CN1845918A - Pyrimidines useful as modulators of voltage-gated ion channels - Google Patents

Pyrimidines useful as modulators of voltage-gated ion channels Download PDF

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CN1845918A
CN1845918A CN 200480025027 CN200480025027A CN1845918A CN 1845918 A CN1845918 A CN 1845918A CN 200480025027 CN200480025027 CN 200480025027 CN 200480025027 A CN200480025027 A CN 200480025027A CN 1845918 A CN1845918 A CN 1845918A
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D·M·威尔逊
E·马丁伯拉夫
T·D·纽伯特
A·P·泰尔民
J·E·冈萨雷斯三世
N·齐默尔曼
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Abstract

The present invention relates to compounds of formula (I) useful as inhibitors of voltage-gated ion channels for the treatment of pain. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Description

The pyrimidine of useful as modulators of voltage-gated ion channels
Technical field
The present invention relates to can be used as the compound of the inhibitor of voltage-gated sodium channels and calcium channel.The present invention also provides pharmaceutically acceptable composition that comprises The compounds of this invention and the method for using the various obstacles of these combination treatments.
Background technology
The Na passage is the core that all excitable cells produce action potential, for example neurone and myocyte.They play the part of pivotal player in excitable tissue, comprise brain, gastrointestinal smooth muscle, skeletal muscle, peripheral nervous system, spinal cord and air flue.Therefore, they play the part of pivotal player in various disease states, for example epilepsy ( Referring to, Moulard, B. and D.Bertrand (2002) " Epilepsy and sodium channel blockers " Expert Opin.Ther. Patents12 (1): 85-91)), pain ( Referring to, Waxman, S.G., S.Dib-Hajj waits people (1999) " Sodium channels and pain " Proc Natl Acad Sci U S A96 (14): 7635-9 and Waxman, S.G., T.R.Cummins waits people (2000) " Voltage-gated sodium channels and the molecular pathogenesisof pain:a review " J Rehabil Res Dev37 (5): 517-28), myotony ( Referring to, Meola, G. and V.Sansone (2000) " Therapy in myotonicdisorders and in muscle channelopathies " Neurol Sci21 (5): S953-61 and Mankodi, A. and C.A.Thornton (2002) " Myotonicsyndromes " Curr Opin Neurol15 (5): 545-52), ataxia ( Referring to, Meisler, M.H., J.A.Kearney waits people (2002) " Mutations ofvoltage-gated sodium channels in movement disorders andepilepsy " Novartis Found Symp241:72-81), multiple sclerosis ( Referring toBlack, J.A., S.Dib-Hajj waits people (2000) " Sensoryneuron-specific sodium channel SNS is abnormally expressed inthe brains of mice with experimental allergic encephalomyelitisand humans with multiple sclerosis " Proc Natl Acad Sci U S A97 (21): 11598-602, and Renganathan, M., M.Gelderblom waits people (2003) " Expression of Na (v) 1.8 sodium channels perturbs thefiring patterns of cerebellar purkinje cells " Brain Res959 (2): 235-42), intestines easily swash ( Referring to, Su, X., R.E.Wachtel waits people (1999) " Capsaicin sensitivity and voltage-gated sodium currents incolon sensory neurons from rat dorsal root ganglia " Am J Physiol277 (6Pt1): G1180-8, and Laird, J.M., V.Souslova waits people (2002) " Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice " J Neurosci22 (19): 8352-6), the urinary incontinence and visceral pain ( Referring to, Yoshimura, N., S.Seki waits people (2001) " Theinvolvement of the tetrodotoxin-resistant sodium channelNa (v) 1.8 (PN3/SNS) in a rat model of visceral pain " J Neurosci21 (21): 8690-6), and a series of psychiatric function obstacle, for example anxiety and depression ( Ginseng See, Hurley, S.C. (2002) " Lamotrigine update and its use in mooddisorders " Ann Pharmacother36 (5): 860-73).
Voltage-gated Na passage comprises the gene family of being made up of 9 kinds of different hypotypes (NaV1.1-NaV1.9).As shown in table 1, these hypotype display organization specific localization effects and function difference ( Referring to, Goldin, A.L. (2001) " Resurgence of sodium channelresearch " Annu Rev Physiol63:871-94).This gene family has three kinds of members (NaV1.8,1.9,1.5) to tolerate in the Na channel blocker TTX that is known to block, prove in this gene family to have hypospecificity.Mutation analysis differentiated L-glutamic acid 387 be the decisive residue of TTX bonded ( Referring to, Noda, M., H.Suzuki waits people (1989) " Asingle point mutation confers tetrodotoxin and saxitoxininsensitivity on the sodium channel II " FEBS Lett259 (1): 213-6).
Table 1 (abbreviation: CNS=central nervous system, PNS=peripheral nervous system, DRG=dorsal root ganglion, TG=gasserian ganglion):
The Na isoform Tissue TTX IC50 Indication
NaV1.1 CNS, PNS neurone body 10nM Pain, epilepsy, neurodegeneration
NaV1.2 CNS concentrates in the aixs cylinder 10nM Neurodegeneration, epilepsy
NaV1.3 CNS, embryo, injured nerve 15nM Pain
NaV1.4 Skeletal muscle 25nM Myotony
NaV1.5 Heart 2μM Irregular pulse, QT prolongs
NaV1.6 Spread all over CNS, the abundantest 6nM Pain, dyskinesia
NaV1.7 PNS, DRG, neuroendocrine end 25nM Pain, the neuroendocrine obstacle
NaV1.8 PNS, the small neuron among the DRG ﹠ TG ＞50μM Pain
NaV1.9 PNS, the small neuron among the DRG ﹠ TG 1μM Pain
Generally speaking, voltage-gated sodium channels (NaV) be responsible for to cause the rapid lifting of neural system excitable tissue action potential, this transmission electrical signal normal and unusual pain perception of writing and encode.The antagonist of NaV passage can weaken these pain signals, can be used for treating multiple antalgesic, includes but not limited to acute, chronic, inflammatory and neuropathic pain.Known NaV antagonist, for example TTX, lignocaine ( Referring to, Mao, J. and L.L.Chen (2000) " Systemic lidocaine for neuropathic PainRelief " Pain 87 (1): 7-17), bupivacaine, Phenytoin Sodium Salt ( Referring to, Jensen, T.S. (2002) " Anticonvulsants in neuropathic pain:rationale and clinicalevidence " Eur J Pain6 (Suppl A): 61-8), lamotrigine ( Referring to, Rozen, T.D. (2001) " Antiepileptic drugs in the management of clusterheada che and trigeminal neuralgia " Headache41 Suppl 1:S25-32 and Jensen, T.S. (2002) " Anticonvulsants in neuropathic pain:rationale and clinical evidence " Eur J Pain6 (Suppl A): 61-8) and Carbamzepine ( Referring to, Backonja, M.M. (2002) " Use of anticonvulsantsfor treatment of neuropathic pain " Neurology59 (5 Suppl 2): S14-7), shown the pain that can be used for weakening the humans and animals model.
The hyperpathia that forms in the presence of tissue injury or inflammation (extremely responsive to certain pain) has reflected on the part degree that at least the excitability of the main afferent neuron of high threshold of domination damage location increases.The activation of voltage sensitivity sodium channel is conclusive for the generation and the propagation of neuron operation current potential.More and more evidences shows, the regulation and control of NaV electric current be the inherent mechanism that is used to control neuronal excitability ( Referring to, Goldin, A.L. (2001) " Resurgence of sodium channel research " Annu Rev Physiol63:871-94).In dorsal root ganglion (DRG) neurone, find to have some kinetics voltage-gated sodium channels different with pharmacology.TTX-tolerance electric current is insensitive to the tetraodotoxin of micro-molar concentration, and compares with other voltage-gated sodium channels, shows the depolarize activation threshold of activation slowly and deactivation kinetics and Geng Gao.TTX-tolerance sodium current mainly is subjected to relating to the restriction of the Sensory neurone subgroup of nociception.Particularly, TTX-tolerance sodium current is almost only expressed in the little neurone of cell paste diameter; Cause aixs cylinder minor diameter, that conduct slowly, and capsicine is had response.A large amount of experimental evidences prove that TTX-tolerance sodium channel is expressed on the C-fiber, play a significant role in the information transmission of experiencing the spinal cord injury.
The intrathecal drug delivery of target antisense widow-deoxynucleotide in unique zone (NaV1.8) in TTX-tolerance sodium channel causes PGE 2The hyperalgesic remarkable minimizing of-inductive ( Referring to, Khasar, S.G., M.S.Gold waits people (1998) " A tetrodotoxin-resistant sodiumcurrent mediates inflammatory pain in the rat " Neurosci Lett256 (1): 17-20).Recently, Wood and colleague have created a kind of rejecting mouse system, and it lacks functional NaV1.8.In the assessment test of animal to the response of proinflammatory agent carrageenin, this sudden change have the analgesia effect ( Referring to, Akopian, A.N., V.Souslova waits people (1999) " The tetrodotoxin-resistant sodium channel SNS has aspecialized function in pain pathways " Nat Neurosci2 (6): 541-8).In addition, in these animals, observe the defective of machinery and temperature sensation.Rejecting the shown analgesia of mutant by NaV1.8 is consistent with observations about the role of TTX-tolerance electric current in nociception.
Immunohistochemistry, hybridization and external electrophysiology experiment all show on the spot, sodium channel NaV1.8 optionally be positioned dorsal root ganglion and gasserian ganglion little Sensory neurone ( Ginseng See, Akopian, A.N., L.Sivilotti waits people (1996) " A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensoryneurons " Nature379 (6562): 257-62).These neuronic dominant roles are detection and transmission that nociception stimulates.Antisense and immunohistochemistry evidence also supported the role of NaV1.8 in neuropathic pain ( Referring to, Lai, J., M.S.Gold waits people (2002) " Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, NaV1.8 " Pain95 (1-2): 143-52, and Lai, J., J.C.Hunter waits people (2000) " Blockadeof neuropathic pain by antisense targeting oftetrodotoxin-resistant sodium channels in sensory neurons " Methods Enzymol314:201-13).NaV1.8 albumen along the not damage C-fiber adjacent with nerve injury by incremental adjustments.Antisense is handled the again distribution of prevention NaV1.8 along nerve, reverses neuropathic pain.Comprehensive gene-rejecting and antisense data have supported NaV1.8 the detection of inflammatory and neuropathic pain and the role in the transmission.
In the neuropathic pain state, there is the transformation of distribution of Na passage and hypotype.In impaired nerve, the expression of NaV1.8 and NaV1.9 has significantly reduced, and the expression of the TTX susceptibility NaV1.3 of subunit by incremental adjustments 5-10 doubly ( Referring to, Dib-Hajj, S.D., J.Fjell waits people (1999) " Plasticity of sodium channel expression inDRG neurons in the chronic constriction injury model ofneuropathic pain. " Pain83 (3): 591-600).In the animal model after nerve injury, the time course that NaV1.3 increases is parallel to the appearance of allodynia.The biophysical peculiar part of NaV1.3 is to show very fast guiding again after the inactivation behind action potential.This produces the height that continues and provides speed, in impaired nerve, often see ( Referring toCummins, T.R., F.Aglieco waits people (2001) " Nav1.3sodium channels:rapid repriming and slow closed-stateinactivation display quantitative differences after expressionin a mammalian cell line and in spinal sensory neurons " J Neurosci21 (16): 5952-61).NaV1.3 is expressed in people's maincenter and peripheral-system.NaV1.9 is similar to NaV1.8, it also optionally be positioned dorsal root ganglion and gasserian ganglion little Sensory neurone ( Referring to, Fang, X., L.Djouhri waits people (2002) " The presence and role of the tetrodotoxin-resistant sodiumchannel Na (v) 1.9 (NaN) in nociceptive primary afferentneurons. " J Neurosci22 (17): 7425-33).It has the speed of inactivation slowly and the voltage-dependent that with regard to activation, moves to left ( Referring to, Dib-Hajj, S., J.A.Black waits people (2002) " NaN/Nav1.9:a sodium channel with uniqueproperties " Trends Neurosci25 (5): 253-9).These two kinds of biophysical properties allow NaV1.9 figure in setting up the neuronic resting membrane electric potential of nociception.The resting potential of ventricular cells of expressing NaV1.9 is-55 to-50mV scope, and other peripheries of great majority and axoneuron are-65mV.This persistence depolarize is owing to continue low-level NaV1.9 passage activation to a great extent.This depolarize allows the easier threshold value of providing action potential in response to nociception stimulates that reaches of neurone.The compound of retardance NaV1.9 passage can be played an important role in the set point of setting up the pain stimulation detection.In the chronic pain state, neural and nerve ending may become swelling and allergy, even to gentle or even not stimulation also show high-frequency action potential granting.The neural swelling of these pathologic are called as neuroma, the main Na passage of being expressed therein be NaV1.8 and NaV1.7 ( Referring to, Kretschmer, T., L.T.Happel waits people (2002) " Accumulation of PN1 and PN3 sodiumchannels in painful human neuroma-evidence fromimmunocytochemistry " Acta Neurochir (Wien)144 (8): 803-10; Discussion 810).NaV1.6 and NaV1.7 are also expressed in dorsal root ganglion neurons, and the little TTX-sensitive component that sees in these cells is had contribution.Except its role in the neuroendocrine excitability, NaV1.7 is special therefore also may be potential pain target ( Referring toKlugbauer, N., L.Lacinova waits people (1995) " Structure andfunctional expression of a new member of thetetrodotoxin-sensitive voltage-activated sodium channelfamily from human neuroendocrine cells " Embo J14 (6): 1084-90).
NaV1.1 ( Referring to, Sugawara, T., E.Mazaki-Miyazaki waits people (2001) " Nav1.1 mutations cause febrile seizures associated withafebrile partial seizures. " Neurology57 (4): 703-5) and NaV1.2 ( Referring toSugawara, T., Y.Tsurubuchi waits people (2001) " A missensemutation of the Na+ channel alpha II subunit gene Na (v) 1.2 ina patient with febrile and afebrile seizures causes channeldysfunction " Proc Natl Acad Sci U S A98 (11): 6384-9) be related with epilepsy, comprise hot outbreak.In NaV1.1, have more than 9 kinds transgenation relevant with hot outbreak ( Referring to, Meisler, M.H., J.A.Kearney waits people (2002) " Mutations of voltage-gated sodium channels in movementdisorders and epilepsy " Novartis Found Symp241:72-81).
Develop the NaV1.5 antagonist, be used for the treatment of irregular pulse.The genetic flaw that produces the bigger non-inactivation component of electric current among the NaV1.5 has prolonged with human QT is related, orally active local anesthetic mexiletine be used to treat this illness ( Referring to, Wang, D.W., K.Yazawa waits people (1997) " Pharmacological targeting of long QTmutant sodium channels. " J Clin Invest99 (7): 1714-20).
Have some kinds of Na channel blockers to be used at present or clinic trial in epilepsy ( Referring to, Moulard, B.and D.Bertrand (2002) " Epilepsy and sodium channelblockers " Expert Opin.Ther.Patents12 (1): 85-91); Acute ( Ginseng See, Wiffen, P., S.Collins waits people (2000) " Anticonvulsant drugsfor acute and chronic pain " Cochrane Database Syst Rev3), chronic ( Referring to, Wiffen, P., S.Collins waits people (2000) " Anticonvulsantdrugs for acute and chronic pain " Cochrane Database Syst Rev3, and Guay, D.R. (2001) " Adjunctive agents in the managementof chronic pain " Pharmacotherapy21 (9): 1070-81), inflammatory ( Referring to, Gold, M.S. (1999) " Tetrodotoxin-resistant Na+ currents andinflammatory hyperalgesia. " Proc Natl Acad Sci U S A96 (14): 7645-9) with neuropathic pain ( Referring to, Strichartz, G.R., Z.Zhou waits people (2002) " Therapeutic concentrations of local anaestheticsunveil the potential role of sodium channels in neuropathicpain " Novartis Found Symp241:189-201, and Sandner-Kiesling, A., G.Rumpold Seitlinger waits people (2002) " Lamotriginemonotherapy for control of neuralgia after nerve section " Acta Anaesthesiol Scand46 (10): 1261-4); Irregular pulse ( Referring to, An, R.H., R.Bangalore waits people (1996) " Lidocaine block of LQT-3 mutanthuman Na+ channels " Circ Res79 (1): 103-8, and Wang, D.W., K.Ya zawa waits people (1997) " Pharmacological targeting of long QTmutant sodium channels " J Clin Inyest99 (7): 1714-20); Neuroprotective ( Referring to, Taylor, C.P.and L.S.Narasimhan (1997) " Sodiumchannels and therapy of central nervous system diseases " Adv Pharmacol39:47-98) and as narcotic ( Referring to, Strichartz, G.R., Z.Zhou waits people (2002) " Therapeutic concentrations of localanaesthetics unveil the potential role of sodium channels inneuropathic pain. " Novartis Found Symp241:189-201).
Calcium channel is the protein of striding film, many subunits, allows Ca to enter from outside atmosphere, with the depolarize of cell membrane potential.The calcium channel functional character that is based on them is classified traditionally, for example low voltage or high-voltage activatory and their kinetics (L, T, N, P, Q).The ability of clone and expression calcium channel subunit has been promoted the understanding that the passage that produces these functions responses is formed.Three kinds of main type constitution calcium channel-α of subunit 1, α 2 δ and β are arranged.α 1 is a subunit of containing access opening and voltage sensor, and α 2 mainly is positioned at the extracellular, is and strides the disulphide that the film delta-subunit is connected, and β right and wrong Portugal baseization subunit combines with the cytoplasmic region of Ca passage α 1 subunit.At present, various calcium channel hypotypes it is believed that and constitute following specific subunit:
● the L-type comprises the α of subunit 1Cα 1Dα 1FOr α 1S, α 2 δ and β 3a
● the N-type comprises the α of subunit 1B, α 2 δ, β 1b
● the P-type comprises the α of subunit 1A, α 2 δ, β 4a
● the Q-type comprises the α of subunit 1A(joint variant), α 2 δ, β 4a
● the R-type comprises the α of subunit 1E, α 2 δ, β 1b
● the T-type comprises the α of subunit 1G, α 1HOr α 1I
Calcium channel is played the part of core roles in neurotransmitter discharges.Ca flows into neural presynaptic ending process binding and produces protein-protein interaction cascade (syntaxin 1A, SNAP-25 and synaptotagmin), finally ends at the fusion of synaptic vesicle and the release of neurotransmitter bag.The retardance of presynaptic calcium channel reduces the inflow of Ca, and causes cube X that neurotransmitter discharges 3Reduce.
N type Ca passage (CaV2.2) is highly expressed at the presynaptic of dorsal root ganglion nerve ending, and it is in I and II layer and posterior horn neurone generation cynapse.Along with they second and third stage neurone on form cynapse, these neurones have a large amount of N type Ca passages at their presynaptic ending then.It is very important to brain that this approach transmits pain information in minute journey.
Pain can roughly be divided into three kinds of different types: acute, inflammatory and neuropathic.Acute pain is the important defencive function of performance in keeping Biosafety not to be subjected to may producing the stimulus effects of tissue injury.If pay no heed to, some temperature, machinery or chemistry input have the potentiality that biology caused grievous injury.The acute pain performance removes the effect of individual infringement environment fast.Acute pain is because its attribute very generally is of short duration lasting and intensive.On the other hand, inflammatory pain can last much longer, and its intensity is more high-grade.Inflammation can betide multiple reason, comprises that tissue injury, autoimmunity are replied with cause of disease to invade.Inflammatory pain is subjected to the mediation of " inflammatory soup ", and it is discharged by P material, histamine, acid, prostaglandin(PG), bradykinin, CGRP, cytokine, ATP and neurotransmitter forms.The 3rd class pain is neuropathic, relates to the nervous lesion that causes neuronal protein and circuit reorganization, forms pathologic " sensitization " state, can produce the chronic pain that lasts for several years.Such pain does not provide the adaptability benefit, is to be difficult to especially with having therapy for treating now.
Pain, particularly neuropathic and intractable pain are the medical needs that is met far away.Millions of individualities suffer from serious pain, not by current therapeutical agent institute control well.The current medicine that is used for the treatment of pain comprises NSAIDS, COX2 inhibitor, OPIOIDS, tricyclic antidepressants and anticonvulsive agent.Neuropathic pain has been difficult to treat especially, because it is not to all having good response until the OPIOIDS that reaches high dosage.Gabapentin be treat at present neuropathic pain desirable therapeutical agent, but it is only effective to 60% patient, and shows the effect of appropriateness.But, this medicine is very safe, and side effect generally can tolerate, but sedative effect is a problem under high dosage more.
N type Ca passage is verified in the mankind, by infusion toxin ziconotide (Ziconotide) treatment intractable pain, cancer pain, OPIOIDS tolerance pain and neuropathic and serious pain in the sheath.The human pain of this toxitherapy has 85% success ratio, renders a service greater than morphine.Orally active N type Ca channel antagonist will be carved up the bigger pain market share.Ziconotide (Ziconotide) causes the mastocyte threshing, produces dosage-dependency maincenter side effect.They comprise dizziness, ocular ataxy, excitement and dysmetria.Under high dosage, in some patient, also there is orthostatic hypotension.The primary hazard of this target relates to takes the seen CNS side effect of Ziconotide in a large number.They comprise dizziness, ocular ataxy, excitement and dysmetria.Under high dosage, in some patient, also there is orthostatic hypotension.It is believed that this may be because Ziconotide induces mastocyte threshing and/or its to the same effect of also expressing the sympathetic ganglion of N type Ca passage of dorsal root ganglion.Preferentially purposes-dependency the compound of retardance should help to minimize these potential side-effect problems in higher frequency scope＞10Hz.The granting speed that human sympathetic nerve spreads out of is positioned at the 0.3Hz scope.The CNS neurone can be provided under high frequency, but general only like this in of short duration action potential outburst.Even have the selectivity of being given by purposes-dependency, it is necessary that the inherent selectivity of antagonism L type calcium channel also remains, because it relates to heart and vascular smooth muscle shrinks.
Unfortunately, as indicated above, the effect that is used for the sodium channel inhibitor of above-mentioned morbid state and calcium channel blocker at present is subjected to the restriction of a large amount of side effects to a great extent.These side effects comprise various CNS disorders, for example blurred vision, dizziness, nauseating and calm, and the irregular pulse of more potential threat life and heart failure.Therefore, still need to develop other Na passages and Ca channel antagonist, particularly have efficient more and those of side effect still less.
Summary of the invention
Have now found that The compounds of this invention and pharmaceutically acceptable composition thereof can be used as the inhibitor of voltage-gated sodium channels.These compounds have general formula I:
Figure A20048002502700481
Perhaps its pharmaceutically acceptable derivates, wherein R 1, R 2, R Z, R 4A is following defined with ring.
These compounds and pharmaceutically acceptable composition can be used for treating or alleviating the seriousness of multiple disease, obstacle or illness, include but not limited to acute, chronic, neuropathic or inflammatory pain, sacroiliitis, migraine, bunch headache, trigeminal neuralgia, herpetic neurodynia, popularity neurodynia, epilepsy or epilepsy, neurodegeneration obstacle, mental disorder (for example anxiety and depression), myotony, irregular pulse, dyskinesia, neuroendocrine obstacle, ataxia, multiple sclerosis, irritable bowel syndrome and incontinence.
Summary of the invention
I. the general remark of The compounds of this invention:
The present invention relates to can be used as the formula I compound of the inhibitor of voltage-gated sodium channels:
Figure A20048002502700491
Perhaps its pharmacy acceptable salt, wherein:
R ZBe-C (O) R 3,-C (O) OR 3Or R Z1
R Z1Be-C (O) N (R ') 2,-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2,-C (O) N (CN) R ', the optional substituted 1-4 of having heteroatomic 5-unit's heteroaryl ring or optional substituted pyrans-4-ketone group that is selected from O, S or N;
R 1And R 2Be hydrogen or optional substituted group independently of one another, described group is selected from C 1-6Aliphatic group, have 0-5 and independently be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur; Perhaps R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical or heteroaryl ring, wherein a R who independently is selected from nitrogen, oxygen or sulphur 1, R 2Perhaps arbitrarily by R 1And R 2The ring that is constituted is occurred for 0-4 time on one or more carbon atoms-R independently of one another alternatively together 5Replace quilt-R on one or more commutable nitrogen-atoms 6Replace;
Ring A has 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings or 8-10 unit's aryl bicyclic ring of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of 3-7 that independently is selected from nitrogen, oxygen or sulphur, alternatively on one or more carbon atoms by 0-5 appearance-R 7Replace, replace quilt-R on the nitrogen-atoms one or more 8Replace;
Each R that occurs 3, R 4, R 5And R 7Be Q-R independently XWherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, if its condition is R ZBe-OR 3, Q-R then XBy carbon atom bonding in Sauerstoffatom;
Wherein each R that occurs is independently selected from hydrogen or optional substituted C 1-6Aliphatic group; Each R ' that occurs is independently selected from hydrogen or optional substituted group, and described group is selected from C 1-8Aliphatic group, C 6-10Aryl, have the heteroaryl of 5-10 annular atoms or have the heterocyclic radical of 3-10 annular atoms, perhaps wherein R and R ' constitute with the atom of their institute's bondings with the R ' of the atom of their institute's bondings or twice appearance and have 0-3 heteroatomic 5-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl that independently is selected from nitrogen, oxygen or sulphur; With
Each R that occurs 6Or R 8Be independently R ' ,-COR ' ,-CO 2(C 1-6Aliphatic group) ,-CON (R ') 2Or-SO 2R ',
If its condition is R ZBe R 3, R then 3By the atom beyond the deoxygenation, preferably by carbon atom bonding in carbonylic carbon atom.
In some other embodiment [KG1], the wherein R of institute's general description just as here and above ZBe-R 3The compounds of this invention:
A) if ring A is unsubstituted phenyl, R 3Be methyl, and R 4Be=S or-SMe, then R 1And R 2Can not be N-morpholino base, N-pyrrolidyl or optional substituted piperazinyl together;
B) if ring A is a N-morpholino base, R 3Be H, and R 4Be Cl or Me, then R 1Be not Et, this moment R 2Be 4-Cl-phenyl, perhaps R 1And R 2Can not be N-morpholino base together;
C) if ring A is the N-pyrrolidyl, and R 3Be H, then:
I) if R 4Be-N (CH 3) COPh, then R 1And R 2Can not be pyrrolidyl together; With
Ii) if R 4Be Cl, R then 1Be not Et, this moment R 2It is the 4-Me-phenyl;
D) if ring A is the N-piperidyl, R 3Be hydrogen, and R 4Be methyl, R then 1And R 2Can not be the N-piperidyl together;
E) if ring A is optional substituted piperazinyl, R 3Be hydrogen, and R 4Be chlorine, then if R 1Be Et, R then 2Not 4-Cl-phenyl, 4-Me-phenyl or 4-F-phenyl, perhaps R 1And R 2Can not be the parathiazan base together;
F) if ring A is 2,5-dimethyl-1H-pyrroles-1-base, R 3Be hydrogen, and R 4Be OMe, then if R 1Be Me, R then 2It or not benzyl;
G) if ring A is 1-oxo bridge-4-parathiazan base, R 3Be hydrogen, and R 4Be OEt, R then 1And R 2Can not be piperazinyl together;
H) if R 3Be CH 3Or optional substituted phenyl, R 1Be hydrogen, R 2Be optional substituted phenyl, methyl, ethyl, COR ', NR ' or CONHR ', and R 4Be=S, Me, SMe or SCH 2CO 2Me, SCH 2CN, then encircling A is not unsubstituted phenyl or 4-C1-phenyl;
I) if R 3Be CH 3, R 1Be hydrogen, R 2Be ethyl, and R 4Be hydrogen, then encircling A is not N-pyrrolidyl, piperazine-1-base, N-morpholinyl or piperidino;
J) if R 3Be N (R ') 2, R 1Be hydrogen, R 2Be 3-, 5-Cl-phenyl, 4-Cl-phenyl, methyl, optional substituted cyclohexyl, 3-Cl, 4-OMe-benzyl, 4-Ac-phenyl, ethyl, sec.-propyl, 4-OEt-phenyl, 4-OMe-phenyl, benzyl or (CH 2) 2OR, and R 4Be CH 3, hydrogen or SMe, then encircling A is not unsubstituted phenyl, piperidyl, optional substituted piperazinyl, morpholinyl, optional substituted pyrrolidyl, 5,8-dihydro-1,7-naphthyridines-7 (6H)-Ji or 5,6-dihydro-8-imidazo [1,2-a] pyrazine-7-base;
K) if R 3Be-CH=CHN (CH 3) 2, CH 3,-(CH 2) 2-N-morpholino base ,-(CH 2) 2-OMe ,-(CH 2) 2-OH ,-CH 2OMe, normal-butyl, pyridine-2-ylmethyl, pyridine-2-base, pyrimidine-5-base, CH 2SO 2Me ,-(CH 2) 2-NMe 2,-(CH 2) 2-N-(4-methylpiperazine base) ,-(CH 2) 2-NH-pyridin-3-yl ,-(CH 2) 2-NH-CH 2-pyridin-3-yl, 1-methyl isophthalic acid H-imidazoles-2-base, 5-amino-1,2-dimethyl-1H-imidazol-4 yl, 4-(dimethylamino) phenyl, 3,4-(methylene-dioxy) phenyl ,-CH 2=CH 2,-CH=CH 2Or-CH (CN) COOEt, R 1Be hydrogen, R 2Be optional substituted benzyl or ethyl, R 4Be SMe or hydrogen, then encircling A is not unsubstituted phenyl or optional substituted pyrrolidyl;
L) if R 1Be hydrogen, and R 2Be hydrogen or 4,6-dimethyl pyrimidine-2-base, ring A is optional substituted phenyl, R 3Be methyl or unsubstituted phenyl, then R 4Be not SMe ,=S, Me or unsubstituted phenyl;
M) if R 1Be hydrogen, and R 2Be optional substituted benzyl, then R 3Not 3,4, the 5-trimethoxyphenyl;
N) if R 1And R 2All be hydrogen, ring A is (2-fluorophenyl methyl)-1H-pyrazolo [3,4-b] pyridin-3-yl, R 3Be ethyl or 2-ethoxyethyl group, then R 4Not hydrogen;
O) if R 1Be hydrogen, R 2Be benzoyl, R then 3, R 4A is not unsubstituted phenyl simultaneously with ring;
P) if R 1And R 2All be hydrogen, ring A is 4-(4 '-morpholinyl)-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base, 4-amino-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base, 4-(4-(4-fluorophenyl)-piperazinyl)-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base, 4-(4,6-dimethyl-pyrimidine-2-base) amino-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base, 4-(N-pyrrolidyl)-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base or unsubstituted phenyl, R 3Be methyl, R then 4Not methyl or SMe;
Q) if R 1And R 2All be hydrogen, R 3Be methyl, R 4Be=S or unsubstituted phenyl that then encircling A is not unsubstituted phenyl; With
R) if R 1And R 2Constitute N-tetramethyleneimine basic ring together, R 3Be-NHCH 2(4-trifluoromethyl), R 4Be H, then encircling A is not N-pyrrolidyl, 3,4-Dimethoxyphenyl, 2-p-methoxy-phenyl, thiene-3-yl-or thiophene-2-base.
With regard to some other embodiment [KG2], if the R in the formula I compound ZBe C (O) N (R ') 2, then:
A) if R 1And R 2All be hydrogen, N (R ') then 2Not NH 2Or NH-C (=NH) NH 2
B) if R 1Be hydrogen, methyl or ethyl, and R 2Be-(CH 2) 2-OH ,-(CH 2) 2-OAc, 3,5-dichlorophenyl or benzyl, R 4Be hydrogen or methyl, ring A is unsubstituted phenyl, then N (R ') 2Not NH 2, NHNH 2, NHMe, NH (CH 2) 2-OH or NH-benzyl;
C) if R 1Be hydrogen, and R 2Be methyl, R 4Be OH, ring A is unsubstituted phenyl, then N (R ') 2Not NHMe;
D) if ring A is optional substituted phenyl, R 1Be hydrogen, and R 2Be optional substituted phenyl, R 4Be optional substituted phenyl or unsubstituted naphthyl, N (R ') then 2Not NH 2
E) if R 1And R 2All be hydrogen, N (R ') 2Be NH 2, NH-(optional substituted phenyl), N (optional substituted C 1-6Aliphatic group) (optional substituted phenyl) or NH (6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-6-yl), R 4Be hydrogen, then encircling A is not 1-imidazolyl, piperidino, unsubstituted phenyl, optional substituted 2-oxo-imidazolidine-1-base or 1-[(2-fluorophenyl) methyl]-the 1H-imidazo-3-yl;
F) if R 1Be hydrogen, R 2Be optional substituted phenyl, ring A is unsubstituted phenyl, R 4Be methyl or hydrogen, N (R ') then 2Not NHEt, N (Et) 2, NH (optional substituted phenyl);
G) if R 1Be hydrogen, R 2Be the 2-pyridyl, ring A is unsubstituted phenyl, R 4Be hydrogen, N (R ') then 2It or not the N-morpholinyl;
H) if R 1Be hydrogen, R 2Be hydrogen or C 1-4Aliphatic group, N (R ') 2Be NH (C 1-4Aliphatic group) or N (C 1-4Aliphatic group) 2, R 4Be hydrogen, then encircling A is not N-piperidyl or optional substituted N-piperazinyl;
I) if R 1Be hydrogen, R 2Be the 4-chloro-phenyl-, ring A is unsubstituted phenyl, R 4Be methyl, N (R ') then 2Not NHCH 2-furans-2-base;
J) ring A is not 2-formyl radical-pyrroline-1-base, optional substituted methylol-tetramethyleneimine-1-base, hydroxy piperidine base or hydroxymethyl piperidine base;
K) get rid of following compounds:
R 1 R 2 N(R′) 2 R 4 Ring A
H Optional substituted cyclohexyl The N-morpholinyl H Phenyl
H Optional substituted cyclohexyl The N-morpholinyl H The N-pyrrolidyl
H Optional substituted cyclohexyl The N-morpholinyl H Phenyl
H Optional substituted cyclohexyl or benzyl NMe 2Or NH (optional substituted cyclohexyl) H N-morpholino base
H H NH (6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-6-yl) H Pyridyl
H The 4-nitrophenyl 4-methylpiperazine base Methyl Phenyl
Methyl Methyl The NH-tetrazyl H Phenyl
H Optional substituted cyclohexyl or benzyl NH (optional substituted benzyl or cyclohexyl) H Optional substituted N-piperazinyl or imidazoles-1-base or 2-hydroxyl pyrryl
H Optional substituted benzyl NH (optional substituted cyclohexyl) H Optional substituted 2,3-dihydro-1H-isoindole-2-base
H Optional substituted benzyl The NH-pyridylmethyl H 2,3-dihydro-1H-isoindole-2-base
H Optional substituted benzyl NH-pyridylmethyl or NHCH 2CH 2-N-morpholino base H 2-aminocarboxyl-tetramethyleneimine-1-base or N-morpholino base or 1H-imidazo [4,5-c] pyridine-(6-CO 2Me)-4,5,6,7-tetrahydrochysene-1-base or 1,2,3,4,6,7-six hydrogen-3-oxo-5H-pyrazolo [4,3-c] pyridine-5-base
H The C that (aryl or heteroaryl) replaces 1-4Aliphatic group H 3, the 4-dihydro-(1H)-isoquinoline 99.9-2-base or 5,6-glyoxalidine also [1,2-a] pyrazine-7 (8H)-Ji or 5,8-dihydro-1,7-naphthyridines-7 (6H)-Ji or 5,7-dihydro-6H-pyrrolo-[3,4-b] pyridine-6-base or 2,3-dihydro-1H-indoles-1-base or 4,5,6,7-tetrahydrochysene-different  azoles is [4,5-c] pyridine-5-base or 6 also, the 7-thiazoline is [5,4-c] pyridine-(4H)-5-base also
H Optional substituted benzyl NH-pyridine-2-ylmethyl H Piperidino
L) if R 1Be H or optional substituted C 1-4Aliphatic group, R 2Be optional substituted benzyl, R 4Be methoxyl group, then encircling A is not optional substituted N-piperazinyl, 3, the 4-dihydro-(1H)-and isoquinoline 99.9-2-base, 5, the 6-glyoxalidine is [1,2-a] pyrazine-7 (8H)-Ji or 6 also, and the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-2-base also;
M) if R 1And R 2All be methyl, R 4Be hydrogen, ring A is 4-[(naphthalene-2-yl) alkylsulfonyl] piperazinyl, then N (R ') 2Not NHOH or NH-O-(tetrahydrochysene-2H-pyrans-2-yl);
N) if R 1Be hydrogen, R 2Be optional substituted benzyl, R 4Be hydrogen, N (R ') 2Be NHCH 2(pyridine-2-yl), then encircling A is not 3-(methylol) 2 (1H)-isoquinolyls; With
O) if R 1Be hydrogen, R 2Be the C that (aryl or heteroaryl) replaces 1-4Aliphatic group, R 4Be hydrogen, then encircling A is not 3, the 4-dihydro-(1H)-isoquinoline 99.9-2-base, 5, the 6-glyoxalidine is [1,2-a] pyrazine-7 (8H)-Ji, 5 also, 8-dihydro-1,7-naphthyridines-7 (6H)-Ji, 5,7-dihydro-6H-pyrrolo-[3,4-b] pyridine-6-base, 2,3-dihydro-1H-indoles-1-base, 4,5,6,7-tetrahydrochysene-different  azoles also [4,5-c] pyridine-5-base or 6, the 7-thiazoline is [5,4-c] pyridine-(4H)-5-base also; With
P) if R 1And R 2Be 4-(2-naphthyl alkylsulfonyl)-1-piperazinyl together, ring A is 4-(2-naphthyl alkylsulfonyl)-1-piperazinyl or 4-(2-naphthyl alkylsulfonyl) amino-piperadine base, and R 4Be hydrogen, R then 3Not NH-O-(tetrahydrochysene-2H-pyrans-2-yl) or NHOH.
In some other embodiment, if R ZBe the R of institute's general description as mentioned and here Z1:
A) if R Z1Be tetrazyl, R 1Be hydrogen, R 2Be hydrogen or optional substituted phenyl, R 4Be hydrogen, then encircling A is not unsubstituted 1-pyrrolidyl, piperidino, N-morpholinyl, 1-azepan base or phenyl.
In some other embodiment, if R ZBe the R of institute's general description as mentioned and here Z1:
A) if R Z1Be-P (O) (OR ') 2, and R ' is C 1-4Aliphatic group, R 1And R 2All be hydrogen, and R 4Be hydrogen, methyl, amino ,-OCH 2OH, then encircling A is not the 1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3,4-b] pyridin-3-yl or unsubstituted phenyl.
In some other embodiment, if R ZBe the R of institute's general description as mentioned and here Z1:
A) if R Z1Be-SO 2NHR ', and R ' is hydrogen, R 1And R 2All be hydrogen, R 4Be amino, then encircling A is not N-morpholino base.
In some other embodiment [KG3], the wherein R of institute's general description as mentioned and here just ZBe-OR 3The compounds of this invention:
A) if R 3Be ethyl, R 4Be hydrogen, ring A is unsubstituted phenyl, and R 1Be hydrogen, R then 2Be not optional substituted 2-pyridyl, optional substituted phenyl, optional substituted benzyl ,-CH 2CO 2H ,-CH 2CN, n-propyl, methyl, ethyl ,-CH 2(4-OMe-phenyl) ,-CH 2CON (Me) CH 2Ph ,-CH 2C ≡ CH ,-CH 2CH 2OMe ,-CH 2CH=CH 2Or-(CH 2) 3OH;
B) if R 3Be ethyl, R 4Be hydrogen, ring A is a thienyl, and R 1Be hydrogen, R then 2It or not optional substituted phenyl;
C) if R 3Be ethyl, R 4If be hydrogen, ring A is unsubstituted phenyl, then R 1Be methyl, ethyl, CH 2CH 2Ph ,-CH 2CH 2The morpholino base ,-CH 2CH 2NEt 2,-CH 2CH 2OMe, normal-butyl or optional substituted phenyl, then R 2Be not-CH 2CH 2CN ,-CH 2CN or-CH 2CH 2OAc, perhaps R 1And R 2Not that optional substituted piperidyl, morpholino base or parathiazan are for base together;
D) if R 3Be ethyl, R 4Be NH 2, Cl, Me or Br, ring A is unsubstituted phenyl or morpholino base, and R 1Be hydrogen, R then 2Not optional substituted phenyl or COR ';
E) if R 3Be ethyl, R 4Be hydrogen, and ring A is unsubstituted phenyl, then R 1And R 2Not methyl simultaneously;
F) if R 3Be methyl, then encircle A, R 4R together 1And R 2Not piperidyl simultaneously;
G) if R 3Be ethyl, R 1Be hydrogen, R 2Be unsubstituted phenyl, and R 4Be methyl or parathiazan for base, then encircling A is not unsubstituted phenyl, 4-OMe-phenyl, 2-pyridyl, 4-Cl-phenyl, 2-Cl-phenyl, 3,4-dichlorophenyl, 4-Me-phenyl, 3,5-dichlorophenyl, 4-OH-phenyl or 3CF 3-, the 4-Cl-phenyl;
H) if R 3Be ethyl, methyl or sec.-propyl, R 1Be hydrogen or ethyl, and R 2Be ethyl, COCH 3, sec.-propyl ,-CH 2CH 2CN, benzyl ,-CH 2CH 2NEt 2,-CH 2CH 2COOEt, perhaps R 1And R 2Be piperazinyl together, and R 4Be hydrogen, then encircling A is not optional substituted piperazinyl, pyrrolidyl, morpholino base or piperidyl;
I) if R 3Be ethyl, and R 1Be hydrogen, R then 2It or not optional substituted cyclohexyl;
J) if R 3Be methyl, and R 4Be N (Me) COPh, then encircle A and R together 1And R 2Not the N-pyrrolidyl simultaneously;
K) if R 3Be ethyl, R 4Be optional substituted phenyl, ring A is optional substituted phenyl, and R 1Be hydrogen, R then 2Not optional substituted naphthyl, methyl, optional substituted phenyl, perhaps R 1And R 2Is that right together quinoline is for base;
L) if R 3Be ethyl, then if R 1And R 2Together or ring one of A be optional substituted piperazinyl, then R 1And R 2Together or the ring A another be not that parathiazan is for base or morpholino base;
M) R 1And R 2Together with ring A not simultaneously is that right quinoline for base or parathiazan for base;
O) if R 3Be methyl, R 4Be hydrogen or OMe, ring A is unsubstituted phenyl, and R 1Be hydrogen, R then 2Not methyl, 2,3-3,5-dimethylphenyl or 3-CF 3Phenyl;
P) if R 3Be ethyl, R 4Be hydrogen, and the ring A be unsubstituted phenyl, then:
I) R 1And R 2Do not constitute 1-pyrrolidyl, 4-methylpiperazine base or piperidino together;
Ii) R 1And R 2Not hydrogen, methyl or ethyl;
Iii) if R 1Be hydrogen, R then 2It or not the 2-hydroxyethyl.
In other embodiments, the wherein R of subclass institute general description as mentioned and here just ZBe-C (O) R 3The compounds of this invention, R 3By the atomic linkage beyond deoxygenation or the nitrogen in carbonylic carbon atom.
In other embodiments, the wherein R of subclass institute general description as mentioned and here just ZBe-C (O) R 3The compounds of this invention, with regard to R 4, Q is not O or S, at this moment R XBe optional substituted furyl or thiophene.
In other embodiments, the wherein R of subclass institute general description as mentioned and here just ZBe-C (O) R 3The compounds of this invention, if R 1Be hydrogen, R 2It is the group except that NR '.
2. compound and definition:
The compounds of this invention comprises those of as above general description, and is further set forth by kind disclosed herein, group and kind.Following definition used herein should be suitable for, and has except the opposite indication.For purposes of the present invention, the discriminating of chemical element is according to the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75 ThEd.In addition, vitochemical General Principle is referring to " Organic Chemistry ", ThomasSorrell, University Science Books, Sausalito:1999 and " March ' sAdvanced Organic Chemistry ", 5 ThEd., Ed.:Smith, M.B.and March, J., John Wiley ﹠amp; Sons, New York:2001, its full content is quoted at this as a reference.
As described herein, The compounds of this invention can be replaced by one or more substituting groups alternatively, for example general elaboration above, and exact nature perhaps for example of the present invention, group and kind are described.Will be appreciated that wording " optional substituted " can be exchanged with wording " replace or unsubstituted " uses.Generally speaking, term " replacement " front has or not term " optional " all to represent to give the hydrogen atom in the fixed structure to roll into a ball designated substituent atomic group replacement.Unless opposite indication is arranged, optional substituted group can have substituting group in each commutable position of this group, when can be selected from the substituting group of specifying group more than one for arbitrarily in the fixed structure an above position to replace, substituting group can be identical or different in each position.The substituting group of being contained by the present invention makes up those that preferably cause stable or chemically feasible compound generation.Basically immovable compound when term used herein " stable " expression is handled when the condition of the production that is subjected to allowing them for one or more purposes disclosed herein, detection, preferred recovery, purifying and use.In some embodiment, stable compound or chemically feasible compound are the compounds that not have change when keeping at least one week under the existence that is not having moisture or other chemical reactivity conditions, under 40 ℃ or following temperature basically.
The replacement or the unsubstituted hydrocarbon chain of term used herein " aliphatic series " or " aliphatic group " expression straight chain, (promptly not branch) or side chain, it is saturated fully or contains one or more unsaturated units, perhaps represent monocyclic hydrocarbon or bicyclic hydrocarbon, it is saturated fully or contains one or more unsaturated units, but be (this paper also is referred to as " carbocyclic ring ", " cyclic aliphatic " or " cycloalkyl ") of aromatics, it has the single point that is connected with the molecule rest part.Unless opposite appointment is arranged, aliphatic group contains 1-20 aliphatic carbon atom.In some embodiment, aliphatic group contains 1-10 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-8 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-6 aliphatic carbon atom, and in other embodiments, aliphatic group contains 1-4 aliphatic carbon atom.In some embodiment, " cyclic aliphatic " (perhaps " carbocyclic ring " or " cycloalkyl ") expression monocycle C 3-8Hydrocarbon or two ring C 8-12Hydrocarbon, it is fully saturated or contains one or more unsaturated units, but aromatics whether, and it has the single point that is connected with the molecule rest part, and to be that 3-7 is first encircle any single ring in the wherein said bicyclic ring system.The aliphatic group that is fit to includes but not limited to replacement or unsubstituted alkyl, thiazolinyl, alkynyl and the heterocomplex thereof of straight or branched, for example (cycloalkyl) alkyl, (cycloalkenyl group) alkyl or (cycloalkyl) thiazolinyl.
Term used herein " heterolipid family " represents that one of them or two carbon atoms are independently by the displaced aliphatic group of one or more oxygen, sulphur, nitrogen, phosphorus or silicon.Heterolipid family group can be to replace or unsubstituted, straight or branched, ring-type or acyclic, comprises " heterocycle ", " heterocyclic radical ", " heterocycle aliphatic series " or " heterocyclic " group.
Term used herein " heterocycle ", " heterocyclic radical ", non-aromatics, the monocyclic, bicyclic or tricyclic ring system of " heterocycle aliphatic series " or " heterocyclic " expression, wherein one or more ring memberses are independent heteroatomss of selecting.In some embodiment, " heterocycle ", " heterocyclic radical ", " heterocycle aliphatic series " or " heterocyclic " group have three to 14 ring memberses, wherein one or more ring memberses are the heteroatomss that independently are selected from oxygen, sulphur, nitrogen or phosphorus, and each ring contains 3 to 7 ring memberses in this system.
One or more oxygen, sulphur, nitrogen, phosphorus or silicon (any oxidised form that comprises nitrogen, sulphur, phosphorus or silicon represented in term " heteroatoms "; Basic nitrogen or heterocycle can replace the quaternized form of nitrogen, for example N (as 3, in the 4-dihydro-2 h-pyrrole base), NH (as in pyrrolidyl) or NR arbitrarily +(in the pyrrolidyl that replaces at N-)).
Term used herein " undersaturated " means that this part has one or more unsaturated units.
Term used herein " alkoxyl group " or " alkylthio " expression are connected with the main body carbochain by oxygen (" alkoxyl group ") or sulphur (" alkylthio ") atom as the defined alkyl of preamble.
Term " haloalkyl ", " haloalkenyl group " and " halogenated alkoxy " expression are depended on the circumstances by alkyl, thiazolinyl or alkoxyl group that one or more halogen atoms replace.Term " halogen " expression F, Cl, Br or I.
Have monocycle, two rings and the three ring ring systems that amount to five to 14 ring memberses separately or as term " aryl " expression that the part of more most of " aralkyl ", " aralkoxy " or " aryloxy alkyl " is used, wherein at least one ring is an aromatics in this system, and wherein in this system each ring contain 3 to 7 ring memberses.Term " aryl " can exchange with term " aryl rings " and use.Term " aryl " also is expressed as follows defined heteroaryl ring system.
Have monocycle, two rings and the three ring ring systems that amount to five to 14 ring memberses separately or as term " heteroaryl " expression that the part of more most of " heteroaralkyl " or " heteroaryl alkoxyl group " is used, wherein at least one ring is an aromatics in this system, at least one ring contains one or more heteroatomss in this system, and wherein in this system each ring contain 3 to 7 ring memberses.Term " heteroaryl " can exchange with term " heteroaryl ring " or term " heteroaromatic " and use.
Aryl (comprising aralkyl, aralkoxy, aryloxy alkyl etc.) or heteroaryl (comprising heteroaralkyl and assorted aralkoxy etc.) can contain one or more substituting groups, thereby can be " optional substituted ".In the above with the present invention in, non-other definition is fallen, the substituting group that is fit on the unsaturated carbon atom of aryl or heteroaryl generally be selected from halogen ,-R 0,-OR 0,-SR 0, 1,2-methylene-dioxy, ethylenedioxy, optional by R 0The phenyl (Ph) that replaces, optional by R 0Replace-O (Ph), optional by R 0Replace-(CH 2) 1-2(Ph), optional by R 0Replace-CH=CH (Ph) ,-NO 2,-CN ,-N (R 0) 2,-NR 0C (O) R 0,-NR 0C (O) N (R 0) 2,-NR 0CO 2R 0,-NR 0NR 0C (O) R 0,-NR 0NR 0C (O) N (R 0) 2,-NR 0NR 0CO 2R 0,-C (O) C (O) R 0,-C (O) CH 2C (O) R 0,-CO 2R 0,-C (O) R 0,-C (O) N (R 0) 2,-OC (O) N (R 0) 2,-S (O) 2R 0,-SO 2N (R 0) 2,-S (O) R 0,-NR 0SO 2N (R 0) 2,-NR 0SO 2R 0,-C (=S) N (R 0) 2,-C (=NH)-N (R 0) 2Or-(CH 2) 0-2NHC (O) R 0, wherein each independent R that occurs 0Be selected from hydrogen, optional substituted C 1-6Aliphatic group, unsubstituted 5-6 unit's heteroaryl or heterocycle, phenyl ,-O (Ph) or-CH 2(Ph), although as above definition is perhaps arranged, twice independent R that occurs on identical substituting group or different substituents 0With each R 0The atom of group institute bonding constitutes together and has 0-3 heteroatomic 3-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl ring that independently is selected from nitrogen, oxygen or sulphur.R 0Aliphatic group on optionally substituting group be selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo C 1-4Aliphatic group, wherein R 0Each above-mentioned C 1-4Aliphatic group is unsubstituted.
Aliphatic series or heterolipid family group or non-aromatic heterocyclic can contain one or more substituting groups.Above the substituting group that is fit on the saturated carbon atom of aliphatic series or heterolipid family group or non-aromatic heterocyclic is selected from about cited those of aryl or heteroaryl unsaturated carbon, and comprise in addition following groups :=O ,=S ,=NNHR *,=NN (R *) 2,=NNHC (O) R *,=NNHCO 2(alkyl) ,=NNHSO 2(alkyl) or=NR *, each R wherein *Be independently selected from hydrogen or optional substituted C 1-6Aliphatic group.R *Aliphatic group on optionally substituting group be selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo C 1-4Aliphatic group, wherein R *Each above-mentioned C 1-4Aliphatic group is unsubstituted.
Optional substituting group is selected from-R on the non-aromatic heterocyclic nitrogen +,-N (R +) 2,-C (O) R +,-CO 2R +,-C (O) C (O) R +,-C (O) CH 2C (O) R +,-SO 2R +,-SO 2N (R +) 2,-C (=S) N (R +) 2,-C (=NH)-N (R +) 2Or-NR +SO 2R +R wherein +Be hydrogen, optional substituted C 1-6Aliphatic group, optional substituted phenyl, optional substituted-O (Ph), optional substituted-CH 2(Ph), optional substituted-(CH 2) 1-2(Ph), optional substituted-CH=CH (Ph) or have one to four heteroatomic unsubstituted 5-6 unit's heteroaryl or heterocycle that independently is selected from oxygen, nitrogen or sulphur, although as above definition is perhaps arranged, twice independent R that occurs on identical substituting group or different substituents +With each R +The atom of group institute bonding constitutes together and has 0-3 heteroatomic 3-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl ring that independently is selected from nitrogen, oxygen or sulphur.R +Aliphatic group or benzyl ring on optionally substituting group be selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo C 1-4Aliphatic group, wherein R +Each above-mentioned C 1-4Aliphatic group is unsubstituted.
Term " alkylidene chain " expression straight or branched carbochain, it can be saturated fully or have one or more unsaturated units, and have two points that are connected with the molecule rest part.
As indicated above, in some embodiment, twice independent R that occurs 0(perhaps R +Or other have the variable of similar definition in this article arbitrarily) constitute with their institute's bonded atoms and have 0-3 heteroatomic 3-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl that independently is selected from nitrogen, oxygen or sulphur.Twice independent R that occurs 0(perhaps R +Or other have the variable factor of similar definition in this article arbitrarily) include but not limited to following with the exemplary ring that atom constituted of each variable factor institute bonding: a) twice independent R that occurs 0(perhaps R +Or other have the variable factor of similar definition in this article arbitrarily) be bonded to same atom, and constitute a ring, for example N (R with this atom 0) 2, two R of Chu Xianing wherein 0Constitute piperidines-1-base, piperazine-1-base or morpholine-4-base with nitrogen-atoms; And b) twice independent R that occurs 0(perhaps R +Or any other has the variable factor of similar definition in this article) be bonded to not homoatomic, and constitute a ring with these atoms, for example Wherein phenyl is by the OR of twice appearance 0Replace the R of this twice appearance 0Constitute 6 yuan of ether rings of condensed with their institute's bonded Sauerstoffatoms: To be understood that twice independent R that occurs 0(perhaps R +Or other have the variable factor of similar definition in this article arbitrarily) can constitute multiple other rings with the atom of each variable institute bonding, it is restrictive that above-mentioned detailed example is not planned.
Unless otherwise prescribed, the structure that this paper described also means all isomeries (for example enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism)) form that comprises this structure; The for example R of each asymmetric center and S configuration are (Z) with (E) double bond isomer and (Z) and (E) conformer.Therefore, the single three-dimensional chemical isomer of these compounds and enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism) mixture all belong to scope of the present invention.Unless opposite regulations is arranged, all tautomeric forms of The compounds of this invention all belong to scope of the present invention.In addition, unless opposite regulations is arranged, the structure that this paper described also means and only comprises compound different in the existence of one or more isotopic enrichment atoms.For example, replaced or the carbon quilt by deuterium or tritium except hydrogen 13C-or 14The compound that has structure of the present invention beyond the carbon of C-enrichment replaces all belongs to scope of the present invention.This compounds for example can be used as analysis tool or the probe in the biological assay.
3. the explanation of exemplary compound:
In some embodiments of the present invention, R ' is a hydrogen.
In some embodiments of the present invention, R ' is independently selected from optional substituted group, is selected from C 1-8Aliphatic group, C 6-10Aryl, have the heteroaryl of 5-10 annular atoms or have the heterocyclic radical of 3-10 annular atoms.
In some embodiments of the present invention, R ' is optional substituted C 1-8Aliphatic group.In some this class embodiment, R ' is C 1-4Aliphatic group, alternatively by halogeno-group, OH, COOH, CN ,-OC 1-4Alkyl replaces.Perhaps, R ' is C 1-4Aliphatic group is contained the first heterocyclic substituted of optional substituent 5-6 alternatively.This class heterocyclic example for example comprises tetrahydrofuran base, pyranyl, piperidyl and piperazinyl.Perhaps, R ' is C 1-4Aliphatic group is contained optional substituent aryl alternatively and is replaced.
In other embodiments of the present invention, R ' is optional substituted C 6-10Aryl.The aryl that is fit to comprises phenyl and naphthyl.
In some other embodiment of The compounds of this invention, R ' is the heteroaryl of the optional substituted 5-10 of having annular atoms.The heteroaryl ring that is fit to comprises 5-unit heteroaryl ring, for example pyrryl, thienyl and thiazolyl.
Perhaps, R ' is the heterocyclic ring of the optional substituted 3-10 of having annular atoms.This class ring for example comprises tetrahydrofuran base, pyranyl, piperidyl and piperazinyl.
In other embodiments of the present invention, the R ' of twice appearance constitutes with the atom of their institute's bondings and has 0-3 heteroatomic 5-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl that independently is selected from nitrogen, oxygen or sulphur.In some embodiments, the R ' of twice appearance constitutes 5-8 unit cycloalkyl ring with the atom of their institute's bondings.In some other embodiment, the R ' of twice appearance constitutes 5-8 unit heterocyclic ring with the atom of their institute's bondings.In some other embodiment, the R ' of twice appearance constitutes with the atom of their institute's bondings and has 0-3 heteroatomic 5-8 unit heterocyclic ring that independently is selected from nitrogen, oxygen or sulphur.In some other embodiment, the R ' of twice appearance constitutes aryl rings or their with the atom of their institute's bondings and constitutes and have 0-3 first ring of heteroatomic 5-8 that independently is selected from nitrogen, oxygen or sulphur.
In some embodiment of the present invention, R 1And R 2Be hydrogen or optional substituted group independently of one another, described group is selected from C 1-6Aliphatic group, have 0-5 and independently be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur; Perhaps R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical or heteroaryl ring, wherein a R who independently is selected from nitrogen, oxygen or sulphur 1, R 2Perhaps arbitrarily by R 1And R 2The ring that is constituted is occurred for 0-4 time on one or more carbon atoms-R independently of one another alternatively together 5Replace quilt-R on one or more commutable nitrogen-atoms 6Replace.
In some embodiments of the present invention, R 1And R 2Not hydrogen.Perhaps, R 1And R 2Be optional substituted C independently of one another 1-6Aliphatic group.
In some other embodiment of the present invention, R 1And R 2Not hydrogen, and R 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
In other embodiments of the present invention, R 1And R 2All be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.Other preferred embodiment in, R 1And R 2One of be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.Preferred R 1And R 2Group is optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl.Preferred R 1And R 2Group comprise as shown in table 2 below those.
In other embodiments of the present invention, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute 5-6 unit heterocycle together.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute optional substituted 1-pyrrolidyl or piperidino together.In another embodiment, R 1And R 2All be methyl or ethyl simultaneously.
In other embodiments of The compounds of this invention, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have 2 first heterocycles of heteroatomic 3-6 at the most.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute optional substituted 1-azetidinyl, 1-pyrrolidyl, piperidino or 1-piperazinyl together.In one embodiment, R 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute 1-tetramethyleneimine basic ring together.In one embodiment, R 1And R 2All be methyl or ethyl simultaneously.
In other embodiments of The compounds of this invention, R 1And R 2All be C simultaneously 1-4Aliphatic group.Preferred R 1And R 2Comprise methyl, ethyl or propyl group.
In other embodiments of The compounds of this invention, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have the 4-6 unit heterocycle of 2 nitrogen heteroatoms at the most.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute optional substituted 1-pyrrolidyl or 1-piperazinyl together.In one embodiment, R 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute 1-tetramethyleneimine basic ring together, R 3Be ethyl or propyl group.In another embodiment, R 1And R 2All be methyl or ethyl.
In one embodiment of the invention, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have the 4-6 unit heterocycle of 2 nitrogen heteroatoms at the most.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute 1-azetidinyl, 1-pyrrolidyl or 2 together, 5-pyrrolin base.Preferably, R 1And R 2All be methyl or ethyl.
In one embodiment of the invention, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have the 4-6 unit heterocycle of 2 nitrogen heteroatoms at the most.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute optional substituted 1-azetidinyl, 1-pyrrolidyl, 2 together, 5-dihydro-1H-pyrryl, piperidino or 1-piperazinyl.In one embodiment, R 1And R 2All be C 1-4Aliphatic group.Preferably, R 1And R 2All be methyl or ethyl.
In one embodiment of the invention, R 1And R 2All be C 1-4Aliphatic group.Preferably, R 1And R 2All be methyl or ethyl.In other embodiments of the present invention, R 1Or R 2One of be hydrogen, R 1Or R 2Another be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
In one embodiment of the invention, R 1Be hydrogen or C 1-6Aliphatic group, and R 2Be optional substituted C 1-6Aliphatic group, perhaps R 1And R 2Constitute the first saturated rings of optional substituted 4-7 together, wherein said ring contains second heteroatoms that is selected from O or N alternatively.In preferred embodiment, R 1Be hydrogen or C 1-6Aliphatic group, and R 2Be optional substituted C 1-6Aliphatic group, furyl methyl, allyl group or benzyl, perhaps R 1And R 2Be 4-ethoxycarbonyl-piperidino, pipecoline base, 2-hydroxymethyl piperidine base, 3-hydroxy piperidine base, 4-isobutylamino manthanoate-piperidino, 3-diethylaminocarbonyl--piperidino, piperidino, 1-pyrrolidyl, 2-ethoxycarbonyl pyrrolidyl, N-morpholino base, 3 together, 5-dimethyl-N-morpholino base, 4-methylpiperazine base, 4-hydroxyethyl piperazine base, 1-pyrryl, 2,4-dihydro-1-pyrryl, 1-azetidinyl or 1-azepan base.Preferably, R 1Be hydrogen or C 1-4Aliphatic group, and R 2Be C 1-4Aliphatic group, furyl methyl, allyl group or benzyl, perhaps R 1And R 2Be 4-ethoxycarbonyl-piperidino, pipecoline base, 4-isobutylamino manthanoate-piperidino, 3-diethylaminocarbonyl--piperidino, piperidino, 1-pyrrolidyl, 2-ethoxycarbonyl pyrrolidyl, 4-methylpiperazine base, 2 together, 4-dihydro-1-pyrryl, 1-azetidinyl or 1-azepan base.Perhaps, R 1Be hydrogen or C 1-4Aliphatic group, and R 2Be C 1-4Aliphatic group, furyl methyl, allyl group or benzyl, perhaps R 1And R 2Be 4-ethoxycarbonyl-piperidino, pipecoline base, piperidino, 1-pyrrolidyl, 4-methylpiperazine base, 2 together, 4-dihydro-1-pyrryl or 1-azetidinyl.
In another embodiment of the invention, R 1And R 2All be methyl, perhaps R 1And R 2Constitute 1-pyrrolidyl, N-morpholinyl, piperidino or 4-methyl piperidine base together.Preferably, R 1And R 2All be methyl, perhaps R 1And R 2Constitute 1-pyrrolidyl, N-morpholinyl, piperidino or 4-methyl piperidine base together.Perhaps, R 1And R 2It all is methyl.Perhaps, R 1And R 2Constitute 1-pyrrolidyl, N-morpholinyl, piperidino or 4-methyl piperidine base together, preferred 4-methyl piperidine base.
In another embodiment of the invention, R 1And R 2One of be hydrogen, C 1-4Aliphatic group, R 1And R 2Another be C 1-4Aliphatic group or benzyl, perhaps R 1And R 2Constitute 1-pyrrolidyl, piperidino or N-morpholine basic ring together.Preferably, R 1And R 2One of be hydrogen, methyl or ethyl, R 1And R 2Another be methyl, ethyl or benzyl.
In other embodiments of the present invention, R 1Or R 2One of be hydrogen, R 1Or R 2Another be to have 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur.In other embodiments, R 1Or R 2One of be hydrogen, R 1Or R 2Another be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
In embodiments of the present invention, R wherein 1Or R 2Be to have 0-5 independently to be selected from heteroatomic 5-or the 6-unit's aryl rings of N, O or S or to have 0-3 the saturated or unsaturated ring of part of heteroatomic 3-7 unit that independently is selected from N, O or S, preferred R 1And R 2Group is selected from:
R wherein 5And R 6Be defined as preamble, z is 0-4.Most preferred ring comprise as shown in table 2 below those.
In other embodiments of the present invention, R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having the first heterocyclic ring of heteroatomic 3-8 that independently is selected from nitrogen, sulphur or oxygen.Some preferred embodiment in, R 1And R 2Nitrogen-atoms with their institute's bondings constitutes 3-8 unit heterocyclic radical, is selected from:
Figure A20048002502700671
R wherein 5And R 6Be defined as preamble, z is 0-4.
In some of the preferred embodiment of the invention, R 1And R 2Be optional substituted azetidine basic ring (bb) together.Perhaps, R 1And R 2Be optional substituted piperidines basic ring (ee) together.Perhaps, R 1And R 2Be optional substituted piperazinyl ring (dd) together.Perhaps, R 1And R 2Be optional substituted tetramethyleneimine basic ring (gg) together.
In other preferred implementations of the present invention, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff), piperidines-1-base (ee), piperazine-1-base (dd) or morpholine-4-base (ee) together.
In some other embodiment of The compounds of this invention, R 1And R 2Be optional substituted C independently of one another 1-6Aliphatic group, perhaps R 1And R 2Constitute optional substituted tetramethyleneimine basic ring together.
In some other embodiment of The compounds of this invention, R 1And R 2Be optional substituted C independently of one another 1-6Aliphatic group, perhaps R 1And R 2Constitute optional substituted piperidines basic ring together.
In some other embodiment of The compounds of this invention, R 1And R 2Be optional substituted C independently of one another 1-6Aliphatic group, perhaps R 1And R 2Constitute optional substituted piperazinyl ring together.
In some other embodiment of The compounds of this invention, R 1And R 2Be optional substituted C independently of one another 1-6Aliphatic group, perhaps R 1And R 2Constitute optional substituted azetidine basic ring together.
In some other embodiment of The compounds of this invention, R 1And R 2Be optional substituted C independently of one another 1-6Aliphatic group, R 1And R 2Constitute optional substituted tetramethyleneimine basic ring, optional substituted piperidines basic ring, optional substituted pyrrolin alkyl ring or optional substituted azetidine basic ring together.
Among the present invention, if R 1Or R 2Be to have 0-5 when independently being selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or having the unsaturated ring of the first saturated or part of 0-3 heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur, perhaps work as R 1And R 2When constituting the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical that independently is selected from nitrogen, oxygen or sulphur or heteroaryl ring with the nitrogen-atoms of their institute's bondings, each ring independently alternatively on one or more carbon atoms by 0-4 appearance-R 5Replace quilt-R on one or more commutable nitrogen-atoms 6Replace.
In preferred implementation of the present invention, z is 0-3.Other preferred embodiment in, z is 0, this ring is unsubstituted.
Preferred R 5Group is halogen, CN, NO when existing 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-NRC (O) OR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 5Group is Cl, Br, F, CF independently of one another 3, CHF 2, Me, Et, propyl group, CN, NO 2,-COOH, NH 2,-N (C 1-4Alkyl) 2,-O (C 1-4Alkyl) OCH 3,-CONH 2,-NHC (O) C 1-4Alkyl ,-NHC (O) (C 5-6Heterocyclic radical) ,-NHC (O) OC 1-4Alkyl ,-NHC (O) O (C 5-6Heterocyclic radical) ,-C (O) OC 1-4Alkyl ,-C (O) O (C 5-6Heterocyclic radical), OH ,-CH 2OH ,-NHCOC 1-4Alkyl ,-NHC (O) (C 5-6Heterocyclic radical) ,-SO 2NH 2Or SO 2N (C 1-4Alkyl) 2In some embodiments, R 5Group is Cl, Br, F, CF independently of one another 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-NHC (O) O (iPr) ,-NHC (O) O-tetrahydrofuran base ,-SO 2NH 2, SO 2N (CH 3) 2Piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.Most preferred R 5Group comprise as shown in table 2 below those.In preferred embodiment, R 6Group is hydrogen or optional substituted group, and described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-C (O) OR ', CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 6Group is H, Me, CF independently of one another 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-C (O) (C 1-4Alkyl) ,-C (O) (C 5-6Heterocyclic radical) ,-C (O) O (C 1-4Alkyl) ,-C (O) O (C 5-6Heterocyclic radical) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.Most preferred R 6Group comprise as shown in table 2 below those.
In some embodiments of the present invention, R 1And R 2Be equal to.
In some embodiments of the present invention, R ZBe-C (O) R 3In other embodiments, R 2Be-C (O) OR 3In some other embodiment, R ZBe-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2Or-C (O) N (CN) R '.In other embodiments, R ZBe the optional substituted 1-4 of having a heteroatomic 5-unit's heteroaryl ring or an optional substituted pyrans-4-ketone group that is selected from O, S or N.
In other embodiments of the present invention, R ZIt is optional substituted  azoles basic ring.In other embodiments, R ZBe-C (O) R 3, R wherein 3Be optional substituted C 1-6Alkyl.In other embodiments, R ZBe-C (O) R 3, R wherein 3Be optional substituted C 1-6Alkyl or optional by the Q-R of 0-5 appearance XThe aryl rings that replaces.
In other embodiments of the present invention, R ZBe optional by the Q-R of 0-5 appearance XThe aryl rings that replaces.Perhaps, R ZBe R '.
In other embodiments of the present invention, R ZBe C (O) R 3, R wherein 3Be optional substituted C 1-6Alkyl, optional by the Q-R of 0-5 appearance XAryl rings, optional substituted pyrans-4-ketone group or the optional substituted 1-4 of having that replaces the first heteroaryl ring of heteroatomic 5-that is selected from O, S or N.
In other embodiments of the present invention, R ZBe R ' ,-C (O) R 3, R wherein 3Be optional substituted C 1-6Alkyl, optional by the Q-R of 0-5 appearance XAryl rings, optional substituted pyrans-4-ketone group or the optional substituted 1-4 of having that replaces the first heteroaryl ring of heteroatomic 5-that is selected from O, S or N.
In other embodiments of the present invention, R ZBe R ', C (O) R 3, R wherein 3Be-N (R ') 2, C (O) R 3, optional substituted C 1-6Alkyl, optional by the Q-R of 0-5 appearance XAryl rings, optional substituted pyrans-4-ketone group or the optional substituted 1-4 of having that replaces the first heteroaryl ring of heteroatomic 5-that is selected from O, S or N.
In other embodiments, R ZBe-C (O) R 3, C (O) OR 3, CN, or optional substituted C 1-6Alkyl, wherein 0-5 carbon atom replaced by O, N, S or carbonyl alternatively.Preferred R ZGroup is as shown in table 2 below.
Preferred R ZGroup is as shown in table 2 below.
In other embodiments of the present invention, R 3By the atomic linkage beyond deoxygenation or the nitrogen in carbonylic carbon atom.
In other embodiments of the present invention, R 3Be further defined as-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is optional substituted C 2-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, its condition be Q by carbon atom bonding in carbonylic carbon atom.
In other embodiments of the present invention, R 3Be further defined as-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is a key, R XBe optional substituted group, be selected from C 2-8Aliphatic group, C 6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the heterocyclic ring of 3-10 annular atoms.
In other embodiments, R 3Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
Other preferred embodiment in, R 3Be H, Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.Most preferred R 3Group comprise as shown in table 2 below those.
In some embodiment of the present invention, R 4Be hydrogen.In other embodiments, R 4Be optional substituted C 1-6Alkyl.In other embodiments, R 4It is optional substituted aryl.In other embodiments, R 4Be hydrogen or optional substituted C 1-6Alkyl.
In preferred embodiment, R 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.Most preferred R 4Group comprise as shown in table 2 below those.
About institute of the present invention general description, ring A has 0-5 the first aryl rings of heteroatomic 5-6 that independently is selected from nitrogen, oxygen or sulphur as above, alternatively on one or more carbon atoms by 0-5 appearance-R 7Replace quilt-R on one or more commutable nitrogen-atoms 8Replace.
In other embodiments of the present invention, ring A has a 0-3 first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur, alternatively on one or more carbon atoms by 0-5 appearance-R 7Replace quilt-R on one or more commutable nitrogen-atoms 8Replace.
In some embodiments of the present invention, ring A is a phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrryl, piperidyl, indyl, indazolyl, the benzotriazole base, pyrazolyl, the benzopyrazoles base, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl,  azoles base, the benzoxazol base, different  azoles base, benzisoxa  azoles base, isothiazolyl, the benzisothiazole base, triazolyl, the benzotriazole base, thiadiazolyl group, thienyl, benzothienyl, furyl (furanoyl), benzofuryl or triazine basic ring, on one or more carbon atoms, occurred for 0-5 time alternatively separately-R 7Replace quilt-R on one or more commutable nitrogen-atoms 8Replace.What will be figured out is that ring A can be connected in pyrimidine-ring (for example thiazole ring can be connected 2-, 4-or 5-position) by available carbon or nitrogen-atoms.Some preferred embodiment in, the ring A be optional substituted phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl:
Figure A20048002502700721
Wherein y is 0-5, and R 7It is institute General Definition as mentioned.
In preferred embodiment, y is 0-3.Other preferred embodiment in, y is 0, and the ring A be unsubstituted.
In another embodiment of the invention, ring A is:
Figure A20048002502700722
In other embodiments of the present invention, ring A is optional substituted piperidines basic ring or optional substituted pyrroles's basic ring.
In some embodiments of the present invention, ring A is optional benzyl ring, optional substituted piperidines basic ring or the optional substituted pyrroles's basic ring that is replaced by one or more halogens.
In other embodiments of the present invention, ring A is optional by the Q-R of 1-5 appearance XThe benzyl ring that replaces, wherein Q is selected from a key, O, N, and R XBe R '.
In other embodiments of the present invention, ring A is optional by the Q-R of 1-5 appearance XThe benzyl ring, optional substituted imidazoles basic ring, optional substituted pyrazole basic ring, optional substituted piperidines basic ring, optional substituted pyrroles's basic ring or the optional substituted indoles basic ring that replace.
In other embodiments of the present invention, ring A is optional benzyl ring, optional substituted piperidines basic ring, the optional substituted pyrroles's basic ring that is replaced by one or more halogens.Perhaps, ring A is optional by the Q-R of 1-5 appearance XThe benzyl ring that replaces, wherein Q is selected from a key, O, N, and R XBe R '.
In some embodiments of the present invention, ring A is optional benzyl ring, optional substituted piperidines basic ring, optional substituted pyrroles's basic ring, the optional substituted thiophene basic ring that is replaced by one or more halogens, and it is optional by the Q-R of 1-5 appearance perhaps encircling A XThe benzyl ring that replaces, wherein Q is selected from a key, O, N, and R XBe selected from R '.
In preferred embodiment, R 7Group is hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, haloalkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 7Group is H, Cl, Br, F, CF independently of one another 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-CHF 2,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.Most preferred R 7Group comprises those any one as shown in table 2 below.In preferred embodiment, R 8Group is or optional substituted group that described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 8Group is H, Me, CF independently of one another 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.Most preferred R 8Group comprise as shown in table 2 below those.
In one embodiment of the invention, ring A has Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.Preferably, ring A is the phenyl that 2-replaces, and wherein said substituting group is Q-R X, wherein Q is a key.
In another embodiment of the invention, ring A is optional substituted phenyl, 5 yuan of heteroaryls or 6-unit heterocyclic ring.Preferred ring A comprises phenyl or has 1 first heteroaryl of heteroatomic 5-that wherein said ring A has two Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.Perhaps, ring A is optional substituted phenyl, piperidyl or pyrryl.Preferred embodiment be such, wherein encircle A and have at the most two and be selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.Perhaps, ring A is phenyl, piperidino or 1-pyrryl, wherein encircles A and has two substituting groups that are selected from halogeno-group or OH at the most.
In another embodiment of the invention, ring A is optional substituted phenyl, 5-unit's heteroaryl or 6-unit heterocyclic radical.Preferred ring A comprises having Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.Perhaps, ring A is optional by the phenyl of halogeno-group or OH replacement.
In another embodiment of the invention, ring A is optional substituted phenyl, 5-6 unit's heterocycle or heteroaryl ring.Preferred ring A comprises phenyl or has 1 heteroatomic 5 yuan of heteroaryl that wherein said ring A has two Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.Perhaps, ring A is phenyl, 1-pyrrolidyl or 1-pyrryl, has at the most two and is selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.
In another embodiment, ring A has two Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.Preferably, ring A is a phenyl, has at the most two and is selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
In another embodiment, ring A is aryl or 5-10 unit's heteroaromatic or heterocyclic radical, has four Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.Preferably, ring A is phenyl, indyl or pyrryl, has at the most two and is selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.Perhaps, ring A is phenyl or pyrryl, has at the most two and is selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.Perhaps, ring A is phenyl or pyrryl, has at the most two and is selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
In another embodiment, ring A is phenyl, piperidino, 1-pyrryl, thienyl, 2-methyl-indoles-1-base, 3, and the 4-methylenedioxyphenyl has two R at the most 7Substituting group, described substituting group is selected from H, Cl, Br, F, CF 3, CN, Me ,-SMe, Et ,-OH ,-OCH 3,-OCF 3,-C (O) CH 3Or phenoxy group.Preferably, ring A is phenyl, piperidino, 1-pyrryl, thienyl, 2-methyl-indoles-1-base, 3, and the 4-methylenedioxyphenyl has two R at the most 7Substituting group, described substituting group is selected from H, Cl, Br, F, CF 3, CN, Me ,-SMe, Et ,-OH ,-OCH 3,-OCF 3,-C (O) CH 3Or phenoxy group.Perhaps, ring A is phenyl, piperidino, 1-pyrryl, thienyl, 2-methyl-indoles-1-base, 3, and the 4-methylenedioxyphenyl has two R at the most 7Substituting group, described substituting group is selected from H, Cl, Br, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCF 3Or phenoxy group.Perhaps, ring A is phenyl, piperidino or 1-pyrryl, has two R at the most 7Substituting group, described substituting group is selected from H, Cl, Br, F, CF 3, Me ,-OH ,-OCF 3Or phenoxy group.
In another embodiment, the invention provides formula IA, formula IB or formula IC compound:
R wherein Z1Be-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2,-C (O) N (CN) R ', the optional substituted 1-4 of having heteroatomic 5-unit's heteroaryl ring or optional substituted pyrans-4-ketone group that is selected from O, S or N.
In a kind of embodiment of formula IA compound, R 1And R 2All be optional substituted C 1-4Aliphatic group, R 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl.Preferred R 1And R 2Comprise methyl, ethyl or propyl group.Preferred R 3Comprise ethyl, propyl group or butyl.Preferred ring A comprises having Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In a kind of embodiment of formula IB compound, R 1And R 2All be optional substituted C 1-4Aliphatic group, R 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A is the first aryl of optional substituted 5-6, heteroaryl or heterocycle.Preferred R 1And R 2Comprise methyl, ethyl or propyl group.Preferred R 3Comprise ethyl, propyl group or butyl.Preferred ring A comprises phenyl or has the 5-6 unit's heteroaryl or the heterocyclic ring of an azo-cycle atom, wherein encircles A and have Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In a kind of embodiment of formula IC compound, R 1And R 2All be optional substituted C 1-4Aliphatic group, R Z1Be optional substituted have 2 first heteroaryl rings of heteroatomic 5-that are selected from O and N at the most, R 4Be hydrogen, and ring A is optional substituted phenyl.Preferred R 1And R 2Comprise methyl, ethyl or propyl group.Preferred ring A comprises having Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In a kind of embodiment of formula IA compound, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute 5-6 unit heterocycle together, R 3Be optional substituted C 1-4Aliphatic group or aryl, R 4Be hydrogen, and ring A is optional substituted phenyl.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute optional substituted 1-pyrrolidyl or piperidino together.Preferred R 3Comprise optional substituted ethyl, propyl group, butyl or phenyl.Preferred ring A comprises having Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In another embodiment, R 1And R 2All be methyl or ethyl, R 3Be ethyl or propyl group, R 4Be hydrogen, and encircle the phenyl that A is the 2-replacement, wherein said substituting group is Q-R X, wherein Q is a key.
In a kind of embodiment of formula IB, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have 2 first heterocycles of heteroatomic 3-6 at the most, R 3Be optional substituted C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl, 5 yuan of heteroaryls or 6-unit heterocyclic radical.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute optional substituted 1-azetidinyl, 1-pyrrolidyl, piperidino or 1-piperazinyl together.Preferred R 3Comprise optional substituted ethyl, propyl group or butyl.Preferred ring A comprises phenyl or has 1 first heteroaryl of heteroatomic 5-that wherein said ring A has two Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In one embodiment, R 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute 1-tetramethyleneimine basic ring together, R 3Be ethyl or propyl group, R 4Be hydrogen, and ring A is optional substituted phenyl, piperidyl or pyrryl.Preferred embodiment be such, wherein encircle A and have at the most two and be selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.
In one embodiment, R 1And R 2All be methyl or ethyl, R 3Be ethyl, R 4Be hydrogen, and the ring A be phenyl, piperidino or 1-pyrryl, wherein encircle A and have two substituting groups that are selected from halogeno-group or OH at the most.
In a kind of embodiment of formula IC, R 1And R 2All be C 1-4Aliphatic group, R Z1Be to have two first heteroaryls of heteroatomic 5-at the most, R 4Be hydrogen, and ring A is optional substituted phenyl.Preferred R 1And R 2Comprise methyl, ethyl or propyl group.Preferred R Z1Comprise optional substituted  azoles base.Preferred ring A comprises having Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In a kind of embodiment of formula IA compound, R 1And R 2All be C 1-4Aliphatic group, R 3Be optional substituted C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl.Preferred R 1And R 2Comprise methyl or ethyl.Preferred R 3Comprise optional substituted ethyl or propyl group.Preferred ring A comprises having Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In a kind of embodiment of formula IA compound, R 1And R 2All be methyl or ethyl, R 3Be ethyl or propyl group, R 4Be hydrogen, and ring A is optional by the phenyl of halogeno-group or OH replacement.
In a kind of embodiment of formula IB, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have the 4-6 unit heterocycle of 2 nitrogen heteroatoms at the most, R 3Be optional substituted C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl or 5-unit heteroaryl.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute optional substituted 1-pyrrolidyl or 1-piperazinyl together.Preferred R 3Comprise optional substituted ethyl, propyl group or butyl.Preferred ring A comprises phenyl or has 1 first heteroaryl of heteroatomic 5-that wherein said ring A has two Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In one embodiment, R 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute 1-tetramethyleneimine basic ring together, R 3Be ethyl or propyl group, R 4Be hydrogen, and ring A is optional substituted phenyl, piperidyl or pyrryl.Preferred embodiment be such, wherein encircle A and have at the most two and be selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.
In one embodiment, R 1And R 2All be methyl or ethyl, R 3Be ethyl, R 4Be hydrogen, and the ring A be phenyl, piperidino or 1-pyrryl, wherein encircle A and have two substituting groups that are selected from halogeno-group or OH at the most.
In a kind of embodiment of formula IA compound, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute 4-6 unit heterocycle together, R 3Be optional substituted C 1-4Aliphatic group or aryl, R 4Be hydrogen, and ring A is optional substituted phenyl, 5-unit's heteroaryl or 6-unit heterocyclic radical.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Formation has the 4-6 unit heterocycle of 2 nitrogen heteroatoms at the most together, comprises 1-azetidinyl, 1-pyrrolidyl or 2,5-pyrrolin base.Preferred R 3Comprise optional substituted ethyl, propyl group, butyl or phenyl.Preferred ring A comprises having Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In a kind of embodiment of formula IA compound, R 1And R 2All be methyl or ethyl, R 3Be ethyl or propyl group, R 4Be hydrogen, ring A is optional by the phenyl of halogeno-group or OH replacement.
In a kind of embodiment of formula IB, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have the 4-6 unit heterocycle of 2 nitrogen heteroatoms at the most, R 3Be optional substituted C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl, 5-6 unit's heterocycle or heteroaryl ring.Preferred R 1And R 2Comprise methyl, ethyl or propyl group; Perhaps R 1And R 2Constitute optional substituted 1-azetidinyl, 1-pyrrolidyl, 2 together, 5-dihydro-1H-pyrryl, piperidino or 1-piperazinyl.Preferred R 3Comprise optional substituted ethyl, propyl group or butyl.Preferred ring A comprises phenyl or has 1 first heteroaryl of heteroatomic 5-that wherein said ring A has two Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In a kind of embodiment of formula IB, R 1And R 2All be C 1-4Aliphatic group, R 3Be ethyl, propyl group or butyl, R 4Be hydrogen, ring A is phenyl, 1-pyrrolidyl or 1-pyrryl, has at the most two and is selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.
In a kind of embodiment of formula IB, R 1And R 2All be methyl or ethyl, R 3Be ethyl, R 4Be hydrogen, ring A is phenyl, 1-pyrrolidyl or 1-pyrryl, has at the most two and is selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.Preferably encircle A in this embodiment and comprise optional substituted piperidino or 1-pyrryl.
In a kind of embodiment of formula IC, R 1And R 2All be C 1-4Aliphatic group, R Z1Be to have two first heteroaryls of heteroatomic 5-at the most, R 4Be hydrogen, and ring A is optional substituted phenyl.Preferred R 1And R 2Comprise methyl, ethyl or propyl group.Preferred R Z1Comprise optional substituted  azoles base, cyano group or aliphatic group-oxygen ylmethyl.Preferred ring A comprises having Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In one embodiment, R 1And R 2All be C 1-4Aliphatic group, R 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A have two Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In one embodiment, R 1And R 2All be methyl or ethyl, R 3Be propyl group, normal-butyl or isobutyl-, R 4Be hydrogen, and ring A is phenyl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
In one embodiment, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute optional substituted have 2 first heterocycles of heteroatomic 5-6 at the most, R together 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A is aryl or 5-10 unit's heteroaromatic or heterocyclic radical, has four Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
In one embodiment, R 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute optional substituted have 2 first heterocycles of heteroatomic 5-6 at the most, R together 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A is phenyl, indyl or pyrryl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
In one embodiment, R 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute optional substituted pyrrolidyl or piperidines basic ring together, R 3Be methyl or ethyl, R 4Be hydrogen, and ring A is phenyl or pyrryl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
In one embodiment, R 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute pyrrolidyl or 3-hydroxy-piperdine basic ring together, R 3Be methyl or ethyl, R 4Be hydrogen, and ring A is phenyl or pyrryl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
In a kind of embodiment of formula IC, R 1And R 2All be C 1-4Aliphatic group, R Z1Be optional substituted phenyl or have at the most 3 heteroatomic 5-unit heteroaromatic group, R 4Be hydrogen, and ring A is phenyl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.Perhaps, R in this embodiment Z1Be-C (O) NH (C 1-4Aliphatic group).
In a kind of embodiment of formula I, R 1And R 2All be methyl or ethyl, R Z1Be optional substituted phenyl or  di azoly, R 4Be hydrogen, and ring A is phenyl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
In another embodiment, ring A is optional substituted phenyl, and formula IIA or formula IIB compound are provided:
Figure A20048002502700821
R wherein 1, R 2, R 3, R 7With y be as mentioned with this paper subclass institute General Definition.
Some preferred embodiment in, R 1And R 2Not hydrogen.In some other embodiment, R 1And R 2Not hydrogen, and R 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.In preferred embodiment, R 1And R 2All be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.Other preferred embodiment in, work as R 1And R 2Be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2During replacement, preferred R 1And R 2Group is optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl.Most preferred R 1And R 2Group comprise as shown in table 2 below those.
Other preferred embodiment in, R 1Or R 2One of be hydrogen, R 1Or R 2Another be to have 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur.In other embodiments, R 1Or R 2One of be hydrogen, R 1Or R 2Another be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
Just above with wherein R described herein 1Or R 2Be those embodiments that have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit's aryl rings or have the first saturated or unsaturated ring of part of 0-3 heteroatomic 3-7 that independently is selected from N, O or S, preferably R 1And R 2Group is selected from:
Figure A20048002502700831
Figure A20048002502700841
R wherein 5And R 6Be defined as preamble, z is 0-4.Most preferred comprise as shown in table 2 below those.
In other embodiments, with regard to formula IIA or formula IIB compound, R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having the first heterocyclic ring of heteroatomic 3-8 that independently is selected from nitrogen, sulphur or oxygen.Some preferred embodiment in, R 1And R 2Nitrogen-atoms with their institute's bondings constitutes 3-8 unit heterocyclic radical, is selected from:
Figure A20048002502700842
R wherein 5And R 6Be defined as preamble, z is 0-4.
Other preferred embodiment in, with regard to formula IIA or formula IIB compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff), piperidines-1-base (dd), piperazine-1-base (cc) or morpholine-4-base (ee) together.
As institute's general description above, work as R 1Or R 2Be to have 0-5 when independently being selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or having the unsaturated ring of the first saturated or part of 0-3 heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur, perhaps work as R 1And R 2When constituting the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical that independently is selected from nitrogen, oxygen or sulphur or heteroaryl ring with the nitrogen-atoms of their institute's bondings, this ring can be by four independent R that occur at the most 5Replace.In preferred embodiment, z is 0-2.Other preferred embodiment in, z is 0, this ring is unsubstituted.Preferred R 5Group is halogen, CN, NO when existing 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ', NRC (O) OR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 5Group is Cl, Br, F, CF independently of one another 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.Most preferred R 5Group comprise as shown in table 2 below those.In preferred embodiment, R 6Group is hydrogen or optional substituted group, and described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-C (O) OR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 6Group is H, Me, CF independently of one another 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.Most preferred R 6Group comprise as shown in table 2 below those.
In other embodiments, with regard to as mentioned with the formula IIA compound of this paper subclass institute general description with regard to, R 3By the atomic linkage beyond deoxygenation or the nitrogen in carbonylic carbon atom.
In other embodiments, with regard to general formula I IA or formula IIB compound, R 3Be further defined as-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is optional substituted C 2-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, its condition be Q by carbon atom bonding in carbonylic carbon atom.
Other preferred embodiment in, with regard to general formula I IA or formula IIB compound, R 3Be further defined as Q-R XWherein Q is a key, R XBe optional substituted group, be selected from C 2-8Aliphatic group, C 6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the heterocyclic ring of 3-10 annular atoms.
Other preferred embodiment in, R 3Be optional substituted group, be selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' or-(CH 2) 2SR '.
Other preferred embodiment in, with regard to general formula I IA or formula IIB compound, R 3Be further defined as-CF 2H ,-CF 3,-CHCl 2,-CHBr 2,-CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is a key, R XBe optional substituted group, be selected from C 2-8Aliphatic group, C 6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the heterocyclic ring of 3-10 annular atoms.
Other preferred embodiment in, R 3Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
Other preferred embodiment in, R 3Be H, Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.Most preferred R 3Group comprise as shown in table 2 below those.
In preferred embodiment, R 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.Most preferred R 4Group comprise as shown in table 2 below those.
In preferred embodiment, y is 0-2.Other preferred embodiment in, y is 0, the ring A be unsubstituted.In preferred embodiment, R 7Group is hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, haloalkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2In preferred embodiment, R 7Group is H, Cl, Br, F, CF independently of one another 3,-CHF 2, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCF 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.Most preferred R 7Group comprise as shown in table 2 below those.
In another embodiment, formula IIB compound have at least one, preferred whole following features:
A.R 1Be hydrogen or C 1-6Aliphatic group, R 2Be optional substituted C 1-6Aliphatic group, perhaps R 1And R 2Constitute the first saturated rings of optional substituted 4-7 together, wherein said ring contains second heteroatoms that is selected from O or N alternatively;
B.R 3Be methyl, ethyl, propyl group, sec.-propyl, butyl ,-CH 2CCH ,-CH 2C (O) CH 3, pyrans-2-ylmethyl, optional substituted phenyl, cyclopentyl, cyclohexyl, 3-chloro-phenyl-or 3-tolyl;
C. encircling A is phenyl, piperidino, 1-pyrryl, thienyl, 2-methyl-indoles-1-base, 3, and 4-methyl dioxy base phenyl has two R at the most 7Substituting group, described substituting group is selected from H, Cl, Br, F, CF 3, CN, Me ,-SMe, Et ,-OH ,-OCH 3,-OCF 3,-C (O) CH 3Or phenoxy group.
In another embodiment, formula IIB compound have at least one, preferred whole following features:
A.R 1Be hydrogen or C 1-6Aliphatic group, R 2Be optional substituted C 1-6Aliphatic group, furyl methyl, allyl group or benzyl, perhaps R 1And R 2Be 4-ethoxycarbonyl-piperidino, pipecoline base, 2-hydroxymethyl piperidine base, 3-hydroxy piperidine base, 4-isobutylamino manthanoate-piperidino, 3-diethylaminocarbonyl--piperidino, piperidino, 1-pyrrolidyl, 2-ethoxycarbonyl pyrrolidyl, N-morpholino base, 3 together, 5-dimethyl-N-morpholino base, 4-methylpiperazine base, 4-hydroxyethyl piperazine base, 1-pyrryl, 2,4-dihydro-1-pyrryl, 1-azetidinyl or 1-azepan base;
B.R 3Be methyl, ethyl, propyl group, sec.-propyl, butyl ,-CH 2CCH ,-CH 2C (O) CH 3, pyrans-2-ylmethyl, optional substituted phenyl, cyclopentyl, cyclohexyl, 3-chloro-phenyl-or 3-tolyl;
C. encircling A is phenyl, piperidino, 1-pyrryl, thienyl, 2-methyl-indoles-1-base, 3, and 4-methyl dioxy base phenyl has two R at the most 7Substituting group, described substituting group is selected from H, Cl, Br, F, CF 3,-CHF 2, CN, Me ,-SMe, Et ,-OH ,-OCH 3,-OCF 3,-C (O) CH 3Or phenoxy group.
In another embodiment, formula IIB compound have at least one, preferred whole following features:
A.R 1Be hydrogen or C 1-4Aliphatic group, R 2Be C 1-4Aliphatic group, furyl methyl, allyl group or benzyl, perhaps R 1And R 2Be 4-ethoxycarbonyl-piperidino, pipecoline base, 4-isobutylamino manthanoate-piperidino, 3-diethylaminocarbonyl--piperidino, piperidino, 1-pyrrolidyl, 2-ethoxycarbonyl pyrrolidyl, 4-methylpiperazine base, 2 together, 4-dihydro-1-pyrryl, 1-azetidinyl or 1-azepan base;
B.R 3Be methyl, ethyl, propyl group, butyl, optional substituted phenyl, cyclopentyl or 3-tolyl methyl;
C.R 4Be hydrogen;
D. encircling A is phenyl, piperidino, 1-pyrryl, thienyl, 2-methyl-indoles-1-base, 3, and 4-methyl dioxy base phenyl has two R at the most 7Substituting group, described substituting group is selected from H, Cl, Br, F, CF 3,-CHF 2, Me, Et ,-OH ,-OCH 3,-OCF 3Or phenoxy group.
In another embodiment, formula IIB compound have at least one, preferred whole following features:
A.R 1Be hydrogen or C 1-4Aliphatic group, R 2Be C 1-4Aliphatic group, furyl methyl, allyl group or benzyl, perhaps R 1And R 2Be 4-ethoxycarbonyl-piperidino, pipecoline base, piperidino, 1-pyrrolidyl, 4-methylpiperazine base, 2 together, 4-dihydro-1-pyrryl or 1-azetidinyl;
B.R 3Be methyl, ethyl or propyl group;
C.R 4Be hydrogen;
D. encircling A is phenyl, piperidino or 1-pyrryl, has two R at the most 7Substituting group, described substituting group is selected from H, Cl, Br, F, CF 3,-CHF 2, Me ,-OH ,-OCF 3Or phenoxy group.
Other preferred embodiment in, y is 1, these compounds have general formula III A:
Figure A20048002502700891
R wherein 1, R 2, R 3And R 4Be as mentioned with this paper institute-as R is described 7Be halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-4Alkyl, aryl, aralkyl ,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
In another embodiment, these compounds have general formula III A, wherein R 7Be hydrogen.
Other preferred embodiment in, The compounds of this invention is according to formula III A definition, one or more or whole R 1, R 2, R 3Or R 4Be further defined according to one or more or whole following groups:
A.R 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace;
B.R 3By the atomic linkage beyond deoxygenation or the nitrogen in carbonylic carbon atom; Perhaps
C.R 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
Other preferred embodiment in, The compounds of this invention is according to formula III A definition, one or more or whole R 1, R 2, R 3Or R 4Be further defined according to one or more or whole following groups:
A.R 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace;
B.R 3Be-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is optional substituted C 2-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, its condition be Q by carbon atom bonding in carbonylic carbon atom; Perhaps
C.R 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
Other preferred embodiment in, The compounds of this invention is according to formula III A definition, one or more or whole R 1, R 2, R 3Or R 4Be further defined according to one or more or whole following groups:
A.R 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace;
B.R 3Be-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is a key, R XBe optional substituted group, be selected from C 2-8Aliphatic group, C 6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the heterocyclic ring of 3-10 annular atoms; Perhaps
C.R 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
Other preferred embodiment in, The compounds of this invention is according to formula III A definition, one or more or whole R 1, R 2, R 3Or R 4Be further defined according to one or more or whole following groups:
A.R 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace;
B.R 3Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2Perhaps
C.R 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
Other preferred embodiment in, The compounds of this invention is according to formula III A definition, one or more or whole R 1, R 2, R 3, R 4Or R 7Be further defined according to one or more or whole following groups:
A.R 1And R 2Be optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl;
B.R 3Be H, Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl;
C.R 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy; Perhaps
D.R 7Be Cl, Br, F, CF 3,-CHF 2, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
Other preferred embodiment in, The compounds of this invention is according to formula III A definition, one or more or whole R 1, R 2, R 3, R 4Or R 7Be further defined according to one or more or whole following groups:
A.R 1And R 2Be optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl;
B.R 3Be H, Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl;
C.R 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy; Perhaps
D.R 7Be hydrogen.
In another embodiment, formula III A compound have at least one, preferred whole following features:
A.R 1And R 2All be methyl, perhaps R 1And R 2Constitute 1-pyrrolidyl, N-morpholinyl, piperidino or 4-methyl piperidine base together;
B.R 7Be hydroxyl, methoxyl group or hydrogen;
C.R 4Be hydrogen; With
D.R 3Be ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, but-1-ene-4-base, cyclopentyl ethyl or phenyl.
In another embodiment, formula III A compound have at least one, preferred whole following features:
A.R 1And R 2All be methyl, perhaps R 1And R 2Constitute 1-pyrrolidyl, N-morpholinyl, piperidino or 4-methyl piperidine base together;
B.R 7Be hydroxyl or hydrogen;
C.R 4Be hydrogen; With
D.R 3Be ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, but-1-ene-4-base, cyclopentyl ethyl or phenyl.
In another embodiment, formula III A compound have at least one, preferred whole following features:
A.R 1And R 2It all is methyl;
B.R 7It is hydroxyl;
C.R 4Be hydrogen; With
D.R 3It is ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group or but-1-ene-4-base.
In another embodiment, formula III A compound have at least one, preferred whole following features:
A.R 1And R 2It all is methyl;
B.R 7It is hydroxyl;
C.R 4Be hydrogen; With
D.R 3Be optional substituted phenyl, preferred unsubstituted phenyl.
In another embodiment, formula III A compound have at least one, preferred whole following features:
A.R 1And R 2Constitute 1-pyrrolidyl, N-morpholinyl, piperidino or 4-methyl piperidine base together;
B.R 7It is hydroxyl;
C.R 4Be hydrogen; With
D.R 3Be ethyl or propyl group.
In another embodiment, formula III A compound have at least one, preferred whole following features:
A.R 1And R 2All be methyl, perhaps R 1And R 2Constitute 4-methyl piperidine base together;
B.R 7It is hydroxyl;
C.R 4Be hydrogen; With
D.R 3It is ethyl, propyl group, butyl, isobutyl-or but-1-ene-4-base.
In another embodiment, formula III A compound have at least one, preferred whole following features:
A.R 1And R 2One of be hydrogen or C 1-4Aliphatic group, R 1And R 2Another be C 1-4Aliphatic group or benzyl, perhaps R 1And R 2Constitute 1-pyrrolidyl, piperidino or N-morpholine basic ring together;
B.R 3Be C 1-4Aliphatic group;
C.R 7Be hydrogen; With
D.R 4Be C 1-4Aliphatic group, phenyl, pyridyl or thienyl.
In another embodiment, formula III A compound have at least one, preferred whole following features:
A.R 1And R 2One of be hydrogen, methyl or ethyl, R 1And R 2Another be methyl, ethyl or benzyl;
B.R 3Be ethyl or propyl group;
C.R 7Be hydrogen; With
D.R 4Be methyl, phenyl, pyridyl or thienyl.
Other preferred embodiment in, y is 1, compound has general formula III B:
Figure A20048002502700941
R wherein 1, R 2, R 3And R 4Be as mentioned with this paper institute general description, R 7Be halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-4Alkyl, aryl, aralkyl ,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2, SO 2R ' or-S (O) 2N (R ') 2
Other preferred embodiment in, The compounds of this invention is according to formula III B definition, one or more or whole R 1, R 2, R 3Or R 4Be further defined according to one or more or whole following groups:
A.R 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace;
B. each R that occurs 3Be optional substituted group independently, be selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' or-CON (R ') 2With
C. each R that occurs 4Be hydrogen, halogen, CN, NO independently 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2, SO 2R ' or-S (O) 2N (R ') 2
Other preferred embodiment in, The compounds of this invention is according to formula III B definition, one or more or whole R 1, R 2, R 3Or R 4Be further defined according to one or more or whole following groups:
A.R 1And R 2Be optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl;
B. each R that occurs 3Be Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH or optional substituted phenyl or benzyl; With
C. each R that occurs 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CO (C 1-4Alkyl) ,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2(C 1-4Alkyl) ,-SO 2NH 2,-SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
Other preferred embodiment in, The compounds of this invention is according to formula III B definition, one or more or whole R 1, R 2, R 3, R 4Or R 7Be further defined according to one or more or whole following groups:
A.R 1And R 2Be optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl;
B. each R that occurs 3Be Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH or optional substituted phenyl or benzyl;
C. each R that occurs 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CO (C 1-4Alkyl) ,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2(C 1-4Alkyl) ,-SO 2NH 2,-SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy; With
D.R 7Be Cl, Br, F, CF 3, OCF 3, Me, Et, propyl group, normal-butyl, the tertiary butyl, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CO (C 1-4Alkyl) ,-CONH 2,-CON (CH 3) 2,-COOCH 3,-OH ,-SCH 3,-CH 2OH ,-NHCOCH 3,-SO 2(C 1-4Alkyl) ,-SO 2NH 2,-SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
In another embodiment, formula III B compound have at least one, preferred whole following features:
A.R 1And R 2One of be hydrogen or C 1-4Aliphatic group, R 1And R 2Another be C 1-4Aliphatic group or benzyl, perhaps R 1And R 2Constitute 1-pyrrolidyl, piperidino or N-morpholine basic ring together;
B.R 3Be C 1-4Aliphatic group;
C.R 7Be hydrogen; With
D.R 4Be C 1-4Aliphatic group, phenyl, pyridyl or thienyl.
In another embodiment, formula III B compound have at least one, preferred whole following features:
A.R 1And R 2One of be hydrogen, methyl or ethyl, R 1And R 2Another be methyl, ethyl or benzyl;
B.R 3Be ethyl or propyl group;
C.R 7Be hydrogen; With
D.R 4Be methyl, phenyl, pyridyl or thienyl.
In another embodiment, ring A is optional substituted phenyl, and formula IIC is provided compound:
Figure A20048002502700971
R wherein 1, R 2, R 3, R 7With y be as mentioned with this paper subclass institute General Definition;
R wherein Z1Be-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2,-C (O) N (CN) R ' or optional substituted ring, described ring is selected from:
Figure A20048002502700972
In some embodiments, R Z1Be-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2,-C (O) N (CN) R '.Preferred R Z1Comprise-SO 2NHR ' ,-NHSO 2R ' or-C (O) N (CN) R '.Some preferred embodiment in, R Z1Be-SO 2R ' ,-NHSO 2R ' or-C (O) N (CN) R '.In some other embodiment, R Z1Be to be selected from following ring:
Figure A20048002502700981
Wherein said ring is alternatively by R ' or OR ' replacement.
Other preferred embodiment in, The compounds of this invention is according to formula IIC definition, one or more or whole R 1, R 2Or R 4Be further defined according to one or more or whole following groups:
A.R 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace; With
B. each R that occurs 4Be hydrogen, halogen, CN, NO independently 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2, SO 2R ' or-SO 2N (R ') 2
Other preferred embodiment in, The compounds of this invention is according to formula IIC definition, one or more or whole R 1, R 2Or R 4Be further defined according to one or more or whole following groups:
A.R 1And R 2Be optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl; With
B. each R that occurs 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CO (C 1-4Alkyl) ,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2(C 1-4Alkyl) ,-SO 2NH 2,-SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
Other preferred embodiment in, The compounds of this invention is according to formula IIC definition, one or more or whole R 1, R 2, R 4Or R 7Further defined according to one or more or whole following groups:
A.R 1And R 2Be optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl;
B. each R that occurs 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CO (C 1-4Alkyl) ,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2(C 1-4Alkyl) ,-SO 2NH 2,-SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy; With
C.R 7Be Cl, Br, F, CF 3, OCF 3, Me, Et, propyl group, normal-butyl, the tertiary butyl, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CO (C 1-4Alkyl) ,-CONH 2, CON (CH 3) 2,-COOCH 3,-OH ,-SCH 3,-CH 2OH ,-NHCOCH 3,-SO 2(C 1-4Alkyl) ,-SO 2NH 2,-SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
In another embodiment, ring A is optional substituted phenyl, and formula III C is provided compound:
Figure A20048002502700991
R wherein 1, R 2, R 3And R 7Be as mentioned with this paper subclass institute General Definition;
R wherein Z1Be-SO 2R ' ,-NHSO 2R ' ,-C (O) N (CN) R ' or optional substituted ring, described ring is selected from:
Figure A20048002502701001
In some embodiment of formula III C, R 1And R 2Be equal to, they all are methyl or ethyl.Perhaps, R 1And R 2Constitute piperidino, 1-piperazinyl or 1-pyrrolidyl together.
In some embodiments, ring A is optional substituted phenyl, and formula IVC is provided compound:
R wherein Z2Be cyano group or halogeno-group, R 7, y, R 1, R 2And R 4Be as hereinbefore defined.In some embodiment of formula IVC compound, if R 1And R 2While all is a hydrogen, then encircles A and is not
Figure A20048002502701003
Wherein X is O, NH, S or CH 2, two benzyl rings are respectively optional naturally substituted.
In some embodiment of formula IVC, get rid of following compounds:
R 1 R 2 R Z1 R 4 Ring A
H The 4-pyridyl F H The 2-F-4-Cl-phenyl
H 3-methyl-pyridin-4-yl I H The 2-F-4-Cl-phenyl
H Quinoline-6-base F H 3-formyl radical phenyl
H Quinoline-6-base Br H The 3-cyano-phenyl
H 1H-indazole-3-base Cl H 2-CF 3-phenyl
H -CH 2-CCH Br H Phenyl
H H Br H Phenyl
H H F H Phenyl
H Phenyl CN H Phenyl
H Phenyl CN H The 4-Cl-phenyl
H The 4-tolyl CN H The 4-Cl-phenyl
H Ph CN H The 4-OMe-phenyl
H The 4-tolyl CN H Phenyl
H The 3-tolyl CN H Phenyl
H The 3-Cl-phenyl CN H Phenyl
H H CN H Phenyl
H Methoxy ethyl CN H Phenyl
H Allyl group CN H Phenyl
H Cyclopropyl CN H Phenyl
H The 1-naphthyl CN H Phenyl
H -CH 2-C(O)NH 2 CN H Phenyl
H -CH 2C(O)OEt CN H Phenyl
Me The cyanogen methyl CN H Phenyl
H 3-CF 3-phenyl CN H Phenyl
H Isobutyl- Cl H Phenyl
H H Cl H Phenyl
H Ph Cl H Phenyl
H Acyl group Br H Phenyl
H Acyl group CN H Phenyl
H The 6-quinolyl Br H The 4-OMe-phenyl
H The 6-quinolyl Br H The 3-Cl-phenyl
H The 6-quinolyl Br H The 3-Br-phenyl
H The 6-quinolyl Br H The 3-OMe-phenyl
H The 6-quinolyl Br H 3-CF 3-4-Cl-phenyl
H The 6-quinolyl Br H 3-CF 3-4-CN-phenyl
H The 6-quinolyl Br H The 4-cyano-phenyl
H The 6-quinolyl F H 4-NO 2-phenyl
H The 6-quinolyl F H 3-NO 2-phenyl
H The 6-quinolyl F H 4-N(Me 2)-phenyl
H The 6-quinolyl F H 4-(N-morpholino base)-phenyl
In some other embodiment of formula IVC, get rid of following compounds:
R 1And R 2Constitute together R Z1 R 4 Ring A
N-morpholino base F H Phenyl
2H-pyridazin-3-one-1-base Cl H Phenyl
The N-piperidyl Cl H Phenyl
N-morpholino base Cl H Phenyl
The N-piperidyl Cl H 4-NO 2-phenyl
N-morpholino base CN H The 2-OH-phenyl
Above the representative example with compound described herein is described in table 2 below.
Compound of the present invention can be used as the inhibitor of ionic channel, preferred voltage-gated sodium channel and N-type calcium channel.In some exemplary embodiment, The compounds of this invention can be used as the inhibitor of NaV1.2.In some exemplary embodiment, The compounds of this invention can be used as the inhibitor of NaV1.5.In some exemplary embodiment, The compounds of this invention can be used as the inhibitor of NaV1.8.In other embodiments, The compounds of this invention can be used as the inhibitor of NaV1.8 and CaV2.2.In other embodiments, The compounds of this invention can be used as the inhibitor of CaV2.2.In other embodiments, The compounds of this invention can be used as the double inhibitor of NaV1.8 and TTX-susceptibility ionic channel, for example NaV1.3 or NaV1.7.
Table 2
Figure A20048002502701021
Figure A20048002502701051
Figure A20048002502701061
Figure A20048002502701071
Figure A20048002502701081
Figure A20048002502701091
Figure A20048002502701101
Figure A20048002502701111
Figure A20048002502701121
Figure A20048002502701131
Figure A20048002502701141
Figure A20048002502701151
Figure A20048002502701161
Figure A20048002502701171
Figure A20048002502701191
Figure A20048002502701211
Figure A20048002502701231
Figure A20048002502701241
Figure A20048002502701281
Figure A20048002502701291
Figure A20048002502701301
Figure A20048002502701321
Figure A20048002502701341
Figure A20048002502701351
Figure A20048002502701361
Figure A20048002502701391
Figure A20048002502701401
4. universal synthesis method:
The compounds of this invention generally can be prepared by the method that those skilled in the art know about similar compound, and following generalized flowsheet and following preparation example are described.
Following flow process I describes the general conditions via amidine and alkoxyl group alkylidene group malonic ester synthesis type IB, IIB, IIIB compound.
Flow process I:
Figure A20048002502701411
Suitable alkoxyl group alkylidene group malonic ester 1 (as follows, flow process III) is handled with amidine 2,4,6 (as follows, flow process II), generated corresponding pyrimidone 3,5,7.With post chlorization with use amine R 1R 2The NH nucleophilic displacement obtains pyrimidines i B, IIB, IIIB.
Following flow process II describes to prepare among the above-mentioned flow process I the synthetic of IB, IIB, the necessary amidine 2,4,6 of IIIB.
Flow process II:
Figure A20048002502701421
Nitrile 2a, 4a, 4c are handled with hexamethyl two silicon Lithium Azides,, generate amidine 2,4,6 succeeded by acid removal monosilane baseization.Select as an alternative, the Pinner reaction of 2a, 4a, 4c generates amidine 2,4,6.
Following flow process III is depicted in and prepares the synthetic of IB, IIB, the necessary alkoxyl group alkylidene group of IIIB malonic ester 1 among the above-mentioned flow process I.
Flow process III:
Figure A20048002502701422
Malonic ester 1a is handled with suitable ortho-formiate, obtain alkoxyl group alkylidene group malonic ester 1.
Following flow process IV describes to use the C2 halogenated pyrimidine via cross-coupling reaction synthetic IB, IIB, IIIB.
Flow process IV:
Alkoxyl group alkylidene group malonic ester 1 usefulness urea is handled, generated carboxyuracil 8, be converted into dichloro pyrimidine 9 with phosphoryl chloride subsequently.Carry out amination at 4, obtain 2-chloropyrimide 10, carry out the Suzuki coupling, obtain required pyrimidines i B, IIB, IIIB at C2.
Following flow process V describes to use the pyrimidine of the synthetic C2 azepine replacement of C2 halogenated pyrimidine, with the heteroatoms nucleophilic reagent displacement pyrimidine C2 that introduces.
Flow process V:
Nucleophilicity amine in the presence of proton scavengers that Chloropyrimide 10 usefulness are suitable is handled, and generates 11; Do not have under the situation of abundant nucleophilicity at the amine of introducing, generate the amine negatively charged ion,, obtain 11 succeeded by with electrophilic reagent 10 arylations with highly basic, for example sodium hydride.
Following flow process VI describes to use C5 halogenated pyrimidine synthetic compound IA.
Flow process VI:
Figure A20048002502701441
Suitable alkynyl ester (alkynoate) 12 or keto esters 13 usefulness amidines are handled, generate pyrimidone 14, the latter experiences the electric bromination of C5 parent, obtains brominated pyrimidine ketone 15.Use the phosphoryl chloride chlorination,, obtain 17 succeeded by with the amine displacement that is fit to.C5 metallization succeeded by with aldehyde reaction, obtain hydroxy pyrimidine 18, the latter can be obtained IA by Mn (IV) oxidation easily.
Following flow process VII describes via polyphone Suzuki strategy synthetic compound IC, IIC, IIIC.
Flow process VII:
The chlorization of bromouracil 19 obtains dichloro brominated pyrimidine 20, and the latter is with suitable amine R 1R 2NH handles, experience C4 amination.At C5 the Suzuki cross-coupling taking place, obtains 2-chloropyrimide 22, subsequently with for boric acid ester 23a, 23b, 23c cross-coupling, obtain IC, IIC, IIIC.
Following flow process VIII describes to use propane dinitrile 24 synthetic C5 nitrile analogues 26,28,30.
Flow process VIII:
Figure A20048002502701461
Alkoxyl group alkylidene group propane dinitrile 24 usefulness amidines 2,4,6 are handled, obtain 5-cyanopyrimidine ketone 25,27,29.Chlorization and use amine R 1R 2The C4 amination that NH handles obtains C5 cyano derivative 26,28,30, and they itself are the useful precursors of IC, IIC, IIIC.
Flow process IX describes the preparation of IB derivative 31,32,33,34, and this also helps the synthetic of Compound I A.
Flow process IX:
Figure A20048002502701462
The saponification of IB obtains C5 carboxylicesters 31 (flow process X as follows); Select as an alternative, obtain alcohol 32 with lithium aluminium hydride reduction, the latter can obtain aldehyde 34 with Williamson ether synthesis method derivatize or with Mn (IV) oxidation.Except via the Grignard addition with reoxidize and generate the IA, aldehyde 34 also has the application (as follows) shown in flow process X.
Flow process X describes the application of carboxylicesters 31 in C5 derivative I C and IB preparation, for example C5 derivative 34 and C5 heteroaryl system 33,36,37.
Flow process X:
The alkylating of carboxylicesters 31 (on seeing, flow process IX) obtains IB, and subsequent transformation is an aldehyde 32, with the reaction of tolylsulfonyl ylmethyl isocyanide, obtains  azoles 33.Select as an alternative, the C5 carboxylicesters of activation 31 and with the nucleophilic reagent reaction that is fit to, obtain C5 acylamino derivative 34, and the reaction of activating carboxy acid's ester and hydrazine obtains hydrazides 35.Hydrazides 35 can be converted into multiple heterocycle, for example triazole 36 and  diazole 37.
Flow process XI describes the further application of nitrile 26 in the preparation of  diazole.
Flow process XI:
Nitrile 26 usefulness oxammonium hydrochlorides are handled, used acyl chlorides acidylate and dehydrocyclization subsequently, obtain 1,3,4- diazole.
Although above describe and describe some exemplary embodiment with this paper, what but will be figured out is that The compounds of this invention can be prepared according to the method for general description above, as long as use suitable raw material, by the general available method of those of ordinary skills.
5. purposes, preparation and administration
Pharmaceutically acceptable composition
Just as discussed above, the invention provides such compound, they are inhibitor of voltage-gated sodium-ion channel, thereby The compounds of this invention can be used for treating disease, obstacle and illness include but not limited to acute, chronic, neuropathic or inflammatory pain, sacroiliitis, migraine, bunch headache, trigeminal neuralgia, herpetic neurodynia, popularity neurodynia, epilepsy or epilepsy, the neurodegeneration obstacle, mental disorder (for example anxiety and depression), myotony, irregular pulse, dyskinesia, the neuroendocrine obstacle, ataxia, multiple sclerosis, irritable bowel syndrome and incontinence.Therefore, the present invention provides pharmaceutically acceptable composition on the other hand, and wherein these compositions comprise compound as described herein arbitrarily, comprise pharmaceutically acceptable carrier, auxiliary agent or vehicle alternatively.In some embodiments, these compositions further comprise one or more other treatment agent alternatively.
What also will be figured out is that some The compounds of this invention can exist for treatment with free form, perhaps takes the circumstances into consideration to be its pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates includes but not limited to the salt of pharmacy acceptable salt, ester, this class ester or other adductss or derivative arbitrarily, in case promptly can directly or indirectly provide compound or its meta-bolites or resistates as described herein to patient's administration of needs.
The salt that term used herein " pharmacy acceptable salt " expression is such, in rational medical judgment scope, they are suitable for contacting with the lower animal tissue with human body, do not have unsuitable toxicity, pungency, transformation reactions etc., match with rational interests/risk ratio.Any non-toxic salts or the ester salt of " pharmacy acceptable salt " expression The compounds of this invention are in case to recipient's administration, promptly can directly or indirectly provide The compounds of this invention or its to suppress active metabolite or resistates.Term used herein " it suppresses active metabolite or resistates " means that its meta-bolites or resistates also are the inhibitor of voltage-gated sodium-ion channel.
Pharmacy acceptable salt is well known in the art.For example, S.M.Berge etc. are at J.Pharmaceutical Sciences, and 1977,66, describe pharmacy acceptable salt among the 1-19 in detail, quote as a reference at this.The pharmacy acceptable salt of The compounds of this invention comprise from the inorganic and organic acid that is fit to and alkali deutero-those.The example of pharmaceutically acceptable non-toxic acid addition salt is the amide that generates with mineral acid or organic acid, mineral acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid for example, organic acid is acetate, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid for example, perhaps utilize the used additive method in this area, for example the salt of ion-exchange formation.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, glucoheptose salt, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, the 2-isethionate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, right-tosylate, the undecane hydrochlorate, valerate etc.Comprise basic metal, alkaline-earth metal, ammonium and N from suitable alkali deutero-salt +(C 1-4Alkyl) 4Salt.The quaternization of any alkaline nitrogen-containing group of compound is as disclosed herein also contained in the present invention.Can obtain water soluble or the oily product that maybe can be dispersed in water or the oil by this class quaternization.Representative basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.When suitable the time, other pharmacy acceptable salts comprise nontoxic ammonium salt, quaternary ammonium salt and amine cationic salts, utilize counter ion to generate, for example halogenide, oxyhydroxide, carboxylate salt, vitriol, phosphoric acid salt, nitrate, low-grade alkane sulfonate and arylsulphonate.
As indicated above, pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, auxiliary agent or vehicle in addition, described in the present invention, they comprise be suitable for required particular dosage form arbitrarily and all solvents, thinner or other liquid excipients, dispersion or suspension aids, tensio-active agent, isotonic agent, thickening or emulsifying agent, sanitas, solid binder, lubricant etc.Remington ' s Pharmaceutical Sciences, SixteenthEdition, E.W.Martin (Mack Publishing Co., Easton, Pa., 1980) known technology that is used to prepare the various carriers of pharmaceutically acceptable composition and is used for its preparation is disclosed.Except any conventional mounting medium is incompatible with The compounds of this invention, for example produce any bad biological effect or interact in any other component of pharmaceutically acceptable composition in harmful mode, its use is contained within the scope of the invention.Some examples that can serve as the material of pharmaceutically acceptable carrier include but not limited to ion-exchanger; Aluminum oxide; Aluminum stearate; Yelkin TTS; Serum protein, for example human serum albumin; Buffer substance, for example phosphoric acid salt; Glycine; Sorbic Acid or potassium sorbate; The partial glyceride mixture of saturated vegetable fatty acid; Water; Salt or ionogen, for example protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt; Colloid silica; Magnesium Trisilicate; Polyvinylpyrrolidone; Polyacrylic ester; The wax class; Polyethylene-polyoxytrimethylene-block polymer; Lanolin; Carbohydrate, for example lactose, dextrose plus saccharose; Starch, for example W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and rhodia; The tragacanth gum of pulverizing; Fructus Hordei Germinatus; Gelatin; Talcum; Vehicle, for example theobroma oil and suppository wax; Oils, for example peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycol, for example propylene glycol or polyoxyethylene glycol; Ester class, for example ethyl oleate and Laurate ethyl; Agar; Buffer reagent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol; Phosphate buffer soln; And other nontoxic compatible lubricant, for example Sodium Lauryl Sulphate BP/USP and Magnesium Stearates; According to preparation personnel's judgement, in composition, also can exist toner, releasing agent, Drug coating, sweeting agent, seasonings and spices, sanitas and antioxidant.
The purposes of compound and pharmaceutically acceptable composition
On the other hand, provide treatment acute, chronic, neuropathic or inflammatory pain, sacroiliitis, migraine, bunch headache, trigeminal neuralgia, herpetic neurodynia, popularity neurodynia, epilepsy or epilepsy, the neurodegeneration obstacle, mental disorder (for example anxiety and depression), myotony, irregular pulse, dyskinesia, the neuroendocrine obstacle, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence or alleviate the method for its seriousness, the curee who comprises this treatment of needs gives the compound of significant quantity or the pharmaceutically acceptable composition of inclusion compound.Some preferred embodiment in, acute, chronic, neuropathic or inflammatory pain of treatment is provided or alleviates the method for its seriousness, comprise that the curee to this treatment of needs gives the compound of significant quantity or the pharmaceutically acceptable composition of inclusion compound.In some embodiments of the present invention, " significant quantity " of compound or pharmaceutically acceptable composition is just to treat that one or more are acute, chronic, neuropathic or inflammatory pain, sacroiliitis, migraine, bunch headache, trigeminal neuralgia, herpetic neurodynia, popularity neurodynia, epilepsy or epilepsy, the neurodegeneration obstacle, mental disorder (for example anxiety and depression), myotony, irregular pulse, dyskinesia, the neuroendocrine obstacle, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence or alleviate the effective amount of its seriousness.
Can utilize according to the compound of the inventive method and composition and just to treat that one or more are acute, chronic, neuropathic or inflammatory pain, sacroiliitis, migraine, bunch headache, trigeminal neuralgia, herpetic neurodynia, popularity neurodynia, epilepsy or epilepsy, the neurodegeneration obstacle, mental disorder (for example anxiety and depression), myotony, irregular pulse, dyskinesia, the neuroendocrine obstacle, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence or alleviate the effective any amount of its seriousness and arbitrarily in addition administration of route of administration.Required definite amount will be different because of the curee, depend on seriousness, the certain drug of curee's kind, age and general state, infection, mode of its administration etc.The compounds of this invention preferably is formulated into dosage unit form, and the consistence of administration of being easy to and dosage is arranged.The drug unit that phraseology used herein " dosage unit form " expression is physically discrete is suitable for the patient who is treated.But will be understood that total every day of the consumption of The compounds of this invention and composition will reasonably determined in the medical judgment scope by the attending doctor.The concrete effective dose level of any specific patient or organism will depend on multiple factor, comprise the illness of being treated and the seriousness of illness; The activity of the particular compound that is adopted; The concrete composition that is adopted; Patient's age, body weight, general health situation, sex and diet; The discharge rate of the approach of time of administration, administration and the particular compound that is adopted; The time length of treatment; With particular compound associating of being adopted or the medicine that uses simultaneously; Other factors of knowing with field of medicaments.Term used herein " patient " expression animal, preferred mammal, optimum is chosen.
Pharmaceutically acceptable composition of the present invention can be oral to people and other animals, in the rectum, parenteral, brain pond, intravaginal, intraperitoneal, part (with pulvis, ointment or drops), cheek, with mouth with or mode administration such as nasal spray, this depends on the seriousness that infection is treated by institute.In some embodiments, The compounds of this invention can be by oral or administered parenterally, dosage level be every day about 0.01mg/kg to about 50mg/kg, preferred about 1mg/kg about 25mg/kg curee's body weight extremely, once a day or repeatedly, to obtain required result of treatment.
The liquid dosage form of oral administration includes but not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active compound, liquid dosage form can contain this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, phenylformic acid benzyl ester, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oil (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, wheat germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and the fatty acid ester of anhydro sorbitol and their mixture.Except inert diluent, oral compositions can also comprise auxiliary agent, for example wetting agent, emulsification and suspension agent, sweeting agent, correctives and spices.
Use the dispersion or wetting agent and the suspension agent that are fit to, can prepare the injectable prepared product according to known technique, for example the water-based of sterile injectable or oiliness suspension.The sterile injectable prepared product also can be at nontoxic parenteral acceptable diluent or sterile injectable solution, suspension or the emulsion in the solvent, for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution.In addition, conventionally adopt aseptic expressed oil as solvent or suspension medium.For this reason, can adopt the fixed oil of any gentleness, comprise synthetic list-or two-glyceryl ester.In addition, in the preparation of injection, also can use lipid acid, for example oleic acid.
Injectable formulation can be sterilized like this, for example filters by the bacterium property held back filter, perhaps mixes the disinfectant of aseptic solid composite form, can be before use with its dissolving be dispersed in aseptic water or other sterile injectable medium in.
In order to prolong the effect of The compounds of this invention, often need delay the absorption of compound after subcutaneous or intramuscularly.This can utilize the crystallinity of poorly water-soluble or the liquid suspension of amorphous substance to realize.The uptake rate of compound depends on its dissolution rate, and the latter may be depended on crystallographic dimension and crystal formation again conversely.Select as an alternative, with compound dissolution or be suspended in the oils carrier, realize that the delay of administered parenterally compound form absorbs.Injectable depot forms is like this preparation, and in Biodegradable polymeric, polylactide-polyglycolide for example generates the microencapsulation matrix of compound.According to the ratio of compound and polymkeric substance and the attribute of the particular polymers that adopts, can control the rate of release of compound.The example of other biological degradable polymer comprises poly-(ortho ester) and poly-(acid anhydrides).The depot injectable formulation also can prepare the compound inclusion in liposome compatible with body tissue or micro emulsion.
Rectum or vagina administration composition be suppository preferably, they can prepare like this, The compounds of this invention is mixed with the nonirritant excipient or the carrier that are fit to, for example theobroma oil, polyoxyethylene glycol or suppository wax, they are solid at ambient temperature, but under body temperature, be liquid, therefore in rectum or vaginal canal, melt, discharge active compound.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granule.In this class solid dosage, active compound is mixed with pharmaceutically acceptable vehicle of at least a inert or carrier, for example Trisodium Citrate or Lin Suanergai, and/or a) weighting agent or expanding material, starch for example, lactose, sucrose, glucose, mannitol and silicic acid, b) tackiness agent, carboxymethyl cellulose for example, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) wetting agent, glycerine for example, d) disintegrating agent, for example agar, lime carbonate, potato or tapioca (flour), alginic acid, some silicate and yellow soda ash, e) dissolving retarding agent, paraffin for example, f) absorption enhancer, for example quaternary ammonium compound, g) wetting agent, for example hexadecanol and glyceryl monostearate, h) absorption agent, for example kaolin and wilkinite, and i) lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and composition thereof.Under the situation of capsule, tablet and pill, described formulation can also comprise buffer reagent.
The solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft or hard filling, and the capsule used excipient is lactose or toffee and high molecular weight polyethylene glycol etc. for example.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example other dressings of knowing of enteric coating and medicine formulation art.They can contain opalizer alternatively, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, alternatively the mode for postponing.The example of operable embedding composition comprises polymeric material and wax class.The solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft and hard filling, and the capsule used excipient is lactose or toffee and high molecular weight polyethylene glycol etc. for example.
Active compound also can be the form of microencapsulation, wherein contains one or more above-mentioned vehicle.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example enteric coating, discharge other dressings that controlled dressing and medicine formulation art are known.In this class solid dosage, active compound can be mixed with at least a inert diluent, for example sucrose, lactose or starch.Under normal circumstances, this class formulation can also comprise other materials except that inert diluent, for example compressing tablet lubricant and other compression aids, for example Magnesium Stearate and Microcrystalline Cellulose.Under the situation of capsule, tablet and pill, formulation can also comprise buffer reagent.They can contain opalizer alternatively, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, alternatively the mode for postponing.The example of operable embedding composition comprises polymeric material and wax class.
The part of The compounds of this invention or transdermal administration formulation comprise ointment, paste, creme, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch.Active ingredient is mixed with pharmaceutically acceptable carrier and any essential sanitas or buffer reagent under aseptic condition, decide as required.Ophthalmic preparation, ear drop and eye drops also covered in the scope of the present invention.In addition, the use of transdermal patch is contained in the present invention, and they have the attendant advantages that the control compound is sent to body.This class formulation can be by with compound dissolution or be dispersed in the appropriate medium and prepare.Can also use absorption enhancer to increase the flux that compound passes skin.Can control speed by rate controlling membranes being provided or compound being dispersed in polymeric matrix or the gel.
As institute's general description above, The compounds of this invention can be used as voltage-gated sodium-ion channel or calcium channel, the inhibitor of preferred N-type calcium channel.In one embodiment, The compounds of this invention and composition are one or more NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, the inhibitor of NaV1.9 or CaV2.2, thereby do not wish to be subjected to any specific theory to limit, compound and composition are particularly useful for a kind of like this disease of treatment, illness or obstacle or alleviate its seriousness, wherein one or more NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, the activation of NaV1.9 or CaV2.2 or hyperactivity are in this disease, implication in illness or the obstacle.When the activation of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9 or CaV2.2 or hyperactivity in specified disease, illness or obstacle during implication, this disease, illness or obstacle also can be called as " disease, illness or the obstacle of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9-mediation " or " illness or the obstacle of CaV2.2-mediation ".Therefore, on the other hand, the invention provides a kind of like this disease of treatment, illness or illness or alleviate the method for its seriousness, the wherein activation of one or more NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9 or CaV2.2 or hyperactivity implication in this morbid state.
The activity that is used as the compound of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9 or CaV2.2 inhibitor can be measured according to the method for this paper embodiment institute general description or according to those of ordinary skills' available method in the present invention.
In some exemplary embodiment, The compounds of this invention can be used as the inhibitor of NaV1.8.In other embodiments, The compounds of this invention can be used as the inhibitor of NaV1.8 and CaV2.2.In other embodiments, The compounds of this invention can be used as the inhibitor of CaV2.2.
What also will be figured out is, compound of the present invention and pharmaceutically acceptable composition can be used in the conjoint therapy, that is to say, compound and pharmaceutically acceptable composition can one or more other required therapeutical agent or medical program simultaneously, before or administration subsequently.Specific therapy (therapeutical agent or the program) combination of week in scheme for combining will be considered required therapeutical agent and/or program and the tolerability of the required result of treatment that will reach.What also will be figured out is, used therapy can (for example reach required effect to same illness, The compounds of this invention can be used for the treatment of the medicine administration simultaneously of same illness with another kind), perhaps they can reach different effects (for example controlling any side effect).As used herein, administration under normal circumstances is called as " is suitable " with the other therapeutical agent of treatment or prevention specified disease or illness with regard to the disease of being treated or illness.
The content of other therapeutical agent in the present composition will be no more than comprise this therapeutical agent as unique composition of active components in common dosage.Preferably, the other amount of therapeutical agent in present disclosed composition will be common to comprise this medicine as about 50% to 100% of the content in the composition of unique therapeutic activity composition.
The compounds of this invention or its pharmaceutically acceptable composition also can be incorporated in the composition that applies implantable medical devices, for example artificial limb, artificial valve, vascular graft, Si Tanteshi die and conduit.Therefore, the present invention comprises the composition that is used to apply implantable device on the other hand, and it comprises as above general describe and at big class and the The compounds of this invention described in the group of this paper be suitable for applying the carrier of described implantable device.On the other hand, the present invention includes the implantable device that scribbles composition, described composition comprises as above general describe and at the The compounds of this invention described in big class of this paper and the group be suitable for applying the carrier of described implantable device.Coating that is fit to and the general preparation method who applies implantable device are described in United States Patent (USP) 6,099, in 562,5,886,026 and 5,304,121.Coating is the polymeric material of bio-compatible normally, for example aquogel polymer, poly-methyl sily oxide, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), vinyl-vinyl acetate copolymer and their mixture.Coating can further be covered by the top layer of the fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its combination that are fit to alternatively, to give the release characteristics of composition.
Another aspect of the present invention relates in biological sample or patient and to suppress one or more NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9 or CaV2.2 activity, and this method comprises the patient is given or makes described biological sample contact I compound or comprise described compound compositions.Term used herein " biological sample " comprises cell culture and extract thereof without limitation; Biopsy material from Mammals or the acquisition of its extract; With blood, saliva, urine, ight soil, seminal fluid, tear or other body fluid or its extract.
In biological sample, suppress one or more NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9 or CaV2.2 activity and can be used for multiple purpose well known by persons skilled in the art.This classification example include but not limited to research to sodium-ion channel in biology and the physiology phenomenon; With comparative assessment to new sodium-ion channel inhibitor.
In order to understand invention described herein more fully, provide the following example.Should be appreciated that these embodiment only supply purposes of illustration, are not interpreted as limiting in any way the present invention.
Embodiment
Embodiment 1
Figure A20048002502701571
In the 250mL three neck round-bottomed flasks of being furnished with magnetic stirrer and reflux exchanger, to the 5-ethoxycarbonyl uridylic 1 that is stirring (3.00g, 16.3mmol) with the disposable adding N of phosphoryl chloride (20mL) suspension, accelerine (2.10mL, 16.3mmol).Suspension was heated 30 minutes under refluxing, slowly form settled solution.Under reduced pressure concentrated solution is poured on resistates on the ice (100g).Solution is alkalized to pH=9.0 with dense sodium bicarbonate aqueous solution.Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic solution drying (MgSO 4), vapourisation under reduced pressure is to doing.Resistates is dissolved in anhydrous THF (30mL), is cooled to 0 ℃.Go through dripping xylidine (16.3mL, 32.6mmol, 2.0M THF solution) in 10 minutes, stir simultaneously.Then solution was stirred 1 hour down at 0 ℃.Concentrated solution under reduced pressure, resistates with 90% hexane/10% eluent ethyl acetate, obtains 2 (1.70g, 7.34mmol, 45% yields) through the silica gel chromatography purifying, is xanchromatic oil.M+1(obs)＝230.1；R t＝3.49。
2 (50mg pack in 5mL microwave reaction container, 0.22mmol), phenyl for boric acid (39mg, 0.32mmol), four (triphenyl phosphine) palladium (0) (25mg, 0.02mmol), yellow soda ash (0.55mL, 0.22mmol, the 0.40M aqueous solution) with the mixture of acetonitrile (0.55mL).With container sealing, heated 10 minutes down at 150 ℃ via microwave radiation, stir simultaneously.Under reduced pressure concentrate organic moiety, resistates with 90% hexane/10% eluent ethyl acetate, obtains 3 (54mg, 0.20mmol, 92% yields) through the silica gel chromatography purifying, is white solid. 1H NMR(CDCl 3)δ1.41(t，3H)，3.18(s，6H)，4.39(q，2H)，7.48-7.52(m，3H)，8.39-8.43(m，2H)，8.79(s，1H)；M+1(obs)＝272.3；R t＝2.97。
Figure A20048002502701581
In the 500mL three neck round-bottomed flasks of being furnished with magnetic stirrer, (3.00g is 22.5mmol) with anhydrous Et to the 2-HOMOVERATRONITRILE 4 that is stirring under 0 ℃ 2O (50mL) solution is gone through and was dripped hexamethyldisilazane base lithium (45.0mL, 45.0mmol, 1.0M hexane solution) in 10 minutes.Solution was stirred 24 hours at ambient temperature.Under 0 ℃, go through the 30 minutes careful 2.0NHCl of the dropping aqueous solution.Solution was stirred 2 hours at ambient temperature.The hydrotropisms partly adds the saturated KOH aqueous solution (50mL) and transfers to strong basicity.Mixture CH 2Cl 2Extraction (5 * 40mL).Merge organic moiety, dry (MgSO 4), vapourisation under reduced pressure obtains 5 (1.20g, 7.99mmol, 36% yields) to doing, and is the light tan solid.M+1(obs)＝151.2；R t＝0.85。
Figure A20048002502701582
In the 250mL three neck round-bottomed flasks of being furnished with magnetic stirrer, under 0 ℃ to the 2-methoxyl group benzamidine 5 (3.00g that stirring, 20.0mmol), diethyl EMME (4.00mL, 4.30g, 20.0mmol) go through 10 minutes dropping sodium ethylate (7.50mL with anhydrous EtOH (25mL) solution, 20.0mmol, 21% EtOH solution).Solution was stirred 1 hour at ambient temperature.Pour mixture into H 2Among the O (50mL), solution is acidified to pH=4 with dense HCl.Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure obtains 6 (4.82g, 17.6mmol, 88% yields) to doing, and is white solid.M+1(obs)＝275.4；R t＝2.90。
Figure A20048002502701591
In the 250mL three neck round-bottomed flasks of being furnished with magnetic stirrer and reflux exchanger, to stirring 6 (4.50g, 16.3mmol) with the disposable adding N of phosphoryl chloride (25mL) suspension, accelerine (2.10mL, 16.3mmol).Suspension was heated 1 hour under refluxing, slowly form settled solution.Under reduced pressure concentrated solution is poured on resistates on the ice (100g).Solution is alkalized to pH=9.0 with dense sodium bicarbonate aqueous solution.Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure obtains 7 (3.10g, 10.6mmol, 65% yields) to doing, and is white solid.M+1(obs)＝293.2；R t＝3.79。
In the 50mL three neck round-bottomed flasks of being furnished with magnetic stirrer, under-78 ℃ to stirring 7 (100mg, 0.34mmol) and CH 2Cl 2(10mL) solution is gone through and was dripped boron tribromide (3.4mL, 3.4mmol, 1.0M CH in 10 minutes 2Cl 2Solution).Solution was stirred 1 hour down at-78 ℃, pour saturated NaHCO then into 3In the aqueous solution (20mL).With organic moiety drying (MgSO 4), vapourisation under reduced pressure obtains 8 (94mg, 0.34mmol, 100% yields) to doing, and is white solid.M+1(obs)＝279.1；R t＝4.50。
Figure A20048002502701593
In the 50mL three neck round-bottomed flasks of being furnished with magnetic stirrer, to stirring 9 (95mg, 0.34mmol), Et 3(0.15mL 1.10mmol) goes through 2 minutes dropping xylidines (0.55mL, 1.10mmol, 2.0M THF solution) with THF (2.0mL) solution to N, stirs simultaneously.Then solution was stirred 1 hour at ambient temperature.Concentrated solution, (10% to 99%CH through the HPLC purifying 3CN), obtain 9,, be white solid for trifluoroacetate (112mg, 0.28mmol, 82% yield).M+1(obs)＝288.0；R t＝3.47。
In the 250mL three neck round-bottomed flasks of being furnished with magnetic stirrer, to stirring 3 (1.00g, 3.70mmol) with EtOH (50mL) solution add the 1.0N NaOH aqueous solution (26.0mL, 26.0mmol).Solution was stirred 2 hours down at 70 ℃.Solution is acidified to pH=4.0 with dense HCl, succeeded by using Et 3The N alkalization.Enriched mixture under reduced pressure, resistates is used 90%CH through the silica gel chromatography purifying 2Cl 2/ 10%MeOH wash-out obtains 10 (0.71g, 2.90mmol, 79% yields), is white solid.M+1(obs)＝244.4；R t＝1.98。
Figure A20048002502701602
In the 250mL three neck round-bottomed flasks of being furnished with magnetic stirrer, to stirring 3 (1.00g 3.70mmol) goes through with anhydrous THF (30mL) solution and added lithium aluminum hydride (5.60mL, 5.60mmol, 1.0M THF solution) in 10 minutes.Solution was at room temperature stirred 20 minutes.Under 0 ℃, go through 5 fens this solution of clockwise and add H 2O (10mL).Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure obtains 11 (0.72g, 3.15mmol, 85% yields) to doing, and is white solid.M+1(obs)＝230.3；R t＝2.16。
Figure A20048002502701611
In the 100mL three neck round-bottomed flasks of being furnished with magnetic stirrer, to stirring 11 (750mg, 3.27mmol) and CH 2Cl 2(10mL) the disposable adding manganese oxide of solution (IV) (2.87g, 33.0mmol).Mixture was at room temperature stirred 3 hours.Mixture is filtered by bed of diatomaceous earth, and vapourisation under reduced pressure filtrate obtains 12 (710mg, 3.12mmol, 96% yields) to doing, and is white solid.M+1(obs)＝228.2；R t＝3.42。
Figure A20048002502701612
In the 100mL three neck round-bottomed flasks of being furnished with magnetic stirrer, under 0 ℃ to stirring 12 (200mg, 0.88mmol) and Et 2O (15mL) solution is gone through and was dripped methylmagnesium-bromide (0.60mL, 1.76mmol, 3.0M Et in 5 minutes 2O solution).Mixture was at room temperature stirred 30 minutes.Make mixture at EtOAc and H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure is to doing.The gained resistates is dissolved in CH 2Cl 2(10mL).(2.87g 33.0mmol), at room temperature stirred mixture 3 hours disposable adding manganese oxide (IV).Mixture is filtered by bed of diatomaceous earth, and vapourisation under reduced pressure filtrate is to doing.(10% to 99%CH through the HPLC purifying for resistates 3CN), obtain 13,, be white solid for trifluoroacetate (196mg, 0.55mmol, 63% yield).M+1(obs)＝242.1；R t＝2.95。
Figure A20048002502701613
In the single neck reaction vessel of the 1mL that is furnished with magnetic stirrer, to stirring 10 (100mg, 0.41mmol), salt of wormwood (170mg, 1.23mmol) with the disposable adding methyl iodide of dry DMF (0.50mL) solution (0.05mL, 0.82mmol).Mixture was at room temperature stirred 2 hours.Mixture is filtered, and (10% to 99%CH through the HPLC purifying for filtrate 3CN), obtain 14,, be white solid for trifluoroacetate (111mg, 0.30mmol, 72% yield).M+1(obs)＝258.2；R t＝2.44。
In the single neck reaction vessel of the 1mL that is furnished with magnetic stirrer, to stirring 10 (100mg, 0.41mmol), tetramethyleneimine (29mg, 0.41mmol), Et 3N (83mg, 0.82mmol) with the disposable adding benzotriazole of dry DMF (1.0mL) solution-1-base oxygen base-three (dimethylamino)  hexafluorophosphate (181mg, 0.41mmol).Mixture was at room temperature stirred 20 minutes.Mixture is filtered, and (10% to 99%CH through the HPLC purifying for filtrate 3CN), obtain 15,, be white solid for trifluoroacetate (135mg, 0.33mmol, 81% yield).M+1(obs)＝297.4；R t＝2.23。
In the single neck reaction vessel of the 1mL that is furnished with magnetic stirrer, to stirring 11 (50mg is 0.22mmol) with the disposable adding sodium hydride of dry DMF (0.50mL) solution (9.0mg, 0.22mmol, 60% mineral oil suspension).Mixture was at room temperature stirred 15 minutes.To the disposable adding 3-of this solution methoxy-benzyl bromine (66mg, 0.33mmol).Mixture is filtered, and (10% to 99%CH through the HPLC purifying for filtrate 3CN), obtain 16,, be white solid for trifluoroacetate (65mg, 0.14mmol, 63% yield).M+1(obs)＝350.4；R t＝3.06。
Figure A20048002502701631
In the single neck reaction vessel of the 1mL that is furnished with magnetic stirrer, to stirring 17 (100mg, 0.39mmol) with the disposable adding salt of wormwood of anhydrous MeOH (0.50mL) solution (180mg, 1.30mmol).Mixture was at room temperature stirred 5 minutes.(91mg 0.47mmol), heats mixture 17 hours down at 60 ℃ disposable adding tolylsulfonyl ylmethyl isocyanide.Concentrated solution under reduced pressure, resistates is used 97%CH through the silica gel chromatography purifying 2Cl 2/ 3%MeOH wash-out obtains 18 (105mg, 0.35mmol, 90% yields), is white solid.M+1(obs)＝297.2；R t＝2.83。
Figure A20048002502701632
In the 100mL three neck round-bottomed flasks of being furnished with magnetic stirrer, under 0 ℃ to the benzamidine hydrochloride 19 (735mg that stirring, 4.70mmol), diethyl EMME (794mg, 4.70mmol) go through 10 minutes dropping sodium ethylate (3.50mL with anhydrous EtOH (10mL) solution, 9.41mmol, 21% EtOH solution).Solution was heated 1 hour under refluxing.Pour mixture into H 2Among the O (25mL), solution is acidified to pH=3 with dense HCl.With sedimentation and filtration, residual solid vacuum-drying obtains the intermediate pyrimidone, for white solid (500mg, 2.54mmol).In the 50ml three neck round-bottomed flasks of being furnished with magnetic stirrer and reflux exchanger, the gained pyrimidone is suspended in the phosphoryl chloride (3mL).To the disposable adding xylidine of this suspension (0.32mL, 2.54mmol).Suspension was heated 1 hour under refluxing, slowly form settled solution.Under reduced pressure concentrated solution is poured on resistates on the ice (100g).Solution is alkalized to pH=9.0 with dense sodium bicarbonate aqueous solution.Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure is to doing.In the 50mL three neck round-bottomed flasks of being furnished with magnetic stirrer, add Et to the gained resistates 3N (0.35mL, 2.54mmol) and THF (2.0mL).Go through 2 minutes dropping xylidines (3.81mL, 7.62mmol, 2.0MTHF solution) to this solution, stir simultaneously.Then solution was stirred 1 hour at ambient temperature.Concentrated solution under reduced pressure, resistates with 80% hexane/20% eluent ethyl acetate, obtains 20 (256mg, 1.14mmol, 24% yields) through the silica gel chromatography purifying, is clarifying oil.M+1(obs)＝225.1；R t＝3.83。
Figure A20048002502701641
In the 250mL three neck round-bottomed flasks of being furnished with magnetic stirrer, under 0 ℃ to the benzamidine hydrochloride 19 (5.00g that stirring, 31.9mmol), ethyl propiolate (3.50mL, 34.3mmol) go through 10 minutes dropping sodium ethylate (6.51mL with anhydrous EtOH (50mL) solution, 63.8mmol, 21% EtOH solution).Solution was heated 2.5 hours under refluxing.Pour mixture into H 2Among the O (25mL), solution is acidified to pH=3 with dense HCl.With sedimentation and filtration, residual solid vacuum-drying obtains 21 (2.9g, 16.8mmol, 53% yields), is white solid.M+1(obs)＝173.20；R t＝1.74。
Figure A20048002502701642
In the 100mL three neck round-bottomed flasks of being furnished with magnetic stirrer and reflux exchanger, with stirring 21 (2.50g 14.5mmol) with the heating 3 hours under refluxing of phosphoryl chloride (17mL) suspension, slowly forms settled solution.Under reduced pressure concentrated solution is poured on resistates on the ice (40g).With the gained sedimentation and filtration, wash with water, vacuum-drying obtains 22 (2.10g, 11.0mmol, 76% yields), is white solid.M+1(obs)＝191.0；R t＝4.22。
Figure A20048002502701651
In the 5mL microwave container, to stirring 22 (150mg, 0.80mmol) and H 2O (1.5mL) solution adds xylidine (1.50mL, 3.00mmol, 2.0M MeOH solution).℃ reach 5 minutes via carry out microwave radiation heating solution to 150 then.(10% to 99%CH through the HPLC purifying for solution 3CN), obtain 23,, be white solid for trifluoroacetate (130mg, 0.28mmol, 52% yield).M+1(obs)＝200.2；R t＝2.32。
Figure A20048002502701652
In the 50mL three neck round-bottomed flasks of being furnished with magnetic stirrer and reflux exchanger, to stirring 21 (100mg, 0.58mmol) with acetate (2.0mL) solution add N-bromine succinimide (103mg, 0.58mmol).Mixture was heated 1 hour down at 60 ℃.Concentrated solution under reduced pressure, resistates is used 97%CH through the silica gel chromatography purifying 2Cl 2/ 3%MeOH wash-out obtains 24 (110mg, 0.44mmol, 76% yields), is white solid. 1H NMR(DMSO-D 6)δ7.44-7.61(m，3H)，8.04-8.16(m，2H)，8.44(s，1H)13.23(s，1H)；M+1(obs)＝251.1；R t＝2.98。
Figure A20048002502701653
In the 50mL three neck round-bottomed flasks of being furnished with magnetic stirrer and reflux exchanger, with stirring 24 (100mg 0.40mmol) with the heating 1 hour under refluxing of phosphoryl chloride (2.0mL) suspension, slowly forms settled solution.Under reduced pressure concentrated solution is poured on resistates on the ice (10g).Solution is alkalized to pH=9.0 with dense sodium bicarbonate aqueous solution.Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure obtains 25 (95mg, 0.035mmol, 88% yields) to doing, and is white solid.M+1(obs)＝271.0；R t＝4.67。
In the 1mL reaction vessel, to stirring 25 (80mg, 0.30mmol), Et 3(0.10mL 0.70mmol) adds xylidine (1.0mL, 2.0mmol, 2.0M THF solution) with THF (2.0mL) solution to N.Solution was at room temperature stirred 15 minutes.(10% to 99%CH through the HPLC purifying for solution 3CN), obtain 26,, be white solid for trifluoroacetate (94mg, 0.24mmol, 79% yield).M+1(obs)＝277.8；R t＝3.23。
In the 2mL microwave container, (23mg 0.33mmol) adds sodium hydride (5.0mg, 0.12mmol, 60% mineral oil suspension) with anhydrous THF (0.50mL) solution to the pyrroles who is stirring.Mixture was stirred 10 minutes at ambient temperature.To this solution add 2 (25mg, 0.11mmol).℃ reach 5 minutes via microwave heating solution to 150 then.(10% to 99%CH through the HPLC purifying for solution 3CN), obtain 27,, be white solid for trifluoroacetate (30mg, 0.08mmol, 74% yield).M+1(obs)＝261.0；R t＝4.28。
In the 100mL three neck round-bottomed flasks of being furnished with magnetic stirrer and reflux exchanger, to stirring 10 (500mg, 1.84mmol), thionyl chloride (1.50mL) and benzene (10mL) solution adds a DMF.Solution was heated 2 hours under refluxing.Under reduced pressure concentrated solution makes resistates and methylbenzene azeotropic (2 * 10mL).Resistates is dissolved in CH 2Cl 2(10mL), succeeded by adding Et 3N (0.50mL, 3.60mmol) and hydrazine (0.11mL, 3.6mmol).Solution was stirred 30 minutes at ambient temperature.The vapourisation under reduced pressure mixture is to doing.Resistates is used 90%CH through the silica gel chromatography purifying 2Cl 2/ 10%MeOH wash-out obtains 28 (350mg, 1.36mmol, 74% yields), is white solid.M+1(obs)＝258.0；R t＝1.66。
Figure A20048002502701671
In the 50mL three neck round-bottomed flasks of being furnished with magnetic stirrer, to stirring 28 (20mg, 0.13mmol), Et 3N (0.05mL, 0.39mmol) and CH 2Cl 2(3.0mL) solution add propionyl chloride (0.02mL, 0.26mmol).Solution was stirred 30 minutes at ambient temperature.Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure is to doing.Resistates is dissolved in anhydrous CH 3CN (2mL) is succeeded by adding POCl 3(0.06mL, 0.65mmol).In the 5mL microwave container, ℃ reach 5 minutes via microwave heating solution to 170.(10% to 99%CH through the HPLC purifying for solution 3CN), obtain 29,, be white solid for trifluoroacetate (33mg, 0.08mmol, 59% yield).M+1(obs)＝296.4；R t＝3.18。
Figure A20048002502701672
In the 10mL three neck round-bottomed flasks of being furnished with magnetic stirrer and reflux exchanger, to stirring 20 (100mg, 0.41mmol), oxammonium hydrochloride (68mg, 0.98mmol) with the disposable adding Et of anhydrous EtOH (0.50mL) solution 3N (0.14mL, 1.00mmol).Suspension was heated 24 hours under refluxing.Under reduced pressure concentrated solution is poured on resistates on the ice (100g).Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure is to doing.Resistates is dissolved in anhydrous CH 2Cl 2(2.0mL), succeeded by adding Et 3N (0.17mL, 1.20mmol) and Acetyl Chloride 98Min. (92mg, 1.20mmol).Then solution was stirred 1 hour at ambient temperature.Concentrated solution under reduced pressure.Resistates is dissolved in dry DMF (0.50mL), succeeded by adding 1,1 '-carbonyl dimidazoles (11mg, 0.07mmol).Solution was heated 1 hour down at 115 ℃.(10% to 99%CH through the HPLC purifying for solution 3CN), obtain 30,, be white solid for trifluoroacetate (19mg, 0.05mmol, 12% yield).M+1(obs)＝282.2；R t＝3.02。
Figure A20048002502701681
In the 50mL three neck round-bottomed flasks of being furnished with magnetic stirrer, (44mg is 0.47mmol) with the disposable adding sodium methylate of anhydrous EtOH (10mL) solution (0.94mL, 0.047mmol, 0.5M MeOH solution) to the acetamidine hydrochloride that is stirring.Suspension was stirred 30 minutes at ambient temperature.Mixture is filtered, to filtrate add 28 (80mg, 0.31mmol).Solution was stirred 24 hours at ambient temperature.Make mixture at CH 2Cl 2With H 2Distribute between the O.With organic moiety drying (MgSO 4), vapourisation under reduced pressure is to doing.Resistates is dissolved in dimethylbenzene/octanol solution (2.0mL, 20/1).Then solution was heated 17 hours under refluxing, remove H by Dean and Stark apparatus simultaneously 2O.Concentrated solution under reduced pressure, (10% to 99%CH through the HPLC purifying 3CN), obtain 31,, be white solid for trifluoroacetate (79mg, 0.20mmol, 43% yield).M+1(obs)＝282.1；R t＝3.01。
Figure A20048002502701691
In the two neck round-bottomed flasks of the 20mL that is furnished with magnetic stirrer, under-78 ℃ to stirring 32 (50.0mg 0.16mmol) goes through with toluene (1.0mL) solution and dripped n-Butyl Lithium (0.10mL, 0.16mmol, 1.60M hexane solution) in 2 minutes.Mixture was stirred 5 minutes down at-78 ℃, succeeded by go through dripped in 2 minutes butyraldehyde (0.02mL, 0.24mmol).Mixture is gone through be warming up to room temperature in 20 minutes.Make gained solution at saturated NH then 4Distribute between the Cl aqueous solution and the EtOAc.With organic moiety drying (MgSO 4), vapourisation under reduced pressure is to doing.Gained oil is dissolved in CH 2Cl 2(5.0mL), succeeded by add manganese oxide (IV) (139mg, 1.6mmol).Mixture was stirred 17 hours at ambient temperature.Mixture is filtered by bed of diatomaceous earth, under reduced pressure concentrated filtrate.Resistates with 10%EtOAc/90% hexane wash-out, obtains 33 (15mg, 0.05mmol, 31% yields) through the silica gel chromatography purifying, is clarifying oil.M+1(obs)＝300.3；R t＝2.55。
Figure A20048002502701692
In the 200mL three neck round-bottomed flasks of being furnished with magnetic stirrer, with stirring 34 (10.0g, 63.6mmol), phosphoryl chloride (25.0mL) and N, (17.0g, 140mmol) solution is 80 ℃ of heating 20 minutes down for accelerine.Concentrated solution under reduced pressure.Resistates is poured in the frozen water (300g) into the saturated NaHCO of mixture 3Aqueous solution alkalization.Make mixture at CH 2Cl 2And distribute between the water.With organic moiety drying (MgSO 4), be cooled to-78 ℃.Add Et to this solution 3(8.70mL 63.0mmol), dripped dimethyl amine (31.8mL, 63.6mmol, 2.0M THF solution) in 10 minutes succeeded by going through to N under-78 ℃.Enriched mixture under reduced pressure.Resistates with 30%EtOAc/70% hexane wash-out, obtains 35 (3.9g, 19.2mmol, 30% yields) through the silica gel chromatography purifying, is yellow solid. 1H NMR(CDCl 3)δ3.01(s，6H)，8.62(s，1H)。
In the single neck round-bottomed flask of the 50mL that is furnished with magnetic stirrer, to stirring 35 (500mg, 2.0mmol) with acetate (3.0mL) solution go through added in 5 minutes in batches zinc powder (810mg, 1.2mmol).Mixture was stirred 1 hour at ambient temperature.Pour mixture into saturated NaHCO 3In the aqueous solution (100mL).Mixture is filtered, at CH 2Cl 2And distribute between the water.With organic moiety drying (MgSO 4), under reduced pressure concentrate.Resistates with 30%EtOAc/70% hexane wash-out, obtains 36 (50mg, 0.29mmol, 15% yields) through the silica gel chromatography purifying, is the tawny solid.M+1(obs)＝173.2；R t＝2.96。
Figure A20048002502701702
In the single neck reaction vessel of the 50mL that is furnished with magnetic stirrer, to stirring 36 (50.0mg, 0.29mmol), Et 3(59.0mg is 0.58mmol) with anhydrous CH for N 2Cl 2(10.0mL) the disposable adding Acetyl Chloride 98Min. of solution (34.0mg, 0.43mmol).Mixture was at room temperature stirred 20 minutes.Concentrated solution under reduced pressure, resistates is used 3%MeOH/97%CH via the silica gel chromatography purifying 2Cl 2Wash-out obtains amide intermediate.Amide intermediate is joined in the microwave container, succeeded by adding CH 3CN (0.50mL), 2-(4,4,5,5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenol (83mg, 0.38mmol), Pd (PPh 3) 4(30.0mg, 0.03mmol) and yellow soda ash (0.50mL, 0.40M H 2O solution).Reach 5 minutes via microwave radiation at 170 ℃ of following heated mixt.Mixture is filtered, and (10% to 99%CH through the HPLC purifying for filtrate 3CN), obtain 37,, be white solid for trifluoroacetate (26mg, 0.07mmol, 23% yield).M+1(obs)＝273.2；R t＝1.77。
(6.00g, 31.4mmol), N, (12.0mL, phosphoryl chloride 94.7mmol) (18mL) solution is heated to 120 ℃ and reaches 2 hours accelerine with 5-bromouracil 1.After being cooled to room temperature, concentrated reaction mixture in a vacuum.Resistates is dissolved in CH 2Cl 2(100mL), carefully add saturated NaHCO 3The aqueous solution is regulated pH to 8-9.Separate each phase, water CH 2Cl 2Extraction (2 * 100mL).Merge organic extract liquid, through MgSO 4Drying concentrates in a vacuum, obtains compound 2, need not to be further purified promptly to can be used for next reactions steps.Under-78 ℃, to THF (100mL) solution of compound 2 (approximately 31mmol) go through the THF solution that slowly added dimethylamine in 15 minutes (2.0M, 13.8mL, 27.6mmol).Remove cooling bath, continue at room temperature to stir 2 hours.Remove in a vacuum and desolvate.(hexane solution of EtOAc 0-15%), obtains compound 3 (2.7g, 36%), is yellow solid through the silicon-dioxide chromatography.LC/MS (10-99%) m/z:238, retention time: 3.19min. 1H NMR (400MHz, DMSO): δ 8.29 (s, 1H), 3.20 (s, 6H).
With compound 3 (237mg, 1.00mmol), the 3-thiophene for boric acid (128mg, 1.00mmol), Pd (PPh 3) 4(58mg, 0.05mmol, 5mol%) and Na 2CO 3(2.00mmol) mixture heating up in acetonitrile (5mL) reaches 75 minutes to refluxing to the aqueous solution for 0.4M, 5mL.After being cooled to room temperature, add CH 2Cl 2(10mL), separate each phase.Water CH 2Cl 2Extraction (2 * 10mL), merge organic extract liquid, through MgSO 4Drying concentrates in a vacuum.(hexane solution of EtOAc 0-20%), obtains compound 4 (132mg, 55%), is xanchromatic oil through the silicon-dioxide chromatography.LC/MS (10-99%) m/z:241, retention time: 3.61min. 1H-NMR (400MHz, DMSO): δ 7.98 (s, 1H), 7.65 (m, 1H), 7.57 (m, 1H), 7.17 (m, 1H), 2.86 (s, 6H).
With compound 4 (36mg, 0.15mmol), 2-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenol (32 μ L, 0.15mmol), Pd (PPh 3) 4(17mg, 0.015mmol, 10mol%) and Na 2CO 3(0.30mmol) mixture in DME (0.75mL) ℃ reaches 600 seconds with carry out microwave radiation heating to 180 to the aqueous solution for 0.4M, 0.75mL.Reaction mixture is filtered,, obtain compound 5, be white solid (tfa salt) through the preparation HPLC purifying.LC/MS (10-99%) m/z:298, retention time: 2.89min.
Following table 3 describe by aforesaid method or basically with the authentication data of the prepared compound of Formula I of above-mentioned similar methods.
Table 3
Compound number LC/MS(m/z) Obs.[M+H] + LCMS RT Min
1 242.1 2.95
2 274.2 2.76
3 280.20 1.08
4 316.00 3.14
5 314.00 3.27
6 273.10 2.76
7 358.00，358.00 3.27，3.39
8 326.30 3.33
9 300.20 3.27
10 350.20 3.83
11 325.20 3.18
12 427.00 3.11
13 299.4 2.31
14 332.2 3.57
15 328.30 2.52
16 314.00 3.78
17 296.2 3.97
18 287.20 1.69
19 298.2 3.10
20 342.20 3.42
21 262.00 3.55
22 308.00，308.30 3.23，3.09
23 368.20 3.29
24 320.00 2.87
25 356.20 3.07
26 287.00 2.58
27 281.20 2.13
28 353.00 4.91
29 288.2 3.21
30 378.3 4.12
31 271.18 3.06
32 320.10 3.11
33 340.30 4.19
34 304.10 3.50
35 326.4 1.74
36 324.00 4.65
37 288.00 3.51
38 228.2 3.42
39 306.00 4.48
40 328.00 4.31
41 340.20 3.60
42 300.4 3.08
43 313.20，327.40 3.93，4.07
44 340.20 3.60
45 339.00 4.91
46 299.30 3.76
Compound number LC/MS(m/z) Obs.[M+H] + LCMS RT Min
47 375.27 4.34
48 314.10 3.36
49 326.20 2.66
50 388.00 3.66
51 357.20 2.19
52 328.2 3.58
53 314.00 2.40
54 314.10 2.67
55 343.20 2.12
56 405.4 2.96
57 300.00 3.69
58 306.10 3.88
59 258.0 3.22
60 328.20 3.05
61 410.29 3.84
62 332.00 4.75
63 272.2 2.85
64 296.00 3.75
65 360.2 4.11
66 292.00 2.36
67 271.4 2.00
68 300.30 3.10
69 300.20 3.37
70 364.00 3.11
71 327.2 2.60
72 272.20 2.41
73 328.20 1.89
74 344.00 2.47
75 329.00 3.55
76 330.00 2.94
77 342.00 3.36
78 400.00 3.41
79 284.00 2.88
80 312.20 3.49
81 286.10，286.10，286.10 3.49，3.16，2.86，3.25
82 334.20 2.56
83 326.2 3.55
84 312.00 2.45
85 290.30 3.49
86 311.21 3.21
87 326.2 3.82
88 346.2 3.94
89 259.20 3.37
90 364.00 3.80
91 390.2 4.04
92 314.00 3.72
93 333.00 3.66
94 308.20 3.46
95 340.00 2.79
96 344.00 3.65
97 313.20 3.79
Compound number LC/MS(m/z) Obs.[M+H] + LCMS RT Min
98 314.00 3.00
99 286.10 2.81
100 273.30 3.50
101 302.00 3.76
102 294.00 4.80
103 312.2 3.62
104 379.00 5.09
105 309.20 2.82
106 342.2 2.84
107 364.2 3.19
108 335.20 3.53
109 346.00 2.67
110 244.4 2.05
111 278.00 4.06
112 408.30 5.41
113 317.00 3.28
114 334.23 3.39
115 339.80 3.57
116 326.00 3.56
117 351.00 3.06
118 294.40 1.77
119 288.00 3.80
120 336.0 3.87
121 336.20 3.25
122 290.00 3.00
123 376.26 3.80
124 324.20 1.17
125 339.2 2.80
126 297.4 2.23
127 378.00 2.99
128 278.0 3.09
129 330.20 2.90
130 261.00 4.28
131 301.40 3.77
132 342.00 2.95
133 318.00 3.41
134 334.2 3.46
135 301.40 3.86
136 316.00 3.04
137 282.2 2.66
138 314.10 3.15
139 288.00 3.51
140 338.00 3.12
141 285.19 3.00
142 297.20 3.71
143 286.1 3.39
144 300.40 3.09
145 359.80 2.79
146 300.30 2.55
147 328.00 3.75
148 300.4 3.08
Compound number LC/MS(m/z) Obs.[M+H] + LCMS RT Min
149 314.2 3.26
150 342.00 3.52
151 306.2 3.36
152 298.20 2.96
153 304.0 3.28
154 325.22 3.40
155 244.4 3.11
156 270.2 3.07
157 299.30 3.35
158 387.28 4.49
159 300.20 3.45
160 358.00 2.60
161 295.00 3.50
162 364.00 3.10
163 312.0 3.38
164 295.20 3.59
165 274.00 3.08
166 354.00 3.42
167 286.2 2.87
168 318.00 4.58
169 443.10 3.66
170 302.2 2.56
171 262.00，262.00 3.19，2.54
172 347.24 3.84
173 332.20 2.40
174 300.40 3.12
175 299.30 3.66
176 361.00 1.94
177 290.00 3.96
178 300.4 3.28
179 309.20 2.76
180 314.10 3.23
181 302.2 3.34
182 380.00 3.31
183 259.20 3.57
184 273.30 3.39
185 264.00 4.28
186 348.00 3.27
187 311.00 4.48
188 302.00 4.01
189 278.0 3.79
190 374.26 3.70
191 265.00 2.81
192 348.00 3.99
193 301.40 1.77
194 341.20 2.06
195 376.2 3.67
196 361.2 2.93
197 328.20 3.28
198 300.20 3.20
199 354.0 3.67
Compound number LC/MS(m/z) Obs.[M+H] + LCMS RT Min
200 328.00 3.58
201 348.24 3.44
202 350.2 3.44
203 287.00 2.41
204 345.00 2.09
205 328.4 3.26
206 351.00 3.06
207 386.00 3.53
208 306.2 2.84
209 328.30 2.48
210 262.00 2.64
211 258.2 2.44
212 333.2 2.59
213 316.20 3.16
214 287.8 2.99
215 259.00 2.83
216 302.00 2.78
217 302.00 3.95
218 332.00 3.20
219 322.20 2.65
220 355.80 4.22
221 345.2 3.31
222 288.00 3.03
223 328.00 4.03
224 335.40 4.26
225 373.00 2.10
226 304.00 4.29
227 260.0 3.94
228 290.30 3.21
229 347.24 4.05
230 243.4 1.88
231 373.27 4.17
232 311.2 2.39
233 316.00 4.24
234 272.20 2.53
235 355.80 4.04
236 409.30 5.06
237 356.00 3.97
238 378.2 3.90
239 314.00 2.58
240 301.20 3.13
241 313.30，327.30 3.50，3.35
242 328.00 2.85
243 404.2 4.21
244 388.27 3.81
245 248.00 3.59
246 279.20 2.99
247 333.23 4.35
248 292.2 3.72
249 282.00 3.01
250 293.00 1.99
Compound number LC/MS(m/z) Obs.[M+H] + LCMS RT Min
251 295.00 0.80
252 323.20 2.20
253 273.20 1.77
254 225.1 3.83
255 289.4 2.41
256 282.20 3.02
257 282.10 3.01
258 297.20 2.83
259 296.20 3.23
260 426.20 4.01
261 253.2 4.09
262 274.4 3.90
263 283.30 3.79
264 283.00 1.99
265 362.00 2.46
266 290.00 3.41
267 275.80 3.07
268 306.2 3.11
269 259.80 2.46
270 293.00 2.13
271 262.0 3.37
272 317.9 4.24
273 384.10 3.43
274 251.0 4.07
275 282.00 2.69
276 296.40 3.18
277 265.2 4.23
278 322.20 3.63
279 264.0 2.34
280 295.00 0.90
281 282.20 2.96
282 304.2 2.96
283 260.2 2.96
284 284.00 2.44
285 308.20 3.25
286 296.4 3.46
287 231.20 1.85
288 278.0 2.83
289 234.2 2.83
290 300.00 2.55
291 310.20 3.40
292 374.00 2.67
293 220.2 2.25
294 294.00 3.63
295 306.20 2.88
296 279.0 4.63
297 267.00 2.83
298 285.00 2.12
299 281.00 2.22
300 272.0 2.97
301 244.2 3.36
Compound number LC/MS(m/z) Obs.[M+H] + LCMS RT Min
302 258.0 2.81
303 306.2 3.34
304 264.20 2.28
Detect and measure the assay method of compound N aV inhibition activity
A) optical means of mensuration compound N aV inhibition activity
The compounds of this invention can be used as the antagonist of voltage-gated sodium-ion channel.The antagonist properties of following assessment test compound.The cell of expressing relevant NaV is placed microtiter plate.After the incubation period, use fluorescein stain to dye in cell to the membrane potential sensitivity.Add test compound to microtiter plate.With chemistry or electric hand section irritation cell, excite the NaV dependency membrane potential that does not block passage to change, detect and measure with membrane potential-susceptibility stain.Antagonist is detected as in response to the membrane potential that stimulates and reduces.The blooming potentiometry adopts voltage-susceptibility FRET transmitter, as described in Gonzalez and the Tsien ( Referring to, Gonzalez, J.E.andR.Y.Tsien (1995) " Voltage sensing by fluorescence resonanceenergy transfer in single cells " Biophys J69 (4): 1272-80, andGonzalez, J.E.and R.Y.Tsien (1997) " Improved indicators ofcell membrane potential that use fluorescence resonance energytransfer " Chem Biol4 (4): 269-77), with the Instrument crosslinking of measuring change in fluorescence, for example voltage/ion probe reader (VIPR ) ( Referring to, Gonzalez, J.E., K.Oades waits people (1999) " Cell-based assays and instrumentation forscreening ion-channel targets " Drug Discov Today4 (9): 431-439).
B) utilize the VIPR of chemical stimulation Blooming potential measurement method
Cell is handled and stain loads
Measure preceding 24 hours at VIPR, the Chinese hamster ovary celI of the voltage-gated NaV of endogenous expression NaV1.2 type is seeded in the flat board that 96 hole polylysines apply 60,000 cells in every hole.In the clone of expressing relevant NaV, carry out other hypotypes in a similar manner.
1) measuring the same day, the suction substratum is bathed solution #2 (BS#2) washed twice with cell with 225 μ L.
2) be prepared as follows 15 μ M CC2-DMPE solution: 5mM tonka bean camphor stock solution is mixed by 1: 1 with 10%Pluronic 127, then mixture is dissolved in the BS#2 of proper volume.
3) from 96 hole flat boards, remove bathe solution after, load 80 μ L CC2-DMPE solution to cell.At room temperature, with flat board incubation 30 minutes in the dark.
4) at cell by the painted while of tonka bean camphor, prepare the BS#2 solution of 15 μ L oxonol.Except DiSBAC 2(3) in addition, this solution also should contain 0.75mM ABSCl and 30 μ L veratridines (from the preparation of 10mM EtOH storing solution, Sigma#V-5754).
5) after 30 minutes, remove CC2-DMPE, with cell with 225 μ L BS#2 washed twice.The same, resid vol should be 40 μ L.
6) remove bathe solution after, load 80 μ L DiSBAC to cell 2(3) solution is then from the DMSO solution of dosing flat board to every hole adding test compound, to reach required for examination concentration, thorough mixing.Volume in the aperture should be about 121 μ L.Then with cell incubation 20-30 minute.
7) in case incubation is finished, can utilize sodium to return and add scheme at VIPR Last mensuration cell.Add 120 μ L and bathe solution #1, to stimulate the depolarize of NaV dependency.Use the antagonist positive control of 200 μ L tetracaine as the NaV channel blocking.
VIPR The analysis of data:
Analytical data is represented with the background deduction emissive porwer ratio of the process normalizing measured in 460nm and 580nm passage.Measure background correction intensity the passage from each then.Background intensity is to obtain like this, in the emissive porwer of identical time phase measurement through the mensuration aperture of same treatment, does not wherein have cell to exist.As the response of the function of time then to utilize following formula gained ratio to represent:
By calculating initial (R i) and final (R f) ratio, further processing data.They are mean ratios during the sample spot during part or all of prestimulatory stage and between stimulation period.Calculate response R=R then to stimulating f/ R iWith regard to Na +Return to add and analyze time window, baseline is 2-7 second, second final response is taken a sample at 15-24.
Contrast response is to obtain like this, have the compound of required character (positive control) in the presence of, for example tetracaine and do not have pharmacological agents in the presence of (negative control) measure.As above calculate response to negative (N) and positive (P) contrast.Compound antagonistic activity A is defined as:
A = R - P N - P * 100
Wherein R is the response ratio of test compound.
Solution [mM]
Bathe solution #1:NaCl 160, KCl 4.5, CaCl 22, MgCl 21, HEPES 10, pH7.4 (NaOH)
Bathe solution #2:TMA-Cl 160, CaCl 20.1, MgCl 21, HEPES 10, and pH7.4 (KOH) (final K concentration～5mM)
CC2-DMPE: be prepared into 5mM DMSO stock solution, be stored under-20 ℃
DiSBAC 2(3): be prepared into 12mM DMSO stock solution, be stored under-20 ℃
ABSCl: be prepared into 200mM distilled water stock solution, store at room temperature
Cell cultures
Make Chinese hamster ovary celI be grown in DMEM (the Eagle substratum of DulbeccoShi improvement; GibcoBRL #10569-010) in, (foetal calf serum quantizes wherein to be supplemented with 10%FBS; GibcoBRL #16140-071) and 1%Pen-Strep (penicillin-Streptomycin sulphate; GibcoBRL#15140-122).Cell is grown in through in the deflated flask with cover, at 90% humidity and 10%CO 2In grow to 100% and merge.Their common trypsinizes are split into 1: 10 or 1: 20, and this depends on the needs of plan, and growth is 2-3 days before division next time.
C) utilize the VIPR of electricity irritation Blooming potential measurement method
Be how to utilize blooming potentiometry #2 measuring N aV1.3 to suppress active example below.In the clone of expressing relevant NaV, carry out other hypotypes in a similar manner.
With the HEK293 cell plating of stably express NaV1.3 in 96 hole microtiter plates.After the suitable incubation period, following with cell voltage-susceptibility stain CC2-DMPE/DiSBAC2 (3) dyeing.
Reagent:
100mg/ml Pluronic F-127 (Sigma #P2443), anhydrous DMSO
10mM DiSBAC 2(3) (Aurora #00-100-010), anhydrous DMSO
10mM CC2-DMPE (Aurora #00-100-008), anhydrous DMSO
200mM ABSCl，H 2O
HankShi balanced salt solution (Hyclone #SH30268.02) is supplemented with 10mM HEPES (Gibco #15630-080)
Loading scheme:
2X CC2-DMPE=20 μ M CC2-DMPE: make 10mM CC2-DMPE and equal-volume 10%pluronic vortex, succeeded by containing the aequum HBSS mesoscale eddies of 10mM HEPES.Each cell flat board will need 5ml 2X CC2-DMPE.Aperture to the cell that contains the process washing adds 50 μ L 2X CC2-DMPE, and causing final dyeing concentration is 10 μ M.Under RT, cell was in the dark dyeed 30 minutes.
2XDISBAC 2(3) with ABSCl=6 μ M DISBAC 2(3) and 1mM ABSCl: the 10mM DISBAC that adds aequum to the 50ml conical tube 2(3), mix with 1 μ L 10%pluronic, with regard to the solution that every ml will prepare, vortex together.Add HBSS/HEPES then and make 2X solution.Add ABSCl at last.
2X DiSBAC 2(3) solution can be used for solvation compound flat board.Notice that the compound flat board is made into the drug level of 2X.Wash once more through hyperchromatic flat board, resid vol is 50 μ L.The 2X DiSBAC that adds 50 μ L/ holes 2(3) w/ABSCl.Under RT, in the dark dyeed 30 minutes.
Used apparatus of electro-stimulation and method are quoted at this as a reference as described in the ionic channel measuring method PCT/US 01/21652.Instrument comprises the dull and stereotyped treater of microtitration, be used for exciting the tonka bean camphor stain write down simultaneously tonka bean camphor and oxonol emission optical system, waveform generator, curtage control amplifier and be used for inserting the device of electrode at aperture.Under the control of hybrid computer, this instrument is carried out the electrical stimulation scheme of process user program to the cell in the microtiter plate aperture.
Reagent:
Measure damping fluid #1:140mM NaCl, 4.5mM KCl, 2mM CaCl 2, 1mM MgCl 2, 10mM HEPES, 10mM glucose, pH7.40,330mOsm
Pluronic storing solution (1000X): 100mg/ml pluronic 127, anhydrous DMSO
Oxonol storing solution (3333X): 10mM DiSBAC 2(3), anhydrous DMSO
Tonka bean camphor storing solution (1000X): 10mM CC2-DMPE, anhydrous DMSO
ABSCl storing solution (400X): 200mM ABSCl, water
The mensuration scheme:
1. insert or use electrode to each aperture to be determined.
2. utilize the amplifier of current control to send the stimulus wave pulse and reach 3 seconds.Carry out the preceding record of stimulation in 2 seconds, to obtain unprovoked intensity.Carry out record after the stimulation in 5 seconds, to check that lax is quiescent condition.
Data analysis
Analytical data is represented with the background deduction emissive porwer ratio of the process normalizing measured in 460nm and 580nm passage.Measure background correction intensity the passage from each then.Background intensity is to obtain like this, in the emissive porwer of identical time phase measurement through the mensuration aperture of same treatment, does not wherein have cell to exist.As the response of the function of time then to utilize following formula gained ratio to represent:
Figure A20048002502701831
By calculating initial (R i) and final (R f) ratio, further processing data.They are mean ratios during the sample spot during part or all of prestimulatory stage and between stimulation period.Calculate response R=R then to stimulating f/ R i
Contrast response is to obtain like this, have the compound of required character (positive control) in the presence of, for example tetracaine and do not have pharmacological agents in the presence of (negative control) measure.As above calculate response to negative (N) and positive (P) contrast.Compound antagonistic activity A is defined as:
A = R - P N - P * 100
Wherein R is the response ratio of test compound.
Active and the inhibiting electrophysiological detection method of test compound NaV
Utilize effect and the selectivity of sheet pincers electrophysiology assessment sodium channel inhibitor to dorsal root ganglion neurons.Separate the rat neurone from dorsal root ganglion, in the presence of NGF (50ng/ml), support 2 to 10 days (substratum is made up of NeurobasalA, is supplemented with B27, glutamine and microbiotic).Naked eyes are differentiated minor diameter neurone (nociceptor, diameter 8-12 μ m), detect with the apicule glass electrode (Axon Instruments) that connects amplifier.Keep cell under-60mV, utilize the IC50 of " voltage clamp " pattern assessment compound.In addition, utilize " current clamp " pattern test compounds blocking in response to the aborning effect of the action potential of current injector.These result of experiment help to define the effect behavior of compound.
Voltage clamp assay method in the DRG neurone
Utilize the TTX-tolerance sodium current of the full cell variant record of sheet tongs technology from the DRG body.Utilize Axopatch 200B amplifier (Axon Instruments) and heavy wall silicon borate glass electrode (WPI; Resistance 3-4M Ω) at room temperature (～22 ℃) carry out record.After setting up full cell structure, cost made volumetric pipette solution in the cell inner equilibrium in about 15 minutes before opening entry.Low-pass filter electric current between 2-5kHz, digital sampling under 10kHz.The series resistance of compensation 60-70% is in the experimental session continuous monitoring.Liquid junction potential in cell between volumetric pipette solution and the external record solution (7mV) is not counted data analysis.Utilize the rapid pouring system (SF-77 of segregation drive; Warner Instruments) uses test solution to cell.
Dosage-response relation is to measure like this, according to the voltage clamp pattern, make cell from the experiment specificity keep current potential repeatedly depolarize for+10mV for the examination current potential, per 60 seconds are once.Carrying out next for allowing retardation effect to reach plateau value before trying concentration.
Solution:
Solution (mM): Cs-F (130) in the cell, NaCl (10), MgCl 2(1), EGTA (1.5), CaCl 2(0.1), HEPES (10), glucose (2), pH=7.42,290mOsm.
Extracellular solution (mM): NaCl (138), CaCl 2(1.26), KCl (5.33), KH 2PO 4(0.44), MgCl 2(0.5), MgSO 4(0.41), NaHCO 3(4), Na 2HPO 4(0.3), glucose (5.6), HEPES (10), CdCl 2(0.4), NiCl 2(0.1), TTX (0.25 * 10 -3).
Compound N aV passage suppresses active current clamp assay method
Utilize Multiplamp 700A amplifier (Axon Inst) in full cell structure, to use current clamp to cell.Fill (mM) to borosilicate volumetric pipette (4-5MOhm): 150 Potassium Gluconates, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl 2(being buffered to pH7.34) with KOH.Cell is bathed (mM): 140 NaCl, 3 KCl, 1 MgCl 2, 1 CaCl 2With 10 Hepes.The volumetric pipette current potential is zero before sealing forms; Liquid junction potential is not proofreaied and correct during obtaining.At room temperature carry out record.
Find that representative compounds of the present invention as shown in table 2 can modulate valtage-gated sodium channel.
Detect and measure the assay method of Compound C aV inhibition activity
A) optical means of mensuration Compound C aV inhibition activity
The compounds of this invention can be used as the antagonist of voltage-gated calcium channel.The antagonist properties of following assessment test compound.The cell of expressing relevant CaV is placed microtiter plate.After the incubation period, use fluorescein stain to dye in cell to the membrane potential sensitivity.Add test compound to microtiter plate.Electricity consumption means irritation cell excites the CaV dependency membrane potential that does not block passage to change, and detects and measures with membrane potential-susceptibility stain.Antagonist is detected as in response to the membrane potential that stimulates and reduces.The blooming potentiometry adopts voltage-susceptibility FRET transmitter, as described in Gonzalez and the Tsien ( Referring to, Gonzalez, J.E.and R.Y.Tsien (1995) " Voltages ensing by fluorescence resonance energytransfer in single cells " Biophys J69 (4): 1272-80, andGonzalez, J.E.and R.Y.Tsien (1997) " Improved indicators ofcell membrane potential that use fluorescence resonance energytransfer " Chem Biol4 (4): 269-77), with the Instrument crosslinking of measuring change in fluorescence, for example voltage/ion probe reader (VIPR ) ( Referring to, Gonzalez, J.E., K.Oades waits people (1999) " Cell-based assays and instrumentation forscreening ion-channel targets " Drug Discov Today4 (9): 431-439).
B) utilize the VIPR of electricity irritation Blooming potential measurement method
Be how to utilize the blooming potentiometry to measure CaV2.2 to suppress active example below.In the clone of expressing relevant CaV, carry out other hypotypes in a similar manner.
With the HEK293 cell plating of stably express CaV2.2 in 96 hole microtiter plates.After the suitable incubation period, following with cell voltage-susceptibility stain CC2-DMPE/DiSBAC2 (3) dyeing.
Reagent:
100mg/ml Pluronic F-127 (Sigma #P2443), anhydrous DMSO
10mM DiSBAC 6(3) (Aurora #00-100-010), anhydrous DMSO
10mM CC2-DMPE (Aurora #00-100-008), anhydrous DMSO
200mM turmeric yellow 17 (Aurora #VABSC), H 2O
370mM bariumchloride (Sigma Cat# B6394), H 2O
Body lotion X:
160mM NaCl(Sigma Cat# S-9888)
4.5mM KCl (Sigma Cat# P-5405)
1mm MgCl 2 (Fluka Cat# 63064)
10mM HEPES (Sigma Cat# H-4034)
pH7.4(NaOH)
Loading scheme:
2X CC2-DMPE=20 μ M CC2-DMPE: make 10mM CC2-DMPE and equal-volume 10%pluronic vortex, succeeded by containing the aequum HBSS mesoscale eddies of 10mM HEPES.Each cell flat board will need 5ml 2X CC2-DMPE.Aperture to the cell that contains the process washing adds 50 μ L 2X CC2-DMPE, and causing final dyeing concentration is 10 μ M.Under RT, cell was in the dark dyeed 30 minutes.
2X CC2DMPE ﹠amp; DISBAC 6(3)=8 μ M CC2DMPE ﹠amp; 2.5 μ M DISBAC 6(3): make two kinds of stains with equal-volume 10%pluronic (DMSO) vortex.In aequum body lotion X with the beta-cyclodextrin vortex.Each 96 porocyte flat board will need 5ml 2X CC2DMPE.Dull and stereotyped with ELx405 and body lotion X washing, resid vol is 50 μ L/ holes.Add 50 μ L2X CC2DMPE ﹠amp to every hole; DISBAC 6(3).Under RT, in the dark dyeed 30 minutes.
1.5X AY 17=750 μ M AY17 and 15mM BaCl 2: add turmeric yellow 17 to the container that contains body lotion X.Thorough mixing.Made solution left standstill 10 minutes.Slowly be blended in 370mM BaCl 2In.This solution can be used for solvation compound flat board.Notice that the compound flat board is made into the drug level of 1.5X, rather than usual 2X.Washing is through the painted flat board of CC2 once more, and resid vol is 50 μ L.The AY17 solution that adds 100 μ L/ holes.Under RT, in the dark dyeed 15 minutes.On the optical readings device, read flat board.
Used apparatus of electro-stimulation and method are quoted at this as a reference as described in the ionic channel measuring method PCT/US 01/21652.Instrument comprises the dull and stereotyped treater of microtitration, be used for exciting the tonka bean camphor stain write down simultaneously tonka bean camphor and oxonol emission optical system, waveform generator, curtage control amplifier and be used for inserting the device of electrode at aperture.Under the control of hybrid computer, this instrument is carried out the electrical stimulation scheme of process user program to the cell in the microtiter plate aperture.
The mensuration scheme:
Insert or use electrode to each aperture to be determined.
Utilize the amplifier of current control to send the stimulus wave pulse and reach 3-5 second.Carry out the preceding record of stimulation in 2 seconds, to obtain unprovoked intensity.Carry out record after the stimulation in 5 seconds, to check that lax is quiescent condition.
Data analysis
Analytical data is represented with the background deduction emissive porwer ratio of the process normalizing measured in 460nm and 580nm passage.Measure background correction intensity the passage from each then.Background intensity is to obtain like this, in the emissive porwer of identical time phase measurement through the mensuration aperture of same treatment, does not wherein have cell to exist.As the response of the function of time then to utilize following formula gained ratio to represent:
Figure A20048002502701871
By calculating initial (R i) and final (R f) ratio, further processing data.They are mean ratios during the sample spot during part or all of prestimulatory stage and between stimulation period.Calculate response R=R then to stimulating f/ R i
Contrast response is to obtain like this, have the compound of required character (positive control) in the presence of, for example tetracaine and do not have pharmacological agents in the presence of (negative control) measure.As above calculate response to negative (N) and positive (P) contrast.Compound antagonistic activity A is defined as:
A = R - P N - P * 100
Wherein R is the response ratio of test compound.
Active and the inhibiting electrophysiological detection method of test compound CaV
Utilize sheet pincers electrophysiology to be evaluated at the effect of the calcium channel blocker of expressing in the HEK293 cell.Naked eyes are differentiated the HEK293 cell of expressing CaV2.2, detect with the apicule glass electrode (Axon Instruments) that connects amplifier.Keep cell under-100mV, utilize the IC50 of " voltage clamp " pattern assessment compound.These result of experiment help to define the effect behavior of compound.
Voltage clamp assay method in the HEK293 cell of expression CaV2.2
Utilize the CaV2.2 calcium current of the full cell variant record of sheet tongs technology from the HEK293 cell.Utilize Axopatch 200B amplifier (Axon Instruments) and heavy wall silicon borate glass electrode (WPI; Resistance 3-4M Ω) at room temperature (～22 ℃) carry out record.After setting up full cell structure, cost made volumetric pipette solution in the cell inner equilibrium in about 15 minutes before opening entry.Low-pass filter electric current between 2-5kHz, digital sampling under 10kHz.The series resistance of compensation 60-70% is in the experimental session continuous monitoring.Liquid junction potential in cell between volumetric pipette solution and the external record solution (7mV) is not counted data analysis.Utilize the rapid pouring system (SF-77 of segregation drive; Warner Instruments) uses test solution to cell.
Dosage-response relation is to measure like this, according to the voltage clamp pattern, make cell from the experiment specificity keep current potential repeatedly depolarize for+20mV reach 50 milliseconds for the examination current potential, frequency is 0.1,1,5,10,15 and 20Hz.Carrying out next for allowing retardation effect to reach plateau value before trying concentration.
Solution:
Solution (mM): Cs-F (130) in the cell, NaCl (10), MgCl 2(1), EGTA (1.5), CaCl 2(0.1), HEPES (10), glucose (2), pH=7.42,290mOsm.
Extracellular solution (mM): NaCl (138), BaCl 2(10), KCl (5.33), KH 2PO 4(0.44), MgCl 2(0.5), MgSO 4(0.41), NaHCO 3(4), Na 2HPO 4(0.3), glucose (5.6), HEPES (10).
According to these technology, find that representative compounds of the present invention possesses required N-type calcium channel regulation activity and selectivity.

Claims (145)

1, the compound that has formula IA:
Figure A2004800250270002C1
Perhaps its pharmacy acceptable salt, wherein:
R 1And R 2Be hydrogen or optional substituted group independently of one another, described group is selected from C 1-6Aliphatic group, have 0-5 and independently be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur; Perhaps R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical or heteroaryl ring, wherein a R who independently is selected from nitrogen, oxygen or sulphur 1, R 2Perhaps arbitrarily by R 1And R 2The ring that is constituted is occurred for 0-4 time on one or more carbon atoms-R independently of one another alternatively together 5Replace quilt-R on one or more commutable nitrogen-atoms 6Replace;
Ring A has 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur, alternatively on one or more carbon atoms by 0-5 appearance-R 7Replace, replace quilt-R on the nitrogen-atoms one or more 8Replace;
Each R that occurs 3, R 4, R 5And R 7Be Q-R independently XWherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN;
Wherein each R that occurs is independently selected from hydrogen or optional substituted C 1-6Aliphatic group; Each R ' that occurs is independently selected from hydrogen or optional substituted group, and described group is selected from C 1-8Aliphatic group, C 6-10Aryl, have the heteroaryl of 5-10 annular atoms or have the heterocyclic radical of 3-10 annular atoms, perhaps wherein R and R ' constitute with the atom of their institute's bondings with the R ' of the atom of their institute's bondings or twice appearance and have 0-3 heteroatomic 5-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl that independently is selected from nitrogen, oxygen or sulphur; With
Each R that occurs 6Or R 8Be independently R ' ,-COR ' ,-CO 2(C 1-6Aliphatic group) ,-CON (R ') 2Or-SO 2R ',
Its condition is R 3By the atomic linkage beyond the deoxygenation in carbonylic carbon atom; Further condition is:
A) if ring A is unsubstituted phenyl, R 3Be methyl, and R 4Be=S or-SMe, then R 1And R 2Can not be N-morpholino base, N-pyrrolidyl or optional substituted piperazinyl together;
B) if ring A is a N-morpholino base, R 3Be H, and R 4Be Cl or Me, then R 1Be not Et, this moment R 2Be 4-Cl-phenyl, perhaps R 1And R 2Can not be N-morpholino base together;
C) if ring A is the N-pyrrolidyl, and R 3Be H, then:
I) if R 4Be-N (CH 3) COPh, then R 1And R 2Can not be pyrrolidyl together; With
Ii) if R 4Be Cl, R then 1Be not Et, this moment R 2It is the 4-Me-phenyl;
D) if ring A is the N-piperidyl, R 3Be hydrogen, and R 4Be methyl, R then 1And R 2Can not be the N-piperidyl together;
E) if ring A is optional substituted piperazinyl, R 3Be hydrogen, and R 4Be chlorine, then if R 1Be Et, R then 2Not 4-Cl-phenyl, 4-Me-phenyl or 4-F-phenyl, perhaps R 1And R 2Can not be that parathiazan is for base together;
F) if ring A is 2,5-dimethyl-1H-pyrroles-1-base, R 3Be hydrogen, and R 4Be OMe, then if R 1Be Me, R then 2It or not benzyl;
G) if ring A is 1-oxo bridge-4-parathiazan base, R 3Be hydrogen, and R 4Be OEt, R then 1And R 2Can not be piperazinyl together;
H) if R 3Be CH 3Or optional substituted phenyl, R 1Be hydrogen, R 2Be optional substituted phenyl, methyl, ethyl, COR ', NR ' or CONHR ', and R 4Be=S, Me, SMe or SCH 2CO 2Me, SCH 2CN, then encircling A is not unsubstituted phenyl or 4-C1-phenyl;
I) if R 3Be CH 3, R 1Be hydrogen, R 2Be ethyl, and R 4Be hydrogen, then encircling A is not N-pyrrolidyl, piperazine-1-base, N-morpholinyl or piperidino;
J) if R 3Be N (R ') 2, R 1Be hydrogen, R 2Be 3-, 5-C1-phenyl, 4-C1-phenyl, methyl, optional substituted cyclohexyl, 3-Cl, 4-OMe-benzyl, 4-Ac-phenyl, ethyl, sec.-propyl, 4-OEt-phenyl, 4-OMe-phenyl, benzyl or (CH 2) 2OR, and R 4Be CH 3, hydrogen or SMe, then encircling A is not unsubstituted phenyl, piperidyl, optional substituted piperazinyl, morpholinyl, optional substituted pyrrolidyl, 5,8-dihydro-1,7-naphthyridines-7 (6H)-Ji or 5,6-dihydro-8-imidazo [1,2-a] pyrazine-7-base;
K) if R 3Be-CH=CHN (CH 3) 2, CH 3,-(CH 2) 2-N-morpholino base ,-(CH 2) 2-OMe ,-(CH 2) 2-OH ,-CH 2OMe, normal-butyl, pyridine-2-ylmethyl, pyridine-2-base, pyrimidine-5-base, CH 2SO 2Me ,-(CH 2) 2-NMe 2,-(CH 2) 2-N-(4-methylpiperazine base) ,-(CH 2) 2-NH-pyridin-3-yl ,-(CH 2) 2-NH-CH 2-pyridin-3-yl, 1-methyl isophthalic acid H-imidazoles-2-base, 5-amino-1,2-dimethyl-1H-imidazol-4 yl, 4-(dimethylamino) phenyl, 3,4-(methylene-dioxy) phenyl ,-CH 2=CH 2,-CH=CH 2Or-CH (CN) COOEt, R 1Be hydrogen, R 2Be optional substituted benzyl or ethyl, R 4Be SMe or hydrogen, then encircling A is not unsubstituted phenyl or optional substituted pyrrolidyl;
1) if R 1Be hydrogen, and R 2Be hydrogen or 4,6-dimethyl pyrimidine-2-base, ring A is optional substituted phenyl, R 3Be Me or unsubstituted phenyl, then R 4Be not SMe ,=S, Me or unsubstituted phenyl;
M) if R 1Be hydrogen, and R 2Be optional substituted benzyl, then R 3Not 3,4, the 5-trimethoxyphenyl;
N) if R 1And R 2All be hydrogen, ring A is (2-fluorophenyl methyl)-1H-pyrazolo [3,4-b] pyridin-3-yl, R 3Be ethyl or 2-ethoxyethyl group, then R 4Not hydrogen;
O) if R 1Be hydrogen, R 2Be benzoyl, R then 3, R 4A is not unsubstituted phenyl simultaneously with ring;
P) if R 1And R 2All be hydrogen, ring A is 4-(4 '-morpholinyl)-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base, 4-amino-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base, 4-(4-(4-fluorophenyl)-piperazinyl)-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base, 4-(4,6-dimethyl-pyrimidine-2-base) amino-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base, 4-(N-pyrrolidyl)-5-methyl-2-phenyl thieno-[2,3-d] pyrimidine-6-base or unsubstituted phenyl, R 3Be methyl, R then 4Not methyl or SMe;
Q) if R 1And R 2All be hydrogen, R 3Be methyl, R 4Be=S or unsubstituted phenyl that then encircling A is not unsubstituted phenyl;
R) if R 1And R 2-formation N-tetramethyleneimine basic ring, R 3Be-NHCH 2(4-trifluoromethyl), R 4Be H, then encircling A is not N-pyrrolidyl, 3,4-Dimethoxyphenyl, 2-p-methoxy-phenyl, thiene-3-yl-or thiophene-2-base.
2, according to the compound of claim 1, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having the first heterocyclic ring of heteroatomic 3-8 that independently is selected from nitrogen, sulphur or oxygen.
3, according to the compound of claim 2, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes the first heterocyclic radical of optional substituted 3-8, is selected from:
Figure A2004800250270005C1
Wherein z is 0-4.
4, according to the compound of claim 3, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes ring bb, dd, ee, ff or gg.
5, according to the compound of claim 1, R wherein 1And R 2All be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
6, according to the compound of claim 1, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
7, according to the compound of claim 5 or 6, R wherein 1And R 2Group is selected from methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl.
8, according to the compound of claim 5 or 7, R wherein 1And R 2Be the same.
9, according to the compound of claim 1, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be to have 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur.
10, according to the compound of claim 9, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be selected from:
11, according to the compound of claim 3 or 10, R wherein 6Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
12, according to the compound of claim 11, R wherein 6Be H, Me, CF independently 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
13, according to the compound of claim 1, R wherein 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
14, according to the compound of claim 13, R wherein 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
15, according to the compound of claim 1, R wherein 3Be-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is optional substituted C 2-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, its condition be Q by carbon atom bonding in carbonylic carbon atom.
16, the compound of claim 15, wherein R 3Be-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is a key, and R XBe optional substituted group, be selected from C 2-8Aliphatic group, C 6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the heterocyclic ring of 3-10 annular atoms.
17, the compound of claim 1, wherein R 3Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
18, the compound of claim 17, wherein R 3Be H, Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
19, compound according to claim 1, wherein encircle A and be selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrryl, piperidyl, indyl, indazolyl, the benzotriazole base, pyrazolyl, the benzopyrazoles base, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl,  azoles base, the benzoxazol base, different  azoles base, benzisoxa  azoles base, isothiazolyl, the benzisothiazole base, triazolyl, the benzotriazole base, thiadiazolyl group, thienyl, benzothienyl, furyl, benzofuryl or triazine basic ring, wherein said ring are occurred for y time on one or more carbon atoms-R alternatively 7Replace quilt-R on one or more commutable nitrogen-atoms 8Replace, wherein y is 0-5.
20, according to the compound of claim 19, wherein encircle A and be selected from phenyl, piperidyl, thienyl, indyl or pyrrolidyl, wherein encircle A on commutable nitrogen-atoms, have occur for 0-2 time-R 7With occur for 0-1 time-R 8
21, according to the compound of claim 20, wherein encircling A is phenyl, piperidyl or pyrrolidyl.
22,, wherein encircle A and be selected from according to the compound of claim 19:
Figure A2004800250270009C1
Wherein y is 0-5.
23, according to the compound of claim 19, wherein y is 0-2.
24, according to the compound of claim 23, wherein y is 0, and ring A is unsubstituted.
25, according to the compound of claim 23, each R wherein 7Be independently selected from hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
26, according to the compound of claim 25, each R wherein 7Be H, Cl, Br, F, CF independently 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
27, according to the compound of claim 23, each R wherein 8Be independently selected from hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
28, according to the compound of claim 27, each R wherein 8Be H, Me, CF independently 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
29, according to the compound of claim 1, R wherein 1And R 2All be optional substituted C 1-4Aliphatic group, R 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl.
30, according to the compound of claim 29, R wherein 1And R 2All be methyl, ethyl or propyl group, R 3Be ethyl, propyl group or butyl, and ring A have Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
31, according to the compound of claim 1, R wherein 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute 5-6 unit heterocycle together, R 3Be optional substituted C 1-4Aliphatic group or aryl, R 4Be hydrogen, and ring A is optional substituted phenyl.
32, according to the compound of claim 31, R wherein 1And R 2All be methyl, ethyl or propyl group, perhaps R 1And R 2Constitute optional substituted 1-pyrrolidyl or piperidino together, R 3Be optional substituted ethyl, propyl group, butyl or phenyl, and ring A have Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
33, according to the compound of claim 32, R wherein 1And R 2All be methyl or ethyl, R 3Be ethyl or propyl group, R 4Be hydrogen, and encircle the phenyl that A is the 2-replacement, wherein said substituting group is Q-R X, wherein Q is a key.
34, according to the compound of claim 1, R wherein 1And R 2All be C 1-4Aliphatic group, R 3Be optional substituted C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl.
35, according to the compound of claim 34, R wherein 1And R 2Comprise methyl or ethyl, R 3Be optional substituted ethyl or propyl group, ring A has Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
36, according to the compound of claim 35, R wherein 1And R 2All be methyl or ethyl, R 3Be ethyl or propyl group, R 4Be hydrogen, and ring A is optional by the phenyl of halogeno-group or OH replacement.
37, according to the compound of claim 1, R wherein 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute 4-6 unit heterocycle together, R 3Be optional substituted C 1-4Aliphatic group or aryl, R 4Be hydrogen, and ring A is optional substituted phenyl, 5-unit's heteroaryl or 6-unit heterocyclic radical.
38, according to the compound of claim 37, R wherein 1And R 2All be methyl, ethyl or propyl group, perhaps R 1And R 2Constitute 1-azetidinyl, 1-pyrrolidyl or 2 together, 5-pyrrolin basic ring, R 3Be optional substituted ethyl, propyl group, butyl or phenyl, and ring A have Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
39, according to the compound of claim 38, R wherein 1And R 2All be methyl or ethyl, R 3Be ethyl or propyl group, R 4Be hydrogen, and ring A is optional by the phenyl of halogeno-group or OH replacement.
40, according to the compound of claim 1, R wherein 1And R 2All be C 1-4Aliphatic group, R 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A have two Q-R at the most XSubstituent phenyl, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
41, according to the compound of claim 40, R wherein 1And R 2All be methyl or ethyl, R 3Be propyl group, normal-butyl or isobutyl-, R 4Be hydrogen, and ring A is phenyl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
42, the compound that has formula IB:
Perhaps its pharmacy acceptable salt, wherein:
R 1And R 2Be hydrogen or optional substituted group independently of one another, described group is selected from C 1-6Aliphatic group, have 0-5 and independently be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur; Perhaps R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical or heteroaryl ring, wherein a R who independently is selected from nitrogen, oxygen or sulphur 1, R 2Perhaps arbitrarily by R 1And R 2The ring that is constituted is occurred for 0-4 time on one or more carbon atoms-R independently of one another alternatively together 5Replace quilt-R on one or more commutable nitrogen-atoms 6Replace;
Ring A has 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur, alternatively on one or more carbon atoms by 0-5 appearance-R 7Replace, replace quilt-R on the nitrogen-atoms one or more 8Replace;
Each R that occurs 3, R 4, R 5And R 7Be Q-R independently XWherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN;
Wherein each R that occurs is independently selected from hydrogen or optional substituted C 1-6Aliphatic group; Each R ' that occurs is independently selected from hydrogen or optional substituted group, and described group is selected from C 1-8Aliphatic group, C 6-10Aryl, have the heteroaryl of 5-10 annular atoms or have the heterocyclic radical of 3-10 annular atoms, perhaps wherein R and R ' constitute with the atom of their institute's bondings with the R ' of the atom of their institute's bondings or twice appearance and have 0-3 heteroatomic 5-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl that independently is selected from nitrogen, oxygen or sulphur;
Each R that occurs 6Or R 8Be independently R ' ,-COR ' ,-CO 2(C 1-6Aliphatic group) ,-CON (R ') 2Or-SO 2R ',
Its condition is:
A) if R 3Be ethyl, R 4Be hydrogen, ring A is unsubstituted phenyl, and R 1Be hydrogen, R then 2Be not optional substituted 2-pyridyl, optional substituted phenyl, optional substituted benzyl ,-CH 2CO 2H ,-CH 2CN, n-propyl, methyl, ethyl ,-CH 2(4-OMe-phenyl) ,-CH 2CON (Me) CH 2Ph ,-CH 2C ≡ CH ,-CH 2CH 2OMe ,-CH 2CH=CH 2Or-(CH 2) 3OH;
B) if R 3Be ethyl, R 4Be hydrogen, ring A is a thienyl, and R 1Be hydrogen, R then 2It or not optional substituted phenyl;
C) if R 3Be ethyl, R 4If be hydrogen, ring A is unsubstituted phenyl, then R 1Be methyl, ethyl, CH 2CH 2Ph ,-CH 2CH 2The morpholino base ,-CH 2CH 2NEt 2,-CH 2CH 2OMe, normal-butyl or optional substituted phenyl, then R 2Be not-CH 2CH 2CN ,-CH 2CN or-CH 2CH 2OAc, perhaps R 1And R 2Not that optional substituted piperidyl, morpholino base or parathiazan are for base together;
D) if R 3Be ethyl, R 4Be NH 2, Cl, Me or Br, ring A is unsubstituted phenyl or morpholino base, and R 1Be hydrogen, R then 2Not optional substituted phenyl or COR ';
E) if R 3Be ethyl, R 4Be hydrogen, and ring A is unsubstituted phenyl, then R 1And R 2Not methyl simultaneously;
F) if R 3Be methyl, then encircle A, R 4R together 1And R 2Not piperidyl simultaneously;
G) if R 3Be ethyl, R 1Be hydrogen, R 2Be unsubstituted phenyl, and R 4Be methyl or parathiazan for base, then encircling A is not unsubstituted phenyl, 4-OMe-phenyl, 2-pyridyl, 4-C1-phenyl, 2-C1-phenyl, 3,4-dichlorophenyl, 4-Me-phenyl, 3,5-dichlorophenyl, 4-OH-phenyl or 3CF 3-, the 4-Cl-phenyl;
H) if R 3Be ethyl, methyl or sec.-propyl, R 1Be hydrogen or ethyl, and R 2Be ethyl, COCH 3, sec.-propyl ,-CH 2CH 2CN, benzyl ,-CH 2CH 2NEt 2,-CH 2CH 2COOEt, perhaps R 1And R 2Be piperazinyl together, and R 4Be hydrogen, then encircling A is not optional substituted piperazinyl, pyrrolidyl, morpholino base or piperidyl;
I) if R 3Be ethyl, and R 1Be hydrogen, R then 2It or not optional substituted cyclohexyl;
J) if R 3Be methyl, and R 4Be N (Me) COPh, then encircle A and R together 1And R 2Not the N-pyrrolidyl simultaneously;
K) if R 3Be ethyl, R 4Be optional substituted phenyl, ring A is optional substituted phenyl, and R 1Be hydrogen, R then 2Not optional substituted naphthyl, methyl, optional substituted phenyl, perhaps R 1And R 2Is that right together quinoline is for base;
1) if R 3Be ethyl, then if R 1And R 2Together or ring one of A be optional substituted piperazinyl, then R 1And R 2Together or the ring A another be not that parathiazan is for base or morpholino base;
M) R 1And R 2Together with ring A not simultaneously is that right quinoline for base or parathiazan for base;
O) if R 3Be methyl, R 4Be hydrogen or OMe, ring A is unsubstituted phenyl, and R 1Be hydrogen, R then 2Not methyl, 2,3-3,5-dimethylphenyl or 3-CF 3Phenyl;
P) if R 3Be ethyl, R 4Be hydrogen, and the ring A be unsubstituted phenyl, then:
I) R 1And R 2Do not constitute 1-pyrrolidyl, 4-methylpiperazine base or piperidino together;
Ii) R 1And R 2Not hydrogen, methyl or ethyl;
Iii) if R 1Be hydrogen, R then 2It or not the 2-hydroxyethyl.
43, according to the compound of claim 42, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having the first heterocyclic ring of heteroatomic 3-8 that independently is selected from nitrogen, sulphur or oxygen.
44, according to the compound of claim 43, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes the first heterocyclic radical of optional substituted 3-8, is selected from:
Figure A2004800250270015C1
Wherein z is 0-4.
45, according to the compound of claim 44, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes ring bb, dd, ee, ff or gg.
46, according to the compound of claim 42, R wherein 1And R 2All be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
47, according to the compound of claim 42, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
48, according to the compound of claim 46 or 47, R wherein 1And R 2Group is selected from methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl.
49, according to the compound of claim 46 or 48, R wherein 1And R 2Be the same.
50, according to the compound of claim 42, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be to have 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur.
51, according to the compound of claim 50, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be selected from:
Figure A2004800250270017C1
52, according to the compound of claim 44 or 51, R wherein 6Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
53, according to the compound of claim 52, R wherein 6Be H, Me, CF independently 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
54, according to the compound of claim 42, R wherein 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
55, according to the compound of claim 54, R wherein 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
56, according to the compound of claim 42, R wherein 3Be-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is optional substituted C 2-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, its condition be Q by carbon atom bonding in carbonylic carbon atom.
57, the compound of claim 56, wherein R 3Be-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is a key, and R XBe optional substituted group, be selected from C 2-8Aliphatic group, C 6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the heterocyclic ring of 3-10 annular atoms.
58, the compound of claim 42, wherein R 3Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
59, the compound of claim 58, wherein R 3Be H, Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
60, compound according to claim 42, wherein encircle A and be selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrryl, piperidyl, indyl, indazolyl, the benzotriazole base, pyrazolyl, the benzopyrazoles base, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl,  azoles base, the benzoxazol base, different  azoles base, benzisoxa  azoles base, isothiazolyl, the benzisothiazole base, triazolyl, the benzotriazole base, thiadiazolyl group, thienyl, benzothienyl, furyl, benzofuryl or triazine basic ring, wherein said ring are occurred for y time on one or more carbon atoms-R alternatively 7Replace quilt-R on one or more commutable nitrogen-atoms 8Replace, wherein y is 0-5.
61, according to the compound of claim 60, wherein encircle A and be selected from phenyl, piperidyl, thienyl, indyl or pyrrolidyl, wherein encircle A on commutable nitrogen-atoms, have occur for 0-2 time-R 7With occur for 0-1 time-R 8
62, according to the compound of claim 61, wherein encircling A is phenyl, piperidyl or pyrrolidyl.
63,, wherein encircle A and be selected from according to the compound of claim 60:
Figure A2004800250270020C1
Wherein y is 0-5.
64, according to the compound of claim 60, wherein y is 0-2.
65, according to the compound of claim 64, wherein y is 0, and ring A is unsubstituted.
66, according to the compound of claim 64, each R wherein 7Be independently selected from hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
67, according to the compound of claim 66, each R wherein 7Be H, Cl, Br, F, CF independently 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
68, according to the compound of claim 64, each R wherein 8Be independently selected from hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
69, according to the compound of claim 68, each R wherein 8Be H, Me, CF independently 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
70, according to the compound of claim 42, R wherein 1And R 2All be optional substituted C 1-4Aliphatic group, R 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A is the first aryl of optional substituted 5-6, heteroaryl or heterocycle.
71, according to the compound of claim 70, R wherein 1And R 2All be methyl, ethyl or propyl group, R 3Be ethyl, propyl group or butyl, ring A is phenyl or the 5-6 that has azo-cycle atom unit's heteroaryl or heterocycle, wherein encircles A and has Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
72, according to the compound of claim 42, R wherein 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have 2 first heterocycles of heteroatomic 3-6 at the most, R 3Be optional substituted C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl, 5 yuan of heteroaryls or 6-unit heterocyclic radical, has 3 heteroatomss that are selected from oxygen, nitrogen or sulphur at the most.
73, according to the compound of claim 72, R wherein 1And R 2All be methyl, ethyl or propyl group, perhaps R 1And R 2Constitute optional substituted 1-azetidinyl, 1-pyrrolidyl, piperidino or 1-piperazinyl together, R 3Be optional substituted ethyl, propyl group or butyl, ring A is phenyl or has 1 first heteroaryl of heteroatomic 5-that wherein said ring A has two Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
74, according to the compound of claim 73, R wherein 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute 1-tetramethyleneimine basic ring together, R 3Be ethyl or propyl group, R 4Be hydrogen, and ring A is optional substituted phenyl, piperidyl or pyrryl, wherein encircles A and have at the most two and be selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.
75, according to the compound of claim 74, R wherein 1And R 2All be methyl or ethyl, R 3Be ethyl, R 4Be hydrogen, and the ring A be phenyl, piperidino or 1-pyrryl, wherein encircle A and have two substituting groups that are selected from halogeno-group or OH at the most.
76, according to the compound of claim 42, R wherein 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have the 4-6 unit heterocycle of 2 nitrogen heteroatoms at the most, R 3Be optional substituted C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl or 5-unit heteroaryl.
77, according to the compound of claim 76, R wherein 1And R 2All be methyl, ethyl or propyl group, perhaps R 1And R 2Constitute optional substituted 1-pyrrolidyl or 1-piperazinyl together, R 3Be optional substituted ethyl, propyl group or butyl, ring A is phenyl or has 1 first heteroaryl of heteroatomic 5-that wherein said ring A has two Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
78, according to the compound of claim 77, R wherein 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute 1-tetramethyleneimine basic ring together, R 3Be ethyl or propyl group, R 4Be hydrogen, and the ring A be phenyl, piperidyl or pyrryl, alternatively by at the most two be selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group replaces.
79, according to the compound of claim 78, R wherein 1And R 2All be methyl or ethyl, R 3Be ethyl, R 4Be hydrogen, and the ring A be phenyl, piperidino or 1-pyrryl, wherein encircle A and have two substituting groups that are selected from halogeno-group or OH at the most.
80, according to the compound of claim 42, R wherein 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute together and have the 4-6 unit heterocycle of 2 nitrogen heteroatoms at the most, R 3Be optional substituted C 1-4Aliphatic group, R 4Be hydrogen, and ring A is optional substituted phenyl, 5-6 unit's heterocycle or heteroaryl ring.
81,0 compound, wherein R according to Claim 8 1And R 2All be methyl, ethyl or propyl group, perhaps R 1And R 2Constitute optional substituted 1-azetidinyl, 1-pyrrolidyl, 2 together, 5-dihydro-1H-pyrryl, piperidino or 1-piperazinyl, R 3Be optional substituted ethyl, propyl group or butyl, and ring A is phenyl or have 1 first heteroaryl of heteroatomic 5-that wherein said ring A has two Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; And each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
82,1 compound, wherein R according to Claim 8 1And R 2All be C 1-4Aliphatic group, R 3Be ethyl, propyl group or butyl, R 4Be hydrogen, ring A is phenyl, 1-pyrrolidyl or 1-pyrryl, has at the most two and is selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.
83,2 compound, wherein R according to Claim 8 1And R 2All be methyl or ethyl, R 3Be ethyl, R 4Be hydrogen, ring A is phenyl, 1-pyrrolidyl or-1 pyrryl, has at the most two and is selected from halogeno-group, OH, OCF 3Or C 1-4The substituting group of aliphatic group.
84,2 compound according to Claim 8, wherein encircling A is optional substituted piperidino or 1-pyrryl.
85, according to the compound of claim 42, R wherein 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute optional substituted have 2 first heterocycles of heteroatomic 5-6 at the most, R together 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A is aryl or 5-10 unit's heteroaryl or heterocyclic radical, has four Q-R at the most XSubstituting group, wherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN.
86,5 compound, wherein R according to Claim 8 1And R 2All be C 1-4Aliphatic group, perhaps R 1And R 2Constitute optional substituted have 2 first heterocycles of heteroatomic 5-6 at the most, R together 3Be C 1-4Aliphatic group, R 4Be hydrogen, and ring A is phenyl, indyl or pyrryl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
87,6 compound, wherein R according to Claim 8 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute optional substituted pyrrolidyl or piperidines basic ring together, R 3Be methyl or ethyl, R 4Be hydrogen, and ring A is phenyl or pyrryl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
88,7 compound, wherein R according to Claim 8 1And R 2All be methyl or ethyl, perhaps R 1And R 2Constitute pyrrolidyl or 3-hydroxy-piperdine basic ring together, R 3Be methyl or ethyl, R 4Be hydrogen, and ring A is phenyl or pyrryl, has at the most two and be selected from halogeno-group, OH, OMe, OCF 3Or C 1-4The substituting group of aliphatic group.
89,, have formula III A or formula III B according to the compound of claim 1 or 42:
Figure A2004800250270024C1
90, composition comprises the compound according to claim 1 or 42, pharmaceutically acceptable carrier, vehicle or thinner and optionally other treatment agent.
91, treat following disease, obstacle or illness or alleviate the method for its seriousness: acute, chronic, neuropathic or inflammatory pain, sacroiliitis, migraine, bunch headache, trigeminal neuralgia, herpetic neurodynia, popularity neurodynia, epilepsy or epilepsy, the neurodegeneration obstacle, mental disorder is anxiety and depression for example, myotony, irregular pulse, dyskinesia, the neuroendocrine obstacle, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, nerve root pain, sciatica, back pain, head and neck pains, seriousness or intractable pain, nociception pain, breakthrough pain, post-operative pain or cancer pain, described method comprise the formula I compound that described patient is given significant quantity:
Perhaps its pharmacy acceptable salt, wherein:
R ZBe-C (O) R 3,-C (O) OR 3Or R Z1
R Z1Be-C (O) N (R ') 2,-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2,-C (O) N (CN) R ', the optional substituted 1-4 of having heteroatomic 5-unit's heteroaryl ring or optional substituted pyrans-4-ketone group that is selected from O, S or N;
R 1And R 2Be hydrogen or optional substituted group independently of one another, described group is selected from C 1-6Aliphatic group, have 0-5 and independently be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur; Perhaps R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical or heteroaryl ring, wherein a R who independently is selected from nitrogen, oxygen or sulphur 1, R 2Perhaps arbitrarily by R 1And R 2The ring that is constituted is occurred for 0-4 time on one or more carbon atoms-R independently of one another alternatively together 5Replace quilt-R on one or more commutable nitrogen-atoms 6Replace;
Ring A has 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings or 8-10 unit's aryl bicyclic ring of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur, alternatively on one or more carbon atoms by 0-5 appearance-R 7Replace, replace quilt-R on the nitrogen-atoms one or more 8Replace;
Each R that occurs 3, R 4, R 5And R 7Be Q-R independently XWherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, if its condition is R ZBe-OR 3, Q-R then XBy carbon atom bonding in Sauerstoffatom;
Wherein each R that occurs is independently selected from hydrogen or optional substituted C 1-6Aliphatic group; Each R ' that occurs is independently selected from hydrogen or optional substituted group, and described group is selected from C 1-8Aliphatic group, C 6-10Aryl, have the heteroaryl of 5-10 annular atoms or have the heterocyclic radical of 3-10 annular atoms, perhaps wherein R and R ' constitute with the atom of their institute's bondings with the R ' of the atom of their institute's bondings or twice appearance and have 0-3 heteroatomic 5-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl that independently is selected from nitrogen, oxygen or sulphur; With
Each R that occurs 6Or R 8Be independently R ' ,-COR ' ,-CO 2(C 1-6Aliphatic group) ,-CON (R ') 2Or-SO 2R ',
If its condition is R ZBe R 3, R then 3By the atom beyond the deoxygenation, preferably by carbon atom bonding in carbonylic carbon atom.
92, according to the method for claim 91, wherein this disease, illness or obstacle implication in voltage-gated sodium channels activation or hyperactivity.
93, according to the method for claim 92, wherein this disease, illness or obstacle implication in voltage-gated calcium channel activation or hyperactivity.
94, according to the method for claim 91, wherein this disease, illness or obstacle are acute, chronic, neuropathic or inflammatory pain.
95, according to the method for claim 91, wherein this disease, illness or obstacle are nerve root pain, sciatica, back pain, head pain or cervical pain.
96, according to the method for claim 91, wherein this disease, illness or obstacle are seriousness or intractable pain, acute pain, post-operative pain, back pain or cancer pain.
97, suppress:
(a) patient; Perhaps
(b) biological sample
In one or more NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaY1.7, NaV1.8, NaV1.9 or the active method of CaV2.2, this method comprises described patient is given or make described biological sample contact I compound:
Perhaps its pharmacy acceptable salt, wherein:
R ZBe-C (O) R 3,-C (O) OR 3Or R Z1
R Z1Be-C (O) N (R ') 2,-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2,-C (O) N (CN) R ', the optional substituted 1-4 of having heteroatomic 5-unit's heteroaryl ring or optional substituted pyrans-4-ketone group that is selected from O, S or N;
R 1And R 2Be hydrogen or optional substituted group independently of one another, described group is selected from C 1-6Aliphatic group, have 0-5 and independently be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur; Perhaps R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical or heteroaryl ring, wherein a R who independently is selected from nitrogen, oxygen or sulphur 1, R 2Perhaps arbitrarily by R 1And R 2The ring that is constituted is occurred for 0-4 time on one or more carbon atoms-R independently of one another alternatively together 5Replace quilt-R on one or more commutable nitrogen-atoms 6Replace;
Ring A has 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings or 8-10 unit's aryl bicyclic ring of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur, alternatively on one or more carbon atoms by 0-5 appearance-R 7Replace, replace quilt-R on the nitrogen-atoms one or more 8Replace;
Each R that occurs 3, R 4, R 5And R 7Be Q-R independently XWherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, if its condition is R ZBe-OR 3, Q-R then XBy carbon atom bonding in Sauerstoffatom;
Wherein each R that occurs is independently selected from hydrogen or optional substituted C 1-6Aliphatic group; Each R ' that occurs is independently selected from hydrogen or optional substituted group, and described group is selected from C 1-8Aliphatic group, C 6-10Aryl, have the heteroaryl of 5-10 annular atoms or have the heterocyclic radical of 3-10 annular atoms, perhaps wherein R and R ' constitute with the atom of their institute's bondings with the R ' of the atom of their institute's bondings or twice appearance and have 0-3 heteroatomic 5-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl that independently is selected from nitrogen, oxygen or sulphur; With
Each R that occurs 6Or R 8Be independently R ' ,-COR ' ,-CO 2(C 1-6Aliphatic group) ,-CON (R ') 2Or-SO 2R ',
If its condition is R ZBe R 3, R then 3By the atom beyond the deoxygenation, preferably by carbon atom bonding in carbonylic carbon atom.
98, according to the method for claim 91 or 97, R wherein ZBe-C (O) R 3
99, according to the method for claim 91 or 97, R wherein ZBe-C (O) OR 3
100, according to the method for claim 91 or 97, R wherein ZBe R Z1
101, according to the method for claim 91 or 97, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having the first heterocyclic ring of heteroatomic 3-8 that independently is selected from nitrogen, sulphur or oxygen.
102, according to the method for claim 101, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes the first heterocyclic radical of optional substituted 3-8, is selected from:
Wherein z is 0-4.
103, according to the method for claim 102, R wherein 1And R 2Nitrogen-atoms with their institute's bondings constitutes ring bb, dd, ee, ff or gg.
104, according to the method for claim 91 or 97, R wherein 1And R 2All be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
105, according to the method for claim 91, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
106, according to the method for claim 104 or 105, R wherein 1And R 2Group is selected from methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl.
107, according to the method for claim 104 or 106, R wherein 1And R 2Be the same.
108, according to the method for claim 91 or 97, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be to have 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur.
109, according to the method for claim 108, R wherein 1Or R 2One of be hydrogen, R 1Or R 2Another be selected from:
110, according to the method for claim 102 or 109, R wherein 6Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
111, according to the method for claim 110, R wherein 6Be H, Me, CF independently 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
112, according to the method for claim 91 or 97, R wherein 4Be hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
113, according to the method for claim 112, R wherein 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
114, according to the method for claim 91 or 97, R wherein 3Be-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is optional substituted C 2-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN, its condition be Q by carbon atom bonding in carbonylic carbon atom.
115, the method for claim 114, wherein R 3Be-CF 2H ,-CF 3,-CHCl 2,-CHBr 2, CH 2CN ,-CH 2OR ' ,-CH 2SR ' ,-CH 2N (R ') 2Or Q-R XWherein Q is a key, and R XBe optional substituted group, be selected from C 2-8Aliphatic group, C 6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the heterocyclic ring of 3-10 annular atoms.
116, claim 91 or 97 method, wherein R 3Be hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
117, the method for claim 116, wherein R 3Be H, Me, CF 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
118, method according to claim 91 or 97, wherein encircle A and be selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrryl, piperidyl, indyl, indazolyl, the benzotriazole base, pyrazolyl, the benzopyrazoles base, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl,  azoles base, the benzoxazol base, different  azoles base, benzisoxa  azoles base, isothiazolyl, the benzisothiazole base, triazolyl, the benzotriazole base, thiadiazolyl group, thienyl, benzothienyl, furyl, benzofuryl or triazine basic ring, wherein said ring are occurred for y time on one or more carbon atoms-R alternatively 7Replace quilt-R on one or more commutable nitrogen-atoms 8Replace, wherein y is 0-5.
119, according to the method for claim 118, wherein encircle A and be selected from phenyl, piperidyl, thienyl, indyl or pyrrolidyl, wherein encircle A on commutable nitrogen-atoms, have occur for 0-2 time-R 7With occur for 0-1 time-R 8
120, according to the method for claim 119, wherein encircling A is phenyl, piperidyl or pyrrolidyl.
121,, wherein encircle A and be selected from according to the method for claim 118:
Wherein y is 0-5.
122, according to the method for claim 118, wherein y is 0-2.
123, according to the method for claim 122, wherein y is 0, and ring A is unsubstituted.
124, according to the method for claim 118, each R wherein 7Be independently selected from hydrogen, halogen, CN, NO 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
125, according to the method for claim 124, each R wherein 7Be H, Cl, Br, F, CF independently 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy.
126, according to the method for claim 125, each R wherein 8Be independently selected from hydrogen or optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2,-CH 2OR ' ,-CH 2SR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2Or-S (O) 2N (R ') 2
127, according to the method for claim 126, each R wherein 8Be H, Me, CF independently 3, ethyl, propyl group, butyl, amyl group, CO (C 1-4Alkyl) ,-CONH 2,-COO (C 1-4Alkyl) ,-CH 2OH ,-SO 2NH 2, SO 2N (CH 3) 2Or optional substituted phenyl.
128, the compound that has formula IC:
Figure A2004800250270034C1
Perhaps its pharmacy acceptable salt, wherein
R Z1Be halogeno-group, cyano group ,-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2,-C (O) N (CN) R ', the optional substituted 1-4 of having heteroatomic 5-unit's heteroaryl ring or optional substituted pyrans-4-ketone group that is selected from O, S or N;
R 1And R 2Be hydrogen or optional substituted group independently of one another, described group is selected from C 1-6Aliphatic group, have 0-5 and independently be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur; Perhaps R 1And R 2Nitrogen-atoms with their institute's bondings constitutes the optional substituted 1-3 of having heteroatomic 3-8 unit's heterocyclic radical or heteroaryl ring, wherein a R who independently is selected from nitrogen, oxygen or sulphur 1, R 2Perhaps arbitrarily by R 1And R 2The ring that is constituted is occurred for 0-4 time on one or more carbon atoms-R independently of one another alternatively together 5Replace quilt-R on one or more commutable nitrogen-atoms 6Replace;
Ring A has 0-5 independently to be selected from heteroatomic 5-6 unit's aryl rings of nitrogen, oxygen or sulphur or to have 0-3 the first saturated or unsaturated ring of part of heteroatomic 3-7 that independently is selected from nitrogen, oxygen or sulphur, alternatively on one or more carbon atoms by 0-5 appearance-R 7Replace, replace quilt-R on the nitrogen-atoms one or more 8Replace;
Each R that occurs 3, R 4, R 5And R 7Be Q-R independently XWherein Q is a key or C 1-6Alkylidene chain, wherein two non-conterminous MU (methylene unit) at the most of Q are alternatively by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace; Each R that occurs XBe independently selected from R ', halogen, NO 2Or CN;
Wherein each R that occurs is independently selected from hydrogen or optional substituted C 1-6Aliphatic group; Each R ' that occurs is independently selected from hydrogen or optional substituted group, and described group is selected from C 1-8Aliphatic group, C 6-10Aryl, have the heteroaryl of 5-10 annular atoms or have the heterocyclic radical of 3-10 annular atoms, perhaps wherein R and R ' constitute with the atom of their institute's bondings with the R ' of the atom of their institute's bondings or twice appearance and have 0-3 heteroatomic 5-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl that independently is selected from nitrogen, oxygen or sulphur; With
Each R that occurs 6Or R 8Be independently R ' ,-COR ' ,-CO 2(C 1-6Aliphatic group) ,-CON (R ') 2Or-SO 2R ',
Its condition is:
A) if R Z1Be tetrazyl, R 1Be hydrogen, R 2Be hydrogen or optional substituted phenyl, R 4Be hydrogen, then encircling A is not unsubstituted 1-pyrrolidyl, piperidino, N-morpholinyl, 1-azepan base or phenyl;
B) if R Z1Be-P (O) (OR ') 2, and R ' is C 1-4Aliphatic group, R 1And R 2All be hydrogen, and R 4Be hydrogen, methyl, amino ,-OCH 2OH, then encircling A is not the 1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3,4-b] pyridin-3-yl or unsubstituted phenyl;
C) if R Z1Be-SO 2NHR ', and R ' is hydrogen, R 1And R 2All be hydrogen, R 4Be amino, then encircling A is not N-morpholino base.
129, according to the compound of claim 128, R wherein Z1Be-SO 2R ' ,-SO 2NHR ' or-NHSO 2R '.
130, according to the compound of claim 128, R wherein Z1Be-P (O) (OR ') 2
131, according to the compound of claim 128, R wherein Z1Be the optional substituted 1-4 of having the heteroatomic 5 yuan of heteroaryl rings that are selected from O, S or N.
132, according to the compound of claim 131, R wherein Z1Be optional substituted  azoles base, triazolyl, thienyl, furyl or tetrazolium basic ring.
133, according to the compound of claim 128, R wherein Z1It is optional substituted pyrans-4-ketone group.
134, according to the compound of claim 128, R wherein Z1Be-C (O) N (CN) R '.
135,, have formula IIC according to the compound of claim 128:
Figure A2004800250270036C1
Wherein y is 0-5;
R Z1Be halogeno-group ,-SO 2R ' ,-SO 2NHR ' ,-NHSO 2R ' ,-P (O) (OR ') 2,-C (O) N (CN) R ' or optional substituted ring are selected from:
Figure A2004800250270036C2
。
136, according to the compound of claim 135, R wherein 1And R 2Be selected from independently of one another and have 0-5 heteroatomic 5-that independently is selected from N, O or S or 6-unit aryl rings, have 0-3 heteroatomic 3-7 first saturated or unsaturated ring of part or optional substituted C that independently is selected from N, O or S 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group are alternatively by NR, O, (CO) O, O (CO), NR (CO), (CO) NR, SO 2(NR) or (NR) SO 2Replace.
137, according to the compound of claim 136, R wherein 1And R 2Be optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2(CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3, the tertiary butyl or normal-butyl.
138, according to the compound of claim 137, R wherein 4Be hydrogen, halogen, CN, NO independently 2Perhaps optional substituted group, described group is selected from C 1-6Alkyl, aryl, aryl (C 1-6) alkyl ,-N (R ') 2,-CH 2N (R ') 2, OR ' ,-CH 2OR ', SR ' ,-CH 2SR ', COOR ' ,-NRCOR ' ,-(CH 2) 2N (R ') 2,-(CH 2) 2OR ' ,-(CH 2) 2SR ' ,-COR ' ,-CON (R ') 2, SO 2R ' or-SO 2N (R ') 2
139, according to the compound of claim 138, R wherein 4Be H, Cl, Br, F, CF 3, Me, Et, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CO (C 1-4Alkyl) ,-CONH 2,-COOCH 3,-OH ,-CH 2OH ,-NHCOCH 3,-SO 2(C 1-4Alkyl) ,-SO 2NH 2, SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy
140, according to the compound of claim 135, R wherein 7Be Cl, Br, F, CF 3, OCF 3, Me, Et, propyl group, normal-butyl, the tertiary butyl, CN, NO 2,-COOH, NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CO (C 1-4Alkyl) ,-CONH 2, CON (CH 3) 2,-COOCH 3,-OH ,-SCH 3,-CH 2OH ,-NHCOCH 3,-SO 2(C 1-4Alkyl) ,-SO 2NH 2,-SO 2N (CH 3) 2, piperidyl, piperazinyl, morpholino base or optional substituted group, described group is selected from C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl or benzyloxy
141,, have formula III C according to the compound of claim 135:
Figure A2004800250270038C1
R wherein Z1Be-SO 2R ' ,-NHSO 2R ' ,-C (O) N (CN) R ' or optional substituted ring, be selected from:
Figure A2004800250270038C2
142, according to the compound of claim 141, R wherein 1And R 2Be the same, they all are methyl or ethyl, perhaps R 1And R 2Constitute piperidino, 1-piperazinyl or 1-pyrrolidyl together.
142, be selected from the compound of table 2.
143, composition comprises compound and pharmaceutically acceptable carrier, vehicle or thinner according to claim 128 or 142.
144, according to the composition of claim 143, further comprise therapeutical agent.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103492392A (en) * 2011-04-01 2014-01-01 森申有限公司 Thieno [2, 3 -d] pyrimidine derivatives and their use to treat arrhythmia
CN105980380A (en) * 2014-02-13 2016-09-28 吉利德科学公司 Solid forms of an ion channel modulator

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103492392A (en) * 2011-04-01 2014-01-01 森申有限公司 Thieno [2, 3 -d] pyrimidine derivatives and their use to treat arrhythmia
CN103492392B (en) * 2011-04-01 2015-11-25 森申有限公司 Thieno-[2,3-d] pyrimidine derivatives and be used for the treatment of ARR purposes
CN105980380A (en) * 2014-02-13 2016-09-28 吉利德科学公司 Solid forms of an ion channel modulator

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