml.) in a 2 dram screw capped vial were added pyridine-3-boronic acid (0.033 g), 5M K3PO4 (1 mL), palladium Il acetate (0.006 g) and, tri-o-tolyl phosphine (0.046 g). The vial was placed into a Lab-Line MAX Q2000 orbital shaker at 80 0C for 8 hours. The mixture was partitioned between brine and ethyl acetate, separated the layers and washed the organic layer three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent. The resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0253 g of the title compound: MS
(ESI+) for C27H29N5O4S m/z 520.33 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.84 (q, 2 H), 3.7 (m, 4 H), 3.9 (m, 6 H), 74.08 (m, 1 H), 4.47 (m, 2 H), 6.86 (s, 1 H), 7.42 (m, 1 H), 7.48 (m, 1 H), 7.56 (m, 1 H), 7.66 (m, 2 H), 7.71 (d, 1 H), 8.62 (s, 1 H), 8.86 (s, 1 H).
EXAMPLE 76
(2R)-3-[(6-Ethyl-4-{4-[(3'-fluoro-1 ,1 '-biphenyl-3-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
To a mixture of pyrimidine of Example 28 (0.1 g) and NMP (2 mL) in a 2 dram screw capped vial were added 3-fluorophenyl boronic acid (0.038 g), 5M K3PO4 (1 mL), palladium Il acetate (0.006 g) and, tri-o-tolyl phosphine (0.046 g). The vial was placed into a Lab-Line MAX Q2000 orbital shaker at 80 0C for 8 hours. The mixture was partitioned between brine and ethyl acetate, separated the layers and washed the organic layer three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using 1 :1 ethyl acetate : hexanes as eluent. The resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0558 g of the title compound: MS (ESI+) for C28H29FN4O4S m/z 537.34 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.84 (q, 2 H), 3.69 (m, 4 H), 3.94 (m, 6 H), 4.08 (m, 1 H), 4.47 (m, 2 H), 6.86 (s, 1 H), 7.05 (m, 1 H), 7.28 (m, 1 H), 7.37 (m, 1H)1 7.41 (m, 2H), 7.52 (m, 2H), 7.64 (m, 2H).
EXAMPLE 77
(2R)-3-({6-Ethyl-4-[4-(3-pyrimidin-5-ylbenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol
To a mixture of pyriήnidine of Example 28 (0.1 g) and NMP (2 mL) in a 2 dram screw capped vial were added pyrimidine-5-boronic acid (0.033 g), 5M K3PO4 (1 mL), palladium Il acetate (0.006 g) and, tri-o-tolyl phosphine (0.046 g). Placed the vial into a Lab-Line MAX Q2000 orbital shaker at 80 0C for 8 hours. The mixture was partitioned between brine and ethyl acetate, separated the layers and washed the organic layer three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent. The resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0101 g of the title compound: MS (ESI+) for C26H28N6O4S m/z 521.34 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.85 (q, 2 H), 3.6-3.8 (m, 4 H), 3.8- 4.05 (m, 6 H), 4.08 (m, 1 H), 4.47 (m, 2 H), 6.87 (s, 1 H), 7.53 (m, 1 H), 7.63 (m, 1 H), 7.69 (m, 2 H), 8.97 (s, 2 H), 9.24 (s, 1 H).
EXAMPLE 78
(2R)-3-[(4-{4-[(3',4'-Difluoro-1 ,1 '-biphenyl-3-yl)carbonyl]piperazin-1-yl}-6-ethylthieno[2,3- d]pyrimidin-2-yl)oxy]propane-1 ,2-diol
To a mixture of pyrimidine of Example 28 (0.1 g) and NMP (2 ml.) in a 2 dram screw capped vial were added 3,4-difluorophenyl boronic acid (0.042 g), 5M K3PO4 (1 ml_), palladium Il acetate (0.006 g) and, tri-o-tolyl phosphine (0.046 g). The vial was placed into a Lab-Line MAX Q2000 orbital shaker at 80 °C for 8 hours. The mixture was partitioned between brine and ethyl acetate, separated the layers and washed the organic layer three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using 1 :1 ethyl acetate:hexanes as eluent. The resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.009 g of the title compound: MS (ESI+) for C28H28F2N4O4S m/z 555.29 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H)1 2.85 (q, 2 H), 3.6-3.8 (m, 4 H), 3.8-4.0 (m, 6 H), 4.08 (m, 1 H)1 4.48 (m, 2 H), 6.87 (s, 1 H), 7.2- 7.35 (m, 2 H), 7.38-7.744 (m, 2 H), 7.51 (m, 1 H), 7.6 (m, 2 H).
EXAMPLE 79
(2R)-3-[(6-Ethyl-4-{4-[(4-phenylpyridin-2-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
To a mixture of diol hydrochloride salt of Example 22 (0.15 g) in NMP (2 mL) was added diisopropylethylamine (0.155 g), 4-phenylpyridine-2-carboxylic acid (0.08 g), and HATU (0.152 g). The mixture was stirred at room temperature for 4 hours at which time the mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed five times with brine, dried over anhydrous magnesium sulfate and concentrated to give 0.0651 g of the title compound: MS (ESI+) for C27H29N5O4S m/z 520.33 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3"H), 2.85 (q, 2 H), 3.6-3.8 (m, 2 H), 3.92 (m, 2 H), 3.96 (m, 4 H), 4.07 (m, 3 H), 4.49 (m, 2 H), 6.9 (s, 1 H), 7.47 (m, 3 H), 7.6 (m, 1 H), 7.67 (m, 2 H), 7.97 (s, 1 H), 8.64 (d, 2 H).
EXAMPLE 80
(2R)-3-[(6-Ethyl-4-{4-[(4'-methyl-1 ,1 '-biphenyl-3-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin- 2-yl)oxy]propane-1 ,2-diol
To a mixture of pyrimidine of Example 28 (0.1 g) and NMP (2 mL) in a 2 dram screw capped vial were added p-tolylboronic acid (0.037 g), 5M K3PO4 (1 mL), palladium Il acetate (0.004 g) and, tri-o-tolyl phosphine (0.008 g). The vial was placed into a Lab-Line MAX Q2000 orbital shaker at 80 0C for 8 hours. The mixture was partitioned between brine and ethyl acetate, separated the layers and washed the organic layer three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using 1 :1 ethyl acetate:hexanes as eluent. The resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0249 g of the title compound: MS (ESI+) for C29H32N4O4S m/z 533.37 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.31 (t, 3 H), 2.39 (s, 3 H), 2.83 (q, 2 H), 3.6-3.8 (m, 4 H), 3.8-4.0 (m, 6 H), 4.07 (m, 1 H), 4.46 (m, 2 H), 6.85 (s, 1 H), 7.15 (m, 1 H), 7.25 (m, 2 H), 7.38 (m, 1 H), 4.48 (m, 2 H), 7.64 (m, 2 H).
EXAMPLE 81 (2R)-3-[(6-Ethyl-4-{4-[3-(4-methoxypyridin-3-yl)benzoyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
To a mixture of pyrimidine of Example 28 (0.114 g) and NMP (2 m L) in a 2 dram screw capped vial were added 2-methoxy-5-pyridyl boronic acid (0.037 g), 5M K3PO4 (0.5 mL), palladium Il acetate (0.012 g) and, tri-o-tolyl phosphine (0.047 g). The vial was placed into a Lab-Line MAX Q2000 orbital shaker at 80 0C for 8 hours. The mixture was partitioned between brine and ethyl acetate, separated the layers and washed the organic layer three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using 1 :1 ethyl acetate : hexanes as eluent. The resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0437 g of the title compound: MS (ESI+) for C28H31N5O5S m/z 550.38 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.3 (t, 3 H), 2.82 (q, 2 H), 3.68 (m, 4 H), 3.95 (m, 6 H), 4.07 (m, 1 H), 4.45 (m, 2 H), 6.83 (m, 2 H), 7.39 (d, 1 H), 7.5 (t, 1 H), 7.58 (m, 2H), 7.77 (dd, 1 H), 8.37 (m, 1 H).
EXAMPLE 82
3'-{[4-(2-{[(2R)-2,3-Dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazin-1- yl]carbonyl}-1 , 1 '-biphenyl-3-carbonitrile
To a mixture of the pyrimidine of Example 28 (0.135 g) and NMP (2 mL) in a 2 dram screw capped vial were added 3-cyanophenyl boronic acid (0.053 g), 5M K3PO4 (0.5 mL), palladium Il acetate (0.005 g) and, tri-o-tolyl phosphine (0.015 g). The vial was placed into a Lab-Line MAX Q2000 orbital shaker at 90 0C for 8 hours. The mixture was partitioned between brine and ethyl acetate, separated the layers and washed the organic layer three times with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using 1:1 ethyl acetate : hexanes as eluent. The resulting residue was dissolved in methanol (3 mL) and 4N HCI in dioxane was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.00271 g of the title compound: MS (ESI+) for C29H29N5O4S m/z 544.33 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.31 (t, 3 H), 2.83 (q, 2 H)1 3.69 (m, 4 H), 3.8-4.0 (m, 6 H), 4.07 (m, 1 H), 4.44 (m, 2 H), 6.85 (s, 1 H), 7.46 (d, 1 H), 7.56 (m, 2 H), 7.65 (m, 3 H), 7.81 (d, 1 H), 7.86 (s, 1 H).
EXAMPLE 83
4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(2-morpholin-4-ylethoxy)thieno[2,3- d]pyrimidine
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. 4-(2-Hydroxyethyl)morpholine (0.08 mL) 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 3 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 to dryness to give 0.0938 g of the title compound: MS (ESI+) for C31H35N5O3S m/z 558.44 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.57 (m, 4 H), 2.83 (m, 4 H), 3.71 (m, 4 H), 3.91 (m, 4 H), 4.48 (m, 2 H), 6.86 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.53 (d, 2 H), 7.61 (d, 2 H), 7.65 (d, 2 H).
EXAMPLE 84
4-t4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(2-piperazin-1-ylethoxy)thieno[2,3- d]pyrimidine
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. 1-(2-Hydroxyethyl) piperazine (0.08 mL) 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 3 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. Water (20 mL) was added to the residue. The resulting solids were filtered and dried under high vacuum to dryness to give 0.109 g of the title compound: MS (ESI+) for C3IH36N6O2S m/z 557.43 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.6 (m, 4 H), 2.8 (m, 4 H), 2.95 (m, 4 H), 3.6-4.0 (m, 8 H), 4.46 (m, 2 H), 6.85 (s, 1 H), 7.36 (m, 1 H), 7.46 (m, 2 H), 7.52 (d, 2 H), 7.59 (d, 2 H), 7.64 (d, 2 H).
EXAMPLE 85
(2S)-4-({4-[4-(1 , 1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yrj-6-ethylthieno[2,3-d]pyrim idin-2- yl}oxy)butane-1 ,2-diol
To a mixture of 2-{2-[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]ethoxy}-6-ethyl-4-piperazin-1 - ylthieno[2,3-d]pyrimidine (Example 29, 0.270 g) in DMF (5 mL) were added diisopropylethylamine (0.196 g), and 4-biphenyl carbonyl chloride (0.150 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. The residue was chromatographed on silica gel (100 mL) using ethyl acetate-hexanes (40/60). The residue was then dissolved in methanol (4 mL) and 4N HCI in dioxane (2 mL) was added. The mixture was stirred at room temperature for 2.5 hours, at which time the mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 0.019 g of the title compound: MS (ESI+) for C29H32N4O4S m/z 533.37 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.8 (q, 2 H), 3.48 (m, 2 H), 3.63 (m, 2 H), 3.8-4.0 (m, 8 H), 4.21 (m, 1 H), 4.62 (m, 2 H), 6.99 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.58 (m, 4 H), 7.65 (m, 2 H).
EXAMPLE 86
4-[4-(1,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(morpholin-2-ylmethoxy)thieno[2,3- djpyrimidine
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 15 for minutes. 2-Hydroxymethyl morpholine (0.076 mL) 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 20 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. Water (20 mL) was added to the residue. The resulting solids were filtered and dried under high vacuum to dryness to give 0.0073 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.85 (m, 3 H), 2.96 (m, 2 H), 3.15 (d, 1 H), 3.6-3.8 (m, 3 H), 3.8-4.1 (m, 8 H), 4.28 (m, 1 H), 4.41 (m, 1 H), 6.85 (s, 1 H), 7.38 (m, 1 H), 7.44 (m, 2 H), 7.53 (d, 2 H)1 7.6 (d, 2 H), 7.66 (d, 2 H).
EXAMPLE 87
4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(3-morpholin-4-ylpropoxy)thieno[2,3- d]pyrimidine
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. 4-(3-Hydroxypropyl) morpholine (0.094 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 96 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. Water (20 mL) was added to the residue. The resulting solids were filtered and dried under high vacuum to dryness to give 0.0574 g of the title compound: MS (ESI+) for C32H37N5O3S m/z 572.42 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.0 (m, 4 H), 2.38 (m, 2 H), 2.54 (m, 2 H), 2.83 (m, 4 H), 3.37 (m, 2 H), 3.8-4.0 (m, 8 H), 4.39 (m, 2 H)1 6.85 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.52 (d, 2 H), 7.59 (d, 2 H), 7.65 •(<_, 2 H).
EXAMPLE 88
Trans-(2R)-3-[(6-ethyl-4-{4-[(2-phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin- 2-yl)oxy]propane-1 ,2-diol
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 layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0674 g of the title compound: 1H NMR (400 MHz, CDCI3) δ 1.31 (t, 3 H), 1.69 (m, 1 H)1 1.96 (m, 1 H), 2.51 (m, 1 H), 2.83 (q, 2 H), 3.6-4.0 (m, 10 H)1 4.09 (m, 1 H), 4.44 (m, 2 H), 6.86 (s, 1 H), 7.1 (m, 2 H), 7.2 (m, 1 H), 7.26 (m, 2 H). EXAMPLE 89 (2R)-3-({6-Ethyl-4-[4-(phenylacetyl)pipera2in-1-y|]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-1 ,2-diol
To a mixture of the diol hydrochloride salt of Example 22 (0.190 g) in DMF (5 mL) was added diisopropylethylamine (0.197 g), and phenyl acetyl chloride (0.067 mL). The mixture was stirred at room temperature for 2.0 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. The residue was chromatographed on silica gel (100 mL) using 5% methanol in ethyl acetate as eluent to give 0.059 g of the title compound: MS (ESI+) for C23H28N4O4S m/z 457.29 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.85 (q, 2 H), 3.61 (m, 2 H), 3.71 (m, 4 H), 3.78 (s, 2 H), 3.81 (m, 2 H)1 3.84 (m, 2 H), 4.07 (m, 1 H), 4.46 (m, 2 H), 6.83 (s, 1 H), 7.27 (m, 3 H), 7.35 (m, 2 H).
EXAMPLE 90
S-^-^^i.i '-Biphenyl^-ylcarbonyOpiperazin-i-ylJ-e-ethylthienop.S-dlpyrimidin^-ylJoxyJpropan- 1-ol
Sodium hydride 60% in mineral oil (0.052 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. 3-[(tert-Butyldimethyl-silyl)oxy]propanol (0.28 mL) was added and the mixture stirred for 30 minutes. The pyrimidine of Example 13 (0.3 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 to give 0.13 g of the title compound: MS (ESI+) for C28H30N4O3S m/z 503.33 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.02 (m, 2 H), 2.66 (m, 1 H), 2.84 (q, 2 H), 3.75 (m, 4 H), 3.92 (m, 6 H), 4.54 (m, 2 H), 6.86 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.53 (d, 2 H), 7.61 (d, 2 H), 7.65 (d, 2 H).
EXAMPLE 91 4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethyl-2-{2-[(2S)-oxiran-2-yl]ethyl}thieno[2,3- d]pyrimidine
Sodium hydride 60% in mineral oil (0.035 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. (S)-(-)-Glycidol (0.057 mL) was added and the mixture stirred for 30 minutes. The pyrimidine of Example 13 (0.2 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-hexanes (50/50)as eluent to give 0.0464 g of the title compound: MS (ESI+) for C28H28N4O3S m/z501.37 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.73 (m, 1 H), 2.85 (m, 3 H), 3.4 (m, 1 H), 3.6-4.0 (m, 8 H), 4.36 (m, 1 H), 4.51 (dd, 1 H), 6.87 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 1 H), 7.51 (d, 2 H), 7.61 (d, 2 H), 7.66 (d, 2 H).
EXAMPLE 92
4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(tetrahydrofuran-3-yloxy)thieno[2,3- d]pyrimidine
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. 3-Hydroxytetrahydrofuran (0.057 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 to give 0.0711 g of the title compound: MS (ESI+) for C29H30N4O3S m/z515.36 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.22 (m, 2 H), 2.86 (q, 2 H), 3.6-4.0 (m, 11 H), 4.11 (m, 1 H), 5.53 (m, 1 H), 6.86 (s, 1 H), 7.39 (m, 1 H), 7.46 (m, 1 H), 7.52 (d, 2 H), 7.60 (d, 2 H), 7.66 (d, 2 H).
EXAMPLE 93
(2R)-4-({4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)butane-1 ,2-diol
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. (4R)-4-(2-Hydroxyethyl)-2,2-dimethyl-1 ,3-dioxolane (0.066 mL) 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 2 hours, at which time the mixture was 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 to dryness to give 0.077 g of the title compound: MS (ESI+) for C29H32N4O4S m/z 533.37 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 1.84 (m, 1 H), 1.96 (m, 1 H), 2.12 (m, 1 H), 2.84 (q, 2 H), 3.52-4.0 (m, 10 H), 4.4 (m, 1 H), 4.75 (m, 1 H), 6.87 (S1 1 H), 7.4 (m, 1 H), 7.46 (m, 2 H), 7.53 (d, 2 H), 7.61 (d, 2 H), 7.66 (d, 2 H).
EXAMPLE 94
(2R)-3-[(4-{4-[(3',4'-Difluoro-1 ,1'-biphenyl-4-yl)carbonyl]pipera2in-1-yl}-6-ethylthieno[2,3- d]pyrimidin-2-yl)oxy]propane-1 ,2-diol
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 K3PO4 (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 0C 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. The residue was chromatographed on silica gel (100 mL) using 1 :1 ethyl acetate:hexanes as eluent. The resulting residue was dissolved in methanol (2 mL) and 4N HCI in dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.029 g of the title compound: MS (ESI+) for C28H28F2N4O4S m/z 555.42 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.85 (q, 2 H), 3.6-4.1 (m, 11 H), 4.48 (m, 2 H)1 6.87 (s, 1 H), 7.23 (m, 1 H), 7.30 (m, 1 H), 7.39 (m, 1 H)1 7.52 (d, 2 H), 7.58 (d, 2 H).
EXAMPLE 95
(2R)-3-[(6-Ethyl-4-{4-[4-(6-methoxypyridin-3-yl)benzoyl]pipera2in-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
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 2-methoxy-5-pyridine boronic acid (0.054 g), 5M K3PO4 (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 0C 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. The residue was chromatographed on silica gel (100 mL) using 60% ethyl acetate in hexanes as eluent. The resulting residue was dissolved in methanol (2 mL) and 4N HCI in dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 3 hours. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0226 g of the title compound: MS (ESI+) for C28H31N5O5S m/z 550.37 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.57 (m, 1 H), 2.85 (q, 2 H), 3.46 (m, 1 H), 3.70 (m, 4 H), 3.9 (m, 4 H), 3.99 (s, 3 H), 4.08 (m, 1 H), 4.47 (m, 2 H), 6.84 (d, 1 H), 6.87 (s, 1 H), 7.53 (d, 2 H), 7.59 (d, 2 H), 7.8 (dd, 1 H), 8.4 (m, 1 H).
EXAMPLE 96
(2R)-3-{t6-Ethyl-4-(4-{[4'-(trifluoromethyl)-1 l1l-biphenyl-4-yl]carbonyl}piperazin-1-yl)thieno[2,3- d]pyrimidin-2-yl]oxy}propane-1 ,2-diol
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 K3PO4 (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 0C 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. The residue was chromatographed on silica gel (100 mL) using 60% ethyl acetate in hexanes as eluent. The resulting residue was dissolved in methanol (2 mL) and 4N HCI in dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.062 g of the title compound: MS (ESI+) for C29H29F3N4O4S m/z 587.38 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.45 (m, 1 H), 2.85 (q, 2 H), 3.4 (m, 1 H), 3.69 (m, 4 H), 3.95 (m, 4 H), 4.08 (m, 1 H), 4.49 (m, 2 H), 6.88 (s, 1 H), 7.56 (d, 2 H), 7.67 (d, 2 H), 7.71 (m, 4 H).
EXAMPLE 97
(2R)-3-({6-Ethyl-4-[4-(4-pyridin-3-ylbenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy) propane- 1 ,2-diol
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 pyridine-3-boronic acid (0.044 g), 5M K3PO4 (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 0C 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. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent. The resulting residue was dissolved in methanol (2 mL) and 4N HCI in dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0078 g of the title compound: MS (ESI+) for C27H29N5O4S m/z 520.28 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.85 (q, 2 H), 3.69 (m, 4 H), 3.94 (m, 6 H), 4.08 (m, 1 H), 4.49 (m, 2 H), 6.88 (s, 1 H), 7.43 (m, 1 H), 7.58 (d, 2 H), 7.66 (d, 2 H), 7.92 (d, 1 H), 8.64 (m, 1 H), 8.87 (m, 1 H).
EXAMPLE 98 2-[({4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)methyl]propane-1 ,3-diol
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. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.019 g of the title compound: MS (ESI+) for C29H32N4O4S m/z 533.31 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.18 (m, 1 H), 2.85 (q, 2 H), 3.6-4.1 (m, 13 H), 4.61 (m, 2 H), 6.88 (s, 1 H), 7.39 (m, 1 H), 7.47 (m, 2 H), 7.53 (d, 2 H), 7.6 (d, 2 H), 7.66 (d, 2 H).
EXAMPLE 99 (2R)-3-({6-Ethyl-4-[4-(phenoxyacetyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-1 ,2- diol
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. The residue was dissolved in methanol (2 mL) and 4M HCI in dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated ant the aqueous layer extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was chromatographed on silica gel (100 mL) using ethyl acetate:acetone:methanol (50:45:5) as eluent to give 0.0957 gfof the title compound: MS (ESI+) for C23H28N4O5S m/z 473.28 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.85 (q, 2 H), 3.73 (m, 2 H), 3.79 (m, 4 H), 3.9 (m, 4 H), 4.08 (m, 1 H), 4.48 (m, 2 H), 4.74 (s, 2 H), 6.86 (s, 1 H), 6.95 (d, 2 H), 6.97 (m, 1 H), 7.31 (m, 1 H).
EXAMPLE 100
(2R)-3-({6-Ethyl-4-[4-(3-phenoxypropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol
To a mixture of the pyrimidine of Example 25 (0.158 g) in NMP (10 ml.) was added diisopropylethylamine (0.107 g), 3-phenoxy propionic acid(0.074 g), and HATU (0.171 g). The mixture was stirred at room temperature for 3 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. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent. Fractions containing product were combined and concentrated. The residue was dissolved in methanol (2 mL) and 4M HCI in dioxane (0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0945 g of the title compound: MS (ESI+) for C24H30N4O5S m/z 487.33 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.34 (t, 3 H), 2.87 (m, 4 H), 3.67-3.8 (m, 4 H), 3.83 (m, 2 H), 3.92 (m, 2 H), 3.98 (m, 2 H), 4.09 (m, 1 H), 4.35 (m, 2 H), 4.49 (m, 2 H), 6.89 (m, 3 H), 6.95 (m, 1 H), 7.25 (m, 2 H).
EXAMPLE 101
(2R)-3-({6-Ethyl-4-[4-(4-pyrimidin-5-ylbenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol
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 K3PO4 (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 0C 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. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent. The resulting residue was dissolved in methanol (2 mL) and chilled in an ice bath. 4M HCI in dioxane was added and the mixture placed in 4°C refrigerator overnight. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.015 g of the title compound: MS (ESI+) for C2BH2SN6O4S m/z 521.40 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3 H), 2.85 (q, 2 H), 3.72 (m, 4 H), 3.95 (m, 6 H), 4.08 (m, 1 H), 4.49 (m, 2 H), 6.88 (s, 1 H), 7.61 (d, 2 H), 7.67 (d, 2 H), 8.97 (s, 2 H), 9.25 (s, 1 H).
EXAMPLE 102
(2R)-3-[(4-{4-[(3',5'-Dif luoro-1 , 1 '-biphenyl-4-yl)carbonyl]piperazin-1 -yl}-6-ethylthieno[2,3- d]pyrimidin-2-yl)oxy]propane-1 ,2-diol
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 K3PO4 (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 0C 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. The residue was chromatographed on silica gel (100 mL) using (60:40) hexanes:ethyl acetate as eluent. The resulting residue was dissolved in methanol (2 mL) and chilled in an ice bath. 4M HCI in dioxane was added and the mixture refrigerated at 4°C overnight. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer dried over anhydrous magnesium sulfate and concentrated to dryness. Hexanes: diethyl ether (90:10) was added to the residue and the solids collected via filtration to give 0.0277 g of the title compound: MS (ESI+) for C28H28N4O4SWz 555.35 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.27 (t, 3 H), 2.80 (q, 2 H), 3.66 (m, 4 H), 3.89 (m, 6 H), 4.03 (m, 1 H), 4.39 (d, 2 H), 6.78 (m, 1 H), 6.83 (s, 1 H), 7.06 (d, 2 H), 7.49 (d, 2 H), 7.57 (d, 2 H).
EXAMPLE 103
4-({4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)-2- methylbutan-2-ol
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. 3-Methyl-1 ,3-butanediol (0.069 mL) 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 to give 0.1018 g of the title compound: MS (ESI+) for C30H34N4O3S m/z 531.48 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.3 (s, 6 H), 1.31 (t, 3 H), 2.01 (m, 2 H), 2.84 (q, 2 H), 3.6-4.03 (m, 8 H), 4.54 (m, 2 H), 6.86 (s, 1 H), 7.39 (m, 1 H), 7.47 (m, 2 H), 7.53 (d, 2 H), 7.61 (d, 2 H), 7.65 (d, 2 H).
EXAMPLE 104
(2R)-3-[(4-{4-[(3,4-Difluorophenyl)acetyl]piperazin-1-yl}-6-ethylthieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
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 residue was dissolved in methanol (2 mL) and chilled in an ice bath. 4M HCI in dioxane (0.5 mL) was added and the mixture was refrigerated at 4 0C overnight. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated ant the aqueous layer extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0646 g of the title compound: MS (ESI+) for C23H26N4O4S m/z 493.37 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.84 (q, 2 H), 3.64 (m, 2 H), 3.71 (m, 4 H), 3.82 (m, 4 H), 3.87 (m, 2 H), 4.08 (m, 1 H), 4.47 (m, 2 H), 6.85 (s, 1 H), 6.97 (m, 1 H), 7.1 (m, 2 H).
EXAMPLE 105
4-(2-{[(2R)-2,3-Dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)-N-(3- methoxybenzyl)piperazine-1-carboxamide
To a mixture of the pyrimidine of Example 25 (0.159 g) in pyridine (2 mL) was added 3- methoxybenzyl isocyanate (0.125 g). The mixture was heated at 80 CC for 18 hours. The mixture was cooled to room temperature and partitioned between brine and dichloromethane. The layers were separated and the organic layer washed three times with 1 N HCI, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using hexanes-ethyl acetate (20/80) as eluent. The fractions containing product were concentrated under reduced pressure. The residue was dissolved in methanol (5m L) and refrigerated at 4 °C for 30 minutes. 4N HCI in dioxane was added and the mixture placed back in refrigerator overnight. The mixture was then partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0595 g of the title compound: MS (ESI+) for C24H31N5O5S m/z 502.32 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.31 (t, 3 H), 2.82 (q, 2 H), 3.6 (m, 4 H), 3.65- 3.8 (m, 6 H), 3.93 (m, 4 H), 4.06 (m, 1 H), 4.43 (m, 4 H), 4.96 (m, 1 H), 6.74-6.88 (m, 4 H), 7.22 (m, 1 H).
EXAMPLE 106 (2S)-5-({4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)pentane-1 ,2-diol
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. 3-[(4S)-2,2-dimethyl-1 ,3-dioxolane-4-yl]-propanol (0.102 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 22 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. 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 0C refrigerator for 18 hours. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the ethyl acetate layer dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 0.0145 g of the title compound: MS (ESI+) for C30H34N4O4S m/z 547.42 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 1.63 (m, 2 H), 1.95 (m, 2 H), 2.84 (q, 2 H)1 3.46 (m, 1 H), 3.6-4.05 (m, 10 H), 4.39 (m, 2 H), 6.86 (s, 1 H), 7.39 (m, 1 H), 7.46 (m, 2 H), 7.53 (d, 2 H), 7.60 (d, 2 H), 7.65 (d, 2 H).
EXAMPLE 107
N-1 ,1'-Biphenyl-4-yl-4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4- yl)piperazine-1 -carboxamide
To a mixture of the pyrimidine of Example 25 (0.24 g) in pyridine (5 mL) was added 4-biphenyl isocyanate (0.248 g). The mixture was heated at 80 0C for 6 hours. The mixture was cooled to room temperature and partitioned between brine and dichloromethane. The layers were separated and the organic layer washed three times with 1N HCI, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (100 mL) using ethyl acetate as eluent. The fractions containing product were concentrated. The residue was dissolved in methanol (5mL) and refrigerated at 4 0C for 30 minutes. 4N HCI in dioxane was added and the mixture placed back in the refrigerator overnight. The mixture was then partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate and concentrated to dryness to give 0.0687 g of the title compound: MS (ESI+) for C28H31N4O4S m/z 534.38 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3 H), 2.84 (q, 2 H), 3.74 (m, 6 H), 4.01 (m, 4 H), 4.1 (m, 1 H), 4.49 (m, 2 H), 6.61 (s, 1 H), 6.9 (s, 1 H), 7.3 (m, 1 H), 7.38-7.5 (m, 4 H), 7.54 (m, 4 H).
EXAMPLE 108 tert-butyl 4-[2-(2,2-diethoxyethoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate
To sodium hydride (60% by weight in mineral oil; 0.026 g) was added N-methylpyrrolidinone (1 mL), followed by glycolaldehyde diethylacetal (0.087 g). After stirring the mixture for 10 min, the carboxylate of Example 12 (0.050 g) was added. The mixture was stirred for 30 min, after which time the mixture was quenched with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, concentrated, and the residue was chromatographed on silica gel using ethyl acetate:hexane (20:80) to give 0.52 g of the title compound. MS [m+H] 481.22; 1H NMR (400 MHz, CDCI3) δ 1.23 (t, 6H), 1.32 (t, 3H), 1.48 and 1.55 (s, s, 9H), 2.84 (q, 2H), 3.57 (m, 4H), 3.64 (m, 2H), 3.76 (m, 2H), 3.84 (m, 4H), 4.36 (d, 2H), 4.89 (t, 1H), 6.86 (s, 1H).
EXAMPLE 109
4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-(2,2-diethoxyethoxy)-6-ethylthieno[2,3- d]pyrimidine
To sodium hydride (60% by weight in mineral oil; 0.0210 g) was added N-methyl pyrrolidinone (1 ml_), followed by glycolaldehyde diethylacetal (0.0706 g). After stirring the mixture for 10 minutes, the pyrimidine of Example 13 (0.0487 g) was added. The mixture was stirred for 35 minutes and then saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel using methanol:dichloromethane (1 :99) to give 0.045 g of the title compound. MS [m+H]561.3; 1H NMR (400 MHz, CDCI3) δ 1.23 (t, 6H), 1.32 (t, 3H), 2.83 (q, 2H), 3.5-4.0 (m, 12H), 4.37 (m, 2H), 4.89 (m, 1H), 6.85 (s, 1 H), 7.35-7.68 (m, 9H).
EXAMPLE 110 ({4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)acetaldehyde
A mixture of the pyrimidine of Example 109 (0.353 g), pyridinium p-toluenesulfonate (0.0009 g), acetone (5 mL), and water (0.2 mL) was stirred at room temperature for 1 hour and then heated at reflux with the addition of pyridinium p-toluenesulfonate (0.35 g) in portions over 4 days. After cooling, the mixture was concentrated and partitioned between ethyl acetate, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate, concentrated, and the residue was chromatographed on silica gel using ethyl acetate:hexane (gradient of 50% to 67% ethyl acetate in hexane) to give 0.124 g of the title compound. MS [m+H] 487.16; 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3H), 2.85 (q, 2H), 3.62-4.0 (m, 8H), 4.77 (s, 2H), 6.88 (s, 1 H), 7.35-7.68 (m, 9H)1 9.74 (s, 1 H).
EXAMPLE 111
({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)acetic acid
To the acetaldehyde of Example 110 (0.1137 g) and dichloromethane (2 mL) cooled in a cold water bath was added 3-chloroperoxybenzoic acid (Aldrich 273031 ; 0.605 g). The mixture was stirred for 1 hour and then chromatographed on silica gel using methanol:dichloromethane:acetic acid (10:90:0.1). The product fractions were combined, concentrated, and azeotroped with toluene under reduced pressure to give 0.102 g of the title compound. MS [m+H] 503.14; 1H NMR (400 MHz, CDCI3) δ 1.30 (t, 3H), 2.82 (q, 2H), 3.6-4.0 (m, 8H), 4.84 (s, 2H), 6.85 (s, 1H), 7.13-7.65 (m, 9H).
EXAMPLE 112
4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yϊ]methoxy}- 6-ethylthieno[2,3-d]pyrimidine
Sodium hydride (60% by weight in mineral oil; 0.0194 g) was washed twice with hexane. To the residue was added N-methylpyrrolidinone (0.6 mL). The mixture was cooled in a cold water bath and (S)-(+)-2,2-dimethyl-1 ,3-dioxolane-4-methanol (0.0642 g) was added. After stirring for 5 min, ice was added to the cold water bath and the pyrimidine of Example 13 (0.150 g) was added, followed by additional N-methylpyrrolidinone (0.2 mL). After stirring the mixture for 1.5 hours at 0 0C, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and then dried over magnesium sulfate. After concentration, the residue was chromatographed on silica gel using ethyl acetate:hexane (50:50) to give 0.167 g of the title compound. MS [m+H] 559.26; 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3H), 1.37 (s, 3H), 1.45 (s, 3H), 2.84 (q, 2H), 3.83-4.0 (m, 9H), 4.15 (m, 1H), 4.28 (m, 1 H), 4.48 (m, 2H)1 6.86 (s, 1H), 7.38-7.7 (m, 9H).
EXAMPLE 113 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-ethylthieno[2,3-d]pyrimidine
Sodium hydride (60% by weight in mineral oil; 0.0194 g) was washed twice with hexane. To the residue was added N-methylpyrrolidinone.(0.6 ml_). The mixture was cooled in a cold water bath and (R)-(-)-2,2-dimethyl-1 ,3-dioxolane-4-methanol (0.0642 g) was added. After stirring for 5 minutes, ice was added to the cold water bath and the pyrimidine of Example 13 (0.150 g) was added, followed by additional N-methylpyrrolidinone (0.2 mL). After stirring the mixture for 1.5 hours at 0 0C, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and then dried over magnesium sulfate. After concentration, the residue was chromatographed on silica gel using ethyl acetate:hexane (50/50) to give 0.150 g of the title compound. MS [m+H] 559.26; 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3H), 1.37 (s, 3H), 1.45 (s, 3H), 2.83 (q, 2H), 3.83-4.0 (m, 9H), 4.13 (m, 1 H), 4.30 (m, 1 H), 4.48 (m, 2H), 6.86 (1H), 7.35-7.70 (9H).
EXAMPLE 114
(2R)-3-({4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol
A mixture of the pyrimidine of Example 112 (0.16 g), pyridinium p-toluenesulfonate (0.079 g), and methanol (3 mL) was stirred at room temperature for 1.5 hours and then at 80 °C for 19.5 hours. After cooling and concentration under reduced pressure, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using methanohdichloromethane (4:96) to give 0.129 g of the title compound. MS [m+H] 519.16; 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3H), 2.46 (br s, 0.5H), 2.85 (q, 2H), 3.38 (br s, 0.5H), 3.65-4.12 (m, 12 H), 4.48 (m, 2H)1 6.88 (s, 1 H), 7.37-7.67 (m, 9H).
EXAMPLE 115
(2S)-3-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)pipera2in-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol
A mixture of the pyrimidine of Example 113 (0.144 g), pyridinium p-toluenesulfonate (0.071 g), and methanol (3 ml_) was stirred at 80 °C for 20 hours. After cooling and concentration under reduced pressure, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using methanokdichloromethane (4:96) to give 0.12 g of the title compound. MS [m+H] 519.18; 1H
NMR (400 MHz, CDCI3) δ 1.33 (t, 3H), 2.48 (br s, 0.5H), 2.85 (q, 2H), 3.40 (br s, 0.5H), 3.65-4.15 (m, 12 H), 4.48 (m, 2H), 6.88 (s, 1 H), 7.38-7.68 (m, 9H).
EXAMPLE 116 N-[2-({4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)ethyl]-N,N-dimethylamine hydrochloride
Sodium hydride (60% by weight in mineral oil; 0.022 g) was washed twice with hexane. To the residue was added N-methylpyrrolidinone (1 mL). The mixture was cooled in a cold water bath and N, N-dimethylethanolamine (0.049 g) was added. After stirring for 5 minutes, ice was added to the cold water bath and the pyrimidine of Example 13 (0.150 g) was added. The mixture was allowed to warm to room temperature over 5.5 hours and then was stored in the refrigerator over the weekend, after which saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and then dried over magnesium sulfate. The residue was concentrated to give 0.106 g of N-[2-({4-[4-(1 ,1 '-biphenyl- 4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)ethyl]-N,N-dimethylamine. MS [m+H] 516.2; 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3H) , 2.33 (s, 6H), 2.73 (m, 2H), 2.83 (q, 2H), 3.65-3.95 (m, 8H), 4.45 (m, 2H), 6.85 (s, 1H), 7.38-7.70 (m, 9H). Addition of HCI-methanol to N- [2-({4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}oxy)ethyl]- N,N-dimethylamine gave the title compound.
EXAMPLE 117 2-({4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)acetamide
To the acetic acid of Example 111 (0.0196 g) in a mixture of dichloromethane (1 ml.) and dioxane (0.1 mL) was added 1 ,1 '-carbonyldiimidazole (0.0070 g). After stirring for 1 hour, ammonia in dioxane (0.5 M solution, 0.39 mL) was added and the mixture was stirred for 4 hours, at which time an additional 0.35 mL of ammonia/dioxane was added. The mixture was stirred for an additional hour and then concentrated to dryness under reduced pressure. Chromatography on silica gel using methanokEthyl acetate (4:96) gave 0.0113 g of the title compound. MS [m+H] 502.3; 1H NMR (400 MHz, CDCI3) δ 1.33 (t, 3H), 2.86 (q, 2H), 3.6-4.0 (m, 8H), 4.83 (s, 2H), 5.51 (br s, 1 H), 6.51 (br s, 1 H), 6.89 (s, 1 H)1 7.37-7.67 (m, 9H).
EXAMPLE 118
4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-ethyl-2-(tetrahydrofuran-2-ylmethoxy)thieno[2,3- djpyrimidine
odium hydride (60% by weight in mineral oil; 0.014 g) was washed twice with hexane. To the residue was added N-methylpyrrolidinone (0.75 mL). (+/-)-Tetrahydrofurfural alcohol (0.0373 g) was added. After stirring for 5 min, the pyrimidine of Example 13 (0.0564 g) was added. After stirring the mixture for 1.2 hours, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and then dried over magnesium sulfate. After concentration, the residue was chromatographed on silica gel using ethyl acetate:hexane (50:50) to give 0.0345 g of the title compound. MS [m+H] 529.3; 1H NMR (400 MHz, CDCI3) δ 1 ,32 (t, 3H), 1.78 (m, 1 H), 1.92 (m, 2H), 2.03 (m, 1 H), 2.84 (q, 2H), 3.6-4.0 (m, 10H), 4.26-4.38 (m, 3H), 6.85 (s, 1H), 7.38-7.66 (m, 9H).
EXAMPLE 119 2-({4-[4-(1 ,1'-biphenyl-3-ylcarbonyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)ethanamine hydrochloride
Sodium hydride (60% by weight in mineral oil; 0.0194 g) was washed twice with hexane. To the residue was added N-methylpyrrolidinone (0.6 mL). The mixture was cooled in a cold water bath and ethanolamine (0.0341 g) was added. After stirring for 5 min, ice was added to the cold water bath and 4-[4-(1 ,1 '-biphenyl-3-ylcarbonyl)piperazin-1 -yl]-2-chloro-6-ethylthieno[2,3-d]pyrimidine (Example 19, 0.0861 g) was added, followed by additional N-methylpyrrolidinone (0.2 mL). After stirring the mixture for 1.5 hours at 0 0C, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and then dried over magnesium sulfate. After concentration, the residue was chromatographed on silica gel using ethyl acetate:hexane (50:50) to give 0.018 g of the title compound after addition of HCI/methanol followed by concentration to dryness.
MS [m+H] 488.3; 1H NMR (400 MHz, CDCI3) δ 1.32 (t, 3H), 2.83 (q, 2H), 3.08 (m, 2H), 3.6-4.0 (m, 8H), 4.36 (m, 2H), 6.85 (s, 1 H), 7.36-7.68 (m, 9H).
EXAMPLE 120
2-({4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethylthieno[2,3-d]pyrimidin-2- yl}oxy)ethanamine hydrochloride
Sodium hydride (60% in oil) was washed three times with hexane to remove oil. DMF (0.5 mL) was added to the NaH, followed by ethanolamine (0.203 mL) in DMF (0.5 mL). After stirring for 10 min, the pyrimidine of Example 13 (0.154 g) in DMF (1 mL) was added. The mixture was stirred for 4 hours, at which time it was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and concentrated to dryness. The residue was dissolved in methanol (0.3 mL) and HCI/methanol (0.35 mol) was added. After standing overnight at room temperature and then in the refrigerator for 4 hours, the resulting solid was collected, washed with a small amount of methanol, and dried to give 0.072 g of the title compound. MS [m+H] 488.3; 1H NMR (400 MHz, CDCI3 + methanol-d4) δ 1.26 (t, 3H), 2.81 (q, 2H), 3.26 (m, 2H), 3.3 (m, 2H), 3.7-4.1 (m, 8H), 4.72 (m, 2H), 6.99 (s, 1 H), 7.30-7.60 (m, 9H).
EXAMPLE 121
N-(3-(4-(2-(((S)-2,2-dimethyl-1 ,3-dioxolan-4-yl)methoxy)-6-ethylthieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl)-3-oxopropyl)-N-phenylbenzamide
A mixture of the beta-alanine of Example 38 (0.102 g, 0.378 mmol) and 1 ,1'-carbonyl diimidazole (0.0736 g, 0.454 mmol) in dichloromethane (0.25 mL) was stirred at room temperature for 2.5 hours, at which time the pyrimidine of Example 25 (0.171 g, 0.454 mmol) was added. After stirring for 23 hours, dichloromethane was removed under reduced pressure and the residue was partitioned between ethyl acetate and 0.5 N HCI, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and chromatographed on silica gel using methanokethyl acetate (4:96) to give 0.123 g of the title compound. MS [m+H] 630.5; 1H NMR (400 MHz, CDCI3) δ 1.33 (3H), 1.38 (3H), 1.46 (3H), 2.84 (4H), 3.76 (4H), 3.85-3.95 (5H), 4.15 (1 H), 4.22 (2H), 4.27 (1 H), 4.44 (2H), 6.86 (1H), 7.05-7.30 (10H).
EXAMPLE 122
N-(3-(4-(2-((R)-2,3-dihydroxypropoxy)-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-3- oxopropyl)-N-phenylbenzam ide
A mixture of the phenylbenzamide of Example 121 (0.112 g, 0.178 mmol), 4M HCI-dioxane (0.18 mL), THF (1 ml_), and methanol (0.2 ml_) was stirred at room temperature for 3 hours, then stored overnight in the refrigerator. The solvents were then removed under reduced pressure and the residue was partitioned between ethyl acetate, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and concentrated to dryness to give 0.082 g of the title compound. MS [m+H] 590.4; 1H NMR (400 MHz, CDCI3) δ 1.33 (3H), 2.85 (4H), 3.73 (3H), 3.77 (4H), 3.89 (2H), 3.96 (2H), 4.08 (1H), 4.21 (2H), 4.48 (2H), 6.88 (1H), 7.07-7.30 (10H).
EXAMPLE 123
(2R)-3-({4-t4-(1,1 '-Biphenyl-4-ylcarbonyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane- 1 ,2-diol
To an ice cooled solution of the pyrimidine of Example 42 (2.3 g) in methanol was added 4N HCI . in dioxane (4 ml) and stirred for 2 hours. The solution was warmed to room temperature and stirred for additional 6 hours at room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and then concentrated under reduced pressure to give title compound: (0.39 g). MS (ESI+) for C26H26N4O4S m/z491.27 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.39-7.76 (m, 11H), 4.7 (m, 1H) 4.55 (m,1 H) 4.3 -4.01 (m,4H) 4.0 (m,3H), 3.9 (b,2H), 3.6 (m,2H), LCMS = 491.22 (M+).
EXAMPLE 124
(2R)-3-({4-[(2S)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1 -yl]-6-ethylthieno[2,3- d]pyrimidin-2-yl}oxy)propane-1 ,2-diol
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 64, 0.066 g) was dissolved in 4N HCI/dioxane (2 mL) at O0C. The mixture was allowed to warm to room temperature and stir for 3 days. The solvent was evaporated under reduced pressure and the residue was triturated with ether. The resulting solid was collected, washed with diethyl ether and dried under reduced pressure to give 0.038 g of the title compound. HRMS (ESI+) for C29H32N4O4S m/z 533.2202 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.76 (d, 2H), 7.65-7.67 (m, 2H), 7.60 (d, 2H), 7.47 (t, 2H), 7.36-7.40 (m, 2H), 4.40-4.70 (m, 3H), 3.45-4.02 (m, 9H), 2.95 (q, 2H), 1.38-1.61 (m, 3H), 1.35 (t, 3H).
EXAMPLE 125
3-{[4-(2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl]carbonyl}-9H-fluoren-9-one
2-{[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1-ylthieno[2,3-d]pyrimidine (Example 25, 0.106 g) was dissolved in THF. To this mixture was added HATU (0.106 g) and DIEA (0.072 g), followed by 9-oxo-9H-fluorene-3-carboxylic acid (0.063 g). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography, eluting with ethyl acetate/hexanes (70/30) to give 0.11 g of the title compound. MS (ESI+) for C32H32N4O5S1 m/z 585.44 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.71 (d, 2H), 7.69 (m, 4H), 7.37 (t, 1 H), 6.85 (s, 1H), 4.52 (m, 2H), 4.35 (m, 1H), 4.16 (m, 2H), 3.92 (br m, 8H), 2.87 (m, 2H), 1.58 (s, 3H), 1.36 (s, 3H), 1.34 (t, 3H).
EXAMPLE 126 4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-ethyl-2-[(3-methyloxetan-3- yl)methoxy]thieno[2,3-d]pyrimidine
Sodium hydride (0.026 g, 60% in mineral oil) was placed into a round bottomed flask and then washed with hexanes and chilled in an ice/acetone bath. NMP (1 ml_) was added and the mixture stirred for 15 minutes. 3-Methyl-3-oxetane methanol (0.064 mL) was added and the mixture was 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 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 to give 0.0787 g of the title compound: MS (ESI+) for C30 H32 N4 O3 S1 m/z 529.35 (M+H)+. 1H NMR (CDCI3) δ 1.33 (t, 3 H), 1.59 (s, 3 H), 2.85 (q, 2 H), 3.6-4.0 (m, 8 H), 4.46 (m, 4 H), 4.62 (m, 2 H), 6.87 (s, 1 H), 7.39 (m, 1 H), 7.41 (m, 1 H), 7.53 (d, 2 H), 7.61 (d, 2 H), 7.66 (d, 2 H).
EXAMPLE 127
(2R)-3-({6-Ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2- yl}oxy) propane- 1 ,2-diol
To an ice cooled solution of 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3,3,3- trifluoropropanoyl)piperazin-1-yl]thieno[2,3-d]pyrimidine (Example 145, 0.084 g) in methanol was added 4N HCI in dioxane (5 mL) and the mixture was stirred for 2 hours. The mixture was warmed to room temperature and stirred for an additional 6 hours at room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate and then concentrated under reduced pressure to give 0.050 g of the title compound. MS (ESI+) for Ci8H23F3N4O4S m/z 449.24 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 6.87 (s, 1 H), 4.50 (m, 2H), 4.10 (m, 1 H)1 3.98 (m, 4H), 3.91 (m, 2H), 3.71 (m, 4H), 3.33 (q, 2H), 2.88 (q, 2H), 1.99 (t, 3H).
EXAMPLE 128
(3-{[4-(2-{[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yi]methoxy}-6-ethylthieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methanone
To a mixture of 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1- ylthieno[2,3-d]pyrimidine (Example 25, 0.6 g) in THF (20 mL) was added diisopropylethylamine (0.6 mL), 3-benzoylbenzoic acid (0.375 g) and HATU (0.632 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed three times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (40/60) to give 0.98 g of the title compound. MS (ESI+) m/z 587.36 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 7.87-7.50 (m, 9H), 6.86 (s, 1 H) 4.51- 4.50 (m, 2H), 4.48 (q, 1H), 4.16 (t, 1H), 4.14-3.90 (br m, 7H), 3.60 (br s, 2H), 2.87 (q, 2H), 1.70 (s, 3H), 1.44 (s, 3H), 1.34 (t, 3H).
EXAMPLE 129
(3-{[4-(2-{[(2R)-2,3-dihydroxypropyl]oxy}-6-ethylthieno[2,3-d]pyrimidin-4-yl)piperazin-1- yl]carbonyl}phenyl)(phenyl)methanone
To an ice cooled solution of the methanone of Example 128 (0.35 g) in methanol was added 4N HCI in dioxane (12 ml) and stirred for 2 hours. The solution was warmed to room temperature and stirred for additional 3 hours at room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and then concentrated under reduced pressure to give 0.12 g of the title compound. MS (ESI+) m/z 547.30 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.83-7.30 (m, 9H), 6.9 (s, 1 H)1 4.40 (m, 2H) 4.0 (m, 8H), 3.67 (b, 3H), 2.8 (t, 2H), 1.31 (t, 3H).
EXAMPLE 130 4-[4-(1 ,1 '-Biphenyl-4-yicarbonyl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-phenylthieno[2,3-d]pyrimidine
[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methanol (0.25 g) was dissolved in NMP and cooled to 0 0C. To this solution was added sodium hydride (60% dispersion, 0.08 g). The mixture was stirred for 10 minutes at 0 0C and then for 30 minutes at room temperature. The mixture was cooled back to 0 CC and 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-phenylthieno[2,3- d]pyrimidine (Example 43, 0.5 g) was added as a solution in NMP (10 ml_). After 15 minutes of stirring the cooling bath was removed and the mixture was stirred an additional 3 hours. The mixture was then partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was then washed with brine, separated, dried over MgSO4, filtered and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate-hexanes (40/60) to give 0.31 g of the title compound. MS (ESI+) m/z 607.41 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.67-7.33 (m, 15H), 4.50 (m, 2H), 4.35 (m, 1H) 4.20 (m, 1 H), 4.15-3.91 (m, 9H), 1.46 (s, 3H), 1.38 (s, 3H).
EXAMPLE 131
4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-methylthieno[2,3-d]pyrimidine
[(4S)-2,2-Dimethyl-1 ,3-dioxolah-4-yl]methanol (0.17 g, 1.33 mmol) was dissolved in NMP (5 mL) and cooled to 0 °C. Hexane washed NaH (0.053 g) was added. The mixture was stirred at 0 °C for 10 minutes followed by stirring at room temperature for 30 minutes. The mixture was cooled again to 00C and 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-methylthieno[2,3- d]pyrimidine (Example 44, 0.3 g) was added as a solution in NMP/DMF (8 ml_/5 mL). The mixture was stirred at 00C for 15 minutes followed by stirring at room temperature overnight. The mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered, dried and concentrated. The resulting residue was purified by silica gel chromatography using ethyl acetate-hexanes (40/60) to give 0.24 g of the title compound. MS (ESI+) m/z 545.38 (M+H)+. 1H NMR (400 MHz, CDCI3) 67.66-7.37 (m, 9H), 6.85 (s, 1 H), 4.52 (m, 2H), 4.28 (m, 1 H), 4.88 (m, 1 H), 3.95-3.89 (m, 9H), 2.25 (s, 3H), 1.57 (s, 3H), 1.44 (s, 3H).
EXAMPLE 132 4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyi-1 ,3-dioxolan-4-yl]methoxy}- 6-propylthieno[2,3-d]pyrimidine
[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methanol (0.17 g) was dissolved in NMP (5 mL) and cooled to 0 0C. Hexane washed NaH (0.05 g) was added. The mixture was stirred at 0 0C for 10 minutes followed by stirring at room temperature for 30 minutes. The mixture was cooled again to 0 °C and 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-propylthieno[2,3- d]pyrimidine (Example 47, 0.3 g) was added as a solution in NMP/DMF (8 mL/5 mL). The mixture was stirred at 0 0C for 15 minutes followed by stirring at room temperature overnight. The mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate and the organic layer was dried over MgSO4, filtered, dried and concentrated. The resulting residue was purified by silica gel chromatography ethyl acetate-hexanes (30/70) to give 0.18 g of the title compound. MS (ESI+) m/z 573.43 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.66-7.36 (m, 9H), 6.86 (S, 1H), 4.50(m, 2H) 4.45 (m, 1H), 4.14 (m, 1H), 3.92 (br m, 9H), 2.76 (t, 2H), 1.74 (q, 2H),1.49 (s, 3H), 1.43 (s, 3H), 1.00 (t, 3H).
EXAMPLE 133
4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-isopropylthieno[2,3-d]pyrimidine
[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methanol (0.17 g) was dissolved in NMP (6 ml.) and cooled to 0 °C. Hexane washed NaH (0.05 g) was added. The mixture was stirred at 0 0C for 10 minutes followed by stirring at room temperature for 30 minutes. The mixture was cooled again to 0 0C and 4-[4-(1 ,1'-biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-chloro-6-isopropylthieno[2,3- d]pyrimidine (Example 48, 0.3 g) was added as a solution in NMP/DMF (8 ml_/5 ml_). The mixture was stirred at 0 0C for 15 minutes followed by stirring at room temperature overnight, after which the mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered, dried and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (30:70) to give 0.21 g of the title compound. MS (ESI+) m/z 573.43 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.70- 7.36 (m, 9H), 6.85 (s, 1 H), 4.49 (m, 2H), 4.31 (m, 1 H), 4.09 (m, 1H), 3.91 (br m, 9H), 3.74 (m, 1H), 1.58 (s, 6H), 1.43 (s, 3H), 1.37 (s, 3H).
EXAMPLE 134
2-{[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-t4-(thien-2-ylacetyl)piperazin-1- yl]thieno[2,3-d]pyrimidine
To a mixture of the pyrimidine of Example 25 (0.106 g) in THF (5 mL) was added diisopropylethylamine (0.11 mL), HATU (0.106 g) and 2-thiophene acetic acid (0.0398 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (70:30) to give 0.096 g of the title compound. MS (ESI+) m/z 503.32 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 7.40 (d, 1 H), 6.66 (m, 2H), 6.60 (s, 1 H), 4.51 (m, 2H), 4.30 (m, 1 H), 4.27 (m, 1 H), 3.95 (s, 2H), 3.88 (br m, 7H), 3.79 (br m, 2H), 2.84 (q, 2H), 1.62 (s, 3H), 1.34 (s, 3H), 1.32 (t, 3H). EXAMPLE 135
(2R)-3-({6-Ethyl-4-[4-(thien-2-ylacetyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane-1 ,2- diol
To an ice cooled solution of the pyrimidine of Example 134 (0.09Og) in methanol was added 4N HCI in dioxane (5 ml) and stirred for 2 hours. The solution was warmed to room temperature and stirred for additional 6 hours at room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate and then concentrated under reduced pressure to give 0.096 g of the title compound. MS (ESI+) m/z 463.21 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.25 (d, 1 H), 6.96 (t, 2H) 6.84 (s, 1 H), 4.49 (m, 4H), 4.05 (m, 1 H), 3.95 (s, 1 H), 3.90-3.66 (m, 11 H), 2.83 (q, 2H), 1.32 (t, 3H).
EXAMPLE 136
2-{[(4S)-2,2-Dimethyl-1 , 3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3-phenoxybenzoyl)piperazin-1- yl]thieno[2,3-d]pyrimidine
To a mixture of the pyrimidine of Example 25 (0.106 g) in THF (5 mL) was added diisopropylethylamine (0.11 mL), HATU (0.106 g) and 3-phenoxybenzoic acid (0.06 g). The mixture was stirred overnight at room temperature. THF was then removed under reduced pressure and the resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (70/30) to give 0.13 g of the title compound. MS (ESI+) m/z 575.41 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 7.40-7.36 (m, 3H), 7.25 (m, 2H), 7.15 (m, 4H), 6.84 (s, 1 H), 4.51 (m, 2H), 4.31 (m, 1 H), 4.15 (m, 1H), 3.9-3.5 (br m, 9H), 2.85 (q, 2H), 1.59 (s, 3H), 1.37 (s, 3H), 1.32 (t, 3H).
EXAMPLE 137
(2R)-3-({6-Ethyl-4-[4-(3-phenoxybenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidin-2-yl}oxy)propane- 1 ,2-diol
To an ice cooled solution of 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3- phenoxybenzoyl)piperazin-1-yl]thieno[2,3-d]pyrimidine (Example 136, 0.127g) in methanol was added 4N HCI in dioxane. The mixture was gradually warmed to room temperature and stirred for 3.5 hours. The mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The ethyl acetate layer was dried over MgSO4, filtered and concentrated to give 0.070 g of the title compound. MS (ESI+) for C28H30N4O5S1 m/z 535.29 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.40 (m, 3H), 7.25 (m, 2H), 7.14 (m, 4H), 6.88 (s, 1 H), 4.48 (t, 2H), 4.07 (br, 7H), 3.69 (m, 4H), 2.86 (q, 2H), 1.34 (t, 3H).
EXAMPLE 138
2-{t(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-4-[4-(3,3-diphenylpropanoyl)piperazin-1-yl]-6- ethylthieno[2,3-d]pyrimidine
To a mixture of the pyrimidine of Example 25 (0.106 g) in THF (5 ml.) was added diisopropylethylamine (0.11 mL), HATU (0.106 g) and 2,2-diphenylpropionic acid (0.063 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (70:30) to give 0.120 g of the title compound. MS (ESI+) for C33H38N4O4S m/z 587.35 (M+H)+. 1H NMR (400 MHz1 CDCI3) δ 7.55-7.23 (m, 10H), 6.70 (s, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.22 (m, 1H), 4.11 (m, 1H), 3.95 (br m, 5H), 3.15 (br s, 4H), 2.75 (q, 2H), 2.30 (s, 1H), 1.82 (s, 2H), 1.85 (s, 3H), 1.75 (t, 3H), 1.25 (t, 3H). EXAMPLE 139
2-{[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(1- phenylcyclopropyl)carbonyl]piperazin-1-yl}thienot2,3-d]pyrimidine
To a mixture of 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1 - ylthieno[2,3-d]pyrimidine (Example 25, 0.106 g) in THF (5 mL) was added diisopropylethylamine (0.11 mL), HATU (0.106g) and phenyl-1 -cyclopropane carboxylic acid (0.0454 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (70/30) to give 0.13 g of the title compound. MS (ESI+) for C28H34N4O4S m/z 523.34 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 7.32 (t, 2H), 7.25 (m, 3H), 6.77 (s, 1 H), 4.51 (m, 4H), 4.24 (m, 1 H), 4.14 (m, 1 H), 3.90 (br m, 7H), 3.79 (br, 4H), 2.81 (q, 2H), 1.89 (s, 3H), 1.66 (s, 3H), 1.60 (t, 3H).
EXAMPLE 140
(2R)-3-[(6-Ethyl-4-{4-[(1-phenylcyclopropyl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
To an ice cooled solution of the pyrimidine of Example 139 (0.127 g) in methanol was added 4N HCI in dioxane (5 mL) and the mixture was stirred for 2 hours. The solution was warmed to room temperature and stirred for additional 6 hours and concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate and then concentrated under reduced pressure to give 0.090 g of the title compound. MS (ESI+) for C25H30N4O4S m/z 483.29 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 7.33 (t, 2H), 7.25 (m, 3H), 6.82 (S, 1 H), 4.49 (t, 2H), 4.24 (t, 1 H), 3.90 (br m, 11 H), 2.84 (q, 2H)1 1.44 (t, 3H), 1.66 (br m, 3H). EXAMPLE 141
2-{[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(4'-ethyl-1 ,1 '-biphenyl-4- yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine
To a mixture of 2-{[(4S)-2,2-dimethyl-1 ,3-dioxoian-4-yl]methoxy}-6-ethyl-4-piperazin-1 - ylthieno[2,3-d]pyrimidine (Example 25, 0.106 g) in THF (5 mL) was added diisopropylethylamine (0.1 I mL), HATU (0.106g) and 4'-ethyl-1 ,1 '-biphenyl-4-carboxylic acid (0.056 g). The mixture, was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (70/30) to give 0.15 g of the title compound. MS (ESI+) for C33H38N4O4S1 m/z 587.35 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 7.65 (d, 2H), 7.53 (m, 4H), 7.30 (d, 2H), 6.86 (s, 1H), 4.52 (m, 2H), 4.31 (m, 1H), 4.88 (m, 1 H), 4.16 (br m, 9H), 2.87 (q, 2H), 2.71 (q, 2H), 1.43 (s, 3H), 1.33 (s, 3H), 1.31 (t, 3H), 1.26 (t, 3 H).
EXAMPLE 142
(2R)-3-[(6-Ethyl-4-{4-[(4'-ethyl-1 ,1'-biphenyl-4-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
To an ice cold solution of 2-{[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(4'- ethyl-1 ,1'-biphenyl-4-yl)carbonyl]piperazin-1-yl}thieno[2,3-d]pyrimidine (Example 141) in methanol was added 4N HCI in dioxane. The mixture was gradually warmed to room temperature and stirred for 3.5 hours. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated to give 0.090 g of the title compound. MS for C30H34N4O4S m/z 547.36 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 7.65 (d, 2H), 7.53 (d, 4H), 7.30 (d, 2H), 6.98 (s, 1 H), 4.50 (t, 2H), 4.09-3.70 (br m,11 H), 2.88 (q, 2H), 2.73 (q, 2H), 1.27 (m, 6H).
EXAMPLE 143 2-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(2-naphthyloxy)acetyl]piperazin-1- yl}thieno[2,3-d]pyrimidine
To a mixture of 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1- ylthieno[2,3-d]pyrimidine (Example 25, 0.106 g) in THF (5 mL) was added diisopropylethylamine (0.11 mL), HATU (0.106 g) and (2-naphthyloxy)acetic acid (0.056 g). The reaction was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (70/30) to give 0.13 g of the title compound. MS (ESI+) for C30H34N4O5S m/z 563.39 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 8.25 (d, 1 H), 7.81 (d, 1 H), 7.35 (m, 3H), 7.20 (t, 1 H) 6.91 (t, 1 H), 6.78 (s, 1 H), 4.94 (s, 2H), 4.50 (m, 2H), 4.27 (m; 1 H), 4.15 (m, 1 H) 3.91 (br m, 9H), 2.83 (q, 2H), 1.79 (s, 3H), 1.55 (s, 3H), 1.36 (t, 3H).
EXAMPLE 144 (2R)-3-[(6-Ethyl-4-{4-[(2-naphthyloxy)acetyl]piperazin-1-yl}thieno[2,3-d]pyrimidin-2- yl)oxy]propane-1 ,2-diol
To an ice cold solution of 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-{4-[(2- naphthyloxy)acetyl]piperazin-1-yl}thieno[2,3-d]pyrimidine (Example 143, 0.097 g) in methanol was added 4N HCI in dioxane. The mixture was gradually warmed to room temperature and stirred for 3.5 hours, after which the mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered and dried to give 0.020 g of the title compound. MS (IESI+) for C27H30N4O5S m/z 523.29 (M+H)+. 1H NMR (400 MHz, CDCI3) δ 8.25 (d, 1H), 7.80 (d, 1 H), 7.45 (m, 3H), 7.38 (t, 1 H), 6.90 (d, 1 H), 6.80 (s, 1 H), 4.98 (s, 2H), 4.45 (t, 2H), 4.22 (t, 1 H), 3.88 (br s, 8H), 3.66 (m, 2H), 2.80 (m, 2H), 1.33 (t, 3H).
EXAMPLE 145
2-{[(4S)-2,2-Dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-[4-(3,3,3-trifluoropropanoyl)piperazin- 1 -yl]thieno[2,3-d]pyrimidine
To 2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-6-ethyl-4-piperazin-1 -ylthieno[2,3- d]pyrimidine (Example 25, 0.150 g) in THF (5 ml.) was added diisopropylethylamine (0.11 mL), HATU (0.200 g) and 3,3,3-trifluoropropanoic acid (0.0659 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was purified on silica gel using ethyl acetate and hexanes (70/30) to give 0.090 g of the title compound. MS (ESI+) for C21H27F3N4O4S m/z 489.22 (M+H)+. 1H NMR (400 MHz, CDCI3). δ 6.85 (s, 1 H), 4.52 (m, 2H), 4.30 (m, 1H), 4.16 (m, 1 H), 3.93 (m, 5H), 3.88 (m, 2H), 3.63 (br m, 2H), 3.32 (q, 2H)1 2.85 (q, 2H), 1.45 (s, 3H), 1.34 (s, 3H), 1.24 (t, 3H).
EXAMPLE 146
(2R)-3-({4-[(3R)-4-(1 ,1 '-Biphenyl-4-ylcarbony!)-3-methylpiperazin-1 -yl]-6-ethylthieno[2,3- d]pyrimidin-2-yl}oxy)propane-1 ,2-diol
4-[(3R)-4-(1 ,1'-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan- 4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine (Example 55, 0.090 g) was dissolved in 3 mL of 4N HCI in dioxane at 0 0C. The mixture was gradually warmed to room temperature and stirred for 2.5 days. The solvent was evaporated and the solid was triturated with diethyl ether and collected, then washed with additional diethyl ether and dried under reduced pressure to give 0.045 g of the title compound. HRMS (ESl+) for C29H32N4O4S m/z 533.2194 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.76 (d, 2H), 7.64-7.67 (m, 2H), 7.55-7.57 (m, 2H), 7.45-7.49 (m, 2H), 7.42 (s, 1H), 7.36-7.40 (m, 1 H), 4.53-4.72 (m, 5H), 3.99-4.05 (m, 2H), 3.82-3.86 (m, 1 H), 3.60-3.68 (m, 4H), 2.95 (q, 2H), 1.35 (t, 6H).
EXAMPLE 147
(2R)-3-({4-[(3S)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1 -yl]-6-ethylthieno[2,3- d]pyrimidin-2-yl}oxy)propane-1 ,2-diol
4-[(3S)-4-(1 ,1 '-Biphenyl-4-ylcarbonyl)-3-methylpiperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan- 4-yl]methoxy}-6-ethylthieno[2,3-d]pyrimidine (Example 56, 0.090 g) was dissolved in 3 mL of 4N HCI in dioxane at 0 0C. The mixture was gradually warmed to room temperature and stirred for 2.5 days. The solvent was evaporated under reduced pressure and the solid was triturated with diethyl ether and collected, then washed with additional diethyl ether and dried under reduced pressusre to give 0.060 g of the title compound. HRMS (ESI+) for C29H32N4O4S m/z 533.2217 (M+H)+ 1H NMR (400 MHz, CD3OD) δ 7.76 (d, 2H), 7.65-7.67 (m, 2H), 7.56 (d, 2H), 7.45-7.57 (m, 2H), 7.41 (s, 1H), 7.36-7.40 (m, 1H), 4.51-4.72 (m, 5H), 3.99-4.05 (m, 2H), 3.82-3.87 (m, 2H), 3.60-3.68 (m, 3H), 2.95 (q, 2H), 1.35 (t, 6H).
EXAMPLE 148
(2R)-3-({4-[(2R)-4-(1 ,1'-Biphenyl-4-ylcarbonyl)-2-methylpiperazin-1 -yl]-6-ethylthieno[2,3- d]pyrimidin-2-yl}oxy)propane-1 ,2-diol
4-[(2R)-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 63, 0.036 g) was dissolved in 4N HCI/dioxane (2 mL) at 0 0C. The mixture was allowed to warm to room temperature and stir for 3 days. The solvent was evaporated under reduced pressure and the residue was triturated with ether. The resulting solid was collected, washed with diethyl ether, and dried under reduced pressure to give 0.046 g of the title compound. HRMS (ESI+) for C29H32N4O4S m/z 533.2233 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.76 (d, 2H), 7.65-7.67 (m, 2H), 7.59 (d, 2H), 7.45-7.49 (m, 2H), 7.37-7.41 (m, 1 H), 7.33 (s, 1 H), 4.41-4.69 (m, 3H), 3.45-4.04 (m, 9H), 2.95 (q, 2H), 1.42- 1.56 (m, 3H), 1.35 (t, 3H).
EXAMPLE 149
(2R)-3-({4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-phenylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol
yl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-phenylthieno[2,3-d]pyrimidine (Example 130, 0.21 g) was dissolved in 4N HCI in dioxane at O0C. The solution was then gradually warmed to room temperature and stirred for 3 hours. The mixture was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was partitioned a second time between ethyl acetate and water. The ethyl acetate was dried over MgSO4, filtered, and concentrated then purified on silica gel (3% methanol/ 97% hexanes) to give 0.075 g of the title compound. MS (ESI+) m/z 567.36 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.7-7.2 (m, 15H), 4.50 (m, 2H), 3.9-4.1 (m, 2H), 4.0 (br s, 6H), 3.7-3.8 (m, 3H).
EXAMPLE 150
(2R)-3-({4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-6-methylthieno[2,3-d]pyrimidin-2- yl}oxy) propane- 1 ,2-diol
4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{t(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-methylthieno[2,3-d]pyrimidine (Example 131 , 0.20 g) was dissolved in 4N HCI in dioxane (8 mL) and stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. -The organic layer was^separated, dried over MgSO4, filtered and concentrated. The crude residue was purified on silica gel using 5% MeOH/ 95% hexanes to give 0.07 g of the title compound. MS (ESI+) m/z 505.26 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 2.5 (s, 3H), 3.65 (m, 4H), 3.85 (b, 8H), 4.1 (t, 1 H), 4.45 (d, 2H), 6.9 (s, 1H), 7.4-7.7 (m, 9H).
EXAMPLE 151
(2R)-3-({4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-6-propylthieno[2,3-d]pyrimidin-2- yl}oxy)propane-1 ,2-diol
4-[4-(1 ,1 '-Biphenyl-4-ylcarbonyl)piperazin-1 -yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-propylthieno[2,3-d]pyrimidine (Example 132, 0.15 g) was dissolved in 4N HCI in dioxane at O0C. The solution was gradually warmed to room temperature and stirred for 8 hours. The mixture was then partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was stirred with diethyl ether and a few drops of acetonitrile from which a white solid precipitated. The solid was collected and dried to give 0.090 g of the title compound. MS (ESI+) m/z 533.37 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 1.0 (t, 3H), 1.5 (m, 2H), 2.8 (t, 2H), 3.7 (m, 2H), 3,9 (b, 8H), 4.05 (t, 1H), 4.5 (d, 2H), 6.9 (s, 1H), 7.4-7.7 (m, 9H).
EXAMPLE 152
(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
4-[4-(1 ,1'-Biphenyl-4-ylcarbonyl)piperazin-1-yl]-2-{[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}- 6-isopropylthieno[2,3-d]pyrimidine (Example 133, 0.17 g) was dissolved in 4N HCI in dioxane at 0 0C. The solution was gradually warmed to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated; The crude residue~was stirred in diethyl ether with a few drops of acetonitrile and the resulting solid was collected and dried under reduced pressure to give 0.07Og of the title compound. MS (ESI+) m/z 533.44 (M+H)+. 1H NMR (400 MHz, CD3OD) 51.34 (d, 6H), 3.2 (m, 1H), 3.7 (m, 2H), 3.95 (b, 8H), 4.1 (t, 1H), 4.5 (m, 2H), 6.9 (s, 1 H), 7.4-7.7 (m, 9H).
Additional compounds of Formula I that can be prepared in accordance with the synthetic . methods of the present invention include those compounds described in Table E.
TABLE E - Formulae
-
-
0. Biological Protocols In vitro assays
1. Inhibition of [33P]2MeS-ADP Binding to Washed Human Platelet Membranes. The ability of a test compound to bind to the P2Y12 receptor was evaluated in a platelet membrane binding assay. In this competitive binding assay, the test compound competed against a radiolabeled agonist for binding to the P2Y12 receptor, which is found on the surface of platelets. Inhibition of binding of the labeled material was measured and correlated to the amount and potency of the test compound. Data from this assay are presented in Table F. Platelet rich plasma ("PRP") was obtained from the Interstate Blood bank, Memphis, Tennessee. Platelet rich plasma was prepared from blood units collected in ACD ((prepared by (1) combining: 2.5 g sodium citrate (Sigma S-4641); 1.5 g citric acid (Sigma C-0706); and, 2.0 g dextrose (Sigma G-7528); (2) bringing pH to 4.5; and (3) adding water to bring volume to 100 ml.) and using the light spin protocol; this protocol involves centrifugation at room temperature for approximately 20 minutes at speeds up to 160xg. Platelet rich plasma is supplied in units of approximately 200 ml. Each unit is distributed into four 50 ml. polypropylene conical tubes for centrifugation. Blood from each donor is maintained separately.
The 50 ml_ tubes were centrifuged for 15 minutes at 1100 rpm in Sorvall RT6000D (with H1000B rotor). Internal centrifuge temperature was maintained at approximately room temperature (22- 240C). This spin pelleted cellular components remaining from the PRP preparation. The supernatant was decanted into fresh 5O mL tubes. To avoid carry over of cellular components following the room temperature centrifugation, approximately 5 ml_ of PRP was left in the tube and discarded. The tubes were capped and inverted 2-3 times and allowed to stand at room temperature for at least 15 minutes following inversion. Optionally, a Coulter Counter may be used to count platelets from the resting samples during the resting phase. Normal human platelet counts are expected to range from 200,000 to 400,000 per μl_ of PRP supernatant.
The 50 mL tubes containing PRP supernatant were centrifuged for 15 minutes at 2300-2400 rpm to loosely pellet the platelets. The supernatant from this spin was decanted immediately into a clean cell culture bottle (Corning bottle) and saved in case further centrifugation was needed. The pellet of each tube was resuspended in 2-4 mL of Wash buffer (pH 6.5) (1 L prepared new daily - 134 mM NaCI (Sigma S-5150); 3 mM KCI (Sigma P-9333); 1 mM CaCI2 (JT Baker 1311- 01); 2 mM MgCI2 (Sigma M-2670); 5 mM glucose (EM 4074-2); 0.3 mM NaH2PO4 (Sigma S- 9638)/12 mM NaHCO3 (JT Baker 3506-01); 5 mM HEPES pH 7.4 (Gibco 12379-012); 0.35% BSA (Sigma A-7906); 330 mg Heparin (bovine lung, Sigma H-4898); and 30 mL of ACD) by repeated gentle aspiration using disposable polypropylene sample pipettes. Wash buffer (pH 6.5) was added to each tube to bring the volume to approximately 40 mL Each tube was incubated for at least 15 minutes at 370C. The tubes were then centrifuged again for 15 minutes at 2300-2400 rpm to loosely pellet the platelets. The supernatant was decanted and discarded. The pellet was resuspended in 2-4 mL of Assay buffer (pH 7.4) (1 L volume - 134 mM NaCI; 3 mM KCI; 1 mM CaCI2; 2 mM MgCI2; 5 mM glucose; 0.3 mM NaH2PCyi2 mM NaHCO3; 5 mM HEPES pH 7.4; and 0.35% BSA) by repeated aspiration using disposable polypropylene sample pipettes. Tubes were combined and gently swirled to mix only when ail pellets were successfully resuspended; pellets that did not resuspend or contained aggregates were not combined.
The pooled platelet preparation was counted using a Coulter Counter. The final concentration of platelets was brought to 1 x 106 per μL using Assay buffer pH 7.4. The platelets were rested for a minimum of 45 minutes at 370C before use in the assay. In one embodiment, the compounds were tested in 96-well microtiter filterplates (Millipore
Multiscreen-FB opaque plates, #MAFBNOB50). These plates were used in the assay and pre- wet with 50 μL of Assay buffer pH 7.4 then filtered through completely with a Millipore plate vacuum. Next, 50 μL of platelet suspension was placed into 96-well filterplates. 5 μL of 2MeS- ADP (100 μM working stock concentration to give final concentration 5 μM in well) and 20 μL Assay buffer were added to background control wells. 25 μl Assay buffer were added to set of wells for total binding.
25 μL of 4X concentrated compound were added in duplicate to the 96-well filterplates. Next, 25 μL [33P]2MeS-ADP (Perkin Elmer NEN custom synthesis, specific activity ~2100Ci/mmol) was added to all wells. (1.6 nM working stock concentration to give 0.4 nM final concentration in well). The mixture was incubated for 60 minutes at room temperature and agitated with gentle shaking. The reaction was stopped by washing the 96-well filterplate three times with 100 μl/well of Cold Wash buffer (1 L volume - 134 mM NaCI; 10 mM Hepes pH 7.4, stored at 40C) on a plate vacuum. The plate was disassembled and allowed to air dry overnight with the filter side up. The filter plates were snapped into adapter plates and 0.1 mL of Microscint 20 Scintillation Fluid (Perkin Elmer # 6013621 ) was added to each well. The top of the filterplate was sealed with plastic plate covers. The sealed filterplate was agitated for 30 minutes at room temperature. A Packard TopCount Microplate Scintillation Counter was used to measure counts. The binding of compound is expressed as a % binding decrease of the ADP samples after correcting for changes in unaggregated control samples.
2. Inhibition of Human Platelet Aggregation
The ability of a test compound to bind to the P2Y12 receptor was evaluated in a platelet aggregation assay. In this functional assay, the test compound competed against an agonist for binding to the P2Y12 receptor, which is found on the surface of platelets. Inhibition of platelet aggregation was measured using standard techniques. Data from this assay are presented in Table F.
As an alternative to the binding assay which measures a candidate compound's ability to bind to the P2Y12 receptor, an assay may be used that measures the effect of the candidate compound on cellular function. The candidate compound competes with ADP, a known agonist, for binding at P2Y12. ADP is sufficient to induce platelet aggregation; the presence of an effective candidate compound inhibits aggregation. The inhibition of platelet aggregation is measured using standard techniques. Whole blood was collected by Pfizer medical personnel from volunteers (100 ml. per volunteer) in 20 mL syringes containing 2 ml. of buffered Citrate. In one embodiment, buffered Citrate is
0.105 M Citrate: 0.0840 M Na3-citrate and 0.0210 M citric acid. In another embodiment, buffered Citrate is 0.109 M Citrate: 0.0945 M Na3-citrate and 0.0175 M citric acid. The contents of the syringes were expelled into two 50 mL polypropylene conical tubes. Blood was combined only when collected from a single donor. The 50 mL tubes were centrifuged for 15 minutes at 1100 rpm in Sorvall RT6000D (with H1000B rotor). The internal centrifuges temperature was maintained between 22-240C and was operating without using the centrifuge brake. This spin pelleted cellular components remaining from the PRP preparation. The PRP layer was collected from each tube and set aside. The supernatant was decanted into fresh 50 mL tubes. To avoid carry over of cellular components following the room temperature centrifugation, approximately 5 mL of PRP was left in the tube and discarded.
The 50 mL tubes were placed back into the centrifuge and spun for 15 minutes at 2800-3000 rpm (with the brake on). This pelleted out most particulate blood constituents remaining, leaving a layer of Platelet Poor Plasma ("PPP"). The PPP was collected and the platelet concentration determined using a Coulter Counter. The PRP layer, previously set aside, was diluted with PPP to a final concentration of approximately 330,000 platelets/μl with the PPP. The final preparation was split into multiple 50 mL conical tubes, each filled with only 25-30 mL of diluted PRP prep. In one embodiment, the tube was filled with 5%C02/95%02 gas, to maintain the pH of the prep. Each tube was tightly capped and stored at room temperature. The human platelet aggregation assay is performed is performed in 96-well plate using microtiter plate reader (SpectraMax Plus 384 with SoftMax Pro software from Molecular Devices). The instrument settings include: Absorbance at 626 nm and run time at 15 minutes with readings in 1- minute intervals and 45 seconds shaking between readings.
The reaction is incubated at 370C. First 18 μl of test compound at 10x final concentration in 5% DMSO is mixed with 144 μl fresh PRP for 30 seconds and incubated at 370C for 5 minutes. Following that incubation period, 18 μl of 200 μM ADP is added to the reaction mix. This addition of ADP is sufficient to induce aggregation in the absence of an inhibitor. Results of the assay are expressed as % inhibition, and are calculated using absorbance values at 15 minutes.
3. Human P2Y12 Recombinant Cell Membrane Binding Assay with 33P 2MeS-ADP. The ability of a test compound to bind to the P2Y12 receptor was~evaluated in a recombinant cell membrane binding assay. In this competitive binding assay, the test compound competed against a radiolabeled agonist for binding to the P2Y12 receptor, expressed on the cell membrane. Inhibition of binding of the labeled material was measured and correlated to the amount and potency of the test compound. Data from this assay are presented in Table F. This binding assay is a modification of the procedure in Takasaki, J. et. al, MoI. Pharmacol., 2001 , VoI. 60, pg. 432.
HEK cells were transfected with the pDONR201 P2Y12 vector and cultured in MEM with GlutaMAX I, Earle's salts, 25 mM HEPES (Gibco # 42360-032) containing 10% dialyzed FBS (Gibco # 26400-044), 100 μM nonessential amino acids (Gibco # 11140-050), 1 mM sodium pyruvate (Gibco # 11360-070), 0.05% geneticin (Gibco #10131-027), 3 μg/mL blasticidin (Fluka brand from Sigma # 15205), and 0.5 μg/mL puromycin (Sigma # P-8833). Confluent cells were washed once with cold DPBS (Gibco # 14190-136). Fresh DPBS was added and the cells were scraped and centrifuged at 500 x g for 5 minutes at 40C. The cell pellets were resuspended in TEE buffer (25 mM Tris, 5 mM EDTA, 5 mM EGTA) containing 1 protease inhibitor cocktail tablet (Roche # 1 873 580) per 50 ml_ (called TEE + Complete) and can be flash frozen at this point.
In one embodiment, frozen cell pellets were used to prepare the membranes. In that embodiment, the frozen cell pellets were thawed on ice. In another embodiment, cell pellets may be used without flash freezing before moving on to the next step.
Cell pellets were resuspended in TEE buffer + Complete and homogenized in a glass dounce for 12 strokes. The cell suspension was centrifuged at 500 x g for 5 minutes at 40C. The supernatant was saved and centrifuged at 20,000 x g for 20 minutes at 40C. This supernatant was discarded and the cell pellet resuspended in TEE buffer + Complete and homogenized in a glass dounce for 12 strokes. This suspension was centrifuged at 20,000 x g for 20 minutes at 4 0C and the supernatant discarded. The pellet was resuspended in assay buffer (50 mM Tris, 100 mM NaCI, 1 mM EDTA) containing one protease inhibitor cocktail tablet per 50 mL, and can be flash frozen as 1 mL aliquots at this point. Dry compounds were diluted as 10 mM DMSO stocks and tested in a seven-point, three-fold dilution series run in triplicate beginning at 10 μM, final concentration. A 1 mM DMSO intermediate stock was made in a dilution plate and from this the seven dilutions were made to 5X the final concentration in assay buffer containing 0.02% BSA.
To a polypropylene assay plate (Costar # 3365) the following were added: a) 30 μL of assay buffer containing one protease inhibitor cocktail tablet per 50 mL; b) 30 μL of 1 nM 33P 2MeS- ADP made in assay buffer containing 0.02% BSA and 12.5 mg/mL ascorbic acid; 30 μL of cold 1.5 μM 2MeS-ADP for the positive control wells, or assay buffer containing 0.02% BSA and 12.5 mg/mL ascorbic acid for the negative control wells, or 5X drug dilution; and 60 μL of 1 ug/well membranes. The plates were incubated at room temperature for 1 hour. The reaction was stopped using a cell harvester to transfer the reaction mixture onto GF/B UniFilter plates (Perkin Elmer # 6005177), and washed three times with wash buffer (50 mMTris), filtering between each wash. The filter plates were dried for approximately 20 minutes in an oven at 50 0C. Back seals were adhered to the filter plates and 25 uL of Microscint 20 scintillation fluid (Perkin Elmer # 6013621) were added. The filter plates were sealed, shaken for 30 minutes, and counted on a Top Count. Data were analyzed using a four-parameter curve fit with a fixed minimum and maximum experimentally defined as the average positive and negative controls on each plate, and with a hill slope equal to one.
4. Human P2Y12 Recombinant Cell Membrane Binding Assay With Human Serum Albumin, Alpha-1 Acid Glycoprotein and 33P 2MeS-ADP
The ability of a test compound to bind to the P2Y12 receptor was evaluated in a recombinant cell membrane binding assay. In this competitive binding assay, the test compound competed against a radiolabeled agonist for binding to the P2Y12 receptor, expressed on the cell membrane. To simulate in vivo conditions, human protein is added to the assay mixture. Inhibition of binding of the labeled material was measured and correlated to the amount and potency of the test compound. Data from this assay are presented in Table F. HEK cells were transfected with the pDONR201 P2Y12 vector and cultured in MEM with GlutaMAX I, Earle's salts, 25 mM HEPES (Gibco # 42360-032) containing containing 10% dialyzed FBS (Gibco # 26400-044), 100 μM nonessential amino acids (Gibco # 11140-050), 1 mM sodium pyruvate (Gibco # 11360-070), 0.05% geneticin (Gibco #10131-027), 3 μg/mL blasticidin (Fluka brand from Sigma # 15205), and 0.5 μg/mL puromycin (Sigma # P-8833). Confluent cells were washed once with cold DPBS (Gibco # 14190-136). Fresh DPBS was added and the cells were scraped and centrifuged at 500 x g for 5 minutes at 4 0C. The cell pellets were resuspended in TEE buffer (25 mM Tris, 5 mM EDTA, 5 mM EGTA) containing 1 protease inhibitor cocktail tablet (Roche # 1 873 580) per 50 mL (called TEE + Complete) and can be flash frozen at this point.
In one embodiment, frozen cell pellets were used to prepare the membranes. In that embodiment, the frozen cell pellets were thawed on ice. In another embodiment, cell pellets may be used without flash freezing before moving on to the next step. Cell pellets were resuspended in TEE buffer + Complete and homogenized in a glass dounce for 12 strokes. The cell suspension was centrifuged at 500 x g for 5 minutes at 4 0C. The supernatant was saved and centrifuged at 20,000 x g for 20 minutes at 40C. This supernatant was discarded and the cell pellet resuspended in TEE buffer + Complete and homogenized in a glass dounce for 12 strokes. This suspension was centrifuged at 20,000 x g for 20 minutes at 4 0C and the supernatant discarded. The pellet was resuspended in assay buffer (50 mM Tris, 100 mM NaCI, 1 mM EDTA) containing one protease inhibitor cocktail tablet per 50 mL, and can be flash frozen as 1 mL aliquots at this point.
Dry compounds were diluted as 10 mM DMSO stocks and tested in a seven-point, three-fold dilution series run in triplicate beginning at 10 μM, final concentration. A 1 mM DMSO intermediate stock was made in a dilution plate and from this the seven "dilutions-were made to 5X the final concentration in assay buffer containing 0.02% BSA.
To a polypropylene assay plate (Costar # 3365)"the following were added: a) 30 μL of assay buffer containing one protease inhibitor cocktail tablet per 50 mL; b) 30 μL of 1 nM 33P 2MeS- ADP made in assay buffer containing 0.02% BSA and 12.5 mg/mL ascorbic acid; c) 30 μL of cold 1.5 μM 2MeS-ADP for the positive control wells, or assay buffer containing 0.02% BSA and 12.5 mg/mL ascorbic acid for the negative control wells, or 5X drug dilution; and d) 60 μL of 1 ug/well membranes containing 0.875% human serum albumin (Sigma # A-3782) and 0.0375% alpha-1 acid glycoprotein (Sigma # G-9885). The plates were incubated at room temperature for 1 hour. The reaction was stopped using a cell harvester to transfer the reaction mixture onto GF/B UniFilter plates (Perkin Elmer # 6005177), and washed three times with wash buffer (50 mM Tris), filtering between each wash. The filter plates were dried for approximately 20 minutes in an oven at 50 0C. Back seals were adhered to the filter plates and 25 uL of Microscint 20 scintillation fluid (Perkin Elmer # 6013621) were added. The filter plates were sealed, shaken for 30 minutes, and counted on a Top Count Scintillation Counter.
Data are analyzed using a four-parameter curve fit with a fixed minimum and maximum, experimentally defined as the average positive and negative controls on each plate and with a Hill slope equal to one. The table below presents the IC50, Kj, and percent inhibition values for compounds tested in either washed human platelets membrane binding assay (assay #1 above) or recombinant cell membrane binding assay (Assay #3, above). Example number refers to the compound prepared as described in the example noted in the section Working Examples, above. The highest concentration of candidate compound tested is listed for each experimental run presented. Multiple data sets indicate multiple experimental runs completed for a given compound.
TABLE F - Data
All mentioned documents are incorporated by reference as if here written. When introducing elements of the present invention or the exemplary embodiment(s) thereof, the articles "a," "an," "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

Claims

"CLAIMS What is claimed is:
1. A compound, or a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula I:
Formula
wherein:
A1, A2, A3, A4, A5, A6, A7 and A8 are independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
R2 is selected from the group consisting of -C(O)R2a, -C(S)R2a, -C(O)OR28, -C(O)NR23R2"; -C(S)NR2aR2b, -R2c1 and -R2c2 wherein:
R2a and R2b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2a and R2b 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, -CN, =0, =S, -NO2, -SR2d, -R2d, -C(0)R2d, -C(S)R2d, - C(O)OR2d ,
-C(S)0R2d , -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -OR2d, -OC(O)R2d, -0C(S)R2d, -0C(0)0R2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d, -S(O)2NR2dR2e, and -SC(O)R2d;
R2c1 is CrCe-alkyl, wherein the R201 CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -Cl, -Br, -I, -CN, =0, =S, -NO2, -SR2d, -C(0)R2d, -C(S)R2d, " ^C(O)OR2d , -C(S)OR2d~C(O)SR2d, -C(O)NR2dR2e,~C(S)NR2dR2e, -OR2dFθC(O)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d, - S(O)2NR2dR2e, and -SC(O)R2d; wherein the alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents of the R2c1 C1-
C6-alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R29, -SR29, -C(O)R29, -C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR29R211, -C(O)OC(O)R29, -C(O)SC(O)R29, -0R2g, -OC(O)R29, -OC(S)R29, -OC(O)OR29, -OC(O)NR29R211, -OC(S)NR29R211, -NR29R2h, -NR2gC(O)R2h, -NR29C(S)R211, -NR2gC(O)OR2h,
-NR29C(S)OR211, -NR29S(O)2R211, -NR2gC(O)NR2hR2i, -S(O)pR2g, -S(O)2N R2gR2h, and -SC(O)R29; R2c2 is selected from the group consisting of C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein the R2c2 C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halogen, -CN, =0, =S, -SR2d, -NO2, -C(0)R2d, -C(S)R2d, -C(O)OR2V C(S)0R2d ,
-C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -0R2d, -0C(0)R2d, -OC(S)R2d, -0C(0)0R2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d, -S(O)2NR2dR2e, and -SC(0)R2d; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents of the R2c2 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R2g, - SR2g, -C(O)R29, -C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR29R211, -C(O)OC(O)R29, - C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR2g, -OC(O)NR2gR2h, -OC(S)N R2gR2h, - NR2gR2h, -NR2gC(O)R2h, -NR2gC(S)R2h, -NR29C(O)OR2h, -NR2gC(S)OR2h, -NR2gS(O)2R2h, -NR29C(O)NR2hR2i, -S(O)PR29, -S(O)2NR2gR2h, and -SC(O)R29; n is 1 or 2; R2d, R2θ and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2d, R2e and R2f 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, -CN, =0, =S, -NO2, -R29, -SR2g, -C(O)R29, -C(S)R29,
-C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29, -C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR29, -OC(O)NR2gR2h, -OC(S)NR2gR2h, - NR2gR2h, -NR29C(O)R211, -NR2gC(S)R2h, -NR2gC(O)OR2h, -NR2gC(S)OR2h, -NR2gS(O)2R2h, -NR29C(O)NR211R21, -S(O)pR2g, -S(O)2NR2gR2h, and -SC(O)R29; p is 1 or 2; R29, R2h and R2i are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2Ql R2h and R2' 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 R2m;
R2m is selected from the group consisting of -CN, -NO2, -NH2, =0, =S, -SR2", alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C(O)R2n, -C(S)R2", -C(O)OR2" , -C(S)OR2" , -C(O)SR2", -C(O)NR211R20, -C(S)NR20R20, -OR2", -OC(O)R2", -OC(S)R2", -OC(O)OR2", -OC(O)NR20R20, -OC(S)NR20R20, -NR2"R20, -NR2nC(O)R2°, -NR2nC(S)R20, -NR2"C(O)OR20, -NR2nC(S)OR20, -NR2nS(O)2R2°, -NR2"C(O)NR2oR2p, -S(0)qR2", -S(O)2NR2"R20, and -SC(O)R2"; q is 1 or 2;
R2", R20 and R2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2m, R2", R20 and R2p alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -SR2q, -R2q, -C(0)RZq,
-C(S)R2q,
-C(0)0R2q , -C(S)OR2q , -C(O)SR2q, -C(O)NR2qR2r, -C(S)NR2qR2r, -C(0)0C(0)R2q, -C(0)SC(0)R2q, -OR2q, -0C(0)R2r, -OC(S)R2q,-OC(O)OR2q,-OC(O)NR2qR2r, -OC(S)NR2qR2r, -NR2qR2r, -NR2qC(O)R2r, -NR2qC(S)R2r, -NR2qC(O)OR2r, -NR2qC(S)OR2r, -NR2qS(O)2R2r, -NR2qC(O)NR2rR2s, -S(O)rR2q, -S(O)2NR2qR2r, and -SC(0)R2q; r is 1 or 2;
R2q, R2r and R2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2q' R2r and R2s 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, hydroxy, -CN, =0, =S, -NO2, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl and alkylamino; X4 is selected from the group consisting of -C(O)-, -C(S)-, -S(O)- and -S(O)2-;
R4 is selected from the group consisting of -CN, -R4a, -0R4a, -C(0)R4a, -OC(O)R43, -NR4aR4b, -NR4aC(O)R4b, -NR4aS(O)2R4b, -SR4a, and -SC(0)R4a; wherein R4a and R4b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R4a and R4b 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, haloalkyl, hydroxyalkyl, =0, =S, -CN, -
NO2, -R4d, -0R4d, -C(0)R4d, -C(O)OR4d, -C(O)NR4dR4β, -0C(0)R4d, -OC(O)NR4dR4e, -
NR4dR4e, -NR4dC(O)R4e, -NR4dS(O)2R4e, -S(O)bR4d, -SC(0)R4d, and -SC(O)NR4dR4e; b is 0, 1 or 2;
R4dand R4e are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; the R4d and R4e 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, haloalkyl, =0, =S, -NO2, -CN, -R4f, -C(O)R4f, -C(O)OR4', -C(O)NR4fR4g, - 0R4f, -OC(O)R4', -OC(O)NR4fR4g, -NR4fR49, -NR4fC(O)R4g, -NR4fS(O)2R4g, -S(O)0R4', -S(O)2NR4fR4g, -SC(O)R4', and -SC(O)NR4fR4g; c is 0, 1 or 2; R4f and R4g are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; the R4' and R4g alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, =0, =S, -CN, -NO2, -SR4h, -R4h, -C(O)R4h, -C(O)OR4h, - C(O)NR4hR4i,
-0R4h, -OC(O)R4', -OC(O)NR4hR4i, -NR4hR4i, -NR4hC(O)R4i, -NR4hS(O)2R4i, -S(O)dR4h, -S(O)2NR4hR4i, -SC(0)R4h, and -SC(O)NR4hR4i; d is 1 or 2;
R4hand R4i are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl;
R5 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, heterocyclyl, and -0R5a; R5a is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl; wherein the R5 and R5a 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;
X6 represents a bond or is -C(O)-; wherein: when X6 is -C(O)-, R6 is selected from the group consisting of halogen, -CN, -NO2, -R6a, -0R6a, -OC(O)R63, -ONR6aR6b, -OC(O)NR6aR6b, -NR6aR6b, -NR6aC(O)R6b, -NR6aS(O)2R6b, -SR6a, -SC(0)R6a and -SC(O)NR6aR6b;
(b) when X6 represents a bond, R6 is selected from the group consisting of halogen, -CN, -NO2, -R6a, -SR6a, -0R6a, -S(O)xR68, -S(O)2NR6aR6b, -OC(O)R63, -S(O)xOR63, -S(O)xOC(O)R63, -OC(O)NR6aR6b, -NR6aR6b, -NR6aC(O)R6b, -NR6aS(O)2R6b, -SR6a, -SC(O)R63, and -SC(O)NR6aR6b; x is 1 or 2;
R6a and R6b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R6a and R6b 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, -CN, =0, =S, -NO2, -SR60, -R6c, -C(O)R60,
-C(O)OR60,
-C(O)NR6cR6d, -C(O)SR60, -OR60, -OC(O)R60, -OC(0)NR6oR6d, -NR6oR6d, -NR6cC(O)R6d, -NR60S(O)2R6d, -S(O)VR60, -S(O)2NR60R6d, -SC(O)R60, and -SC(O)NR6°R6d; v is 1 or 2; and
R60 and R6d are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, carboxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl.
2. The compound of claim 1 , wherein:
A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen; R2 is selected from the group consisting of -R2c1 and -R202; X4 is -C(O)-;
R4 is selected from the group consisting of -R4a, -0R4a, and -NR4aR4b; R4a and R4b are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R4a and R4b alkyl, cycloalkyl, aryl, and heterocyclyl substituents may be optionally substituted as provided in claim 1 ;
R5 is selected from the group consisting of hydrogen, halogen, alkyl, and -0R5a, wherein the R5 alkyl substituent may be optionally substituted as provided in claim 1 , and R5a is defined as provided in claim 1 ; and
R6 is selected from the group consisting of -R6a and -0R6a, wherein R6a is defined as provided in claim 1.
3. The compound of claim 1 , wherein: A1, A2, A3, A4, A5, A6, A7 and A8 are each hydrogen;
R2 is selected from the group consisting of -R2c1 and -R2c2;
X4 is -C(O)-;
R4 is -R4a;
R4a is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl, wherein the R4a alkyl, cycloalkyl, aryi and heterocyclyl substituents may be optionally substituted as provided in claim 1 ;
R5 is hydrogen;
R6 is selected from the group consisting of -R6a and -0R6a; and
R6a is selected from the group consisting of hydrogen, alkyl and aryl, wherein the R6a alkyl and aryl substituents may be optionally substituted as provided in claim 1.
4. A compound, or a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula II:
wherein R2 is selected from the group consisting of -R2Q1 and -R2c2; wherein R2c1 is d-Cβ-alkyl, wherein the R2c1 CrC6-alkyl substituent is substituted with one or more substituents independently selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -Cl, -Br, -I, -CN, =O, =S, -SR2d, -C(O)R2d, -C(S)R2d, -C(O)OR2d , - C(S)OR2d , -C(O)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2e, -OR2d, -OC(O)R2d, -OC(S)R2d, -OC(O)OR2d, -OC(O)NR2dR2e, -OC(S)NR2dR2e, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2e, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d, -S(O)2NR2dR2e, and -SC(O)R2d; wherein the alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl substituents of the R2c1 C1- C6-alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -R2g, -SR29, -C(O)R29, -C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29, -C(O)SC(O)R29, -0R2g, -OC(O)R29, -OC(S)R29, -OC(O)OR29, -OC(O)NR29R2h, -OC(S)NR2gR2h, -NR2gR2h, -NR2gC(O)R2h, -NR2gC(S)R2h, -NR2gC(O)OR2h, -NR2gC(S)OR2h, -NR2gS(O)2R2h, -NR2gC(O)NR2hR2i, -S(O)pR2g, -S(O)2N R2gR2h, and -SC(O)R29; R2c2 is selected from the group consisting of C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein the R2c2 C7-C20-alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, halogen, -CN, =0, =S, -NO2, -SR2d, -C(0)R2d, -C(S)R2d, -C(0)0R2d , - C(S)OR2d ,
-C(0)SR2d, -C(O)NR2dR2e, -C(S)NR2dR2β, -0R2d, -0C(0)R2d, -OC(S)R2d, -0C(0)0R2d, -OC(O)NR2dR2β, -0C(S)NR2dR2β, -NR2dR2e, -NR2dC(O)R2e, -NR2dC(S)R2e, -NR2dC(O)OR2β, -NR2dC(S)OR2e, -NR2dS(O)2R2e, -NR2dC(O)NR2eR2f, -S(O)nR2d, -S(O)2NR2dR2e, and -SC(0)R2d; "whereirrthe alkyl, alkenyl; alkynyl, cycloalkyl, aryl, and heterocyclyl substituents of the R2c2 substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN; =0, =S, -NO2, -R2g, - SR29, -C(O)R29, -C(S)R29, -C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29, - C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR29, -OC(O)NR2gR2h, -OC(S)NR2gR2h, - NR2gR2h, -NR29C(O)R2h, -NR2gC(S)R2h, -NR2gC(O)OR2h, -NR2gC(S)OR2h, -NR2gS(O)2R2h, -NR29C(O)NR2hR2i, -S(O)pR2g, -S(O)2NR2gR2h, and -SC(O)R29; n is 1 or 2; R2d, R2e and R2f are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2d, R2e and R2f 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, -CN, =0, =S, -NO2, -R2g, -SR2g, -C(O)R29, -C(S)R29,
-C(O)OR29 , -C(S)OR29 , -C(O)SR29, -C(O)NR2gR2h, -C(S)NR2gR2h, -C(O)OC(O)R29, -C(O)SC(O)R29, -OR29, -OC(O)R29, -OC(S)R2g,-OC(O)OR29, -OC(O)NR2gR2h, -OC(S)NR2gR2h, - NR2gR2h, -NR2gC(O)R2h, -NR2gC(S)R2h, -NR2gC(O)OR2h, -NR2gC(S)OR2h, -NR2gS(O)2R2h, -NR29C(O)NR211R21, -S(O)pR29, -S(O)2N R2gR2h, and -SC(O)R2g; p is 1 or 2;
R2g, R2h and R2' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2g' R2h and R2' 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 R2m;
R2m is selected from the group consisting of -CN, -NO2, -NH2, =0, =S, -SR2π, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C(O)R2", -C(S)R2", -C(O)OR2" , -C(S)OR2"
-C(O)SR2", -C(O)NR20R20, -C(S)NR20R20, -0R2n, -OC(O)R2", -OC(S)R2", -OC(O)OR2", -OC(O)NR2nR20, -OC(S)NR2nR20, -NR2nR20, -NR2"C(O)R20, -NR2nC(S)R2°, -NR211C(O)OR20, -NR20C(S)OR20, -NR20S(O)2R20, -NR2nC(O)NR2oR2p, -S(O)qR2°, -S(O)2NR20R20, and -SC(O)R2"; q is 1 or 2;
R2", R20 and R2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2m, R2", R20 and R2p alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, =0, =S, -NO2, -SR2q, -R2q, -C(O)R2q, -C(S)R2q, -C(0)0R2q , -C(S)OR2q , -C(O)SR2q, -C(O)N R2qR2r, -C(S)NR2qR2r, -OR2q, -0C(0)R2r, -OC(S)R2q,-OC(O)OR2q,-OC(O)NR2qR2r, -OC(S)NR2qR2r, -NR2qR2r, -NR2qC(O)R2r, -NR2qC(S)R2r, -NR2qC(O)OR2r, -NR2qC(S)OR2r, -NR2qS(O)2R2r, -NR2qC(O)NR2rR2s, -S(O)rR2q, -S(O)2NR2qR2r, and -SC(O)R2"; r is 1 or 2; R2q, R2r and R2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl; wherein the R2q' R2r and R2s 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, hydroxy, -CN, =0, =S, -SH, -NO2, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkylamino and alkoxycarbonyl;
R4 is selected from the group consisting of -R4i, -OR4', and -NR4)R4k; wherein R4' and R4k are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocycloxyalkyl, aryloxyaryl, heterocycloxyheterocyclyl, aryloxyheterocyclyl, heterocycloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonyl(aryl)aminoalkyl, and heterocyclylcarbonyl(aryl)aminoalkyl; wherein the R4' and R4k substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyalkyl, =0, =S, -NO2, -CN, -R41, -SR41, -OR41, -C(O)R4', -C(O)OR41, -C(O)NR4lR4m, -OC(O)R41, -ONR41R4"1, -NR4lR4m, -NR4lC(O)R4m, -NR4lS(O)2R4m, -S(O)bR41, -SC(O)R41 and -SC(O)NR41R4"1; b is 1 or 2;
R4' and R4m are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy and haloalkoxy;
X6 represents a bond or is -C(O)-; wherein:
(a) when X6 is -C(O)-, R6 is selected from the group consisting of -R6a and -0R6a;
(b) when X6 represents a bond, R6 is selected from the group consisting of halogen, -R6a and -0R6a; R6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl; wherein: the R6a alkyl, cycloalkyl and aryl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, =0, =S, -CN, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl and heterocyclyl.
5. — The compound of claim 4, wherein R5 is hydrogen; X6 represents a bond; and R6 is -R6a, and wherein R6a is unsubstituted alkyl.
6. The compound of claim 4, wherein R4 is -R4' or -OR4i; wherein R41 is selected from the group consisting of alkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl; and wherein the R41 substituents may be optionally substituted as provided in claim 4.
7. The compound of claim 34, wherein R4 is -R4J or -OR4'; wherein R4) is selected from the group consisting of (Ci-C6)-alkyl, (C3-C10)-aryl, (C3-C14)- heterocyclyl, (C3-C10)-aryl -(CrC6)-alkyl, (C3-C14)-heterocyclyl-(CrC6)-alkyl, (C3-C10)-aryl-(C3-C6)- cycloalkyl, (C3-C6)-cycloalkyl-(C3-C10)-aryl, (C3-C10)-aryl-(C3-C14)-heterocyclyl, (C3-C10)-aryl-O- (C3-C1o)-arylI (C3-C1o)-aryl-(C3-C1o)-arylJ (C3-C14)-heterocyclyl-0-(C3-C1o)-aryl> (C3-C1o)-aryl-C(0)- (C3-C10)-aryl, wherein the R4' substituents may be optionally substituted as provided in claim 4.
8. The compound of claim 34, wherein R4 is -R4' or -OR4'; wherein R4Ms 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, oxadiazolyl, thiophenyl, thiazolyl, thiadiazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, morpholinyl, dioxanyl, tetrahydro-2H-pyranyl, 2H- pyranyl, 4H-pyranyl, thiomorpholinyl, indolyl, dihydrobenzofuranyl, quinolinyl and fluorenyl; and wherein the R4] substituents may be optionally substituted as provided in claim 4.
9. A compound, or a pharmaceutically acceptable salt of the compound, wherein the compound has the structure of Formula III:
wherein R2 is selected from the group consisting of alkyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, alkoxyalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyi, alkylaminocarbonylalkyl, aryiaminocarbonylalkyl and aminocarbonylcycloalkyl; wherein the R2 alkyl substituent is substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, carboxy, amino, alkylamino, alkoxy, and aminocarbonyl; and wherein the R2 carboxyalkyl, cycloalkyl, carboxycycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, alkoxyalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyi, alkylaminocarbonylalkyl, aryiaminocarbonylalkyl and aminocarbonylcycloalkyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, carboxy, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, amino, aminoalkyl, and aminocarbonyl;
R4 is -R4i or -OR4i; wherein R4' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylam inoalkyl; wherein the R4i substituents each may be optionally substituted with one or more substituents independently selected from the group consisting of =0, -CN, halogen, alkyl, phenyl, . alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; and
R6 is hydrogen, halogen, alkyl and haloalkyl.
10. The compound of claim 9; "Wherein R2 is selected front the group consisting of hydroxyalkyl, oxoalkyl, aminoalkyl, carboxyalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylaminoalkyl and am inocarbonylalkyl; wherein the R2 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
R4 is -R4i; wherein R4' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocycloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl; wherein the R4' substituents each may be optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, aikoxycarbonyl, and aminocarbonyl; and R6 is hydrogen, halogen, alkyl and haloalkyl.
11. The compound of claim 9; wherein R2 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 R2 substituent may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, methyl methoxy and ethoxy; R4 is -R4i; wherein R4) is selected from the group consisting of R4) is selected from the group consisting of methyl, ethyl propyl, butyl, phenyl, fluorenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylphenylmethyl, diphenylethyl, phenyloxymethyl, phenyloxyethyl, phenyloxyphenyl, naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl, phenylcarbonylaminoethyl, phenylcarbonyl(phenyl)aminoethyl, thiophenylmethyl, phenyl- oxadiazolyl, oxadiazolylphenyl, thiazolylphenyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, pyridinylphenyl and pyrim idinylphenyl; wherein the R4) substituents each may be optionally substituted with one or more substituents independently selected from the group consisting of oxo, cyano, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl and aminocarbonyl; and
R6 is ethyl.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1.
13. A method of treating a platelet dependent thrombosis or a platelet dependent thrombosis-related condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , wherein the platelet dependent thrombosis or a platelet dependent thrombosis-related condition is selected from the group consisting of acute coronary syndrome; unstable angina; non Q-wave myocardial infarction; non- ST segment elevation myocardial infarction; acute myocardial infarction; deep vein thrombosis; pulmonary embolism; ischemic necrosis of tissue; atrial fibrillation; thrombotic stroke; embolic stroke; recent myocardial infarction; peripheral arterial disease; peripheral vascular disease; refractory ischemia; preeclampsia; eclampsia; acute ischemic stroke; disseminated intravascular coagulation; and thrombotic cytopenic purpura.
14. A method of treating thrombotic or restenotic complications or reocclusion in a subject, comprising administering to the subject a therapeutically-effective amount of a compound of claim 1 , wherein the thrombotic or restenotic complications or reocclusion are selected from the group consisting of angioplasty, percutaneous coronary intervention, carotid endarterectomy, post-coronary arterial bypass graft surgery, vascular graft surgery, stent placements, lower limb arterial graft, atrial fibrillation, prosthetic heart valve placement, hemodialysis and insertion of endovascular devices and prostheses.
15. A method of reducing the risk in a subject of experiencing vascular events comprising administering to the subject a therapeutically-effective amount of a compound of claim 1 , wherein the vascular events are selected from the group consisting of myocardial infarction, stable angina, coronary artery disease, ischemic stroke, transient ischemic attack and peripheral arterial disease.
EP06710294A 2005-01-26 2006-01-17 Thieno[2,3-d]pyrimidine compounds as inhibitors of adp-mediated platelets aggregation Withdrawn EP1844052A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US64734005P 2005-01-26 2005-01-26
US65933705P 2005-03-07 2005-03-07
PCT/IB2006/000172 WO2006079916A1 (en) 2005-01-26 2006-01-17 Thieno [2,3-d] pyrimidine compounds as inhibitors of adp-mediated platelets aggregation

Publications (1)

Publication Number Publication Date
EP1844052A1 true EP1844052A1 (en) 2007-10-17

Family

ID=36218343

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06710294A Withdrawn EP1844052A1 (en) 2005-01-26 2006-01-17 Thieno[2,3-d]pyrimidine compounds as inhibitors of adp-mediated platelets aggregation

Country Status (3)

Country Link
EP (1) EP1844052A1 (en)
CA (1) CA2595882A1 (en)
WO (1) WO2006079916A1 (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008290329B2 (en) 2007-08-22 2011-12-22 Astrazeneca Ab Cyclopropyl amide derivatives
CN101909631B (en) * 2007-10-25 2012-09-12 健泰科生物技术公司 Process for making thienopyrimidine compounds
TWI389913B (en) * 2008-09-08 2013-03-21 Lg Life Sciences Ltd Fused heterocyclic compound
TW201039825A (en) 2009-02-20 2010-11-16 Astrazeneca Ab Cyclopropyl amide derivatives 983
JP5647998B2 (en) * 2009-03-13 2015-01-07 カトリーケ ユニバーシテイト ルーヴェン、ケー．ユー． ルーヴェン アール アンド ディー Thiazolopyrimidine modulators as immunosuppressants
CA2788444A1 (en) 2010-02-18 2011-08-25 Astrazeneca Ab New crystalline form of a cyclopropyl benzamide derivative
GB201114212D0 (en) 2011-08-18 2011-10-05 Ucb Pharma Sa Therapeutic agents
AR090037A1 (en) 2011-11-15 2014-10-15 Xention Ltd DERIVATIVES OF TIENO AND / OR FURO-PYRIMIDINES AND PYRIDINES INHIBITORS OF THE POTASSIUM CHANNELS

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115741B2 (en) * 2001-09-06 2006-10-03 Levy Daniel E 4-thieno[2,3-D]pyrimidin-4-YL piperazine compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006079916A1 *

Also Published As

Publication number Publication date
CA2595882A1 (en) 2006-08-03
WO2006079916A1 (en) 2006-08-03

Similar Documents

Publication Publication Date Title
US20080176857A1 (en) 4-Piperazinnylthieno[2,3-d]Pyrimidine Compounds as Platelet Aggregation Inhibitors
WO2006079916A1 (en) Thieno [2,3-d] pyrimidine compounds as inhibitors of adp-mediated platelets aggregation
CA2649775C (en) Pyridine[3,4-b]pyrazinones
US6579882B2 (en) Cell adhesion-inhibiting antiinflammatory compounds
JP6259824B2 (en) Imidazopyrazine derivatives as modulators of TNF activity
US7119203B2 (en) Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors
US20080200475A1 (en) 4-Piperazinothieno[2,3-D] Pyrimidine Compounds As Platelet Aggregation Inhibitors
US20080194590A1 (en) 4-Piperazinylthieno [2,3-D] Pyrimidine Compounds as Platelet Aggregation Inhibitors
CA2646977C (en) Tetrahydro-pyrimidoazepines as modulators of trpv1
DK2654750T3 (en) HIS UNKNOWN CONDENSED PYRIDINE COMPOUNDS AS CASEIN-KINASE INHIBITORS
WO2006126081A2 (en) Pyridino [2 , 3-b] pyrazinones as pde-5 inhibitors
JP2002517396A (en) Anti-inflammatory compounds that inhibit cell adhesion
CA2608672A1 (en) Pyridine [3,4-b] pyrazinones as pde-5 inhibitors
EP1896483A2 (en) 4-piperazinylthieno [2, 3-d] pyrimidine compounds as platelet aggregation inhibitors
WO2007135529A2 (en) Azabenzimidazolyl compounds as mglur2 potentiators
AU2003246972A1 (en) Condensed pyridines and pyrimidines with tie2 (tek) activity
CA2530281A1 (en) Substituted tetrahydrobenzothienopyrimidinamine compounds useful for treating hyper-proliferative disorders
JP2021524475A (en) Aromatic heterocyclic compounds and their pharmaceutical compositions
WO2007020521A1 (en) Pyridoyrazinones as pde-5 inhibitors
CA2714654A1 (en) Chlorothiophene-amides as inhibitors of coagulation factors xa and thrombin
CA2682849C (en) Sulfonamides and pharmaceutical compositions thereof
WO2005061485A1 (en) Process for making substituted pyrazoles

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070827

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

17Q First examination report despatched

Effective date: 20071219

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080430