CN105121424A - mGluR regulators - Google Patents
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- CN105121424A CN105121424A CN201380073290.6A CN201380073290A CN105121424A CN 105121424 A CN105121424 A CN 105121424A CN 201380073290 A CN201380073290 A CN 201380073290A CN 105121424 A CN105121424 A CN 105121424A
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- 0 *C1N(*)CC1(*)C#C* Chemical compound *C1N(*)CC1(*)C#C* 0.000 description 4
- NGUZLZRQOZXVSQ-UHFFFAOYSA-N COC1(CNCC1)OC Chemical compound COC1(CNCC1)OC NGUZLZRQOZXVSQ-UHFFFAOYSA-N 0.000 description 2
- FSZVSRVDBGQHTL-UHFFFAOYSA-N FC1(CNCC1)C#Cc1ncccc1 Chemical compound FC1(CNCC1)C#Cc1ncccc1 FSZVSRVDBGQHTL-UHFFFAOYSA-N 0.000 description 2
- MTHAZASDMMKNNA-UHFFFAOYSA-N CC(C)(C)OC(N(C1)CC1(C#Cc1cc2ccccc2[o]1)F)=O Chemical compound CC(C)(C)OC(N(C1)CC1(C#Cc1cc2ccccc2[o]1)F)=O MTHAZASDMMKNNA-UHFFFAOYSA-N 0.000 description 1
- YXAAECJWBAEYDO-UHFFFAOYSA-N CN(CC1)CC1(OC)OC Chemical compound CN(CC1)CC1(OC)OC YXAAECJWBAEYDO-UHFFFAOYSA-N 0.000 description 1
- SLPUTJFVMJPMKV-UHFFFAOYSA-N CN(CC1)CC1=O Chemical compound CN(CC1)CC1=O SLPUTJFVMJPMKV-UHFFFAOYSA-N 0.000 description 1
- MJGRKFMGIBDBCL-UHFFFAOYSA-N COC(CC1)(CN1OC(c1ccccc1)=O)OC Chemical compound COC(CC1)(CN1OC(c1ccccc1)=O)OC MJGRKFMGIBDBCL-UHFFFAOYSA-N 0.000 description 1
- JABILXBJRZQOJR-UHFFFAOYSA-N COC(CC1)(CN1c1ccccc1)OC Chemical compound COC(CC1)(CN1c1ccccc1)OC JABILXBJRZQOJR-UHFFFAOYSA-N 0.000 description 1
- JJYPMNFTHPTTDI-UHFFFAOYSA-N Cc1cc(N)ccc1 Chemical compound Cc1cc(N)ccc1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 1
- MPEOPBCQHNWNFB-UHFFFAOYSA-N Clc1ccccc1I Chemical compound Clc1ccccc1I MPEOPBCQHNWNFB-UHFFFAOYSA-N 0.000 description 1
- FXJIBUJVEHFLQJ-UHFFFAOYSA-N FC1(CNC1)C#Cc1cc(cccc2)c2[o]1 Chemical compound FC1(CNC1)C#Cc1cc(cccc2)c2[o]1 FXJIBUJVEHFLQJ-UHFFFAOYSA-N 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N Ic1ccccc1 Chemical compound Ic1ccccc1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- GTZAZJLKSXIJOF-UHFFFAOYSA-N O=C(CC1)CN1c1ccccc1 Chemical compound O=C(CC1)CN1c1ccccc1 GTZAZJLKSXIJOF-UHFFFAOYSA-N 0.000 description 1
- KXWQKLSBEJJKET-UHFFFAOYSA-N OC(CC1)(CN1C1=CC=CCC1)C#Cc1ncccc1 Chemical compound OC(CC1)(CN1C1=CC=CCC1)C#Cc1ncccc1 KXWQKLSBEJJKET-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
Provided herein are compounds of the formula I: (I), as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment or prevention of mGluR5 mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain.
Description
Technical field
The present invention relates to the compound of formula I:
Or its pharmacologically acceptable salt, and relate to the pharmaceutical composition comprising described compound or pharmaceutically acceptable salt thereof, wherein R
1, R
2, R
3, X, Y and a be defined as follows definition.Compound disclosed herein and composition are mGluR5 receptor antagonist, the illness being used for the treatment of or preventing mGluR5 to mediate, such as acute and/or chronic neurological illness, cognitive disorder and lethe and acute and chronic pain.
Below the All Files quoting or rely on by reference to being clearly incorporated to herein.
Background technology
L-glutamic acid is the most significant neurotransmitter in body, and its amount exceedes 50% of nervous tissue.L-glutamic acid mediates its effect by two groups of principal recipient: ionic and metabotropic.Ionotropic glutamate receptor is the ion channel receptor being usually responsible for fast excitatory transmission.They are divided into N-methyl-D-aspartate (NMDA), alpha-amino group-3-hydroxy-5-methyl base-4-isoxazole propionic acid (AMPA) and kainite acceptor usually.By contrast, metabotropic glutamate receptor (mGluR) belongs to C class G-protein linked receptor (GPCR) protein families and the main adjustment participating in fast excitatory and transmit.Therefore, they are the noticeable therapy target being used for the treatment of the illness relating to L-glutamic acid teleseme dysfunction.Based on amino acid sequence homology, signal transduction mechanism and pharmacological properties, mGluR is further divided into three groups (I, II and III groups).I group acceptor comprises mGluR1 and mGluR5, and II group comprises mGluR2 and mGluR3, and III group comprises mGluR4, mGluR6, mGluR7 and mGluR8.The G-albumen coupling of I group mGluR1 and mGluR5 acceptor and Gq family; Gq and G11 and activation thereof cause the activation of Phospholipase C; make membrane phospholipid acyl inositol (4; 5)-bisphosphate is hydrolyzed into DG; it is activated protein kinase C and InsP3 subsequently; InsP3 and then activate inositol triphosphate receptor again, thus the release promoting intracellular Ca2+.
Anatomical research confirms that mGluRs has wide in range and optionally distributes in mammalian nervous system.Such as, mGluR5 acceptor great expression in striatum, cortex, hippocampus caudate putamen; See such as: Shigemoto, R., Nomura, S., Hidemitsu, S., etal.NeuroscienceLett1993,163,53-57.Because these brain area have demonstrated participate in emotion, excitability process, learning and Memory and motion control, mGluR 5 modulators has been considered to have the treatment potentiality for multiple indication for a long time.
MGluR5 receptor antagonist can be used for the illness regulating the activity of mGluR5 acceptor and be used for the treatment of or prevent mGluR5 to mediate, such as acute and chronic neurological illness, cognitive disorder and lethe, and acute and chronic pain.The other diseases taken into account comprises cerebral ischemia, comprises the chronic neurodegenative of Huntington Chorea, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis, alzheimer's disease, Parkinson's disease, psychosis, schizophrenia, mood disorder, emotional handicap, the outer motor function illness of pyramidal tract, fat, pulmonary system and respiratory condition, motion control and function, attention deficit illness, be absorbed in power obstacle (concentrationdisorders), backwardness (comprising the backwardness relevant to Fragile X syndrome), antalgesic, neurodegenerative disorders, epilepsy, convulsive disorder, migraine, dyskinesia, eating disorder, vomiting, muscle spasm, urinary disorders, somnopathy, sexual dysfunction, circadian rhythm disease (circadiandisorders), drug withdrawal, drug habit, compulsive disorder, anxiety, panic disorder, dysthymia disorders, skin disorder, retinal ischemia, retinal degeneration, glaucoma, the illness relevant to organ transplantation, asthma, local asphyxia and astrocytoma, cardiovascular system diseases, gastrointestinal system disorder (such as gastroesophageal reflux disease and irritable bowel syndrome), endocrine system disease, external secretion systemic disease, tetter, cancer and eye system disease.The development and application of mglur 5 antagonists has been summarised in a lot of summary, such as: Gasparini, F., Bilbe, G., Gomez-Mancilla, G., andSpooren, W., CurrentOpinioninDrugDiscovery & Development11 (5): 655-665, 2008, Rocher, J.-P., Bonnet, B., Bol é a, C., etal., CurrentTopicsinMedicinalChemistry2011, 11, 680-695, Dekundy, A., Gravius, A., Hechenberger, M, etal., J.NeuralTransm2011, 118, 1703-1716 and Niswender, C.M.andConn, P.J., AnnuRevPharmacolToxicol2010, 50, 295-322.
Summary of the invention
The present invention relates to the compound or pharmaceutically acceptable salt thereof of formula I, containing their pharmaceutical composition and the method for disease therapy and illness.Compound disclosed herein and composition are mGluR5 receptor antagonists, are used for the treatment of the illness that mGluR5 regulates, comprise acute and/or chronic neurological illness, cognitive disorder and lethe, and acute and chronic pain.
detailed Description Of The Invention
In embodiments of the present invention, the compound of formula I is provided:
Or its pharmacologically acceptable salt,
Wherein:
X is-F ,-Cl ,-CN ,-CF
3,-OH or-O-CH
3;
R
1be the heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl that to be selected from N, O and S containing 1-3, wherein this 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-O-CF
3,-S (CH
3) ,-O-alkyl ,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl ,-S (O
2)-aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O) Heterocyclylalkyl, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace, or
5-10 unit monocycle or bicyclic aryl, wherein this 5-10 unit's monocycle or bicyclic aryl are independently selected from following 1-3 substituting group selectivity and are replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-O-alkyl ,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl, wherein said substituting group can in conjunction with formed 5-7 unit condense and selectivity replace carbocyclic ring or heterocycle;
R
2it is alkyloyl; Aromatic yl silane terephthalamide yl; Aryl sulfonyl; Heteroarylsulfonyl; Carbalkoxy; Aryl alkyl carbonyl oxygen; Or
Independently be selected from heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl of N, O and S containing 0-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces, or
5-10 unit monocycle or bicyclic aryl, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces;
R
3be-H, or by the alkyl that selectivity replaces, wherein alkyl is optionally containing N, O or S heteroatoms.；
A is 0 or 1.
In the embodiment that the present invention is other, provide the compound according to formula I
Or its pharmacologically acceptable salt,
Wherein:
R
1independently be selected from C
1-C
4the 2-pyridyl of 1 or 2 substituting group selectivity replacement of alkyl: wherein C
1-C
4-alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, or
R
1be benzofuryl or halogenophenyl, wherein halo is preferably chloro;
X is F, Cl ,-OH or-O-CH
3;
R
2be the heteroatomic 5-10 unit's monocycle or bicyclic aryl or heteroaryl that are independently selected from N, O and S containing 1,2 or 3, wherein this 5-10 ring system is independently selected from 1,2 or 3 following substituting group selectivity and is replaced: C
1-C
4-alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro ,-CF
3,-OCF
3,-O-C
1-C
4-alkyl ,-SCH
3,-S (O)-CH
3,-S (O
2)-CH
3,-CO
2cH
3,-C (O) NH
2,-C (O) NH (CH
3) ,-C (O) N (CH
3)
2, phenyl, wherein C
1-C
4-alkyl is preferably methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl;-O-C
1-C
4-alkyl is preferably methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy,
Wherein this 5-10 ring system is preferably phenyl, pyridyl, naphthyl, quinolyl, or
R
2-C (O)-C
1-C
5-alkyl ,-CO
2-C
1-C
5-alkyl ,-C (O)-benzyl ,-CO
2-benzyl ,-C (O)-phenyl ,-CO
2-phenyl, benzyl, styroyl ,-S (O
2)-phenyl, its by be independently selected from methyl, ethyl, propyl group, Cl, F, Br substituting group selectivity replace further, wherein C
1-C
5-alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, tert-pentyl, neo-pentyl;
R
3h;
A is 0 or 1.
In the further embodiment of the present invention, provide the compound according to formula Ia
Or its pharmacologically acceptable salt,
Wherein:
X is-F ,-Cl ,-CN, CF
3,-OH or-O-CH
3;
R
1be the heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl that to be selected from N, O and S containing 1-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-O-CF
3,-S (CH
3) ,-O-alkyl ,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl ,-S (O
2)-aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O) Heterocyclylalkyl, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace, or
5-10 unit monocycle or bicyclic aryl, wherein this 5-10 unit's monocycle or bicyclic aryl are independently selected from following 1-3 substituting group selectivity and are replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-O-alkyl ,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace;
R
2it is alkyloyl; Aromatic yl silane terephthalamide yl; Aryl sulfonyl; Heteroarylsulfonyl; Carbalkoxy; Aryl alkyl carbonyl oxygen; Or
Independently be selected from heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl of N, O and S containing 0-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces, or
5-10 unit monocycle or bicyclic aryl, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces;
R
3be-H, or by the alkyl that selectivity replaces, wherein alkyl is optionally containing N, O or S heteroatoms.。
In another embodiment, provide the compound or pharmaceutically acceptable salt thereof according to formula Ia,
Wherein:
X is-F ,-Cl ,-OH or-O-CH
3;
R
1the substituted or unsubstituted ring be selected from following list:
R
4for-H or low alkyl group;
R
2be the heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl that are independently selected from N, O and S containing 0-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement the wherein said substituting group of low alkyl group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces, or
5-10 unit monocycle or bicyclic aryl, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces;
R
3be-H, or by the alkyl that selectivity replaces, wherein alkyl is optionally containing N, O or S heteroatoms.
In further embodiment, provide the compound or pharmaceutically acceptable salt thereof according to formula Ia, wherein:
R
1it is the 2-pyridyl of 2-pyridyl or replacement;
X is F, Cl ,-OH or-O-CH
3;
R
2optionally monosubstituted or dibasic monocycle or bicyclic aryl, optionally monosubstituted or dibasic monocycle or bicyclic heteroaryl,
R
3h;
In the further embodiment of the present invention, provide the compound or pharmaceutically acceptable salt thereof according to formula Ia, wherein:
R
1independently be selected from C
1-C
4the 2-pyridyl of 1 or 2 substituting group selectivity replacement of alkyl, wherein C
1-C
4-alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, or
R
1be benzofuryl or halogenophenyl, wherein said halo is preferably chloro;
X is F, Cl ,-OH or-O-CH
3;
R
2be the heteroatomic 5-10 unit's monocycle or bicyclic aryl or heteroaryl that are independently selected from N, O and S containing 1,2 or 3, wherein this 5-10 ring system is independently selected from 1,2 or 3 following substituting group selectivity and is replaced: C
1-C
4-alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro ,-CF
3,-OCF
3,-O-C
1-C
4-alkyl ,-SCH
3,-S (O)-CH
3,-S (O
2)-CH
3,-CO
2cH
3,-C (O) NH
2,-C (O) NH (CH
3) ,-C (O) N (CH
3)
2, phenyl, wherein C
1-C
4-alkyl is preferably methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl;-O-C
1-C
4-alkyl is preferably methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy,
Wherein this 5-10 ring system is preferably phenyl, pyridyl, naphthyl, quinolyl, or
R
2-C (O)-C
1-C
5-alkyl ,-CO
2-C
1-C
5-alkyl ,-C (O)-benzyl ,-CO
2-benzyl ,-C (O)-phenyl ,-CO
2-phenyl, benzyl, styroyl ,-S (O
2)-phenyl, its by be independently selected from methyl, ethyl, propyl group, Cl, F, Br substituting group selectivity replace further, wherein C
1-C
5-alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, tert-pentyl, neo-pentyl,
R
3h.
In the further embodiment of the present invention, provide the compound according to formula Ib:
Or its pharmacologically acceptable salt,
Wherein:
X is-F ,-Cl ,-OH or-O-CH
3;
R
1the substituted or unsubstituted ring being selected from following table:
R
4for-H or low alkyl group
R
2be the heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl that are independently selected from N, O and S containing 0-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, or
5-10 unit monocycle or bicyclic aryl, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl, or replace low alkyl group;
R
3-H.
In further embodiment, provide the compound or pharmaceutically acceptable salt thereof according to formula Ib, wherein:
R
1it is the 2-pyridyl of 2-pyridyl or replacement;
X is F, Cl ,-OH or-O-CH
3;
R
2optionally monosubstituted or dibasic monocycle or bicyclic aryl, optionally monosubstituted or dibasic monocycle or bicyclic heteroaryl,
R
3h;
In the embodiment that the present invention is other, provide the compound or pharmaceutically acceptable salt thereof according to formula Ib, wherein:
R
1independently be selected from C
1-C
4the 2-pyridyl of 1 or 2 substituting group selectivity replacement of alkyl, wherein C
1-C
4-alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, or
R
1be benzofuryl or halogenophenyl, wherein said halo is preferably chloro;
X is F, Cl ,-OH or-O-CH
3;
R
2be the heteroatomic 5-10 unit's monocycle or bicyclic aryl or heteroaryl that are independently selected from N, O and S containing 1,2 or 3, wherein this 5-10 ring system is independently selected from 1,2 or 3 following substituting group selectivity and is replaced: C
1-C
4-alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro ,-CF
3,-OCF
3,-O-C
1-C
4-alkyl ,-SCH
3,-S (O)-CH
3,-S (O
2)-CH
3,-CO
2cH
3,-C (O) NH
2,-C (O) NH (CH
3) ,-C (O) N (CH
3)
2, phenyl, wherein C
1-C
4-alkyl is preferably methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl;-O-C
1-C
4-alkyl is preferably methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy,
Wherein this 5-10 ring system is preferably phenyl, pyridyl, naphthyl, quinolyl, or
R
2-C (O)-C
1-C
5-alkyl ,-CO
2-C
1-C
5-alkyl ,-C (O)-benzyl ,-CO
2-benzyl ,-C (O)-phenyl ,-CO
2-phenyl, benzyl, styroyl ,-S (O
2)-phenyl, its by be independently selected from methyl, ethyl, propyl group, Cl, F, Br substituting group selectivity replace further, wherein C
1-C
5-alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, tert-pentyl, neo-pentyl,
R
3h.
In the further embodiment of the present invention, provide pharmaceutical composition, it comprises compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier of the formula I of effective therapeutic dose.
Should be appreciated that the object of term used herein describes embodiment, be not intended to have limited.In addition, although can use and those any means similar or of equal value, device and materials described herein in practice of the present invention or test, there is described herein preferred method, device and material.
As used herein, term " alkyl " separately or with other groups in conjunction with time refer to 1-20 carbon atom, a preferred 1-16 carbon atom, the more preferably side chain of 1-10 carbon atom or linear monovalent radical of saturated aliphatic alkyl.
As used herein, term " thiazolinyl " separately or with other groups in conjunction with time refer to 2-20 carbon atom, a preferred 2-16 carbon atom, the more preferably straight or branched hydrocarbyl residue with ethylene linkage of 2-10 carbon atom.
Term " cycloalkyl " refers to 3-10, the monovalent monocyclic of a preferred 3-6 carbon atom or polycyclic moiety.This term is by the further example of all groups described as follows: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, bornyl (norbornyl), adamantyl, indanyl etc.In a preferred embodiment, " cycloalkyl " part can be replaced by one, two, three or four substituting group selectivity, should understand described substituting group and then can not be substituted, unless illustrated in addition in embodiment below or claims further.Each substituting group can be independently alkyl, alkoxyl group, halogen, amino, hydroxyl or oxygen (O=), unless otherwise expressly noted.The suberyl etc. that the cyclohexylene (cyclohexylene) that the cyclohexyl that the cyclopentenyl that the cyclopentyl that the cyclobutyl that the example of cycloalkyl moiety includes but not limited to cyclopropyl that selectivity replaces, selectivity replaces, selectivity replace, selectivity replace, selectivity replace, selectivity replace, selectivity replace, or those including but not limited to concrete example in this article.
Term " Heterocyclylalkyl " represents monocycle or many paracyclophanes basic ring, one of them, two or three carboatomic ring atoms are replaced by the heteroatoms of such as N, O and S.The example of Heterocyclylalkyl includes but not limited to morpholinyl, thio-morpholinyl, piperazinyl, piperidyl, pyrrolidyl, THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane base etc.Heterocyclylalkyl can be unsubstituted or replace, and can connect via its carbon framework or via suitable heteroatoms, described substituting group should be understood can not be substituted further again, unless illustrated in addition in embodiment below or claims further.
Term " low alkyl group " separately or with other groups in conjunction with time refer to 1-9 carbon atom, preferred 1-6 carbon atom, the more preferably branched-chain or straight-chain alkyl of 1-4 carbon atom.This term is by the further example of all groups described as follows: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, 3-methyl butyl, n-hexyl, 2-ethyl-butyl etc.
Term " aryl " refers to aromatic monocyclic or the polycyclic moiety of 6-12 the carbon atom with at least one aromatic ring.The example of this type of group includes but not limited to phenyl, naphthyl, 1,2,3,4-naphthane, 1,2-dihydronaphthalene, indanyl, 1H-indenyl etc.
Alkyl, low sugar alkyl and aryl can be substituted or unsubstituted.When replacing, usually there is such as 1-4 substituting group, described substituting group should be understood and then can not be substituted, unless illustrated in addition in embodiment below or claims further.Alkyl, low alkyl group or aryl that these substituting group alternatives are connected with it form ring.Substituting group such as can comprise: carbon-containing group, such as alkyl, aryl, arylalkyl (such as, replace with unsubstituted phenyl, replace and unsubstituted benzyl), halogen atom and halogen-containing group be haloalkyl (such as, trifluoromethyl) such as, oxy radical is alcohol (such as, hydroxyl such as, hydroxyalkyl, aryl (hydroxyl) alkyl), ether (such as, alkoxyl group, aryloxy, alkoxyalkyl, aryloxyalkyl group, more preferably, such as methoxyl group and oxyethyl group), aldehyde (such as, formaldehyde), ketone (such as, alkyl-carbonyl, Alkylcarbonylalkyl, aryl carbonyl, aromatic yl alkyl carbonyl, aryl alkyl carbonyl), acid (such as, carboxyl, carboxyalkyl), acid derivative is ester (such as, carbalkoxy such as, alkoxycarbonyl alkyl, alkyl carbonyl oxygen base, alkyl carbonyl oxygen base alkyl), acid amides (such as, aminocarboxyl, list-alkyl amino-carbonyl or two-alkyl amino-carbonyl, Aminocarbonylalkyl, list-alkyl amino alkyl carbonyl or two-alkyl amino alkyl carbonyl, aromatic yl aminocarbonyl), carbamate (such as, alkoxycarbonyl amido, aryloxycarbonylamino group, amino-carbon acyloxy, list-amino-carbon acyloxy or two-alkylamino carbon acyloxy, arylamino carbon acyloxy) and urea (such as, list-alkyl amino-carbonyl-amino or two-alkyl amino-carbonyl-amino, or list-arylaminocarbonylamino or two-arylaminocarbonylamino), nitrogen-containing group is amine (such as, amino, list-alkylamino or two-alkylamino, aminoalkyl group, list-alkylaminoalkyl group or two-alkylaminoalkyl group), nitrine, nitrile (such as, cyano group, cyanoalkyl), nitro such as, sulfur-containing group is mercaptan, thioether, sulfoxide and sulfone (such as, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyl-thio-alkyl, alkylsulfinylalkyl, alkyl sulfonyl alkyl, arylthio, aryl sulfonyl kia, aryl sulfonyl, arylthioalkyl, aryl sulfonyl kia alkyl, aryl sulfonyl alkyl) such as, containing one or more heteroatomic heterocyclic group (such as, thienyl, furyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl group, aziridinyl, azetidinyl, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, pyrazolidyl, tetrahydrofuran base, pyranyl, pyrans ketone group, pyridyl, pyrazinyl, pyridazinyl, piperidyl, six hydrogen azepine bases, piperazinyl, morpholinyl, thianaphthenyl, benzofuryl, isobenzofuran-base, indyl, oxygen base indyl, pseudoindoyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, tonka bean camphor base (coumarinyl), isocoumarinyl, quinolyl, isoquinolyl, naphthyridinyl (naphthridinyl), cinnolines base, quinazolyl, pyridopyridine base, benzoxazinyl, quinoxalinyl, benzopyranyl, coumaran base, different coumaran base, phthalazinyl and carbolinyl).
Term " heteroaryl " refers to that having at least one contains 1,2 or 3 heteroatoms being selected from N, O and S and residue ring atom is aromatic monocyclic or the polycyclic moiety of 5-12 atom of the aromatic ring of C.One or two annular atoms of heteroaryl can use carbonyl substituted.The example of this type of group includes but not limited to pyrimidyl, pyridyl, indyl, quinolyl, pyridone-2-base, isoquinolyl, 5, 6, 7, 8-tetrahydric quinoline group, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl group, pyrazolidyl, pyrazinyl, pyridazinyl, thianaphthenyl, benzofuryl, isobenzofuran-base, oxygen base indyl, pseudoindoyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, tonka bean camphor base (coumarinyl), isocoumarinyl, isoquinolyl, naphthyridinyl, cinnolines base, quinazolyl, pyridopyridine base, benzoxazinyl, quinoxalinyl, benzopyranyl, coumaran base, different coumaran base, phthalazinyl etc.
Above-mentioned heteroaryl can with one, two or three substituting groups independently replace, described substituting group should be understood and then can not be substituted, unless illustrated in addition in embodiment below or claims further.Together with the heteroaryl that these substituting groups can connect with it, selectivity forms ring.Substituting group can comprise such as: carbon-containing group, such as alkyl, aryl, arylalkyl (such as, replace with unsubstituted phenyl, replace and unsubstituted benzyl), halogen atom and halogen-containing group be haloalkyl (such as, trifluoromethyl) such as, oxy radical is alcohol (such as, hydroxyl such as, hydroxyalkyl, aryl (hydroxyl) alkyl), ether (such as, alkoxyl group, aryloxy, alkoxyalkyl, aryloxyalkyl group), aldehyde (such as, formaldehyde), ketone (such as, alkyl-carbonyl, Alkylcarbonylalkyl, aryl carbonyl, aromatic yl alkyl carbonyl, aryl alkyl carbonyl), acid (such as, carboxyl, carboxyalkyl), acid derivative is ester (such as, carbalkoxy such as, alkoxycarbonyl alkyl, alkyl carbonyl oxygen base, alkyl carbonyl oxygen base alkyl), acid amides (such as, aminocarboxyl, list-alkyl amino-carbonyl or two-alkyl amino-carbonyl, Aminocarbonylalkyl, list-alkyl amino alkyl carbonyl or two-alkyl amino alkyl carbonyl, aromatic yl aminocarbonyl), carbamate (such as, alkoxycarbonyl amido, aryloxycarbonylamino group, amino-carbon acyloxy, list-alkylamino carbon acyloxy or two-alkylamino carbon acyloxy, arylamino carbon acyloxy) and urea (such as, list-alkyl amino-carbonyl-amino or two-alkyl amino-carbonyl-amino, or list-arylaminocarbonylamino or two-arylaminocarbonylamino), nitrogen-containing group is amine (such as, amino, list-alkylamino or two-alkylamino, aminoalkyl group, list-alkylaminoalkyl group or two-alkylaminoalkyl group), nitrine, nitrile (such as, cyano group, cyanoalkyl), nitro such as, sulfur-containing group is mercaptan, thioether, sulfoxide and sulfone (such as, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyl-thio-alkyl, alkylsulfinylalkyl, alkyl sulfonyl alkyl, arylthio, aryl sulfonyl kia, aryl sulfonyl, arylthioalkyl, aryl sulfonyl kia alkyl, aryl sulfonyl alkyl) such as, containing one or more heteroatomic heterocyclic group (such as, thienyl, furyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl group, aziridinyl, azetidinyl, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, pyrazolidyl, tetrahydrofuran base, pyranyl, pyrans ketone group, pyridyl, pyrazinyl, pyridazinyl, piperidyl, six hydrogen azepine bases, piperazinyl, morpholinyl, thianaphthenyl, benzofuryl, isobenzofuran-base, indyl, oxygen base indyl, pseudoindoyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, tonka bean camphor base (coumarinyl), isocoumarinyl, quinolyl, isoquinolyl, naphthyridinyl (naphthridinyl), cinnolines base, quinazolyl, pyridopyridine base, benzoxazinyl, quinoxalinyl, benzopyranyl, coumaran base, different coumaran base, phthalazinyl and carbolinyl).
As used herein, term " alkoxyl group " refers to alkyl-O-; And " alkyloyl " refers to alkyl-CO-.Alkoxy substituent group or can be replaced by such as one or more alkyl group containing the group of alkoxy substituent, should understand described substituting group and then can not be substituted, unless illustrated in addition in embodiment below or claims further.
As used herein, term " halogen " refers to fluorine, chlorine, bromine or iodine base, preferred fluorine, chlorine or bromine base, more preferably fluorine or chlorine base.
Formula I can have one or more unsymmetrical carbon and can following form exist: optical purity enantiomorph, mixture of enantiomers (such as such as racemic modification), optics alcohol diastereomer, non-enantiomer mixture, diastereo-isomerism racemic modification or diastereo-isomerism raceme mixture.Optical active forms is by such as racemate resolution, obtain by asymmetric synthesis or asymmetric red, orange, green, blue, yellow (ROGBY) (utilizing the red, orange, green, blue, yellow (ROGBY) that chiral sorbent or eluent carry out).The present invention includes all these forms.
As used herein, term " pharmacologically acceptable salt " refers to any pharmacologically acceptable salt of formula I.Salt from pharmaceutically acceptable non-toxic acid or alkali preparation, can comprise inorganic and organic bronsted lowry acids and bases bronsted lowry.This type of acid comprises such as acetic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, dichloro acetic acid, formic acid, fumaric acid, glyconic acid, L-glutamic acid, urobenzoic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, oxalic acid, palmoxiric acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, oxalic acid, tosic acid etc.Particularly preferably be fumaric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, succsinic acid, sulfuric acid and methylsulfonic acid.Acceptable alkali comprises basic metal (such as, sodium, potassium), alkaline-earth metal (such as, calcium, magnesium) and aluminium salt.
In the enforcement of the inventive method, by any one compound of the present invention of significant quantity, or the composition of any compound of the present invention, or its pharmacologically acceptable salt, commonly used and any one in acceptable method by known in the art, administration alone or in combination.Described compound or composition therefore, it is possible to oral (such as, oral cavity), sublingual, parenteral (such as, intramuscular, vein or subcutaneous), rectum (such as, by suppository or washing lotion), through skin (such as, skin electroporation) or by sucking (such as, passing through aerosol) and using with solid, liquid or gaseous dosage (comprising tablet and suspensoid).This is used to treat with single unit formulation and continuously and carries out or arbitrarily carry out with single-dose treatment.Therapeutic composition can also be oil emulsion or dispersion and combine the form of the Lipophilic salts of such as palmoxiric acid, or is used for subcutaneous or intramuscular administration with the form of biodegradable buffering salt.
Useful pharmaceutical carrier for the preparation of composition can be solid, liquid or gas.Therefore; composition can take tablet, pill, capsule, suppository, pulvis, enteric coating or other are through protection preparation (such as, be bonded on ion exchange resin or be packaged in lipid-protein vesicle), sustained release preparation, solution, suspensoid, elixir, aerosol etc.Carrier can be selected from various oils, comprise oil, animal, plant or synthesis origin those, peanut oil, soybean oil, mineral oil, sesame wet goods.Water, salt solution, aqueous glucose and ethylene glycol are preferred liquid vehicles, when particularly (when isotonic with blood) is for Injectable solution.Such as, intravenously uses preparation to comprise the aseptic aqueous solution of effective constituent, and it is by obtaining the aqueous solution by soluble in water for solid effective constituent and make this solution sterile and obtain.Suitable drug excipient comprises starch, fibrous bundle, talcum, glucose, lactose, mica, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica, Magnesium Stearate, sodium stearate, glyceryl monostearate, sodium-chlor, skimmed milk powder, glycerine, propylene glycol, water, ethanol etc.Composition can receive conventional medicine additive, such as sanitas, stablizer, wetting agent or emulsifying agent, adjustment osmotic pressure salt, buffer reagent etc.Suitable pharmaceutical carrier and preparation thereof are described in the Remington'sPharmaceuticalSciences of E.W.Martin.In any case such composition by the active compound containing significant quantity and suitable carrier so that for the preparation of the appropriate dosage forms being suitably applied to acceptor.
The dosage of the compounds of this invention depends on many factors, such as such as, application process, the age of object and body weight, and the situation of object to be treated, and it is determined by attending doctor or animal doctor the most at last.The amount of this active compound determined by attending doctor or animal doctor is being called " treatment significant quantity " herein and in claim.Such as, the dosage of the compounds of this invention usually in every day about 1 within the scope of about 1000mg.Preferably, this treatment significant quantity in every day about 1 within the scope of about 500mg.
Should be understood that the compound of formula of I of the present invention can derive in functional group, the derivative getting back to parent compound can be transformed in body to provide.Physiological can accept and the derivative of metabolism instability can produce the compound of general formula I in body, and these also within the scope of the present invention.
The preparation of the compounds of this invention can start from commercially available former material and utilize general synthetic technology well known by persons skilled in the art and step.Chemical can purchased from the company of such as such as Aldrich, ArgonautTechnologies, VWR and Lancaster.
The compound of formula I is by following general reaction scheme preparation:
Scheme 1
In scheme 1, the compound of formula 1, wherein R
1 'for the R of formula I
1or be derivative, R needed for Compound I in this derivative
1exist with potential form, process it by synthesis phase protecting group below and functional group and can be converted into R needed for Compound I
1.Skilled organic chemist by understand where and how the best realize this kind of conversion.In organic synthesis, adopt protecting group to have systematic review, such as, at Wuts, P.G.andGreene, T.W., Greene ' sProtectiveGroupsinOrganicSynthesis, 4edition, Wiley, in 2006.The compound of formula I is known, and is commercially available compound in a lot of situation, or the method fully determined can be utilized to prepare.Such as 1, R
1 '=2-pyridyl or 3-pyridyl derive from the some suppliers comprising Sigma-Aldrich.
When commercial offers is difficult to obtain, aryl and heteroaryl alkynes can utilize Corey-Fuchs method to prepare (Corey, E.J.andFuchs, P.L., TetrahedronLett.1972,3769 from corresponding aryl or heteroaryl aldehyde; Summary: Han, Xiaojun.Editor (s): Li, JieJack.NameReactionsforHomologations (2009), (Pt.1), 393-403.Publisher:JohnWiley & Sons, Inc.).Or aryl or heteroaryl aldehyde change into aryl or heteroaryl alkynes (Ona, I., Xavier by processing in neutral conditions with C-silylanizing-diazonium phosphine, B., Cazoria, A.M., etal., JournalofOrganicChemistry2006,71,5320).
When suitable aldehyde is difficult to obtain, aryl or heteroaryl alkynes can also can experience the aryl of the group functionalization of transition metal-catalyzed cross-coupling reaction with alkynes or prepared by heteroaryl compound from utilizing.It will be understood by those skilled in the art that the reaction collocation thing how selecting to be suitable for.Such as, United States Patent (USP) 7,462,619 synthesis describing 3-alkynyl pyridine: reacted by transition metal-catalyzed with suitably functionalized alkynes by 3-bromopyridine or 3-fluoroform sulphonyl pyridine, the end alkynes making terminal position have protecting group afterwards goes protection.If protecting group is TMS (TMS), then compound can process to realize its removal with aqueous bases (such as potassium hydroxide or salt of wormwood) in methyl alcohol.When alkynes is formed for the aromatic ring of the suitable functional group of cross-coupling reaction or the transition metal-catalyzed reaction between hetero-aromatic ring (such as bromide) and 2-methyl-3-butyne-2-alcohol through having, go to protect generation terminal alkyne can realize via heating under existing at the alkali of catalytic amount such as sodium hydride in such as toluene in suitable solvent.Following reference is listed in multiple example of this type of conversion in published document: Holmes, B.T., Pennington, W.T., Hanks, T.W., SyntheticCommunications, 2003,33,2447-2461; Negishi, E.-i., Xu, C., Tan, Z., Kotora, M., Heterocycles1997,46,209-214.Common variant is called as a Sonogashira linked reaction, and it is in Chinchilla, R., N á jera, and C., RecentAdvancesinSonogashirareactions, ChemicalSocietyReviews, comment in 2011,40,5084-5121.
In scheme 1; the compound (wherein PG is protecting group, such as 1,1-dimethylethoxy-carbonyl (Boc) group) of formula 2 is known; and in a lot of situation, be commercially available compound or the method fully determined can be utilized to prepare.Such as 2, a=1 or 2, PG=1-(1,1-dimethylethyloxy) carbonyl (Boc), and R
3 '=H, derives from the some suppliers comprising Sigma-Aldrich and WuxiAppTec.At expectation R
3 'in compound for the formula 2 of alkyl or substituted alkyl, these compounds are prepared by known program or by the variant of known procedure.Such as, homochiral 1-(1,1-dimethylethyloxy) carbonyl-2-replace-azetine-3-ketone by rhodium acetate exist under prepared by the cyclisation derived from amino acid whose α-diazo ketone; Podlech, J., Seebach, D., Helv.Chim.ACTA1995,78,1238-1246.2-alkyl-[(1, 1-dimethylethyloxy) carbonyl]-4-oxo-pyrroli (pyrroldines) and 2-aryl-[(1, 1-dimethylethyloxy) carbonyl]-4-oxo-pyrroli (pyrroldines) prepared by multiple method, comprising according to the step described in following document: the oxidative cyclization of N-acetyl-2-allyl group benzylamine, be hydrolyzed afterwards, protection and oxidation: Hashihayata, T., Sakoh, H., etal.Chem.Pharm.Bull.2002, 50, 423-425, or as at Dong, C., Wang, J., J.Org.Chem.2008, 73, the cyclisation of the rhodium catalysis of-5-(to the toluene-sulfonamido) valerate that the α described in 1971-1974-diazonium-3-ketone group-5-replaces.
Compound 1 and 2 reacts and forms alcohol 3, processes alkynes 1, realize with the deprotonation reaching alkynes end CH by the enough strong alkali of (such as THF) use in suitable inert solvent.Common alkali for this object comprises Grignard reagent, such as ethylmagnesium bromide, or organolithium reagent, such as n-Butyl Lithium.These reactions are carried out at the low temperature of such as-78 DEG C usually.Then the negatively charged ion of so formation and ketone 2 is made to react, until reaction terminates, and routine techniques can be utilized to be separated the new compound 3 formed, such as by reacting with aqueous solution quencher, afterwards by product extraction in organic solution, wash with water, drying also carries out chromatography analysis (if necessary) through silica gel.
The converting compounds of structure 3 be fluorochemical 4 by following formation: the solution of the solution of 3 and fluorination reagent (such as DAST (diethylaminosulfur trifluoride)) combine in suitable inert solvent (such as methylene dichloride), reaction usual earlier maintenance at low temperatures (such as-78 DEG C).This type of reaction utilizes conventional procedure process, such as, uses water quencher, extracts and carries out stratographic analysis as required.
The protecting group removed in 4 will depend on the concrete selection of protecting group used with the condition producing the compound of structure 5.The program that skilled organic chemist is familiar with various potential protection and removes for it.In this regard, mention that the outline of protecting group may be useful, such as above-cited OrganicSynthesis, 4
thed. the grignard protecting group in.In one easily embodiment, Boc ((1,1-dimethylethyloxy) carbonyl) group can be adopted.In this case, it is removed and the compound of generating structure 4 is easily realized by conventional processing after processing at suitable solvent (such as methylene dichloride) middle sour (such as trifluoroacetic acid (TFA)).
The compound of structure 5 be further converted to compound of the present invention, or depend on the circumstances by R
1 'and R
2 ", R
5or R
6on functional group and protecting group transform and make compound easily transform compound of the present invention, will required objectives compound be depended on.When needing to introduce alkylsulfonyl with the compound of generating structure 9, the compound of structure 5 can process with activation sulfonyl-derivatives 6, and wherein Lv is leavings group, such as muriate.Implement in the suitable solvent of this type of conversion usually at such as methylene dichloride under organic bases or mineral alkali (such as triethylamine) exist.Skilled organic chemist is familiar with general reaction range, and suitable condition can be selected for interested target compound.
At acid amides or the carbamate (R of Structure of need 10
6=aryl, heteroaryl, alkyl, alkoxyl group or alkoxy aryl) situation in, the compound of structure 5 can process with activate ester derivative 7, and wherein Lv is the suitable leavings group for acylation reaction, such as chlorine atom, such as muriate.Implement under a variety of condition that this type of reaction can be known skilled organic chemist.In a set condition, wherein Lv can be made to be that the acyl chlorides 7 of chlorion reacts in the inert solvent of such as methylene dichloride with amine 5 under suitable temperature such as room temperature under alkali such as triethylamine exists, carry out conventional processing afterwards, comprise and use aqueous solution quencher, by product extraction in organic solvent, drying, evaporation, and as required chromatogram purification is carried out to residue.
When required compound is N-aryl or the N-heteroaryl derivative of structure 11, the compound of structure 5 can react with the compound of structure 7, and in the compound of structure 7, Lv representative is suitable for the leavings group participating in reaction, and R
2 "represent R of the present invention
2or introduce after linked reaction through R of the present invention can be changed into the process of substituting group and protecting group
2functional group.Typical group comprises iodide, bromide and muriate.Reaction is carried out usually in the presence of a base under palladium catalyst and suitable part exist, and this alkali can be the highly basic of such as LiHMDS or the weak base of such as cesium carbonate.Selection for the concrete required alkali, solvent and the part that transform can obtain the guidance of aforementioned documents.One section of useful summary is: Surry, D.S.andBuchwald, S.L, Chem.Sci.2011,2,27-50.For the aryl of leavings group with high activity and heteroaryl moieties (such as 2-fluorine pyridine), the direct reaction carried out at the temperature raised (such as 100-120 DEG C) under suitable alkali (such as salt of wormwood) exists between this compound and compound 5 can affect its conversion to the compound of structure 11.
Scheme 2
The alternative method of the compound of preparation formula I is shown in scheme 2.In this case, use protection alkynes, the acetylene 12 of such as TMS protection, reacts with ketone 13, R in ketone 13
3 'r of the present invention
3or derivative, this derivative is subsequently by optionally process functional group and protecting group can be converted into R of the present invention
3, R
7protecting group or correspond to R as above
2 ', prerequisite is in this case, R
2 'do not carry any any functional group that reactions vary causes with being converted into 13 needed for compound of the present invention.Compound 12 and 13 can the highly basic in as above about scheme 1 described in 1 and 2 reactions exist under reaction, produce the compound of structure 14.The conversion of 14 to 15 is by realizing with the DAST process described in scheme 1; it may be required that alkynyl protects as cobalt complex by prerequisite in this conversion process, as at vanNeil, M.B.; Collins; I., Beer, M.S.; etal.; J.Med.Chem.1999, described in 42,2087-2104.Acetylene series protecting group (if present) is by oxidation removal, and such as, by using ceric ammonium nitrate process, and TMS group can utilize above-mentioned condition to remove.The alkynes 17 of gained then can the compound experience Buchwald type cross-coupling reaction of structure 16 in advance, in the compound of structure 16, and R
1 'r of the present invention
1or if necessary can be converted into R by functional group and protecting group process
1.Skilled organic chemist should understand this type of demand transformed and its embodiment.
To further describe the present invention in the following embodiments now, described embodiment intention is only as setting forth but not limiting the scope of the invention.
Embodiment
Embodiment 1
The preparation of 3-hydroxyl-3-(pyridine-2-ethyl-acetylene base) azetidine-1-t-butyl formate:
Compound 1 (3.00g, 29.1mmol) is dissolved in anhydrous THF (60mL).Solution is cooled to 0 DEG C, and adds EtMgBr solution (3.0M, 10.6mL, 32mmol).Reaction mixture is at room temperature stirred and within 10 minutes, is then heated to 40 DEG C, continue 1 hour.Add the 20mLTHF solution of compound 2 (5.48g, 32.0mmol).By mixture room temperature for overnight, use saturated NH
4the quencher of Cl solution, then uses EtOAc (2 × 50mL) to extract.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes its purifying (PE/EA, 1/2), obtain required compound by silicagel column.(yield: 56%).
The preparation process of the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) azetidine-1-t-butyl formate:
3-hydroxyl-3-(pyridine-2-ethyl-acetylene base) azetidine-1-t-butyl formate (5.5g, 20.0mmol) is dissolved in anhydrous methylene chloride (60mL).Solution is cooled to-78 DEG C, and slowly adds DAST (6.5g, 40.0mmol).Reaction mixture is stirred 1h at-78 DEG C and rises to room temperature.After will reacting quencher with water, with dichloromethane solution extraction (3 × 50mL).The organic layer merged is through anhydrous Na
2sO
4dry, filter, be concentrated into drying and (use EA/PE wash-out by silica column purification, 1/5, v/v), obtain required compound, it identifies (3.0g, yield: 55.5%) by comparing (H13883-133-2A) with reference standard by TLC.
Embodiment 2
The preparation of 2-alkynyl-3-picoline:
The preparation process of 3:
To 1 (3400.0mg, 20.0mmol) at the degassed Et of 30mL
3cuI (380.9mg, 2.0mmol), 2 (2160.8mg, 22.0mmol) and PdCl are added successively in solution in N
2(PPh
3)
2(731.7mg, 1.0mmol).Then by mixture at N
2under atmosphere degassed 20 minutes and in stirred overnight at room temperature.Filter reaction mixture.By 60mLH
2o adds in black filtrate.Stir after 10 minutes, filtrate extracts with EtOAc (3 × 30mL).Organic layer washed with brine (2 × 30mL) through anhydrous dry Na
2sO
4, filter and evaporate, obtaining rough thing, by making its purifying (methylene dichloride) through plug of silica gel, obtaining required product (2.5g, yield=65.8%).
The preparation process of 4:
Compound 3 (2500mg, 13.2mmol) is dissolved in MeOH/ methylene dichloride (60mL/30mL).Solution be cooled to 0 DEG C and add KOH (1482mg, 26.4mmol).Reaction mixture is stirred 0.5h, then uses H
2o quencher, with dichloromethane extraction (2 × 30mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and concentrates, and obtains required compound (1.5g, yield=99.8%).
Embodiment 3
The preparation of the fluoro-3-of 3-[(3-picoline-2-base)-ethynyl] azetidine
The preparation process of 6:
Compound 4 (585.0mg, 5.0mmol) is dissolved in anhydrous THF (20mL).Solution is cooled to-78 DEG C, and adds BuLi (2.5M, 2.2mL, 5.5mmol).Reaction mixture is at room temperature stirred 1 hour, then the THF solution of compound 5 (941.0mg, 5.5mmol) is added into wherein.React and stir 2h at-78 DEG C, by adding 1NNH
4cl quencher, and be extracted with ethyl acetate.The organic phase merged, through water, salt water washing, through dried over sodium sulfate, is filtered and concentrates.Residue is through preparation TLC purifying (1.1g, yield=78.5%).
The preparation process of 7:
Compound 6 (600.0mg, 2.08mmol) is dissolved in anhydrous methylene chloride (20mL).Solution is cooled to-78 DEG C, and adds DAST (670.6mg, 4.16mmol).Reaction mixture is stirred 1h at-78 DEG C, and rises to room temperature.After water quencher, solution extracted with EtOAc (2 × 15mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes its purifying (using EA/PE wash-out, 1/10, v/v) by silicagel column, obtains required compound (400.0mg, yield=66.7%).
The preparation process of 8:
Compound 7 (116.0mg, 0.4mmol) is dissolved in anhydrous methylene chloride (4.0mL) and TFA (0.8mL).By solution stirring at room temperature 2 hours, and be concentrated into drying.Residue is dissolved in minimum water gaging, with saturated sodium carbonate neutralization (pH=8), is extracted with ethyl acetate.The organic phase merged is through water, salt water washing, dry and concentrated through sulfuric acid.Residue, through preparation TLC purifying, obtains the fluoro-3-of 3-[(3-picoline-2-base)-ethynyl] azetidine (50.0mg, yield=65.7%).
Embodiment 4
The preparation of the fluoro-3-of 3-[(4-picoline-2-base)-ethynyl] azetidine
The preparation process of 3:
To 1 (3400.0mg, 20.0mmol) at the degassed Et of 30mL
3cuI (380.9mg, 2.0mmol), 2 (2160.8mg, 22.0mmol) and PdCl are added successively in the solution of N
2(PPh
3)
2(731.7mg, 1.0mmol).Then by mixture at N
2under atmosphere degassed 20 minutes and in stirred overnight at room temperature.Filter reaction mixture.By 60mLH
2o adds in black filtrate.Stir after 10 minutes, filtrate extracts with EtOAc (3 × 30mL).Organic layer washed with brine (2 × 30mL) through anhydrous Na
2sO
4drying, filters and evaporates, and obtains rough thing, by making its purifying (methylene dichloride) through plug of silica gel, obtains required product (2.4g, yield=63.1%).
The preparation process of 4:
Compound 3 (2.4g, 12.6mmol) is dissolved in MeOH/ methylene dichloride (40mL/20mL).Solution be cooled to 0 DEG C and add KOH (1.4g, 25.2mmol).Reaction mixture is stirred 0.5h, then uses H
2o quencher, with dichloromethane extraction (2 × 3mL).The organic layer merged is through anhydrous dry Na
2sO
4, filter and concentrate, obtaining required compound (1.2g, yield=81.5%).
The preparation process of 6:
Compound 4 (585.0mg, 5.0mmol) is dissolved in anhydrous THF (20mL).Solution is cooled to-78 DEG C and adds BuLi (2.5M, 2.2mL, 5.5mmol).Reaction mixture is at room temperature stirred 1 hour, then the THF solution of compound 5 (941.0mg, 5.5mmol) is added into wherein.React and stir 2h at-78 DEG C, by adding 1NNH
4cl quencher, and be extracted with ethyl acetate.The organic phase merged, through water, salt water washing, through dried over sodium sulfate, is filtered and concentrates.Residue is through preparation TLC purifying (1.0g, yield=71.4%).
The preparation process of 7:
Compound 6 (600.0mg, 2.08mmol) is dissolved in anhydrous methylene chloride (20mL).Solution is cooled to-78 DEG C and adds DAST (670.6mg, 4.16mmol).Reaction mixture is stirred 1h at-78 DEG C and rises to room temperature.After water quencher, solution extracted with EtOAc (2 × 15mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes its purifying (using EA/PE wash-out, 1/10, v/v) by silicagel column, obtains required compound (380.0mg, yield=64.0%).
The preparation process of 8:
Compound 7 (116.0mg, 0.4mmol) is dissolved in anhydrous methylene chloride (4.0mL) and TFA (0.8mL).By solution stirring at room temperature 2 hours, and be concentrated into drying.Residue is dissolved in minimum water gaging, with saturated sodium carbonate neutralization (pH=8), is extracted with ethyl acetate.The organic phase merged is through water, salt water washing, dry and concentrated through sulfuric acid.Residue, through preparation TLC purifying, obtains the fluoro-3-of 3-[(4-picoline-2-base)-ethynyl] azetidine (40.0mg, yield=52.6%).
Embodiment 5
The preparation of the fluoro-3-of 3-[(5-picoline-2-base)-ethynyl] azetidine
The preparation process of 3:
To 1 (1000mg, 1.2mmol) at the degassed Et of 15mL
3add CuI111mg, 0.58mmol successively in the solution of N), 2 (628mg, 6.4mmol) and Pd (PPh
3)
2cl
2(213mg, 0.29mmol).Then by mixture at N
2under atmosphere degassed 20 minutes and in stirred overnight at room temperature.Filter reaction mixture.By 60mLH
2o adds in black filtrate.Stir after 10 minutes, filtrate extracts with EtOAc (3 × 30mL).Organic layer washed with brine (2 × 30mL) through anhydrous Na
2sO
4drying, filters and evaporates, and obtains rough thing, by making its purifying (methylene dichloride) through plug of silica gel, obtains required product 3 (0.6g, yield: 54.5%).
The preparation process of 4:
Compound 3 (600mg, 3.17mmol) is dissolved in MeOH/ methylene dichloride (2mL/1mL).Solution be cooled to 0 DEG C and add KOH (355mg, 6.34mmol).Reaction mixture is stirred 0.5h, then uses H
2o quencher, with dichloromethane extraction (2 × 3mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and concentrates, and obtains required compound 4 (300mg, yield: 80.8%).
The preparation process of 6:
Compound 4 (174mg, 1.49mmol) is dissolved in anhydrous THF (5mL).Solution is cooled to-78 DEG C and adds n-BuLi solution (2.5M, 0.7mL, 1.63mmol).Reaction mixture is stirred 1 hour, be then added on the compound 5 (280mg, 1.63mmol) in 2mLTHF.Mixture is stirred 2 hours, then use saturated NH
4the quencher of Cl solution, then uses EtOAc (2 × 20mL) to extract.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, is passed through preparation TLC purifying, obtains required compound 6 (170mg, yield: 39.7%).
The preparation process of 7:
Compound 6 (170mg, 0.59mmol) is dissolved in anhydrous methylene chloride (10mL).Solution is cooled to-78 DEG C and adds DAST (190mg, 1.18mmol).Reaction mixture is stirred 1h at-78 DEG C and rises to room temperature.After water quencher, solution extracted with EtOAc (2 × 15mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, is passed through preparation TLC purifying, obtains required compound 7 (110mg, yield: 64.2%).
The preparation process of 8:
To in methylene dichloride (3ml) solution of compound 7 (110mg, 0.38mmol), at N
2tFA (1ml) is slowly added at 0 DEG C under atmosphere.By mixture stirring at room temperature 2 hours.Reaction mixture is concentrated into drying, obtains the fluoro-3-of rough 3-[(5-picoline-2-base)-ethynyl] azetidine (60mg, yield: 83.2%).
Embodiment 6
The preparation of cumarone-2-ethyl-acetylene compound 210-:
The preparation process of compound 4:
To 1 (2.0g, 10.2mmol) at the degassed Et of 30mL
3cuI (0.194g, 1.026mmol), 2 (1.1g, 11.2mmol) and 3 (0.37g, 0.51mmol) are added successively in N solution.Then by mixture at N
2under atmosphere degassed 20 minutes and in stirred overnight at room temperature.Filter reaction mixture.60mLH
2o adds in black filtrate.Stir after 10 minutes, filtrate extracts with EtOAc (3 × 30mL).Organic layer washed with brine (2 × 30mL) through anhydrous Na
2sO
4drying, filters and evaporates, and obtains rough thing, by making its purifying (methylene dichloride) through plug of silica gel, obtains required product (1.9g, yield: 86%).
The preparation process of compound 5:
Compound 4 (1.90g, 9.31mmol) is dissolved in MeOH-DCM (v/v:2:1) (20mL).Solution be cooled to 0 DEG C and add KOH (1.04g, 18.63mmol).Reaction mixture is stirred 5 minutes at 0 DEG C, then makes it rise to room temperature and again stir 0.5 hour.
TLC shows starting raw material and reacts completely.20mL water is added in mixture.Distribute mixture.Aqueous phase DCM extraction (15mL × 3).The organic phase that washing merges, through anhydrous Na
2sO
4drying is also concentrated, produces cumarone-2-ethyl-acetylene (1.3g, yield: 98%).
Embodiment 7
The preparation process of the fluoro-3-of 3-(cumarone-2-base) azetine:
Compound 5 (500mg, 3.52mmol) is dissolved in anhydrous THF (10mL).Solution is cooled to-78 DEG C and drips n-BuLi solution (in hexane 2.5M, 1.5mL, 3.87mmol)).Reaction mixture is stirred 1 hour at-78 DEG C.Then the compound 6 (663mg, 3.87mmol) in 3mLTHF is added.Mixture is stirred 12 hours at the same temperature.Saturated NH is used in reaction
4the quencher of Cl solution, then uses EtOAc (2 × 20mL) to extract.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes it pass through preparation TLC purifying, obtains required compound (600mg, yield: 54.5%).
The preparation process of compound 8:
Compound 7 (200mg, 0.639mmol) is dissolved in anhydrous methylene chloride (3mL).Solution is cooled to-78 DEG C and adds DAST (206mg, 1.278mmol).Reaction mixture is stirred 1h at-78 DEG C and rises to room temperature.Use H
2after O quencher, with dichloromethane extraction solution (2 × 3mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes it pass through preparation TLC purifying (using EA/PE wash-out, 1/5, v/v), obtains required compound.(100mg, yield: 49.7%)
LCMS:m/z,260.1[M-55(
tBu)]
+。
The preparation process of compound 8:
TFA (2mL) is dripped in 0 DEG C of DCM to 8 (100mg, 0.317mmol) (10mL) solution.After interpolation, by reaction mixture 0 DEG C of continuously stirring 15 minutes.Then mixture is made to rise to room temperature and stir ~ 1 hour.Reaction is checked by LCMS.The saturated Na of reaction mixture
2cO
3neutralization, until pH>8, then uses DCM (5 × 50mL) to extract.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes it pass through preparation TLC purifying, obtains the fluoro-3-of 3-(cumarone-2-base) azetine (50mg, yield: 73.5%).
Embodiment compound 63
The preparation process of compound 63:
To 1 (20mg, 0.11mmol), 2 (45mg, 0.22mmol) and Cs
2cO
3dMF (1mL) solution of (180mg, 0.55mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9,9-dimethyl xanthene (Xantphos) of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.By mixture in microwave in 120 DEG C of radiation 1 hour.LCMS shows most of starting raw material and reacts completely.Reaction mixture EA (5mL) is diluted and uses salt solution (2mL) to wash twice.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 63 (10mg, yield: 37%).
LCMS:m/z,253.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.60～8.61(m,1H),7.67～7.71(m,1H),7.48～7.50(m,1H),7.22～7.31(m,3H),6.79～6.84(m,1H),6.48～6.51(m,2H),4.26～4.39(m,4H)。
Embodiment compound 64
The preparation process of compound 64:
By compound 7 (20mg, 0.11mmol), compound 2 (31mg, 0.13mmol), Cs
2cO
3(143mg, 0.44mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (5mg, 0.01mol) in DMF (1.0mL) of (6mg, 0.01mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (15mg, 50% yield).
LCMS:m/z,287.0(M+H)
+；
1HNMR(400MHz,CDCl
3)δ4.17～4.31(m,4H),6.26～6.28(m,1H),6.38(t,J＝2.0Hz,1H),6.69～6.71(m,1H),7.07(t,J＝8.0Hz,1H),7.19～7.24(m,1H),7.42(d,J＝7.2Hz,1H),7.60～7.65(m,1H),8.53～8.55(m,1H)。
Embodiment compound 68
The preparation of 2-((1-(3-chloro-phenyl-)-3-fluorine azetidine-3-base) ethynyl) pyridine compounds 64,67,68 and 69:
The preparation of 2-((TMS) ethynyl) pyridine:
To 2-bromopyridine (1800mg, 11.4mmol) at the degassed Et of 30mL
3add CuI217mg, 1.14mmol successively in N solution), trimethylsilanylethyn (1227mg, 12.5mmol) and two (triphenylphosphine) palladium chloride (417mg, 0.57mmol).Then by mixture at N
2under atmosphere degassed 20 minutes and in stirred overnight at room temperature.Filter reaction mixture by 60mLH
2o adds in black filtrate.Stir after 10 minutes, filtrate extracts with EtOAc (3 × 30mL).Organic layer washed with brine (2 × 30mL) through anhydrous Na
2sO
4drying, filters and evaporates, and obtains rough thing, by making its purifying (methylene dichloride) through plug of silica gel, obtains 2-((TMS) ethynyl) pyridine (1.6g, 81% yield).
The preparation of 2-ethynyl pyridine:
2-((TMS) ethynyl) pyridine (175mg, 1.0mmol) is dissolved in MeOH/ methylene dichloride (2mL/1mL).Solution be cooled to 0 DEG C and add KOH (112mg, 2.0mmol).Reaction mixture is stirred 0.5h, then uses H
2o quencher, with dichloromethane extraction (2 × 3mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and concentrates, and obtains 2-ethynyl pyridine (80mg, 80% yield).
The preparation process of 3-hydroxyl-3-(pyridine-2-ethyl-acetylene base) azetidine-1-t-butyl formate:
2-ethynyl pyridine (800mg, 7.77mmol) is dissolved in anhydrous THF (30mL).Solution is cooled to 0 DEG C, and adds EtMgBr solution (3.0M, 2.85mL, 8.54mmol).Reaction mixture is at room temperature stirred and within 10 minutes, is then heated to 40 DEG C, continue 1 hour.Be added on the 3-aza-oxo-cyclobutane-1-t-butyl formate (1.46g, 8.54mmol) in 2mLTHF.Mixture is at room temperature stirred and spends the night, use saturated NH
4the quencher of Cl solution, then uses EtOAc (2 × 20mL) to extract.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, and residue, through silica column purification (PE/EA, 1/2), obtains 3-hydroxyl-3-(pyridine-2-ethyl-acetylene base) azetidine-1-t-butyl formate (1.3g, 62% yield).
LCMS:m/z,274.1(M+H)
+；
The preparation of the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) azetidine:
3-hydroxyl-3-(pyridine-2-ethyl-acetylene base) azetidine-1-t-butyl formate (600mg, 2.18mmol) is dissolved in anhydrous methylene chloride (20mL).Solution is cooled to-78 DEG C and adds DAST (702mg, 4.36mmol).Reaction mixture is stirred 1h at-78 DEG C and rises to room temperature.Use H
2with dichloromethane extraction solution (2 × 15mL) after O quencher.The organic layer merged is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, and residue (uses EA/PE wash-out through silica column purification, 1/10, v/v), the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) azetidine-1-t-butyl formate (compound 68) (380mg, 64% yield) is obtained.
LCMS:m/z,276.3(M+H)
+；
The preparation process of 2-((3-fluorine azetidine-3-base) ethynyl) pyridine:
Fluoro-for 3-3-(pyridine-2-ethyl-acetylene base) azetidine-1-t-butyl formate (250mg, 0.9mmol) is dissolved in anhydrous methylene chloride (5.0mL), then adds 0.5mLTFA at 0 DEG C.By reaction mixture in stirred overnight at room temperature.Remove solvent and residue is used saturated Na
2cO
3solution washing (pH=8), with dichloromethane extraction (3 × 5mL).The organic layer merged is through anhydrous dry Na
2sO
4, filter and concentrate, obtaining 2-((3-fluorine azetidine-3-base) ethynyl) pyridine (140mg, 87% yield).
LCMS:m/z,177.1(M+H)
+；
The preparation of 2-((1-(3-chloro-phenyl-)-3-fluorine azetidine-3-base) ethynyl) pyridine compounds 64:
By 2-((3-fluorine azetidine-3-base) ethynyl) pyridine (20mg, 0.11mmol), the chloro-iodobenzene (31mg, 0.13mmol) of 3-, Cs
2cO
3(143mg, 0.44mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (5mg, 0.01mol) in DMF (1.0mL) of (6mg, 0.01mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain 2-((1-(3-chloro-phenyl-)-3-fluorine azetidine-3-base) ethynyl) pyridine (15mg, 50% yield).
LCMS:m/z,287.0(M+H)
+；
1HNMR(400MHz,CDCl
3)δ4.17～4.31(m,4H),6.26～6.28(m,1H),6.38(t,J＝2.0Hz,1H),6.69～6.71(m,1H),7.07(t,J＝8.0Hz,1H),7.19～7.24(m,1H),7.42(d,J＝7.2Hz,1H),7.60～7.65(m,1H),8.53～8.55(m,1H)。
Embodiment compound 91
The preparation process of compound 91:
By compound 1 (15mg, 0.085mmol), compound 2 (23mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous dry Na
2sO
4, filter and be condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (13mg, 57% yield).
LCMS:m/z,278.1(M+H)
+；
1HNMR(400MHz,CDCl
3)δ4.31～4.45(m,4H),6.67～6.73(m,2H),7.06～7.10(m,1H),7.31～7.35(m,2H),7.52(d,J＝8.0Hz,1H),7.65～7.73(m,1H),8.56(d,J＝4.8Hz,1H)。
Embodiment compound 93
The preparation process of compound 93:
By compound 1 (15mg, 0.085mmol), compound 2 (24mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (12mg, 50% yield).
LCMS:m/z,287.1(M+H)
+；
1HNMR(400MHz,CDCl
3)δ4.25～4.39(m,4H),6.41～6.44(m,2H),7.19～7.23(m,2H),7.30～7.34(m,1H),7.52(d,J＝7.2Hz,1H),7.70～7.74(m,1H),8.64(d,J＝4.4Hz,1H)。
Embodiment compound 94
The preparation process of compound 94:
By compound 1 (15mg, 0.085mmol), compound 2 (24mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous dry Na
2sO
4, filter and be condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (10mg, 42% yield).
LCMS:m/z,287.1(M+H)
+；
1HNMR(400MHz,CDCl
3)δ4.41～4.58(m,4H),6.54(dd,J＝1.6Hz,8.0Hz,1H),6.78～6.83(m,1H),7.14～7.17(m,1H),7.22～7.24(m,1H),7.26～7.30(m,1H),7.51(d,J＝4.0Hz,1H),7.68～7.72(m,1H),8.62(d,J＝4.4Hz,1H)。
Embodiment compound 97
The preparation process of compound 97:
By compound 1 (15mg, 0.085mmol), compound 2 (25mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/1, v/v), obtain required compound (14mg, 56% yield).
LCMS:m/z,298.1(M+H)
+；
1HNMR(400MHz,CDCl
3)δ4.32～4.44(m,4H),6.73～6.76(m,1H),7.24～7.28(m,1H),7.30～7.35(m,1H),7.37(t,J＝8.0Hz,1H),7.51(d,J＝7.6Hz,1H),7.61～7.63(m,1H),7.65～7.73(m,1H),8.63(d,J＝4.8Hz,1H)。
Embodiment compound 98
The preparation of compound 98:
Experimental section:
The preparation process of compound 98:
By compound 1 (15mg, 0.085mmol), compound 2 (25mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (13mg, 52% yield).
LCMS:m/z,296.1(M+H)
+；
1HNMR(400MHz,CDCl
3)δ4.24～4.44(m,4H),6.32～6.35(m,1H),6.66(s,1H),6.75(d,J＝8.0Hz,1H),7.26～7.35(m,1H),7.50(d,J＝7.6Hz,1H),7.64～7.73(m,1H),8.62(d,J＝4.8Hz,1H)。
Embodiment compound 99
The preparation process of compound 99:
By compound 1 (15mg, 0.085mmol) and Et
3n (34mg, 0.34mmol) is dissolved in methylene dichloride (1.0mL), then adds compound 2 (17mg, 0.17mmol).By reaction mixture stirring at room temperature 1 hour.Reaction mixture H
2o washs.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 5/1, v/v), obtain required compound (14mg, 78% yield).
LCMS:m/z,233.1(M+H)
+；
1HNMR(400MHz,CDCl
3)δ1.93(s,3H),4.31～4.65(m,4H),7.29～7.33(m,1H),7.50(d,J＝7.6Hz,1H),7.64～7.73(m,1H),8.60～8.68(m,1H)。
Embodiment compound 100
The preparation process of compound 100:
To compound 1 (15mg, 0.09mmol) and Et
3the solution of N (34mg, 0.34mmol) in methylene dichloride (3ml) adds compound 2 (18mg, 0.10mmol), by mixture in stirred overnight at room temperature.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous dry Na
2sO
4and be concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 100 (17.6mg, yield: 65%).
LCMS:m/z,317.0(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.52～8.54(m,1H),7.80～7.82(m,2H),7.50～7.64(m,4H),7.25～7.38(m,1H),7.20～7.25(m,1H),4.20～4.25(m,2H),4.07～4.18(m,2H)。
Embodiment compound 115
The preparation process of compound 115:
Solution to 1 (17.6mmol, 0.1mmol) and 2 (36mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (10mg, yield: 30%).
LCMS:m/z,336.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ4.17～4.45(m,4H),6.13～6.24(m,1H),6.27～6.33(m,1H),6.57～6.60(m,1H),7.14～7.25(m,2H),7.42～7.44(m,1H),7.61～7.65(m,1H),8.54～8.55(m,1H)。
Embodiment compound 116
The preparation process of compound 116:
Solution to 1 (17.6mgl, 0.1mmol) and 2 (36mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (10mg, yield: 30%).
LCMS:m/z,321.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ4.23～4.37(m,4H),6.54～6.59(m,2H),6.97～6.99(m,1H),7.22～7.29(m,2H),7.42～7.44(m,1H),7.61～7.66(m,1H),8.53～8.56(m,1H)。
Embodiment compound 117
The preparation process of compound 117:
Solution to 1 (17.6mmol, 0.1mmol) and 2 (32.7mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (7mg, yield: 27%).
LCMS:m/z,267.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.32(s,3H),4.23～4.38(m,4H),6.31～6.32(m,1H),6.64～6.66(m,1H),7.12～7.16(m,2H),7.31～7.34(m,1H),7.51～7.52(m,1H),7.71～7.75(m,1H),8.63～8.64(m,1H)。
Embodiment 118
The preparation process of compound 118):
Solution to 1 (17.6mmol, 0.1mmol) and 2 (40mg, 0.15mmol) adds Pd
2(dba)
3(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (11mg, yield: 39%).
LCMS:m/z,383.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ3.80(s,3H),4.24～4.39(m,4H),6.02～6.03(m,1H),6.10～6.12(m,1H),6.6437～6.40(m,1H),7.14～7.18(m,1H),7.28～7.29(m,1H),7.48～7.50(m,1H),7.67～7.71(m,1H),8.61～8.62(m,1H)。
Embodiment compound 120
The preparation process of compound 120:
To 1 (10mg, 0.057mmol), 2 (31mg, 0.114mmol) and Cs
2cO
3dMF (1mL) solution of (95mg, 0.29mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then reaction mixture EA (5mL) diluted and use salt solution (2mL) to wash twice.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 120 (6mg, yield: 33.3%).
LCMS:m/z,321.0(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.65(s,1H),7.67(t,J＝7.2,1H),7.45(d,J＝7.6,1H),7.27(t,J＝6.0,1H),6.70(s,1H),6.23(d,J＝1.2,2H),4.14～4.30(m,4H)。
Embodiment compound 121
The preparation process of compound 121:
To 1 (10mg, 0.057mmol), 2 (25mg, 0.114mmol) and Cs
2cO
3dMF (1mL) solution of (95mg, 0.29mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 2 hours at 120 DEG C.LCMS shows starting raw material completely consumed.Then reaction mixture EA (5mL) diluted and use salt solution (2mL) to wash twice.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 121 (5mg, yield: 27.8%).
LCMS:m/z,321.0(M+H)
+,
1HNMR:(d-CDCl
3,400MHz):8.86(s,1H),7.80(t,J＝7.0,1H),7.56(d,J＝8.0,1H),7.37(t,J＝5.6,1H),7.25(s,1H),6.49(d,J＝2.4,1H),6.28(dd,J
1＝2.8,J
2＝8.4,1H),4.11～4.33(m,4H)。
Embodiment compound 132,141,142
The preparation of 1-(3-chloro-phenyl-)-3-fluoro-3-(2-pyridinylethynel) tetramethyleneimine
Compound 132 & compound 140 & compound 141
& compound 142 & compound 146
Experimental section:
The preparation process of compound 140:
At-78 DEG C to 1 (500mg, 4.9mmol) THF (20mL) solution add n-BuLi (3ml, 7.4mmol), by mixture-78 DEG C stir 1h, add the compound 2 (1.1g, 5.8mmol) in THF (2ml).Mixture is stirred 30 minutes at-78 DEG C.By mixture in stirred overnight at room temperature, use saturated NH
4the quencher of Cl solution, then uses EtOAc (2 × 20mL) to extract.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes it pass through preparation TLC purifying, obtains required compound (500mg, yield: 36%).
LCMS:m/z,289.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ1.41(s,9H),2.25～2.29(m,2H),3.49～3.85(m,4H),5.29,5.68(s,1H,total),7.17～7.22(m,1H),7.30～7.38(m,1H),7.58～7.64(m,1H),8.49～8.52(m,1H)。
The preparation process of compound 146:
Compound 140 (500mg, 1.74mmol) is dissolved in dry CH
2cl
2(20mL) in.Solution is cooled to-78 DEG C and adds DAST (560mg, 3.476mmol).Reaction mixture is stirred 1h at-78 DEG C and rises to room temperature.After water quencher, solution extracted with EtOAc (2 × 15mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes its purifying (using EA/PE wash-out, 1/10, v/v) by silicagel column, obtains required compound (350mg, yield: 59%)
LCMS:m/z,291.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ1.40(s,9H),2.18～2.34(m,1H),2.39～2.51(m,1H),3.41～3.54(m,3H),3.71～3.98(m,1H),7.21～7.24(m,1H),7.41～7.43(m,1H),7.60～7.65(m,1H),8.54～8.55(m,1H)。
The preparation process of 3:
TFA (1ml) is added at 0 DEG C of DCM to compound 146 (350mg, 1.2mmol) (5ml) solution.Mixture is at room temperature stirred 1.5 hours.Remove solvent, use CH
2cl
2(40ml) dilute, and use saturated Na
2cO
3(20ml) wash.Organic phase is through Na
2sO
4drying, concentrated, obtain title product (200mg, yield: 87%).
The preparation process of compound 132,141 and 142:
To 3 (19mg, 0.11mmol), 4 (35.1mg, 0.15mmol) and Cs
2cO
3dMF (1mL) solution of (98mg, 0.3mmol) adds 6mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 6mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.By mixture in 120 DEG C at N
2stir 3 hours.LCMS shows starting raw material completely consumed.Then reaction mixture EtOAc (20mL) dilution, and wash three times with salt solution (10mL).Organic solution is through anhydrous Na
2sO
4dry filter, concentrating under reduced pressure also by preparation TLC purifying, obtains racemic compound 132 (8mg, yield: 26%).6mg compound 132, for SFC, produces two kinds of enantiomorphs: 1.50mg compound 141,1.43mg compound 142.
Compound 132
MS:m/z,301.1(M+H)
+；
1HNMR:(CDCl
3,400MHz):δ2.45～2.62(m,1H),2.66～2.75(m,1H),3.49～3.52(m,2H),3.81～3.88(m,2H),6.41～6.44(m,1H),6.53～6.54(m,1H),6.69～6.71(m,1H),7.13～7.17(m,1H),7.28～7.32(m,1H),7.50～7.51(m,1H),7.68～7.72(m,1H),8.63～8.67(m,1H)。
Compound 141
MS:m/z,301.1(M+H)
+；
1HNMR:(CDCl
3,400MHz):δ2.37～2.55(m,1H),2.59～2.69(m,1H),3.46～3.50(m,2H),3.74～3.80(m,2H),6.46～6.47(m,1H),6.62～6.64(m,1H),6.69～6.71(m,1H),7.06～7.10(m,1H),7.22～7.25(m,1H),7.43～7.45(m,1H),7.62～7.66(m,1H),8.55～8.56(m,1H)。
Compound 142
MS:m/z,301.1(M+H)
+；
1HNMR:(CDCl
3,400MHz):δ2.38～2.54(m,1H),2.57～2.67(m,1H),3.45～3.49(m,2H),3.74～3.80(m,2H),6.34～6.36(m,1H),6.46～6.47(m,1H),6.62～6.64(m,1H),7.06～7.10(m,1H),7.19～7.25(m,1H),7.43～7.45(m,1H),7.61～7.66(m,1H),8.55～8.56(m,1H)。
Racemic compound 132 (6mg) is dissolved in MeOH (1.5ml).This solution is injected at 5cm × 50cmChiralcelOJ250 × 30mmI.D. via pump, on 20 μm of posts.Under 50ml/min flow velocity, realize stratographic analysis at 38 DEG C, the UV detected is at 220nm.Moving phase is by A: supercritical CO
2, B:MEOH is (containing 0.1%NH
3.H
2o) mixture composition, A:B=65:35, under 50ml/min.After three injections amount to 6mg racemic modification, under applied chromatographiccondition, go out two kinds of enantiomorphs from the first fraction seperation collected between 8 ~ 9.5 minutes and 9.8 ~ 12 minutes.By the cut combination containing corresponding enantiomorph, produce 1.50mg and 1.43mg enantiomorph, enantiomeric purity is respectively 98.9% and 96.5%.Following analysis post measures enantiomeric purity: ChiralpakAD-H250 × 4.6mmI.D., 5um, moving phase: CO
2in ethanol (0.05%DEA), 5%-40%, flow velocity: 2.35mL/min, wavelength: 220nm.
Embodiment compound 134
The preparation process of compound 134:
DMF (1ml) solution to 1 (17.6mg, 0.1mmol) and 2 (35mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (15mg, yield: 50%).
LCMS:m/z,316.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ4.29～4.42(m,4H),6.34～6.37(m,1H),6.99～6.01(m,1H),7.24～7.27(m,1H),7.43～7.45(m,1H),7.63～7.67(m,1H),8.55～8.56(m,1H)。
Embodiment compound 135
Experimental section:
The preparation process of 2:
DMF (1ml) solution to 1 (35mmol, 0.22mmol) and 2 (65mg, 0.3mmol) adds Pd (dba)
2(12mg, 0.02mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (12mg, 0.02mmol) and Cs
2cO
3(200mg, 0.6mmol).By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, solution extracted with EtOAc (3 × 30mL).Organic layer washed with brine (2 × 30mL) through anhydrous Na
2sO
4drying, filters and evaporates, and obtains rough thing, and it utilizes preparation TLC purifying, obtains title product (15mg, yield: 30%)
The preparation process of compound 135:
Dioxane (2ml) solution to 1 (15mg, 0.054mmol) under agitation adds NaBO
3.4H
2o (57mg, 0.44mmol) and H
2o (2mL).Mixture is stirred 16h at 80 DEG C, cooling, add H
2o, and by mixture dichloromethane extraction.Title product is checked by LC/MS.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (5mg, yield: 31%)
LCMS:m/z,296.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ4.23～4.38(m,4H),5.51(s,1H),5.89(s,1H),6.55～6.58(m,1H),6.92～6.93(m,1H),7.06～7.08(m,1H),7.21～7.26(m,2H),7.43～7.45(m,1H),7.62～7.67(m,1H),8.54～8.56(m,1H)。
Embodiment compound 137
The preparation process of compound 137:
By compound 8 (19.0mg, 0.1mmol), 2 (26.1mg, 0.11mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (5.8mg, 0.01mmol) and Cs
2cO
3(65.1mg, 0.2mmol) mixture in DMF (1mL) degassed 3 times under a nitrogen, then at N
2lower to Pd
2(dba)
3(9.2mg, 0.01mmol) adds in mixture.Reaction mixture is heated at 100 DEG C and stirs 2 hours under a nitrogen.Reaction mixture passes through the water quencher of interpolation and is extracted with ethyl acetate.The organic phase merged, through water, salt water washing, through dried over sodium sulfate, is filtered and concentrates.Residue is through preparation TLC purifying (8.9mg, yield=29.6%).
LCMS:m/z301.1[M+H]
+；
1HNMR(CDCl3400MHz):δ2.29(s,3H),4.16～4.31(m,4H),6.25(dd,J＝3.2,8.0Hz,1H),6.37(t,J＝2.2Hz,1H),6.68(dd,J＝2.8,8.0Hz,1H),7.04(d,J＝5.2Hz,1H),7.07(d,J＝8.0Hz,1H),7.26(s,1H),8.38(d,J＝5.2Hz,1H)。
Embodiment compound 138
The preparation of compound 138
The preparation process of compound 138:
To the fluoro-3-of 3-[(5-picoline-2-base)-ethynyl] azetidine (15mg, 0.079mmol), 9 (38mg, 0.158mmol) and Cs
2cO
3(129mg, 0.395mmol) solution in DMF (2mL) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 2 hours at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 138 (2.42mg, yield: 10.2%).
LCMS:m/z,301.0(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.37～8.38(m,1H),7.42～7.44(m,1H),7.32(d,J＝8Hz,1H),7.08(t,J＝8Hz,1H),6.69～6.71(m,1H),6.38(t,J＝2Hz,1H),6.26～6.29(m,1H),4.24～4.31(m,2H),4.17～4.22(m,2H),2.30(s,3H)。
Embodiment compound 144
Synthetic schemes
The preparation process of compound 144:
By compound 1 (15mg, 0.085mmol), compound 2 (25mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (5mg, 21% yield).
LCMS:m/z,310.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.40～2.70(m,2H),3.45～3.49(m,2H),3.75(d,J＝13.6Hz,2H),6.33～6.37(m,1H),6.48(s,1H),6.62(dd,J＝1.2Hz,8.0Hz,1H),7.23～7.25(m,1H),7.44(d,J＝8.0Hz,1H),7.63～7.67(m,1H),8.56(dd,J＝0.8Hz,4.8Hz,1H)。
Embodiment compound 145
The preparation of compound 145:
Experimental section:
The preparation process of compound: 145:
By compound 1 (15mg, 0.085mmol), compound 2 (24mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (5mg, 21% yield).
LCMS:m/z,303.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.39～2.67(m,2H),3.44(dd,J＝4.4Hz,9.6Hz,2H),3.70～3.80(m,2H),6.10～6.12(m,1H),6.22～6.27(m,1H),6.92～6.99(m,1H),7.24(dd,J＝4.8Hz,8.0Hz,1H),7.44(d,J＝7.6Hz,1H),7.61～7.66(m,1H),8.55(dd,J＝0.8Hz,4.8Hz,1H)。
Embodiment compound 149
The preparation process of compound 149:
To compound 1 (15mg, 0.079mmol) and Et
3methylene dichloride (3ml) solution of N (32mg, 0.32mmol), then adds compound 2 (17mg, 0.095mmol).By mixture in stirred overnight at room temperature.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying
.residue, through preparation TLC purifying, obtains title compound 149 (17.64mg, yield: 67.6%).
LCMS:m/z,331.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.51～8.52(m,1H),7.77～7.79(m,2H),7.59～7.63(m,1H),7.52～7.54(m,1H),7.46～7.50(m,2H),7.36～7.38(m,1H),7.20～7.24(m,1H),3.77～3.85(m,1H),3.56～3.70(m,2H),3.31～3.37(m,1H),2.36～2.45(m,1H),2.15～2.31(m,1H)。
Embodiment compound 150
The preparation of compound 150:
Experimental section:
The preparation process of compound 150:
To compound 1 (15mg, 0.079mmol) and Et
3methylene dichloride (3ml) solution of N (32mg, 0.32mmol) then adds compound 2 (18mg, 0.095mmol), by mixture in stirred overnight at room temperature.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying
.residue, through preparation TLC purifying, obtains title compound 150 (12.22mg, yield: 44.9%).
LCMS:m/z,345.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.51～8.53(m,1H),7.63～7.67(m,2H)7.59～7.62(m,1H),7.36～7.38(m,1H),7.25～7.27(m,2H),7.20～7.24(m,1H),3.75～3.83(m,1H),3.53～3.68(m,2H),3.31～3.36(m,1H),2.39～2.45(m,1H),2.36(s,3H),2.14～2.31(m,1H)。
Embodiment compound 151
Synthetic schemes
The preparation of compound 151:
Experimental section:
The preparation process of compound 151:
To compound 1 (15mg, 0.079mmol) and Et
3methylene dichloride (3ml) solution of N (32mg, 0.32mmol) then adds compound 2 (20mg, 0.095mmol), by mixture in stirred overnight at room temperature.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 151 (14.96mg, yield: 51.9%).
Embodiment compound 152
Synthetic schemes
The preparation of compound 152:
Experimental section:
The preparation process of compound 152:
By compound 1 (38.0mg, 0.2mmol), 2 (52.2mg, 0.22mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (11.6mg, 0.02mmol) and Cs
2cO
3(130.2mg, 0.4mmol) mixture in DMF (1mL) degassed 3 times under a nitrogen, then at N
2lower to Pd
2(dba)
3(9.218.4mg, 0.02mmol) adds in mixture.Reaction mixture is heated at 100 DEG C and stirs under a nitrogen and spends the night.Reaction mixture passes through the water quencher of interpolation and is extracted with ethyl acetate.The organic phase merged, through water, salt water washing, through dried over sodium sulfate, is filtered and concentrates.Residue is through preparation TLC purifying (7.5mg, yield=25.0%).
LCMS:m/z301.1[M+H]
+；
1HNMR(d-CDCl3400MHz):δ2.40～2.63(m,2H),3.44～3.48(m,2H),3.72(s,1H),3.78(d,J＝3.6Hz,1H),6.38(dd,J＝3.6,12.0Hz,2H),7.1(d,J＝12.0Hz,2H),7.22～7.25(m,1H),7.43(d,J＝8.0Hz,1H),7.61(dt,J＝2.4,8.0Hz,1H),8.54(d,J＝3.6Hz,1H)。
Embodiment compound 153
The preparation of compound 153:
Experimental section:
The preparation process of compound 153:
TEA (20.2mg, 0.2mmol) and compound 2 (18.7mg, 0.11mmol) is added successively at 0 DEG C of DCM to compound 1 (19.0mg, 0.1mmol) (1mL) solution.Solution is at room temperature stirred 0.5 hour under a nitrogen.Reaction mixture is extracted with ethyl acetate by water quencher, organic phase by salt water washing, through Na
2sO
4drying, filters and concentrates.Residue is through preparation TLC purifying (7.5mg, yield=23.1%).
LCMS:m/z325.2[M+H]
+。
Embodiment compound 154
The preparation of compound 154:
Experimental section:
The preparation process of compound: 154:
To 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 154 (10mg, yield: 40%).
LCMS:m/z,317.1(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.66(s,1H),8.19(t,J＝4.6,1H),7.82(d,J＝4.6,1H),7.71(t,J＝7.6,1H),7.46～7.53(m,4H),7.38(t,J＝8.0,1H),7.30(t,J＝6.4,1H),7.05(d,J＝7.2,1H),3.73～3.97(m,3H),3.38～3.43(m,1H),2.65～2.74(m,2H)。
Embodiment compound 155
The preparation of compound 155:
Experimental section:
The preparation process of compound 155:
To 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 155 (12mg, yield: 48%).
LCMS:m/z,317.2(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.64(s,1H),7.56～7.67(m,4H),7.47(d,J＝7.2,1H),7.30(t,J＝7.6,2H),7.11～7.15(m,1H),6.88(d,J＝8.0,1H),6.69(s,1H),3.83～3.94(m,2H),3.61(d,J＝7.6,2H),2.43～2.65(m,2H)。
Embodiment compound 156
The preparation of compound 156:
Experimental section:
The preparation process of compound 156:
To 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 156 (8mg, yield: 32%).
LCMS:m/z,318.1(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.56～8.59(m,2H),7.90～7.96(m,2H),7.64(t,J＝7.2,1H),7.45(d,J＝7.6,1H),7.24(t,J＝6.2,2H),7.10(d,J＝8.8,1H),6.59(d,J＝1.6,1H),3.85～3.95(m,2H),3.58～3.64(m,2H),2.44～2.73(m,2H)。
Embodiment compound 157
The preparation of compound 157:
Experimental section:
The preparation process of compound 157:
K is added to 1 (15mg, 0.079mmol) in 2 (5mL)
2cO
3(78mg, 0.57mmol).Mixture is stirred 6 hours at 110 DEG C.LCMS shows starting material completely consumed.Then filter reaction mixture and use 5mL washed with dichloromethane filter cake.Concentrated filtrate, to dry, make its purifying by p-TLC, obtains title compound 157 (9mg, yield: 42.8%).
LCMS:m/z,268.1(M+H)
+；
1HNMR:(d-MeOD,400MHz):δ8.65(b,1H),8.10(d,J＝5.6,1H),7.66(t,J＝7.2,1H),7.41～7.47(m,2H),7.19～7.27(m,1H),6.55(t,J＝6.4,1H),6.33(d,J＝8.4,1H),3.72～4.08(m,2H),3.55～3.61(m,2H),2.41～2.66(m,2H)。
Embodiment compound 158
The preparation of compound 158:
Experimental section:
The preparation process of compound 158:
To 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 158 (8mg, yield: 38%).
LCMS:m/z,268.1(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.55(d,J＝4.4,1H),7.94～8.15(m,2H),7.64(t,J＝5.8,1H),7.45(d,J＝7.2,1H),7.23(d,J＝3.2,2H),6.89(d,J＝6.4,1H),3.85(s,1H),3.79(s,1H),3.52～3.56(m,2H),2.42～2.71(m,2H)。
Embodiment compound 159
The preparation of compound 159:
Experimental section:
The preparation process of compound 159:
To 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 159 (10mg, yield: 38.4%).
LCMS:m/z,335.1(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.59(s,1H),7.64(d,J＝6.8,1H),7.45(d,J＝7.2,1H),7.26(s,1H),7.17(s,1H),6.52(s,1H),6.30(dd,J＝8.8,1H),3.70～3.80(m,2H),3.40～3.46(m,2H),2.38～2.68(m,2H)。
Embodiment compound 160
The preparation of compound 160:
Experimental section:
The preparation process of compound 160:
To 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 160 (12mg, yield: 46.1%).
LCMS:m/z,335.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.59(s,1H),7.65(d,J＝7.6,1H),7.45(d,J＝7.6,1H),7.26(s,1H),6.63(s,1H),6.32(s,2H),3.76(s,1H),3.69(s,1H),3.45(d,J＝9.2,2H),2.37～2.65(m,2H)。
Embodiment compound 161
The preparation of compound 161:
Experimental section:
The preparation process of compound 161:
By compound 1 (15mg, 0.085mmol), compound 2 (24mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (6mg, 25% yield).
LCMS:m/z,303.0(M+H)+；
1HNMR(400MHz,CDCl
3):δ2.47～2.73(m,2H),3.49～3.55(m,2H),3.78(s,1H),3.85(s,1H),6.02～6.06(m,2H),6.15～6.19(m,1H),7.30～7.34(m,1H),7.51(d,J＝8.0Hz,1H),7.69～7.73(m,1H),8.63(d,J＝4.4Hz,1H)。
Embodiment compound 162
The preparation of compound 162:
Experimental section:
The preparation process of compound 162:
By compound 1 (15mg, 0.085mmol), compound 2 (22mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 1/2, v/v), obtain required compound (6mg, 25% yield).
LCMS:m/z,286.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.48～2.64(m,1H),2.70～2.79(m,1H),3.54～3.63(m,2H),3.84(s,1H),3.90(s,1H),6.52～6.55(m,1H),7.32(dd,J＝5.2Hz,7.2Hz,1H),7.52(d,J＝7.6Hz,1H),7.68～7.71(m,1H),7.81(s,1H),7.88(s,1H),8.63(d,J＝0.8Hz,4.8Hz,1H)。
Embodiment compound 165
The preparation of compound 165:
Experimental section:
The preparation process of compound 165:
To compound 1 (15mg, 0.079mmol) and Et
3methylene dichloride (3ml) solution of N (32mg, 0.32mmol) then adds compound 2 (10mg, 0.095mmol), by mixture in stirred overnight at room temperature.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying
.residue, through preparation TLC purifying, obtains title compound 165 (6.83mg, yield: 33.3%).
LCMS:m/z,261.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.55(s,1H),7.61～7.67(m,1H),7.43(d,J＝8Hz,1H),7.20～7.26(m,1H),3.97～4.16(m,1H),3.54～3.90(m,3H),2.56～2.63(m,2H),2.34～2.55(m,1H),1.10～1.19(m,6H)。
Embodiment compound 166
The preparation process of compound 166:
To compound 1 (15mg, 0.079mmol) and Et
3methylene dichloride (3ml) solution of N (32mg, 0.32mmol) then adds compound 2 (10mg, 0.095mmol), by mixture in stirred overnight at room temperature.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 166 (9.66mg, yield: 44.7%).
LCMS:m/z,275.1(M+H)
+:
1HNMR(d-CDCl
3,400MHz):δ8.54～8.55(m,1H),7.61～7.64(m,1H),7.43(d,J＝8Hz,1H),7.23～7.25(m,1H),4.16(b,1H),3.87～3.90(m,1H),3.79～3.82(m,1H),3.64～3.71(m,1H),2.51(b,1H),2.28(b,1H),1.18～1.22(m,9H)。
Embodiment compound 167
The preparation of compound 167:
Experimental section:
The preparation process of compound 167:
To compound 1 (15mg, 0.079mmol) and Et
3methylene dichloride (3ml) solution of N (32mg, 0.32mmol) then adds compound 2 (12mg, 0.095mmol), by mixture in stirred overnight at room temperature.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 167 (16.02mg, yield: 74.2%).
LCMS:m/z,275.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.60(s,1H),7.69～7.70(m,1H),7.47～7.49(m,1H),7.26～7.32(m,1H),3.89～4.38(m,2H),3.58～3.85(m,2H),2.39～2.68(m,2H),2.22～2.30(m,2H),1.62～1.65(m,2H),1.34～1.39(m,2H),0.92(t,J＝7.2Hz,3H)。
Embodiment compound 168
The preparation of compound 168:
Experimental section:
The preparation process of compound 168:
To compound 1 (15mg, 0.079mmol) add compound 2 (11mg with 3 (36mg, 0.095mmol), 4 (31mg, the 0.237mmol) solution in DCM (3ml), 0.095mmol), by mixture in stirred overnight at room temperature.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying
.residue, through preparation TLC purifying, obtains title compound 168 (12.16mg, yield: 53.3%).
LCMS:m/z,289.2(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.53～8.55(m,1H),7.61～7.65(m,1H),7.41～7.44(m,1H),7.20～7.25(m,1H),3.79～4.32(m,2H),3.65～3.76(m,2H),2.20～2.24(m,2H),2.15～2.19(m,2H),1.47～1.53(m,3H),0.84～0.87(m,6H)。
Embodiment compound 169
The preparation of compound 169:
Experimental section:
The preparation process of compound 169:
To 1 (30mg, 0.158mmol), 2 (72mg, 0.316mmol) and Cs
2cO
3dMF (2mL) solution of (256mg, 0.79mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 2 hours at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 169 (16.23mg, yield: 35.3%).
LCMS:m/z,292.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.54～8.56(m,1H),7.62～7.66(m,1H),7.43～7.46(m,1H),7.20～7.26(m,2H),6.91～6.93(m,1H),6.65～6.68(m,2H),3.78(d,J＝27.2Hz,2H),3.47～3.51(m,2H),2.62～2.71(m,1H),2.40～2.57(m,1H)。
Embodiment compound 170
The preparation of compound 170:
Experimental section:
The preparation process of compound 170:
To 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and Cs
2cO
3dMF (2mL) solution of (129mg, 0.395mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 2 hours at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying
.residue, through preparation TLC purifying, obtains title compound 170 (6.56mg, yield: 31.2%).
LCMS:m/z,267.1(M+H)
+；
1HNMR(CDCl
3,400MHz):δ8.54～8.56(m,1H),7.61～7.65(m,1H),7.43～7.45(m,1H),7.16～7.24(m,3H),6.67(t,J＝7.4Hz,1H),6.49～6.51(m,2H),3.76～3.83(m,2H),3.47～3.51(m,2H),2.10～2.64(m,2H)。
Embodiment compound 171
The preparation of compound 171:
Experimental section:
The preparation process of compound 171:
To 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and Cs
2cO
3dMF (2mL) solution of (129mg, 0.395mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg, 5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 2 hours at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 171 (6.62mg, yield: 29.4%).
LCMS:m/z,285.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.61～8.63(m,1H),7.68～7.73(m,1H),7.50～7.52(m,1H),7.30～7.32(m,1H),7.14～7.20(m,1H),6.41～6.45(m,1H),6.22～6.32(m,2H),3.81(s,1H),3.87(s,1H),3.53～3.56(m,2H),2.59～2.66(m,1H),2.38～2.55(m,1H)。
Embodiment compound 172
The preparation of compound 172:
Experimental section:
The preparation process of compound 172:
NaBO is added to 1 (15mg, 0.05mmol) in dioxane (1mL)
3.4H
2o (15mg, 0.1mmol) and H
2o (1mL).Mixture is stirred 16 hours at 80 DEG C.React by adding water quencher and using dichloromethane extraction.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying
.residue, through preparation TLC purifying, obtains title compound 172 (6.08mg, yield: 38.2%).
LCMS:m/z,310.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.54～8.56(m,1H),7.62～7.66(m,1H),7.44～7.48(m,1H),7.20～7.25(m,2H),6.98～7.01(m,2H),6.61～6.64(m,1H),6.06(b,1H),5.59(b,1H),3.76～3.86(m,2H),3.49～3.58(m,2H),2.39～2.69(m,2H)。
Embodiment compound 173
The preparation of compound 173:
Experimental section:
The preparation process of 2:
NaH (12mg, 0.3mmol) is added to 1 (60mg, 0.2mmol) in anhydrous THF (2mL) at 0 DEG C.After stirring at room temperature 30 minutes, drip the CH in anhydrous THF (1mL)
3i (42mg, 0.3mmol) solution.By mixture subsequently stirring at room temperature 2 hours.TLC and LCMS shows starting material and changes into required product completely.Then also three times are extracted with EA (5mL) with ice quencher reaction mixture.The organic layer washed with brine merged, through anhydrous Na
2sO
4drying, is concentrated into drying, makes its purifying by p-TLC, obtains required compound 2 (50mg, yield: 79.3%).
LCMS:m/z,303.2(M+H)
+。
The preparation process of 3:
TFA (0.4mL) is dripped at 0 DEG C of anhydrous methylene chloride to 2 (50mg, 0.165mmol) (2mL) solution.Then reaction mixture is condensed into residue at stirring at room temperature 2h.Then saturated aqueous Na is used
2cO
3process this residue, until pH=10, and extract with methylene dichloride (5mL × 3).The organic layer merged is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes its purifying by p-TLC, obtains required compound 3 (25mg, yield: 75.7%).
LCMS:m/z,203.2(M+H)
+。
The preparation process of compound 173:
To 3 (10mg, 0.05mmol), 4 (24mg, 0.1mmol) and Cs
2cO
3dMF (1mL) solution of (80mg, 0.25mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 173 (6mg, yield: 40%).
LCMS:m/z,313.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.52(d,J＝4.8,1H),7.57～7.61(m,1H),7.38(d,J＝7.6,1H),7.18(t,J＝5.6,1H),7.04(t,J＝8.0,1H),6.57(dd,J
1＝1.2,J
2＝8.0,1H),6.43(t,J＝2.0,1H),6.32(dd,J
1＝2.0,J
2＝8.4,1H),3.57～3.63(m,2H),3.37～3.42(m,5H),2.31～2.46(m,2H)。
Embodiment compound 174
The preparation of compound 174:
Experimental section:
The preparation process of compound 174:
To 1 (10mg, 0.05mmol), 2 (20mg, 0.1mmol) and Cs
2cO
3dMF (1mL) solution of (80mg, 0.25mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 174 (7mg, yield: 50%).
LCMS:m/z,279.2(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.60(s,1H),7.65～7.69(m,1H),7.46(d,J＝7.6,1H),7.22～7.28(m,3H),6.70(t,J＝7.6,1H),6.56(d,J＝8.0,1H),3.68～3.74(m,2H),3.48～3.50(m,5H),2.40～2.53(m,2H)。
Embodiment compound 175
The preparation of compound 175:
Experimental section:
The preparation process of compound 175):
Solution to 1 (21mg, 0.11mmol) and 2 (35mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (10mg, yield: 35%).
LCMS:m/z,297.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.44～2.74(m,2H),3.49～3.50(m,4H),3.81(s,3H),3.83～3.89(m,2H),6.11～6.12(m,1H),6.18～6.20(m,1H),6.31～6.34(m,1H),7.14～7.19(m,1H),7.29～7.32(m,1H),7.51～7.53(m,1H),7.69～7.73(m,1H),8.62～8.64(m,1H)。
Embodiment compound 176
The preparation of compound 176:
Experimental section:
The preparation process of compound 176:
Solution to 1 (21mg, 0.11mmol) and 2 (35mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (10mg, yield: 39%).
LCMS:m/z,351.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.39～2.70(m,2H),3.47～3.51(m,2H),3.75～3.82(m,2H),6.27～6.29(m,1H),6.37～6.39(m,1H),6.50～6.52(m,1H),7.14～7.25(m,2H),7.43～7.46(m,1H),7.62～7.66(m,1H),8.55～8.57(m,1H)。
Embodiment compound 177
Synthetic schemes
The preparation of compound 177:
Experimental section:
The preparation process of compound 177:
Solution to 1 (21mg, 0.11mmol) and 2 (35mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (10mg, yield: 39%).
LCMS:m/z,330.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.43～2.74(m,2H),3.51～3.59(m,2H),3.79～3.86(m,2H),6.41～6.45(m,1H),7.11～7.12(m,1H),7.19～7.27(m,12H),7.44～7.46(m,1H),7.63～7.67(m,1H),8.55～8.57(m,1H)。
Embodiment compound 178
The preparation of compound 178:
Experimental section:
The preparation process of compound 178:
Solution to 1 (21mg, 0.11mmol) and 2 (42mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (11mg, yield: 29%).
LCMS:m/z,345.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.43～2.74(m,2H),3.05(s,3H),3.58～3.67(m,2H),3.88～3.95(m,2H),6.75～6.78(m,1H),7.06～7.07(m,1H),7.24～7.25(m,2H),7.30～7.33(m,1H),7.39～7.43(m,1H),7.70～7.74(m,1H),8.62～8.64(m,1H)。
Embodiment compound 179
The preparation of compound 179:
Experimental section:
The preparation process of compound 179:
Solution to 1 (21mg, 0.11mmol) and 2 (40mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (12mg, yield: 32%).
LCMS:m/z,335.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.43～2.70(m,2H),3.51～3.55(m,2H),3.79～3.86(m,2H),6.61～6.68(m,2H),6.89～6.91(m,1H),7.22～7.297(m,2H),7.44～7.46(m,2H),7.62～7.66(m,1H),8.57～8.61(m,1H)。
Embodiment compound 180
The preparation of compound 180:
Experimental section:
The preparation process of compound 180:
Solution to 1 (21mg, 0.11mmol) and 2 (40mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (10mg, yield: 28%).
LCMS:m/z,325.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.44～2.77(m,2H),3.59～3.64(m,2H),3.88～3.95(m,5H),6.73～6.75(m,1H),7.23～7.33(m,3H),7.40～7.42(m,2H),7.51～7.53(m,1H),7.69～7.73(m,1H),8.62～8.63(m,1H)。
Embodiment compound 181
The preparation of compound 181:
Experimental section:
The preparation process of compound 181:
Solution to 1 (21mg, 0.11mmol) and 2 (40mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (5mg, yield: 14%).
LCMS:m/z,338.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.43～2.70(m,2H),2.92～3.03(s,6H),3.45～3.54(m,2H),3.76～3.83(m,2H),6.49～6.51(m,2H),6.64～6.66(m,1H),7.16～7.25(m,2H),7.43～7.45(m,1H),7.61～7.65(m,1H),8.54～8.56(m,1H)。
Embodiment compound 182
The preparation of compound 182:
Experimental section:
The preparation process of compound 182:
Solution to 1 (21mg, 0.11mmol) and 2 (40mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (7mg, yield: 19%).
LCMS:m/z,324.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.44～2.71(m,2H),2.93～3.07(s,3H),3.46～3.54(m,2H),3.76～3.83(m,2H),6.49～6.51(m,2H),6.64～6.66(m,1H),7.16～7.25(m,2H),7.43～7.45(m,1H),7.61～7.65(m,1H),8.54～8.56(m,1H)。
Embodiment compound 184
The preparation of compound 184:
Experimental section:
The preparation process of compound 184:
By compound 1 (38.0mg, 0.2mmol), 2 (52.2mg, 0.22mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (11.6mg, 0.02mmol) and Cs
2cO
3(130.2mg, 0.4mmol) mixture in DMF (1mL) degassed 3 times under a nitrogen, then at nitrogen to by Pd
2(dba)
3(9.218.4mg, 0.02mmol) is added in mixture.Reaction mixture is heated at 100 DEG C and stirs under a nitrogen and spends the night.Reaction mixture passes through the water quencher of interpolation and is extracted with ethyl acetate.The organic phase merged, through water, salt water washing, through dried over sodium sulfate, is filtered and concentrates.Residue is through preparation TLC purifying (7.5mg, yield=25.0%).
LCMS:m/z301.1[M+H]
+；
1HNMR(d-CDCl
3400MHz):δ2.42～2.63(m,2H),3.42(dt,J＝2.8,8.4Hz,1H),3.73～3.86(m,2H),4.16(dd,J＝12.0,32.0Hz,1H),6.83(dt,J＝1.4,8.1Hz,1H),7.15(dt,J＝1.6,7.2Hz,1H),7.26～7.33(m,2H),7.50(d,J＝8.0Hz,1H),7.67(dt,J＝1.6,7.6Hz,1H),8.61(d,J＝3.6Hz,1H)。
Embodiment compound 185
The preparation of compound 185:
Experimental section:
The preparation process of compound 185:
TEA (20.2mg, 0.2mmol) and compound 2 (17.0mg, 0.11mmol) is added successively at 0 DEG C of DCM to compound 1 (19.0mg, 0.1mmol) (1mL) solution.Solution is at room temperature stirred 0.5 hour under a nitrogen.Reaction mixture is extracted with ethyl acetate by water quencher, organic phase by salt water washing, through Na
2sO
4drying, filters and concentrates.Residue is through preparation TLC purifying (10.5mg, yield=34.1%).
LCMS:m/z309.2[M+H]
+；
1HNMR(d-CDCl3400MHz):δ2.18～2.47(m,2H),3.56～3.83(m,5H),3.96～4.16(m,1H),7.17～7.28(m,6H),7.40(d,J＝7.6Hz,1H),7.60～7.65(m,1H),8.53(d,J＝7.6Hz,1H)。
Embodiment compound 187
The preparation of compound 187:
Experimental section:
The preparation process of compound 187:
TEA (20.2mg, 0.2mmol) and compound 2 (11.9mg, 0.11mmol) is added successively at 0 DEG C of DCM to compound 1 (19.0mg, 0.1mmol) (1mL) solution.Solution is at room temperature stirred 0.5 hour under nitrogen protection.Reaction mixture is extracted with ethyl acetate by water quencher, organic phase by salt water washing, through Na
2sO
4drying, filters and concentrates.Residue is through preparation TLC purifying (11.5mg, yield=43.9%).
LCMS:m/z263.1[M+H]
+；
1HNMR(d-CDCl
3400MHz):δ1.19(t,J＝7.2Hz,3H),2.22～2.38(m,1H),2.46～2.53(m,1H),3.48～3.56(m,1H),3.59～3.75(m,2H),3.87～4.00(m,1H),4.06(q,J＝7.2Hz,2H),7.21(dd,J＝4.8,7.2Hz,1H),7.41(d,J＝7.8Hz,1H),7.60(dt,J＝1.6,8.0Hz,1H),8.53(d,J＝4.8Hz,1H)。
Embodiment compound 188
The preparation of compound 188:
Experimental section:
The preparation process of compound 188:
TEA (20.2mg, 0.2mmol) and compound 2 (17.2mg, 0.11mmol) is added successively at 0 DEG C of DCM to compound 1 (19.0mg, 0.1mmol) (1mL) solution.Solution is at room temperature stirred 0.5 hour under nitrogen protection.Reaction mixture is extracted with ethyl acetate by water quencher, organic phase by salt water washing, through Na
2sO
4drying, filters and concentrates.Residue is through preparation TLC purifying (11.5mg, yield=43.9%).
LCMS:m/z311.1[M+H]
+；
1HNMR(d-CDCl
3400MHz):δ2.28～2.63(m,2H),3.61～3.93(m,3H),4.03～4.16(m,1H),7.06(dd,J＝1.2,7.2Hz,2H),7.11(t,J＝8.0Hz,1H),7.22(t,J＝6.0Hz,1H),7.27(t,J＝8.0Hz,1H),7.42(d,J＝7.8Hz,1H),7.61(dt,J＝0.8,8.0Hz,1H),8.54(d,J＝4.8Hz,1H)。
Embodiment compound 191
The preparation of compound 191:
Experimental section:
The preparation process of compound 191:
Solution to 1 (21mg, 0.11mmol) and 2 (42mg, 0.15mmol) adds Pd (dba)
2(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (11mg, yield: 35%).
LCMS:m/z,281.2(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.42(s,3H),2.61～2.73(m,2H),3.57～3.58(m,2H),3.83～3.89(m,2H),6.38～6.39(m,2H),6.56～6.58(m,1H),7.13～7.17(m,1H),7.29～7.32(m,1H),7.50～7.52(m,1H),7.69～7.73(m,1H),8.632～8.63(m,1H)。
Embodiment compound 192
The preparation of compound 192:
Experimental section:
The preparation process of compound 192:
TEA (20.2mg, 0.2mmol) and compound 2 (15.0mg, 0.11mmol) is added successively at 0 DEG C of DCM to compound 1 (19.0mg, 0.1mmol) (1mL) solution.Solution is at room temperature stirred 0.5 hour under nitrogen protection.Reaction mixture is extracted with ethyl acetate by water quencher, organic phase by salt water washing, through Na
2sO
4drying, filters and concentrates.Residue is through preparation TLC purifying (10.5mg, yield=36.1%).
LCMS:m/z291.1[M+H]
+；
1HNMR(d-CDCl
3400MHz):δ0.85(t,J＝7.2Hz,3H),1.28～1.37(m,2H),1.51～1.59(m,2H),2.23～2.53(m,2H),3.48～3.75(m,3H),3.87～4.05(m,3H),7.21(dd,J＝5.4,7.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.60(dt,J＝1.6,8.0Hz,1H),8.53(d,J＝4.4Hz,1H)。
Embodiment compound 193
The preparation of compound 193:
Experimental section:
The preparation process of compound 193:
By compound 1 (38.0mg, 0.2mmol), 2 (54.9mg, 0.22mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (11.6mg, 0.02mmol) and Cs
2cO
3(130.3mg, 0.4mmol) mixture in DMF (2mL) degassed 3 times under a nitrogen, then under a nitrogen by Pd
2(dba)
3(18.4mg, 0.02mmol) adds in this mixture.Reaction mixture is heated at 100 DEG C and stirs 2 hours under a nitrogen.Reaction mixture passes through the water quencher of interpolation and is extracted with ethyl acetate.The organic phase merged, through water, salt water washing, through dried over sodium sulfate, is filtered and concentrates.Residue is by preparation TLC purifying.(15.6mg, yield=25.0%).
LCMS:m/z312.1[M+H]
+；
1HNMR(d-CDCl
3400MHz):δ2.50～2.74(m,2H),3.59～3.63(m,2H),3.86～3.93(m,2H),6.78(dd,J＝2.6,8.2Hz,1H),7.24～7.34(m,3H),7.49～7.55(m,2H),7.67(dt,J＝1.8,8.1Hz,1H),8.60～8.62(m,1H)。
Embodiment compound 194
The preparation of compound 194:
Experimental section:
The preparation process of 2:
Solution to 1 (21mg, 0.11mmol) and 2 (40mg, 0.15mmol) adds Pd
2(dba)
3(6mg, 0.01mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (6mg, 0.01mmol) and Cs
2cO
3(98mg, 0.3mmol).Suspension degassed under vacuo and with nitrogen purge for several times.Suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1h at 100 DEG C, is cooled to room temperature, LCMS shows starting raw material completely consumed.Then reaction mixture EA (80mL) diluted and use salt solution (20mL) to wash three times.Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also utilizes preparation TLC purifying, obtains title product (20mg, yield: 47%).
The preparation process of 194:
TFA (1ml) is added at 0 DEG C of DCM to 1 (20mg, 0.052mmol) (5ml) solution.By mixture at stirring at room temperature 1.5h, then remove solvent, with diluting EtOAc (2 × 20mL) and using salt water washing.The organic layer be separated is through anhydrous dry Na
2sO
4, filter and be concentrated into drying, making it pass through preparation TLC purifying, obtain required compound (5mg, yield: 10%).
LCMS:m/z,282.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.35～2.64(m,2H),3.44～3.48(m,2H),3.5(s,2H),3.73～3.79(m,3H),5.83～3.84(m,1H),5.941～5.962(m,1H),6.03～6.06(m,1H),6.95～6.99(m,1H),6.03～6.06(m,1H),6.95～6.99(m,1H),7.21～7.24(m,1H),7.43～7.45(m,1H),7.61～7.65(m,1H),8.55～8.56(m,1H)。
Embodiment compound 196
The preparation of compound 196:
Experimental section:
The preparation process of compound 196:
To 1 (15mg, 0.079mmol), 2 (36mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then reaction mixture diluted ethyl acetate (10mL) is washed twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 196 (6mg, yield: 22.2%).
LCMS:m/z,343.1(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):8.63(s,1H),7.69～7.73(m,1H),7.61(t,J＝2.2,2H),7.52(t,J＝3.8,1H),7.43(t,J＝7.2,2H),7.29～7.36(m,3H),6.97(d,J＝8.0,1H),6.75(t,J＝2.0,1H),6.57(dd,J
1＝2.0,J
2＝8.4,1H),3.97(s,1H),3.90(s,1H),3.59～3.67(m,2H),2.50～2.76(m,2H)。
Embodiment compound 197
The preparation process of compound 197:
By compound 1 (15mg, 0.078mmol), compound 2 (20mg, 0.117mmol) and K
2cO
3(32mg, 0.234mmol) mixture in DMF (1.0mL) is heated to 100 DEG C, continues 2 hours.After cooling, by preparation TLC purification of crude thing (EA/PE, 1/3, v/v), obtain required compound (11mg, 50% yield).
LCMS:m/z,281.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.46(t,J＝6.8Hz,1H),2.52(t,J＝6.8Hz,1H),2.61～2.68(m,1H),2.94～3.06(m,2H),3.19～3.27(m,1H),3.71(d,J＝3.2Hz,2H),7.24～7.36(m,6H),7.45(d,J＝8.0Hz,1H),7.67(t,J＝8.0Hz,1H),8.59(d,J＝4.4Hz,1H)。
Embodiment compound 198
The preparation process of compound 198:
By compound 1 (15mg, 0.078mmol), compound 2 (22mg, 0.117mmol) and K
2cO
3(32mg, 0.234mmol) mixture in DMF (1.0mL) is heated to 100 DEG C, continues 2 hours.After cooling, by preparation TLC purification of crude thing (EA/PE, 1/3, v/v), obtain required compound (10mg, 45% yield).
LCMS:m/z,295.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.49(t,J＝7.2Hz,1H),2.53(t,J＝7.2Hz,1H),2.64～2.70(m,1H),2.74～2.85(m,4H),2.99～3.09(m,2H),3.29～3.37(m,1H),7.19～7.29(m,6H),7.47(d,J＝7.6Hz,1H),7.67(t,J＝6.0Hz,1H),8.61(d,J＝4.8Hz,1H)。
Embodiment compound 202
The preparation process of compound 202:
To 1 (10mg, 0.053mmol), 2 (26mg, 0.106mmol) and Cs
2cO
3(86mg, 0.265mmol) solution in DMF (2mL) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 202 (2.02mg, yield: 12.4%).
LCMS:m/z,310.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.57(s,1H),7.64～7.67(m,1H),7.45～7.47(m,1H),7.32～7.37(m,1H),7.25～7.28(m,1H),6.18～6.27(m,2H),3.74～3.85(m,2H),3.53～3.57(m,2H),2.63～2.74(m,1H),2.42～2.59(m,1H)。
Embodiment compound 203
The preparation of compound 203:
Experimental section:
The preparation process of compound 203:
To 1 (30mg, 0.157mmol), 2 (70mg, 0.315mmol) and Cs
2cO
3dMF (2mL) solution of (256mg, 0.785mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 203 (4.74mg, yield: 10.6%).
LCMS:m/z,285.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.54～8.56(m,1H),7.61～7.66(m,1H),7.44(d,J＝8Hz,1H),7.19～7.25(m,1H),6.88～6.92(m,2H),6.39～6.43(m,2H),3.78～3.83(m,1H),3.73～3.78(m,1H),3.44～3.47(m,2H),2.54～2.63(m,1H),2.42～2.47(m,1H)。
Embodiment compound 204
The preparation of compound 204:
Experimental section:
The preparation process of compound 204:
To 1 (30mg, 0.157mmol), 2 (78mg, 0.315mmol) and Cs
2cO
3dMF (2mL) solution of (256mg, 0.785mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 204 (5.15mg, yield: 10.5%).
LCMS:m/z,310.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.55～8.57(m,1H),7.64～7.68(m,1H),7.45～7.48(m,1H),7.38～7.42(m,1H),7.24～7.28(m,1H),6.39～6.44(m,1H),6.24～6.28(m,1H),4.12～4.20(m,1H),4.03～4.09(m,1H),3.70～3.82(m,2H),2.60～2.69(m,1H),2.35～2.53(m,1H)。
Embodiment compound 205
The preparation process of compound 205:
To 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 205 (6mg, yield: 27.2%).
LCMS:m/z,285.1(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):8.55(d,J＝5.2,1H),7.61～7.65(m,1H),7.44(d,J＝7.6,1H),7.19～7.24(m,1H),6.91～6.96(m,2H),6.59～6.68(m,2H),3.81～4.06(m,2H),3.46～3.64(m,2H),2.36～2.62(m,2H)。
Embodiment compound 207
Experimental section:
The preparation process of compound 207:
To 1 (15mg, 0.079mmol), 2 (44mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then reaction mixture diluted ethyl acetate (10mL) is washed twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 207 (10mg, yield: 37%).
LCMS:m/z,343.1(M+H)
+；
1HNMR(CDCl
3,400MHz):8.55(d,J＝5.2,1H),7.62～7.66(m,1H),7.44～7.49(m,5H),7.31～7.38(m,2H),7.21～7.25(m,2H),6.57(d,J＝8.8,2H),3.88(s,1H),3.81(s,1H),3.52～3.57(m,2H),2.43～2.66(m,2H)。
Embodiment compound 210
The preparation process of compound 210:
By compound 9 (15mg, 0.07mmol), 10 (22mg, 0.07mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (12mg, 0.021mmol) and CsCO
3(137mg, 0.42mmol) mixture in DMF (5mL) degassed 3 times under a nitrogen, then adds Pd (dba) under a nitrogen in this mixture
3(6mg, 0.007mmol).Reaction mixture is heated at 100 DEG C and stirs 2 hours under a nitrogen.Reaction mixture is checked it by LCMS after being cooled to room temperature.Use H
2o (5mL) and EA (5mL) distributes this mixture.Dry organic phase, concentrate and pass through to prepare TLC purifying, obtaining ~ rough required the product of 5mg.By this raw product H14535-019,031 processes together, obtains product needed for 6mg, pays purity 97%.(yield: 26.5%)
LCMS:m/z,326.0(M+H)
+；
1HNMR(CDCl
3,400MHz):δ7.90(s,1H),7.65(s,1H),7.52(m,1H),7.43(m,1H),7.30(m,1H),7.20(m,1H),7.00(s,1H),6.45(d,J＝7.6Hz1H),4.35(m,4H)。
Embodiment compound 212
The preparation of compound 212:
Experimental section:
The preparation process of compound 212:
By compound 1 (15mg, 0.085mmol), compound 2 (23mg, 0.1mmol), Cs
2cO
3(110mg, 0.34mmol), Pd (dba)
2the two mixture of diphenylphosphine-9,9-dimethyl xanthene (4mg, 0.0085mol) in DMF (1.0mL) of (5mg, 0.0085mmol) and 4,5-is degassed under a nitrogen, is then heated to 100 DEG C, continues 1 hour.After cooling, filter reaction mixture.Filtrate water washs, and extracts with EtOAc.Organic layer is through anhydrous Na
2sO
4drying, filters and is condensed into residue.Make it pass through preparation TLC purifying (EA/PE, 2/1, v/v), obtain required compound (4mg, 20% yield).
LCMS:m/z,298.1(M+H)+；
1HNMR(400MHz,CDCl
3):δ2.46～2.76(m,2H),3.54～3.63(m,1H),3.78(s,1H),3.81(s,3H),3.91(s,1H),6.35(t,J＝2.4Hz,1H),7.26～7.31(m,1H),7.52(d,J＝8.0Hz,1H),7.65(d,J＝2.4Hz,1H),7.68～7.73(m,1H),7.75(d,J＝2.4Hz,1H),7.88(s,1H),8.63(d,J＝5.2Hz,1H)。
Embodiment compound 214
The preparation process of compound 214:
To 1 (10mg, 0.053mmol), 2 (25mg, 0.106mmol) and Cs
2cO
3dMF (2mL) solution of (86mg, 0.265mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 214 (1.74mg, yield: 10.9%).
LCMS:m/z,303.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.61～8.62(m,1H),7.67～7.72(m,1H),7.51(d,J＝8Hz,1H),7.26～7.31(m,1H),6.74～6.84(m,3H),4.10～4.20(m,1H),3.79～3.92(m,2H),3.53～3.57(m,1H),2.31～2.57(m,2H)。
Embodiment compound 215
The preparation process of compound 215:
To 1 (30mg, 0.157mmol), 2 (81mg, 0.315mmol) and Cs
2cO
3dMF (2mL) solution of (256mg, 0.785mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 215 (6.15mg, yield: 12.3%).
LCMS:m/z,319.0(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.62～8.63(m,1H),7.68～7.72(m,1H),7.50～7.52(m,1H),7.28～7.32(m,1H),7.09～7.12(m,1H),6.91～6.93(m,2H),4.06～4.17(m,1H),3.68～3.77(m,2H),3.33～3.38(m,1H),2.46～2.69(m,2H)。
Embodiment compound 216
The preparation process of compound 216:
To 1 (30mg, 0.157mmol), 2 (78mg, 0.315mmol) and Cs
2cO
3dMF (2mL) solution of (256mg, 0.785mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 216 (4.24mg, yield: 8.7%).
LCMS:m/z,310.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.55～8.57(m,1H),7.63～7.67(m,1H),7.46(d,J＝8Hz,1H),7.19～7.28(m,2H),6.44(t,J＝8Hz,1H),6.34(d,J＝8Hz,1H),4.04～4.23(m,2H),3.77～3.85(m,2H),2.60～2.69(m,1H),2.36～2.53(m,1H)。
Embodiment compound 217
The preparation process of compound 217:
To 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then reaction mixture diluted ethyl acetate (10mL) is washed twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 217 (6mg, yield: 27.2%).
LCMS:m/z,286.1(M+H)
+；
1HNMR(CDCl
3,400MHz):δ8.62(d,J＝4.8,1H),8.17(d,J＝5.6,1H),8.08(d,J＝5.2,1H),7.69～7.74(m,1H),7.52(d,J＝8.0,1H),7.31～7.33(m,1H),6.47(dd,J
1＝5.6,J
2＝8.0,1H),4.03～4.15(m,2H),3.71～3.78(m,2H),2.58～2.74(m,1H),2.40～2.46(m,1H)。
Embodiment compound 218
The preparation process of compound 218:
To 1 (15mg, 0.079mmol), 2 (30mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 6 hours at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 218 (4mg, yield: 16.6%).
LCMS:m/z,302.0(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.55(d,J＝4.4,1H),7.89(s,1H),7.80(s,1H),7.62～7.66(m,1H),7.44(d,J＝8.0,1H),6.74(t,J＝2.0,1H),3.83(s,1H),3.76(d,J＝3.2,1H),3.49～3.54(m,2H),2.42～2.72(m,2H)。
Embodiment compound 219
The preparation process of compound 219:
To 1 (15mg, 0.079mmol), 2 (38mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous dry Na
2sO
4, filter, concentrating under reduced pressure also by p-TLC purifying, obtains required compound 219 (4mg, yield: 16.6%).
LCMS:m/z,303.1(M+H)
+；
1HNMR:(d-CDCl
3,400MHz):δ8.55(d,J＝4.8,1H),7.61～7.65(m,1H),7.44(d,J＝7.6,1H),7.19～7.25(m,1H),6.81～6.88(m,1H),7.25～7.32(m,2H),3.83～4.05(m,2H),3.46～3.60(m,2H),2.33～2.63(m,2H)。
Embodiment compound 220
The preparation process of compound 220:
To 1 (15mg, 0.079mmol), 2 (30mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 6 hours at 120 DEG C.LCMS shows starting raw material completely consumed.Then reaction mixture diluted ethyl acetate (10mL) is washed twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 220 (5mg, yield: 20.8%).
LCMS:m/z,309.1(M+H)
+；
1HNMR:(d-CDCl
3(400MHz):δ8.54～8.55(m,1H),7.61～7.65(m,1H),7.44(d,J＝7.6,1H),7.21～7.24(m,1H),7.12(t,J＝5.8,1H),6.56(d,J＝7.6,1H),6.32～6.36(m,2H),3.84(s,1H),3.77(s,1H),3.45～3.53(m,2H),2.75～2.82(m,1H),2.56～2.66(m,1H),2.37～2.53(m,1H),1.19(d,J＝4.8,6H)。
Embodiment compound 221
The preparation process of compound 221:
To 1 (15mg, 0.079mmol), 2 (33mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 6 hours at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 221 (3mg, yield: 12%).
LCMS:m/z,323.2(M+H)
+；
1HNMR(CDCl
3,400MHz):δ8.62(d,J＝4.8,1H),7.68～7.73(m,1H),7.52(d,J＝7.6,1H),7.30(t,J＝6.4,1H),7.20(t,J＝8.0,1H),6.79(d,J＝7.2,1H),6.58(s,1H),6.41(d,J＝5.6,1H),3.92(s,1H),3.86(s,1H),3.56～3.60(m,2H),2.61～2.74(m,1H),2.47～2.56(m,1H),1.32(s,9H)。
Embodiment compound 222
The preparation process of compound 222:
To 1 (15mg, 0.079mmol), 2 (33mg, 0.158mmol) and Cs
2cO
3dMF (1mL) solution of (128mg, 0.395mmol) adds 2mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 2mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 6 hours at 120 DEG C.LCMS shows starting raw material completely consumed.Then by reaction mixture with diluted ethyl acetate (10mL), and to wash twice with salt solution (2mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by p-TLC purifying, obtains required compound 222 (6mg, yield: 24%).
LCMS:m/z,325.2(M+H)
+；
1HNMR:(CDCl
3,400MHz):8.54(d,J＝3.6,1H),7.61～7.65(m,1H),7.43(d,J＝8.0,1H),7.21～7.24(m,1H),7.06(t,J＝8.2,1H),6.23(dd,J
1＝2.0,J
2＝8.0,1H),6.09(dd,J
1＝2.2,J
2＝8.2,1H),6.04(t,J＝2.4,1H),4.45～4.51(m,1H),3.80(s,1H),3.74(s,1H),3.42～3.50(m,2H),2.55～2.65(m,1H),2.36～2.53(m,1H),1.27(t,J＝4.8,6H)。
Embodiment compound 223
The preparation of compound 223:
Experimental section:
The preparation process of 3:
Compound 1 (500mg, 3.68mmol) is dissolved in (10mL) in anhydrous THF.Solution is cooled to-78.0 DEG C, and drips n-BuLi solution (in hexane 2.5M, 2.2mL, 5.52mmol)).Reaction mixture is stirred 1 hour at-78 DEG C.Then the compound 2 (1.06g, 5.33mmol) in 2mLTHF is added.Mixture is stirred 1 hour at the same temperature.Saturated NH is used in reaction
4the quencher of Cl solution, then uses EtOAc (2 × 10mL) to extract.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes it pass through preparation TLC purifying, obtains required compound (450mg, yield: 37%).
The preparation process of 4:
Compound 1 (321mg, 1mmol) is dissolved in anhydrous methylene chloride (15mL).Solution is cooled to-78 DEG C and adds DAST (322mg, 2mmol).Reaction mixture is stirred 30 minutes at-78 DEG C and rises to room temperature.After water quencher, solution extracted with EtOAc (2 × 15mL).The organic layer merged is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes its purifying (using EA/PE wash-out, 1/10, v/v) by silicagel column, obtains required compound (150mg, yield: 46%).
The preparation process of 5:
TFA (1ml) is dripped to 1 (150mg, 0.46mmol) in anhydrous methylene chloride (5ml) at 0 DEG C.Then reaction mixture is condensed into residue at stirring at room temperature 2h.Then saturated aqueous Na is used
2cO
3process this residue, until pH=10, and with dichloromethane extraction (50mL × 10).The organic layer merged is through anhydrous Na
2sO
4drying, filters and concentrates, and obtains required product (50mg, yield: 48%).
The preparation process of compound 223:
To 1 (23mg, 0.1mmol), 2 (34mg, 0.15mmol) and Cs
2cO
3dMF (1mL) solution of (98mg, 0.3mmol) adds 6mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 6mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 100 DEG C under a nitrogen.LCMS shows starting raw material completely consumed.Then reaction mixture diluted ethyl acetate (20mL) is washed three times with salt solution (10mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by preparation TLC purifying, obtains title compound (10mg, yield: 31%).
LCMS:m/z,265.1(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.42～2.69(m,1H),2.75～2.77(m,1H),3.56～3.60(m,2H),3.75～3.90(m,2H),6.52～6.56(m,1H),7.26～7.31(m,1H),7.26～7.38(m,2H),7.48～7.49(m,1H),7.81～7.83(m,1H),7.87～7.88(m,1H)。
Embodiment compound 224
The preparation of compound 224:
The preparation process of 2:
Compound 1 (500mg, 2.7mmol) is diluted with anhydrous MeOH (15ml) and adds the PPTS (10mgg) of catalytic amount.Reaction mixture is stirred 1h and then uses dchloromethane, and use saturated NaHCO
3solution-treated.Separating layer, water layer is with dichloromethane extraction (2 × 15ml).The organic moiety merged is through Na
2sO
4drying, filters and vacuum concentration, obtains title product (500mg, 79%).
The preparation process of 3:
MeOH (15ml) solution under a nitrogen to 2 (500mg, 1.89mol) adds Pd/C (15mg).Make suspension degassed under vacuo and with hydrogen purge for several times, by mixture under hydrogen balloon stirring at room temperature 3 hours.Filtered through celite pad by suspension, filter cake MeOH (10mL) washs.The filtrate of merging is concentrated into drying, obtains product (180mg, 72%).
The preparation process of 5:
To 3 (131mg, 1mmol), 4 (304mg, 1.5mmol) and Cs
2cO
3dMF (5mL) solution of (980mg, 3mmol) adds 60mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 60mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.By mixture in 120 DEG C at N
2stir 3 hours.LCMS shows starting raw material completely consumed.Then reaction mixture diluted ethyl acetate (20mL) is washed three times with salt solution (10mL).Organic solution is through anhydrous Na
2sO
4drying, filters, and concentrating under reduced pressure also by preparation TLC purifying, obtains title compound (50mg, yield: 24%).
The preparation process of 5:
TFA (1mL) is dripped at 0 DEG C of anhydrous methylene chloride to 1 (80mg, 0.39mmol) (3ml) solution.Then reaction mixture is condensed into residue at stirring at room temperature 2h.Then saturated aqueous Na is used
2cO
3process this residue, until pH=10, and with dichloromethane extraction (50mL × 10).The organic layer merged is through anhydrous Na
2sO
4drying, filters and concentrates, and obtains required product (30mg, yield: 48%).
The preparation process of compound 224:
Compound 1 (24mg, 0.24mmol) is dissolved in anhydrous THF (5mL).Solution is cooled to-78 DEG C, and drips n-BuLi solution (in hexane 2.5M, 0.12ml, 0.29mmol)).Reaction mixture is stirred 1 hour at-78 DEG C.Then the compound 2 (30mg, 0.19mmol) in 2mLTHF is added.Mixture is stirred 1 hour at the same temperature.Saturated NH is used in reaction
4the quencher of Cl solution, then uses EtOAc (2 × 10mL) to extract.The organic layer be separated is through anhydrous Na
2sO
4drying, filters and is concentrated into drying, makes it pass through preparation TLC purifying, obtains required compound (15mg, yield: 27%)
LCMS:m/z,319.0(M+H)
+；
1HNMR(400MHz,CDCl
3):δ2.43～2.54(m,2H),3.50～3.66(m,4H),3.79～3.82(m,1H),6.55～6.69(m,2H),6.71～6.73(m,1H),7.22～7.27(m,3H),7.44～7.6(m,1H),7.65～7.69(m,1H),8.57～8.58(m,1H)。
Embodiment compound 225
The preparation process of compound 225:
To 1 (30mg, 0.157mmol), 2 (81mg, 0.315mmol) and Cs
2cO
3dMF (2mL) solution of (256mg, 0.785mmol) adds 1mgPd (dba)
2and two diphenylphosphine-9, the 9-dimethyl xanthene of 1mg4,5-.By suspension degassed under vacuo and with nitrogen purge for several times.Mixture is stirred 1 hour at 120 DEG C.React by adding water quencher and being extracted with ethyl acetate.The organic phase washed with water merged, salt water washing, through anhydrous Na
2sO
4drying is also concentrated into drying.Residue, through preparation TLC purifying, obtains title compound 225 (8.52mg, yield: 17.9%).
LCMS:m/z,319.1(M+H)
+；
1HNMR(d-CDCl
3,400MHz):δ8.55～8.56(m,1H),7.62～7.66(m,1H),7.43～7.46(m,1H),7.22～7.25(m,1H),6.85～6.88(m,1H),6.70～6.83(m,1H),6.46～6.50(m,1H),3.82～4.16(m,2H),3.59～3.66(m,1H),3.49～3.54(m,1H),2.34～2.63(m,2H)。
Embodiment compound 226
The preparation process of compound 226:
By compound 1 (15mg, 0.07mmol), 2 (14mg, 0.07mmol), 4,5-two diphenylphosphine-9,9-dimethyl xanthene (12mg, 0.021mmol) and CsCO
3(137mg, 0.42mmol) mixture in DMF (5mL) degassed 3 times under a nitrogen, then under a nitrogen by Pd (dba)
3(6mg, 0.007mmol) adds in mixture.Reaction mixture is heated at 100 DEG C and stirs 2 hours under a nitrogen.Reaction mixture is checked it by LCMS after being cooled to room temperature.Mixture H
2o (5mL) and EA (5mL) distributes.Dry organic phase, concentrate and pass through to prepare TLC purifying, obtaining product needed for 3mg (15%), purity 97%.
LCMS:m/z,292.1(M+H)
+；
1HNMR(CDCl
3,400MHz):δ7.52(m,1H),7.40(m,1H),7.30(m,1H),7.20(m,3H),6.96(s,1H),6.75(m,1H),6.45(m,2H),4.25(m,4H)。
Embodiment 8
Function calcium throughput assay (FunctionalCalciumCluxAssayMethodology)
About functional profile, the HEK293 cell of the mouse mGluR5 that recombinated by stably express to be inoculated in 384-orifice plate and to utilize Fluo-8 to load dyestuff.Then washed cell is to remove unblended dyestuff.Test compounds incubation is carried out antagonist evaluation after 15 minutes, adds the L-glutamic acid of time peak concentration afterwards.Fluorescent agent Imaging Plate Reader (FLIPR, MolecularDevices) is utilized to carry out cellular calcium ([Ca
2+]
i) measure.[the Ca of L-glutamic acid when test compounds is existed-bring out
2+]
iincrease and corresponding the comparing to independent L-glutamic acid (positive control).Utilize iterative non linear curve fitting algorithm, make antagonist suppress curve and provide IC
50the 4-parameter logistic equation matching of value and Hill coefficient.
Following table provides the data of the IC50 in this mensuration.In activity row, A=IC
50>1,000 and≤5,000nM; B=IC
50>500 and≤1,000nM, C=IC
50≤ 500nM.
Table 1
Table 2
Embodiment 9
Utilize the radioligand-binding assay of the film preparation thing of expressing mouse mGluR5
Utilize radiolabeled isomery antagonist [
3h]-2-methyl-6-(phenylene-ethynylene) pyridine (MPEP, the interactional ability in the MPEP site AmericanRadiolabeledChemical) on evaluation test compound and mGluR5, as described in [MolPharmacol78:1105-1123,2010] such as Rodriguez.Film preparation is from the HEK293 cell of expressing mouse mGluR5.Containing buffer reagent (15mMTrispH7.4,120mMNaCl, 100mMKCl, 25mMMgCl
2, 25mMCaCl
2) 96-orifice plate (Corning) in carry out radioligand-binding assay, it is final that to measure volume be 250 μ L and 40 μ g film/holes.
By increase 12 concentration [
3h]-MPEP (0.1-100nM) exist under carry out incubation to measure saturation isotherm, and utilize fixed concentration (4nM) [
3h] test compounds (1-30,000nM) that increases 12 concentration of-MPEP is at war with under existing test.Incubation carries out 1 hour at 4 DEG C.100 μMs of MTEP are utilized to assess non-specific binding.At the end of incubation, at room temperature make membrane filtration 2 hours through the GF/C filter plate (PerkinElmer) of pre-soaking in 0.1%BSA.Then use ice-cold buffer (15mMTris, pH7.4 add 0.1%BSA) to utilize PackardFiltermateHarvester that filter plate is washed 5 times, and in 37 DEG C of baking ovens dried overnight.50 μ Lmicroscint20 (PerkinElmer) are added in each hole, and by plate orbital shaker incubation 15 minutes, counts on MicrobetaTrilux afterwards, 2min/ hole.
Should be understood that and the invention is not restricted to the specific embodiment of the present invention recited above, because can carry out the change of described embodiment, and it still falls within the scope of claims.
Claims (16)
1. the compound of formula I:
Or its pharmacologically acceptable salt,
Wherein:
X is-F ,-Cl ,-CN, CF
3,-OH or-O-CH
3;
R
1be the heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl that to be selected from N, O and S containing 1-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-O-CF
3,-S (CH
3) ,-O-alkyl ,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl ,-S (O
2)-aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O) Heterocyclylalkyl, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace, or
5-10 unit monocycle or bicyclic aryl, wherein this 5-10 unit's monocycle or bicyclic aryl are independently selected from following 1-3 substituting group selectivity and are replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-O-alkyl ,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace;
R
2it is alkyloyl; Aromatic yl silane terephthalamide yl; Aryl sulfonyl; Heteroarylsulfonyl; Carbalkoxy; Aryl alkyl carbonyl oxygen; Or
Independently be selected from heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl of N, O and S containing 0-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces, or
5-10 unit monocycle or bicyclic aryl, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces;
R
3be-H, or by the alkyl that selectivity replaces, wherein alkyl is optionally containing N, O or S heteroatoms;
A is 0 or 1.
2. structure according to claim 1 is the compound of Ia, wherein:
Or its pharmacologically acceptable salt,
Wherein:
X is-F ,-Cl ,-CN, CF
3,-OH or-O-CH
3;
R
1be the heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl that to be selected from N, O and S containing 1-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-O-CF
3,-S (CH
3) ,-O-alkyl ,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl ,-S (O
2)-aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O) Heterocyclylalkyl, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace, or
5-10 unit monocycle or bicyclic aryl, wherein this 5-10 unit's monocycle or bicyclic aryl are independently selected from following 1-3 substituting group selectivity and are replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-O-alkyl ,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace;
R
2it is alkyloyl; Aromatic yl silane terephthalamide yl; Aryl sulfonyl; Heteroarylsulfonyl; Carbalkoxy; Aryl alkyl carbonyl oxygen; Or
Independently be selected from heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl of N, O and S containing 0-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces, or
5-10 unit monocycle or bicyclic aryl, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces;
R
3be-H, or by the alkyl that selectivity replaces, wherein alkyl is optionally containing N, O or S heteroatoms.
3. compound or pharmaceutically acceptable salt thereof according to claim 2, wherein:
X is-F ,-Cl ,-OH or-O-CH
3;
R
1be selected from the substituted or unsubstituted ring in following list:
R
4for-H or low alkyl group,
R
2for being independently selected from heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl of N, O and S containing 0-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement the wherein said substituting group of low alkyl group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces, or
5-10 unit monocycle or bicyclic aryl, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl or replacement low alkyl group, wherein said substituting group can in conjunction with forming the 5-7 unit's fused iso or heterocycle that selectivity replaces;
R
3be-H, or by the alkyl that selectivity replaces, wherein alkyl is optionally containing N, O or S heteroatoms.
4. compound or pharmaceutically acceptable salt thereof according to claim 3, wherein: R
1it is the 2-pyridyl of 2-pyridyl or replacement; X is F ,-OH or-O-CH
3; R
2optionally monosubstituted or dibasic monocycle or aryl bicyclic, or optionally monosubstituted or dibasic monocycle or bicyclic heteroaryl,
R
3h.
5. the compound of structure I b according to claim 1,
Or its pharmacologically acceptable salt,
Wherein:
X is-F ,-Cl ,-OH or-O-CH
3;
R
1be selected from the ring not replacing or replace in following list:
R
4for-H or low alkyl group
R
2for being independently selected from heteroatomic 5-10 unit's monocycle or the bicyclic heteroaryl of N, O and S containing 0-3, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl, or the low alkyl group replaced, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace, or;
5-10 unit monocycle or bicyclic aryl, wherein 5-10 ring system is independently selected from following 1-3 substituting group selectivity and is replaced: alkyl ,-F ,-Cl ,-Br ,-OH ,-CN, nitro, alkoxyl group ,-CF
3,-OCF
3,-S (CH
3) ,-OCH
3,-S-alkyl ,-S (O)-alkyl ,-S (O
2)-alkyl, S (O
2) aryl ,-CH
2-aryl, heteroaryl, alkyloyl ,-O-aryl ,-O-CH
2-aryl ,-N (CH
3)
2, cycloalkyl, Heterocyclylalkyl ,-C (O) cycloalkyl ,-C (O)-Heterocyclylalkyl, or the low alkyl group replaced, wherein said substituting group can in conjunction with the 5-7 unit fused iso or heterocycle forming selectivity and replace;
R
3-H.
6. compound or pharmaceutically acceptable salt thereof according to claim 5, wherein: R
1it is the 2-pyridyl of 2-pyridyl or replacement; X is F ,-OH or-O-CH
3; R
2optionally monosubstituted or dibasic monocycle or aryl bicyclic, or optionally monosubstituted or dibasic monocycle or bicyclic heteroaryl.
7. compound according to claim 6 or or its pharmacologically acceptable salt, wherein R
1it is the 2-pyridyl of 2-pyridyl or replacement.
8. compound according to claim 1 or or its pharmacologically acceptable salt, wherein said compound is:
2-((the fluoro-1-Phenylpyrrolidine of 3--3-base) ethynyl) pyridine,
2-((1-(3-chloro-phenyl-)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
The fluoro-5-of 3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) benzonitrile,
2-((1-(3,4-difluorophenyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((1-(4-chloro-phenyl-)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((the fluoro-1-of 3-(naphthalene-1-base)-pyrrolidin-3-yl) ethynyl) pyridine,
2-((the fluoro-1-of 3-(naphthalene-2-base)-pyrrolidin-3-yl) ethynyl) pyridine,
2-((the fluoro-1-of 3-(pyridin-3-yl) pyrrolidin-3-yl) ethynyl) pyridine,
6-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) quinolone,
2-((the fluoro-1-of 3-(pyridine-2-base) pyrrolidin-3-yl) ethynyl) pyridine,
2-((1-(3,4-dichlorophenyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((1-(3,5-dichlorophenyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((1-(3,5-difluorophenyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
The fluoro-5-of 3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) pyridine,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) benzonitrile,
2-((the fluoro-1-of 3-(3-fluorophenyl) pyrrolidin-3-yl) ethynyl) pyridine,
2-((the fluoro-1-of 3-(3-methoxyphenyl) pyrrolidin-3-yl) ethynyl) pyridine,
2-((the fluoro-1-of 3-(the fluoro-5-nitrophenyl of 3-) pyrrolidin-3-yl) ethynyl) pyridine,
2-((the fluoro-1-of 3-(3-(trifluoromethyl) phenyl) pyrrolidin-3-yl) ethynyl) pyridine,
2-((1-(2-chloro-phenyl-)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((the fluoro-1-of 3-(tolyl) pyrrolidin-3-yl) ethynyl) pyridine,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) aniline,
2-((1-(3-benzyl phenyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((1-([1,1'-biphenyl]-3-base)--3-fluoropyrrolidine-3-base) ethynyl) pyridine,
The fluoro-4-of 2-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) benzonitrile,
2-((the fluoro-1-of 3-(4-fluorophenyl) pyrrolidin-3-yl) ethynyl) pyridine,
The fluoro-2-of 4-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) benzonitrile,
2-((the fluoro-1-of 3-(2-fluorophenyl) pyrrolidin-3-yl) ethynyl) pyridine,
2-((1-([1,1'-biphenyl]-4-base)--3-fluoropyrrolidine-3-base) ethynyl) pyridine,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl)-5-methoxypyridine,
2-((1-(2,6-difluorophenyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((1-(the chloro-4-fluorophenyl of 2-)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
The fluoro-6-of 2-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) benzonitrile,
The chloro-5-of 3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) pyridine,
2-((1-(2,5-difluorophenyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((the fluoro-1-of 3-(3-isopropyl phenyl) pyrrolidin-3-yl) ethynyl) pyridine,
2-((1-(3-(tertiary butyl) phenyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((the fluoro-1-of 3-(3-isopropyl phenyl) pyrrolidin-3-yl) ethynyl) pyridine,
The fluoro-4-of 3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) pyridine,
2-((1-(the chloro-2-fluorophenyl of 3-)-3-fluoropyrrolidine-3-base) ethynyl) pyridine,
2-((the fluoro-1-of 3-(3-(trifluoromethoxy) phenyl) pyrrolidin-3-yl) ethynyl) pyridine.
9. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is:
The fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) tetramethyleneimine-1-t-butyl formate,
The fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) tetramethyleneimine-1-benzyl formate,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) benzamide,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) benzsulfamide,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) methyl benzoate,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl)-N, N-dimethyl benzamide,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl)-N-methyl-benzamide,
The fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) tetramethyleneimine-1-ethyl formate,
The fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) tetramethyleneimine-1-butyl formate,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl)-N-phenylbenzamaide,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) phenol benzoate.
10. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein said compound is:
2-((3-fluoro-1-tosyl group pyrrolidin-3-yl) ethynyl) pyridine,
2-((the fluoro-1-of 3-(benzene sulfonyl) pyrrolidin-3-yl) ethynyl) pyridine,
2-((1-((3-chloro-phenyl-) sulphonyl)-3-fluoropyrrolidine-3-base) ethynyl) pyridine.
11. compound or pharmaceutically acceptable salt thereofs according to claim 1, wherein said compound is:
1-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl)-2-methyl-prop-1-ketone,
1-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl)-2,2-dimethyl propylene-1-ketone,
1-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl) penta-1-ketone,
1-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl)-4-methylpent-1-ketone,
1-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) pyrrolidin-1-yl)-2-Phenyl ethyl ketone,
2-((3-fluoro-1-styroyl pyrrolidin-3-yl) ethynyl) pyridine,
2-((1-benzyl-3-fluoropyrrolidine-3-base) ethynyl) pyridine.
12. compound or pharmaceutically acceptable salt thereofs according to claim 1, wherein said compound is:
2-((3-fluoro-1-phenyl azetidine alkane-3-base)-ethynyl) pyridine,
2-((1-(4-chloro-phenyl-)-3-fluorine azetidine-3-base) ethynyl) pyridine,
3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) azetidine-1-base)-benzonitrile,
2-((the fluoro-1-of 3-(3-fluorophenyl) azetidine-3-base)-ethynyl) pyridine,
2-((1-(3-chloro-phenyl-)-3-fluorine azetidine-3-base) ethynyl) pyridine,
2-((1-(2-chloro-phenyl-)-3-fluorine azetidine-3-base) ethynyl) pyridine,
2-((the fluoro-1-of 3-(3-nitrophenyl) azetidine-3-base)-ethynyl) pyridine,
The fluoro-5-of 3-(the fluoro-3-of 3-(pyridine-2-ethyl-acetylene base) azetidine-1-base)-benzonitrile,
2-((the fluoro-1-of 3-(3-(trifluoromethoxy) phenyl) azetidine-3-base)-ethynyl) pyridine,
2-((the fluoro-1-of 3-(3-(trifluoromethyl) phenyl) azetidine-3-base)-ethynyl) pyridine,
2-((the fluoro-1-of 3-(tolyl) azetidine-3-base)-ethynyl) pyridine,
2-((the fluoro-1-of 3-(3-methoxyphenyl) azetidine-3-base)-ethynyl) pyridine,
2-((1-(3,5-dichlorophenyl)-3-fluorine azetidine-3-base) ethynyl) pyridine,
2-((1-(3,4-dichlorophenyl)-3-fluorine azetidine-3-base) ethynyl) pyridine,
2-((the fluoro-1-of 3-(the fluoro-5-nitrophenyl of 3-) azetidine-3-base)-ethynyl) pyridine,
2-((1-(3-chloro-phenyl-)-3-fluorine azetidine-3-base) ethynyl)-5-picoline,
2-((1-(3-chloro-phenyl-)-3-fluorine azetidine-3-base) ethynyl)-4-picoline,
3-(cumarone-2-ethyl-acetylene base)-1-(3-chloro-phenyl-)-3-fluorine azetidine.
13. compound or pharmaceutically acceptable salt thereofs as claimed in claim 1 are as the purposes of medicine.
14. compound or pharmaceutically acceptable salt thereofs as claimed in claim 1 are preventing, treating or are delaying in digestive tube, urethra or central nervous system wholly or in part by the purposes in the abnormal relevant disease progression of mGluR5 receptor-mediated L-glutamic acid signal transmission.
15. 1 kinds of pharmaceutical compositions, it comprises compound or pharmaceutically acceptable salt thereof as claimed in claim 1 and pharmaceutically acceptable carrier or thinner.
16. 1 kinds of treatments are to the abnormal relevant illness of L-glutamic acid signal transmission and partially or completely by the method for the receptor-mediated neurological conditions of mGluR5, and described method comprises the compound or pharmaceutically acceptable salt thereof as claimed in claim 1 using effective therapeutic dose to this type of object for the treatment of of needs.
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| Application Number | Priority Date | Filing Date | Title |
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| PCT/CN2013/071644 WO2014124560A1 (en) | 2013-02-18 | 2013-02-18 | Mglur regulators |
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| CN105121424A true CN105121424A (en) | 2015-12-02 |
| CN105121424B CN105121424B (en) | 2019-01-22 |
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| CN201380073290.6A Active CN105121424B (en) | 2013-02-18 | 2013-02-18 | MGluR regulator |
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| CN (1) | CN105121424B (en) |
| WO (1) | WO2014124560A1 (en) |
Cited By (1)
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| WO2017117708A1 (en) * | 2016-01-05 | 2017-07-13 | Hua Medicine (Shanghai) Ltd. | Pyrazole derivatives |
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| KR20180026438A (en) | 2015-07-15 | 2018-03-12 | 에프. 호프만-라 로슈 아게 | Ethynyl derivatives as metabotropic glutamate receptor modulators |
| CN106632243B (en) * | 2015-10-28 | 2019-03-15 | 华领医药技术（上海）有限公司 | Pyrrolidin derivatives |
| MX2019000442A (en) | 2016-07-18 | 2019-06-20 | Hoffmann La Roche | Ethynyl derivatives. |
| MX2020007342A (en) | 2018-01-09 | 2020-09-09 | Basf Se | Silylethynyl hetaryl compounds as nitrification inhibitors. |
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| CN101163662A (en) * | 2005-04-25 | 2008-04-16 | 诺瓦提斯公司 | Phenylacetylene derivatives having mglur5 receptor affinity |
| CN101287726A (en) * | 2005-02-22 | 2008-10-15 | 诺瓦提斯公司 | Pyrrolidine and piperidine acetylene derivatives for use as MGLUR5 antagonists |
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| WO2017117708A1 (en) * | 2016-01-05 | 2017-07-13 | Hua Medicine (Shanghai) Ltd. | Pyrazole derivatives |
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| WO2014124560A1 (en) | 2014-08-21 |
| CN105121424B (en) | 2019-01-22 |
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