CN108341819A - Phosphodiesterase inhibitors and application thereof - Google Patents

Phosphodiesterase inhibitors and application thereof Download PDF

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Publication number
CN108341819A
CN108341819A CN201810021338.3A CN201810021338A CN108341819A CN 108341819 A CN108341819 A CN 108341819A CN 201810021338 A CN201810021338 A CN 201810021338A CN 108341819 A CN108341819 A CN 108341819A
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alkyl
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base
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optionally
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CN108341819B (en
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吴永谦
王琳
杨小菊
田玉伟
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Yaojie Ankang (Nanjing) Technology Co.,Ltd.
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Transthera Bioscience Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention belongs to pharmaceutical technology fields, more particularly to phosphodiesterase 9 (PDE9) inhibitor shown in formula I, its pharmaceutically acceptable salt, solvated compounds, polymorph and isomers, the invention further relates to the pharmaceutical preparation of these compounds, pharmaceutical composition and its applications.Compound involved in the present invention and its pharmaceutically acceptable salt, solvated compounds, polymorph and isomers can be applied to the treatment of the relevant disease of phosphodiesterase 9 (PDE9) unconventionality expression mediation.

Description

Phosphodiesterase inhibitors and application thereof
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to phosphodiesterase inhibitors shown in formula I pharmaceutically may be used Salt, solvated compounds, polymorph and the isomers of receiving, compound involved in the present invention can be applied to phosphodiesterase 9 (PDE9) treating correlative diseases that unconventionality expression mediates.
Background technology
Phosphodiesterase (phosphodiesterass, PDEs) is a kind of protease, and degradation that can be selective is important in vivo Second messenger cGMP (cyclic guanosine monophosphate) and cAMP (cyclic adenosine monophosphate), to participate in important physiology course in vivo.Foundation The sequence homology of gene and selectivity to cGMP or cAMP, PDEs can be divided into (PDE1-PDE11) 11 members.Wherein, PDE9A is important a member in PDE families, and wide expression is in testis, brain, small intestine, bone flesh, heart, lung, thymus gland and pancreas It is dirty.As research in recent years is goed deep into, having more document reports and clinical data proves, PDE9A inhibitor for treat by Disease in terms of the cognitive impairment caused by central nervous system disorder, such as senile dementia and schizophrenia, brain Neurodegenerative process disease.
Both nucleotide of cAMP and cGMP are important second messenger, and core work is played in cell signaling processes With；Their main activated protein kinases：Protein kinase A (PKA) is referred to as by cAMP activation, is swashed by the albumen that is referred to as of cGMP activation Enzyme G (PKG).The PKA and PKG being activated can with many cytological effect albumen of phosphorylation, such as ion channel, G- protein couplings by Body, structural proteins, transduction factors.Therefore, cAMP and cGMP may control most of lifes in many organs in this way Reason process.Meanwhile cAMP and cGMP can also directly act on effect protein, it is above-mentioned identical to play the role of.Many institute's weeks Know, cGMP can directly act on ion receptor, to influence the ion concentration in cell.Phosphodiesterase (PDEs) hydrolyzes ring Shape phosplate cAMP and cGMP are translated into the phosplate AMP and GMP of inactivation.
The PDE9A of the mankind was most cloned and was sequenced early in 1998, was reported so far to cGMP selectivity highests PDE.The binding constant (Km) of PDE9A and cGMP is 170nM, and is up to 230000nM to the binding constant value of cAMP, is selected Property is more than 1000 times.Compare with PDE2A and PDE5A, since PDE9A does not have the calmodulin binding domain CaM of cGMP, the catalysis of PDE9A to live Property can't be enhanced by cGMP, so PDE9A inhibitor may improve baseline cGMP concentration.
Traditional PDE inhibitor cannot inhibit mankind PDE9A, therefore, drug IBMX, dipyridamole, SKF94120, Rolipram and vinpocetine does not have inhibitory activity or very low to PDE9A.Currently on the market without PDE9A inhibitor medicines Object is more only being in the inhibitor of clinical development.It is public by the PF-04447943 and BI of Pfizer companies respectively The two class PDE9A inhibitor of BI-409306 of department, structural formula difference are as follows：
Mesh the first two compound is in a phase and the second stage of clinical stage.Although being researched and developed by Liang Jia different companies, this two class PDE9A inhibitor is all based on parent nucleus 4- hydroxypyrazoles simultaneously [3,4-d] pyrimidine.
Invention content
The purpose of invention is to provide a kind of PDE9 kinase inhibitors, and the compounds of this invention presses down with good PDE9A kinases System activity and druggability, can be applied to the treatment of the relevant disease mediated by PDE9 unconventionality expressions.
The technical solution adopted by the present invention is as follows：
Scheme one, a kind of PDE9 kinases (phosphodiesterase 9) inhibitor indicated by the following general formula (I) or its pharmaceutically Acceptable salt, solvated compounds, polymorph and isomers：
Wherein, n is selected from 0,1 or 2；
X is selected from N or CR1；
R1Independently selected from hydrogen, C1-6Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-6Naphthenic base, halogenated C1-6Alkyl ,-(CH2)m’- C3-6Naphthenic base, m '=1 or 2；
R2It is independent to be selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C3-6Naphthenic base Oxygroup, C3-6Cycloalkyl amino, halogenated C3-6Naphthenic base, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl sulphonyl, C3-8First naphthenic base sulphur Acyl group, C1-6Alkyl sulfenyl, C2-8Alkenyl (C3-6) naphthenic base, C2-8Alkynyl (C3-6) naphthenic base, C1-6Alkyl-carbonyl, C3-6Naphthenic base Carbonyl ,-(CH2)n’- 3-14 members naphthenic base ,-(CH2)n’- 5-14 members aromatic ring ,-(CH2)n’- 5-10 circle heterocyclic rings base ,-(CH2)n’-5- 10 unit's heteroaryls, the heterocycle, heteroaryl contain 1-3 O, S and/or N atom, wherein the arbitrary annular atom of heterocycle, heteroaryl Sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O), n '=0,1 or 2, ring Alkyl, heterocycle, aromatic ring, hetero-aromatic ring can be optionally by 1-3 R5Substitution；
Wherein, when X is selected from CR1When, and R1For hydrogen when, R2Cannot be
R3Independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C3-6Naphthenic base, C1-6Alkoxy, C3-6Cycloalkyl oxy, halogenated C1-6Alkoxy, halogenated C1-6Alkyl, halogenated C3-6Naphthenic base, C2-8Alkenyl, C2-8Alkynes Base, amino C1-6Alkyl, C3-6Cycloalkyl amino, C1-6Alkyl sulphonyl, 3-8 membered rings alkyl sulphonyl, C1-6Alkyl-carbonyl, C3-6 Naphthene base carbonyl, C1-6Alkyl sulfenyl, 3-14 members naphthenic base, 5-14 members aromatic ring, -5-10 circle heterocyclic rings base, -5-10 unit's heteroaryls, institute State heterocycle, heteroaryl contains 1-3 O, S and/or N atom, wherein the arbitrary annular atom sulphur of heterocycle, heteroaryl can be optionally by oxygen Turn to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O), naphthenic base, aromatic ring, hetero-aromatic ring, heterocycle It can be optionally by 1-3 R6Substitution；
R4Independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C3-6Cycloalkyl oxy, halogenated C1-6Alkoxy, halogenated C1-6Alkyl, halogenated C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl, amino C1-6 Alkyl, C3-6Cycloalkyl amino, C1-6Alkyl sulphonyl, 3-8 membered rings alkyl sulphonyl, C1-6Alkyl-carbonyl or C3-6Naphthenic base carbonyl Base, C1-6Alkyl sulfenyl or-(CH2)n’- 3-7 members naphthenic base ,-(CH2)n’- 5-6 members aromatic ring ,-(CH2)n' -- 5-7 circle heterocyclic rings base ,- (CH2)n’-- 5-6 unit's heteroaryls, the heterocycle, heteroaryl contain 1-3 O, S and/or N atom, wherein heterocycle, heteroaryl Arbitrary ring S can optionally be oxidized to S (O) or S (O)2, arbitrary ring carbon is optionally oxidized to C (O), n '=0,1 or 2, ring Alkyl, aromatic ring, hetero-aromatic ring, heterocycle can be optionally by 1-3 R7Substitution；
R5It is independent be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, trifluoromethyl, methoxyl group ,- (CH2)n’- 3-14 members naphthenic base ,-(CH2)n’- 5-14 members aromatic ring ,-(CH2)n’-- 5-10 circle heterocyclic rings base ,-(CH2)n’-- 5-10 members Heteroaryl, the heterocycle, heteroaryl contain 0-3 O, S and/or N atom, wherein n '=0,1 or 2；
R6、R7It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, trifluoromethyl, C1-6Alkyl, C1-4Alkoxy, C1-6Alkyl sulphonyl, C1-6Alkyl sulphonyl C1-6Alkyl, C1-6Alkyl sulphonyl C1-6Alkoxy, aminosulfonyl Amino C1-6Alkyl, methoxyl group, cyclopropyl ,-(CH2)m’-C3-6Naphthenic base, m '=1 or 2.
Scheme two, the PDE9 kinase inhibitors as described in scheme one or its pharmaceutically acceptable salt, solvated compounds, Polymorph and isomers, wherein general structure is such as shown in (II)：
N is selected from 0,1 or 2；
X is selected from N or CR1；
R1Independently selected from hydrogen, methyl, ethyl, cyclopropyl ,-CH2Cyclopropyl, trifluoromethyl；
Ring A is selected from optional-(CH2)n’- 3-14 members naphthenic base ,-(CH2)n’- 5-14 members aromatic ring ,-(CH2)n’- 5-10 members are miscellaneous Ring group ,-(CH2)n’- 5-10 unit's heteroaryls, the heterocycle, heteroaryl contain 1-3 O, S and/or N atom, wherein ring A is optional By 1-3 R5Substitution, arbitrary annular atom sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally by oxygen Turn to C (O)；N '=0,1 or 2；
Wherein, when X is selected from CR1When, and R1For hydrogen when, R2Cannot be
R5It is independent be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, trifluoromethyl, methoxyl group ,- (CH2)n’- 3-14 members naphthenic base ,-(CH2)n’- 5-14 members aromatic ring ,-(CH2)n’- 5-10 circle heterocyclic rings base ,-(CH2)n’- 5-10 members are miscellaneous Aryl, the heterocycle, heteroaryl contain 0-3 O, S and/or N atom, wherein n '=0,1 or 2.
3. scheme three, the PDE9 kinase inhibitors as described in scheme two or its pharmaceutically acceptable salt, solvent chemical combination Object, polymorph and isomers, wherein general structure is such as shown in (III-1), (III-2)：
Wherein,
Ring A ' be selected from 5-7 members naphthenic base, 5-7 members aromatic ring, -5-7 circle heterocyclic rings base or -5-7 member hetero-aromatic rings, the heterocycle, Heteroaryl contains 1-3 O, S and/or N atom, and arbitrary annular atom sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom Carbon is optionally oxidized to C (O)；
Ring A " be selected from 5-7 members naphthenic base, 5-7 members aromatic ring, -5-7 circle heterocyclic rings base or -5-7 member hetero-aromatic rings, the heterocycle, Heteroaryl contains 1-3 O, S and/or N atom, and arbitrary annular atom sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom Carbon is optionally oxidized to C (O)；
Wherein, ring A " cannot be
Ring A ' and ring A " is optionally by 1-3 R5Substitution,
R5It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, cyclopropyl, trifluoro Methyl ,-CH2Cyclopropyl.
Scheme four, the PDE9 kinase inhibitors as described in scheme three or its pharmaceutically acceptable salt, solvated compounds, Polymorph and isomers, wherein
Ring A ' is selected from 5-7 members naphthenic base, 5-7 circle heterocyclic ring bases, and the heterocycle contains 1-3 O, S and/or N atom, arbitrary ring Atomic sulfur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O)；
Ring A " is selected from 5-7 members naphthenic base, 5-7 circle heterocyclic ring bases, and the heterocycle contains 1-3 O, S and/or N atom, arbitrary ring Atomic sulfur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O)；
Wherein, ring A " cannot be
Ring A ' and ring A " is optionally by 1-3 R5Substitution,
R5It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, cyclopropyl, trifluoro Methyl ,-CH2Cyclopropyl；
R3It is described independently selected from hydrogen, 3-7 members naphthenic base, 5-7 members aromatic ring, -5-7 circle heterocyclic rings base or -5-7 member hetero-aromatic rings Heterocycle, heteroaryl contain 1-3 O, S and/or N atom, wherein naphthenic base, heterocycle, aryl, heteroaryl are optionally by 1 or 2 A R6Substitution, the arbitrary annular atom sulphur S of heterocycle, heteroaryl can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon can Optionally it is oxidized to C (O)；
R6It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, ring Propyl, trifluoromethyl, C1-4Alkyl sulphonyl, C1-4Alkyl sulphonyl C1-4Alkyl, C1-4Alkyl sulphonyl C1-4Alkoxy, amino Sulfonamido C1-4Alkyl ,-CH2Cyclopropyl.
Scheme five, the PDE9 kinase inhibitors as described in scheme four or its pharmaceutically acceptable salt, solvated compounds, Polymorph and isomers, wherein
Ring A ' is selected from 5-7 circle heterocyclic ring bases, and the heterocycle contains 1-3 O, S and/or N atom, and arbitrary annular atom sulphur can be optional It is oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O)；
Ring A " is selected from 5-7 circle heterocyclic ring bases, and the heterocycle contains 1-3 O, S and/or N atom, and arbitrary annular atom sulphur can be optional It is oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O)；
Wherein, ring A " cannot be
Ring A ' and ring A " is optionally by 1-3 R5Substitution,
R5It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, cyclopropyl, trifluoro Methyl ,-CH2Cyclopropyl；
R4It is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C3-6 Cycloalkyl oxy, halogenated C1-4Alkoxy, C3-6Cycloalkyl amino ,-CH2Cyclopropyl, C1-4Alkyl sulphonyl, 3-8 member naphthenic base Sulfonyl, C1-4Alkyl-carbonyl or C3-6Naphthene base carbonyl.
Scheme six, the PDE9 kinase inhibitors as described in scheme five or its pharmaceutically acceptable salt, solvated compounds, Polymorph and isomers, wherein
Wherein,
R3It preferably is selected from following group：Hydrogen,
Ring A ' and ring A " are respectively and independently selected from following group：
Preferred compounds of the invention, its pharmaceutically acceptable salt, solvated compounds, polymorph and isomers：
Detailed description of the invention：
" halogen " of the present invention refers to fluorine, chlorine, bromine, iodine etc., preferably fluorine atom, chlorine atom.
" oxo " of the present invention, which refers to any carbon atom in substituent structure, to be replaced by "-C (O)-"；If containing Hetero atom, hetero atom can form oxide, such asIt can quiltIt replaces, such as arbitrary ring S is optionally oxidized to S (O) Or S (O)2。
It is of the present invention it is " halogenated " refer to that any carbon atom in substituent group can be by one or more identical or different Halogen replaces." halogen " as defined hereinabove.
" C of the present invention1-6Alkyl " refers to the hydrocarbon part containing 1-6 carbon atom and removes straight chain derived from a hydrogen atom Or the alkyl of branch, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary butyl, n-pentyl, different Amyl, 2- methyl butyls, neopentyl, 1- ethyl propyls, n-hexyl, isohesyl, 4- methyl amyls, 3- methyl amyls, 2- methyl Amyl, 1- methyl amyls, 3,3- dimethylbutyls, 2,2- dimethylbutyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,3- dimethylbutyls, 2- ethyl-butyls and 1- methyl -2- methyl-propyls etc.." the C1-4Alkyl " refers to Examples detailed above containing 1-4 carbon atom.
" C of the present invention1-6Alkyl-carbonyl-amino ", " C1-6Alkyl amino-carbonyl ", " C1-6Alkyl sulphonyl " is difference Refer to C1-6Alkyl-C (O)-NH-, C1-6Alkyl-NH-C (O)-, C1-6Alkyl-S (O)2-；" the C1-6Alkyl " as defined hereinabove, Preferably " C1-4Alkyl ".
" C of the present invention1-6Alkoxy " refers to " C defined hereinabove1-6Alkyl " passes through oxygen atom and parent molecule The group of part connection, i.e. " C1-6Alkyl-O- " groups, such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy, uncle Butoxy, n-pentyloxy, neopentyl oxygen and positive hexyloxy etc.." the C1-4Alkoxy " refers to above-mentioned containing 1-4 carbon atom Example, i.e. " C1-4Alkyl-O- " groups.
" naphthenic base " of the present invention, can be 3-14 member naphthenic base, including monocyclic cycloalkyl or condensed ring naphthenic base, Can be saturation, fractional saturation or it is unsaturated, but be not armaticity.Monocyclic cycloalkyl can be 3-8 members naphthenic base, 5- 7 yuan of naphthenic base, the example include but not limited to：Cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, ring Octyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, 1,4- cyclohexadienyls, cycloheptenyl, 1,4- cycloheptadiene base, ring are pungent Alkenyl, 1,5- cyclo-octadiene bases etc..Condensed ring naphthenic base includes simultaneously ring naphthenic base, bridge ring alkyl, spiro cycloalkyl group, can be saturation , fractional saturation or it is undersaturated, but be not armaticity.
Described and ring naphthenic base can be 6-12 member and ring naphthenic base, 7-10 member and ring naphthenic base, the example include but It is not limited to：Bicyclic [3.1.1] heptane base, bicyclic [2.2.1] heptane base, bicyclic [2.2.2] octyl, bicyclic [3.2.2] nonane Base, bicyclic [3.3.1] nonyl and bicyclic [4.2.1] nonyl.
The loop coil base can be 6-12 member loop coils base, 7-11 member loop coil bases, and the example includes but not limited to：
The bridged ring base can be 6-12 member bridged rings base, 7-11 member bridged ring bases, and the example includes but not limited to：
" heterocycle " of the present invention refers to that any carbon atom can be by the hetero atom selected from oxygen, sulphur, nitrogen in " naphthenic base " Substitution, preferably 1-3 hetero atom, while including that carbon atom, nitrogen-atoms and sulphur atom can be by oxos.
" heterocycle " refers to monocyclic heterocycles base, bicyclic heterocycle based system or the multiring heterocyclic system of 5-14 members, including full With the heterocycle of fractional saturation, but include aromatic ring." 3-8 " member saturated heterocyclyl, the example includes but not limited to azacyclo- third Alkyl, oxirane base, thiirane base, azetidinyl, oxa- azetidinyl, Thietane base, tetrahydrochysene Furyl, nafoxidine base, tetrahydro-thienyl, imidazolidinyl, pyrazolidinyl, 1,2- oxazolidine radicals, 1,3- oxazolidine radicals, 1,2- Thiazolidinyl, 1,3- thiazolidinyls, tetrahydrochysene -2H- pyranoses, tetrahydrochysene -2H- thiapyrans base, piperidyl, piperazinyl, morpholinyl, 1,4- Dioxane base, 1,4- thioxane bases；" 3-8 " member fractional saturation heterocycle, the example includes but not limited to 4, 5- dihydro-isoxazoles base, 4,5- dihydro-oxazoles base, 2,5- dihydro-oxazoles base, 2,3- dihydro-oxazoles base, 3,4- dihydro-2 h-pyrroles Base, 2,3- dihydro -1H- pyrrole radicals, 2,5- dihydro -1H- imidazole radicals, 4,5- dihydro -1H- imidazole radicals, 4,5- dihydro-1 h-pyrazoles Base, 4,5- dihydro -3H- pyrazolyls, 4,5- dihydro-thiazolyls, 2,5- dihydro-thiazolyls, 2H- pyranoses, 4H- pyranoses, 2H- thiophenes It mutters base, 4H- thiapyrans base, 2,3,4,5- tetrahydro pyridyls, 1,2- Yi oxazinyls, 1,4- Yi oxazinyls or 6H-1,3- oxazinyls etc.. Bicyclic heterocycle be by and spiral shell, bridge in a manner of be fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycles base or monocycle heteroaryl The bicyclic heterocyclic system of base.Described and heterocycle can be 6-12 members and heterocycle, 7-10 members and heterocycle, 6-12 members saturation And heterocycle, 7-8 members saturation and heterocycle, 8 yuan of saturations and heterocycle, the example include but not limited to：3- azabicyclos [3.10.] hexyl, 3,6- diazabicyclos [3.2.0] heptane, 3,8- diazabicyclos [4.2.0] octyl, 3,7- phenodiazines Miscellaneous bicyclic [4.2.0] octyl, octahydro pyrrolo- [3,4-c] pyrroles, octahydro pyrrolo- [3,4-b] pyrroles, octahydro pyrrolo- [3, 4-b] [1,4] oxazinyls, octahydro -1H- pyrrolo-es [3,4-c] pyridine, 2,3- Dihydrobenzofuranes -2- bases, 2,3- dihydrobenzos Furyl -3- bases, indoline -1- bases, indoline -2- bases, indoline 3- bases, -2 base of 2,3 dihydrobenzo thiophene, eight Hydrogen -1H- indyls, octahydro benzofuranyl, octahydro cyclopenta [c] pyrroles, hexahydro cyclopenta [c] furans, 2,2- Dioxo hexahydro cyclopenta [c] thiophene.
The spiro heterocyclic radical can be 6-12 members spiro heterocyclic radical, 7-11 members spiro heterocyclic radical, 6-12 members be saturated spiro heterocyclic radical, 7 yuan of saturation spiro heterocyclic radicals, the example include but not limited to：
The bridge heterocycle can be 6-12 member bridges heterocycle, 7-11 member bridges heterocycle, 6-12 members saturation bridged ring base, 7- 8 yuan saturation bridged ring base examples include but not limited to：
In certain embodiments, bicyclic heterocyclic radical is monocyclic cycloalkyl, 5 yuan or the 6 yuan of lists for being fused to phenyl ring, 5 yuan or 6 yuan 5 yuan or 6 unit monocycle heterocyclic rings of ring cycloalkenyl group, 5 yuan or 6 unit monocycle heterocycles or 5 yuan or 6 unit monocycle heteroaryls, feature It is that bicyclic heterocyclic radical is replaced by one or two group selectivity as independent oxo base or sulfenyl.
" 5-14 members aryl " refers to the cyclic aromatic group containing 5-14 carbon atom, including " 6-8 unit monocycle virtues Base ", such as phenyl, cyclo-octene base etc.；Including " 8-14 members fused ring aryl ", such as pentalene, naphthalene, phenanthrene etc..Art used herein Language " aryl " refers in phenyl (that is, monocyclic aryl) or aromatics bicyclic system containing at least one phenyl ring or contains only carbon atom Bicyclic system.Bicyclic aryl can be azulenyl, naphthalene or be fused to monocyclic cycloalkyl, monocyclic cycloalkenyl or monocyclic heterocycles Phenyl.Any carbon atom or former with any carbon of naphthalene or Azulene ring contained by phenyl moiety of the bicyclic aryl by bicyclic system Son is attached in parent molecule class.The condensed monocyclic cycloalkyl or monocyclic heterocycles base portion of bicyclic aryl point is by one or two oxo base And/or thia group selectivity substitution.
The term as used herein " heteroaryl " refers to the bicyclic heteroaryl or bicyclic of the 5-14 members containing at least one hetero-aromatic ring System.Bicyclic heteroaryl can be one 5 yuan or 6 membered rings.5 membered rings are by two double bonds and one, two, three or four nitrogen original Son and an oxygen atom or sulphur atom composition.6 membered rings are made of three double bonds and one, two, three or four nitrogen-atoms. 5 yuan or 6 unit's heteroaryls are connected to parent molecule class by the arbitrary carbon atom or nitrogen-atoms contained in heteroaryl.Monocyclic heteroaryl The representative example of base include but are not limited to furyl, imidazole radicals, isoxazolyl, thiazolyl, isothiazolyl, oxadiazoles base, Oxazolyl, isoxazolyl, pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrazolyl, pyrrole radicals, tetrazole radical, thiadiazolyl group, thiophene Oxazolyl, thienyl, triazolyl and triazine radical.Bicyclic heteroaryl is by being fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocycle The bicyclic heteroaryl of heterocycle or bicyclic heteroaryl forms.The naphthenic base or heterocyclyl moieties of condensed bicyclic heteroaryl are by conduct Independent oxo base or the substitution of one or two group selectivity of sulfenyl.When bicyclic heteroaryl contains condensed naphthenic base, cyclenes When base or heterocyclic ring, then any carbon atom or nitrogen that bicyclic heteroaryl is contained by the monocyclic heteroaryl moiety of bicyclic system are former Son is connected to parent molecule class.It is bicyclic miscellaneous when bicyclic heteroaryl is to be fused to the bicyclic heteroaryl of phenyl ring or bicyclic heteroaryl Aryl is connected to parent molecule class by any carbon atom in bicyclic system or nitrogen-atoms.The representative example of bicyclic heteroaryl Including but not limited to benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazole base, benzothiazolyl, cinnoline base, 5,6- dihydroquinoline -2- bases, 5,6- dihydro-isoquinoline -1- bases, indazolyl, indyl, isoquinolyl, naphthyridines base, purine radicals, quinoline Quinoline base, 5,6,7,8- tetrahydroquinoline -2- bases, 5,6,7,8 tetrahydric quinoline groups, 5,6,7,8- tetrahydroquinoline -4- bases, 5,6,7,8- tetra- Hydrogen isoquinoline -1- bases, 4,5,6,7- tetrahydrochysenes simultaneously [c] [1,2,5] oxadiazoles and 6,7- dihydros simultaneously [c] [1,2,5] oxadiazoles -4 (5H) -one base.In certain embodiments, fused bicyclic heteroaryl group be fused to benzyl ring, 5 yuan or 6 unit monocycle naphthenic base, 5 yuan Or 5 yuan or 6 unit monocycle hetero-aromatic rings of 6 unit monocycle cycloalkenyl groups, 5 yuan or 6 unit monocycle formula heterocycles or 5 yuan or 6 unit monocycle heteroaryls, Wherein condensed naphthenic base, cycloalkenyl group and heterocycle is taken by one or two group selectivity as independent oxo base or sulfenyl Generation.
Any compound of the invention or its stereoisomer or its pharmaceutically acceptable salt, molten is also claimed in the present invention The pharmaceutical preparation of immunomodulator compounds, polymorph and isomers, it is characterised in that include one or more pharmaceutical carriers.
Pharmaceutical carrier of the present invention can one or more be suitable for solid that people uses or liquid filler or solidifying Glue substance.The pharmaceutical carrier preferably has enough purity and sufficiently low toxicity, and has with inventive compound Compatibility and unobvious lower the drug effect of active constituent.For example, pharmaceutical carrier can be with filler, adhesive, disintegrant, lubrication Agent, aqueous solvent or non-aqueous solvent etc..
Pharmaceutically acceptable arbitrary dosage form can be made, with any suitable administration in pharmaceutical preparation of the present invention Mode, such as the patient or tested for needing this treatment is applied to by modes such as oral, parenteral, rectum or transpulmonary administrations Person.When for being administered orally, tablet, capsule, pill, granule etc. can be made.When for parenteral administration, it can be made Injection, injection sterile powder etc..
Any compound of the invention or its stereoisomer or its pharmaceutically acceptable salt, molten is also claimed in the present invention The pharmaceutical composition of immunomodulator compounds, polymorph and isomers further includes one or more second therapeutically active agents, described The second therapeutically active agent be antimetabolite, growth factor receptor inhibitors, have silk classify inhibitor, antitumor steroids, alkylating agent Class, metal class, topoisomerase enzyme inhibitor, hormone drug, immunomodulator, tumor suppressor gene, Theratope, immunologic test point or The relevant antibody of immunotherapy of tumors and small-molecule drug.
Any compound of the invention or its stereoisomer or its pharmaceutically acceptable salt, molten is also claimed in the present invention The use of immunomodulator compounds, polymorph and isomers in the drug for preparing the relevant disease that treatment is mediated by PDE9 unconventionality expressions On the way, the relevant disease of PDE9 unconventionality expressions mediation is：
(a) disease treatment for being used to by inhibition PDE9 to reach；
(b) it is used to treat CNS diseases, the CNS diseases are：With selected from consciousness, attention, cognition, study or memory Disease or the related cognitive impairment of illness, Ahl tribulus sea silent sickness or the related cognitive impairment of Ahl tribulus sea silent sickness, with essence Refreshing Split disease or cognitive impairment related with schizophrenia, cognitive impairment related with depression or bipolar disorder, year Age related memory is lost, vascular dementia, craniocerebral trauma, apoplexy, the dementia occurred after apoplexy, and dementia posttraumatica is general Attention is damaged, and child attention damage is denaturalized silly with study and memory problems, Alzheimer disease, dementia with Lewy body, frontal lobe Slow-witted, corticobasal degeneration is dull-witted, amyotrophic lateral sclerosis, Huntington disease, multiple sclerosis, thalamus denaturation, library Jia Shi is dull-witted, and HIV is dull-witted, schizophrenia, korsakoff's neurosis.
(c) it is used to treat disease or illness selected from the following：Sleep disturbance, bipolar disorder, metabolic syndrome, obesity Disease, diabetes, hyperglycemia, dyslipidemia, glucose tolerance reduces or testis, brain, small intestine, skeletal muscle, heart, lung, thymus gland Or disease, the sickle blood disease of spleen.
" pharmaceutically acceptable salt " of the present invention refers to the addition salts and solvate of pharmaceutical bronsted lowry acids and bases bronsted lowry.This The officinal salt of sample includes the salt of acid such as below：Hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, Methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid (such as acetic acid, HOOC- (CH2)n- COOH (wherein n is 0~4)) etc..Nontoxic pharmaceutical base addition salts include the salt of alkali such as below：Sodium, potassium, calcium, ammonium etc..This Field technology personnel know a variety of nontoxic pharmaceutically acceptable addition salts.
" isomers " of formula (I) compound of the present invention refers to that will produce when formula (I) compound is there are when asymmetric carbon atom Enantiomter；When compound is there are when carbon-carbon double bond or cyclic structure, cis-trans-isomer will produce；When compound there are ketone or When oxime, tautomer will produce, it is the enantiomters of all formula (I) compounds, diastereoisomer, racemization isomers, suitable Trans isomer, tautomer, geometric isomer, epimer and its mixture, are included in the scope of the invention.
The general note presented for structure：
Compound with stereogenic centres：The structure being plotted in hereafter experimental section may not show all of compound Spatial chemistry possibility, but only show one kind.However, in these cases, such as it is " trans-racemic mixture " or " suitable The addition of the terms such as formula-racemic mixture " indicates that other spatial chemistry select after depicted structure.
Specific implementation mode
Embodiment：The synthesis of compound 1：
Step 1：The synthesis of intermediate 1-1：
LiCl (8.45g, 0.12mmol, 0.1eq), acetonitrile (4.0L), 3- methylbutyraldehyds are added in 5L four-hole bottles (99.14g, 1.15mol, 1.0eq) and diethoxy phosphonium mesitoyl base Ethyl formate (258.05g, 1.15mol, 1.0eq), room temperature (28 DEG C) it is stirred to react 15min, DBU (192.44g, 1.27mol, 1.1eq) is added, room temperature (28 DEG C) is stirred to react 2h.Concentration, adds Enter saturated aqueous ammonium chloride (about 500mL), EA extracts (100mL × 3), merges EA phases, and anhydrous magnesium sulfate drying is filtered, dense Contract to obtain crude product.
Step 2：The synthesis of intermediate 1-2：
Crude product obtained by previous step is dissolved in THF (200mL), water (200mL) and a hydronium(ion) lithia is added (144.76g, 3.45mol, 3.0eq) is heated to 70 DEG C of reactions overnight (10h).It is cooled to 0 DEG C, pH is adjusted with 1mol/L HCl EA extractions (100mL × 2) are added to 1 or so in value, merge organic phase, anhydrous magnesium sulfate drying, and filtering is concentrated to give brown color oil Shape object (46.35g, yield:32%)
Step 3：The synthesis of intermediate 1-3：
Intermediate 1-2 (25.00g, 0.20mol, 1.0eq), DCM (500mL) and DMF (1mL) are added in 1L four-hole bottles, Oxalyl chloride (27.92g, 0.22mol, 1.1eq) is added dropwise at 15 DEG C or less for ice bath temperature control, is warmed to room temperature (25 DEG C) reaction 8h, concentration Obtain pale tan oil.Be added in another 1L four-hole bottle (R) -4- oxazolyl phenyl alkane -2- ketone (32.64g, 0.20mol, 1.0eq), THF, LiCl (8.48g, 0.20mol, 1.0eq) and TEA (40.48g, 0.40mol, 2.0eq), room temperature (25 DEG C) are stirred 0.5h is mixed, ice bath is cooled to 0 DEG C, and DMAP (2.44g, 0.02mol, 0.1eq) is added, and the above-mentioned palm fibre that THF (500mL) dissolves is added dropwise Yellow oil is warmed to room temperature (20-25 DEG C) reaction 10h.Saturation Na is added2CO3Solution (500mL), liquid separation, water phase EA extractions (150mL × 2) merge organic phase, and saturation NaCl aqueous solutions are washed (300mL × 5), and anhydrous magnesium sulfate drying is filtered, concentration, slightly Product are through silica gel column chromatography (PE:EA=15:1) white solid (12.78g, yield 23.4%) is purified to obtain.
Step 4：The synthesis of intermediate 1-4：
Compound 1-3 (12.78g, 46.8mmol, 1.0eq) and toluene (200mL) are added in 1L four-hole bottles, under stirring N- (methoxyl methyl)-N- (trimethyl silicane methyl) benzylamine (1.32g, 56.1mmol, 1.2eq), (25 DEG C) stirrings of room temperature are added 0.5h, ice bath are cooled to 0 DEG C, and TFA (1mL) and DCM (8mL) mixed solution is added dropwise, and are slowly increased to (25 DEG C) reaction 8h of room temperature.Add Enter saturated sodium bicarbonate aqueous solution (300mL), liquid separation, the drying of toluene phase anhydrous magnesium sulfate is filtered, and concentration, crude product is first through silica gel Column chromatography (PE:EA=15:1-5:1) PE (100mL) then, is added to be beaten, filtering, dries to obtain white solid (10.89g, receipts Rate:57.3%).
Step 5：The synthesis of intermediate 1-5：
Intermediate 1-4 (50.0g, 123.0mmol, 1.0eq) and THF (459mL), ice bath are added in 1000mL two-mouth bottles It is cooled to 0 DEG C, a hydronium(ion) lithia (12.9g, 307.5mmol, 2.5eq), H is added dropwise2O2(34.9g,307.5mmol, 2.5eq) and H2O, 0 DEG C of reaction 2h.Na is added2S2O3(3.0eq) stirs 0.5h, liquid separation, water phase EA extractions (50mL × 2), ice Bath is lower to be added NaH2PO4(3.3eq), with 6mol/L HCl tune pH value to 4-5, with DCM and i-PrOH (3:1) extract (200mL × 6), organic phase anhydrous magnesium sulfate is dried, and filtering is concentrated to give yellow oil (31g, yield:96.87%).
Step 6：The synthesis of intermediate 1-6：
Intermediate 1-5 (30.45g, 116.5mmol, 1.0eq), THF (300mL), MeCN are added in 250mL single port bottles (300mL), DIPEA (30.1g, 233.0mmol, 2.0eq) and HATU (48.75g, 128.2mmol, 1.1eq), room temperature (25 DEG C) 5h is stirred, 1- amino -1H- pyrroles -2- carboxamide hydrochlorides (18.81g, 116.5mmol, 1.0eq) are added, room temperature (25 DEG C) is stirred 8h is mixed, is concentrated, EA (500mL), liquid separation is added, organic phase is washed (150mL × 5) with saturation NaCl aqueous solutions, and anhydrous magnesium sulfate is dry It is dry, it filters, concentration, crude product is through silica gel column chromatography (DCM:MeOH=50:1-20:1) pale yellow powder shape solid is purified to obtain (27.0g, yield:64.3%).
Step 7：The synthesis of intermediate 1-7：
Intermediate 1-6 (24.00g, 65.0mmol, 1.0eq) and EtOH (360mL), stirring are added in 100mL single port bottles KOH (10.92g, 195.0mmol, 3.0eq) and water is added in dissolving, is heated to vigorous reflux reaction 20h.Ice water is added in concentration (300mL), DCM extract (300mL × 2), merge organic phase, and anhydrous magnesium sulfate drying is filtered, and concentration, crude product is through silica gel column layer Analyse (DCM:MeOH=50:1) pale yellow oil (10.0g, yield are purified to obtain:44.1%).
Step 8：The synthesis of intermediate 1-8：
Intermediate 1-7 (10.0g, 28.5mmol, 1.0eq), DCM (110mL) and TFA are added in 100mL single port bottles (55mL) adds drying tube, ice bath to be cooled to 0 DEG C, and NBS (4.57g, 25.7mmol, 0.9eq) is added portionwise, and keeps the temperature 2h, rises to room (20 DEG C) reaction 8h, LCMS detections of temperature are without starting material left.Concentration, is dissolved with DCM, is saturated Na2CO3Aqueous solution (200mL) is washed, and is had Machine phase anhydrous magnesium sulfate is dried, and is filtered, and concentration, crude product is through silica gel column chromatography (DCM:MeOH=400:1) it purifies faint yellow Solid (7.0g, yield:57.4%).
Step 9：The synthesis of intermediate 1-9：
Intermediate 1-8 (0.20g, 0.466mmol) is dissolved in toluene (4mL), addition morphine beautiful jade (48.7mg, 0.559mmol)、Pd2(dba)3(8.6mg, 0.009mmol), sodium tert-butoxide (62.9mg, 0.652mmol), BINAP (11.9mg, 0.019mmol)。N2110 DEG C of back flow reaction 8h are heated under protection.TLC monitoring reactions terminate, and water is added in reaction solution concentration (10mL) extracts (3 × 25mL) with dichloromethane, and organic phase merges, and is washed with water successively (2 × 10mL), saturated common salt washing (1 × 20mL), anhydrous sodium sulfate drying is filtered, and concentration, crude product (uses DCM successively through silica gel column chromatography:MeOH=200:1,DCM: MeOH=150:1,DCM:MeOH=100:1 elutes) obtain yellow solid (170mg, yield:84.2%).
Step 10：The synthesis of intermediate 1-10：
Intermediate 1-9 (170mg, 0.39mmol, 1.0eq) MeOH (5mL) are dissolved, Pd/C (cat.), displacement is added Three times, (20 DEG C) reactions of room temperature are overnight for hydrogen.Filtering, with a small amount of methanol filter wash cake, filtrate is concentrated to give yellow product (134.73mg, yield:100.0%).
Step 11：The synthesis of compound 1：
Intermediate 1-10 (134.73mg, 0.39mmol) is dissolved in DCM (6mL), 4- aldehyde radical -1- picolines -2 are added (1H) -one (64.2mg, 0.468mmol) and NaBH (OAc)3(206.6mg, 0.975mmol), is stirred overnight at room temperature.TLC is supervised The reaction was complete for survey, and saturated sodium bicarbonate aqueous solution (5mL) is added, and extracts (3 × 10mL) with DCM, merges organic phase, be washed with water (2 × 5mL), anhydrous sodium sulfate drying is filtered, concentration, and crude product purifies to obtain white solid (10.0mg, yield through preparing HPLC: 5.5%).
1HNMR(400MHz,CDCl3)δ(ppm):9.96(s,1H),7.36-7.34(d,1H),6.99-6.98(d,1H), 6.45(s,1H),6.41-6.40(d,1H),5.96-5.95(d,1H),3.92(s,4H),3.60-3.57(d,1H),3.53(s, 2H),3.40-3.29(m,4H),3.18-3.15(t,2H),2.99-2.96(d,1H),2.48-2.44(m,3H),1.95-1.90 (t,1H),1.64-1.62(d,1H),1.41-1.34(m,2H),1.29-1.26(m,1H),0.92-0.88(m,6H).
Molecular formula:C25H34N6O3Molecular weight:466.59 LC-MS (m/z)=467.28 [M+H+].
Embodiment：The synthesis of compound 2：
Step 1：The preparation of intermediate 2-1：
Compound 1 (47.0g, 0.55mol, 1.0eq), DCM (186.0mL), MeCN are added in 3L four-hole bottles (940.0mL) and TEMPO (4.30g, 0.03mol, 0.05eq), be added portionwise iodobenzene diacetate (186.0g, 0.58mol, 1.05eq), (10-15 DEG C) reaction 8h of room temperature.Saturated sodium bicarbonate aqueous solution (1.0L) and DCM (1.0L), liquid separation, water phase is added DCM extracts (200mL × 1), merges organic phase, anhydrous magnesium sulfate drying, and filtering is less than 30 DEG C of reduced pressures, obtains about 600mL The MeCN solution of product, yield:In terms of 100%.
Step 2：The synthesis of intermediate 2-2：
LiCl (34.1g, 0.83mmol, 1.5eq), acetonitrile (1.5L), diethoxy phosphonium mesitoyl base are added in 3L four-hole bottles Ethyl formate (147.9g, 0.66mol, 1.2eq) and DBU (126.3g, 0.66mol, 1.2eq), stir 1h, and ice bath is cooled to 0 DEG C, the solution (600mL, 0.55mol, 1.0eq) of the above-mentioned intermediate 2-1 prepared is added dropwise, is slowly increased to room temperature (10-15 DEG C) React 8h.Concentration, addition EA (500mL), cooling sodium bicarbonate aqueous solution (1.0L), liquid separation, EA phases are water-soluble with saturation NaCl Liquid is washed, and anhydrous magnesium sulfate drying, filtering, concentration crude product is through silica gel column chromatography (EA:PE=0-1:20) colorless transparent oil is purified to obtain Shape object (43.8g, yield:51.7%).
Step 3：The synthesis of intermediate 2-3：
Intermediate 2-2 (43.8g, 0.28mol, 1.0eq), THF (200.0mL) and water are added in the four-hole bottle of 1.0L The one hydronium(ion) lithia (35.8g, 0.85mol, 3.0eq) of (200.0mL) dissolving is heated to (70 DEG C) reaction 8h of reflux.Ice Bath is cooled to 0 DEG C, and with 6mol/L salt acid for adjusting pH value to 1 or so, liquid separation, water phase EA extractions (50mL × 2) merge organic phase, Anhydrous magnesium sulfate is dried, and filtering is concentrated to give pale yellow oil (30.9g, yield:87.3%).
Step 4：The synthesis of intermediate 2-4：
Intermediate 2-3 (20.0g, 0.16mol, 1.0eq), DCM (400mL) and DMF (1mL) are added in 1L four-hole bottles, Oxalyl chloride (22.1g, 0.17mol, 1.1eq) is added dropwise at 15 DEG C or less for ice bath temperature control, is warmed to room temperature (10 DEG C) reaction 3h, is concentrated to give Pale tan oil.(R) -4- oxazolyl phenyl alkane -2- ketone (27.7g, 0.17mol), THF are added in another 1L four-hole bottle (200mL), LiCl (7.78g, 0.18mol, 1.1eq) and TEA (32.38g, 0.32mol, 2.0eq), (10 DEG C) stirrings of room temperature 2h, ice bath are cooled to 0 DEG C, and DMAP (1.95g, 0.016mol, 0.1eq) is added, above-mentioned yellow oil is added dropwise, rises to room naturally (0-10 DEG C) reaction of temperature.Saturation Na is added2CO3Solution (300mL), liquid separation, water phase EA extractions (100mL × 2) merge organic phase, Anhydrous magnesium sulfate is dried, and is filtered, and concentration, crude product is through silica gel column chromatography (PE:EA=6:1) white solid (21.5g, receipts are purified to obtain Rate 50.0%).
Step 5：The synthesis of intermediate 2-5：
Intermediate 2-4 (21.5g, 79.2mmol, 1.0eq), toluene (200.0mL) and compound is added in 1.0L four-hole bottles N- (methoxyl methyl)-N- (trimethyl silicane methyl) benzylamine (20.2g, 87.2mmol, 1.1eq) stirs 1h, and ice bath is cooled to 0 DEG C, TFA (0.7mL) and DCM (5.6mL) is slowly added dropwise, is slowly increased to (15 DEG C) reaction 10h of room temperature, it is molten that saturated sodium bicarbonate water is added Liquid (300mL), liquid separation, the drying of organic phase anhydrous magnesium sulfate are filtered, and concentration, crude product is first through silica gel column chromatography (PE:EA=10:1- 6:1) it purifies, is then beaten to obtain leucoplast (13.00g, yield with PE:40.6%).
Step 6：The synthesis of intermediate 2-6：
Intermediate 2-5 (11.0g, 27.2mmol, 1.0eq) is added in 1L four-hole bottles, THF (200.0mL), ice bath is down to 0 DEG C, H is added dropwise2O2The aqueous solution (25mL) of (6.17g, 54.4mol, 2.0eq) stirs 0.5h, 0 DEG C of one hydronium(ion) lithia of dropwise addition The aqueous solution (25mL) of (2.85g, 68.0mmol, 2.5eq), 0 DEG C of reaction 1.5h.Na is added2S2O3(3.0eq), water (50.0L), 1h is stirred at room temperature, EA (200.0mL), liquid separation is added, water phase EA extracts (100.0mL × 1), and water phase ice bath is down to 0 DEG C of addition NaH2PO4(3.3eq), adds Na2S2O3(3.0eq), room temperature (15 DEG C) reactions 8h, DCM extract (100mL × 8), anhydrous magnesium sulfate Dry, filtering is concentrated to give off-white powder (7.10g, yield:In terms of 100%.
Step 7：The synthesis of intermediate 2-7：
Intermediate 2-6 (6.00g, 23.13mmol, 1.0eq), THF (60.0mL) are added in 500.0mL single port bottles, MeCN (120.0mL) and HATU (9.67g, 25.44mmol, 1.1eq), (15-20 DEG C) reaction 5h of room temperature, is added compound 1- ammonia Base -1H- pyrroles -2- carboxamide hydrochlorides (3.74g, 23.13mmol, 1.0eq), (10-15 DEG C) stirring 10h of room temperature.Concentration, adds Entering EA (250.0mL), saturated sodium-chloride water solution is washed (200.0mL × 5), and the drying of organic phase anhydrous magnesium sulfate is filtered, concentration, Crude product (uses DCM successively through silica gel column chromatography；MeOH=150:1,DCM:MeOH=100:1,DCM:MeOH=70:1,DCM: MeOH=30:1) pale yellow powder (3.80g, yield are purified to obtain:44.7%).
Step 8：The synthesis of intermediate 2-8：
Intermediate 2-7 (1.00g, 2.73mmol, 1.0eq) and EtOH (10mL) is added in 100mL single port bottles, stirring is molten The aqueous solution (10mL) of KOH (0.23g, 4.1mmol, 1.5eq) is added in solution, is heated to vigorous reflux reaction 10h.Concentration is added THF (20.0mL), ultrasonic 5min is added in methanol (20mL), concentration, and a small amount of anhydrous magnesium sulfate drying, filtering, a small amount of THF is added Filter wash cake, filtrate concentration, crude product is through silica gel column chromatography (PE:EA=2:1-1:1) white solid (0.42g, yield are purified to obtain: 44.0%).
Step 9：The synthesis of intermediate 2-9：
Intermediate 2-8 (0.42g, 1.21mmol, 1.0eq) is added in 100mL single port bottles, DCM is added under ice bath (15mL) and TFA (8.0mL), stirs 0.5h, and ice bath is down to 0 DEG C, NBS (0.19g, 1.08mmol, 0.9eq) is added portionwise, about 1h is added, and there are about 15% starting material lefts for (15 DEG C) reaction 8h, LCMS detections of room temperature, are cooled to 0 DEG C, add the NBS of 0.1eq, (15 DEG C) reaction 2h of room temperature.DCM (50.0mL) is added in concentration, and saturated sodium bicarbonate aqueous solution (20.0mL) stirs 5min, point Liquid, water phase DCM extractions (50mL × 1) merge organic phase, anhydrous magnesium sulfate drying, and it is pure through silica gel column chromatography to concentrate crude product for filtering Change (PE:EA=4:1-2:1) off-white powder (400.0mg, yield are obtained:77.3%).
Step 10：The synthesis of intermediate 2-10：
Intermediate 2-9 (0.20g, 0.468mmol) is dissolved in toluene (4mL), addition morpholine (48.9mg, 0.5616mmol)、Pd2(dba)3(9.0mg, 0.0094mmol), sodium tert-butoxide (63.2mg, 0.655mmol) and BINAP (11.7mg, 0.019mmol), N2110 DEG C of back flow reaction 8h are heated under protection.TLC monitoring reactions terminate, reaction solution concentration, Water (10mL) is added, extracts (3 × 25mL) with dichloromethane, (2 × 10mL) is washed with water, washes (20mL) with saturated common salt, nothing Aqueous sodium persulfate is dried, and is filtered, and concentration, crude product (uses DCM successively through silica gel column chromatography:MeOH=200:1, DCM:MeOH=150: 1, DCM:MeOH=100:1 elutes) obtain yellow solid (80mg, yield:39.6%).
Step 11：The synthesis of intermediate 2-11：
Intermediate 2-10 (100mg, 0.23mmol 1.0eq) MeOH (4mL) and DCM (20mL) are dissolved, Pd/C is added (cat.), three times, (20 DEG C) reactions of room temperature are overnight for replacing hydrogen.Filtering, with a small amount of methanol filter wash cake, filtrate is concentrated to give yellow production Object (30.0mg, yield:37.5%).
Step 12：The synthesis of compound 2：
Intermediate 2-11 (30mg, 0.087mmol) is dissolved in DCM (2mL), 4- aldehyde radical -1- picolines -2 are added (1H) -one (14.3mg, 0.104mmol), NaBH (OAc)3(46.1mg,0.218mmol).It is stirred overnight at room temperature.TLC is monitored Saturated sodium bicarbonate aqueous solution (5mL) is added in reaction, extracts (3 × 10mL) with DCM, merges organic phase, be washed with water (2 × 5mL), anhydrous sodium sulfate is dried, and is filtered, and concentration, crude product is through silica gel column chromatography (DCM:MeOH=200:1-20:1) purifying obtains White solid (5.8mg, yield:14.5%).
1HNMR(400MHz,CDCl3)δ(ppm):9.92(s,1H),7.36-7.34(d,1H),6.99-6.98(d,1H), 6.45(s,1H),6.42-6.40(d,1H),5.96-5.94(d,1H),3.92-3.89(m,4H),3.61-3.58(d,1H), 3.53(s,2H),3.42-3.37(m,2H),3.32-3.27(m,2H),3.19-3.14(m,2H),3.00-2.93(m,3H), 2.48-2.44(m,2H),2.03-1.99(t,2H),1.53(s,2H),1.27(s,4H).
Molecular formula:C25H32N6O3Molecular weight:464.57 LC-MS (m/z)=465.3 [M+H+].
3 7- of embodiment (1,1- dioxotetrahydro -2H- thiapyran -4- bases) -2- ((3S, 4S) -4- isobutyl groups -1- ((1- first Base -2- oxo -1,2- dihydropyridine -4- bases) methyl) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) - The synthesis of ketone (compound 10)
Step:
Step 1:2- ((3S, 4S) -1- benzyl -4- isobutyl groups pyrrolidin-3-yl) -7- (3,6- dihydro -2H- thiapyrans -4- Base) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one synthesis:
By 2- (3S, 4S) -1- benzyl -4- isobutyl groups pyrrolidin-3-yl) -7- bromos pyrrolo- [2,1-f] [1,2,4] three Piperazine -4 (3H) -one (1.0g, 2.33mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (30mL), and 2- (3,6- dihydro -2H- thiapyrans-are added 4- yls) -4,4,5,5- tetramethyl -1,3,2- dioxa boron pentamethylene (632.3mg, 2.796mmol), potassium carbonate (644.1mg, 4.66mmol)、Pd(dppf)Cl2(2.05g mg, 2.796mmol) and water (15mL).100 DEG C of reflux are heated under nitrogen protection Reaction 8 hours, TLC monitoring reactions terminate, and reaction solution concentration is added dichloromethane (150mL) and dissolves, filtering, filtrate concentration, slightly Product are through silica gel column chromatography (DCM:MeOH=400:1-100:1) product 2- ((3S, 4S) -1- benzyl -4- isobutyl groups pyrrolidines-is obtained 3- yls) -7- (3,6- dihydro -2H- thiapyran -4- bases) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (580mg, yield: 55.5%).
Step 2:2- ((3S, 4S) -1- benzyl -4- isobutyl group pyrroles -3- bases) -7- (1,1- dioxy -3,6- dihydro -2H- thiophenes Mutter -4- bases) synthesis of pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one:
By 2- ((3S, 4S) -1- benzyl -4- isobutyl groups pyrrolidin-3-yl) -7- (3,6- dihydro -2H- thiapyran -4- bases) pyrrole It coughs up simultaneously [2,1-f] [1,2,4] triazine -4 (3H) -one (200.0mg, 0.446mmol) and is dissolved in methanol (10mL), ice salt bath is cooled to 0 DEG C, water (6mL) solution of Oxone (1.096g) is added, is stirred 2 hours under ice salt bath.TLC monitorings are after the reaction was complete, ice salt bath Lower addition water (60mL), ethyl acetate extract (3 × 40mL), merge organic phase, anhydrous magnesium sulfate drying, and filtering is concentrated to give white Color solid (100.0mg crude products).
Step 3:7- (1,1- dioxotetrahydro -2H- thiapyran -4- bases) -2- ((3S, 4S) -4- isobutyl groups pyrrolidin-3-yl) The synthesis of pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one:
By 2- ((3S, 4S) -1- benzyl -4- isobutyl group pyrroles -3- bases) -7- (1,1- dioxy -3,6- dihydro -2H- thiapyrans - 4- yls) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (100.0mg crude products) is dissolved in methanol (5mL), Pd/C is added (5.0mg), hydrogenation reaction 6 hours, the reaction was complete for TLC monitorings.Suction filtered through kieselguhr, filtrate decompression are concentrated to give 7- (1,1- dioxos Tetrahydrochysene -2H- thiapyran -4- bases) -2- ((3S, 4S) -4- isobutyl groups pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (88.0mg)
Step 4:7- (1,1- dioxotetrahydro -2H- thiapyran -4- bases) -2- ((3S, 4S) -4- isobutyl groups -1- ((1- methyl - 2- oxo -1,2- dihydropyridine -4- bases) methyl) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one Synthesis:
By 7- (1,1- dioxotetrahydro -2H- thiapyran -4- bases) -2- ((3S, 4S) -4- isobutyl groups pyrrolidin-3-yl) pyrroles And [2,1-f] [1,2,4] triazine -4 (3H) -one (81.64mg) is dissolved in DCM (4mL), and 4- aldehyde radical -1- picolines -2 are added (1H) -one (34.23mg, 0.25mmol) and sodium triacetoxy borohydride (110.2mg, 0.52mmol), it is stirred at room temperature Night.The reaction was complete for TLC monitorings, and saturated sodium bicarbonate aqueous solution (5mL) is added, and (3 × 10mL) is extracted with DCM, and organic phase merges, It washes (2 × 5mL), anhydrous sodium sulfate drying is filtered, and concentration, crude product is through preparing TLC separation (DCM:MeOH=10:1) Obtain white solid 7- (1,1- dioxotetrahydro -2H- thiapyran -4- bases) -2- ((3S, 4S) -4- isobutyl groups -1- ((1- methyl -2- oxygen Generation -1,2- dihydropyridine -4- bases) methyl) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (4.0mg, yield:3.7%).
1HNMR(400MHz,DMSO-d6)δ(ppm):11.44(s,1H),7.61-7.59(d,1H),6.81-6.80(d, 1H),6.42-6.41(d,1H),6.33(s,1H),6.16-6.14(d,1H),3.45-3.43(d,3H),3.37(s,5H), 3.15-3.09(t,3H),2.92-2.90(d,2H),2.82(s,2H),2.71-2.66(d,2H),2.32-2.21(m,5H), 2.17-2.09(m,2H),1.55-1.50(m,2H),1.48-1.31(m,3H),0.87-0.83(m,6H).
Molecular formula:C26H35N5O4S molecular weight:513.66 LC-MS (Pos, m/z)=514.5 [M+H+].
4 7- of embodiment (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl groups -1- ((1- methyl -2- oxygen Generation -1,2- dihydropyridine -4- bases) methyl) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (chemical combination Object 15) synthesis
Step:
Step 1:2- ((3S, 4S) -1- benzyl -4- isobutyl group pyrroles -3- bases) -7- (1,1- titanium dioxide thio-morpholinyls) pyrrole Cough up the synthesis of simultaneously [2,1-f] [1,2,4] triazine -4 (3H) -one:
By 2- (3S, 4S) -1- benzyl -4- isobutyl groups pyrrolidin-3-yl) -7- bromos pyrrolo- [2,1-f] [1,2,4] three Piperazine -4 (3H) -one (1.0g, 2.33mmol) is dissolved in toluene (20mL), and thiomorpholine 1,1- dioxide. HCls is added (956.2mg,5.592mmol)、Pd2(dba)3(88.0mg, 0.093mmol), sodium tert-butoxide (1.35g, 13.98mmol) and BINAP (116.3mg, 0.186mmol), N2110 DEG C of back flow reactions are heated under protection to stay overnight.TLC monitoring reactions terminate, and react Liquid concentrates, and water (10mL) is added, and dichloromethane extracts (3 × 25mL), and organic phase merges, and washes (2 × 10mL), uses saturated common salt It washes (20mL), anhydrous sodium sulfate drying is filtered, and concentration, crude product is through silica gel column chromatography (DCM:MeOH=200:1-10:1) Product (380mg, yield:33.8%).
Step 2:(3S, 4S) -3- (7- (1,1- sulfur dioxide is for morpholino) -4- oxo -3,4- pyrrolin simultaneously [2,1- F] [1,2,4] triazine -2- bases) -4- isobutyl group pyrrolidines -1- t-butyl formates synthesis:
By 2- ((3S, 4S) -1- benzyl -4- isobutyl group pyrroles -3- bases) -7- (1,1- titanium dioxide thio-morpholinyls) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (380.0mg, 0.786mmoL) is dissolved in dichloromethane (1.5mL) and methanol (1.5mL), is added di-tert-butyl dicarbonate (171.63mg, 0.786mmoL) and Pd/C (19.0mg), replacing hydrogen three times, add Hydrogen is stayed overnight, and the reaction was complete for TLC monitorings, and suction filtered through kieselguhr, filtrate decompression is concentrated to give (3S, 4S) -3- (7- (1,1- sulfur dioxide generations Morpholino) -4- oxo -3,4- pyrrolin simultaneously [2,1-f] [1,2,4] triazine -2- bases) -4- isobutyl group pyrrolidines -1- formic acid uncles Butyl ester (390.0mg crude products)
Step 3:7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl group pyrroles -3- bases) pyrrolo- [2, 1-f] [1,2,4] triazine -4 (3H) -one synthesis:
By (3S, 4S) -3- (7- (1,1- sulfur dioxide is for morpholino) -4- oxo -3,4- pyrrolin simultaneously [2,1-f] [1, 2,4] triazine -2- bases) -4- isobutyl group pyrrolidines -1- t-butyl formates (390.0mg crude products) are dissolved in dichloromethane (5mL), and 0 Trifluoroacetic acid (2.5mL) is added dropwise at DEG C, is slowly increased to room temperature reaction 2 hours, the reaction was complete for TLC monitorings.Reaction solution is concentrated under reduced pressure Obtain 7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl group pyrroles -3- bases) pyrrolo- [2,1-f] [1,2,4] Triazine -4 (3H) -one (390.0mg crude products).
Step 4:7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl groups -1- ((1- methyl -2- oxos - 1,2- dihydropyridine -4- bases) methyl) pyrrolidin-3-yl) and pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one synthesis:
By 7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl group pyrroles -3- bases) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (309.1mg) is dissolved in DCM (6mL), and -2 (1H) -one of 4- aldehyde radical -1- picolines is added (128.9mg, 0.94mmol) and sodium triacetoxy borohydride (416.5mg, 1.965mmol), is stirred overnight, TLC at room temperature The reaction was complete for monitoring, and saturated sodium bicarbonate aqueous solution (5mL) is added, and (3 × 10mL) is extracted with DCM, and organic phase merges, washing (2 × 5mL), anhydrous sodium sulfate drying is filtered, and concentration, crude product purifies (DCM through silica gel column chromatography:MeOH=100:1-20:1) Yellow solid 7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl groups -1- ((1- methyl -2- oxos -1,2- two Pyridinium hydroxide -4- bases) methyl) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (80.0mg, yield: 19.8%)
1HNMR(400MHz,DMSO-d6)δ(ppm):7.61-7.59(d,1H),6.79-6.78(d,1H),6.31(s, 1H),6.17-6.15(m,2H),3.67-3.66(d,4H),3.44-3.43(d,2H),3.38(s,3H),3.29-3.28(d, 4H),2.94-2.85(m,2H),2.82-2.80(d,1H),2.78-2.67(m,2H),2.29-2.26(m,1H),1.54-1.50 (m,2H),1.38-1.33(m,2H),0.87-0.83(m,6H).
Molecular formula:C25H34N6O4S molecular weight:514.65 LC-MS (Pos, m/z)=515.2 [M+H+].
5 2- of embodiment ((3S, 4S) -4- (Cvclopropvlmethvl) -1- ((1- methyl -2- oxo -1,2- dihydropyridines -4- Base) methyl) pyrrolidin-3-yl) -7- (1,1- titanium dioxide thio-morpholinyls) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) - The synthesis of ketone (compound 16)
Step:
Step 1:2- ((3S, 4S) -1- benzyls -4- (Cvclopropvlmethvl) pyrrolidin-3-yl) -7- (1,1- sulfur dioxide generations Morpholinyl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one synthesis:
By 2- ((3S, 4S) -1- benzyls -4- (Cvclopropvlmethvl) pyrrolidin-3-yl) -7- bromos pyrrolo- [2,1-f] [1, 2,4] triazine -4 (3H) -one (200.0mg, 0.468mmol) is dissolved in toluene (5mL), and thiomorpholine 1,1- titanium dioxides is added Object hydrochloride (192.2mg, 1.124mmol), Pd2(dba)3(17.86mg, 0.0188mmol), sodium tert-butoxide (270.8mg, 2.808mmol) and BINAP (23.76mg, 0.038mmol), 110 DEG C of back flow reactions are heated under nitrogen protection 8 hours.TLC is supervised It surveys reaction to terminate, water (10mL) is added in reaction solution concentration, and (3 × 25mL) is extracted with dichloromethane, and organic phase merges, washing (2 × 10mL), saturated common salt washes (1 × 20mL), and anhydrous sodium sulfate drying is filtered, and concentration, crude product is through silica gel column chromatography (DCM: MeOH=200:1-100:1) product 2- ((3S, 4S) -1- benzyls -4- (Cvclopropvlmethvl) pyrrolidin-3-yl) -7- (1,1- are obtained Titanium dioxide thio-morpholinyl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (160mg, yield:71.1%)
Step 2:(3S, 4S) -3- (Cvclopropvlmethvl) -4- (7- (1,1- dioxothiomorpholin generations) -4- oxos -3,4- Pyrrolin simultaneously [2,1-f] [1,2,4] triazine -2- bases) pyrrolidines -1- carboxylic acid tert-butyl esters synthesis:
By 2- ((3S, 4S) -1- benzyls -4- (Cvclopropvlmethvl) pyrrolidin-3-yl) -7- (1,1- titanium dioxide thiomorpholines Base) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (160.0mg, 0.332mmoL) be dissolved in dichloromethane (3.0mL) and Methanol (3.0mL), is added di-tert-butyl dicarbonate (73.6mg, 0.332mmoL) and Pd/C (8.0mg), replacing hydrogen three times, add Hydrogen is stayed overnight, and the reaction was complete for TLC monitorings, and suction filtered through kieselguhr, filtrate decompression is concentrated to give (3S, 4S) -3- (Cvclopropvlmethvl) -4- (7- (1,1- dioxothiomorpholin generations) -4- oxo -3,4- pyrrolin simultaneously [2,1-f] [1,2,4] triazine -2- bases) pyrrolidines -1- Carboxylic acid tert-butyl ester (165.3mg crude products).
Step 3:2- ((3S, 4S) -4- (Cvclopropvlmethvl) pyrrolidin-3-yl) -7- (1,1- sulfur dioxide is for morpholino) The synthesis of pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one:
By (3S, 4S) -3- (Cvclopropvlmethvl) -4- (7- (1,1- dioxothiomorpholin generations) -4- oxo -3,4- dihydros Pyrrolo- [2,1-f] [1,2,4] triazine -2- bases) pyrrolidines -1- carboxylic acid tert-butyl esters (162.1mg crude products) are dissolved in dichloromethane In (4mL), trifluoroacetic acid (2mL) is added dropwise at 0 DEG C, is slowly increased to room temperature reaction 2 hours, the reaction was complete for TLC monitorings, reaction solution 2- ((3S, 4S) -4- (Cvclopropvlmethvl) pyrrolidin-3-yl) -7- (1,1- sulfur dioxide is for morpholino) pyrroles is concentrated under reduced pressure to obtain And [2,1-f] [1,2,4] triazine -4 (3H) -one (130.5mg, crude product)
Step 4:2- ((3S, 4S) -4- (Cvclopropvlmethvl) -1- ((1- methyl -2- oxo -1,2- dihydropyridine -4- bases) Methyl) pyrrolidin-3-yl) -7- (1,1- titanium dioxide thio-morpholinyls) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one Synthesis:
By 2- ((3S, 4S) -4- (Cvclopropvlmethvl) pyrrolidin-3-yl) -7- (1,1- sulfur dioxide is for morpholino) pyrroles And [2,1-f] [1,2,4] triazine -4 (3H) -one (129.98mg) is dissolved in DCM (6mL), and 4- aldehyde radical -1- picolines -2 are added (1H) -one (54.6mg, 0.398mmol) and sodium triacetoxy borohydride (254.3mg, 1.2mmol), it is stirred at room temperature Night.The reaction was complete for TLC monitorings, and saturated sodium bicarbonate aqueous solution (5mL) is added, and extracts (3 × 10mL) with DCM, merges organic phase, It washes (2 × 5mL), anhydrous sodium sulfate drying is filtered, and concentration, crude product is through silica gel column chromatography (DCM:MeOH=100:1-20:1) Purify to obtain white solid 2- ((3S, 4S) -4- (Cvclopropvlmethvl) -1- ((1- methyl -2- oxo -1,2- dihydropyridine -4- bases) Methyl) pyrrolidin-3-yl) -7- (1,1- titanium dioxide thio-morpholinyls) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (39.5mg, yield:23.2%)
1HNMR(400MHz,CDCl3)δ(ppm):7.35-7.33(d,1H),6.97-6.96(d,1H),6.46(s,1H), 6.39-6.37(d,1H),6.01-6.00(d,1H),3.77-3.76(d,4H),3.63-3.60(d,1H),3.54-3.48(t, 3H),3.43-3.36(m,2H),3.22(s,3H),3.08-3.07(d,1H),3.00-2.93(t,2H),2.92-2.91(t, 1H),2.50-2.46(m,2H),2.02-2.00(t,1H),1.48-1.43(m,2H),0.47-0.44(t,2H),0.11-0.08 (m,2H).
Molecular formula:C25H32N6O4S molecular weight:512.63 LC-MS (Pos, m/z)=513.2 [M+H+].
6 7- of embodiment (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl groups -1- (pyrimidine -5- Ji Jia Base) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (compound 29) synthesis
Step:
Step 1:2- ((3S, 4S) -1- benzyl -4- isobutyl group pyrroles -3- bases) -7- (1,1- titanium dioxide thio-morpholinyls) pyrrole Cough up the synthesis of simultaneously [2,1-f] [1,2,4] triazine -4 (3H) -one:
By 2- (3S, 4S) -1- benzyl -4- isobutyl groups pyrrolidin-3-yl) -7- bromos pyrrolo- [2,1-f] [1,2,4] three Piperazine -4 (3H) -one (1.0g, 2.33mmol) is dissolved in toluene (20mL), and thiomorpholine 1,1- dioxide. HCls is added (956.2mg,5.592mmol)、Pd2(dba)3(88.0mg, 0.093mmol), sodium tert-butoxide (1.35g, 13.98mmol) and BINAP (116.3mg, 0.186mmol), N2110 DEG C of back flow reactions are heated under protection to stay overnight.TLC monitoring reactions terminate, and react Liquid concentrates, and water (10mL) is added, and dichloromethane extracts (3 × 25mL), and organic phase merges, and washes (2 × 10mL), uses saturated common salt It washes (20mL), anhydrous sodium sulfate drying is filtered, and concentration, crude product is through silica gel column chromatography (DCM:MeOH=200:1-10:1) Product (700mg, yield:62.5%)
Step 2:(3S, 4S) -3- (7- (1,1- sulfur dioxide is for morpholino) -4- oxo -3,4- pyrrolin simultaneously [2,1- F] [1,2,4] triazine -2- bases) -4- isobutyl group pyrrolidines -1- t-butyl formates synthesis:
By 2- ((3S, 4S) -1- benzyl -4- isobutyl group pyrroles -3- bases) -7- (1,1- titanium dioxide thio-morpholinyls) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (380.0mg, 0.786mmoL) is dissolved in dichloromethane (1.5mL) and methanol (1.5mL), is added di-tert-butyl dicarbonate (171.63mg, 0.786mmoL) and Pd/C (19.0mg), replacing hydrogen three times, add Hydrogen is stayed overnight, and the reaction was complete for TLC monitorings, and suction filtered through kieselguhr, filtrate decompression is concentrated to give (3S, 4S) -3- (7- (1,1- sulfur dioxide generations Morpholino) -4- oxo -3,4- pyrrolin simultaneously [2,1-f] [1,2,4] triazine -2- bases) -4- isobutyl group pyrrolidines -1- formic acid uncles Butyl ester (620.0mg, crude product).
Step 3:7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl group pyrroles -3- bases) pyrrolo- [2, 1-f] [1,2,4] triazine -4 (3H) -one synthesis:
By (3S, 4S) -3- (7- (1,1- sulfur dioxide is for morpholino) -4- oxo -3,4- pyrrolin simultaneously [2,1-f] [1, 2,4] triazine -2- bases) -4- isobutyl group pyrrolidines -1- t-butyl formates (600mg crude products) are dissolved in dichloromethane (5mL), and 0 DEG C Lower dropwise addition trifluoroacetic acid (2.5mL) is slowly increased to room temperature reaction 2 hours, and the reaction was complete for TLC monitorings.Reaction solution is concentrated under reduced pressure 7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl group pyrroles -3- bases) pyrrolo- [2,1-f] [1,2,4] three Piperazine -4 (3H) -one (620mg crude products).
Step 4:7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl groups -1- (pyrimidine -5- ylmethyls) Pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one synthesis:
By 7- (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl group pyrroles -3- bases) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (188.76mg) is dissolved in DCM (4mL), be added pyrimidine -5-formaldehyde (62.27mg, It 0.576mmol) with sodium triacetoxy borohydride (254.3mg, 1.2mmol), is stirred overnight at room temperature, TLC monitorings have been reacted Entirely, saturated sodium bicarbonate aqueous solution (5mL) is added, (3 × 10mL) is extracted with DCM, organic phase merges, and washes (2 × 5mL), nothing Aqueous sodium persulfate is dried, and is filtered, and concentration, crude product purifies (DCM through silica gel column chromatography:MeOH=100:1-20:1) white solid 7- is obtained (1,1- titanium dioxide thio-morpholinyls) -2- ((3S, 4S) -4- isobutyl groups -1- (pyrimidine -5- ylmethyls) pyrrolidin-3-yl) pyrroles And [2,1-f] [1,2,4] triazine -4 (3H) -one (130.0mg, yield:56.03%)
1HNMR(400MHz,CDCl3)δ(ppm):9.70(s,1H),9.20(s,1H),8.77(s,2H),6.99-6.98 (d,1H),6.02-6.00(d,1H),3.79-3.66(m,6H),3.32-3.28(t,1H),3.07-3.05(d,1H),2.88- 2.60(m,1H),2.59-2.56(t,1H),2.42-2.41(d,1H),1.94-1.90(t,1H),1.65-1.60(m,1H), 1.49-1.36(m,2H),0.92-0.86(m,6H).
Molecular formula:C23H31N7O3S molecular weight:485.61 LC-MS (Neg, m/z)=484.0 [M-H]-.
7 7- of embodiment (1,1- titanium dioxide thio-morpholinyls) -2- ((trans-) -4- isobutyl groups -1- ((6- ((sulfonyloxy methyls Base) methyl) pyridin-3-yl) methyl) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (compound 31) synthesis
Step:
Step 1:6- (((methyl sulphonyl) oxygroup) methyl) methyl nicotinate must synthesize:
6- (methylol) methyl nicotinate is dissolved in DCM (10mL), is cooled to 0 DEG C, sequentially add triethylamine (2.43g, 12mmol) with mesyl chloride (2.06g, 18mmol), it is slowly increased to room temperature reaction overnight.The reaction was complete for TLC monitorings, and saturation is added Aqueous ammonium chloride solution (5mL), liquid separation, water phase extract (3 × 10mL) with DCM, merge organic phase, wash (2 × 5mL), anhydrous sulphur Sour sodium drying, filtering are concentrated to give 6- (((methyl sulphonyl) oxygroup) methyl) methyl nicotinate (3.2g crude products)
Step 2:The synthesis of 6- ((methyl mercapto) methyl) niacin:
6- (((methyl sulphonyl) oxygroup) methyl) methyl nicotinate (2.94g, 12mmol) is dissolved in DMF (10mL), is added Sodium methyl mercaptide (1.0g, 14.4mmol), room temperature reaction is overnight.TLC monitoring the reaction was complete, be concentrated under reduced pressure, be added ethyl acetate and Water, liquid separation, water phase are extracted with ethyl acetate, and merge organic phase, washing, saturated common salt washing is dry, and filtering is concentrated to give 6- ((methyl mercapto) methyl) niacin (2.0g crude products).
Step 3:The synthesis of 6- ((methyl mercapto) methyl) methyl nicotinate:
6- ((methyl mercapto) methyl) niacin (2.0g crude products) is dissolved in DCM (15mL), ice bath is cooled to 0 DEG C, and oxalyl is added DMF (0.05mL) is added at 0 DEG C, 2h is stirred at 0 DEG C for chlorine (4.2g, 32.8mmol), and methanol (20mL), TLC monitorings is slowly added dropwise The reaction was complete, is concentrated under reduced pressure, crude product is through silica gel column chromatography (PE:EA=10:1) yellow solid 6- ((methyl mercapto) methyl) niacin is obtained Methyl esters (140.0mg).
Step 4:The synthesis of 6- ((methyl sulphonyl) methyl) methyl nicotinate:
6- ((methyl mercapto) methyl) methyl nicotinate (140.0mg, 0.71mmol) is dissolved in DCM (3mL), ice bath is cooled to 0 DEG C, metachloroperbenzoic acid (300.0mg, 0.852mmol) is added, is slowly increased to room temperature reaction 2 hours, TLC monitorings have been reacted Entirely, dichloromethane (10mL) and saturated sodium bicarbonate aqueous solution (10mL) is added, the extraction of water phase dichloromethane merges organic phase, Anhydrous sodium sulfate is dried, and filtering is concentrated to give 6- ((methyl sulphonyl) methyl) methyl nicotinate (180.0mg crude products).
Step 5:The synthesis of (6- ((methyl sulphonyl) methyl) pyridin-3-yl) methanol:
Lithium Aluminium Hydride (44.9mg, 1.18mmol) is added in anhydrous tetrahydro furan (6mL), ice bath is cooled to 0 DEG C, adds Enter tetrahydrofuran (3mL) solution of 6- ((methyl sulphonyl) methyl) methyl nicotinate (180.0mg), is stirred 1 hour at 0 DEG C, TLC The reaction was complete for monitoring, sequentially adds water (44.9mg), 10%NaOH aqueous solutions (44.9mg) and water (134.7mg), stirs 10 points Clock, diatomite filtering, filtrate are concentrated to give (6- ((methyl sulphonyl) methyl) pyridin-3-yl) methanol (130.0mg crude products).
Step 6:The synthesis of 6- ((methyl sulphonyl) methyl) cigarette aldehyde:
(6- ((methyl sulphonyl) methyl) pyridin-3-yl) methanol (130.0mg crude products) is dissolved in dichloromethane (8mL) In, manganese dioxide (904.2mg, 10.4mmol) is added, is stirred overnight at room temperature, the reaction was complete for TLC monitorings, diatomite filtering, filter Liquid concentrates, and crude product obtains white solid 6- ((methyl sulphonyl) methyl) cigarette aldehyde (50.0mg) through preparing TLC separation.
Step 7:7- (1,1- titanium dioxide thio-morpholinyls) -2- ((trans-) -4- isobutyl groups -1- ((6- ((methyl sulphonyl) Methyl) pyridin-3-yl) methyl) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one synthesis:
By 7- (1,1- titanium dioxide thio-morpholinyls) -2- ((trans-) -4- isobutyl group pyrroles -3- bases) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (41.2mg) is dissolved in DCM (3mL), and 6- ((methyl sulphonyl) methyl) cigarette aldehyde is added (25.0mg, 0.126mmol mmol) and sodium triacetoxy borohydride (55.74mg, 0.263mmol), it is stirred at room temperature Night.The reaction was complete for TLC monitorings, and saturated sodium bicarbonate (5mL) is added, and (3 × 10mL) is extracted with DCM, merges organic phase, washing (2 × 5mL), anhydrous sodium sulfate drying is filtered, and concentration, crude product purifies (DCM through silica gel column chromatography:MeOH=100:1-20:1) 7- (1,1- titanium dioxide thio-morpholinyls) -2- ((trans-) -4- isobutyl groups -1- ((6- ((methyl sulphonyl) methyl) pyridine -3- Base) methyl) pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (20.0mg, yield:33.1%).
1HNMR(400MHz,DMSO)δ(ppm):11.27(s,1H),8.53(s,1H),7.79-7.77(d,1H),7.48- 7.46(d,1H),6.79-6.78(d,1H),6.15-6.14(d,1H),4.61(s,2H),3.66(s,5H),3.01(s,3H), 2.96-2.82(m,3H),2.80-2.67(m,2H),2.33-2.29(t,1H),1.53-1.51(m,1H),1.38-1.33(m, 2H),0.87-0.83(m,6H).
Molecular formula:C26H36N6O5S2Molecular weight:576.73, LC-MS (Pos, m/z)=577.3 [M+H+].
((the trans-)-4- isobutyl groups-1- (pyridin-4-yl methyl) of 8 7- of embodiment (1,1- titanium dioxide thio-morpholinyls)-2- Pyrrolidin-3-yl) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (compound 32) synthesis
Step 1：((trans-)-4- isobutyl groups-1- (pyridin-4-yl methyl) pyrroles of 7- (1,1- titanium dioxide thio-morpholinyls)-2- Cough up alkane -3- bases) synthesis of pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one
By 7- (1,1- titanium dioxide thio-morpholinyls) -2- ((trans-) -4- isobutyl group pyrroles -3- bases) pyrrolo- [2,1-f] [1,2,4] triazine -4 (3H) -one (66mg, 0.168mmol, 1.0eq) is dissolved in DCM, be added different cigarette aldehyde (21.55mg, 0.201mmol, 1.2eq) and sodium triacetoxy borohydride (88.86mg, 0.419mmol, 2.5eq), stir 4h, TLC monitorings The reaction was complete.NaHCO is added3Solution (10mL) and DCM (10mL), liquid separation, water phase extract (10mL × 3) with DCM, merge organic Phase, dry, concentration, crude product is through silica gel column chromatography (DCM:MeOH=150:1-5:1) product (46mg, yield are purified to obtain 56.6%).
1HNMR(400MHz,DMSO-d6)δ(ppm):8.52(m,2H),7.32(m,2H),6.81(m,1H),6.12(m, 1H),3.68-3.75(m,5H),2.91-2.95(m,1H),2.81-2.85(m,1H),2.61-2.67(m,2H),2.31-2.36 (m,2H),1.25-1.72(m,4H),0.81-0.92(m,6H).
Molecular formula:C24H32N6O3S molecular weight:484.62 LC-MS (Neg, m/z)=485.2 [M-H+].
Biological Examples
According to following biological Examples, the present invention may be better understood.However, those skilled in the art is easy reason It solves, content is merely to illustrate the present invention described in embodiment, is retouched in detail without that should will not limit in claims The present invention stated.Compound belonging to the present invention can be used for treating or prevent the related disease mediated by PDE9 unconventionality expressions Disease.
The external zymetology activity experiment of the compounds of this invention
Test sample：The compounds of this invention described in table 1, structure and preparation method are as described above.
Experimental method：
1. in 384 hole sample panels, it is added 2 μ l 5X PDE9A solution per hole, with 2 μ l 1X in full negative control hole The complete reaction buffers of IMAP replace.
2. the test medicine diluted in 4 μ l 2.5X above-mentioned steps B is added per hole, full negative control hole and solvent are cloudy The complete reaction buffers of 1X IMAP of 4 μ l 2%DMSO are added in property control wells.
3. 4 μ l 2.5X cGMP substrate working solutions are added per hole along hole wall.
4. being protected from light after sealing plate, after whole plate 700rpm × 1min centrifugations, it is incubated at room temperature 60min, wherein preceding 5min shakes in shaking table It swings.
5. 20 μ l IMAP combination buffers are added per hole along hole wall.It is protected from light after sealing plate, whole plate 700rpm × 1min centrifugations Afterwards, room temperature shakes 5min in shaking table, then is incubated at room temperature 3h.
6.Teacan fluorescence microplate readers read each hole fluorescence values.
7. inhibiting rate takes each parallel hole average value, computational methods as follows：(test medicine fluorescence intensity-is complete negative right by 100- According to hole fluorescence intensity) * 100/ (the full negative control hole fluorescence intensity of solvent negative control hole fluorescence intensity -).It is tested by 10 The IC of test medicine is calculated using the non-linear S types curvilinear regression of GraphPad Prism for the data that drug concentration obtains50 Value.
The external zymetology inhibitory activity (IC of 1 the compounds of this invention of table50)
Compound To PDE9A inhibitory activity IC50(nM)
Compound 1 13
Compound 2 52
Compound 10 16
Compound 15 26
Compound 16 52
Compound 29 18
Compound 31 2
Compound 32 5
By table 1 as it can be seen that the compound of the present invention has good PDE9A inhibitory activity, can be used for treating by PDE9 exceptions Express the relevant disease mediated.

Claims (10)

1. a kind of PDE9 kinases (phosphodiesterase 9) inhibitor indicated by the following general formula (I) or its is pharmaceutically acceptable Salt, solvated compounds, polymorph and isomers：
Wherein, n is selected from 0,1 or 2；
X is selected from N or CR1；
R1Independently selected from hydrogen, C1-6Alkyl, C2-8Alkenyl, C2-8Alkynyl, C3-6Naphthenic base, halogenated C1-6Alkyl ,-(CH2)m’-C3-6 Naphthenic base, m '=1 or 2；
R2It is independent to be selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C3-6Cycloalkyl oxy, C3-6Cycloalkyl amino, halogenated C3-6Naphthenic base, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl sulphonyl, C3-8Membered ring alkyl sulphonyl, C1-6Alkyl sulfenyl, C2-8Alkenyl (C3-6) naphthenic base, C2-8Alkynyl (C3-6) naphthenic base, C1-6Alkyl-carbonyl, C3-6Naphthene base carbonyl ,- (CH2)n’- 3-14 members naphthenic base ,-(CH2)n’- 5-14 members aromatic ring ,-(CH2)n’- 5-10 circle heterocyclic rings base ,-(CH2)n’- 5-10 members are miscellaneous Aryl, the heterocycle, heteroaryl contain 1-3 O, S and/or N atom, wherein the arbitrary annular atom sulphur of heterocycle, heteroaryl can appoint Choosing is oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O), n '=0,1 or 2, naphthenic base, miscellaneous Ring group, aromatic ring, hetero-aromatic ring can be optionally by 1-3 R5Substitution；
Wherein, when X is selected from CR1When, and R1For hydrogen when, R2Cannot be
R3Independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C3-6Naphthenic base, C1-6Alcoxyl Base, C3-6Cycloalkyl oxy, halogenated C1-6Alkoxy, halogenated C1-6Alkyl, halogenated C3-6Naphthenic base, C2-8Alkenyl, C2-8Alkynyl, amino C1-6Alkyl, C3-6Cycloalkyl amino, C1-6Alkyl sulphonyl, 3-8 membered rings alkyl sulphonyl, C1-6Alkyl-carbonyl, C3-6Naphthenic base carbonyl Base, C1-6Alkyl sulfenyl, 3-14 members naphthenic base, 5-14 members aromatic ring, -5-10 circle heterocyclic rings base, -5-10 unit's heteroaryls, the heterocycle Base, heteroaryl contain 1-3 O, S and/or N atom, wherein the arbitrary annular atom sulphur of heterocycle, heteroaryl can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O), and naphthenic base, aromatic ring, hetero-aromatic ring, heterocycle can be optional By 1-3 R6Substitution；
R4Independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C3-6Cycloalkanes Base oxygroup, halogenated C1-6Alkoxy, halogenated C1-6Alkyl, halogenated C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl, amino C1-6Alkyl, C3-6Cycloalkyl amino, C1-6Alkyl sulphonyl, 3-8 membered rings alkyl sulphonyl, C1-6Alkyl-carbonyl or C3-6Naphthene base carbonyl, C1-6 Alkyl sulfenyl or-(CH2)n’- 3-7 members naphthenic base ,-(CH2)n’- 5-6 members aromatic ring ,-(CH2)n’-- 5-7 circle heterocyclic rings base ,- (CH2)n’-- 5-6 unit's heteroaryls, the heterocycle, heteroaryl contain 1-3 O, S and/or N atom, wherein heterocycle, heteroaryl Arbitrary ring S can optionally be oxidized to S (O) or S (O)2, arbitrary ring carbon is optionally oxidized to C (O), n '=0,1 or 2, ring Alkyl, aromatic ring, hetero-aromatic ring, heterocycle can be optionally by 1-3 R7Substitution；
R5It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, trifluoromethyl, methoxyl group ,-(CH2)n’- 3-14 members naphthenic base ,-(CH2)n’- 5-14 members aromatic ring ,-(CH2)n’-- 5-10 circle heterocyclic rings base ,-(CH2)n’-- 5-10 unit's heteroaryls, The heterocycle, heteroaryl contain 0-3 O, S and/or N atom, wherein n '=0,1 or 2；
R6、R7It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, trifluoromethyl, C1-6Alkyl, C1-4Alkane Oxygroup, C1-6Alkyl sulphonyl, C1-6Alkyl sulphonyl C1-6Alkyl, C1-6Alkyl sulphonyl C1-6Alkoxy, aminosulfonyl amino C1-6Alkyl, methoxyl group, cyclopropyl ,-(CH2)m’-C3-6Naphthenic base, m '=1 or 2.
2. PDE9 kinase inhibitors or its pharmaceutically acceptable salt, solvated compounds, polymorph and different as described in power 1 Structure body, wherein general structure is such as shown in (II)：
N is selected from 0,1 or 2；
X is selected from N or CR1；
R1Independently selected from hydrogen, methyl, ethyl, cyclopropyl ,-CH2Cyclopropyl, trifluoromethyl；
Ring A is selected from optional-(CH2)n’- 3-14 members naphthenic base ,-(CH2)n’- 5-14 members aromatic ring ,-(CH2)n’- 5-10 circle heterocyclic rings Base ,-(CH2)n’- 5-10 unit's heteroaryls, the heterocycle, heteroaryl contain 1-3 O, S and/or N atom, wherein ring A optionally quilts 1-3 R5Substitution, arbitrary annular atom sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon optionally aoxidized For C (O)；N '=0,1 or 2；
Wherein, when X is selected from CR1When, and R1For hydrogen when, R2Cannot be
R5It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, trifluoromethyl, methoxyl group ,-(CH2)n’- 3-14 members naphthenic base ,-(CH2)n’- 5-14 members aromatic ring ,-(CH2)n’- 5-10 circle heterocyclic rings base ,-(CH2)n’- 5-10 unit's heteroaryls, institute State heterocycle, heteroaryl contains 0-3 O, S and/or N atom, wherein n '=0,1 or 2.
3. PDE9 kinase inhibitors or its pharmaceutically acceptable salt, solvated compounds, polymorph and different as described in power 2 Structure body, wherein general structure is such as shown in (III-1), (III-2)：
Wherein,
Ring A ' is selected from 5-7 members naphthenic base, 5-7 members aromatic ring, -5-7 circle heterocyclic rings base or -5-7 member hetero-aromatic rings, the heterocycle, heteroaryl Base contains 1-3 O, S and/or N atom, and arbitrary annular atom sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon can Optionally it is oxidized to C (O)；
Ring A " is selected from 5-7 members naphthenic base, 5-7 members aromatic ring, -5-7 circle heterocyclic rings base or -5-7 member hetero-aromatic rings, the heterocycle, heteroaryl Base contains 1-3 O, S and/or N atom, and arbitrary annular atom sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon can Optionally it is oxidized to C (O)；
Wherein, ring A " cannot be
Ring A ' and ring A " is optionally by 1-3 R5Substitution,
R5It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, cyclopropyl, trifluoromethyl ,- CH2Cyclopropyl.
4. PDE9 kinase inhibitors or its pharmaceutically acceptable salt, solvated compounds, polymorph and different as described in power 3 Structure body, wherein
Ring A ' is selected from 5-7 members naphthenic base, 5-7 circle heterocyclic ring bases, and the heterocycle contains 1-3 O, S and/or N atom, arbitrary annular atom Sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O)；
Ring A " is selected from 5-7 members naphthenic base, 5-7 circle heterocyclic ring bases, and the heterocycle contains 1-3 O, S and/or N atom, arbitrary annular atom Sulphur can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O)；
Wherein, ring A " cannot be
Ring A ' and ring A " is optionally by 1-3 R5Substitution,
R5It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, cyclopropyl, trifluoromethyl ,- CH2Cyclopropyl；
R3Independently selected from hydrogen, 3-7 members naphthenic base, 5-7 members aromatic ring, -5-7 circle heterocyclic rings base or -5-7 member hetero-aromatic rings, the heterocycle Base, heteroaryl contain 1-3 O, S and/or N atom, wherein naphthenic base, heterocycle, aryl, heteroaryl are optionally by 1 or 2 R6 Substitution, the arbitrary annular atom sulphur S of heterocycle, heteroaryl can optionally be oxidized to S (O) or S (O)2, arbitrary annular atom carbon can be optional Ground is oxidized to C (O)；
R6It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, cyclopropyl, Trifluoromethyl, C1-4Alkyl sulphonyl, C1-4Alkyl sulphonyl C1-4Alkyl, C1-4Alkyl sulphonyl C1-4Alkoxy, aminosulfonyl ammonia Base C1-4Alkyl ,-CH2Cyclopropyl.
5. PDE9 kinase inhibitors or its pharmaceutically acceptable salt, solvated compounds, polymorph and different as described in power 4 Structure body, wherein
Ring A ' is selected from 5-7 circle heterocyclic ring bases, and the heterocycle contains 1-3 O, S and/or N atom, and arbitrary annular atom sulphur can be optionally by oxygen Turn to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O)；
Ring A " is selected from 5-7 circle heterocyclic ring bases, and the heterocycle contains 1-3 O, S and/or N atom, and arbitrary annular atom sulphur can be optionally by oxygen Turn to S (O) or S (O)2, arbitrary annular atom carbon is optionally oxidized to C (O)；
Wherein, ring A " cannot be
Ring A ' and ring A " is optionally by 1-3 R5Substitution,
R5It is independent to be selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, cyclopropyl, trifluoromethyl ,- CH2Cyclopropyl；
R4It is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C3-6Naphthenic base Oxygroup, halogenated C1-4Alkoxy, C3-6Cycloalkyl amino ,-CH2Cyclopropyl, C1-4Alkyl sulphonyl, 3-8 membered rings alkyl sulphonyl, C1-4Alkyl-carbonyl or C3-6Naphthene base carbonyl.
6. PDE9 kinase inhibitors or its pharmaceutically acceptable salt, solvated compounds, polymorph and different as described in power 5 Structure body, wherein
Wherein,
R3It preferably is selected from following group：Hydrogen,
Ring A ' and ring A " are respectively and independently selected from following group：
7. such as power 1-6 any one of them PDE9 kinase inhibitors or its pharmaceutically acceptable salt, solvated compounds, polycrystalline Type object and isomers,
8. containing claim 1-7 any one of them compound or its pharmaceutically acceptable salt, solvated compounds, polymorphic The pharmaceutical preparation of object and isomers, it is characterised in that include one or more pharmaceutical carriers.
9. containing claim 1-7 any one of them compound or its pharmaceutically acceptable salt, solvated compounds, polymorphic The pharmaceutical preparation of object and isomers, it is characterised in that further include one or more second therapeutically active agents, described second Therapeutically active agent is antimetabolite, growth factor receptor inhibitors, has silk classification inhibitor, antitumor steroids, alkylating agents, metal Class, topoisomerase enzyme inhibitor, hormone drug, immunomodulator, tumor suppressor gene, Theratope, immunologic test point or tumour are exempted from The treatment-related antibody of epidemic disease and small-molecule drug.
10. such as claim 1-7 any one of them compound or its pharmaceutically acceptable salt, solvated compounds, polymorphic The purposes of object and isomers in the drug for preparing the relevant disease that treatment is mediated by PDE9 unconventionality expressions, the PDE9 are abnormal Expressing the relevant disease mediated is：
(a) disease treatment for being used to by inhibition PDE9 to reach；
(b) it is used to treat CNS diseases；
(c) it is used to treat disease or illness selected from the following：Sleep disturbance, bipolar disorder, metabolic syndrome, obesity, Diabetes, hyperglycemia, dyslipidemia, glucose tolerance reduces or testis, brain, small intestine, skeletal muscle, heart, lung, thymus gland or spleen Disease, sickle blood disease.
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WO2021010492A1 (en) * 2019-07-17 2021-01-21 Ono Pharmaceutical Co., Ltd. Compound having kdm5 inhibitory activity and pharmaceutical use thereof
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* Cited by examiner, † Cited by third party
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CN111471059A (en) * 2019-01-23 2020-07-31 南京药捷安康生物科技有限公司 PDE9 inhibitors and uses thereof
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Patentee before: NANJING TRANSTHERA BIOSCIENCES Co.,Ltd.