Compounds and derivatives of 2H-pyrido (3,2-b)(1, 4) oxazin 3)4H)-ones as raf kinase and LRRK2 inhibitors

The present invention provides pharmaceutical compound of formula:wherein A and B are individually an C or N and R1 is an alkyl and R2 is a substituted phenyl, wherein the substituted phenyl comprises 1 to 3 functional groups and R3-R6 are individually a hydrogen, an amine or a halogen disposed in a pharmaceutical carrier.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a non-provisional patent application of U.S. provisional patent application 61/467,274 filed on Mar. 24, 2011 and entitled “Compounds and Derivatives of 2H-Pyrido(3,2-b)(1,4)Oxazin3)4H)-ones as raf Kinase and LRRK2 Inhibitors”, which is hereby incorporated by reference in its entirety.

STATEMENT OF FEDERALLY FUNDED RESEARCH

Not Applicable.

SEQUENCE LISTING

Not Applicable.

Not Applicable.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to the field of pharmaceutical compositions and synthesis, and more particularly, to novel compositions and methods for preparing the compound and its pharmaceutical use.

BACKGROUND OF THE INVENTION

U.S. patent application Ser. No. 5,696,117 entitled, Benzoxazine antimicrobial Agents, discloses benzoxazine and pyrido-oxazine antibacterial compounds, pharmaceutical compositions containing the compounds, and methods for their production and use. These compounds are effective in inhibiting the action of a bacterial histidine protein kinase and are thus useful as anti-infective agents against a variety of bacterial organisms, including organisms which are resistant to other known antibiotics.

U.S. patent application Ser. No. 5,707,990 entitled, 2-substituted amino and thio alkyl benzoxazine antimicrobial agents discloses benzoxazine and pyrido-oxazine antibacterial compounds with a fused phenyl or fused pyridyl moiety and a substituted amine or substituted thio moiety as herein described, pharmaceutical compositions containing the compounds, methods for their production and their use in treating bacterial infections.

BRIEF SUMMARY OF THE INVENTION

One embodiment of the present invention provides a compound of formula or pharmaceutical salts thereof:

wherein A and B are individually an C, O, N or S and R1 is an alkyl or an alkenyl and R2 is a phenyl, benzyloxyl, pyridyl, indolone, pyrrol, carbamoyl, pyridine, substituted phenyl, substituted benzyloxyl, substituted pyridine, or substituted pyridyl and R3-R6 are individually a hydrogen, an anime or a halogen.

One embodiment of the present invention also provides a compound of formula or pharmaceutical salts thereof:

wherein A and B are individually an C, O, N or S and R1 is an alkyl or an alkenyl and R2 is a phenyl, benzyloxyl, pyridyl, indolone, pyrrol, carbamoyl, pyridine, substituted phenyl, substituted benzyloxyl, substituted pyridine, or substituted pyridyl and R3 is a hydrogen or a halogen. In some embodiments, A is a C, B is a N and R1 is a CH and in other embodiments R1-R10are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. R8is a C1-C6Alkyl group, a C1C6alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an ether group, an ester group, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group.

One embodiment of the present invention provides a compound of formula or pharmaceutical salts thereof:

wherein A, A′, B and B′ are individually an C, O, N or S and R1 is an alkyl or an alkenyl and R2 is a phenyl, benzyloxyl, pyridyl, indolone, pyrrol, carbamoyl, pyridine, substituted phenyl, substituted benzyloxyl, substituted pyridine, or substituted pyridyl and R3 is a hydrogen or a halogen. In some embodiments, A and B′ are C, R1 is a CH, and B and A′ are N and in other embodiments R1-R10are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. R8is a C1-C6Alkyl group, a C1-C6alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an ether group, an ester group, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group.

One embodiment of the present invention provides a compound of formula or pharmaceutical salts thereof:

wherein A and B are individually an C, O, N or S and R1-R8are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. In some embodiments, A is a C, R1 is a CH, and B is a N or A is a N, R1 is a CH, and B is a C.

One embodiment of the present invention provides a compound of formula or pharmaceutical salts thereof:

wherein R1 is an alkyl or an alkenyl and R2 is a phenyl, benzyloxyl, pyridyl, indolone, pyrrol, carbamoyl, pyridine, substituted phenyl, substituted benzyloxyl, substituted pyridine, or substituted pyridyl, and R3 and R4 are independently a hydrogen, a halogen, an alkyl or an alkenyl.

One embodiment of the present invention provides a compound of formula or pharmaceutical salts thereof:

wherein A′, and B′ are selected from C, N, S, O. R2-R4are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. R8is a C1-C6Alkyl group, a C1-C6alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an ether group, an ester group, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group. R9-R13are independently selected from a H, a C1-C6Alkyl; a C1-C6Alkenyl, a halo, a substituted C1-C6alkyl, a substituted C1-C6alkenyl, a carbonyl, a carbonate ester, an acetoxy group, a an acetyl group, an ether, an ester, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl”, “alkenyl”, “alkynyl” and “alkylene” denotes hydrocarbon chains typically ranging from about 1 to about 12 carbon atoms in length, preferably 1 to about 6 atoms, and includes straight and branched chains. Unless otherwise noted, the preferred embodiment of any alkyl or alkylene referred to herein is C1-C6 alkyl (e.g., methyl or ethyl).

The term “cycloalkyl” denotes a saturated or unsaturated cyclic hydrocarbon chain, including bridged, fused, or spiro cyclic compounds, preferably comprising 3 to about 12 carbon atoms, more preferably 3 to about 8.

The term “aryl” denotes one or more aromatic rings, each of 5 or 6 core carbon atoms. Multiple aryl rings may be fused, as in naphthyl or unfused, as in biphenyl. Aryl rings may also be fused or unfused with one or more cyclic hydrocarbon, heteroaryl, or heterocyclic rings.

The term “heteroaryl” denotes an aryl group containing from one to four heteroatoms, preferably N, O, or S, or a combination thereof, which heteroaryl group is optionally substituted at carbon or nitrogen atom(s) with C1-C6 alkyl, —CF3, phenyl, benzyl, or thienyl, or a carbon atom in the heteroaryl group together with an oxygen atom form a carbonyl group, or which heteroaryl group is optionally fused with a phenyl ring. Heteroaryl rings may also be fused with one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings. Heteroaryl includes, but is not limited to, 5-membered heteroaryls having one hetero atom (e.g., thiophenes, pyrroles, furans); 5-membered heteroaryls having two heteroatoms in 1, 2 or 1,3 positions (e.g., oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteroaryls having three heteroatoms (e.g., triazoles, thiadiazoles); 5-membered heteroaryls having 3 heteroatoms; 6-membered heteroaryls with one heteroatom (e.g., pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heteroaryls with two heteroatoms (e.g., pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heteroaryls with three heteroatoms (e.g.; 1,3,5-triazine); and 6-membered heteroaryls with four heteroatoms.

The term “heterocycle” or “heterocyclic” denotes one or more rings of 5-12 atoms, preferably 5-7 atoms, with or without unsaturation or aromatic character and at least one ring atom which is not carbon. Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused.

The term “alkylene” denotes a divalent alkyl group as defined above, such as methylene (—CH2—), propylene (—CH2CH2CH2—), chloroethylene (—CHClCH2—), 2-thiobutene —CH2CH(SH)CH2CH2, 1-bromo-3-hydroxyl-4-methylpentene (—CHBrCH2CH(OH)CH(CH3)CH2—), and the like.

The term “alkenyl” denotes branched or unbranched hydrocarbon chains containing one or more carbon-carbon double bonds.

The term “alkynyl” denotes branched or unbranched hydrocarbon chains containing one or more carbon-carbon triple bonds.

The term “aryl” denotes a chain of carbon atoms which form at least one aromatic ring having preferably between about 6-14 carbon atoms, such as phenyl, naphthyl, and the like, and which may be substituted with one or more functional groups which are attached commonly to such chains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl, imidazolylmethylphenyl, and the like.

The term “alkoxy” denotes—OR—, wherein R is alkyl.

The term “amido” denotes an amide linkage: —C(O)NHR (wherein R is hydrogen or alkyl).

The term “amino” denotes an amine linkage: —NR—, wherein R is hydrogen or alkyl. The term “carboxyl” denotes—C(O)O—, and the term “carbonyl” denotes—C(O)—.

The term “alkylcarboxyl” denote an alkyl group as defined above substituted with a C(O)O group, for example, CH3C(O)O—, CH3CH2C(O)O—, etc.

The term “carbocycle” denotes cyclic hydrocarbon chain having about 5 to about 8 ring carbons such as cyclopentyl, cylcohexyl, etc. These groups can be optionally substituted with one or more functional groups as defined under “alkyl” above.

The term “halogen” includes chlorine, fluorine, bromine, iodine and mixtures thereof

The term “heterocycle” denotes straight chain or ring system that may contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.

The term “carbamoyl” denotes the group—C(O)NH2.

The term “hydroxyalkyl” denotes an alkyl group as defined above which is substituted by a hydroxy group.

The term “alkylcarbonyl”, alone or in combination, means an acyl group derived from an alkanecarboxylic acid, i.e. alkyl-C(O)—, such as acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl etc.

One embodiment of the present invention provides compound of the general formula:

wherein A, A′, B, B′ and C are selected from C, N, S, O. R1-R7are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. R8is a C1-C6Alkyl group, a C1-C6alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an ether group, an ester group, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group. R9-R13are independently selected from a H, a C1-C6Alkyl; a C1-C6Alkenyl, a halo, a substituted C1-C6alkyl, a substituted C1-C6alkenyl, a carbonyl, a carbonate ester, an acetoxy group, a an acetyl group, an ether, an ester, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group.

One embodiment of the present invention provides compound of the general formula:

wherein A′, and B′ are selected from C, N, S, O. R2-R6are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. R8is a C1-C6Alkyl group, a C1-C6alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an ether group, an ester group, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group. R9-R13are independently selected from a H, a C1-C6Alkyl; a C1-C6Alkenyl, a halo, a substituted C1-C6alkyl, a substituted C1-C6alkenyl, a carbonyl, a carbonate ester, an acetoxy group, a an acetyl group, an ether, an ester, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group.

One embodiment of the present invention provides compound of the general formula:

wherein A′, and B′ are selected from C, N, S, O. R2-R4are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. R8is a C1-C6Alkyl group, a C1-C6alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an ether group, an ester group, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group. R9-R13are independently selected from a H, a C1-C6Alkyl; a C1-C6Alkenyl, a halo, a substituted C1-C6alkyl, a substituted C1-C6alkenyl, a carbonyl, a carbonate ester, an acetoxy group, a an acetyl group, an ether, an ester, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group.

One embodiment of the present invention provides compound of the general formula:

For example, in the formula above A is a N; B is a O; Z is a N; R1, R3, R4, R5, R8, and R12are a H; R2and R6are not present; R7is a C; R9and R11are Br; and R7is a OAc. For example, in the formula above A is a N; B is a O; Z is a N; R1, R3, R4, R5, R8, and R12are a H; R2and R6are not present; R7is a C; R9and R11are H; and R7is a N(CH3)2. For example, in the formula above A is a N; B is a O; Z is a N; R1, R3, R4, R5, R8, and R12are a H; R2and R6are not present; R7is a C; and R9, R7and R11are OMe. For example, in the formula above A is a N; B is a O; Z is a N; R1, R3, R4, R5, R8, and R12are a H; R2and R6are not present; R7is a C; R9and R11, are Br; and R7is a H. For example, in the formula above A is a N; B is a O; Z is a N; R1, R3, R4, R5, R8, and R12are a H; R2and R6are not present; R7is a C; R9and R11are Br; and R7is a OH. For example, in the formula above A is a N; B is a O; Z is a N; R1, R4, R5, R8, and R12are a H; R2and R6are not present; R7is a C; R3is a Cl; R9and R11are Br; and R7is a OAc. For example, in the formula above A is a N; B is a O; Z is a N; R1, R4, R5, R8, and R12are a H; R2and R6are not present; R7is a C; R3is a CH3; R9and R11, are Br; and R7is a OAc. For example, in the formula above A is a N; B is a O and Z is a N; R1, R3, R4, R5, R8, and R12are a H; R2and R6are not present; R7is a C; R9and R11are Br; and R7is a OAc.

For example,

One embodiment of the present invention provides compound of the general formula:

wherein R2-R4are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. R8is a C1-C6Alkyl group, a C1-C6alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an ether group, an ester group, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group. R9-R12are independently selected from a H, a C1-C6Alkyl; a C1-C6Alkenyl, a halo, a substituted C1-C6alkyl, a substituted C1-C6alkenyl, a carbonyl, a carbonate ester, an acetoxy group, a an acetyl group, an ether, an ester, an alkyl alkanoate group, an alkoxy group, a keto group, and an oxo group.

For example,

A compound of formula or pharmaceutical salts thereof:

wherein A and B are individually an C, O, N or S and R1 is an alkyl or an alkenyl and R2 is a phenyl, benzyloxyl, pyridyl, indolone, pyrrol, carbamoyl, pyridine, substituted phenyl, substituted benzyloxyl, substituted pyridine, or substituted pyridyl and R3 is a hydrogen, a halogen, an amino, an alkyl or an alkenyl.

A compound of formula or pharmaceutical salts thereof:

wherein A and B are individually an C, O, N or S and R1-R10are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. For example,

A compound of formula or pharmaceutical salts thereof:

wherein A and B are individually an C, O, N or S and R1-R8are independently selected from a H, a C1-C6Alkyl group, a C1-C6Alkenyl group, a halo group, a substituted C1-C6alkyl group, a substituted C1-C6alkenyl group, a carbonyl group, a carbonate ester group, an C1-C6ether group, an C1-C6ester group, an C1-C6alkyl alkanoate group, an C1-C6alkoxy group, a keto group, and an oxo group. For example: