JP2008534570A - 4-piperazinylthieno [2,3-d] pyrimidine compounds as platelet aggregation inhibitors - Google Patents

Abstract

Disclosed are compounds having the structure of formula I and pharmaceutically acceptable salts thereof, wherein A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , A ⁸ , X ⁴ , X ⁶ , R ^2k , R ^2l , R ⁴ , R ⁵ and R ⁶ are defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
[Chemical 1]

Description

This application claims priority from US Provisional Patent Application No. 60 / 665,734 (March 28, 2005).

FIELD OF THE INVENTION The present invention includes a novel class of thieno [2,3-d] pyrimidine compounds (including tautomers and salts of these compounds) having the structure of formula I, and pharmaceuticals comprising compounds of formula I A composition is included. The invention also includes a method of treating a subject by administering to the subject a therapeutically effective amount of a compound of formula I. In general, these compounds totally or partially inhibit ADP-mediated platelet aggregation. The present invention further includes methods for preparing compounds of formula I and corresponding intermediates.

Background of the Invention Thrombosis is a pathological process in which platelet aggregates and / or fibrin clots occlude blood vessels. Arterial thrombosis can result in ischemic necrosis of tissue supplied by the artery. Venous thrombosis can cause edema and inflammation of tissue drained by veins. Administering a compound that inhibits platelet function to patients suffering from or susceptible to atherosclerotic cardiovascular disease, cerebrovascular disease and peripheral arterial disease to reduce the patient's risk of occlusive arterial events it can. Commercial drugs that inhibit platelet function generally belong to one to three classes of drugs that antagonize different molecular targets: (1) cyclooxygenase inhibitors, such as aspirin (see: Awtry, EH et al., Circulation, 2000, Vol. (2) glycoprotein IIb-IIIa antagonists such as tirofiban (see: Scarborough, RM 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 the use of the P2Y12 receptor antagonists ticlopidine and clopidogrel. First, both compounds selectively inhibit platelet aggregation by blocking the P2Y12 receptor, but such inhibition is irreversible and increases the risk of bleeding for the patient. Secondly, both ticlopidine and clopidogrel each have a relatively slow onset of action. Both compounds appear to be prodrugs that must first be metabolized by the liver to the corresponding active metabolite. Third, many patients are resistant to treatment with clopidogrel. Such resistance may be due, in whole or in part, to drug-drug interactions between clopidogrel and other drugs commonly administered to atherosclerotic patients. Fourth, both ticlopidine and clopidogrel are 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 being useful for the treatment of cardiovascular events such as thrombosis:
US2003 / 0153566 A1 (published 14 August 2003) describes a group of piperazine compounds as ADP receptor antagonists;
WIPO International Patent Application Publication No. WO 99/05144 A1 (published February 4, 1999) describes a group of triazolo [4,5-d] pyrimidine compounds as P2T antagonists;
WIPO International Patent Application Publication No. WO 99/36425 A1 (published July 22, 1999) describes a group of tricyclic compounds as ADP receptor antagonists;
WIPO International Patent Application Publication No. WO 01/57037 A1 (published August 9, 2001) describes a group of compounds including sulfonylureas as ADP receptor antagonists;
US 5,057,517 (issued 15 October 1991) describes a group of heteroaromatic compounds including 6-piperazinopurines as antidiabetics;
US 4,459,296 (issued July 10, 1984) describes a group of N- (benzimidazolyl, indolyl, prynyl or benzotriazolyl) -piperazine compounds as antihypertensive agents;
Humphries et al. Have described several purine compounds as selective ADP receptor antagonists in thrombotic animal models; Trends in Pharmacological Sciences, 1995, Vol. 16, pg. 179. These compounds are further described in Ingall, AH et al., Journal of Medicinal Chemistry, 1999, Vol. 42, pg. 213.

  Accordingly, there remains a need for new drug therapies for treating subjects suffering from or susceptible to conditions mediated by platelet aggregation. In particular, there remains a need for new P2Y12 antagonists with one or more properties (eg, safety profile, efficacy, or physical properties) that are improved compared to currently used P2Y12 antagonists.

SUMMARY OF THE INVENTION In one embodiment, the present invention includes a group of compounds having the structure of Formula I, including pharmaceutically acceptable salts of those compounds:

A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , A ⁸ , X ⁴ , X ⁶ , R ^2k , R ^2l , R ⁴ , R ⁵ and R ⁶ in the formula are Defined in the detailed description of the invention.
In other embodiments, the present invention includes pharmaceutical compositions comprising a compound having the structure of Formula I.

  In another aspect, the invention includes a method of treating a subject condition by administering to the subject a therapeutically effective amount of a compound having the structure of Formula I. Conditions that can be treated according to the present invention include, but are not limited to, atherosclerotic cardiovascular disease, cerebrovascular disease and peripheral arterial disease. Other conditions that can be treated according to the present invention include hypertension and angiogenesis.

In other embodiments, the invention includes a method of inhibiting platelet aggregation in a subject by administering to the subject a therapeutically effective amount of a compound having the structure of Formula I.
In other embodiments, the present invention includes methods of synthesizing compounds having the structure of Formula I.

In other embodiments, the present invention includes intermediates useful in the synthesis of compounds having the structure of Formula I.
DETAILED DESCRIPTION OF THE INVENTION This detailed description of each embodiment provides the invention to other persons skilled in the art so that others skilled in the art can apply and utilize the various forms of the invention as best suited to their particular application needs. It is only to inform the principle and its practical application. Therefore, the present invention is not limited to the embodiments described herein, and can be variously modified.

A. Abbreviations and definitions

  The term “alkyl” refers to a straight or branched chain saturated hydrocarbon substituent (ie, a substituent containing only carbon and hydrogen): in one embodiment, containing from about 1 to about 20 carbon atoms; In embodiments of from about 1 to about 12 carbon atoms; in other embodiments from about 1 to about 10 carbon atoms; in other embodiments from about 1 to about 6 carbon atoms; In other embodiments, from about 1 to about 4 carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and t-butyl), pentyl, iso-amyl, Includes hexyl.

  The term “alkenyl” refers to a straight or branched chain hydrocarbon substituent containing one or more double bonds and from about 2 to about 20 carbon atoms: in other embodiments from about 2 to about 12 In other embodiments, from about 2 to about 6 carbon atoms; in other embodiments, from about 2 to about 4 carbon atoms. Examples of alkenyl include ethenyl (also known as vinyl), allyl, propenyl (including 1-propenyl and 2-propenyl) and butenyl (including 1-butenyl, 2-butenyl and 3-butenyl). The term “alkenyl” includes substituents having “cis” and “trans” orientations, or “E” and “Z” orientations.

  The term “alkynyl” refers to a straight or branched chain hydrocarbon substituent having one or more triple bonds and from about 2 to about 20 carbon atoms: in other embodiments from about 2 to about 12 carbons. In other embodiments, from about 2 to about 6 carbon atoms; in other embodiments, from about 2 to about 4 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” refers to a methyl group substituted with phenyl, ie the structure:

  The term “carbocyclyl” refers to 3 to 14 carbon ring atoms (“ring atoms” are atoms that are bonded together to form one or more rings of a cyclic substituent). Represents a saturated cyclic (ie, “cycloalkyl”), partially saturated cyclic (ie, “cycloalkenyl”), or fully unsaturated cyclic (ie, “aryl”) hydrocarbon substituent. Carbocyclyls may be monocyclic and these generally contain 3 to 6 ring atoms. Examples of such monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. Alternatively, carbocyclyl is fused to two or three rings such as naphthalenyl, tetrahydronaphthalenyl (also known as “tetranylyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (“phenalenyl” May also be fluorenyl and decalinyl.

  The term “cycloalkyl” refers to a saturated carbocyclic substituent having from about 3 to about 14 carbon atoms. In other embodiments, the cycloalkyl substituent contains about 3 to about 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

  The term “cycloalkylalkyl” refers to an alkyl substituted with a cycloalkyl. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The term “cycloalkenyl” refers to a partially unsaturated carbocyclic substituent. Examples of cycloalkenyl include cyclobutenyl, cyclopentenyl and cyclohexenyl.
The term “aryl” refers to a carbocyclic aromatic system containing 1, 2 or 3 rings, which may be linked to each other in a pendant manner or fused together. The term “aryl” refers to aromatic substituents such as phenyl, naphthyl and anthracenyl.

The term “arylalkyl” refers to an alkyl substituted with an aryl.
In some cases, the number of carbon atoms in a hydrocarbon substituent (eg, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix “C _x -C _y- ”, where x is the substitution The minimum in the group, y is the maximum number of carbon atoms. For example, “C ₁ -C ₆ -alkyl” refers to an alkyl substituent containing from 1 to 6 carbon atoms. Further, for example, C ₃ -C ₆ -cycloalkyl represents a saturated carbocycle containing 3 to 6 carbon ring atoms.

The term “hydrogen” refers to a hydrogen substituent and may be described as —H.
The term “hydroxy” refers to —OH. When used in combination with other terms, the prefix “hydroxy” indicates that the prefixed substituent is substituted with one or more hydroxy substituents. Compounds having carbons to which one or more hydroxy substituents are attached include, for example, alcohols, enols and phenols.

  The term “hydroxyalkyl” refers to an alkyl substituted with at least one hydroxy substituent. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

The term “nitro” means —NO ₂ .
The term “cyano” (also called “nitrile”) represents —CN,

It can also be described.
The term “carbonyl” refers to —C (O),

It can also be described.
The term “amino” refers to —NH ₂ .
The term “alkylamino” refers to an amino group in which at least one alkyl chain is bonded to an amino nitrogen instead of a hydrogen atom. Examples of alkylamino substituents include: monoalkylamino, such as methylamino (exemplified by the formula —NH (CH ₃ )), which is

And dialkylamino, such as dimethylamino (exemplified by the formula —N ((CH ₃ ) ₂ ), which is

It can also be described.
The term “aminocarbonyl” refers to —C (O) —NH ₂

It can also be described.
The term “halogen” refers to fluorine (which can be described as —F), chlorine (which can be described as —Cl), bromine (which can be described as —Br), or iodine (which can be described as —I). Can represent). In one embodiment, the halogen is chlorine. In other embodiments, the halogen is fluorine.

  The prefix “halo” indicates that the prefixed substituent is substituted with one or more independently selected halogen substituents. For example, haloalkyl represents alkyl substituted with at least one halogen substituent. When one or more hydrogens are replaced with halogens, the halogens may be the same or different. Examples of haloalkyl include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoroethyl, Pentafluoroethyl, difluoropropyl, dichloropropyl and heptafluoropropyl are included. Further, for example, “haloalkoxy” represents alkoxy substituted with at least one halogen substituent. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as “perfluoromethyloxy”), and 2,2,2-trifluoroethoxy It is. It should be appreciated that when a substituent is substituted with one or more halogen substituents, the halogen substituents may be the same or different (unless otherwise stated).

The prefix “perhalo” indicates that each hydrogen substituent on the prefixed substituent is replaced with an independently selected halogen substituent. If all halogen substituents are identical, this prefix can identify the halogen substituent. For example, the term “perfluoro” means that any hydrogen substituent on the prefixed substituent is replaced with a fluorine substituent. For example, the term “perfluoroalkyl” refers to an alkyl substituent with a fluorine substituent in place of the respective hydrogen substituent. Examples of perfluoroalkyl substituents include trifluoromethyl (—CF ₃ ), perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl. Further, for example, the term “perfluoroalkoxy” refers to an alkoxy substituent in which each hydrogen substituent is replaced with a fluorine substituent. Examples of perfluoroalkoxy substituents include trifluoromethoxy (—O—CF ₃ ), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy and perfluorodecoxy.

The term “oxo” represents ═O.
The term “oxy” represents an ether substituent and can be described as —O—.
The term “alkoxy” represents an alkyl bonded to oxygen and may also be described as —OR, where R represents an alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.

The term “alkylthio” refers to —S-alkyl. For example, “methylthio” is —S—CH ₃ . Other examples of alkylthio include ethylthio, propylthio, butylthio and hexylthio.

  The term “alkylcarbonyl” refers to —C (O) -alkyl. For example, “ethylcarbonyl”

Can be described. Examples of other alkylcarbonyl include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl and hexylcarbonyl.

The term “aminoalkylcarbonyl” refers to —C (O) -alkyl-NH ₂ . For example, “aminomethylcarbonyl”

Can be described.
The term “alkoxycarbonyl” refers to —C (O) —O-alkyl. For example, “ethoxycarbonyl”

Can be described. Examples of other alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl and hexyloxycarbonyl. In other embodiments, when the carbon atom of the carbonyl is attached to the carbon atom of the second alkyl, the resulting functional group is an ester.

  The term “carbocyclylcarbonyl” refers to —C (O) -carbocyclyl. For example, “phenylcarbonyl”

Can be described. Similarly, the term “heterocyclylcarbonyl”, alone or in combination with other terms (one or more), represents —C (O) -heterocyclyl.
The term “carbocyclylalkylcarbonyl” refers to —C (O) -alkyl-carbocyclyl. For example, “Phenylethylcarbonyl”

Can be described. Similarly, the term “heterocyclylalkylcarbonyl”, alone or in combination with other terms (one or more), represents —C (O) -alkyl-heterocyclyl.

  The term “carbocyclyloxycarbonyl” refers to —C (O) —O-carbocyclyl. For example, “phenyloxycarbonyl”

Can be described.
The term “carbocyclylalkoxycarbonyl” refers to —C (O) —O-alkyl-carbocyclyl. For example, “phenylethoxycarbonyl”

Can be described.
The terms “thio” and “thia” represent a divalent sulfur atom, and such substituents may be described as —S—. For example, thioethers are indicated as “alkyl-thio-alkyl” or alkyl-S-alkyl. The term “thiol” refers to a sulfhydryl substituent and may be described as —SH.

The term “thione” stands for ═S.
The term “sulfonyl” represents —S (O) ₂ —

It can also be described. For example “alkyl-sulfonyl-alkyl” refers to alkyl-S (O) ₂ -alkyl. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl and propylsulfonyl.

The term “aminosulfonyl” refers to —S (O) ₂ —NH ₂

It can also be described.
The terms “sulfinyl” and “sulfoxide” represent —S (O) —

It can also be described. For example, “alkylsulfinylalkyl” or “alkylsulfoxide alkyl” refers to alkyl-S (O) -alkyl. Examples of the alkylsulfinyl group include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.

  The term “heterocyclyl” refers to a saturated, partially saturated or fully unsaturated ring structure containing a total of 3 to 14 ring atoms. At least one ring atom is a heteroatom (ie, oxygen, nitrogen or sulfur) and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur.

  Heterocyclyls may be monocyclic and generally contain 3 to 7 ring atoms, more typically 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Including. Examples of such monocyclic heterocyclyls include: furanyl, dihydrofuranyl, tetrahydrofuranyl, 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, azolyryl, diazothylyl Oxathiazolyl, oxadiazolyl (oxadiazolyl, 1,2,4-oxadiazolyl (referred to as “azoxymil”) ), 1,2,5-oxadiazolyl (also known as “furazanyl”), or 1,3,4-oxadiazolyl), oxatriazolyl (1,2,3,4-oxatriazolyl) Or 1,2,3,5-oxatriazolyl), dioxazolyl (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 (pyridazinyl ("" Includes pyridinyl (also known as “1,3-diazinyl” or “pyrimidyl”), or pyrazinyl (also known as “1,4-diazinyl”) , Piperazinyl, triazinyl (also known as s-triazinyl (also known as “1,3,5-triazinyl”), as-triazinyl (also known as 1,2,4-triazinyl), and v-triazinyl (“1,2 , 3-triazinyl ”), oxazinyl (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 (1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thie Nil, and diazepinyl.

  Alternatively, the heterocyclyl can include two or three rings fused together, at least one of which includes a heteroatom (eg, nitrogen, oxygen or sulfur) as a ring atom. Examples of 2-fused cyclic heterocyclyl include: indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolidinyl, purinyl, naphthyridinyl, pyridopyridinyl (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, benzooxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazo Le, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzoisoxazolyl benzoxazinyl and tetrahydroisoquinolinyl. Other examples of fused cyclic heterocyclyl include, for example, the following benzo-fused heterocyclyl: indolyl, isoindolyl (also known as “isobenzazolyl” or “ploid isoindolyl”), indoleninyl (“pro Ididodolyl "(also known as" Idoindolyl "), isoindazolyl (also known as" benzopyrazolyl "), benzazinyl (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 (“chromanyl” or "Isoku Including mannyl ”, benzothiopyranyl (also known as“ thiochromanyl ”), benzoxazolyl, indoxazinyl (also known as“ benzoisoxazolyl ”), anthranilyl, benzodioxolyl, benzodioxa Nyl, benzooxadiazolyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzothienyl (also known as “benzothiophenyl”, “thionaphthenyl” or “benzothiofuranyl”), isobenzo Thienyl (also known as “isobenzothiophenyl,” isothionaphthenyl, ”or“ isobenzothiofuranyl ”), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (1,3 , 2-Benzoxazinyl, 1,4,2-benzene Benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), benzoisoxazinyl (1,2-benzisoxazinyl or 1,4-benzoiso) Oxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenylnyl, and acridinyl.

  The term “heteroaryl” refers to an aromatic heterocyclyl containing 5 to 14 ring atoms. The heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered cyclic substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered cyclic substituents such as triazolyl, imidazolyl, 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 cyclic substituents such as benzothiofura Nyl, isobenzothiofuranyl, benzoisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6 / 6-membered condensed rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl Included.

The term “heterocyclylalkyl” refers to an alkyl substituted with a heterocyclyl.
The term “heterocycloalkyl” refers to fully saturated heterocyclyl.

  A substituent is “substitutable” if it contains at least one carbon, sulfur, oxygen or nitrogen atom bonded to one or more hydrogen atoms. For example, hydrogen, halogen and cyano do not belong to this definition.

  When a substituent is described as “substituted”, there is a non-hydrogen substituent in place of the hydrogen substituent on the carbon or nitrogen of the substituent. For example, a substituted alkyl substituent is an alkyl substituent that has at least one non-hydrogen substituent instead of a hydrogen substituent on the alkyl substituent. For example, monofluoroalkyl is alkyl substituted with one fluoro substituent and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be appreciated that when there are one or more substitutions on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise stated).

  When a substituent is described as “optionally substituted”, the substituent may be either (1) unsubstituted or (2) substituted. When it is stated that a carbon of a substituent may be substituted with one or more of the list of substituents, one or more hydrogens (if any) on that carbon are separately and / or together, It may be substituted with an optional substituent selected independently. When it is stated that a nitrogen of a substituent may be substituted with one or more of the list of substituents, each of one or more hydrogens (if any) on the nitrogen is independently selected. May be substituted with an optional substituent.

  An example of a substituent can be described as -NR'R ", where R 'and R" can form a heterocyclic ring with the nitrogen atom to which they are attached. The heterocyclic ring formed from R ′ and R ″ with the nitrogen atom to which they are attached may be partially saturated or fully saturated. In one embodiment, the heterocyclic ring is 3-7 In other embodiments, the heterocyclic ring is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, pyridyl and thiazolyl.

In this specification, the terms “substituent” and “radical, group” are used interchangeably.
When comprehensively stated that a group of substituents may be substituted with one or more of the list of substituents, the group can include: (1) Substituents that cannot be substituted; (2) Substitutable substituents that are not substituted with optional substituents and / or (3) Substitutable substituents that are substituted with one or more optional substituents .

  When a substituent is described as being optionally substituted with up to a certain number of non-hydrogen substituents, the substituent may be any of the following: (1) not substituted; or ( 2) Substitution with non-hydrogen substituents up to the specified number or up to the maximum number of substitutable positions on the substituent (whichever is less). For example, if a substituent is described as a heteroaryl that may be substituted with up to three non-hydrogen substituents, any heteroaryl having a substitutable position of less than 3 is It may be substituted with a non-hydrogen substituent only up to the same number of substitutable positions of. For example, tetrazolyl (which has only one substitutable position) may be substituted with up to one non-hydrogen substituent. Further, for example, if it is stated that the amino nitrogen may be substituted with up to two non-hydrogen substituents, if the amino nitrogen is a primary nitrogen, the nitrogen is not substituted with up to two hydrogens. It may be substituted with a group. In contrast, if the amino nitrogen is a secondary nitrogen, the nitrogen may be substituted with up to only one non-hydrogen substituent.

The prefix attached to the multi-part substituent only applies to the first part. For example, the term “alkylcycloalkyl” includes two moieties: alkyl and cycloalkyl. Thus, the C ₁ -C ₆ -alkylcycloalkyl prefix C ₁ -C ₆ -means that the alkyl moiety contains 1 to 6 carbon atoms; the prefix C ₁ -C ₆ -is cycloalkyl The part is not mentioned. Further, for example, the prefix “halo” in haloalkoxyalkyl indicates that only the alkoxy portion of the alkoxyalkyl substituent is substituted with one or more halogen substituents. Alternatively, or in addition, where halogen substitution may occur for an alkyl moiety, the substituent will be described as “halogen substituted alkoxyalkyl” rather than “haloalkoxyalkyl”. Finally, if halogen substitution can only occur on the alkyl moiety, the substituent will instead be described as “alkoxyhaloalkyl”.

  If the substituent is composed of multiple moieties, the final moiety shall be used as the point of attachment to the rest of the molecule unless otherwise indicated. For example, in the substituent A-B-C, the moiety C is bonded to the rest of the molecule. In the substituent A-B-C-D, the moiety D is attached to the rest of the molecule. Similarly, in the substituent aminocarbonylmethyl, the methyl moiety is attached to the rest of the molecule and the substituent is

It can also be described. In the substituent trifluoromethylaminocarbonyl, the carbonyl moiety is attached to the rest of the molecule and the substituent is

It can also be described.
When a substituent is described as “independently selected” from a group, each substituent is selected regardless of its order. Accordingly, each substituent may be the same as or different from other substituents (one or more).

B. Compounds The present invention includes, 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 discloses, in part, a group of compounds having the structure of Formula I and pharmaceutically acceptable salts or tautomers of the compounds:

In the formula:
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 ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl, which are independently one or more substituents selected from —R ^2m May be substituted;
R ^2m is halogen, oxo, = S, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (S) R ²ⁿ , -C (O) OR ²ⁿ , -C (S) OR ²ⁿ , -C (O) SR ²ⁿ , -C (O) NR ²ⁿ R ^2o , -C (S) NR ²ⁿ R ^2o , -OR ²ⁿ , -OC (O ) R ²ⁿ , -OC (S) R ²ⁿ , -NR ²ⁿ R ^2o , -NR ²ⁿ C (O) R ^2o , -NR ²ⁿ C (S) R ^2o , -NR ²ⁿ C (O) OR ^2o , -NR ²ⁿ C (S) OR ^2o , -NR ²ⁿ S (O) ₂ R ^2o , -NR ²ⁿ C (O) NR ^2o R ^2p , -S (O) _q R ²ⁿ , -S (O) ₂ NR ²ⁿ R ^2o And selected from the group consisting of -SC (O) R ²ⁿ ;
q is 0, 1 or 2;
R ²ⁿ , R ^2o and R ^2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In that case, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents of R ^2m , R ²ⁿ , R ^2o and R ^2p are independently halogen, cyano, nitro, oxo, = S, -R ^2q , -C (O) R ^2q , -C (S) R ^2q , -C (O) OR ^2q , -C (S) OR ^2q , -C (O) SR ^2q , -C (O) NR ^2q R ^2r , -C (S) NR ^2q R ^2r , -OR ^2q , -OC (O) R ^2r , -OC (S) R ^2q , -NR ^2q R ^2r , -NR ^2q C (O) R ^2r , -NR ^2q C (S) R ^2r , -NR ^2q C (O) OR ^2r , -NR ^2q C (S) OR ^2r , -NR ^2q S (O) ₂ R ^2r , -NR ^2q C (O) NR ^2r R ^2s , ^{_{-S (O) r R 2q,}} -S (O) 2 NR 2q R 2r and -SC (O) may be substituted with one or more substituents selected from the group consisting of R ^2q;
r is 0, 1 or 2;
R ^2q , R ^2r and R ^2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In which R ^2q , R ^2r and R ^2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are independently halogen, hydroxy, cyano, oxo, = S, -SH, nitro, alkyl Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;
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 —R ^4j , —OR ^4j and —NR ^4j R ^4k ;
R ^4j and R ^4k are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cyclo Alkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl , Aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxya Kill is selected arylcarbonyl heterocyclyl, heterocyclylcarbonyl aryl, arylcarbonylamino alkyl, heterocyclylcarbonyl aminoalkyl, from the group consisting arylcarbonylaminoalkyl and heterocyclylcarbonyl aminoalkyl;
In this case, the substituents of R ^4j and R ^4k are independently halogen, haloalkyl, hydroxyalkyl, oxo, = S, nitro, cyano, -R ^4l , -OR ^4l , -C (O) R ^4l , -C (O) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S Substituted with one or more substituents selected from the group consisting of (O) ₂ R ^4m , -S (O) _b R ^4l , -SC (O) R ^4l and -SC (O) NR ^4l R ^4m May be;
b is 0, 1 or 2;
R ^4l and R ^4m are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
In which R ^4l and R ^4m alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl substituents are independently halogen, hydroxy, cyano, oxo, ═S, nitro, —SH, amino, alkyl, Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl and alkylamino;
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) —;
(a) when X ⁶ is —C (O) —, R ⁶ is selected from the group consisting of —R ^6a and —OR ^6a ;
(b) when X ⁶ represents a bond, R ⁶ is selected from the group consisting of halogen, cyano, —R ^6a and —OR ^6a ;
R ^6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
Wherein the alkyl, cycloalkyl and aryl substituents of R ^6a are independently a group consisting of halogen, hydroxy, oxo, = S, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, carboxy, aryl and heterocyclyl. It may be substituted with one or more substituents selected from

In one embodiment of the compounds of formula (I), A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ and A ⁸ are each hydrogen. In other embodiments, A ¹ , A ² , A ⁴ , A ⁵ , A ⁶ , A ⁷ and A ⁸ are each hydrogen and A ³ is methyl. In still other embodiments, A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ and A ⁸ are each hydrogen and A ¹ is methyl.

In another embodiment of the compound of formula (I), R ⁵ is selected from the group consisting of hydrogen, halogen and alkyl, wherein the alkyl substituent of R ⁵ may be substituted as described above. In yet another embodiment, R ⁵ is selected from the group consisting of hydrogen, halogen and methyl. In yet other embodiments, R ⁵ is hydrogen.

In another embodiment of the compounds of formula (I), R ⁶ is selected from the group consisting of halogen, —R ^6a and —OR ^6a , wherein R ^6a is defined as shown in the other embodiments herein. The In one embodiment, R ⁶ is halogen. In other embodiments, R ⁶ is fluorine. In other embodiments, R ⁶ is chlorine. In other embodiments, R ⁶ is bromine. In other embodiments, R ⁶ is cyano.

In still other embodiments, X ⁶ represents a bond and R ⁶ is —R ^6a , where R ^6a is defined as shown in other embodiments herein. In still other embodiments, X ⁶ is —C (O) — and R ⁶ is —OR ^6a , wherein R ^6a is defined as set forth in claim 1. In still other embodiments, R ⁶ is selected from the group consisting of —R ^6a and —OR ^6a , wherein R ^6a is selected from the group consisting of hydrogen, alkyl, and aryl, wherein the alkyl and aryl substituents of R ^6a are , May be substituted as shown in other embodiments herein. In still other embodiments, X ⁶ represents a bond, R ⁶ is —R ^6a , R ^6a is hydrogen and alkyl, wherein the alkyl substituent of R ^6a is defined in other embodiments herein. May be substituted as shown in.

In still other embodiments, X ⁶ represents a bond, R ⁶ is —R ^6a ; R ^6a is hydrogen.
In yet another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl and phenyl. In yet another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl. In yet another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl. In yet another embodiment, X ⁶ represents a bond, R ⁶ is —R ^6a ; R ^6a is unsubstituted alkyl.

In yet another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^6a substituent Is substituted with one or more halogen substituents. In yet another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^6a substituent Is substituted with one or more fluorine substituents. In another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^6a substituent is Substituted with one or more chlorine substituents. In another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^6a substituent is Substituted with one or more bromine substituents.

In other embodiments of the compounds of formula (I), X ⁴ is —C (O) —.
In other embodiments of the compounds of formula (I), R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ; wherein R ^4j and R ^4k are independently hydrogen, Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, Heterocyclyl heterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyary , Arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclyl Selected from the group consisting of carbonylaminoalkyl; wherein the substituents of R ^4j and R ^4k may be substituted as shown in other embodiments herein.

In other embodiments of the compounds of formula (I), R ⁴ is —R ^4j ; where R ^4j is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl , Heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, Heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbo Selected from the group consisting of leheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclylcarbonylaminoalkyl Wherein R ^4j substituents are independently halogen, haloalkyl, hydroxyalkyl, oxo, ═S, nitro, cyano, —R ^4l , —OR ^4l , —C (O) R ^4l , —C (O ) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S (O ) ₂ R ^4m , —S (O) _b R ^4l , —SC (O) R ^4l and —SC (O) NR ^4l R ^4m may be substituted with one or more substituents selected from the group consisting of well; where b is 0, 1 or 2; R ^4l and R ^4m are independently hydrogen, alkyl, c Alkyl, alkenyl, selected from cycloalkyl, aryl and the group consisting of heterocyclyl; this time, alkyl of R ^4l and R ^4m, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl substituent is herein It may be substituted as shown in other embodiments.

In other embodiments of the compounds of formula (I), R ⁴ is —OR ^4j ; where R ^4j is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl , Heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, Heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbo Selected from the group consisting of leuheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclylcarbonylaminoalkyl Wherein R ^4j substituents are independently halogen, haloalkyl, hydroxyalkyl, oxo, ═S, nitro, cyano, —R ^4l , —OR ^4l , —C (O) R ^4l , —C (O ) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S (O ) ₂ R ^4m , —S (O) _b R ^4l , —SC (O) R ^4l and —SC (O) NR ^4l R ^4m may be substituted with one or more substituents selected from the group consisting of well; where b is 0, 1 or 2; R ^4l and R ^4m are independently hydrogen, alkyl, c Alkyl, alkenyl, selected from cycloalkyl, aryl and the group consisting of heterocyclyl; this time, alkyl of R ^4l and R ^4m, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl substituent is herein It may be substituted as shown in other embodiments.

In other embodiments of the compounds of formula (I), R ⁴ is —NR ^4j R ^4k ; where R ^4j and R ^4k are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cyclo Alkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl , Cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclyl From the group consisting of arylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclylcarbonylaminoalkyl Wherein R ^4j and R ^4k substituents are independently halogen, haloalkyl, hydroxyalkyl, oxo, ═S, nitro, cyano, —R ^4l , —OR ^4l , —C (O) R ^4l , -C (O) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR Substituted with one or more substituents selected from the group consisting of ^4l S (O) ₂ R ^4m , -S (O) _b R ^4l , -SC (O) R ^4l and -SC (O) NR ^4l R ^4m Where b is 0, 1 or 2; R ^4l and R ^4m are independently Selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl; wherein R ^4l and R ^4m alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl substituents are , May be substituted as shown in other embodiments herein. In other embodiments, R ^4k is hydrogen and R ^4j is as indicated above.

In other embodiments of the compounds of formula (I), R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein R 4 ^4l of alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents may be substituted as shown in other embodiments herein. In another embodiment, R ⁴ is an -R ^4j; R ^4j is phenyl, oxadiazolyl thiazolyl, pyridinyl, cyclopropyl, cyclobutyl, selected from the group consisting of methyl, ethyl and fluorenyl; this time, R ^4l substituent May be substituted as indicated in other embodiments herein. In still other embodiments, R ⁴ is —OR ^4j ; R ^4j is selected from the group consisting of methyl and ethyl, wherein the R ^4l substituent is as shown in other embodiments herein. May be substituted. In still other embodiments, R ⁴ is —NR ^4j R ^4k ; R ^4j is methyl and R ^4k is hydrogen, wherein the methyl of R ^4a is as shown in other embodiments herein. May be substituted as described.

In still other embodiments, R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl, wherein the R ^4a substituent is one or more halogen substituted Substituted with a group. In yet another embodiment, R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^4j substituent is one or more fluorine substituted Substituted with a group. In other embodiments, R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^4j substituent is one or more chlorine substituents Has been replaced by In other embodiments, R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^4a substituent is one or more bromine substituents Has been replaced by

In other embodiments of the compounds of formula (I), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated heterocyclyl, which are other embodiments herein. May be substituted as shown in. In other embodiments of the compounds of formula (I), R ^2k and R ²¹ together with the nitrogen atom to which they are attached form a fully saturated heterocyclyl, which are other embodiments herein. May be substituted as shown in.

  Another class of compounds of particular interest includes compounds having the structure of Formula II and pharmaceutically acceptable salts of the compounds:

In the formula:
R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl, which are independently one or more substituents selected from —R ^2m May be substituted;
R ^2m is halogen, oxo, = S, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (S) R ²ⁿ , -C (O) OR ²ⁿ , -C (S) OR ²ⁿ , -C (O) SR ²ⁿ , -C (O) NR ²ⁿ R ^2o , -C (S) NR ²ⁿ R ^2o , -OR ²ⁿ , -OC (O ) R ²ⁿ , -OC (S) R ²ⁿ , -NR ²ⁿ R ^2o , -NR ²ⁿ C (O) R ^2o , -NR ²ⁿ C (S) R ^2o , -NR ²ⁿ C (O) OR ^2o , -NR ²ⁿ C (S) OR ^2o , -NR ²ⁿ S (O) ₂ R ^2o , -NR ²ⁿ C (O) NR ^2o R ^2p , -S (O) _q R ²ⁿ , -S (O) ₂ NR ²ⁿ R ^2o And selected from the group consisting of -SC (O) R ²ⁿ ;
q is 0, 1 or 2;
R ²ⁿ , R ^2o and R ^2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In that case, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents of R ^2m , R ²ⁿ , R ^2o and R ^2p are independently halogen, cyano, nitro, oxo, = S, -R ^2q , -C (O) R ^2q , -C (S) R ^2q , -C (O) OR ^2q , -C (S) OR ^2q , -C (O) SR ^2q , -C (O) NR ^2q R ^2r , -C (S) NR ^2q R ^2r , -OR ^2q , -OC (O) R ^2r , -OC (S) R ^2q , -NR ^2q R ^2r , -NR ^2q C (O) R ^2r , -NR ^2q C (S) R ^2r , -NR ^2q C (O) OR ^2r , -NR ^2q C (S) OR ^2r , -NR ^2q S (O) ₂ R ^2r , -NR ^2q C (O) NR ^2r R ^2s , ^{_{-S (O) r R 2q,}} -S (O) 2 NR 2q R 2r and -SC (O) may be substituted with one or more substituents selected from the group consisting of R ^2q;
r is 0, 1 or 2;
R ^2q , R ^2r and R ^2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In which R ^2q , R ^2r and R ^2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are independently halogen, hydroxy, cyano, oxo, = S, -SH, nitro, alkyl Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;
R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ;
R ^4j and R ^4k are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cyclo Alkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl , Aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxya Kill, arylcarbonyl heterocyclyl, heterocyclylcarbonyl aryl, arylcarbonylamino alkyl, heterocyclylcarbonyl aminoalkyl, selected arylcarbonylaminoalkyl, and from the group consisting of heterocyclyl carbonyl amino alkyl;
In this case, the substituents of R ^4j and R ^4k are independently halogen, haloalkyl, hydroxyalkyl, oxo, = S, nitro, cyano, -R ^4l , -OR ^4l , -C (O) R ^4l , -C (O) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S Substituted with one or more substituents selected from the group consisting of (O) ₂ R ^4m , -S (O) _b R ^4l , -SC (O) R ^4l and -SC (O) NR ^4l R ^4m May be;
b is 0, 1 or 2;
R ^4l and R ^4m 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) —;
(a) when X ⁶ is —C (O) —, R ⁶ is selected from the group consisting of —R ^6a and —OR ^6a ;
(b) when X ⁶ represents a bond, R ⁶ is selected from the group consisting of halogen, cyano, —R ^6a and —OR ^6a ;
R ^6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
Wherein the alkyl, cycloalkyl and aryl substituents of R ^6a are independently selected from the group consisting of halogen, oxo, = S, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, carboxy, aryl and heterocyclyl. Optionally substituted with one or more substituents.

  In other embodiments, the compound of formula (II) has any of the structures shown in Table B:

In these, the heterocyclyl may be substituted as shown in other embodiments herein.
In other embodiments of the compounds of formula (II), R ⁵ is selected from the group consisting of hydrogen, halogen, alkyl, and —OR ^5a , wherein the alkyl substituent of R ⁵ is other embodiments herein. And R ^5a is defined as shown in other embodiments herein. In other embodiments, R ⁵ is selected from the group consisting of hydrogen, halogen, and alkyl, wherein the alkyl substituent of R ⁵ may be substituted as shown in other embodiments herein. In yet another embodiment, R ⁵ is selected from the group consisting of hydrogen, halogen and methyl. In yet other embodiments, R ⁵ is hydrogen.

In other embodiments of the compounds of formula (II), R ⁶ is selected from the group consisting of halogen, -R ^6a and -OR ^6a , wherein R ^6a is defined as shown in other embodiments herein. The In one embodiment, R ⁶ is halogen. In other embodiments, R ⁶ is fluorine. In other embodiments, R ⁶ is chlorine. In other embodiments, R ⁶ is bromine.

In still other embodiments of the compounds of formula (II), X ⁶ represents a bond and R ⁶ is —R ^6a , where R ^6a is defined as shown in other embodiments herein. In still other embodiments, X ⁶ is —C (O) — and R ⁶ is —OR ^6a , wherein R ^6a is defined as set forth in claim 1. In still other embodiments, 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, cycloalkyl, aryl and heterocyclyl, wherein R ^6a The alkyl, cycloalkyl, aryl and heterocyclyl substituents of may be substituted as indicated in other embodiments herein. In still other embodiments, R ⁶ is selected from the group consisting of —R ^6a and —OR ^6a , wherein R ^6a is selected from the group consisting of hydrogen, alkyl, and aryl, wherein the alkyl and aryl substituents of R ^6a are , May be substituted as shown in other embodiments herein. In still other embodiments, X ⁶ represents a bond, R ⁶ is —R ^6a ; R ^6a is hydrogen and alkyl, wherein the alkyl substituent of R ^6a is defined in other embodiments herein. May be substituted as shown in.

In yet another embodiment of formula (II), X ⁶ represents a bond, R ⁶ is —R ^6a ; R ^6a is hydrogen.
In yet another embodiment of formula (II), X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl and phenyl . In yet another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl. In yet another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl and pentyl. In other embodiments, X ⁶ represents a bond, R ⁶ is —R ^6a ; R ^6a is unsubstituted alkyl.

In yet another embodiment of formula (II), X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, The R ^6a substituent is substituted with one or more halogen substituents. In yet another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^6a substituent Is substituted with one or more fluorine substituents. In another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^6a substituent is Substituted with one or more chlorine substituents. In another embodiment, X ⁶ represents a bond and R ⁶ is —R ^6a ; R ^6a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, wherein the R ^6a substituent is Substituted with one or more bromine substituents.

In other embodiments of the compounds of formula (II), R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ; R ^4j and R ^4k are independently hydrogen, alkyl, Selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, wherein R ^4j and R ^4k alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are as defined herein. It may be substituted as shown in other embodiments. In other embodiments, R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j, and —NR ^4j R ^4k ; R ^4j is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heterocyclyl. Wherein the alkyl, cycloalkyl, aryl and heterocyclyl substituents of R ^4j may be substituted as shown in other embodiments herein; R ^4k consists of hydrogen and alkyl Selected from the group, wherein the alkyl substituent of R ^4k may be substituted as shown in other embodiments herein.

In other embodiments of the compounds of formula (II), R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ; R ^4j and R ^4k are independently hydrogen, alkyl, Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclyl Heterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, a Arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclyl Selected from the group consisting of carbonylaminoalkyl; wherein R ^4j and R ^4k alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, Heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterosa Kuryl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, Heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclylcarbonylaminoalkyl substituents May be substituted as indicated in other embodiments herein.

In other embodiments of the compounds of formula (II), R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ; R ^4j and R ^4k are independently hydrogen, alkyl, Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclyl Heterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, a Arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclyl Selected from the group consisting of carbonylaminoalkyl; wherein R ^4j and R ^4k alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, Heterocyclylcycloalkyl, cycloalkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterosa Kuryl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl, aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, Heterocyclylcarbonylheterocyclyl, aryloxyalkyl, arylcarbonylheterocyclyl, heterocyclylcarbonylaryl, arylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl, arylcarbonylaminoalkyl, and heterocyclylcarbonylaminoalkyl substituents Is independently halogen, haloalkyl, hydroxyalkyl, oxo, = S, nitro, cyano, -R ^4l , -OR ^4l , -C (O) R ^4l , -C (O) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S (O) ₂ R ^4m , -SR ^4l , -S (O) R ^4l , -S (O) ₂ R ^4l , -SC (O) R ^4l and -SC (O) NR ^4l R ^4m may be substituted with one or more substituents selected from the group consisting of R ^4m ; wherein R ^4l and R ^4m are independently hydrogen, alkyl, haloalkyl, alkenyl, Selected from the group consisting of cycloalkyl, aryl and heterocyclyl; wherein the alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl substituents of R ^4l and R ^4m are other embodiments herein. May be substituted as shown in.

In other embodiments of the compound of formula (II), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated heterocyclyl, which are other embodiments herein. May be substituted as shown in. In other embodiments of the compounds of formula (I), R ^2k and R ²¹ together with the nitrogen atom to which they are attached form a fully saturated heterocyclyl, which are other embodiments herein. May be substituted as shown in.

  Another class of compounds of particular interest includes compounds having the structure of formula III and pharmaceutically acceptable salts of the compounds:

In the formula:
R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl, which are independently one or more substituents selected from —R ^2m May be substituted;
R ^2m is halogen, oxo, = S, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (S) R ²ⁿ , -C (O) OR ²ⁿ , -C (S) OR ²ⁿ , -C (O) SR ²ⁿ , -C (O) NR ²ⁿ R ^2o , -C (S) NR ²ⁿ R ^2o , -OR ²ⁿ , -OC (O ) R ²ⁿ , -OC (S) R ²ⁿ , -NR ²ⁿ R ^2o , -NR ²ⁿ C (O) R ^2o , -NR ²ⁿ C (S) R ^2o , -NR ²ⁿ C (O) OR ^2o , -NR ²ⁿ C (S) OR ^2o , -NR ²ⁿ S (O) ₂ R ^2o , -NR ²ⁿ C (O) NR ^2o R ^2p , -S (O) _q R ²ⁿ , -S (O) ₂ NR ²ⁿ R ^2o And selected from the group consisting of -SC (O) R ²ⁿ ;
q is 0, 1 or 2;
R ²ⁿ , R ^2o and R ^2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In that case, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents of R ^2m , R ²ⁿ , R ^2o and R ^2p are independently halogen, cyano, nitro, oxo, = S, -R ^2q , -C (O) R ^2q , -C (S) R ^2q , -C (O) OR ^2q , -C (S) OR ^2q , -C (O) SR ^2q , -C (O) NR ^2q R ^2r , -C (S) NR ^2q R ^2r , -OR ^2q , -OC (O) R ^2r , -OC (S) R ^2q , -NR ^2q R ^2r , -NR ^2q C (O) R ^2r , -NR ^2q C (S) R ^2r , -NR ^2q C (O) OR ^2r , -NR ^2q C (S) OR ^2r , -NR ^2q S (O) ₂ R ^2r , -NR ^2q C (O) NR ^2r R ^2s , ^{_{-S (O) r R 2q,}} -S (O) 2 NR 2q R 2r and -SC (O) may be substituted with one or more substituents selected from the group consisting of R ^2q;
r is 0, 1 or 2;
R ^2q , R ^2r and R ^2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In which R ^2q , R ^2r and R ^2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are independently halogen, hydroxy, cyano, oxo, = S, -SH, nitro, alkyl Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;
R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ;
R ^4j and R ^4k are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cyclo Alkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl , Aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxya Kill, arylcarbonyl heterocyclyl, heterocyclylcarbonyl aryl, arylcarbonylamino alkyl, heterocyclylcarbonyl aminoalkyl, selected arylcarbonylaminoalkyl, and from the group consisting of heterocyclyl carbonyl amino alkyl;
In this case, the substituents of R ^4j and R ^4k are independently halogen, haloalkyl, hydroxyalkyl, oxo, = S, nitro, cyano, -R ^4l , -OR ^4l , -C (O) R ^4l , -C (O) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S Substituted with one or more substituents selected from the group consisting of (O) ₂ R ^4m , -S (O) _b R ^4l , -SC (O) R ^4l and -SC (O) NR ^4l R ^4m May be;
b is 0, 1 or 2;
R ^4l and R ^4m are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
R ⁶ is selected from the group consisting of halogen, cyano, —R ^6a and —OR ^6a ;
R ^6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
Wherein the alkyl, cycloalkyl and aryl substituents of R ^6a are independently selected from the group consisting of halogen, oxo, = S, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, carboxy, aryl and heterocyclyl. Optionally substituted with one or more substituents.

In other embodiments of the compounds of formula (III), R ⁶ is selected from the group consisting of —R ^6a and —OR ^6a , where R ^6a is defined as shown in other embodiments herein. In yet another embodiment of the compounds of formula (III), 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, The alkyl, cycloalkyl and aryl substituents of R ^6a may be substituted as shown in other embodiments herein.

In other embodiments of the compound of formula (III), R ^6a is alkyl, wherein the alkyl substituent of R ^6a may be substituted as shown in other embodiments herein. In yet another embodiment of the compounds of formula (III), R ^6a is unsubstituted alkyl.

In other embodiments of the compounds of formula (III), R ⁴ is —NR ^4j R ^4k ; wherein the R ^4j and R ^4k substituents are substituted as shown in other embodiments herein. Also good. In still other embodiments of the compounds of formula (III), R ^4j and R ^4k are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl, wherein R ^4j and R ^4k are alkyl and aryl May be substituted as indicated in other embodiments herein. In yet other embodiments, R ^4j and R ^4k are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, phenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylpropyl, and phenylbutyl; In that case, methyl, ethyl, propyl, butyl, phenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylpropyl, and phenylbutyl in R ^4j and R ^4k are substituted as shown in other embodiments herein. It may be.

In other embodiments of the compounds of formula (III), R ⁴ is —NR ^4j R ^4k ; wherein the R ^4j and R ^4k substituents are independently selected from the group consisting of hydrogen, phenylmethyl, and phenylphenyl. In which case the phenylmethyl and phenylphenyl of R ^4j and R ^4k may be substituted as indicated in other embodiments herein.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is alkyl, aryl, cycloalkyl, heterocyclyl, arylaryl, arylalkyl, heterocyclyl. Selected from the group consisting of alkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocyclyloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl; wherein the R ^4j substituent is , May be substituted as shown in other embodiments herein.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cyclo Alkyl, (C ₃ -C ₁₀ ) -aryl, (C ₃ -C ₁₄ ) -heterocyclyl, (C ₃ -C ₁₀ ) -aryl- (C ₁ -C 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 -C ₁₀ )- Aryl, (C ₃ -C ₁₀ ) -aryl- (C ₃ -C ₁₀ ) -aryl, (C ₃ -C ₁₄ ) -heterocyclyl-O- (C ₃ -C ₁₀ ) -aryl, (C _3- C ₁₀₎ - _{aryl--C (O) - (C 3} -C 10) - aryl, (C ₃ -C ₁₀₎ - aryl -O- (C ₁ -C ₆₎ - alkyl, and (C ₃ -C ₁₀ ) -Aryl-C (O) -amino- (C ₁ -C ₆ ) -alkyl; wherein the R ^4j substituent is as defined herein It may be substituted as shown in the embodiment.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, anthracenyl, Pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, furanyl, dioxolanyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, thiadiazolyl, diazolyl, pyridinyl, pyridinyl, pyridinyl , Triazinyl, morpholinyl, dioxanyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, thiomorpholinyl, indolyl, dihydrobenzo Ranil, is selected from the group consisting of quinolinyl and fluorenyl; case, R ^4j substituents may be optionally substituted as shown in the other embodiments herein.

In still other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is phenylphenyl, phenylnaphthyl, phenylanthracenyl, naphthylphenyl, naphthylnaphthyl, naphthyl Selected from the group consisting of anthracenyl, anthracenylphenyl, anthracenylnaphthyl and anthracenylanthracenyl; wherein the R ^4j substituent is substituted as indicated in other embodiments herein May be.

In still other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is 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, cyclopropyl Anthracenyl, cyclobutylphenyl, cyclobutylnaphthyl, cyclobutylanthracenyl, cyclopentylphenyl, cyclopentylnaphthyl, cyclopentylanthracenyl, cyclohexylphenyl, cyclohexylnaphthyl, cyclohexylanthracenyl, phenylphenylmethyl, phenylphenylethyl, phenylphenylpropyl, Selected from the group consisting of phenylphenylbutyl, diphenylmethyl, diphenylethyl, diphenylpropyl, and diphenylbutyl; wherein the R ^4j substituent may be substituted as shown in other embodiments herein.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, phenyloxybutyl, naphthyloxymethyl , Naphthyloxyethyl, naphthyloxypropyl, naphthyloxybutyl, anthracenyloxymethyl, anthracenyloxyethyl, anthracenyloxypropyl, anthracenyloxybutyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl, methoxy Naphthyl, ethoxynaphthyl, propoxynaphthyl, butoxynaphthyl, phenyloxyphenyl, phenyloxynaphthyl, phenyloxyanthracenyl, naphthyloxyphenyl, naphthyloxynaphthyl, naphthyloxyanthraceni , Anthracenyloxy phenyl is selected from the group consisting of anthracenyloxy naphthyl and anthracenyloxy anthracenyl; case, R ^4j substituent is substituted as shown in the other embodiments herein It may be.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is phenylcarbonylphenyl, phenylcarbonylnaphthyl, phenylcarbonylanthracenyl, naphthylcarbonylphenyl, naphthyl Carbonylnaphthyl, naphthylcarbonylanthracenyl, anthracenylcarbonylphenyl, anthracenylcarbonylnaphthyl, anthracenylcarbonylanthracenyl, phenylcarbonylaminomethyl, phenylcarbonylaminoethyl, phenylcarbonylaminopropyl, phenylcarbonylaminobutyl, naphthyl Carbonylaminomethyl, naphthylcarbonylaminoethyl, naphthylcarbonylaminopropyl, naphthylcarbonylaminobutyl, anthracenylcarbonylaminomethyl, anthra Cycloalkenyl carbonyl aminoethyl, anthracenyl carbonylamino propyl, anthracenyl carbonyl amino butyl, phenyl carbonylamino methyl, phenyl carbonyl aminoethyl, selected from phenylcarbonyl aminopropyl and the group consisting of phenyl carbonylamino butyl; this time, R ^4j Substituents may be substituted as shown in other embodiments herein.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is 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, imi Zolinylmethyl, imidazolinylethyl, imidazolinylpropyl, imidazolinylbutyl, imidazolylmethyl, imidazolylethyl, imidazolylpropyl, imidazolylbutyl, pyrazolidinylmethyl, pyrazolidinylethyl, pyrazolidinylpropyl, pyrazolidinini Rubutyl, pyrazolinylmethyl, pyrazolinylethyl, pyrazolinylpropyl, pyrazolinylbutyl, pyrazolylmethyl, pyrazolylethyl, pyrazolylpropyl, pyrazolylbutyl, oxazolylmethyl, oxazolylethyl, oxazolylpropyl, Oxazolylbutyl, isoxazolylmethyl, isoxazolylethyl, isoxazolylpropyl, isoxazolylbutyl, oxadiazolylmethyl, oxadiazolylethyl, oxadiazolylpropyl, Oxadiazolylbutyl, thiophenylmethyl, thiophenylethyl, thiophenylpropyl, thiophenylbutyl, thiazolylmethyl, thiazolylethyl, thiazolylpropyl, thiazolylbutyl, thiadiazolylmethyl, thiadiazolylethyl, thiadiazolylpropyl, thiadiazolyl Butyl, triazolylmethyl, triazolylethyl, triazolylpropyl, triazolylbutyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl, piperidinylbutyl, pyridinylmethyl, pyridinylethyl, pyridinylpropyl , Pyridinylbutyl, piperazinylmethyl, piperazinylethyl, piperazinylpropyl, piperazinylbutyl, pyrazinylmethyl, pyrazinylethyl, pyrazinylpropyl, pyrazinylbutyl, Midinylmethyl, 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-pyranylethyl Rupropyl, 4H-pi Nylbutyl, thiomorpholinylmethyl, thiomorpholinylethyl, thiomorpholinylpropyl, thiomorpholinylbutyl, quinolinylmethyl, quinolinylethyl, quinolinylpropyl, quinolinylbutyl, fluorenylmethyl, fluorenylethyl, fluorenyl Selected from the group consisting of propyl and fluorenylbutyl; wherein the R ^4j substituent may be substituted as indicated in other embodiments herein.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is phenylpyrrolidinyl, naphthylpyrrolidinyl, anthracenylpyrrolidinyl, phenylpyrrolyl Nyl, naphthylpyrrolinyl, anthracenylpyrrolinyl, phenylpyrrolyl, naphthylpyrrolyl, anthracenylpyrrolyl, phenyltetrahydrofuranyl, naphthyltetrahydrofuranyl, anthracenyltetrahydrofuranyl, phenylfuranyl, naphthylfuranyl, anthraceni Rufuranyl, phenyl dioxolanyl, naphthyl dioxolanyl, anthracenyl dioxolanyl, phenyl imidazolidinyl, naphthyl imidazolidinyl, anthracenyl imidazolidinyl, phenyl imidazolinyl, naphthyl imidazolyl, anthracenyl imidazolinyl The Nilimidazolyl, naphthylimidazolyl, anthracenylimidazolyl, phenylpyrazolidinyl, naphthylpyrazolidinyl, anthracenylpyrazolidinyl, phenylpyrazolinyl, naphthylpyrazolinyl, anthracenylpyrazolinyl, phenylpyrazolyl , Naphthylpyrazolyl, anthracenylpyrazolyl, phenyloxazolyl, naphthyloxazolyl, anthracenyloxazolyl, phenylisoxazolyl, naphthylisoxazolyl, anthracenylisoxazolyl, phenyl-oxadiazolyl, Naphthyl-oxadiazolyl, anthracenyl-oxadiazolyl, phenylthiophenyl, naphthylthiophenyl, anthracenylthiophenyl, phenylthiazolyl, naphthylthiazolyl, anthracenylthiazolyl, Enylthiadiazolyl, naphthylthiadiazolyl, anthracenylthiadiazolyl, phenyltriazolyl, naphthyltriazolyl, anthracenyltriazolyl, phenylpiperidinyl, naphthylpiperidinyl, anthracenylpiperidinyl, phenylpyridinyl Dinyl, naphthylpyridinyl, anthracenylpyridinyl, phenylpiperazinyl, naphthylpiperazinyl, anthracenylpiperidinyl, phenylpyrazinyl, naphthylpyrazinyl, anthracenylpyrazinyl, phenylpyrimidinyl, naphthyl Pyrimidinyl, anthracenyl pyrimidinyl, phenylpyrazinyl, naphthylpyridazinyl, anthracenylpyridazinyl, phenyltriazinyl, naphthyltriazinyl, anthracenyltriazinyl, phenylmorpholinyl, naphthy Morpholinyl, 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, anthracenylthiomol Selected from the group consisting of folinyl, phenylquinolinyl, naphthylquinolinyl, anthracenylquinolinyl, phenylfluorenyl, naphthylfluorenyl and anthracenylfluorenyl; wherein the R ^4j substituent is Substituted as indicated in other embodiments herein. It can have.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is pyrrolidinyloxyphenyl, pyrrolidinyloxynaphthyl, pyrrolidinyloxyanthracenyl Pyrrolinyloxyphenyl, pyrrolinyloxynaphthyl, pyrrolinyloxyanthracenyl, pyrrolyloxyphenyl, pyrrolyloxynaphthyl, pyrrolyloxyanthracenyl, tetrahydrofuranyloxyphenyl, tetrahydrofuranyloxynaphthyl, tetrahydrofuranyloxyanthrace Nyl, furanyloxyphenyl, furanyloxynaphthyl, furanyloxyanthracenyl, dioxolanyloxyphenyl, dioxolanyloxynaphthyl, dioxolanyloxyanthracenyl, imidazolidinyloxyphenyl, imidazolidinyloxy Phthyl, imidazolidinyloxyanthracenyl, imidazolinyloxyphenyl, imidazolinyloxynaphthyl, imidazolinyloxyanthracenyl, imidazolyloxyphenyl, imidazolyloxynaphthyl, imidazolyloxyanthracenyl, pyrazolidinyloxyphenyl , Pyrazolidinyloxynaphthyl, pyrazolidinyloxyanthracenyl, pyrazolinyloxyphenyl, pyrazolinyloxynaphthyl, pyrazolinyloxyanthracenyl, pyrazolyloxyphenyl, pyrazolyloxynaphthyl, pyrazolyloxyanthracenyl, oxazolyl Ruoxyphenyl, oxazolyloxynaphthyl, oxazolyloxyanthracenyl, isoxazolyloxyphenyl, isoxazolyloxynaphthyl, isoxa Ryloxyanthracenyl, oxadiazolyloxyphenyl, oxadiazolyloxynaphthyl, oxadiazolyloxyanthracenyl, thiophenyloxyphenyl, thiophenyloxynaphthyl, thiophenyloxyanthracenyl, thiazolyloxyphenyl, thia Zolyloxynaphthyl, thiazolyloxyanthracenyl, thiadiazolyloxyphenyl, thiadiazolyloxynaphthyl, thiadiazolyloxyanthracenyl, triazolyloxyphenyl, triazolyloxynaphthyl, triazolyloxyanthra Senyl, piperidinyloxyphenyl, piperidinyloxynaphthyl, piperidinyloxyanthracenyl, pyridinyloxyphenyl, pyridinyloxynaphthyl, pyridinyloxyanthracenyl, pipepe Razinyloxyphenyl, piperazinyloxynaphthyl, piperazinyloxyanthracenyl, pyrazinyloxyphenyl, pyrazinyloxynaphthyl, pyrazinyloxyanthracenyl, pyrimidinyloxyphenyl, pyrimidinyloxynaphthyl, pyrimidinyloxyanthra Cenyl, pyridazinyloxyphenyl, pyridazinyloxynaphthyl, pyridazinyloxyanthracenyl, triazinyloxyphenyl, triazinyloxynaphthyl, triazinyloxyanthracenyl, morpholinyloxy Phenyl, morpholinyloxynaphthyl, morpholinyloxyanthracenyl, dioxanyloxyphenyl, dioxanyloxynaphthyl, dioxanyloxyanthracenyl, tetrahydro-2H-pyranyloxyphenyl, tetrahy Dro-2H-pyranyloxynaphthyl, tetrahydro-2H-pyranyloxyanthracenyl, 2H-pyranyloxyphenyl, 2H-pyranyloxynaphthyl, 2H-pyranyloxyanthracenyl, 4H-pyranyloxyphenyl, 4H-pyranyloxynaphthyl, 4H-pyranyloxyanthracenyl, thiomorpholinyloxyphenyl, thiomorpholinyloxynaphthyl, thiomorpholinyloxyanthracenyl, quinolinyloxyphenyl, quinolinyloxynaphthyl Selected from the group consisting of quinolinyloxyanthracenyl, fluorenyloxyphenyl, fluorenyloxynaphthyl and fluorenyloxyanthracenyl; wherein the R ^4j substituent is It may be substituted as shown in the embodiment.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is pyrrolidinylphenyl, pyrrolidinylnaphthyl, pyrrolidinylanthracenyl, pyrrolinylphenyl Pyrrolinylnaphthyl, pyrrolinylanthracenyl, pyrrolylphenyl, pyrrolylnaphthyl, pyrrolylanthracenyl, tetrahydrofuranylphenyl, tetrahydrofuranylnaphthyl, tetrahydrofuranylanthracenyl, furanylphenyl, furanylnaphthyl, furanylanthracenyl , Dioxolanyl phenyl, dioxolanyl naphthyl, dioxolanyl anthracenyl, imidazolidinyl phenyl, imidazolidinyl naphthyl, imidazolidinyl anthracenyl, imidazolinyl phenyl, imidazolinyl naphthyl, imidazolinyl anthracenyl Midazolylphenyl, imidazolylnaphthyl, imidazolylanthracenyl, pyrazolidinylphenyl, pyrazolidinylnaphthyl, pyrazolidinylanthracenyl, pyrazolinylphenyl, pyrazolinylnaphthyl, pyrazolinylanthracenyl, pyrazolyl Phenyl, pyrazolyl naphthyl, pyrazolyl anthracenyl, oxazolyl phenyl, oxazolyl naphthyl, oxazolyl anthracenyl, isoxazolyl phenyl, isoxazolyl naphthyl, isoxazolyl anthracenyl, oxadiazolyl phenyl, Oxadiazolylnaphthyl, oxadiazolyl anthracenyl, thiophenylphenyl, thiophenylnaphthyl, thiophenylanthracenyl, thiazolylphenyl, thiazolylnaphthyl, thiazolyl anthracenyl, thi Asiazolylphenyl, thiadiazolyl naphthyl, thiadiazolyl anthracenyl, triazolyl phenyl, triazolyl naphthyl, triazolyl anthracenyl, piperidinyl phenyl, piperidinyl naphthyl, piperidinyl anthracenyl Dinylphenyl, pyridinylnaphthyl, pyridinylanthracenyl, piperazinylphenyl, piperazinylnaphthyl, piperazinylanthracenyl, pyrazinylphenyl, pyrazinylnaphthyl, pyrazinylanthracenyl, pyrimidinylphenyl, Pyrimidinylnaphthyl, pyrimidinylanthracenyl, pyridazinylphenyl, pyridazinylnaphthyl, pyridazinylanthracenyl, triazinylphenyl, triazinylnaphthyl, triazinylanthracenyl, morpholinylphenyl, mol Linylnaphthyl, morpholinylanthracenyl, dioxanylphenyl, dioxanylnaphthyl, dioxanylanthracenyl, tetrahydro-2H-pyranylphenyl, tetrahydro-2H-pyranylnaphthyl, tetrahydro-2H-pyranylanthracenyl, 2H -Pyranylphenyl, 2H-pyranylnaphthyl, 2H-pyranylanthracenyl, 4H-pyranylphenyl, 4H-pyranylnaphthyl, 4H-pyranylanthracenyl, thiomorpholinylphenyl, thiomorpholinylnaphthyl, thiomorpholinylanthra Selected from the group consisting of senyl, quinolinylphenyl, quinolinylnaphthyl, quinolinylanthracenyl, fluorenylphenyl, fluorenylnaphthyl and fluorenylanthracenyl; wherein the R ^4j substituent is Substituted as indicated in other embodiments herein. It may be.

In other embodiments of the compounds of formula (III), R ⁴ is —R ^4j or —OR ^4j ; where R ^4j is methyl, ethyl, propyl, butyl, cyclobutyl, phenyl, fluorenyl, phenylphenyl, phenylmethyl , Phenylethyl, phenylphenylmethyl, diphenylethyl, phenyloxymethyl, phenyloxyethyl, phenyloxyphenyl, naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl, phenylcarbonylaminoethyl, phenylcarbonylaminoethyl, thiophenylmethyl, phenyl Selected from the group consisting of -oxadiazolyl, thiazolylphenyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, pyridinylphenyl and pyrimidinylphenyl; wherein the R ^4j substituent is as defined herein It may be substituted as shown in other embodiments.

In another embodiment of the compounds of formula (III), R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ; wherein R ^4j and R ^4k are independently Selected from the group:

In that case, the substituents of R ^4j and R ^4k may be substituted as shown in other embodiments of the present specification.
In other embodiments of the compound of formula (III), the substituents for R ^4j and R ^4k are each independently oxo, cyano, chloro, bromo, fluoro, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoro It may be substituted with one or more substituents selected from the group consisting of methyl, trifluoromethylmethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxy, methoxycarbonyl and aminocarbonyl.

In other embodiments of the compounds of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl, which are as defined herein. It may be substituted as shown in other embodiments.

In other embodiments of the compounds of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; where the heterocyclyl is , Independently oxo, cyano, nitro, amino, -SR ²ⁿ , alkyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (O) OR ²ⁿ , -C (O) NR ^{2n Optionally} substituted by one or more substituents selected from the group consisting of R ^2o , —OR ²ⁿ , and —NR ²ⁿ R ^2o ; R ²ⁿ and R ^2o are independently hydrogen, alkyl, cycloalkyl , Aryl and heterocyclyl; ^wherein the alkyl, cycloalkyl, aryl and heterocyclyl substituents of R ²ⁿ and R ^2o are independently halogen, oxo, —SR ^2q , —R ^{2q , -C (O) R 2q,} -C (O) oR 2q, -C (O) NR 2q R 2r, -OR 2q, and -NR ^2q R ^2r Made may be substituted with one or more substituents selected from the group; R ^2q and R ^2r is selected from the group consisting of hydrogen and alkyl independently; this time, alkyl of R ^2q and R ^2r Substituents are independently one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, —SH, nitro, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl. May be substituted.

In another embodiment of the compound of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; where the heterocyclyl is Optionally substituted with one or more substituents selected from the group consisting of oxo, alkyl, —C (O) OR ²ⁿ , and —OR ²ⁿ ; R ²ⁿ and R ^2o are independently Selected from the group consisting of hydrogen and alkyl; wherein R ²ⁿ and R ^2o alkyl, cycloalkyl, aryl and heterocyclyl substituents may be substituted with one or more —OR ^2q substituents; R ^2q and R ^2r are independently selected from the group consisting of hydrogen and alkyl; wherein the alkyl substituents of R ^2q and R ^2r are independently halogen, hydroxy, cyano, oxo, = S,- SH, nitro, alkyl, haloalkyl, hydroxy It may be substituted with one or more substituents selected from the group consisting of sialkyl, carboxy, alkoxy and alkoxycarbonyl.

In another embodiment of the compound of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; where the heterocyclyl is Optionally substituted with one or more substituents selected from the group consisting of oxo, alkyl, —C (O) OR ²ⁿ , and —OR ²ⁿ ; R ²ⁿ and R ^2o are independently Selected from the group consisting of hydrogen and alkyl; wherein R ²ⁿ and R ^2o alkyl, cycloalkyl, aryl and heterocyclyl substituents may be substituted with one or more —OR ^2q substituents; R ^2q and R ^2r are independently selected from the group consisting of hydrogen and alkyl; wherein the alkyl substituents of R ^2q and R ^2r are independently halogen, hydroxy, cyano, oxo, = S,- SH, nitro, alkyl, haloalkyl, hydroxy It may be substituted with one or more substituents selected from the group consisting of sialkyl, carboxy, alkoxy and alkoxycarbonyl.

In other embodiments of the compounds of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; where the heterocyclyl is , Independently oxo, = S, cyano, nitro, amino, -SR ²ⁿ , alkyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (O) OR ²ⁿ , -C (O ) Optionally substituted with one or more substituents selected from the group consisting of NR ²ⁿ R ^2o , —OR ²ⁿ , and —NR ²ⁿ R ^2o ; R ²ⁿ and R ^2o are independently hydrogen, alkyl , Cycloalkyl, aryl and heterocyclyl; ^wherein the alkyl, cycloalkyl, aryl and heterocyclyl substituents of R ²ⁿ and R ^2o are independently halogen, oxo, —SR ^2q , -R ^2q , -C (O) R ^2q , -C (O) OR ^2q , -C (O) NR ^2q R ^2r , -OR ^2q , and -NR ^2q R ² optionally substituted with one or more substituents selected from the group consisting of ^r ; R ^2q and R ^2r are independently selected from the group consisting of hydrogen and alkyl; wherein R ^2q and R ^2r Wherein the alkyl substituent is independently one or more substitutions selected from the group consisting of halogen, hydroxy, cyano, oxo, = S, -SH, nitro, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl Optionally substituted with a group; R ⁴ is —R ^4j or —OR ^4j ; R ^4j is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl , Arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocyclyl Selected from the group consisting of aryloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl; wherein each R ^4j substituent is independently oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, Optionally substituted with one or more substituents selected from the group consisting of alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; R ⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl, and haloalkyl Is done.

In another embodiment of the compound of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; where the heterocyclyl is Optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, alkyl, alkylalkoxycarbonyl, hydroxyalkyl and hydroxyalkoxyalkyl; R ⁴ is —R ^4j ; R ^4j is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocyclyloxy Aryl, arylcarbonylaryl, And R ^4j substituents are each independently oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, And optionally substituted with one or more substituents selected from the group consisting of aminocarbonyl; R ⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl and haloalkyl.

In another embodiment of the compounds of formula (III), R ^2k and R ^2l, together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; this time, R ^2k and R Heterocyclyls formed from ^2l with the nitrogen atom to which they are attached are independently halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy Optionally substituted with one or more substituents selected from the group consisting of: alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of aryl and arylalkyl; this time, R ^4j substituents each independently oxo Cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl can be substituted by one or more substituents selected from the group consisting of; R ⁶ is , Hydrogen, halogen, cyano, alkyl and haloalkyl.

In other embodiments of the compounds of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated heterocyclyl; where R ^2k and R ^2l The heterocyclyl formed together with the nitrogen atom to which is attached is independently halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, may also be substituted with one or more substituents selected from hydroxy alkoxy and the group consisting of aminocarbonyl; R ⁴ is an -R ^4j; R ^4j is It is selected from aryl, aryl and the group consisting of arylalkyl; this time, each of R ^4j substituent, oxo independently, cyano, halo Emissions, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and may be substituted with one or more substituents selected from the group consisting of aminocarbonyl; R ⁶ is hydrogen , Halogen, cyano, alkyl and haloalkyl.

In other embodiments of the compounds of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a fully saturated heterocyclyl; where R ^2k and R ^2l The heterocyclyl formed together with the nitrogen atom to which is attached is independently halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, Optionally substituted with one or more substituents selected from the group consisting of alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl; R ⁴ is —R ^4j ; R ^4j is It is selected from aryl, aryl and the group consisting of arylalkyl; this time, each of R ^4j substituent, oxo independently, cyano, halo Emissions, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and may be substituted with one or more substituents selected from the group consisting of aminocarbonyl; R ⁶ is hydrogen , Halogen, cyano, alkyl and haloalkyl.

In another embodiment of the compounds of formula (III), R ^2k and R ^2l, together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; this time, R ^2k and R Heterocyclyls formed from ^2l with the nitrogen atom to which they are attached are independently halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy Optionally substituted with one or more substituents selected from the group consisting of: alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of phenyl, phenyl and phenylmethyl; this time, each of R ^4j substituent, oxo independently, Ano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl can be substituted by one or more substituents selected from the group consisting of; R ⁶ is , Hydrogen, halogen, cyano, alkyl and haloalkyl. In still other embodiments, R ^4j is phenylphenyl; wherein R ^4j phenylphenyl is independently oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxy It may be substituted with one or more substituents selected from the group consisting of carbonyl and aminocarbonyl. In yet other embodiments, R ^4j is phenylmethyl; wherein R ^4j phenylmethyl is independently oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxy It may be substituted with one or more substituents selected from the group consisting of carbonyl and aminocarbonyl.

In other embodiments of the compounds of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated heterocyclyl; where R ^2k and R ^2l The heterocyclyl formed together with the nitrogen atom to which is attached is independently halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, may also be substituted with one or more substituents selected from hydroxy alkoxy and the group consisting of aminocarbonyl; R ⁴ is an -R ^4j; R ^4j is It is selected from phenyl and the group consisting of phenylmethyl, this time, each of R ^4j substituent, oxo independently, cyano, halogen , Alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and it may be substituted with one or more substituents selected from the group consisting of aminocarbonyl; R ⁶ is hydrogen, Selected from the group consisting of halogen, cyano, alkyl and haloalkyl. In still other embodiments, R ^4j is phenylphenyl; wherein R ^4j phenylphenyl is independently oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxy It may be substituted with one or more substituents selected from the group consisting of carbonyl and aminocarbonyl. In yet other embodiments, R ^4j is phenylmethyl; wherein R ^4j phenylmethyl is independently oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxy It may be substituted with one or more substituents selected from the group consisting of carbonyl and aminocarbonyl.

In other embodiments of the compounds of formula (III), R ^2k and R ^2l together with the nitrogen atom to which they are attached form a fully saturated heterocyclyl; wherein R ^2k and R ^2l The heterocyclyl formed together with the nitrogen atom to which alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, may also be substituted with one or more substituents selected from hydroxy alkoxy and the group consisting of aminocarbonyl; R ⁴ is an -R ^4j; R ^4j is It is selected from phenyl and the group consisting of phenylmethyl, this time, each of R ^4j substituent, oxo independently, cyano, halogen , Alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and it may be substituted with one or more substituents selected from the group consisting of aminocarbonyl; R ⁶ is hydrogen, Selected from the group consisting of halogen, cyano, alkyl and haloalkyl. In still other embodiments, R ^4j is phenylphenyl; wherein R ^4j phenylphenyl is independently oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxy It may be substituted with one or more substituents selected from the group consisting of carbonyl and aminocarbonyl. In yet other embodiments, R ^4j is phenylmethyl; wherein R ^4j phenylmethyl is independently oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxy It may be substituted with one or more substituents selected from the group consisting of carbonyl and aminocarbonyl.

In other embodiments of the compounds of formula (III), the heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is morpholinyl, piperazinyl, piperazinyl and pyrrolidinyl Wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, alkyl, alkylalkoxycarbonyl, hydroxyalkyl and hydroxyalkoxyalkyl Well; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of ^arylaryl and arylalkyl; where each R ^4j substituent is independently oxo, cyano, halogen, alkyl, phenyl, alkoxy , Haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxy Carbonyl and may be substituted with one or more substituents selected from the group consisting of aminocarbonyl,; R ⁶ is hydrogen, halogen, cyano, is selected from the group consisting of alkyl and haloalkyl.

In other embodiments of the compounds of formula (III), the heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is morpholinyl, piperazinyl, piperazinyl and pyrrolidinyl Wherein the heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, alkyl, alkylalkoxycarbonyl, hydroxyalkyl and hydroxyalkoxyalkyl Well; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of phenylphenyl, phenylphenylmethyl and phenylmethyl; wherein each R ^4j substituent is independently oxo, cyano, halogen, alkyl , Phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino Carboxy, alkoxycarbonyl may be substituted with and one or more substituents selected from the group consisting of aminocarbonyl,; R ⁶ is hydrogen, is selected from the group consisting of halogen and alkyl.

In other embodiments of the compounds of formula (III), the heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is morpholinyl, piperazinyl, piperazinyl, methyl Methoxycarbonylpiperazinyl, dimethylmethoxycarbonylpiperazinyl, trimethylmethoxycarbonylpiperazinyl, methylpiperazinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxyethylpiperazinyl, hydroxyethylpiperazinyl, hydroxyethoxy ethylpiperazinyl and oxo piperazinyl is selected from the group consisting of Le; heterocyclyl formed together with R ^2k and R nitrogen atom to which they from ^2l attached is halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl , Haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and may be substituted with one or more substituents selected from the group consisting of aminocarbonyl; R ⁴ Is -R ^4j ; R ^4j is methyl, ethyl, propyl, butyl, phenyl, fluorenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylphenylmethyl, diphenylethyl, phenyloxymethyl, phenyloxyethyl, phenyloxyphenyl, Naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl, phenylcarbonylaminoethyl, thiophenylmethyl, phenyloxadiazolyl, oxadiazolylphenyl, thiazoli Phenyl, phenyl-thiazolyl, phenyl pyridinylcarbonyl, phenyl pyrimidinyl, selected from pyridinylalkyl phenyl and the group consisting of pyrimidinyl phenyl; this time, each of R ^4j substituent, oxo independently, cyano, halogen, alkyl, Optionally substituted by one or more substituents selected from the group consisting of phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl; R ⁶ is hydrogen, methyl, ethyl , Propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl.

In other embodiments of the compounds of formula (III), the heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is morpholinyl, piperazinyl, piperazinyl, methyl Methoxycarbonylpiperazinyl, dimethylmethoxycarbonylpiperazinyl, trimethylmethoxycarbonylpiperazinyl, methylpiperazinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxyethylpiperazinyl, hydroxyethylpiperazinyl, hydroxyethoxy It is selected from ethyl-piperazinyl and the group consisting of oxopiperazinyl; R ⁴ is an -R ^4j; R ^4j are methyl, ethyl propyl, butyl, phenyl, fluorenyl, phenyl, phenylmethyl, phenylethyl, phenyl Methyl Diphenylethyl, phenyloxymethyl, phenyloxyethyl, phenyloxyphenyl, naphthyloxymethyl, phenylcyclopropyl, phenylcarbonylphenyl, phenylcarbonylaminoethyl, phenylcarbonyl (phenyl) aminoethyl, thiophenylmethyl, phenyl-oxadiazolyl, oxadiazo Selected from the group consisting of arylphenyl, thiazolylphenyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, pyridinylphenyl and pyrimidinylphenyl; wherein each R ^4j substituent is independently oxo, Cyano, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy, butoxy, dimethylamino, carboxyl It may be substituted with one or more substituents selected from the group consisting of ruboxy, methoxycarbonyl and aminocarbonyl; R ⁶ is ethyl.

In other embodiments of the compounds of formula (III), the heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is morpholinyl, piperazinyl, piperazinyl, methyl Methoxycarbonylpiperazinyl, dimethylmethoxycarbonylpiperazinyl, trimethylmethoxycarbonylpiperazinyl, methylpiperazinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxyethylpiperazinyl, hydroxyethylpiperazinyl, hydroxyethoxy R ⁴ is selected from the group consisting of ethylpiperazinyl and oxopiperazinyl; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of phenylphenyl and phenylmethyl; R ⁶ is ethyl.

In other embodiments of the compound of formula (III), the heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is morpholinyl; where morpholinyl is halogen, hydroxy , Cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl Optionally substituted with one or more substituents; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of phenylphenyl and phenylmethyl; R ⁶ is ethyl.

In another embodiment of the compound of formula (III), the heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is piperazinyl; where piperazinyl is From the group consisting of halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl Optionally substituted with one or more selected substituents; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of phenylphenyl and phenylmethyl; R ⁶ is ethyl.

In another embodiment of the compounds of formula (III), heterocyclyl which is formed together with the nitrogen atom to which they are bonded they from R ^2k and R ^2l is piperazinyl (piperadinyl); case, piperazinyl, From the group consisting of halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl Optionally substituted with one or more selected substituents; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of phenylphenyl and phenylmethyl; R ⁶ is ethyl.

In another embodiment of the compound of formula (III), the heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is pyrrolidinyl; where pyrrolidinyl is halogen, hydroxy , Cyano, oxo, = S, nitro, -SH, amino, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl Optionally substituted by one or more substituents; R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of phenylphenyl and phenylmethyl; R ⁶ is ethyl.

Another embodiment of the compound of formula (I) is selected from the group consisting of the compounds listed in Table E herein.
Another embodiment of the compound of formula (I) is selected from the group consisting of:
6-ethyl-2-morpholin-4-yl-4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidine;
4- {6-ethyl-4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidin-2-yl} piperazine-1-carboxylate t-butyl;
6-ethyl-4- [4- (phenylacetyl) piperazin-1-yl] -2-piperidin-1-ylthieno [2,3-d] pyrimidine;
6-ethyl-2- (4-methylpiperazin-1-yl) -4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidine;
1- {4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} pyrrolidin-3-ol;
4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethyl-2-piperazin-1-ylthieno [2,3-d] pyrimidine;
((2S) -1- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} pyrrolidine -2-yl) methanol;
((2R) -1- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} pyrrolidine -2-yl) methanol;
2- (4- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} piperazine-1 -Yl) ethanol;
2- [2- (4- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} Piperazin-1-yl) ethoxy] ethanol; and
4- {4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} piperazin-2-one.

C. When an asymmetric carbon center is present in a compound of isomer formula (I)-(IV), the compound may exist in the form of an optical isomer (enantiomer). In one embodiment, the present invention includes enantiomers and mixtures (including racemic mixtures) of compounds of formula (I)-(IV). In other embodiments, for compounds of formulas (I)-(IV) having more than one asymmetric center, the invention includes diastereomeric compounds (individual diastereomers and mixtures thereof). If the compounds of formulas (I) to (IV) contain alkenyl groups or alkenyl moieties, geometric isomers may be formed.

D. Tautomeric forms The present invention includes tautomeric forms of the compounds of formulas (I) to (IV). If structural isomers can be interconverted via a low energy barrier, tautomeric isomerism (tautomerism) can occur. This may take the form of proton tautomerism, for example in compounds of the formula I which contain imino, keto or oxime groups, or so-called valence tautomerism in compounds which contain aromatic moieties. That is, a single compound may exhibit more than one type of isomerism. The various ratios of tautomers in solid and liquid form depend on the individual crystallization methods used to isolate the various substituents and compounds on the molecule.

E. Salts The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, the salt of the compound may be advantageous because of one or more physical properties of the salt, such as high pharmaceutical stability at various temperatures and humidity, or desirable solubility in water or oil. is there. Optionally, a salt of the compound can be used as an aid in the isolation, purification and / or dissolution of the compound.

  If the salt is to be administered to a patient (eg, not for use in an in vitro concept), examples of salts are pharmaceutically acceptable. The term “pharmaceutically acceptable” refers to a compound of formula (I)-(IV) and an acid whose anion is generally considered suitable for human consumption, or its cation is generally suitable for human consumption. Represents a salt prepared by admixing a possible base. Pharmaceutically acceptable salts are particularly useful as products of the process of the present invention because of their high water solubility compared to the parent compound. For use in medicine, the salts of the compounds of the present invention are non-toxic "pharmaceutically acceptable salts". Salts included in the term “pharmaceutically acceptable salts” are referred to as non-toxic salts of the compounds of the present invention. These are generally prepared by reacting the free base with a suitable organic or inorganic acid.

  Where appropriate pharmaceutically acceptable acid addition salts of the compounds of the present invention are possible, they include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, Nitric acid, carbonic acid, sulfonic acid and sulfuric acid, and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, Included are those derived from malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid and trifluoroacetic acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic acids, carboxylic acid and sulfonic acid class organic acids.

  Specific examples of suitable organic acids generally include: acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactic acid Salt, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, mesylate, Stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, Toluenesulfonate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid , Β-hydroxybutyric acid, galactrate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate Salt, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectate, 3-phenylpropionate, picrate, pivalate, thiocyanate , Tosylate and undecanoate.

  In other embodiments, examples of suitable addition salts formed include: acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / Sulfate, borate, camsylate, citrate, edicylate, esylate, formate, fumarate, glucoceptate, gluconate, glucuronate, hexafluorophosphate, hibenzic acid Salt, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, nitrate, orotate, oxalate, palmitic acid Salts, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, saccharates, stearates, succinates, tartrate, tosylates and trifluoroacetates. In other embodiments, representative salts include benzene sulfonate, hydrobromide, and hydrochloride.

  In addition, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; Salts formed with various organic ligands, such as quaternary ammonium salts are included. In other embodiments, the base salt is formed from a base that forms a non-toxic salt, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and Zinc salts are included.

Organic salts are secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and Formed from procaine. Groups containing basic nitrogen can be substituted with halogenated lower alkyl (C ₁ -C ₆ ) (eg, chloride, bromide and methyl iodide, ethyl, propyl and butyl), dialkyl sulfate (eg, dimethyl sulfate, diethyl, dibutyl and diamyl) Can be quaternized with reagents such as long chain halides (eg decyl chloride, bromide and iodide, lauryl, myristyl and stearyl), arylalkyl halides (eg benzyl bromide and phenethyl bromide).

In one embodiment, acid and base half salts, such as hemisulfate and half calcium salts, can also be formed.
The compounds of the present invention can exist in both solvated and unsolvated forms. The term “solvate” is used herein to denote a molecular complex composed of a compound of the present invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. Used. The term “hydrate” is used when the solvent is water. The scope of the present invention, unlike these solvates, includes complexes such as clathrate, drug-host inclusion complexes where the drug and host are present in stoichiometric or non-stoichiometric amounts. It is. Also included are drug conjugates containing two or more organic and / or inorganic components, which may be either stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

F. Prodrugs The scope of the present invention also includes so-called “prodrugs” of the compounds of formulas (I) to (IV). For example, certain derivatives of compounds of any of formulas (I)-(IV), which themselves have little or no pharmacological activity, can be administered, for example, by hydrolysis when administered on or into the body. It may be converted to any compound of formula (I) to (IV) having the desired activity by decomposing cleavage. Such derivatives are called “prodrugs”. Detailed information on the use of prodrugs can 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 (Editor) EB Roche, American Pharmaceutical Association). Prodrugs according to the present invention can be obtained, for example, by exchanging suitable functional groups present in any of the compounds of formulas (I) to (IV) with specific moieties known to those skilled in the art as "pro moieties". For example, as described in “Design of Prodrugs”, by H Bundgaard (Elseview, 1985).

G. Methods of treatment The present invention further provides that in a subject suffering from or susceptible to a condition, by administering to the subject a therapeutically effective amount of one or more compounds of formula (I)-(IV) above. A method of treating an abnormal condition. In one embodiment, the treatment is prophylactic treatment. In other embodiments, the treatment is symptomatic treatment. In other embodiments, the treatment is a recovery promotion treatment.

1. Conditions Conditions that can be treated according to the present invention include conditions mediated by platelet aggregation, such as atherosclerotic cardiovascular conditions, cerebrovascular conditions, and peripheral arterial conditions, particularly thrombosis-related conditions. In other embodiments, conditions mediated by platelet aggregation can be treated. In yet other embodiments, the compounds of the invention can be used to treat platelet-dependent thrombosis or a platelet-dependent thrombosis-related condition.

  In one embodiment, the compounds of the invention can be used to treat acute coronary syndrome. Acute coronary syndromes include angina (eg, unstable angina) and myocardial infarction (eg, non-ST-segment elevation myocardial infarction, non-Q-wave myocardial infarction, and Q-wave myocardial infarction). It is not limited.

  In other embodiments, the compounds of the invention can be used to treat strokes (eg, thrombotic stroke, ischemic stroke, embolic stroke and transient ischemic stroke). In other embodiments, the compounds of the invention can be used to treat a subject suffering from at least one event selected from the group consisting of myocardial infarction and stroke. In other embodiments, the compounds of the invention can be used to treat atherosclerotic events selected from the group consisting of myocardial infarction, transient ischemic stroke, stroke (stroke), and vascular death.

  In other embodiments, the compounds of the invention can be used for the treatment of thrombotic and restenotic complications, or for the treatment of reocclusion following an invasive procedure, including angioplasty, percutaneous coronary intervention, intracarotid These include membrane resection, aortic coronary artery bypass grafting (“CABG”), vascular grafting, stent placement, lower limb arterial grafting, prosthetic valve placement, hemodialysis, and insertion of endovascular devices and prostheses. It is not limited.

  In another embodiment, the compound of the present invention comprises acute coronary syndrome; unstable angina; non-Q wave myocardial infarction; non-ST-segment elevation myocardial infarction; acute myocardial infarction; deep vein thrombosis; Ischemic necrosis of tissue; atrial fibrillation; thrombotic stroke; embolic stroke; recent myocardial infarction; peripheral artery disease; peripheral vascular disease; refractory ischemia; pre-eclampsia, eclampsia; It can be used to treat platelet-dependent thrombosis or a platelet-dependent thrombosis-related condition selected from the group consisting of intravascular coagulation; and thrombotic cytopenic purpura.

  In other embodiments, the compounds of the invention can be used to treat thrombotic or restenotic complications or reocclusions. In yet other embodiments, the thrombotic or restenotic complication or re-occlusion is performed after angioplasty, percutaneous coronary intervention, carotid endarterectomy, aortic coronary artery bypass grafting, vascular grafting, stent placement, lower limb artery Selected from the group consisting of transplantation, atrial fibrillation, prosthetic valve placement, hemodialysis, and insertion of endovascular devices and prosthetics.

  In other embodiments, the compounds of the invention can be used to reduce the risk of developing vascular events in a subject. In yet other embodiments, the vascular event is selected from the group consisting of myocardial infarction, stable angina, coronary artery disease, ischemic stroke, transient ischemic stroke and peripheral arterial disease.

In other embodiments, the compounds of the invention can be used to treat hypertension.
In other embodiments, the compounds of the invention can be used to treat angiogenesis.

2. Administration and Dosage In general, the compounds described herein are administered in an amount effective to inhibit ADP-mediated platelet aggregation. The compounds of the invention are administered by any suitable route as a pharmaceutical composition in a form suitable for such a route, in a dose effective for the intended treatment. The therapeutically effective amount of the compound of the present invention necessary for preventing or stopping the progression of the pathological condition is easily determined by those skilled in the art according to preclinical methods and clinical methods commonly used in the medical art. I can confirm.

  The compound of the present invention can be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or the compound may enter directly into the bloodstream from the oral cavity by using buccal or sublingual administration.

  In other embodiments, the compounds of the invention can be administered directly into the bloodstream, intramuscularly or into the viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous administration. Devices suitable for parenteral administration include needle (including microneedles) syringes, needleless syringes and infusion techniques.

  In other embodiments, the compounds of the present invention can also be administered topically to the skin or mucosa; ie, dermal or transdermal administration. In other embodiments, the compounds of the invention can be administered intranasally or by inhalation. In other embodiments, the compounds of the present invention can be administered rectally or vaginally. In other embodiments, the compounds of the invention can be administered directly to the eye or ear.

  The mode of administration of the compounds of the present invention and / or compositions containing the compounds of the present invention is based on a variety of factors, including patient type, age, weight, sex and pathological condition; severity of the condition; As well as the effectiveness of the individual compounds used. Therefore, the mode of administration can be varied widely. Dose levels on the order of about 0.01 to about 100 mg / kg body weight per day are useful for the treatment of the condition. In one embodiment, the total daily dose (administered in single or divided doses) of the compounds of formulas (I)-(IV) is generally about 0.01 to about 100 mg / kg. In other embodiments, the total daily dosage of the compounds of formulas (I)-(IV) is about 0.1 to about 50 mg / kg, in other embodiments about 0.5 to about 30 mg / kg (ie per kg body weight). Mg of compounds of formulas (I) to (IV). In one embodiment, the dosage is 0.01-10 mg / kg / day. In other embodiments, the dosage is 0.1-1.0 mg / kg / day. The dosage unit composition may contain such an amount, or may contain about that amount and be in a daily dose. In many cases, administration of the compound is repeated multiple times a day (generally not more than 4 times). Multiple daily administrations can generally be employed to increase the total daily dosage if desired.

  For oral administration, the composition of the present invention is 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, It can be provided in the form of tablets containing 100, 125, 150, 175, 200, 250 and 500 mg of active ingredient. A medicament generally contains from about 0.01 to about 500 mg of the active ingredient, or in other embodiments, from about 1 to about 100 mg of the active ingredient. If intravenous, the dose during constant rate infusion may be from about 0.1 to about 10 mg / kg / min.

  Suitable subjects for treatment according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents, rabbits, primates, and the like, and intrauterine mammals. In one embodiment, a human is a suitable subject. The human subject may be any sex and may be in any developmental stage.

H. Use in the manufacture of a medicament In one embodiment, the invention relates to a platelet aggregation mediated condition combining a compound of formula (I)-(IV) with one or more pharmaceutically acceptable carriers and / or other active ingredients. And a method for producing a pharmaceutical composition (or “medicament”) for use in the treatment of

In other embodiments, the invention includes the use of one or more compounds of formulas (I)-(IV) in the manufacture of a medicament for treating acute coronary syndrome.
In other embodiments, the invention includes the use of one or more compounds of formulas (I)-(IV) in the manufacture of a medicament for alleviating atherosclerotic events.

In other embodiments, the invention includes the use of one or more compounds of formula (I)-(IV) in the manufacture of a medicament for treating thrombosis.
In other embodiments, the invention includes the use of one or more compounds of formula (I)-(IV) in the manufacture of a medicament for co-administration before, during or after a revascularization procedure; Includes, but is not limited to, lower limb arterial transplantation, carotid endarterectomy, aortic coronary artery bypass grafting, atrial fibrillation, prosthetic valve placement, hemodialysis, and mechanical device placement.

I. Pharmaceutical Compositions To treat the above conditions, the compounds of formulas (I) to (IV) can be administered as the compounds themselves. Alternatively, pharmaceutically acceptable salts are suitable for medical use because of their higher water solubility than the parent compound.

  In other embodiments, the present invention comprises a pharmaceutical composition. Such pharmaceutical compositions comprise a compound of formula (I)-(IV) provided with a pharmaceutically acceptable carrier. The carrier can be a solid, liquid or both and can be formulated with the compound of the present invention as a unit dose composition, for example a tablet, which can contain from 0.05 to 95% by weight of the active ingredient. Compounds of formula (I)-(IV) can be combined with polymers suitable as targetable drug carriers. Other pharmacologically active substances may be present.

  The active compounds of the present invention can be administered by any suitable route, along with one example of a pharmaceutical composition dosage form, at a dose effective for the intended treatment. The active compounds and compositions of the invention can be administered, for example, orally, rectally, parenterally or topically.

  Oral administration of solid dosage forms can be carried out, for example, in discrete units, for example as hard or soft capsules, pills, cachets, lozenges or tablets each containing a predetermined amount of at least one compound of the invention. . In other embodiments, oral administration can be in the form of powder or granules. In other embodiments, the oral dosage form may be sublingual, such as a lozenge. In such solid dosage forms, the compounds of formulas (I)-(IV) are usually combined with one or more adjuvants. Such capsules or tablets can contain controlled release formulations. In the case of capsules, tablets and pills, these dosage forms may contain a buffering agent or may be prepared with an enteric coating. In other embodiments, oral administration can also be performed in a liquid dosage form. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing, for example, inert diluents commonly used in the art (eg, water). It is. Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (eg sweetening agents) and / or flavoring agents.

  In other embodiments, the present invention includes parenteral dosage forms. “Parenteral administration” includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection and infusion. Injectable formulations (eg, sterile injectable aqueous or oleaginous suspensions) can be formulated according to known techniques using suitable dispersing, wetting agents and / or suspending agents.

In other embodiments, the present invention includes topical dosage forms. “Topical administration” includes transdermal administration, eg intradermal administration, intraocular administration, or intranasal administration or inhalation administration, such as through a transdermal patch or iontophoresis device. Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams. Topical formulations may contain compounds that facilitate the absorption or penetration of the active ingredient into the skin and other affected areas. When the compound of the present invention is administered by a transdermal administration device, the administration will be performed using a reservoir and a patch of either a porous membrane type or a solid matrix type. Common formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusts, dressings, foams, films, skin patches, wafers, implants, sponges , Fibers, bandages and microemulsions. Liposomes can also be used. Common carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Permeation enhancers may be included-see, for example, J Pharm Sci, 88 (10), 955-958, Finnin and Morgan (October 1999).

  In other embodiments, the compounds of the invention can be administered in combination with treatment of restenosis caused by angioplasty. This procedure includes, but is not limited to, inserting a stent into the angioplasty site. The stent itself contains a compound of the present invention and is used as a carrier for local delivery of the compound of the present invention to a target vessel. The compounds of the present invention, alone or in combination with other active drugs and pharmaceutically acceptable carriers, adjuvants, binders, etc., may be coated, adhered, fixed, or otherwise formed on the surface of the stent. Be present in or on the matrix.

  An example of a stent includes a compound of the present invention in the form of a sustained release composition that provides the compound of the present invention over an extended period of time. Other examples of stents include hydrogels encapsulating the compounds of the present invention, in which case the hydrogel is attached directly to the stent or attached to a polymer coated stent. This hydrogel encapsulating the compound of the present invention can be used as a top coat on a stent for immediate release bolus-like topical administration of the encapsulated compound. Under this hydrogel / therapeutic agent topcoat, other biodegradable polymer coatings (eg, polyesteramides with covalently bound or incorporated drugs) are placed to create sustained release local drug / biodelivery systems. be able to. This hydrogel system is exemplified in USP No. 6,716,445 (issued April 6, 2004).

  Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of the present invention is dissolved or suspended in a suitable carrier. A general formulation suitable for administration to the eye or ear may be in the form of a fine suspension or drops of solution in a pH adjusted isotonic sterile saline solution. Other formulations suitable for ophthalmic and otic administration include ointments, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicone) implants, wafers, lenses and granules. Or vesicular systems such as niosomes or liposomes. Crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers such as gelatin gum together with preservatives such as benzalkonium chloride It can be included. Such formulations can also be delivered by iontophoresis.

  For intranasal administration or administration by inhalation, the active compound of the invention is inhaled or extruded from a pump spray container in the form of a solution or suspension, or as a pressurized container or nebulizer as an aerosol spray formulation. Are conveniently delivered by a suitable propellant. Formulations suitable for intranasal administration are generally in the form of a dry powder (alone, in a dry blend with eg lactose as a mixture or mixed with a phospholipid such as phosphatidylcholine as a mixed component particle) From propellers, pumps, nebulizers, atomizers (one example of atomizers can employ electrohydrodynamics to generate fine mist) or nebulizers from inhalers or as aerosol sprays, suitable propellants such as 1, It is administered with or without 1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal administration, the powder may contain a bioadhesive agent, for example, chitosan or cyclodextrin.

  In other embodiments, the present invention includes rectal dosage forms. Such rectal dosage forms may be, for example, suppositories. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

  Other carrier materials and modes of administration known in the pharmaceutical arts can also be used. The pharmaceutical composition of the present invention can be produced by any well-known formulation technique, such as effective formulation and administration methods. The foregoing considerations regarding effective formulation and administration methods are well known in the art and are described in standard texts. Drug formulations are described, for example, by Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Editor Liberman, et al., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Editor Kibbe , et al., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.

J. et al. Co-administered compounds of the present invention can be used alone or in combination with other therapeutic agents to treat a variety of conditions or disease states. The compound (s) of the invention and the other therapeutic agent (s) can be administered simultaneously (in the same dosage form or in separate dosage forms) or sequentially.

  Administration of two or more compounds “in combination” means that two or more compounds are administered at a time when the presence of one is close enough to change the biological effect of the other. Two or more compounds can be administered simultaneously, sequentially or sequentially. Further, simultaneous administration can be performed by mixing the compounds prior to administration or by administering the compounds at the same time but at different anatomical sites or using different routes of administration. .

The phrases “sequential administration”, “co-administration”, “simultaneous administration” and “administer simultaneously” mean that the compounds are administered in combination.
In one embodiment, the compounds of formulas (I)-(IV) can be co-administered with an oral antiplatelet agent, including aspirin, dipyridamole, cilostazol and anegrilide hydrochloride Is included, but is not limited thereto. In yet other embodiments, compounds of formula (I)-(IV) can be co-administered with aspirin.

  In other embodiments, the compounds of formulas (I)-(IV) can be co-administered with a glycoprotein IIb / IIIa inhibitor, including abciximab, eptifibatide and tirofiban Including, but not limited to. In yet other embodiments, the compounds of formulas (I)-(IV) can be co-administered with eptifibatide.

  In other embodiments, the compounds of formulas (I)-(IV) can be co-administered with heparin or heparinoid, including heparin sodium, enoxaparin sodium, dalteparin sodium, alde Including, but not limited to, ardeparin sodium, nadroparin calcium, reviparin sodium, tinzaparin sodium and fondaparinux sodium .

  In other embodiments, the compounds of formulas (I)-(IV) can be co-administered directly with thrombin inhibitors, including danaparoid, hirudin, bivalirudin and lepirudin. ), But is not limited thereto.

  In other embodiments, the compounds of formulas (I)-(IV) can be co-administered with anticoagulants, including warfarin, warfarin sodium, 4-hydroxycoumarin, dicoumarol, fenprocumone ( phenprocoumon), anisindione, acenocoumerol, and phenindione, but are not limited to these. In yet another embodiment, the compounds of formulas (I)-(IV) can be co-administered with warfarin sodium.

  In other embodiments, compounds of formula (I)-(IV) can be co-administered with an oral factor Xa inhibitor, including ximelagatran, melagatran, dabigatran, etexilate (Etexilate) and argatroban, including but not limited to. In yet other embodiments, the compounds of formulas (I)-(IV) can be co-administered with ximelagatran.

  In other embodiments, compounds of formula (I)-(IV) can be co-administered with a fibrinolytic agent, including streptokinase, urokinase, tissue plasminogen activator, tenecteplase, reteplase ( reteplase), alteplase and aminocaproic acid, but are not limited to these.

  In other embodiments, compounds of formula (I)-(IV) can be co-administered with inventive compounds useful for the treatment of platelet aggregation, including BAY 59-7939, YM-60828, M-55532, Including but not limited to M-55190, JTV-803 and DX-9065a.

K. Kits The present invention further includes 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 containing an amount of one or more compounds of the invention sufficient to perform the method of the invention, and a container for the dosage form.

  In other embodiments, the kits of the invention comprise one or more compounds of formulas (I)-(IV) and oral antiplatelet agents including, but not limited to, aspirin, dipyridamole, cilostazol and aneglylide hydrochloride including. In yet another embodiment, the kit of the invention comprises one or more compounds of formulas (I)-(IV) and aspirin.

  In other embodiments, the kits of the invention comprise one or more compounds of Formulas (I)-(IV) and glycoprotein IIb / IIIa inhibitors, including but not limited to abciximab, eptifibatide and tirofiban. . In yet another embodiment, the kit of the invention comprises one or more compounds of formula (I)-(IV) and eptifibatide.

  In another embodiment, the kit of the invention comprises one or more compounds of formulas (I) to (IV), as well as heparin sodium, enoxaparin sodium, dalteparin sodium, ardeparin sodium), nadroparin calcium, leviparin sodium Heparin and heparinoids including, but not limited to, tinzeparin sodium and fondaparinux sodium.

  In other embodiments, the kits of the invention comprise one or more compounds of formulas (I)-(IV) and direct thrombin inhibitors, including but not limited to danaparoid, hirudin, bivalirudin and repirudine.

  In other embodiments, the kit of the present invention comprises one or more compounds of formulas (I)-(IV), as well as warfarin, warfarin sodium, 4-hydroxycoumarin, dicoumarol, fenprocumone, anisindione, acenocumerol and phenindione (these) Anticoagulants including but not limited to). In yet another embodiment, the kit of the invention comprises one or more compounds of formulas (I)-(IV) and warfarin sodium.

  In other embodiments, the kits of the invention comprise one or more compounds of formulas (I)-(IV), and oral factor Xa inhibition, including but not limited to ximelagatran, melagatran, dabigatran, etexilate and argatroban Contains medicine. In yet another embodiment, the kit of the invention comprises one or more compounds of formulas (I)-(IV) and ximelagatran.

  In other embodiments, the kits of the invention comprise one or more compounds of formulas (I)-(IV) and streptokinase, urokinase, tissue plasminogen activator, tenecteplase, reteplase, alteplase and aminocaproic acid (including these). Fibrinolytics including but not limited to).

  In other embodiments, the kit of the invention comprises one or more compounds of formulas (I)-(IV), and BAY 59-7939, YM-60828, M-55532, M-55190, JTV-803 and DX- Inventive compounds useful for the treatment of platelet aggregation, including but not limited to 9065a.

L. Intermediates In other embodiments, the present invention relates to novel intermediates useful for the preparation of thieno [2,3-d] pyrimidine compounds of formulas (I)-(IV).

M.M. General Synthetic Schemes The starting materials used herein are either commercially available or standard textbooks such as routine methods known in the art (eg COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience)). The method shown in FIG. The compound of the present invention can be produced using the methods shown in the general synthesis method and experimental method described in detail below. The general synthesis method is given for illustration and not for limitation.

Scheme A. The thienopyrimidines of the present invention can be produced by various methods. One method for preparing thienopyrimidine 7 is shown in Scheme A. Commercially available aldehyde / ketone 1 and ester 2 are coupled by the general method of Tinney et al. (J. Med. Chem. (1981) 24 , 878-882) in the presence of sulfur to give thiophene 3. 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 added with a chloride source, such as phosphorus oxychloride, thionyl chloride or phosphorus pentachloride, in the presence or absence of a tertiary amine or concentrated HCl, with or without addition of an inert solvent such as dimethylformamide Without treatment at a temperature of 75-175 ° C., optionally in an excess of phosphorus oxychloride, in a closed vessel at 130-175 ° C., yields 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 or other bases well known to those skilled in the art, and a solvent such as THF, Treatment with a temperature from room temperature to the reflux temperature of the solvent in the presence of acetonitrile, dichloromethane, dialkyl ether, toluene, DMF, N-methylpyrrolidinone, etc. gives thienopyrimidine 7.

Scheme B. Scheme B shows the preparation of intermediate 6. Protected piperazine 8 is commercially available, or (1) a suitable protecting group, including but not limited to Boc, Cbz, Fmoc and benzyl, is attached to one of the ring nitrogen atoms of piperazine and ( 2) It can be produced by reacting with alkyl OCOCl or (alkyl OCO) ₂ O. The protected piperazine 8 is then acylated with acyl reagent 9. In this case, acyl reagent 9 is used in acid form (X = OH) in the presence of a binder. Suitable binders include, but are not limited to DCC, EDC, DEPC, HATU, HBTU and CDI. An alternative method for preparing intermediate 6 is to use acyl reagent 9 in the form of acid halide (X = Cl, Br, F) or acid anhydride (X = O (COR ₄ )), trialkylamine, pyridine. Or in the presence of bases including but not limited to alkaline earth metal carbonates and the presence of inert solvents such as THF, dichloromethane, acetonitrile, toluene, dialkyl ethers, DMF, N-methylpyrrolidinone, dimethylacetamide, etc. Below is used at temperatures from ice / water temperature to the reflux temperature of the solvent to give bisamide 10. Bisamide 10 is converted to piperazine 6 by methods well known to those skilled in the art. Many of these methods are discussed by Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley-Interscience, pp. 502-550. When the protecting group of bisamide 10 is a benzyl group, removal of the benzyl group to obtain intermediate 6 can be accomplished using standard methods known in the art (e.g. Greene and Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley -Interscience, pp. 502-550).

Scheme C. In order to utilize commercially available materials or to avoid reactivity in other parts of the molecule, the order in which various functional groups are attached to the thienopyrimidine can be altered. An alternative method for preparing thienopyrimidine 7 in a different order than that of Scheme A is shown in Scheme C. Dichloropyrimidine 5 (Scheme A) is aminated with 8 (Scheme B) in an inert solvent at a temperature from room temperature to the boiling point of the solvent to give pyrimidine 11. This amination can be carried out with an excess of 8 or in the presence of a base including but not limited to trialkylamine, pyridine or alkaline earth metal carbonate. Removal of the protecting group to give pyrimidine-piperazine 12 can be achieved by standard deprotection methods such as those discussed by Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley-Interscience, pp. 502-550. Achieved by: Thienopyrimidine 7 is obtained by binding acyl reagent 9 (X = OH) and pyrimidine-piperazine 11 with a binder. Many of the binders are well known to those skilled in the art and include, but are not limited to, DCC, EDC, DEPC, HATU, HBTU and CDI. Alternatively, 9 was included in the form of an acid halide (X = Cl, Br, F) or an acid anhydride (X = O (COR ₄ )) with a trialkylamine, pyridine or alkaline earth metal carbonate (these From an ice / water temperature in the presence of a base and in the presence of an inert solvent including but not limited to THF, dichloromethane, acetonitrile, toluene, dialkyl ether, DMF, N-methylpyrrolidinone, and the like. Use at temperatures up to the reflux temperature of the solvent.

Scheme D. Preparation of substituted thienopyrimidine 14 from thienopyrimidine 7 is accomplished by treating thienopyrimidine 7 with H-NHR ² (13), where H-NHR ² is either commercially available or one of ordinary skill in the art. Can be produced by a known method.

Reagent 13 and thienopyrimidine 7 are coupled in the presence of a base and an inert solvent. Reagent 13 can be used in 1 to 10-fold excess, an example of a base is a trialkylamine base, an example of a solvent is N-methylpyrrolidinone or butanol, and the temperature is from room temperature to 160 ° C. Instead of adding a base, one may choose to use an excess of HNHR ₇ as the base instead. To reduce undesired reactions, reagent 13 can be first protected (ie, R ² is in protected form), ie, reagent 13A, to give the substituted thienopyrimidine 14A. In so doing, the protecting group can be removed at a later stage to give the substituted thienopyrimidine 14. Reagent 13A is commercially available or can be prepared by methods well known to those skilled in the art. For example, if R _{7 is} to be an alkyl diol, the diol H-NHR ² can be protected by methods known in the art. Methods for the synthesis and removal of diol protecting groups are discussed by Greene and Wuts, “Protective Groups in Organic Synthesis”, 3rd edition, Wiley-Interscience, pp. 201-245.

Alternatively, R ² of 14A may be a protected form of an alkyl aldehyde or alkyl ketone. A number of protected aldehydes and ketones 13A are commercially available. Conventional methods for synthesizing and removing aldehyde and ketone protecting groups are known in the art (eg Greene and Wuts, “Protective Groups in Organic Synthesis”, 3rd edition, Wiley-Interscience, pp. 201- 245). After removal of the aldehyde or ketone protecting group to the substituted thienopyrimidine 14B, the aldehyde or ketone can be further manipulated. For example, treatment of an aldehyde with an oxidizing agent such as 3-chloroperoxybenzoic acid provides thienopyrimidine 14 where R ² contains a carboxylic acid. When an aldehyde or ketone is treated 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, R ² contains an amino group Substituted thienopyrimidine 14 is obtained.

If R ₄ is phenyl or heteroaryl substituted with Br, I, Cl and O-triflate, then R ⁴ can be further manipulated using standard methods known in the art. For example, a substituted thienopyrimidine 14A with an aryl- or heteroaryl-boronic acid or ester (many of which are commercially available) is reacted in the presence of a metal catalyst to give a biaryl-substituted thienopyrimidine 14C. For example, aryl or heteroaryl boronic acids, or heteroaryl or aryl boronic esters, such as [(aryl or heteroaryl) -B (OH) ₂ ] or [(aryl or heteroaryl) -B (OR ^a ) (OR ^b (Wherein R ^a and R ^b are each C ₁ -C ₆ alkyl or, if R ^a and R ^b are taken together, C ₂ -C ₁₂ alkylene)]] Treatment under an inert solvent with or without a base gives biaryl substituted thienopyrimidine 14C. Metal catalysts in these transformations include Cu, Pd or Ni salts and phosphine complexes such as Cu (OAc) ₂ , PdCl ₂ (PPh ₃ ) ₂ , NiCl ₂ (PPh ₃ ) ₂ It is not limited to. Bases include alkaline earth metal carbonates, alkaline earth metal hydrogen carbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, alkali metal hydrides, alkali metals Examples include, but are not limited to, alkoxides, alkaline earth metal hydrides, alkali metal dialkylamides, alkali metal bis (trialkylsilyl) amides, trialkylamines or aromatic amines.

  In one embodiment, the alkali metal hydride is sodium hydride. In other embodiments, the alkali metal alkoxide is sodium methoxide. In other embodiments, the alkali metal alkoxide is sodium ethoxide. In other embodiments, the alkali metal dialkylamide is lithium diisopropylamide. In other embodiments, the alkali metal bis (trialkylsilyl) amide is sodium bis (trimethylsilyl) amide. In other embodiments, the trialkylamine is diisopropylethylamine. In other embodiments, the trialkylamine is triethylamine. In other embodiments, the aromatic amine is pyridine.

  Inert solvents can include acetonitrile, dialkyl ether, cyclic ether, N, N-dialkylacetamide (dimethylacetamide), N, N-dialkylformamide, dialkyl sulfoxide, aromatic hydrocarbons or haloalkanes. It is not limited.

  In one embodiment, the dialkyl ether is diethyl ether. In other embodiments, the cyclic ether is tetrahydrofuran. In other embodiments, the cyclic ether is 1,4-dioxane. In other embodiments, the N, N-dialkylacetamide is dimethylacetamide. In other embodiments, the N, N-dialkylformamide is dimethylformamide. In other embodiments, the dialkyl sulfoxide is dimethyl sulfoxide. In other embodiments, the aromatic hydrocarbon is benzene. In other embodiments, the aromatic hydrocarbon is toluene. In other embodiments, the haloalkane is methylene chloride.

An example of the reaction temperature is a temperature from room temperature to the boiling point of the solvent used. Non-commercial boronic acids or boronic esters can be obtained from the corresponding optionally substituted aryl halides as described in Tetrahedron, 50, 979-988 (1994). Alternatively, convert the R ⁴ substituent to the corresponding boronic acid or boronic ester (OH) ₂ B- or (OR ^a ) (OR ^b ) B- as described in Tetrahedron, 50, 979-988 (1994) The same product as described above can be obtained by treatment with a halogenated or aryl or heteroaryl triflate. The protecting group on R ′ ^{2 of} 14C is then removed by the conditions described above to give 14.

Scheme E. In the production of substituted thienopyrimidines 14, the order of addition of the various functional groups of thienopyrimidine can be altered to utilize commercially available materials or to avoid reactivity at other parts of the molecule. Another method for preparing substituted thienopyrimidines 14 is shown in Scheme E. In this case, piperazinyl pyrimidine 11 is combined with reagent 13 to give disubstituted thienopyrimidine 15. In this case, H-NHR ₇ is commercially available or can be produced by methods well known to those skilled in the art. Reagent 13 and piperazinyl pyrimidine 11 are coupled in the presence of a base and an inert solvent to give disubstituted thienopyrimidine 15. Reagent 13 can be used in 1 to 10 times excess, examples of bases are trialkylamine bases, examples of solvents are N-methylpyrrolidinone or butanol, and the temperature is from room temperature to 160 ° C. Instead of adding a base, the use of excess HYR ₇ (13) as a base may be chosen instead. The disubstituted thienopyrimidine 15 is then mixed with a reagent suitable for removal of the protecting group to give amine 16. The appropriate means for removal of the protecting group depends on the nature of the group. For example, to remove the protecting group BOC, a disubstituted thienopyrimidine may be dissolved in a trifluoroacetic acid / dichloromethane mixture. The method of the second example is the addition of hydrogen chloride gas dissolved in an alcohol or ether such as methanol or dioxane. Once complete, the solvent is removed under reduced pressure to give the corresponding amine as the corresponding salt, ie trifluoroacetate or hydrochloride. However, if desired, the amine can be further purified by means well known to those skilled in the art, such as recrystallization. In addition, if a non-salt form is desired, it can be obtained by means known to those skilled in the art, for example, by treating the salt under mild basic conditions to prepare the free base amine.

Other deprotection conditions and deprotection conditions for other protecting groups are found in TW Green and PGM Wuts, “Protective Groups in Organic Chemistry”, John Wiley and Sons, 1999, pp. 502-550. Thienopyrimidine 14 is obtained by coupling acyl reagent 9 (X = OH) and amine 16 with a coupling reagent. Binding reagents include, but are not limited to, DCC, EDC, DEPC, HATU, HBTU, CDI. Alternatively, 9 was included in the form of an acid halide (X = Cl, Br, F) or an acid anhydride (X = O (COR ₄ )) with a trialkylamine, pyridine or alkaline earth metal carbonate (these Temperature from ice / water temperature to the reflux temperature of the solvent in the presence of a base) and in the presence of an inert solvent such as THF, dichloromethane, acetonitrile, toluene, dialkyl ether, DMF, N-methylpyrrolidinone, etc. Used in. Depending on the nature of the various substituents, it may be desirable to change the order of addition of the substituents. For example, 11 protecting groups can be removed as described in Scheme C to give 12. Pyrimidine piperazine 12 and 13 can then be reacted in the same way as described for the conversion of 7 to 14 in Scheme D to give 16. Alternatively, pyrimidine piperazine 12 can be reacted with the protected form of 13, ie 13A, to give 17. R ⁴ COX (9) is added to 17 to give 14A, which can then be further manipulated as described in Scheme D. Alternatively, amine 17 can be converted to 16 by the method described in Scheme D for the conversion of 14A to 14.

N. Examples Synthesis of various compounds of the present invention is shown below. Other compounds within the scope of the present invention can be prepared using the methods set forth in these examples alone or in combination with methods 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), methyl cyanoacetate (19.8 g) and triethylamine (15 mL) were added under nitrogen. When the mixture was stirred for 10 minutes, butyraldehyde (18 mL) was added dropwise at a rate sufficient to maintain the temperature at 50 ° C. 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 was washed 3 times with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel with ethyl acetate-hexane (10/90) to give a solid. This solid was suspended in hexane, collected and dried to give 25.74 g of the desired product as an off-white solid: m / z 186.0598 (M + H) ^{+ for} MS (ESI +) C8 H11 N1 O2 S ₁ ¹ H NMR (300 MHz, CDCl ₃ ) 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 methyl 2-amino-5-ethylthiophene-3-carboxylate (Example 1; 25.2 g) in glacial acetic acid (450 mL) and water (45 mL) was added potassium cyanide (30.9 g) in water ( In 150 mL) was added dropwise. The mixture exothermed to 33 ° C and generated a small amount of gas. A white precipitate formed during the addition. The mixture was stirred at room temperature for 20 hours. Ice water (300 mL) was added to the mixture and the solid was collected by filtration and washed with water (200 mL). The solid was transferred to a round bottom flask and 6% aqueous sodium hydroxide (500 mL) was added thereto. The mixture was refluxed for 2 hours and then cooled to room temperature. The temperature was further reduced to 5 ° C. in an ice water bath. The pH was adjusted to about 6 with concentrated hydrochloric acid. The resulting solid was collected, washed with water and dried under reduced pressure to give 16.39 g of the title compound as an off-white solid. This material was subsequently azeotroped with THF / toluene to remove residual water: MS (ESI +) for C8 H8 N2 O2 S ₁ m / z 197.0 (M + H) ⁺ ; ¹ H NMR 400 MHz, DMSO -d 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

6-Ethyl-4a, 7a-dihydrothieno [2,3-d] pyrimidine-2,4-diol (Example 2; 4.0 g,) was placed in a glass pressure vessel with phosphorus oxychloride (35 mL). . The mixture was heated to 150 ° C. for 1.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The remaining phosphorus oxychloride was azeotroped twice with toluene (50 mL) under reduced pressure. The residue was partitioned between saturated sodium bicarbonate and dichloromethane. The formed layers were separated and decolorizing carbon (1 g) was added to the organic layer. The organic layer was filtered through anhydrous magnesium sulfate and the filtrate was concentrated to dryness under reduced pressure to give 3.96 g of the title compound: MS (ESI +) for C8 H6 Cl2 N2 S ₁ m / z 233.0 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.4 (t, 3 H), 3.0 (q, 2 H), 7.1 (s, 1 H).

Example 4
4- (Phenylacetyl) piperazine-1-carboxylate t-butyl

To a mixture of Boc-piperazine (4.2 g) in dry THF (30 mL) was added triethylamine (3.14 mL) in a round bottom flask in an ice water bath. Phenylacetyl chloride (2.9 mL) was added dropwise such that the temperature was maintained below 15 ° C. When the addition was complete, the mixture was removed from the ice bath and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between brine and ethyl acetate. The layers were separated and the organic layer was washed with brine. The organic layer was then dried over anhydrous magnesium sulfate and concentrated. Hexane was added and the resulting solid was collected by filtration to give 6.24 g of the title compound: MS (ESI +) for C17 H24 N2 O ₃ m / z 327.0 (M + H + Na) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) 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 t-butyl 4- (phenylacetyl) piperazine-1-carboxylate (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 solvent was removed under reduced pressure and the residue was partitioned between saturated sodium bicarbonate and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The dichloromethane extracts were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel with methanol-dichloromethane (8/92) containing 0.1% ammonium hydroxide to give 2.01 g of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75 (s, 1 H), 2.66 (t, 2 H), 2.8 (t, 2 H), 3.4 (t, 2 H), 3.6 (t, 2 H), 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 2,4-dichloro-6-ethylthieno [2,3-d] pyrimidine (Example 3; 1.53 g) in dry THF (60 mL) was added diisopropylethylamine (4.6 mL) and 1- (phenylacetyl). ) Piperazine (Example 5; 1.35 g) was added. The mixture was stirred at room temperature for 2.5 hours, at which point the mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel with methanol-dichloromethane (2/98) to give 2.28 g of the title compound: MS (ESI +) for C20 H21 Cl1 N4 O1 S ₁ m / z 401.0 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) 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
6-Ethyl-2-morpholin-4-yl-4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidine

2-chloro-6-ethyl-4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidine (Example 6; 0.2 g), 1-butanol (2.0 mL) and morpholine (0.087 g) was placed in a 2-dram screw-capped vial and placed in a Lab-Line MAX Q2000 orbital shaker at 110 ° C. for 24 hours. The vial was removed from the orbital shaker and the contents were allowed to cool. The solvent was then evaporated in a vacuum oven heated to 40 ° C. To the residue was added THF (10 mL), isocyanate resin (1.1 g; Aldrich, loading 1.84 mmol NCO / g), and tetraalkylammonium carbonate resin (0.7 g; Aldrich, loading 2.86 mmol / g). The vial was then shaken on a shaker block for 2 hours at room temperature. The mixture was then filtered through diatomaceous earth and decolorizing carbon. The filtrate was concentrated to dryness and the residue was crystallized from ethyl acetate-hexane to give 0.14 g of the title compound: MS (ESI +) for C24 H29 N5 O2 S ₁ m / z 452.2 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.26 (t, 3 H), 2.8 (q, 2 H), 3.6 (s, 3 H), 3.75 (s, 7 H), 3.8 (s, 3 H) , 6.7 (s, 1 H), 7.28 (m, 3 H), 7.35 (m, 2 H).

Example 8
4- {6-ethyl-4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidin-2-yl} piperazine-1-carboxylate t-butyl

2-chloro-6-ethyl-4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidine (Example 6; 0.1 g), 1-butanol (2.0 mL), and BOC piperazine (0.096 g) was placed in a 2-drum screw cap vial and placed in a Lab-Line MAX Q2000 orbital shaker at 110 ° C. for 24 hours. Boc-piperazine (0.048 g) was added and heating continued for an additional 24 hours. The vial was removed from the orbital shaker and the contents were allowed to cool. The solvent was then evaporated in a vacuum oven heated to 40 ° C. To the residue was added THF (10 mL), isocyanate resin (1.1 g; Aldrich, loading 1.84 mmol NCO / g), and tetraalkylammonium carbonate resin (0.7 g; Aldrich, loading 2.86 mmol / g). The vial was then shaken on a shaker block for 2 hours at room temperature. Diatomaceous earth and decolorizing carbon were added and the vial was shaken for an additional hour. The filtrate was concentrated to dryness and the residue was crystallized from ethyl acetate-hexane to give 0.207 g of the title compound: m / z 551.2 (M + H) ^{+ for} MS (ESI +) C29 H38 N6 O3 S ₁ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.28 (t, 3 H), 1.49 (s, 5 H), 1.55 (s, 4 H), 2.8 (q, 2 H), 3.47 (m, 4 H) , 3.61 (s, 4 H), 3.75 (m, 6 H), 3.8 (s, 4 H), 6.71 (s, 1 H), 7.28 (m, 3 H), 7.34 (m, 2 H).

Example 9
6-Ethyl-4- [4- (phenylacetyl) piperazin-1-yl] -2-piperidin-1-ylthieno [2,3-d] pyrimidine

2-chloro-6-ethyl-4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidine (Example 6; 0.1 g), 1-butanol (2.0 mL), and Piperazine (0.051 mL) was placed in a 2-drum screw cap vial and placed in a Lab-Line MAX Q2000 orbital shaker at 110 ° C. for 24 hours. Piperidine (0.025 mL) was added and heating continued for an additional 24 hours. The vial was removed from the orbital shaker and the contents were allowed to cool. The solvent was then evaporated in a vacuum oven heated to 40 ° C. To the residue was added THF (10 mL), isocyanate resin (1.1 g; Aldrich, loading 1.84 mmol NCO / g), and tetraalkylammonium carbonate resin (0.7 g; Aldrich, loading 2.86 mmol / g). The vial was then shaken on a shaker block for 2 hours at room temperature. Diatomaceous earth and decolorizing carbon were added and the vial was shaken for an additional hour. The filtrate was concentrated and the residue was chromatographed on silica gel with ethyl acetate-hexane (10/90) to give 0.056 g of the title compound: MS (ESI +) for C25 H31 N5 O1 S ₁ / z 450.2 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.28 (t, 3 H), 1.57 (s, 7 H), 1.59 (m, 2 H), 2.82 (q, 2 H), 3.6 (s, 3 H), 3.79 (m, 5 H), 3.9 (s, 3 H), 6.7 (s, 1 H), 7.28 (m, 3 H), 7.37 (m, 2 H) .

Example 10
6-Ethyl-2- (4-methylpiperazin-1-yl) -4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidine

2-chloro-6-ethyl-4- [4- (phenylacetyl) piperazin-1-yl] thieno [2,3-d] pyrimidine (Example 6; 0.1 g), 1-butanol (2.0 mL), and N-methylpiperazine (0.057 mL) was placed in a 2-drum screw cap vial and placed in a Lab-Line MAX Q2000 orbital shaker at 110 ° C. for 24 hours. N-methylpiperazine (0.029 g) was added and heating continued for an additional 24 hours. The vial was removed from the orbital shaker and the contents were allowed to cool. The solvent was then evaporated in a vacuum oven heated to 40 ° C. To the residue was added THF (10 mL), isocyanate resin (1.1 g; Aldrich, loading 1.84 mmol NCO / g), and tetraalkylammonium carbonate resin (0.7 g; Aldrich, loading 2.86 mmol / g). The vial was then shaken on a shaker block for 2 hours at room temperature. Diatomaceous earth and decolorizing carbon were added and the vial was shaken for an additional hour. The filtrate was concentrated and the residue was chromatographed on silica gel with methanol-dichloromethane (2/98) to give 0.032 g of the title compound: MS (ESI +) for C25 H32 N6 O1 S ₁ m / z 465.2 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.3 (t, 3 H), 2.34 (s, 3 H), 2.46 (m, 4 H), 2.8 (q, 2 H ), 3.6 (s, 5 H), 3.75 (m, 9 H), 6.73 (s, 1 H), 7.28 (m, 3 H), 7.34 (m, 2 H).

Example 11
4- (2-Chloro-6-ethylthieno [2,3-d] pyrimidin-4-yl) piperazine-1-carboxylate t-butyl

To a mixture of 2,4-dichloro-6-ethylthieno [2,3-d] pyrimidine (Example 3; 10.38 g) in dry THF (60 mL) was added diisopropylethylamine (19.4 mL) and Boc-piperazine (9.9%). g) was added. The mixture was stirred at room temperature for 6 hours, at which time the solvent was removed under reduced pressure and the residue was partitioned between brine and dichloromethane. The layers were separated and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to dryness to give 15.35 g of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.36 (t, 3 H), 1.49 (s, 9 H), 2.89 (q, 2 H), 3.62 (m, 4 H), 3.91 (m, 4 H), 6.95 (s, 1 H).

Example 12
2-Chloro-6-ethyl-4-piperazin-1-ylthieno [2,3-d] pyrimidine dihydrochloride

HCl gas was bubbled into dry 1,4-dioxane (400 mL) for 15 minutes. The mixture was cooled to room temperature and t-butyl 4- (2-chloro-6-ethylthieno [2,3-d] pyrimidin-4-yl) piperazine-1-carboxylate in dry 1,4-dioxane (Examples) 11; 22.1 g) was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, dichloromethane was added and the resulting solid was collected by filtration to give 19.22 g of the title compound: ¹ H NMR 400 MHz, DMSO-d ₆ ) 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 13
4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -2-chloro-6-ethylthieno [2,3-d] pyrimidine

To a mixture of 2-chloro-6-ethyl-4-piperazin-1-ylthieno [2,3-d] pyrimidine dihydrochloride (Example 12; 1.02 g) in DMF (5.0 mL) was added diisopropylethylamine (2.0 mL). mL) and 4-biphenylcarbonyl chloride (0.63 g) were added. The mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed 4 times with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in ethyl acetate, adsorbed onto silica gel, and placed on a 1/2 inch silica gel plug in a 60 mL sintered glass wax. The silica was washed with dichloromethane to remove impurities, then eluted with ethyl acetate and concentrated to give 0.966 g of the title compound: MS (ESI +) for C25 H23 Cl1 N4 O1 S ₁ m / z 465.14 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) 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
4- (1,1'-biphenyl-4-ylcarbonyl) piperazine-1-carboxylate t-butyl

To a mixture of Boc-piperazine (5.0 g) in THF (100 mL) was added 4-biphenylcarbonyl chloride (3.9 g) and diisopropylethylamine (6.0 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between brine and ethyl acetate. The layers were separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate to give 6.0 g of the title compound: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.47 (s, 9 H), 3.4 -3.8 (m, 8H), 3.73 (m, 1H), 7.43-7.48 (m, 4H), 7.57-7.64 (m, 4H).

Example 15
1- (1,1'-biphenyl-4-ylcarbonyl) piperazine hydrochloride

HCl gas was bubbled into methanol (100 mL) for 20 minutes and the solution was cooled to room temperature. 4- (1,1′-biphenyl-4-ylcarbonyl) piperazine-1-carboxylate t-butyl (Example 14; 6.0 g) was added. The mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure and hexane was added to the residue. The resulting solid was collected by filtration to give 4.8 g of the title compound: ¹ H NMR 400 MHz, DMSO-d ₆ ) 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-Chloro-6-ethyl-4-piperazin-1-ylthieno [2,3-d] pyrimidine

HCl gas was dissolved in methanol (100 mL) 4- (2-chloro-6-ethylthieno [2,3-d] pyrimidin-4-yl) piperazine-1-carboxylate t-butyl (Example 11; 6.36 Infused into g) for 1 minute. The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 3.65 g of the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) 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 17
1- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} pyrrolidin-3-ol

4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -2-chloro-6-ethylthieno [2,3-d] pyrimidine (Example 13; 0.15 g) To the mixture in 1-butanol (1.5 mL) was added 3-pyrrolidinol (0.059 g). The mixture was placed in a vial with a 2-drum screw cap. The vial was placed in a Lab-Line MAX Q2000 orbital shaker at 105 ° C. for 18 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate as eluent to give 0.159 g of the title compound: MS (ESI +) for C29 H31 N5 O2 S ₁ m / z 514.41 (M + H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 1.3 (t, 3 H), 1.65 (m, 2 H), 2.04 (m, 1 H), 2.1 (m, 1 H), 2.79 (q, 2 H ), 3.6-4.9 (m, 10 H), 4.56 (m, 1 H), 6.73 (s, 1 H), 7.4 (m, 1 H), 7.46 (m, 2 H), 7.51 (d, 2 H ), 7.6 (d, 2 H), 7.66 (d, 2 H).

Example 18
4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethyl-2-piperazin-1-ylthieno [2,3-d] pyrimidine

4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -2-chloro-6-ethylthieno [2,3-d] pyrimidine (Example 13; 1.05 g) To the mixture in 1-butanol (3.0 mL), Boc-piperazine (0.89 g) was added. The mixture was placed in a vial with a 2-drum screw cap. The vial was placed in a Lab-Line MAX Q2000 orbital shaker at 105 ° C. for 18 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate-hexane (50/50) as eluent. Appropriate fractions were combined, concentrated to dryness and then dissolved in methanol (10 mL). HCl gas was bubbled through the mixture for 30 seconds and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was chromatographed on silica gel using methanol-dichloromethane (8/92) as eluent to give 0.228 g of the title compound: MS (ESI +) for C29 H32 N6 O1 S ₁ m / z 513.40 (M + H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.3 (t, 3 H), 2.79 (q, 2 H), 3.0 (m, 4 H), 3.6-4.0 (m, 12 H ), 6.74 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.51 (d, 2 H), 7.6 (d, 2 H), 7.66 (d, 2 H).

Example 19
((2S) -1- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} pyrrolidine -2-yl) methanol

4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -2-chloro-6-ethylthieno [2,3-d] pyrimidine (Example 13; 0.2 g) To the mixture in 1-butanol (1.5 mL) was added (S)-(+)-2-pyrrolidinemethanol (0.092 g). The mixture was placed in a vial with a 2-drum screw cap. After placing the vial in a Lab-Line MAX Q2000 orbital shaker at 105 ° C. for 18 hours, the mixture was cooled to room temperature and partitioned between brine and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel using ethyl acetate-hexane (70/30) as eluent to give 0.151 g of the title compound: MS (ESI +) for C30 H33 N5 O2 S ₁ m / z 528.46 (M + H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.3 (t, 3 H), 1.66 (m, 1 H), 1.8-2.0 (m, 2 H), 2.1 (m, 1 H), 2.79 (q, 2 H), 3.5-4.0 (m, 12 H), 4.3 (m, 1 H), 6.7 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.51 (d, 2 H), 7.62 (d, 2 H), 7.66 (d, 2 H).

Example 20
((2R) -1- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} pyrrolidine -2-yl) methanol

4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -2-chloro-6-ethylthieno [2,3-d] pyrimidine (Example 13; 0.16 g) To the mixture in 1-butanol (1.5 mL) was added (R)-(−)-2-pyrrolidinemethanol (0.073 g). The mixture was placed in a vial with a 2-drum screw cap. The vial was placed in a Lab-Line MAX Q2000 orbital shaker at 105 ° C. for 18 hours. The mixture was cooled to room temperature and partitioned between brine and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel using ethyl acetate-hexane (70/30) as eluent to give 0.0676 g of the title compound: MS (ESI +) for C30 H33 N5 O2 S ₁ m / z 528.46 (M + H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.3 (t, 3 H), 1.66 (m, 1 H), 1.8-2.0 (m, 2 H), 2.1 (m, 1 H), 2.79 (q, 2 H), 3.5-4.0 (m, 12 H), 4.3 (m, 1 H), 6.7 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.51 (d, 2 H), 7.62 (d, 2 H), 7.66 (d, 2 H).

Example 21
2- (4- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} piperazine-1 -Il) ethanol

4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -2-chloro-6-ethylthieno [2,3-d] pyrimidine (Example 13; 0.15 g) To the mixture in 1-butanol (2.0 mL) was added 1- (2-hydroxyethyl) piperazine (0.089 g). The mixture was placed in a vial with a 2-drum screw cap. The vial was placed in a Lab-Line MAX Q2000 orbital shaker at 105 ° C. for 18 hours. The mixture was cooled to room temperature and concentrated. The residue was chromatographed on silica gel using methanol-ethyl acetate (10/90) as eluent to give 0.0636 g of the title compound: MS (ESI +) for C31 H36 N6 O2 S ₁ m / z 557.49 (M + H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.3 (t, 3 H), 2.57 (m, 6 H), 2.8 (qw, 2 H), 3.6-4.0 (m, 14 H), 6.74 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.53 (d, 2 H), 7.60 (d, 2 H), 7.66 (d, 2 H) .

Example 22
2- [2- (4- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} Piperazin-1-yl) ethoxy] ethanol

4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -2-chloro-6-ethylthieno [2,3-d] pyrimidine (Example 13; 0.15 g) To the mixture in 1-butanol (2.0 mL) was added 1- [2- (2-hydroxyethoxy) ethylpiperazine (0.118 g). The mixture was placed in a vial with a 2-drum screw cap. The vial was placed in a Lab-Line MAX Q2000 orbital shaker at 105 ° C. for 18 hours. The mixture was cooled to room temperature and concentrated. The residue was chromatographed on silica gel using methanol-ethyl acetate (10/90) as eluent to give 0.1024 g of the title compound: MS (ESI +) for C33 H40 N6 O3 S ₁ m / z 601.58 (M + H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.3 (t, 3 H), 2.57 (m, 4 H), 2.62 (m, 2 H), 2.79 (q, 2 H) , 3.6-4.0 (m, 18 H), 6.73 (s, 1 H), 7.38 (m, 1 H), 7.46 (m, 2 H), 7.51 (d, 2 H), 7.6 (d, 2 H) , 7.66 (d, 2 H).

Example 23
4- {4- [4- (1,1'-biphenyl-4-ylcarbonyl) piperazin-1-yl] -6-ethylthieno [2,3-d] pyrimidin-2-yl} piperazin-2-one

4- [4- (1,1′-biphenyl-4-ylcarbonyl) piperazin-1-yl] -2-chloro-6-ethylthieno [2,3-d] pyrimidine (Example 13; 0.15 g) To the mixture in NMP (3.0 mL) and DIEA (0.084 g) was added piperazinone (0.035 g). The mixture was placed in a vial with a 2-drum screw cap. The vial was placed in a Lab-Line MAX Q2000 orbital shaker at 105 ° C. for 36 hours. The mixture was cooled to room temperature and then partitioned between brine and ethyl acetate. The layers were separated and the organic layer was washed 3 times with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel using ethyl acetate as eluent to give 0.1173 g of the title compound: MS (ESI +) for C29 H30 N6 O2 S ₁ m / z 527.32 (M + H) ^{+ 1} H NMR (400 MHz, CDCl ₃ ) δ 1.31 (t, 3 H), 2.81 (q, 2 H), 3.46 (m, 2 H), 3.6-4.0 (m, 8 H), 4.03 (m, 2 H), 4.41 (s, 2 H), 6.19 (s, 1 H), 6.77 (s, 1 H), 7.4 (m, 1 H), 7.46 (m, 2 H), 7.51 (m, 2 H ), 7.61 (m, 2 H), 7.66 (m, 2 H).

Example 24
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 minutes at which point 2-chloro-6-ethyl-4-piperazin-1-ylthieno [2,3-d] pyrimidine dihydrochloride (Example 12; 0.750 g) and trimethylamine (0.33 mL) Of slurry in dichloromethane (15 mL) and DMF (1 mL). The mixture was stirred overnight and then partitioned between dichloromethane, saturated 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; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H), 2.88 (2H), 3.6-4.1 ( 8 H), 6.93 (1H), 7.36-7.53 (5H), 7.58 (2H), 7.67 (2H).

  Other compounds of formula I that can be prepared by the method of the present invention include those listed in Table E.

O. Biological protocol
In vitro assay Inhibition of [ ³³ P] 2MeS-ADP binding to washed human platelet membranes The ability of test compounds to bind to the P2Y12 receptor was assessed in a platelet membrane binding assay. In this competitive binding assay, test compounds competed with the radiolabeled agonist for binding to the P2Y12 receptor on the surface of the platelets. The binding inhibition of the labeled substance was measured, and the correlation with the amount and titer of the test compound was examined. Data obtained from this assay are shown in Table F. Platelet rich plasma ("PRP") was obtained from the Interstate Blood bank (Memphis, TN). Platelet rich plasma was prepared by ACD (prepared by: (1) 2.5 g sodium citrate (Sigma S-4641); 1.5 g citric acid (Sigma C-0706); and 2.0 g dextrose (Sigma G-7528) Prepared from a blood unit collected in (2) pH to 4.5; and (3) Water added to bring the volume to 100 mL) using a light centrifugation protocol; With centrifugation at a speed of up to 160 × g for about 20 minutes at room temperature. Platelet rich plasma is supplied in units of about 200 ml. Dispense each unit into four 50 mL polypropylene conical tubes for centrifugation. Store blood from each donor individually.

  These 50 mL tubes were centrifuged at 1100 rpm for 15 minutes with Sorvall RT6000D (with H1000B rotor). The internal temperature of the centrifuge was maintained at about room temperature (22-24 ° C.). This centrifugation pelleted residual cellular components from the PRP preparation. The supernatant was decanted into a new 50 mL tube. In order to avoid carrying cell components after centrifugation at room temperature, approximately 5 mL of PRP was left in the test tube and discarded. The test tube was capped and inverted 2-3 times, after which it was allowed to stand at room temperature for at least 15 minutes.

  If desired, platelets may be counted from the remaining sample using a Coulter counter during this standing period. Normal human platelet count is expected to be 200,000-400,000 per μL of PRP supernatant.

The 50 mL tube containing the PRP supernatant was centrifuged at 2300-2400 rpm for 15 minutes to loosely pellet the platelets. The supernatant from this centrifugation was immediately decanted into a clean cell culture bottle (Corning bottle) and stored for further centrifugation. Pellet each tube with 2-4 mL of wash buffer (pH 6.5) (freshly prepared daily 1 L-134 mM NaCl (Sigma S-5150); 3 mM KCl (Sigma P-9333)); 1 mM CaCl ₂ (JT Baker 1311-01); 2 mM MgCl ₂ (Sigma M-2670); 5 mM glucose (EM 4074-2); 0.3 mM NaH ₂ PO ₄ (Sigma S-9638) / 12 mM NaHCO ₃ (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 ACD) Resuspended by gently and repeatedly aspirating with a disposable polypropylene sample pipette.

Washing buffer (pH 6.5) was added to each tube to a volume of about 40 mL. Each tube was incubated at 37 ° C for at least 15 minutes.
The tubes were then centrifuged at 2300-2400 rpm for 15 minutes to loosely pellet the platelets. The supernatant was decanted and discarded. Pellets were added to 2-4 mL of assay buffer (pH 7.4) (volume 1 L-134 mM NaCl; 3 mM KCl; 1 mM CaCl ₂ ; 2 mM MgCl ₂ ; 5 mM glucose; 0.3 mM NaH ₂ PO ₄ / (12 mM NaHCO ₃ ; 5 mM HEPES pH 7.4; and 0.35% BSA) and resuspended by repeated repeated aspiration with a disposable polypropylene sample pipette. Only when all pellets were resuspended, the tubes were shaken gently together; pellets that were not resuspended or contained aggregates were not mixed.

The pooled platelet preparation was counted with a Coulter counter. The final concentration of platelets was 1 × 10 ⁶ / μL using assay buffer (pH 7.4). Platelets were left at 37 ° C. for at least 45 minutes prior to use in the assay.

  In one embodiment, the compounds were tested in 96 well microtiter filter plates (Millipore Multiscreen-FB opaque plates, # MAFBNOB50). These plates were used in the assay and pre-wetted with 50 μL assay buffer (pH 7.4) and then filtered thoroughly through a Millipore plate vacuum. 50 μL of the platelet suspension was then placed in these 96 well filter plates. To background control wells, 5 μL of 2MeS-ADP (100 μM working stock concentration; resulting in a final well concentration of 5 μM) and 20 μL of assay buffer were added. 25 μl of assay buffer was added to a series of wells for total binding.

25 μL of 4-fold concentration of compound was added to a 96 well filter plate as a duplicate test. 25 μL of [ ³³ P] 2MeS-ADP (Perkin Elmer NEN custom synthesis, specific activity of about 2100 Ci / mmol) was then added to all wells (1.6 nM working stock concentration; final in-well concentration 0.4 nM) ). The mixture was incubated at room temperature for 60 minutes and stirred gently by shaking.

  The reaction was stopped by washing the 96-well filter plate 3 times with 100 μl / well cold wash buffer (volume 1 L-134 mM NaCl; 10 mM Hepes pH 7.4, stored at 4 ° C.) on the plate vacuum. . The plate was disassembled and air dried overnight with the filter side up. The filter plate was fitted into the adapter plate and 0.1 mL of Microscint 20 scintillation fluid (Perkin Elmer # 6013621) was added to each well. The upper side of the filter plate was sealed with a plastic plate cover. The sealed filter plate was stirred for 30 minutes at room temperature. Counting was done using a Packard TopCount microplate scintillation counter. Compound binding is expressed as a percent reduction in binding of the ADP sample after correction for changes in the non-aggregated-control sample.

2. Inhibition of human platelet aggregation The ability of test compounds to bind to the P2Y12 receptor was assessed in a platelet aggregation assay. In this functional assay, test compounds competed with agonists for binding to the P2Y12 receptor on the surface of platelets. Inhibition of platelet aggregation was measured by standard methods. Data obtained from this assay are shown in Table F.

  As an alternative to binding assays that measure the ability of candidate compounds to bind to the P2Y12 receptor, assays that measure the effect of candidate compounds on cellular function can be employed. Candidate compounds compete with the known agonist ADP for binding to the P2Y12 receptor. ADP is sufficient to induce platelet aggregation; the presence of effective candidate compounds inhibits aggregation. Inhibition of platelet aggregation is measured by standard methods.

  Pfizer Medical Department collected whole blood (100 mL per volunteer) from volunteers in 20 mL syringes containing 2 mL of buffered citrate. In one embodiment, the buffered citrate is 0.105 M citrate, ie 0.0840 M trisodium citrate and 0.0210 M citric acid. In other embodiments, the buffered citrate is 0.109 M citrate, ie 0.0945 M trisodium citrate and 0.0175 M citric acid. The contents of the syringe were extruded into two 50 mL polypropylene conical test tubes. Blood was mixed only if it was taken from a single donor. These 50 mL tubes were centrifuged at 1100 rpm for 15 minutes with Sorvall RT6000D (with H1000B rotor). The internal temperature of the centrifuge was maintained at 22-24 ° C. and operated without using a centrifugal brake. This centrifugation pelleted residual cellular components from the PRP preparation. A PRP layer was collected from each tube and set aside. The supernatant was decanted into a new 50 mL tube. In order to avoid carrying cell components after centrifugation at room temperature, approximately 5 mL of PRP was left in the test tube and discarded.

The 50 mL test tube was returned to the centrifuge and centrifuged for 15 minutes at 2800-3000 rpm (with brake on). This pelleted most of the remaining blood particle components, leaving a layer of poor platelet plasma ("PPP"). The PPP was collected and the platelet concentration was measured with a Coulter counter. The PRP layer set aside was diluted with PPP to approximately 330,000 platelets / μl (PPP). This final preparation was dispensed into multiple 50 mL conical tubes, each loaded with only 25-30 mL of diluted PRP preparation. In one embodiment, the test tube was filled with 5% CO ₂ /95% O ₂ gas to maintain the pH of the preparation. Each test tube was covered tightly and stored at room temperature.

  Human platelet aggregation assays are performed in 96-well plates with a microtiter plate reader (SpectraMax Plus 384; with SoftMax Pro software; from Molecular Devices). Counter settings include: Absorbance at 626 nm, run time 15 minutes, read at 1 minute intervals, shake 45 seconds between readings.

  The reaction is incubated at 37 ° C. First, 18 μl of 10-fold test compound in 5% DMSO is mixed with 144 μl of fresh PRP for 30 seconds and incubated at 37 ° C. for 5 minutes. After this incubation period, 18 μl of 200 μM ADP is added to the reaction mix. This ADP addition is sufficient to induce aggregation in the absence of inhibitors. The assay results are expressed as% inhibition and are calculated using the absorbance value at 15 minutes.

3. Human P2Y12 Recombinant Cell Membrane Binding Assay Using ³³ P 2MeS-ADP The ability of test compounds to bind to the P2Y12 receptor was evaluated in a human P2Y12 recombinant cell membrane binding assay. In this competitive binding assay, test compounds competed with the radiolabeled agonist for binding to the P2Y12 receptor expressed on the cell membrane. The binding inhibition of the labeled substance was measured, and the correlation with the amount and titer of the test compound was examined. Data obtained from this assay are shown in Table F. This binding assay is a modification of the method of Takasaki, J. et. Al, Mol. Pharmacol., 2001, Vol. 60, pg.

  HEK cells were transfected with the pDONR201P2Y12 vector and cultured in MEM containing: GlutaMAX I, Earle's salts, 25 mM HEPES (Gibco # 42360-032), containing: 10% Dialysis FBS (Gibco # 26400-044), 100 μM non-essential amino acids (Gibco # 11140-050), 1 mM sodium pyruvate (Gibco # 11360-070), 0.05% geneticin (Gibco # 10131-027 ), 3 μg / mL blasticidin (trade name of Fluka; # 15205 from Sigma), and 0.5 μg / mL puromycin (Sigma # P-8833).

  Confluent cells were washed once with cold DPBS (Gibco # 14190-136). Fresh DPBS was added, the cells were scraped, and centrifuged at 500 × g, 4 ° C. for 5 minutes. Resuspend the cell pellet in TEE buffer (25 mM Tris, 5 mM EDTA, 5 mM EGTA) (referred to as TEE + Complete) containing one protease inhibitor cocktail tablet (Roche # 1 873 580) per 50 mL. Suspended. This can be quickly frozen at this point.

  In one embodiment, membranes were prepared using frozen cell pellets. In that embodiment, the frozen cell pellet was thawed on ice. In one embodiment, the cell pellet can be used without rapid freezing before moving to the next step.

  The cell pellet was resuspended in TEE buffer + Complete and homogenized 12 times in a glass dounce. This cell suspension was centrifuged at 500 × g and 4 ° C. for 5 minutes. The supernatant was collected and centrifuged at 20,000 × g and 4 ° C. for 20 minutes. The supernatant was discarded and the cell pellet was resuspended in TEE buffer + Complete and homogenized 12 times in glass dounce. This suspension was centrifuged at 20,000 × g and 4 ° C. for 20 minutes, and the supernatant was discarded. The pellet was resuspended in assay buffer (50 mM Tris, 100 mM NaCl, 1 mM EDTA) containing one protease inhibitor cocktail tablet per 50 mL. This can be quickly frozen in 1 mL portions.

  The dried compound was diluted as a 10 mM DMSO stock solution and triplicate tested in a 7-point 3-fold dilution series experiment; starting from a final concentration of 10 μM. A 1 mM DMSO intermediate stock solution was prepared in a dilution plate, from which seven dilutions were made in assay buffer containing 0.02% BSA to give a final concentration five times.

The following was added to a polypropylene assay plate (Costar # 3365): a) 30 μL assay buffer: containing 1 protease inhibitor cocktail tablet per 50 mL; b) 30 μL 1 nM ³³ P 2MeS- ADP: Prepared in assay buffer containing 0.02% BSA and 12.5 mg / mL ascorbic acid; 30 μL non-radioactive 1.5 μM 2MeS-ADP (for positive control wells), or 0.02% BSA and 12.5 mg / Assay buffer containing mL of ascorbic acid (for negative control wells), or 5 × drug dilution; and 60 μL of 1 ug / well membrane.

  Plates were incubated for 1 hour at room temperature. The reaction mixture was transferred onto a GF / B UniFilter plate (Perkin Elmer # 6005177) with a cell harvester to stop the reaction, washed 3 times with washing buffer (50 mM Tris), and filtered between each wash. The filter plate was dried in an oven at 50 ° C. for about 20 minutes. A back seal was attached to the filter plate and 25 uL of Microscint 20 scintillation fluid (Perkin Elmer # 6013621) was added. The filter plate was sealed, shaken for 30 minutes, and counted with a Top Count.

Data were analyzed by four-parameter curve fitting, with experimentally defined constant minimums and maximums as the average positive and negative controls on each plate, with a Hill slope of 1.
4). Human P2Y12 Recombinant Cell Membrane Binding Assay Using Human Serum Albumin, α-1 Acid Glycoprotein and ³³ P 2MeS-ADP The ability of test compounds to bind to the P2Y12 receptor was evaluated in a recombinant cell membrane binding assay. In this competitive binding assay, test compounds competed with the radiolabeled agonist for binding to the P2Y12 receptor expressed on the cell membrane. To mimic in vivo conditions, human protein is added to the assay mixture. The binding inhibition of the labeled substance was measured, and the correlation with the amount and titer of the test compound was examined. Data obtained from this assay are shown in Table F.

  HEK cells were transfected with the pDONR201P2Y12 vector and cultured in MEM containing: GlutaMAX I, Earl's salts, 25 mM HEPES (Gibco # 42360-032), containing: 10% dialyzed FBS ( Gibco # 26400-044), 100 μM non-essential amino acids (Gibco # 11140-050), 1 mM sodium pyruvate (Gibco # 11360-070), 0.05% geneticin (Gibco # 10131-027), 3 μg / mL Blasticidin (trade name of Fluka; # 15205 from Sigma), and 0.5 μg / mL puromycin (Sigma # P-8833).

  Confluent cells were washed once with cold DPBS (Gibco # 14190-136). Fresh DPBS was added, the cells were scraped, and centrifuged at 500 × g, 4 ° C. for 5 minutes. Resuspend the cell pellet in TEE buffer (25 mM Tris, 5 mM EDTA, 5 mM EGTA) (referred to as TEE + Complete) containing one protease inhibitor cocktail tablet (Roche # 1 873 580) per 50 mL. Suspended. This can be quickly frozen at this point.

  In one embodiment, membranes were prepared using frozen cell pellets. In that embodiment, the frozen cell pellet was thawed on ice. In one embodiment, the cell pellet can be used without rapid freezing before moving to the next step.

  The cell pellet was resuspended in TEE buffer + Complete and homogenized 12 times in glass dounce. This cell suspension was centrifuged at 500 × g and 4 ° C. for 5 minutes. The supernatant was collected and centrifuged at 20,000 × g and 4 ° C. for 20 minutes. The supernatant was discarded and the cell pellet was resuspended in TEE buffer + Complete and homogenized 12 times in glass dounce. This suspension was centrifuged at 20,000 × g and 4 ° C. for 20 minutes, and the supernatant was discarded. The pellet was resuspended in assay buffer (50 mM Tris, 100 mM NaCl, 1 mM EDTA) containing one protease inhibitor cocktail tablet per 50 mL. This can be quickly frozen in 1 mL portions.

  The dried compound was diluted as a 10 mM DMSO stock solution and triplicate tested in a 7-point 3-fold dilution series experiment; starting from a final concentration of 10 μM. A 1 mM DMSO intermediate stock solution was prepared in a dilution plate, from which seven dilutions were made in assay buffer containing 0.02% BSA to give a final concentration five times.

The following was added to a polypropylene assay plate (Costar # 3365): a) 30 μL assay buffer: containing 1 protease inhibitor cocktail tablet per 50 mL; b) 30 μL 1 nM ³³ P 2MeS- ADP: prepared in assay buffer containing 0.02% BSA and 12.5 mg / mL ascorbic acid; c) 30 μL non-radioactive 1.5 μM 2MeS-ADP (for positive control wells), or 0.02% BSA and 12.5 Assay buffer containing mg / mL ascorbic acid (for negative control wells) or 5-fold drug dilution; and d) 60 μL of 1 ug / well membrane: 0.875% human serum albumin (Sigma #A -3782) and 0.0375% α-1 acidic glycoprotein (Sigma # G-9885).

  Plates were incubated for 1 hour at room temperature. The reaction mixture was transferred onto a GF / B UniFilter plate (Perkin Elmer # 6005177) with a cell harvester to stop the reaction, washed 3 times with washing buffer (50 mM Tris), and filtered between each wash. The filter plate was dried in an oven at 50 ° C. for about 20 minutes. A back seal was attached to the filter plate and 25 uL of Microscint 20 scintillation fluid (Perkin Elmer # 6013621) was added. The filter plate was sealed, shaken for 30 minutes, and counted with a Top Count scintillation counter.

Data were analyzed by four-parameter curve fitting, with experimentally defined constant minimums and maximums as the average positive and negative controls on each plate, with a Hill slope of 1.
The following table shows IC ₅₀ , K _i , and% inhibition values for compounds tested in the washed human platelet membrane binding assay (Assay 1 above) or recombinant cell membrane binding assay (Assay 3 above). The example numbers represent the compounds prepared as described in the examples given in the Examples section above. For each experiment presented, the highest concentration of candidate compound tested is listed. Multiple data sets indicate that multiple experiments were performed on the compound.

  All cited references are incorporated as described herein. When citing an element of the present invention or an exemplary embodiment thereof (one or more), the article shall mean that there is one or more element. The terms “including”, “included”, and “having” mean that they are included and that there may be other elements besides those listed. Although the invention has been described with reference to specific embodiments, the details of these embodiments should not be construed as limiting.

Claims (15)

A compound having the structure of formula I or a pharmaceutically acceptable salt of the compound:

[Where:
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 ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl, which are independently one or more substituents selected from —R ^2m May be substituted;
R ^2m is halogen, oxo, = S, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (S) R ²ⁿ , -C (O) OR ²ⁿ , -C (S) OR ²ⁿ , -C (O) SR ²ⁿ , -C (O) NR ²ⁿ R ^2o , -C (S) NR ²ⁿ R ^2o , -OR ²ⁿ , -OC (O ) R ²ⁿ , -OC (S) R ²ⁿ , -NR ²ⁿ R ^2o , -NR ²ⁿ C (O) R ^2o , -NR ²ⁿ C (S) R ^2o , -NR ²ⁿ C (O) OR ^2o , -NR ²ⁿ C (S) OR ^2o , -NR ²ⁿ S (O) ₂ R ^2o , -NR ²ⁿ C (O) NR ^2o R ^2p , -S (O) _q R ²ⁿ , -S (O) ₂ NR ²ⁿ R ^2o And selected from the group consisting of -SC (O) R ²ⁿ ;
q is 0, 1 or 2;
R ²ⁿ , R ^2o and R ^2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In that case, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents of R ^2m , R ²ⁿ , R ^2o and R ^2p are independently halogen, cyano, nitro, oxo, = S, -R ^2q , -C (O) R ^2q , -C (S) R ^2q , -C (O) OR ^2q , -C (S) OR ^2q , -C (O) SR ^2q , -C (O) NR ^2q R ^2r , -C (S) NR ^2q R ^2r , -OR ^2q , -OC (O) R ^2r , -OC (S) R ^2q , -NR ^2q R ^2r , -NR ^2q C (O) R ^2r , -NR ^2q C (S) R ^2r , -NR ^2q C (O) OR ^2r , -NR ^2q C (S) OR ^2r , -NR ^2q S (O) ₂ R ^2r , -NR ^2q C (O) NR ^2r R ^2s , ^{_{-S (O) r R 2q,}} -S (O) 2 NR 2q R 2r and -SC (O) may be substituted with one or more substituents selected from the group consisting of R ^2q;
r is 0, 1 or 2;
R ^2q , R ^2r and R ^2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In which R ^2q , R ^2r and R ^2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are independently halogen, hydroxy, cyano, oxo, = S, -SH, nitro, alkyl Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;
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 —R ^4j , —OR ^4j and —NR ^4j R ^4k ;
R ^4j and R ^4k are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cyclo Alkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl , Aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxya Kill is selected arylcarbonyl heterocyclyl, heterocyclylcarbonyl aryl, arylcarbonylamino alkyl, heterocyclylcarbonyl aminoalkyl, from the group consisting arylcarbonylaminoalkyl and heterocyclylcarbonyl aminoalkyl;
In this case, the substituents of R ^4j and R ^4k are independently halogen, haloalkyl, hydroxyalkyl, oxo, = S, nitro, cyano, -R ^4l , -OR ^4l , -C (O) R ^4l , -C (O) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S Substituted with one or more substituents selected from the group consisting of (O) ₂ R ^4m , -S (O) _b R ^4l , -SC (O) R ^4l and -SC (O) NR ^4l R ^4m May be;
b is 0, 1 or 2;
R ^4l and R ^4m are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
In which R ^4l and R ^4m alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl substituents are independently halogen, hydroxy, cyano, oxo, ═S, nitro, —SH, amino, alkyl, Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl and alkylamino;
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) —;
(a) when X ⁶ is —C (O) —, R ⁶ is selected from the group consisting of —R ^6a and —OR ^6a ;
(b) when X ⁶ represents a bond, R ⁶ is selected from the group consisting of halogen, cyano, —R ^6a and —OR ^6a ;
R ^6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
Wherein the alkyl, cycloalkyl and aryl substituents of R ^6a are independently a group consisting of halogen, hydroxy, oxo, = S, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, carboxy, aryl and heterocyclyl. And may be substituted with one or more substituents selected from A compound having the structure of formula II or a pharmaceutically acceptable salt of the compound:

[Where:
R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl, which are independently one or more substituents selected from —R ^2m May be substituted;
R ^2m is halogen, oxo, = S, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (S) R ²ⁿ , -C (O) OR ²ⁿ , -C (S) OR ²ⁿ , -C (O) SR ²ⁿ , -C (O) NR ²ⁿ R ^2o , -C (S) NR ²ⁿ R ^2o , -OR ²ⁿ , -OC (O ) R ²ⁿ , -OC (S) R ²ⁿ , -NR ²ⁿ R ^2o , -NR ²ⁿ C (O) R ^2o , -NR ²ⁿ C (S) R ^2o , -NR ²ⁿ C (O) OR ^2o , -NR ²ⁿ C (S) OR ^2o , -NR ²ⁿ S (O) ₂ R ^2o , -NR ²ⁿ C (O) NR ^2o R ^2p , -S (O) _q R ²ⁿ , -S (O) ₂ NR ²ⁿ R ^2o And selected from the group consisting of -SC (O) R ²ⁿ ;
q is 0, 1 or 2;
R ²ⁿ , R ^2o and R ^2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In that case, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents of R ^2m , R ²ⁿ , R ^2o and R ^2p are independently halogen, cyano, nitro, oxo, = S, -R ^2q , -C (O) R ^2q , -C (S) R ^2q , -C (O) OR ^2q , -C (S) OR ^2q , -C (O) SR ^2q , -C (O) NR ^2q R ^2r , -C (S) NR ^2q R ^2r , -OR ^2q , -OC (O) R ^2r , -OC (S) R ^2q , -NR ^2q R ^2r , -NR ^2q C (O) R ^2r , -NR ^2q C (S) R ^2r , -NR ^2q C (O) OR ^2r , -NR ^2q C (S) OR ^2r , -NR ^2q S (O) ₂ R ^2r , -NR ^2q C (O) NR ^2r R ^2s , ^{_{-S (O) r R 2q,}} -S (O) 2 NR 2q R 2r and -SC (O) may be substituted with one or more substituents selected from the group consisting of R ^2q;
r is 0, 1 or 2;
R ^2q , R ^2r and R ^2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In which R ^2q , R ^2r and R ^2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are independently halogen, hydroxy, cyano, oxo, = S, -SH, nitro, alkyl Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;
R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ;
R ^4j and R ^4k are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cyclo Alkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl , Aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxya Kill, arylcarbonyl heterocyclyl, heterocyclylcarbonyl aryl, arylcarbonylamino alkyl, heterocyclylcarbonyl aminoalkyl, selected arylcarbonylaminoalkyl, and from the group consisting of heterocyclyl carbonyl amino alkyl;
In this case, the substituents of R ^4j and R ^4k are independently halogen, haloalkyl, hydroxyalkyl, oxo, = S, nitro, cyano, -R ^4l , -OR ^4l , -C (O) R ^4l , -C (O) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S Substituted with one or more substituents selected from the group consisting of (O) ₂ R ^4m , -S (O) _b R ^4l , -SC (O) R ^4l and -SC (O) NR ^4l R ^4m May be;
b is 0, 1 or 2;
R ^4l and R ^4m 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) —;
(a) when X ⁶ is —C (O) —, R ⁶ is selected from the group consisting of —R ^6a and —OR ^6a ;
(b) when X ⁶ represents a bond, R ⁶ is selected from the group consisting of halogen, cyano, —R ^6a and —OR ^6a ;
R ^6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
Wherein the alkyl, cycloalkyl and aryl substituents of R ^6a are independently selected from the group consisting of halogen, oxo, = S, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, carboxy, aryl and heterocyclyl. Optionally substituted with one or more substituents]. A compound having the structure of formula III or a pharmaceutically acceptable salt of the compound:

[Where:
R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl, which are independently one or more substituents selected from —R ^2m May be substituted;
R ^2m is halogen, oxo, = S, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (S) R ²ⁿ , -C (O) OR ²ⁿ , -C (S) OR ²ⁿ , -C (O) SR ²ⁿ , -C (O) NR ²ⁿ R ^2o , -C (S) NR ²ⁿ R ^2o , -OR ²ⁿ , -OC (O ) R ²ⁿ , -OC (S) R ²ⁿ , -NR ²ⁿ R ^2o , -NR ²ⁿ C (O) R ^2o , -NR ²ⁿ C (S) R ^2o , -NR ²ⁿ C (O) OR ^2o , -NR ²ⁿ C (S) OR ^2o , -NR ²ⁿ S (O) ₂ R ^2o , -NR ²ⁿ C (O) NR ^2o R ^2p , -S (O) _q R ²ⁿ , -S (O) ₂ NR ²ⁿ R ^2o And selected from the group consisting of -SC (O) R ²ⁿ ;
q is 0, 1 or 2;
R ²ⁿ , R ^2o and R ^2p are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In that case, the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents of R ^2m , R ²ⁿ , R ^2o and R ^2p are independently halogen, cyano, nitro, oxo, = S, -R ^2q , -C (O) R ^2q , -C (S) R ^2q , -C (O) OR ^2q , -C (S) OR ^2q , -C (O) SR ^2q , -C (O) NR ^2q R ^2r , -C (S) NR ^2q R ^2r , -OR ^2q , -OC (O) R ^2r , -OC (S) R ^2q , -NR ^2q R ^2r , -NR ^2q C (O) R ^2r , -NR ^2q C (S) R ^2r , -NR ^2q C (O) OR ^2r , -NR ^2q C (S) OR ^2r , -NR ^2q S (O) ₂ R ^2r , -NR ^2q C (O) NR ^2r R ^2s , ^{_{-S (O) r R 2q,}} -S (O) 2 NR 2q R 2r and -SC (O) may be substituted with one or more substituents selected from the group consisting of R ^2q;
r is 0, 1 or 2;
R ^2q , R ^2r and R ^2s are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl;
In which R ^2q , R ^2r and R ^2s alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl substituents are independently halogen, hydroxy, cyano, oxo, = S, -SH, nitro, alkyl Optionally substituted with one or more substituents selected from the group consisting of haloalkyl, hydroxyalkyl, carboxy, alkoxy and alkoxycarbonyl;
R ⁴ is selected from the group consisting of —R ^4j , —OR ^4j and —NR ^4j R ^4k ;
R ^4j and R ^4k are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, heterocyclylcycloalkyl, cyclo Alkylaryl, cycloalkylheterocyclyl, arylaryl, heterocyclylheterocyclyl, arylheterocyclyl, heterocyclylaryl, cycloalkoxyalkyl, heterocyclyloxyalkyl, aryloxyaryl, heterocyclyloxyheterocyclyl , Aryloxyheterocyclyl, heterocyclyloxyaryl, arylcarbonylaryl, heterocyclylcarbonylheterocyclyl, aryloxya Kill, arylcarbonyl heterocyclyl, heterocyclylcarbonyl aryl, arylcarbonylamino alkyl, heterocyclylcarbonyl aminoalkyl, selected arylcarbonylaminoalkyl, and from the group consisting of heterocyclyl carbonyl amino alkyl;
In this case, the substituents of R ^4j and R ^4k are independently halogen, haloalkyl, hydroxyalkyl, oxo, = S, nitro, cyano, -R ^4l , -OR ^4l , -C (O) R ^4l , -C (O) OR ^4l , -C (O) NR ^4l R ^4m , -OC (O) R ^4l , -ONR ^4l R ^4m , -NR ^4l R ^4m , -NR ^4l C (O) R ^4m , -NR ^4l S Substituted with one or more substituents selected from the group consisting of (O) ₂ R ^4m , -S (O) _b R ^4l , -SC (O) R ^4l and -SC (O) NR ^4l R ^4m May be;
b is 0, 1 or 2;
R ^4l and R ^4m are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, aryl and heterocyclyl;
R ⁶ is selected from the group consisting of halogen, cyano, —R ^6a and —OR ^6a ;
R ^6a is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
Wherein the alkyl, cycloalkyl and aryl substituents of R ^6a are independently selected from the group consisting of halogen, oxo, = S, cyano, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, carboxy, aryl and heterocyclyl. Optionally substituted with one or more substituents]. ^4. The compound of claim 3, wherein R ^{< 6a>} is alkyl and the alkyl substituent of R ^<6a> may be substituted as described in claim 1. R ⁴ is -NR ^4j R ^4k ;
R ^4j and R ^4k are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl, wherein the alkyl and aryl of R ^4j and R ^4k may be substituted as defined in claim 1 The compound of claim 3, which is good. R ⁴ is -R ^4j or -OR ^4j ;
R ^4j is alkyl, aryl, cycloalkyl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkylaryl, arylheterocyclyl, aryloxyaryl, heterocyclyloxyaryl, aryl Selected from the group consisting of carbonylaryl, and arylcarbonylaminoalkyl, wherein the substituent of R ^4j may be substituted as described in claim 1;
4. A compound according to claim 3. R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; where the heterocyclyl is independently oxo, cyano, nitro, amino, -SR ²ⁿ , alkyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (O) OR ²ⁿ , -C (O) NR ²ⁿ R ^2o , -OR ²ⁿ , and -NR ²ⁿ R ^Optionally substituted with one or more substituents selected from the group consisting of ^2o ;
R ²ⁿ and R ^2o are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heterocyclyl;
In so doing, the alkyl, cycloalkyl, aryl, and heterocyclyl substituents of R ²ⁿ and R ^2o are independently halogen, oxo, -SR ^2q , -R ^2q , -C (O) R ^2q , -C ( Optionally substituted with one or more substituents selected from the group consisting of O) OR ^2q , —C (O) NR ^2q R ^2r , —OR ^2q , and —NR ^2q R ^2r ;
R ^2q and R ^2r are independently selected from the group consisting of hydrogen and alkyl;
Wherein R ^2q and R ^2r alkyl substituents are independently selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, —SH, nitro, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, and alkoxycarbonyl. Optionally substituted with one or more selected substituents,
4. A compound according to claim 3. R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated or fully saturated heterocyclyl; where the heterocyclyl is independently oxo, ═S, cyano, nitro , Amino, -SR ²ⁿ , alkyl, cycloalkyl, aryl, heterocyclyl, -C (O) R ²ⁿ , -C (O) OR ²ⁿ , -C (O) NR ²ⁿ R ^2o , -OR ²ⁿ , ^and- Optionally substituted with one or more substituents selected from the group consisting of NR ²ⁿ R ^2o ;
R ²ⁿ and R ^2o are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heterocyclyl;
In so doing, the alkyl, cycloalkyl, aryl, and heterocyclyl substituents of R ²ⁿ and R ^2o are independently halogen, oxo, -SR ^2q , -R ^2q , -C (O) R ^2q , -C ( Optionally substituted with one or more substituents selected from the group consisting of O) OR ^2q , —C (O) NR ^2q R ^2r , —OR ^2q , and —NR ^2q R ^2r ;
R ^2q and R ^2r are independently selected from the group consisting of hydrogen and alkyl;
Wherein R ^2q and R ^2r alkyl substituents are independently selected from the group consisting of halogen, hydroxy, cyano, oxo, ═S, —SH, nitro, alkyl, haloalkyl, hydroxyalkyl, carboxy, alkoxy, and alkoxycarbonyl. Optionally substituted with one or more selected substituents;
R ⁴ is —R ^4j or —OR ^4j ; R ^4j is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylaryl, arylalkyl, heterocyclylalkyl, arylcycloalkyl, cycloalkyl Selected from the group consisting of aryl, arylheterocyclyl, aryloxyaryl, heterocyclyloxyaryl, arylcarbonylaryl, and arylcarbonylaminoalkyl;
In this case, each substituent of R ^4j is independently selected from the group consisting of oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl. Optionally substituted with more than one substituent;
R ⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl and haloalkyl;
4. A compound according to claim 3. R ^2k and R ^2l together with the nitrogen atom to which they are attached form a partially saturated heterocyclyl;
The heterocyclyl formed together with the nitrogen atom to which they are attached from R ^2k and R ^2l is independently halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl Optionally substituted with one or more substituents selected from the group consisting of: haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl;
R ⁴ is -R ^4j ;
R ^4j is selected from the group consisting of phenylphenyl and phenylmethyl;
In this case, each substituent of R ^4j is independently selected from the group consisting of oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl. Optionally substituted with more than one substituent;
R ⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl and haloalkyl;
4. A compound according to claim 3. R ^2k and R ^2l together with the nitrogen atom to which they are attached form a fully saturated heterocyclyl;
The heterocyclyl formed together with the nitrogen atom to which they are attached from R ^2k and R ^2l is independently halogen, hydroxy, cyano, oxo, = S, nitro, -SH, amino, alkyl Optionally substituted with one or more substituents selected from the group consisting of: haloalkyl, hydroxyalkyl, carboxy, alkoxy, alkoxycarbonyl, alkylamino, aminoalkyl, hydroxyalkyl, hydroxyalkoxy and aminocarbonyl;
R ⁴ is -R ^4j ;
R ^4j is selected from the group consisting of phenylphenyl and phenylmethyl;
In this case, each substituent of R ^4j is independently selected from the group consisting of oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl. Optionally substituted with more than one substituent;
R ⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl and haloalkyl;
4. A compound according to claim 3. The heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is selected from the group consisting of morpholinyl, piperazinyl, piperazinyl and pyrrolidinyl;
Wherein the heterocyclyl may be independently substituted with one or more substituents selected from the group consisting of oxo, hydroxy, alkyl, alkylalkoxycarbonyl, hydroxyalkyl and hydroxyalkoxyalkyl;
R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of arylaryl and arylalkyl;
In this case, each substituent of R ^4j is independently selected from the group consisting of oxo, cyano, halogen, alkyl, phenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, and aminocarbonyl. Optionally substituted with more than one substituent;
R ⁶ is selected from the group consisting of hydrogen, halogen, cyano, alkyl and haloalkyl;
4. A compound according to claim 3. Heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is morpholinyl, piperazinyl, piperazinyl, methylmethoxycarbonylpiperazinyl, dimethylmethoxycarbonylpiperazinyl, trimethylmethoxycarbonylpiperazinyl. Selected from the group consisting of thiol, methylpiperazinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxyethylpiperazinyl, hydroxyethylpiperazinyl, hydroxyethoxyethylpiperazinyl and oxopiperazinyl;
R ⁴ is -R ^4j ;
R ^4j is methyl, ethyl, propyl, butyl, phenyl, fluorenyl, phenylphenyl, phenylmethyl, phenylethyl, phenylphenylmethyl, diphenylethyl, phenyloxymethyl, phenyloxyethyl, phenyloxyphenyl, naphthyloxymethyl, phenylcyclo Propyl, phenylcarbonylphenyl, phenylcarbonylaminoethyl, phenylcarbonyl (phenyl) aminoethyl, thiophenylmethyl, phenyl-oxadiazolyl, oxadiazolylphenyl, thiazolylphenyl, phenylthiazolyl, phenylpyridinyl, phenylpyrimidinyl, Selected from the group consisting of pyridinylphenyl and pyrimidinylphenyl;
In this case, each substituent of R ^4j is independently oxo, cyano, -Cl, -Br, -F, methyl, ethyl, propyl, butyl, phenyl, methoxy, trifluoromethyl, trifluoromethoxy, ethoxy, propoxy. May be substituted with one or more substituents selected from the group consisting of, butoxy, dimethylamino, carboxy, methoxycarbonyl and aminocarbonyl;
R ⁶ is ethyl,
4. A compound according to claim 3. Heterocyclyl formed from R ^2k and R ^2l together with the nitrogen atom to which they are attached is morpholinyl, piperazinyl, piperazinyl, methylmethoxycarbonylpiperazinyl, dimethylmethoxycarbonylpiperazinyl, trimethylmethoxycarbonylpiperazinyl. Selected from the group consisting of thiol, methylpiperazinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, hydroxyethylpiperazinyl, hydroxyethylpiperazinyl, hydroxyethoxyethylpiperazinyl and oxopiperazinyl;
R ⁴ is —R ^4j ; R ^4j is selected from the group consisting of phenylphenyl and phenylmethyl;
R ⁶ is ethyl,
4. A compound according to claim 3.   A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1.   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 the compound of claim 1.