CN1784391B - Quinazolines useful as modulators of ion channels - Google Patents

Quinazolines useful as modulators of ion channels Download PDF

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CN1784391B
CN1784391B CN200480011981.4A CN200480011981A CN1784391B CN 1784391 B CN1784391 B CN 1784391B CN 200480011981 A CN200480011981 A CN 200480011981A CN 1784391 B CN1784391 B CN 1784391B
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CN1784391A (en
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J·E·冈萨雷斯三世
D·M·韦尔森
A·P·特门
P·D·J·格鲁滕休斯
张玉莲
B·J·佩佐尔德
L·T·D·范宁
T·D·纽伯特
R·D·汤
E·马丁波罗
N·齐默曼
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Abstract

The present invention relates to quinazoline compounds of formula (I) useful as inhibitors of voltage-gated sodium channels and calcium channels. 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. or a pharmaceutically acceptable derivative thereof, wherein R<1>,X, R<3>, x, and ring A are as defined in the present application.

Description

The quinazoline of useful as modulators of ion channels
Priority information
According to 35U.S.C. § 119, the application requires following U.S. Provisional Application No.: No.60/451,458, on March 3rd, 2003 submitted to, was entitled as " composition that can be used as the inhibitor of voltage-gated sodium channel ", and No.60/463,797, on April 18th, 2003 submitted to, was entitled as " composition that can be used as the inhibitor of voltage-gated sodium channel ", and the full content of each these application is quoted at this as a reference.
Technical field
The present invention relates to can be used as the compound of inhibitors of ion channels.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 easy excitatory cells produce action potential, for example neurone and myocyte.They play the part of pivotal player in excitable tissure, 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, et al. (1999) " Sodium channels and pain " Proc Natl Acad Sci U SA96 (14): 7635-9 and Waxman, S.G., T.R.Cummins, et al. (2000) " Voltage-gated sodium channels and the molecularpathogenesis of pain:a review " J Rehabil Res Dev37 (5): 517-28), myotony ( Referring to, Meola, G.and V.Sansone (2000) " Therapyin myotonic disorders and inmuscle channelopathies " Neurol Sci21 (5): S953-61 and Mankodi, A.and C.A.Thornton (2002) " Myotonic syndromes " Curr Opin Neurol15 (5): 545-52), ataxia ( Referring to, Meisler, M.H., J.A.Kearney, et al. (2002) " Mutations of voltage-gated sodium channels in movementdisorders and epilepsy " Novartis Found Symp241:72-81), multiple sclerosis ( Referring toBlack, J.A., S.Dib-Hajj, et al. (2000) " Sensoryneuron-Specific sodium channel SNS is abnormally expressed inthe brains of mice with experimental allergicencephalomyelitis and humans with multiple sclerosis " Proc Natl Acad Sci USA97 (21): 11598-602, and Renganathan, M., M.Gelderblom, et al. (2003) " Expression of Na (v) 1.8 sodiumchannels perturbs the firing patterns of cerebellar purkinjecells " Brain Res959 (2): 235-42), intestines easily swash ( Referring to, Su, X., R.E.Wachtel, et al. (1999) " Capsaicin sensitivity andvoltage-gated sodium currents in colon sensory neurons from ratdorsal root ganglia " Am J Physiol277 (6 Pt 1): G1180-8, andLaird, J.M., V.Souslova, et al. (2002) " Deficits in visceralpain 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, et al. (2001) " The involvement of thetetrodotoxin-resistant sodium channel Na (v) 1.8 (PN3/SNS) in arat model of visceral pain " J Neurosci21 (21): 8690-6), and a series of psychiatric function obstacle, for example anxiety and depression ( Referring to, Hurley, S.C. (2002) " Lamotrigine update and its use in mood disorders " 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 sodiumchannel research " 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, et al. (1989) " A single point mutation confers tetrodotoxin andsaxitoxin insensitivity 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 channel (NaV) be responsible for to cause rapid lifting of neural system excitable tissure 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 pain relief " Pain87 (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 clusterheadache and trigeminal neuralgia " Headache41 Suppl 1:S25-32and Jensen, T.S. (2002) " Anticonvulsants in neuropathic pain:rationale and clinical evidence " Bur 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 action 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, et al. (1998) " Atetrodotoxin-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, et al. (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, in situ hybridization and the experiment of external electrophysiology all show, sodium channel NaV1.8 optionally be positioned dorsal root ganglion and gasserian ganglion little Sensory neurone ( Ginseng See, Akopian, A.N., L.Sivilotti, et al. (1996) " Atetrodotoxin-resistant voltage-gated sodium channel expressedby sensory neurons " Nature379 (6562): 257-62).These neuronic main effects are detection and transmission that nociception stimulates.Antisense and immunohistochemistry evidence also proved the effect of NaV1.8 in neuropathic pain ( Referring toLai, J., M.S.Gold, et al. (2002) " Inhibition of neuropathic pain by decreasedexpression of the tet rodotoxin-resistant sodium channel; NaV1.8 " Pain 95 (1-2): 143-52, and Lai, J., J.C.Hunter, etal. (2000) " Blockade of neuropathic pain by antisense targetingof tetrodotoxin-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 proved that NaV1.8 is in the detection of inflammatory and neuropathic pain and the effect 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, et al. (1999) " Plasticity of sodium channel expressionin DRG 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 passage 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, et al. (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, et al. (2002) " The presence and role of the tetrodotoxin-resistant sodiumchannel Na (v) 1.9 (NaN) in nociceptive primary afferent neurons J Neurosci22 (17): 7425-33).It has deactivation rate slowly and the voltage-dependent that with regard to activation, moves to left ( Referring to, Dib-Hajj, S., J.A.Black, et al. (2002) " NaN/Nav1.9:a sodium channel with unique properties " 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, et al. (2002) " Accumulation of PN1 and PN3 sodium channels inpainful human neuroma-evidence from immunocytochemistry " 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, et al. (1995) " Structure and functional expressionof a new member of the tetrodotoxin-sensitive voltage-activatedsodium channel family from human neuroendocrine cells " Embo J14 (6): 1084-90).
NaV1.1 ( Referring to, Sugawara, T., E.Mazaki-Miyazaki, et al. (2001) " Nav1.1 mutations cause febrile seizures associated withafebrile partial seizures. " Neurology57 (4): 703-5) and NaV1.2 ( Referring toSugawara, T., Y.Ts urubuchi, et al. (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 USA98 (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, et al. (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, et al. (1997) " Pharmacological targeting of long QTmutant sodium channels. " J Clin Invest99 (7): 1714-20).
Have at present some kinds of Na channel blockers be used to or remain clinic trial in the treatment epilepsy ( Referring to, Moulard, B.and D.Bertrand (2002) " Epilepsy and sodiumchannel blockers " Expert Opin.Ther.Patents12 (1): 85-91); Acute ( Referring to, Wiffen, P., S.Collins, et al. (2000) " Anticonvulsantdrugs for acute and chronic pain " Cochrane Database Syst Rev3), chronic ( Referring to, Wiffen, P., S.Collins, et al. (2000) " Anticonvulsant drugs for acute and chronic pain " Cochrane Database Syst Rev3, and Guay, D.R. (2001) " Adjunctive agentsin the management of chronic pain " Pharmacotherapy21 (9): 1070-81), inflammatory ( Referring to, Gold, M.S. (1999) " Tetrodotoxin-resistantNa+currents and inflammatory hyperalgesia. " Proc Natl Acad Sci USA96 (14): 7645-9) with neuropathic pain ( Referring to, Strichartz, G.R., Z.Zhou, et al. (2002) " Therapeutic concentrations of localanaesthetics unveil the potential role of sodium channels inneuropathic pain " Novartis Found Symp241:189-201, andSandner-Kiesling, A., G.Rumpold Seitlinger, et al. (2002) " Lamotrigine monotherapy for control of neuralgia after nervesection " Acta Anaesthesiol Scand46 (10): 1261-4); Irregular pulse ( Ginseng See, An, R.H., R.Bangalore, et al. (1996) " Lidocaine block ofLQT-3 mutant human Na+ channels " Circ Res79 (1): 103-8, andWang, D.W., K.Yazawa, et al. (1997) " Pharmacological targetingof long QT mutant sodium channels " J Clin Invest99 (7): 1714-20); Neuroprotective ( Referring to, Taylor, C.P.and L.S.Narasimhan (1997) " Sodium channels and therapy of central nervous systemdiseases " Adv Pharmacol39:47-98) and as narcotic ( Referring to, Strichartz, G.R., Z.Zhou, et al. (2002) " Therapeuticconcentrations of local anaesthetics unveil the potential roleof sodium channels in neuropathic 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 is a non-glucosylation 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(splice 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 1C, α 1HOr α 11
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 I I 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 special attribute 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 pathogenic agent 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 Qi Kaonuo peptide 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.The Qi Kaonuo peptide 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 Qi Kaonuo peptide 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 since the mastocyte threshing of Qi Kaonuo inducing peptide 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 mentioned 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, preferably 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 voltage-gated sodium channel and the inhibitor of calcium channel.These compounds have general formula I:
Or its pharmaceutically acceptable derivates, wherein R 1, X, R 3, x and ring A be following defined.
These compounds and pharmaceutically acceptable composition can be used for treating multiple disease, obstacle or illness or alleviate its seriousness 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, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, nerve root pain, sciatica, back pain, head or neck pain, seriousness or intractable pain, nociception pain, breakthrough pain, post-operative pain or cancer pain.
Detailed description of the invention
1. the general remark of The compounds of this invention:
The present invention relates to can be used as the formula I compound of voltage-gated sodium channel and ockers:
Figure G2004800119814D00112
Or its pharmacy acceptable salt, wherein:
X is O or NR 2
R wherein 1And R 2Be optional substituted group independently of one another, be selected from hydrogen, C 1-6Aliphatic group or Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or 3-12 unit is saturated or undersaturated monocycle of part or two rings, and described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps R 1And R 2With their institute's bonded nitrogen-atoms constitute optional substituted 3-12 unit monocycle or two ring fillings, part is unsaturated or complete undersaturated ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition; R wherein 1And R 2Perhaps by R 1And R 2Together the ring of Gou Chenging separately randomly and independently on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, wherein z is 0-5;
Ring A is 5-7 unit's monocyclic aryl or 8-10 unit aryl bicyclic, described aryl has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein encircle A randomly by y independent occur-R 5Replace, wherein y is 0-5, and in addition randomly by q the independent R that occurs 5aReplace, wherein q is 0-2;
X is 0-4;
Each R that occurs 3, R 4And R 5Be 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 randomly and independently by-NR-,-S-,-O-,-CS-,-CO 2-,-OCO-,-CO-,-COCO-,-CONR-,-NRCO-,-NRCO 2-,-SO 2NR-,-NRSO 2-,-CONRNR-,-NRCONR-,-OCONR-,-NRNR-,-NRSO 2NR-,-SO-,-SO 2-,-PO-,-PO 2-,-OP (O) (OR)-or-POR-replaces; Each R that occurs XBe independently selected from-R ' ,=O ,=NR ', halogen ,-NO 2,-CN ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2
Each R that occurs 5aBe optional substituted C independently 1-6Aliphatic group, halogen ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2With
Each R that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group; Each R ' that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group, 3-8 unit is saturated, part is unsaturated or complete undersaturated monocycle, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, perhaps 8-12 unit is saturated, part is unsaturated or complete undersaturated second cycle line system, and described second cycle line system has 0-5 heteroatoms that independently is selected from nitrogen, oxygen or sulphur; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance constitutes with their institute's bonded atoms that optional substituted 3-12 unit is saturated, part is unsaturated or complete undersaturated monocycle or two rings, and described ring has 0-4 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.
In some embodiment of above-claimed cpd:
I) if x is 1, R 3Be optional substituted 6-phenyl or 6-pyridyl, R 1Be hydrogen, R then 2Not Cy 1With
Ii) piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-(2-furyl carbonyl)-one hydrochloride and piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolyl)-and 4-[(2,3-dihydro-1,4-benzo dioxin-2-yl) carbonyl]-foreclose.
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 table of elements (thePeriodic Table of the Elements, CAS version, Handbook ofChemistry and Physics, 75th Ed).In addition, vitochemical General Principle is referring to " Organic Chemistry ", Thomas Sorrell, University ScienceBooks, Sausalito:1999 and " March ' s Advanced Organic Chemistry ", 5th Ed., 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 randomly be replaced by one or more substituting groups, 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 exchange and use with wording " replace or unsubstituted ".Generally speaking, term " replacement " front has or not term " to choose wantonly " and represents that all rolling into a ball designated substituent atomic group to the hydrogen atom in the fixed structure replaces.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 lacking 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 "; The quaternized form or the heterocyclic of basic nitrogen can replace nitrogen arbitrarily, for example N (as 3, in the 4-dihydro-2 h-pyrrole base), NH (as in pyrrolidyl) or NR +(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 o,-OR o,-SR o, optional by R oThe phenyl (Ph) that replaces, optional by R oReplace-O (Ph), optional by R oReplace-(CH 2) 1-2(Ph), optional by R oReplace-CH=CH (Ph) ,-NO 2,-CN ,-N (R o) 2,-NR oC (O) R o,-NR oC (S) R o,-NR oC (O) N (R o) 2,-NR oC (S) N (R o) 2,-NR oCO 2R o,-NR oNR oC (O) R o,-NR oNR oC (O) N (R o) 2,-NR oNR oCO 2R o,-C (O) C (O) R o,-C (O) CH 2C (O) R o,-CO 2R o,-C (O) R o,-C (S) R o,-C (O) N (R o) 2,-C (S) N (R o) 2,-OC (O) N (R o) 2,-OC (O) R o,-C (O) N (OR o) R o,-C (NOR o) R o,-S (O) 2R o,-S (O) 3R o,-SO 2N (R o) 2,-S (O) R o,-NR oSO 2N (R o) 2,-NR oSO 2R o,-N (OR o) R o,-C (=NH)-N (R o) 2,-P (O) 2R o,-PO (R o) 2,-OPO (R o) 2,-(CH 2) 0-2NHC (O) R o, optional by R oThe phenyl (Ph) that replaces, optional by R oReplace-O (Ph), optional by R oReplace-(CH 2) 1-2(Ph) or optional by R oReplace-CH=CH (Ph); Wherein each independent R that occurs oBe selected from hydrogen, optional substituted C 1-6Aliphatic group, unsubstituted 5-6 unit's heteroaryl or heterocycle, phenyl (Ph) ,-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 oWith each R oThe atom of group institute bonding constitute together that optional substituted 3-12 unit is saturated, part is unsaturated or undersaturated fully, have 0-4 heteroatomic monocycle or two rings that independently are selected from nitrogen, oxygen or sulphur.
R oAliphatic group on optional 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 oEach 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, thereby can be " optional substituted ".Unless above definition is arranged in addition with this paper, 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.
Unless above with this paper definition is arranged in addition, substituting group optional on the non-aromatic heterocyclic nitrogen generally is selected from-R +,-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 + 1) 2,-C (=NH)-N (R +) 2Or-NR +SO 2R +R wherein +Be hydrogen, optional substituted C 1-6Aliphatic group, optional substituted phenyl (Ph), optional substituted-O (Ph), optional substituted-CH 2(Ph), choose substituted-(CH wantonly 2) 1-2(Ph), optional substituted-CH=CH (Ph) or unsubstitutedly have one to four heteroatomic 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 that optional substituted 3-12 unit is saturated, part is unsaturated or the undersaturated 0-4 of having heteroatomic monocycle or two rings that independently are selected from nitrogen, oxygen or sulphur fully.
R +Aliphatic group or benzyl ring on optional 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 mentioned above, in some embodiment, twice independent R that occurs o(perhaps R +, R, R ' or other have the variable of similar definition in this article arbitrarily) constitute that optional substituted 3-12 unit is saturated, part is unsaturated or the undersaturated 0-4 of having heteroatomic monocycle or two rings that independently are selected from nitrogen, oxygen or sulphur fully with their institute's bonded atoms.
Twice independent R that occurs o(perhaps R +, R, 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) two independent R that occur o(perhaps R +, R, 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 o) 2, two R of Chu Xianing wherein oConstitute piperidines-1-base, piperazine-1-base or morpholine-4-base with nitrogen-atoms; And b) two independent R that occur o(perhaps R +, R, R ' or any other have the variable factor of similar definition in this article) be bonded to not homoatomic, and constitute a ring, for example with these atoms
Wherein phenyl is by the OR of twice appearance oReplace the R of this twice appearance oSauerstoffatom with their institute's bondings constitutes condensed 6-unit ether ring:
To be understood that twice independent R that occurs o(perhaps R +, R, 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:
As institute's general description above, with regard to The compounds of this invention, X is O or NR 2Therefore, in some embodiments, X is NR 2, compound has formula I-A structure:
In other embodiments, X is O, and compound has formula I-B structure:
In some embodiment of general formula I-A compound, R 1Or R 2One of be hydrogen, R 1And R 2Another be selected from optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace, or Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or 3-12 unit is saturated or undersaturated monocycle of part or two rings, and described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.
In other embodiments, R 1And R 2Be selected from Cy independently of one another 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or 3-12 unit is saturated or undersaturated monocycle of part or two rings, and described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps be selected from optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.
In other embodiments, with regard to formula I-A compound, 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 randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.In other embodiments, this optional substituted C 1-4Aliphatic group is by Cy 1Replace, wherein Cy 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or 3-12 unit is saturated or undersaturated monocycle of part or two rings, and described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1Randomly by 0-5 independent occur-R 5Replace.In other embodiments, R 1Or R 2One of be hydrogen or C 1-4Alkyl, R 1Or R 2Another be-CH 2-Cy 1
In other embodiments, with regard to formula I-B compound, R 1Be optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.
In other embodiments, with regard to formula I-A compound, R 1And R 2Not hydrogen, R 1And R 2Be selected from Cy independently of one another 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-1O unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or 3-12 unit is saturated or undersaturated monocycle of part or two rings, and described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps be selected from optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.In other embodiments, 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 randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.
In some embodiment, with regard to formula I, I-A or I-B compound, Cy 1Be selected from:
Figure G2004800119814D00211
R wherein 4Be defined as preamble, z is 0-4.Other exemplary rings comprise as shown in table 2 below those.
In other embodiments, with regard to formula I, I-A or I-B compound, exemplary R 1And R 2Group has 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 3Or normal-butyl.Other exemplary R 1And R 2Group comprise as shown in table 2 below those.
In other embodiments, with regard to formula I-A compound, R 1And R 2Constitute the first heterocyclic ring of optional substituted 3-12 with their institute's bonded nitrogen-atoms, described ring has 1-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen.Some preferred embodiment in, R 1And R 2Constitute with their institute's bonded nitrogen-atoms and to be selected from following group:
Wherein by R 1And R 2Together the ring that is constituted randomly on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, z is 0-5.
In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd), piperazine-1-base (cc) or morpholine-4-base (ee) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidinyl-1-Ji (dd) or piperazine-1-base (cc) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together.
In some embodiments, z is 0-2.In other embodiments, z is 0, and this ring is unsubstituted.Preferred R 4Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.Other exemplary R 4Group has Cl, Br, F, CF 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl.Other exemplary R 4Group comprise as shown in table 2 below those.
In some embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-NRSO 2R ' ,-NRCOOR ' or-NRCOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRSO 2R '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together, wherein z is 1 or 2, R 4Be Cl, Br, F, CF 3, CH 3, or-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR ' ,-NRSO 2R ' ,-NRCOOR ' or-OCON (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRSO 2R '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRCOOR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-SOR ' ,-CON (R ') 2,-SO 2N (R ') 2,-COR ' or-COOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-CON (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SO 2N (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COR '.
As institute's general description above, with regard to formula I, I-A or I-B compound, the quinazoline ring can be by four independent R that occur at the most 3Replace.In some embodiments, x is 0-2.In other embodiments, x is 1 or 2.In other embodiments, x is 1, R 3Be substituted in the 6-or the 7-position of quinazoline ring.When the quinazoline ring is substituted (x is 1-4), R 3Group is halogen, CN, NO 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.In other embodiments, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy.In other embodiments, x is 1 or 2, each R 3Group is halogen, CN, optional substituted C independently 1-6Alkyl, OR ', N (R ') 2, CON (R ') 2Or NRCOR '.In other embodiments, x is 1 or 2, each R 3Group is-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.Other exemplary R 3Group comprise as shown in table 2 below those.
As institute's general description above, with regard to formula I, I-A or I-B compound, ring A is 5-7 unit's monocyclic aryl or 8-10 unit aryl bicyclic, described aryl has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein encircle A randomly by y independent occur-R 5Replace, wherein y is 0-5, and in addition randomly by q the independent R that occurs 5aReplace, wherein q is 0-2.
In some embodiments, ring A is selected from:
In some other embodiment, ring A is selected from optional substituted phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl or pyrroles-1-base.
In some embodiment, y is 0-5, and q is 0-2, R 5And R 5aGroup is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-NRCOR ' ,-CON (R ') 2,-S (O) 2N (R ') 2,-OCOR ' ,-COR ' ,-CO 2R ' ,-OCON (R ') 2,-NR ' SO 2R ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2,-OPO (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, y is 0-5, and q is 1 or 2, each R that occurs 5aBe Cl, Br, F, CF independently 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy.
In other embodiments, y is 0, and q is 1, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OR ', the R of another time appearance 5aBe F.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OH, the R of another time appearance 5aBe F.
In other embodiments, ring A is a phenyl, and y is 0, and q is 1, R 5aBe the F that is substituted in this benzyl ring 2-position.In other embodiments, ring A is a phenyl, and y is 0, and q is 1, R 5aBe the OR ' that is substituted in this benzyl ring 2-position.In other embodiments, ring A is a phenyl, and y is 0, and q is 1, R 5aBe the OH that is substituted in this benzyl ring 2-position.In other embodiments, ring A is a phenyl, and y is 0, and q is 2, once the R of Chu Xianing 5aBe OR ', the R of another time appearance 5aBe F, wherein OR ' is substituted in the 2-position of this benzyl ring, and F is substituted in the 6-position of this benzyl ring.In other embodiments, ring A is a phenyl, and y is 0, and q is 2, once the R of Chu Xianing 5aBe OH, the R of another time appearance 5aBe F, wherein OH is substituted in the 2-position of this benzyl ring, and F is substituted in the 6-position of this benzyl ring.
Other exemplary R 5And R 5aGroup comprise as shown in table 2 below those.
Generally with regard to this section above-claimed cpd, compound can be used as the inhibitor of ionic channel, the sodium channel of preferred voltage-gate and N-type calcium channel.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 inhibitors of NaV1.8 and a kind of TTX-susceptibility ionic channel, for example NaV1.3 or NaV1.7.
Describe above some other embodiment of general described compound below in detail.For example:
I. formula IA compound:
Or its pharmacy acceptable salt, wherein:
R 1And R 2With their institute's bonded nitrogen-atoms constitute optional substituted 3-12 unit monocycle or two ring fillings, part is unsaturated or complete undersaturated ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition; Wherein by R 1And R 2Together the ring of Gou Chenging randomly on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, wherein z is 0-5;
Ring A is 5-7 unit's monocyclic aryl or 8-10 unit aryl bicyclic, described aryl has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein encircle A randomly by y independent occur-R 5Replace, wherein y is 0-5, and in addition randomly by q the independent R that occurs 5aReplace, wherein q is 0-2;
X is 0-4;
Each R that occurs 3, R 4And R 5Be 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 randomly and independently by-NR-,-S-,-O-,-CS-,-CO 2-,-OCO-,-CO-,-COCO-,-CONR-,-NRCO-,-NRCO 2-,-SO 2NR-,-NRSO 2-,-CONRNR-,-NRCONR-,-OCONR-,-NRNR-,-NRSO 2NR-,-SO-,-SO 2-,-PO-,-PO 2-,-OP (O) (OR)-or-POR-replaces; Each R that occurs XBe independently selected from-R ', halogen ,=O ,=NR ' ,-NO 2,-CN ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2
Each R that occurs 5aBe optional substituted C independently 1-6Aliphatic group, halogen ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2With
Each R that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group; Each R ' that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group, 3-8 unit is saturated, part is unsaturated or complete undersaturated monocycle, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, perhaps 8-12 unit is saturated, part is unsaturated or complete undersaturated second cycle line system, and described second cycle line system has 0-5 heteroatoms that independently is selected from nitrogen, oxygen or sulphur; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance constitutes with their institute's bonded atoms that optional substituted 3-12 unit is saturated, part is unsaturated or complete undersaturated monocycle or two rings, and described ring has 0-4 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.
In some embodiments, with regard to above-claimed cpd:
A) if R 1And R 2Constitute the saturated or undersaturated ring of part of optional substituted 4-unit's monocycle with their institute's bonded nitrogen-atoms, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition, 2-oxazolidone then, 3-[(3R, 4R)-2-oxo-1-(2-phenyl-4-quinazolyl)-4-[2-(3-pyridyl) vinyl]-the 3-azetidinyl]-the 4-phenyl-, (4S)-foreclose;
B) if R 1And R 2Constitute the saturated or undersaturated ring of part of optional substituted 5-unit's monocycle with their institute's bonded nitrogen-atoms, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition, then:
I. encircling A is not optional substituted six hydrogen-1H-1, the 4-diaza -1-base; With
Ii. benzsulfamide, 2-methoxyl group-5-[2-[[1-(2-phenyl-4-quinazolyl)-3-pyrrolidyl] amino] ethyl]-, (R)-, two (trifluoroacetates) and benzsulfamide, 2-methoxyl group-5-[2-[[1-(2-phenyl-4-quinazolyl)-3-pyrrolidyl] amino] ethyl]-, (S)-, two (trifluoroacetates) foreclose;
Iii.3-pyrroles's alkanamine, 1-(2-phenyl-4-quinazolyl)-and (R)-3-pyrroles's alkanamine, 1-(2-phenyl-4-quinazolyl)-, (S)-foreclose;
Iv. if R 1And R 2Be unsubstituted tetramethyleneimine-1-base together, ring A is unsubstituted phenyl, and x is 1, then R 3Not 6-OMe or 6-OH;
V. if R 1And R 2Be unsubstituted tetramethyleneimine-1-base together, ring A is unsubstituted phenyl, and x is 2, then two R 3Group is not 6-OMe and 7-OMe;
Vi. if R 1And R 2Be unsubstituted tetramethyleneimine-1-base together, then encircling A is not unsubstituted tetramethyleneimine-1-base, optional substituted piperazine-1-base, unsubstituted morpholine-1-base or unsubstituted piperidines-1-base;
Vii. if R 1And R 2Be tetramethyleneimine-1-base together, x is 0, and ring A is unsubstituted phenyl, and then this tetramethyleneimine-1-base does not replace at 3-position quilt-OH or 2-methoxyl group phenoxy group;
Viii. if R 1And R 2Be unsubstituted tetramethyleneimine-1-base together, x is 0, then encircling A is not 2,3-xylyl, 3-aminomethyl phenyl, unsubstituted phenyl, 4-bromo-phenyl, 4-chloro-phenyl, 3-nitro-phenyl, unsubstituted pyridine-3-base, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-propoxy-phenyl, 3-aminomethyl phenyl, 3,4,5-trimethoxyphenyl, 2-chloro-phenyl-, unsubstituted pyridine-4-base, 2-hydroxy phenyl or 4-(1, the 1-dimethyl ethyl) phenyl;
C) if R 1And R 2Constitute optional substituted 6-unit's monocycle or two ring fillings or the undersaturated ring of part with their institute's bonded nitrogen-atoms, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition, then:
I. if R 1And R 2Constitute unsubstituted morpholino basic ring together, ring A is unsubstituted phenyl, and then x is not 0, if perhaps x is 1 or 2, and R so 3Not 6-fluorine, 6,7-dimethoxy, 6-nitro, 6-AcHN-, 6-methoxyl group, 6-NH 2, 6-OCHN-, 6-OH, 6-AcMeN-, 6-TsHN-, 6-Me 2N-, 7-OH, 6-amino-thiazolyl--2-base, 6-NHCOCOOEt or 6-(4-phenyl-amino-thiazolyl--2-yl);
Ii. if R 1And R 2Constitute unsubstituted morpholino basic ring together, ring A is unsubstituted cyclohexyl, unsubstituted pyridine-3-base, unsubstituted 2-furyl, 2-fluorophenyl, 3-thienyl, cumarone, pyridazine, phenyl, one or more 3,4 or 5-position at this benzyl ring are substituted, and x is 1 or 2, then R 3Not 6-NH 2, 6-OHCHN-, 6-OH, 7-OH, 6-MsHN-, 6-AcHN-, 6-fluorine or 6-OMe;
Iii. if R 1And R 2Constitute piperidin-4-one-, piperidines-4-alcohol or the parathiazan morpholino basic ring for base or dimethyl replacement together, ring A is unsubstituted phenyl, and x is 1, then R 3Not 6-OH;
Iv. if x is 0, A is a unsubstituted phenyl, 3,4,5-trimethoxyphenyl or 3,4-Dimethoxyphenyl, then R 1And R 2Not optional substituted piperidyl or optional substituted piperazinyl together;
V. be 2 or 3 as if x, R 3Be 6,7-two OMe or 6,7,8-three OMe, then R 1And R 2Not optional substituted piperidines-1-base, piperazine-1-base or morpholine-1-base together;
Vi. if x is 0, ring A is unsubstituted phenyl, then R 1And R 2Not optional substituted or condensed piperazinyl together;
Vii. if x is 0, ring A is a phenyl, randomly is substituted in one or more 3-, 4-or the 5-position of this benzyl ring, then R 1And R 2Not optional substituted piperazine-1-base or morpholine-1-base together;
Viii. if x is 0, ring A is 2-F-phenyl, then R 1And R 2Not 4-(2-Cl-phenyl)-piperazine-1-base, 4-(3-Cl-phenyl)-piperazine-1-base or unsubstituted morpholine-1-base together;
Ix. if x is 0, ring A is 2-Cl-phenyl, then R 1And R 2Not unsubstituted morpholine-1-base, 4-Me-piperazine-1-base, 4-Et-piperazine-1-base, 4-phenyl-Piperazine-1-base or 4-CH together 2Ph 2-piperazine-1-base;
X. if x is 0, ring A is 2-OH-phenyl, then R 1And R 2Not unsubstituted morpholine-1-base, 4-(2-OMe-phenyl)-piperazine-1-base, 4-CH together 2Ph-piperazine-1-base, 4-Et-piperazine-1-base or 4-Me-piperazine-1-base;
Xi. if x is 0, x is 1, R 3Be 6-Br, perhaps x is 2, R 3Be 6,7-two OMe, ring A are optional substituted 2-or 3-thienyl, then R 1And R 2Not 4-Ph-piperazine-1-base, 4-(3-CF together 3-phenyl)-piperazine-1-base, 4-(2-OEt-phenyl)-piperazine-1-base, 4-Me-piperazinyl or unsubstituted morpholine-1-base;
Xii. if x is 0, ring A is unsubstituted pyridine-3-base or pyridin-4-yl, then R 1And R 2Not optional substituted morpholine-1-base or optional substituted piperazine-1-base together;
Xiii. if x is 0, ring A is optional substituted 1H-imidazoles-2-base or 1H-imidazoles-1-base, then R 1And R 2Not unsubstituted morpholine-1-base, 4-Me-piperazine-1-base or 4-CH together 2CH 2OH-piperazine-1-base;
Xiv. if x is 0, ring A is 5-NO 2-thiazol-2-yl, then R 1And R 2Not 4-Me-piperazine-1-base together;
Xv. if x is 0, ring A is 5-NO 2-2-furyl, then R 1And R 2Not 4-CH together 2CH 2OH-piperazine-1-base, 4-Me-piperazine-1-base or unsubstituted morpholine-1-base;
Xvi. be 1 as if x, R 3Be 6-OH, ring A is unsubstituted phenyl, then R 1And R 2Not unsubstituted morpholine-1-base or 4-Me-piperazine-1-base together;
Xvii. be 0 as if x, R 1And R 2Be unsubstituted piperidyl together, then encircling A is not 2-OH-phenyl, 4-OMe-phenyl, 4-F-phenyl, 4-NO 2-phenyl, pyridin-3-yl, pyridin-4-yl, 2-Cl-phenyl, 4-OnPr-phenyl, 3,4-dichlorophenyl, 2-F-phenyl, 4-Br-phenyl, 4-Cl-phenyl, 3-NO 2-phenyl or 2,4 dichloro benzene base;
Xviii. if x is 0, ring A is 4-Br-phenyl, 2-F-phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 4-OnPr-phenyl, 2, the 4-dichlorophenyl, 3,4-dichlorophenyl, 4-Me-phenyl, 3-Me-phenyl, pyridin-3-yl, pyridin-4-yl, 2-OH-phenyl, 4-NO 2-phenyl, 4-tBu-phenyl, then R 1And R 2Not 2-Me-piperidines-1-base, 4-CH together 2-Ph-piperidines-1-base, 4-Me-piperidines-1-base, 3-COOEt-piperidines-1-base, 4-COOEt-piperidines-1-base, 2-Et-piperidines-1-base, 3-Me-piperidines-1-base, 3,5-two Me-piperidines-1-base, 4-CONH 2-piperidines-1-base, (4-piperidyl, 4-acid amides)-piperidines-1-base, 1,4-two oxa-s-8-azaspiro [4.5] decane, 3,4-dihydro-2 (1H)-isoquinolyl or piperidin-4-one-;
Xix. be 1 as if x, R 3Be 6-Br, 6-Cl, 6-OH, 6-OMe or 6-Me, ring A is 4-bromophenyl, 4-CH 2P (O) is (OEt) phenyl or unsubstituted phenyl, then R (OH) 1And R 2Not optional substituted piperidyl together;
Xx. be 2 as if x, R 3Be 6,7-dimethoxy, A are unsubstituted phenyl, then R 1And R 2Not 1 together, 4-two oxa-s-8-azaspiro [4.5] decane or 3,4-dihydro-2 (1H)-isoquinolyl;
Xxi. if x is the R of 3, three appearance 3Be 5-OAc, 6-OAc and 8-piperidyl, ring A is unsubstituted phenyl, then R 1And R 2Not unsubstituted piperidines basic ring together;
Xxii. if x is the R of 3, three appearance 3Be 6-Me, 7-COOEt and 8-Me, ring A is 2-Cl-phenyl, then R 1And R 2Not 4-phenyl-piperidines-1-base, 4-(4-Cl-phenyl)-piperazine-1-base, unsubstituted piperazine-1-base, 4-CH together 2Ph-piperazine-1-base, 4-(2-Cl-phenyl) piperazine-1-base or 4-COOEt-piperazine-1-base;
C) if R 1And R 2Constitute optional substituted 7-unit's monocycle or two ring fillings or the undersaturated ring of part with their institute's bonded nitrogen-atoms, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition, then:
I. benzsulfamide, 2-methoxyl group-5-[2-[5-(2-phenyl-4-quinazolyl)-2,5-diazabicylo [2.2.1] heptan-2-yl] ethyl]-and two (trifluoroacetates) 2,5-diazabicylo [2.2.1] heptane, 2-(2-phenyl-4-quinazolyl)-foreclose;
Ii. if x is the R of 2, twice appearance 3All be OMe, ring A is 4-Cl-phenyl, then R 1And R 2Not unsubstituted six hydrogen-1H-azepine together -1-base;
Iii. be 0 as if x, R 1And R 2Be unsubstituted six hydrogen-1H-azepine together -1-base, then encircling A is not unsubstituted phenyl, 4-F-phenyl, 4-NO 2-phenyl, pyridin-4-yl, 3,4-two Cl-phenyl, 2-Cl-phenyl, 2,4-two Cl-phenyl, 2,4-two Cl-phenyl, 3-NO 2-phenyl, 4-Cl-phenyl, 4-OnPr-phenyl, 3-Me-phenyl, 3,4-OMe-phenyl, 3,4,5-OMe-phenyl, pyridin-3-yl or 2-OH-phenyl;
D) if R 1And R 2Constitute optional substituted 8-unit's monocycle or two ring fillings or the undersaturated ring of part with their institute's bonded nitrogen-atoms, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition, then:
I. benzsulfamide, 2-methoxyl group-5-[2-[8-(2-phenyl-4-quinazolyl)-3,8-diazabicylo [3.2.1] oct-3-yl] ethyl]-, two (trifluoroacetates) 3,8-diazabicylo [3.2.1] octane, 3-(phenyl methyl)-8-(2-phenyl-4-quinazolyl)-3,8-diazabicylo [3.2.1] octane, 8-(2-phenyl-4-quinazolyl)-; Quinazoline, 2-(3-aminomethyl phenyl)-4-(1,3,3-trimethylammonium-6-azabicyclic [3.2.1] suffering-6-yl)-, a hydrochloride; Quinazoline, 2-(4-nitrophenyl)-4-(1,3,3-trimethylammonium-6-azabicyclic [3.2.1] suffering-6-yl)-, a hydrochloride; Quinazoline, 2-(3-aminomethyl phenyl)-4-(1,3,3-trimethylammonium-6-azabicyclic [3.2.1] suffering-6-yl)-; Quinazoline, 2-(4-aminomethyl phenyl)-4-(1,3,3-trimethylammonium-6-azabicyclic [3.2.1] suffering-6-yl)-; And quinazoline, 2-(4-nitrophenyl)-4-(1,3,3-trimethylammonium-6-azabicyclic [3.2.1] suffering-6-yl)-foreclose; With
E) if R 1And R 2Constitute optional substituted 9-unit's monocycle or two ring fillings or the undersaturated ring of part with their institute's bonded nitrogen-atoms, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition, then:
Piperazine, 1-[4-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-6,7-dimethoxy-2-quinazolyl]-4-(2-furyl carbonyl)-foreclose.
In other embodiments, with regard to above-claimed cpd, by R 1And R 2The ring that is constituted is selected from together:
Figure G2004800119814D00351
Wherein by R 1And R 2Together the ring that is constituted randomly on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, z is 0-5.
In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd), piperazine-1-base (cc) or morpholine-4-base (ee) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd) or piperazine-1-base (cc) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted or piperazine-1-base (cc) together.
With regard to above-claimed cpd, z is 0-5, R 4Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl.
In some embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-NRSO 2R ' ,-NRCOOR ' or-NRCOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRSO 2R '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-6 base (jj) together, wherein z is 1, R 4Be-NRCOR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together, wherein z is 1 or 2, R 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR ' ,-NRSO 2R ' ,-NRCOOR ' or-OCON (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-6 base (dd) together, wherein z is 1, R 4Be F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRSO 2R '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-6 base (dd) together, wherein z is 1, R 4Be-NRCOOR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-SOR ' ,-CON (R ') 2,-SO 2N (R ') 2,-COR ' or-COOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-CON (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SO 2N (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COR '.
With regard to above-claimed cpd, in some embodiment, x is 0-4, R 3Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, x is 1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy.
In other embodiments, x is 1 or 2, each R 3Group is halogen, CN, optional substituted C independently 1-6Alkyl, OR ', N (R ') 2, CON (R ') 2Or NRCOR '.
In other embodiments, x is 1 or 2, each R 3Group is-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF3 ,-OCH 3Or-OCH 2CH 3
In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
With regard to above-claimed cpd, in some embodiments, ring A is selected from following group:
Figure G2004800119814D00401
In other embodiments, ring A is optional substituted phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl or pyrroles-1-base.
With regard to above-claimed cpd, in some embodiment, y is 0-5, and q is 0-2, R 5And R 5aGroup is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-NRCOR ' ,-CON (R ') 2,-S (O) 2N (R ') 2,-OCOR ' ,-COR ' ,-CO 2R ' ,-OCON (R ') 2,-NR ' SO 2R ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2,-OPO (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, y is 0-5, and q is 1 or 2, each R that occurs 5aBe Cl, Br, F, CF independently 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy.
In other embodiments, y is 0, and q is 1, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OR ', the R of another time appearance 5aBe F.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OH, the R of another time appearance 5aBe F.
In other embodiments, ring A is optional substituted phenyl, and compound has structure I A-i:
Figure G2004800119814D00411
Wherein:
Y is 0-5;
Q is 0-2; With
Each R that occurs 5aBe optional substituted C independently 1-6Aliphatic group, halogen ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2
In some exemplary embodiment, by R 1And R 2The ring that is constituted is selected from together:
Figure G2004800119814D00421
Wherein by R 1And R 2Together the ring that is constituted randomly on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, z is 0-5.
In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd), piperazine-1-base (cc) or morpholine-4-base (ee) together.In other embodiments, with regard to formula I A-i compound, R 1And R 2Be optional substituted azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd) or piperazine-1-base (cc) together.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted or piperazine-1-base (cc) together.
With regard to formula IA-i compound, z is 0-5, R 4Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.In other embodiments, z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl.
In some embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-NRSO 2R ' ,-NRCOOR ' or-NRCOR '.In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRSO 2R '.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOOR '.In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOR '.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together, wherein z is 1 or 2, R 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' ,-CH 2OR ' ,-NRSO 2R ' ,-NRCOOR ' or-OCON (R ') 2In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRSO 2R '.In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRCOOR '.In other embodiments, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-SOR ' ,-CON (R ') 2,-SO 2N (R ') 2,-COR ' or-COOR '.In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SOR '.In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COOR '.In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-CON (R ') 2In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SO 2N (R ') 2In some other embodiment, with regard to formula IA-i compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COR '.
In some embodiment, with regard to formula IA-i compound, x is 0-4, R 3Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, x is 1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy.
In other embodiments, x is 1 or 2, each R 3Group is halogen, CN, optional substituted C independently 1-6Alkyl, OR ', N (R ') 2, CON (R ') 2Or NRCOR '.
In other embodiments, x is 1 or 2, each R 3Group is-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In some embodiment with regard to formula IA-i compound, y is 0-5, and q is 0-2, R 5And R 5aGroup is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-NRCOR ' ,-CON (R ') 2,-S (O) 2N (R ') 2,-OCOR ' ,-COR ' ,-CO 2R ' ,-OCON (R ') 2,-NR ' SO 2R ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2,-OPO (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, y is 0-5, and q is 1 or 2, each R that occurs 5aBe Cl, Br, F, CF independently 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy.
In other embodiments, ring A is a phenyl, and y is 0, and q is 1, R 5aBe the F that is substituted in this benzyl ring 2-position.In other embodiments, ring A is a phenyl, and y is 0, and q is 1, R 5aBe the OR ' that is substituted in this benzyl ring 2-position.In other embodiments, ring A is a phenyl, and y is 0, and q is 1, R 5aBe the OH that is substituted in this benzyl ring 2-position.In other embodiments, ring A is a phenyl, and y is 0, and q is 2, once the R of Chu Xianing 5aBe OR ', the R of another time appearance 5aBe F, wherein OR ' is substituted in the 2-position of this benzyl ring, and F is substituted in the 6-position of this benzyl ring.In other embodiments, ring A is a phenyl, and y is 0, and q is 2, once the R of Chu Xianing 5aBe OH, the R of another time appearance 5aBe F, wherein OH is substituted in the 2-position of this benzyl ring, and F is substituted in the 6-position of this benzyl ring.
In other embodiments, with regard to formula IA-i compound, q is 1, R 5aBe positioned at the 2-position of benzyl ring, compound has structure I A-ii:
Figure G2004800119814D00461
Wherein:
A) by R 1And R 2The ring that is constituted is selected from together:
By R 1And R 2Together the ring that is constituted randomly on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, z is 0-5;
B) wherein z is 0-5, R 4Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl;
C) wherein x is 0-4, R 3Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl;
D) wherein y is 0-5, R 5Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-NRCOR ' ,-CON (R ') 2,-S (O) 2N (R ') 2,-OCOR ' ,-COR ' ,-CO 2R ' ,-OCON (R ') 2,-NR ' SO 2R ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2,-OPO (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl; With
E) R 5aBe Cl, Br, F, CF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy.
In other embodiments, with regard to formula IA-ii compound, q is 1, R 5aBe positioned at the 2-position of benzyl ring, compound has structure I A-ii:
Figure G2004800119814D00481
Wherein:
A) R 1And R 2Be optional substituted ring together, be selected from azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd) or piperazine-1-base (cc);
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) x is 1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy;
D) wherein y is 0-4, R 5Group is Cl, Br, F, CF when existing independently of one another 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy; With
E) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base ,-OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In other embodiments, with regard to formula IA-ii compound, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, R 5aBe Cl, F, CF 3, Me, Et, OR ' ,-OH ,-OCH 3,-OCH 2CH 3
In other embodiments, R 5aBe OR '.In other embodiments, R 5aBe F.
In other exemplary embodiment, compound has formula IA-ii:
Wherein:
A) R 1And R 2Be optional substituted ring together, be selected from azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd) or piperazine-1-base (cc);
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) x is 1, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-OH or-OCH 3
D) wherein y is 0 or 1, R 5Group is Cl, Br, F, CF when existing independently of one another 3, Me ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2With
E) R 5aBe F ,-OR ' or NHSO 2R '.
In some embodiment with regard to above-claimed cpd, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, R 5aBe OR ', x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 5aBe OR ', x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, R 5aBe OH, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 5aBe OH, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, R 5aBe F, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 5aBe F, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together.In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together.In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together.In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted or piperazine-1-base (cc) together.
In some embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-NRSO 2R ' ,-NRCOOR ' or-NRCOR '.In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRSO 2R '.In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOOR '.In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOR '.In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together, wherein z is 1 or 2, R 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR ' ,-NRSO 2R ' ,-NRCOOR ' or-OCON (R ') 2In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRSO 2R '.In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRCOOR '.In other embodiments, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-SOR ' ,-CON (R ') 2,-SO 2N (R ') 2,-COR ' or-COOR '.In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SOR '.In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COOR '.In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-CON (R ') 2In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SO 2N (R ') 2In some other embodiment, with regard to formula IA-ii compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COR '.
Generally with regard to this section above-claimed cpd, compound can be used as the inhibitor of ionic channel, the sodium channel of preferred voltage-gate and N-type calcium channel.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 inhibitors of NaV1.8 and a kind of TTX-susceptibility ionic channel, for example NaV1.3 or NaV1.7.
II. formula IA-ii compound:
Figure G2004800119814D00521
R wherein 1And R 2Be optional substituted group independently of one another, be selected from C 1-6Aliphatic group, Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; R wherein 1And R 2Separately randomly and independently on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, wherein z is 0-5;
X is 0-4;
Y is 0-4;
Each R that occurs 3, R 4And R 5Be 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 randomly and independently by-NR-,-S-,-O-,-CS-,-CO 2-,-OCO-,-CO-,-COCO-,-CONR-,-NRCO-,-NRCO 2-,-SO 2NR-,-NRSO 2-,-CONRNR-,-NRCONR-,-OCONR-,-NRNR-,-NRSO 2NR-,-SO-,-SO 2-,-PO-,-PO 2-,-OP (O) (OR)-or-POR-replaces; Each R that occurs XBe independently selected from-R ' ,=O ,=NR ', halogen ,-NO 2,-CN ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2
R 5aBe optional substituted C 1-6Aliphatic group, halogen ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2With
Each R that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group; Each R ' that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group, 3-8 unit is saturated, part is unsaturated or complete undersaturated monocycle, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, perhaps 8-12 unit is saturated, part is unsaturated or complete undersaturated second cycle line system, and described second cycle line system has 0-5 heteroatoms that independently is selected from nitrogen, oxygen or sulphur; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance constitutes with their institute's bonded atoms that optional substituted 3-12 unit is saturated, part is unsaturated or complete undersaturated monocycle or two rings, and described ring has 0-4 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.
In some embodiments, with regard to above-claimed cpd,
A) if x is 0, R 1Be hydrogen, R 5aBe Cl, Me, CF 3, Br or F, then R 2Be not-(CH 2) 2-4-Cy 1,-SO 2CH 2Cy 1Or-CH 2SO 2Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-8 unit, and described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur;
B) if x is 0, R 5aBe Cl, Me, NO 2Or OH, then:
I. if R 1Be hydrogen, R then 2Be not Me, iBu, nBu ,-COCH 3,-CH 2COOEt ,-CH 2COOMe ,-CH 2CH 2OH, iPr ,-CH 2-pyridyl ,-CH 2Ph ,-(CH 2) 3NH 2,-(CH 2) 2-morpholinyl or-CH 2CH 2Ph;
Ii.R 1And R 2Not Et or Me simultaneously; With
Iii. if R 1Be Et, R then 2Not 4-Me-phenyl, 4-OMe-phenyl or 2-Me-phenyl;
C) if x is 1, R 3Be 6-Cl or 7-F, perhaps x is 0, R 5aBe-OPrn or Cl, then if R 1Be hydrogen, R then 2Be not-(CH 2) 2-morpholino base or-CH 2(cumarone); With
D) if x is 2, the R of Chu Xianing once 3Be 6-OMe, the R of another time appearance 3Be 7-OMe, R 5aBe F, then if R 1Be hydrogen, R then 2Be not-(CH 2) 3N (CH 3) 2
In some other embodiment, with regard to above-claimed cpd,
A) R 1Or R 2One of be hydrogen, R 1And R 2Another be selected from:
I.Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps
Ii. optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps
B) R 1And R 2Be selected from Cy independently of one another 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.
In other embodiments, Cy 1Be:
Figure G2004800119814D00551
In other embodiments, with regard to above-claimed cpd, R 1Be hydrogen or optional substituted C 1-4Aliphatic group, R 2Be-CHR-Cy 1, wherein R is hydrogen or C 1-4Alkyl, Cy 1Be:
In other embodiments, R 1And R 2Be optional substituted C independently of one another 1-4Aliphatic group, and be selected from 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 3Or normal-butyl.
With regard to above-claimed cpd, z is 0-5, R 4Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl.
In other embodiments, with regard to above-claimed cpd, x is 0-4, R 3Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, with regard to above-claimed cpd, x is 1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy.
In other embodiments, x is 1 or 2, each R 3Group is halogen, CN, optional substituted C independently 1-6Alkyl, OR ', N (R ') 2, CON (R ') 2Or NRCOR '.
In other embodiments, x is 1 or 2, each R 3Group is-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.
In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
With regard to above-claimed cpd, y is 0-4, and q is 0-2, R 5And R 5aGroup is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-NRCOR ' ,-CON (R ') 2,-S (O) 2N (R ') 2,-OCOR ' ,-COR ' ,-CO 2R ' ,-OCON (R ') 2,-NR ' SO 2R ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2,-OPO (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, y is 0-4, and q is 1 or 2, each R that occurs 5aBe Cl, Br, F, CF independently 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy.
In other embodiments, y is 0, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 1, R 5aBe OR ', R 5Be F, wherein OR ' is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.In other embodiments, y is 1, R 5aBe OH, R 5Be F, wherein OH is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.
In other embodiments with regard to above-mentioned formula IA-ii compound:
A) R 1Or R 2One of be hydrogen, R 1And R 2Another be selected from Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace perhaps optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps R 1And R 2Be selected from optional substituted C independently of one another 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replacement, perhaps Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace;
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) x is 0,1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy;
D) wherein y is 0-4, R 5Group is Cl, Br, F, CF when existing independently of one another 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy; With
E) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In other embodiments, with regard to above-claimed cpd, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3
In other embodiments, y is 0, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 1, R 5aBe OR ', R 5Be F, wherein OR ' is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.In other embodiments, y is 1, R 5aBe OH, R 5Be F, wherein OH is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.
In other embodiments with regard to above-mentioned formula IA-ii compound:
A) R 1Or R 2One of be hydrogen, R 1And R 2Another be selected from Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace perhaps optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps R 1And R 2Be selected from optional substituted C independently of one another 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replacement, perhaps Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace Cy 1Be selected from:
Perhaps R 1And R 2Be optional substituted C independently of one another 1-4Aliphatic group is selected from 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 3Or normal-butyl;
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) x is 0,1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy;
D) wherein y is 0-4, R 5Group is Cl, Br, F, CF when existing independently of one another 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy;
E) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In other embodiments, with regard to above-claimed cpd, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3
In other embodiments, y is 0, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 1, R 5aBe OR ', R 5Be F, wherein OR ' is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.In other embodiments, y is 1, R 5aBe OH, R 5Be F, wherein OH is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.
Generally with regard to this section above-claimed cpd, compound can be used as the inhibitor of ionic channel, the sodium channel of preferred voltage-gate and N-type calcium channel.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 inhibitors of NaV1.8 and a kind of TTX-susceptibility ionic channel, for example NaV1.3 or NaV1.7.
III. formula IA-i compound:
Or its pharmacy acceptable salt,
R wherein 1And R 2Be optional substituted group independently of one another, be selected from C 1-6Aliphatic group, Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; R wherein 1And R 2Separately randomly and independently on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, wherein z is 0-5;
X is 1, R 3Be substituted in the 6-or the 7-position of quinazoline ring;
Y is 0-4;
Q is 0,1 or 2;
Each R that occurs 3, R 4And R 5Be 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 randomly and independently by-NR-,-S-,-O-,-CS-,-CO 2-,-OCO-,-CO-,-COCO-,-CONR-,-NRCO-,-NRCO 2-,-SO 2NR-,-NRSO 2-,-CONRNR-,-NRCONR-,-OCONR-,-NRNR-,-NRSO 2NR-,-SO-,-SO 2-,-PO-,-PO 2-,-OP (O) (OR)-or-POR-replaces; Each R that occurs XBe independently selected from-R ' ,=O ,=NR ', halogen ,-NO 2,-CN ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2
Each R that occurs 5aBe optional substituted C independently 1-6Aliphatic group, halogen ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2And
Each R that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group; Each R ' that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group, 3-8 unit is saturated, part is unsaturated or complete undersaturated monocycle, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, perhaps 8-12 unit is saturated, part is unsaturated or complete undersaturated second cycle line system, and described second cycle line system has 0-5 heteroatoms that independently is selected from nitrogen, oxygen or sulphur; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance constitutes with their institute's bonded atoms that optional substituted 3-12 unit is saturated, part is unsaturated or complete undersaturated monocycle or two rings, and described ring has 0-4 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.
In some embodiments, with regard to above-claimed cpd,
A) if R 3Be positioned at the 7-position of quinazoline ring, then:
I. if R 3Be Cl or Me, ring A is unsubstituted naphthyl, R 1Be hydrogen, R then 2Be not-(CH 2) 3NMe 2
Ii. if R 3Be Cl, q and y sum are 1, and benzyl ring is replaced by Br in the 4-position, R 1Be hydrogen, R then 2Not Cy 1, Cy wherein 1Pass through optional substituted C with nitrogen-atoms 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace;
Iii. if R 3Be Cl or OMe, q and y sum are 1, and benzyl ring is replaced R in the 4-position by OMe or Cl 1Be hydrogen, R then 2Be not-CH (CH 3) (CH 2) 3N (Et) 2
Iv. if R 3Be Me, OMe or NO 2, q and y are 0, then R 1And R 2It not all is methyl;
V. if R 3Be OMe, q and y are 0, R 1Be hydrogen, R then 2Be not-SO 2(4-Me-phenyl);
Vi. if R 3Be F, q and y sum are 1, and benzyl ring is replaced by Cl in the 2-position, R 1Be hydrogen, R then 2Be not-(CH 2) the morpholino base;
B) if R 3Be positioned at the 6-position of quinazoline ring, then:
I. if R 3Be NH 2, Me, Cl, Br ,-NHAc, q and y sum are 1, benzyl ring is replaced by F in the 4-position, perhaps encircling A is naphthyl, R 1Be hydrogen, R then 2Be not-(CH 3) 3-4N (R ') 2
Ii. if R 3Be-OCH 2Ph or OH, if q and y are 0, then R 1Be hydrogen, R then 2Be not Me, nBu or-(CH 2) 2Morpholino base, perhaps R 1And R 2Not Me or Et simultaneously;
Iii. if R 3Be Me or Cl, q and y sum are 1, and then benzyl ring is not replaced by Br in the 4-position;
Iv. if R 3Be Cl, q and y are 0, R 1Be hydrogen, R then 2Be not-SO 2(4-Me-phenyl);
V. if R 3Be OMe, q and y are 0, R 1Be hydrogen, R then 2Be not-CH 2CH 2OH or-CH 2CH 2Pyrrolidyl;
Vi. if R 3Be Cl or Br, q and y sum are 1, and benzyl ring is at 4-position quilt-CH 2PO (OR ') 2Replace, then if R 2Be-Me, then R 1Not hydrogen, perhaps R 1And R 2Not Me or Et simultaneously;
Vii. if R 3Be OH, q and y are 0, then R 1And R 2Be not simultaneously-CH 2CH 2OMe;
Viii. if R 3Be Cl, q and y sum are 1, and benzyl ring is replaced by OnPr in the 2-position, R 1Be hydrogen, R then 2Be not-CH 2(1,3-benzodioxole base);
Ix. if R 3Be OMe, OH, Br, Cl, NO 2, Me, if q and y are 0, then R 1Be hydrogen, R then 2Be not Me ,-CH 2CH 2COOMe ,-CH 2COOMe or-(CH 2) 3CH 3, perhaps R 1And R 2Not Me simultaneously; And
X. if R 3Be Cl, q and y sum are 1, and benzyl ring is replaced by Cl in the 4-position, then R 1And R 2Not Me or iPr simultaneously.
In some other embodiment, with regard to above-claimed cpd,
A) R 1Or R 2One of be hydrogen, R 1And R 2Another be selected from:
I.Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps
Ii. optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps
B) R 1And R 2Be selected from Cy independently of one another 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.
In other embodiments, Cy 1Be:
Figure G2004800119814D00681
In other embodiments, R 1Be hydrogen or optional substituted C 1-4Aliphatic group, R 2Be-CHR-Cy 1, wherein R is hydrogen or C 1-4Alkyl, Cy 1Be:
In other embodiments, R 1And R 2Group is optional substituted C independently of one another 1-4Aliphatic group, and be selected from optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3Or normal-butyl.
In other embodiments, with regard to above-claimed cpd, z is 0-5, R 4Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl.
In other embodiments, with regard to above-claimed cpd, R 3Be halogen, CN, NO 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, R 3Be Cl, Br, F, CF 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy.
In other embodiments, R 3Be halogen, CN, optional substituted C 1-6Alkyl, OR ', N (R ') 2, CON (R ') 2Or NRCOR '.
In other embodiments, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, with regard to above-claimed cpd, y is 0-5, and q is 0-2, R 5And R 5aGroup is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-NRCOR ' ,-CON (R ') 2,-S (O) 2N (R ') 2,-OCOR ' ,-COR ' ,-CO 2R ' ,-OCON (R ') 2,-NR ' SO 2R ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2,-OPO (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, y is 0-5, and q is 1 or 2, each R that occurs 5aBe Cl, Br, F, CF independently 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy.
In other embodiments, y is 0, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 1, R 5aBe OR ', R 5Be F, wherein OR ' is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.In other embodiments, y is 1, R 5aBe OH, R 5Be F, wherein OH is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.
In other embodiments, R 3Be substituted in the 6-position of quinazoline ring, q is 1, and y is 0, and compound has formula III:
In some embodiments, with regard to above-claimed cpd,
A) R 1And R 2Be optional substituted group independently of one another, be selected from C 1-6Aliphatic group, Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; R wherein 1And R 2Separately randomly and independently on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, wherein z is 0-5;
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) R 3Be Cl, Br, F, CF 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy;
D) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2, OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base ,-OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In other embodiments, with regard to above-claimed cpd, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 3Be-CON (R ') 2Or NRCOR '.In other embodiments, R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3
In other embodiments, y is 0, R 5aBe F.In other embodiments, be 0, q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.
In some other embodiment, with regard to above-claimed cpd,
A) Cy 1Be:
Figure G2004800119814D00741
Perhaps R 1And R 2Be optional substituted C independently of one another 1-4Aliphatic group is selected from 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 3Or normal-butyl;
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) R 3Be Cl, Br, F, CF 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy;
D) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In some embodiments, with regard to above-claimed cpd, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 3Be-CON (R ') 2Or NRCOR '.In other embodiments, R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3In other embodiments, y is 0, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.
In other embodiments, R 3Be substituted in the 7-position of quinazoline ring, q is 1, and y is 0, and compound has formula IV:
A) R 1And R 2Be optional substituted group independently of one another, be selected from C 1-6Aliphatic group, Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; R wherein 1And R 2Separately randomly and independently on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, wherein z is 0-5;
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) R 3Be Cl, Br, F, CF 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy;
D) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In some embodiments, with regard to above-claimed cpd, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 3Be-CON (R ') 2Or NRCOR '.In other embodiments, R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3In other embodiments, y is 0, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.
In some other embodiment, with regard to above-claimed cpd,
A) Cy 1Be:
Perhaps R 1And R 2Be optional substituted C independently of one another 1-4Aliphatic group is selected from 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 3Or normal-butyl;
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) R 3Be Cl, Br, F, CF 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy; And
D) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base ,-OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In some other embodiment, with regard to above-claimed cpd, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 3Be-CON (R ') 2Or NRCOR '.In other embodiments, R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3, and-OCH 2CH 3In other embodiments, y is 0, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.
Generally with regard to this section above-claimed cpd, compound can be used as the inhibitor of ionic channel, the sodium channel of preferred voltage-gate and N-type calcium channel.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 inhibitors of NaV1.8 and a kind of TTX-susceptibility ionic channel, for example NaV1.3 or NaV1.7.
IV. formula V compound:
R wherein 1And R 2Be optional substituted group independently of one another, be selected from C 1-6Aliphatic group, Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps R 1And R 2With their institute's bonded nitrogen-atoms constitute optional substituted 3-12 unit monocycle or two ring fillings, part is unsaturated or complete undersaturated ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, sulphur or oxygen in addition; R wherein 1And R 2Perhaps by R 1And R 2Together the ring of Gou Chenging separately randomly and independently on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, wherein z is 0-5;
X is 0-4;
Y is 0-2;
Each R that occurs 3, R 4And R 5Be 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 randomly and independently by-NR-,-S-,-O-,-CS-,-CO 2-,-OCO-,-CO-,-COCO-,-CONR-,-NRCO-,-NRCO 2-,-SO 2NR-,-NRSO 2-,-CONRNR-,-NRCONR-,-OCONR-,-NRNR-,-NRSO 2NR-,-SO-,-SO 2-,-PO-,-PO 2-,-OP (O) (OR)-or-POR-replaces; Each R that occurs XBe independently selected from-R ' ,=O ,=NR ', halogen ,-NO 2,-CN ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2
R 5aBe optional substituted C 1-6Aliphatic group, halogen ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2And
Each R that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group; Each R ' that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group, 3-8 unit is saturated, part is unsaturated or complete undersaturated monocycle, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, perhaps 8-12 unit is saturated, part is unsaturated or complete undersaturated second cycle line system, and described second cycle line system has 0-5 heteroatoms that independently is selected from nitrogen, oxygen or sulphur; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance constitutes with their institute's bonded atoms that optional substituted 3-12 unit is saturated, part is unsaturated or complete undersaturated monocycle or two rings, and described ring has 0-4 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.
In some embodiments, with regard to above-claimed cpd, if x is 1, R 3Be 6-OMe, R 1Be hydrogen, y and q are 0, then R 2Be not-CH 2CH 2OCH 2CH 2An OH or a mesylate.
In some other embodiment, with regard to above-claimed cpd,
A) R 1Or R 2One of be hydrogen, R 1And R 2Another be selected from:
I.Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps
Ii. optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps
B) R 1And R 2Be selected from Cy independently of one another 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.
In other embodiments, Cy 1Be:
Figure G2004800119814D00821
In other embodiments, R 1Be hydrogen or optional substituted C 1-4Aliphatic group, R 2Be-CHR-Cy 1, wherein R is hydrogen or C 1-4Alkyl, Cy 1Be:
Figure G2004800119814D00822
In other embodiments, R 1And R 2Be optional substituted C independently of one another 1-4Aliphatic group, and be selected from 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 3Or normal-butyl.
In other embodiments with regard to above-claimed cpd, R 1And R 2Constitute the first heterocyclic ring of optional substituted 3-12 with their institute's bonded nitrogen-atoms, described ring has 1-3 heteroatoms that independently is selected from nitrogen or oxygen, perhaps forms the 3-12 unit heterocyclic radical that is selected from following group:
Figure G2004800119814D00832
Wherein by R 1And R 2Together the ring that is constituted randomly on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, z is 0-5.
In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd), piperazine-1-base (cc) or morpholine-4-base (ee) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd) or piperazine-1-base (cc) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted or piperazine-1-base (cc) together.
In other embodiments, with regard to above-claimed cpd, z is 0-5, R 4Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl.
In some embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-NRSO 2R ' ,-NRCOOR ' or-NRCOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRSO 2R '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together, wherein z is 1 or 2, R 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR ' ,-NRSO 2R ' ,-NRCOOR ' or-OCON (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRSO 2R '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRCOOR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-SOR ' ,-CON (R ') 2,-SO 2N (R ') 2,-COR ' or-COOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-CON (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SO 2N (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COR '.
In other embodiments, x is 0-4, R 3Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, x is 1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy.
In other embodiments, x is 1 or 2, each R 3Group is halogen, CN, optional substituted C independently 1-6Alkyl, OR ', N (R ') 2, CON (R ') 2Or NRCOR '.In other embodiments, x is 1 or 2, each R 3Group is-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, with regard to above-claimed cpd, y is 0-2, and q is 0-2, R 5And R 5aGroup is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-NRCOR ' ,-CON (R ') 2,-S (O) 2N (R ') 2,-OCOR ' ,-COR ' ,-CO 2R ' ,-OCON (R ') 2,-NR ' SO 2R ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2,-OPO (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, y is 0-2, and q is 1 or 2, each R that occurs 5aBe Cl, Br, F, CF independently 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy.
In other embodiments, y is 0, and q is 1, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OR ', the R of another time appearance 5aBe F.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OH, the R of another time appearance 5aBe F.
In other embodiments,
A) R 1And R 2Be optional substituted ring together, be selected from azetidine-1-base (jj), tetramethyleneimine-1-base (ff), piperidines-1-base (dd) or piperazine-1-base (cc); R 1Or R 2One of be hydrogen, R 1And R 2Another be selected from Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace perhaps optional substituted C 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps R 1And R 2Be selected from optional substituted C independently of one another 1-4Aliphatic group, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replacement, perhaps Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace;
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) x is 0,1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy;
D) wherein y is 0-2, R 5Group is Cl, Br, F, CF when existing independently of one another 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy; With
E) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted or piperazine-1-base (cc) together.
In some embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-NRSO 2R ' ,-NRCOOR ' or-NRCOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRSO 2R '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted azetidine-1-base (jj) together, wherein z is 1, R 4Be-NRCOR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted tetramethyleneimine-1-base (ff) together, wherein z is 1 or 2, R 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be Cl, Br, F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR ' ,-NRSO 2R ' ,-NRCOOR ' or-OCON (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be F, CF 3, CH 3,-CH 2CH 3,-OR ' or-CH 2OR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRSO 2R '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperidines-1-base (dd) together, wherein z is 1, R 4Be-NRCOOR '.In other embodiments, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1 or 2, at least once the R of Chu Xianing 4Be-SOR ' ,-CON (R ') 2,-SO 2N (R ') 2,-COR ' or-COOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COOR '.In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-CON (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-SO 2N (R ') 2In some other embodiment, with regard to formula I-A compound, R 1And R 2Be optional substituted piperazine-1-base (cc) together, wherein z is 1, R 4Be-COR '.
In other embodiments with regard to above-claimed cpd, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3In other embodiments, y is 0, and q is 1, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OR ', the R of another time appearance 5aBe F.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OH, the R of another time appearance 5aBe F.
In some embodiments, with regard to above-claimed cpd,
A) Cy 1Be:
Perhaps R 1And R 2Be optional substituted C independently of one another 1-4Aliphatic group is selected from optional substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO) OCH independently of one another 2CH 3, (CH 2) 2OCH 3, CH 2CO) OCH 2CH 3, CH 2(CO) OCH 3, CH (CH 3) CH 2CH 3Or normal-butyl;
B) z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) x is 0,1 or 2, each R that occurs 3Be Cl, Br, F, CF independently 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy;
D) wherein y is 0-5, R 5Group is Cl, Br, F, CF when existing independently of one another 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy; With
E) R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) or-COCH 3
In other embodiments with regard to above-claimed cpd, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, x is 1, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, x is 1, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, x is 1, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3,-OCH 2CH 3In other embodiments, y is 0, and q is 1, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OR ', the R of another time appearance 5aBe F.In other embodiments, y is 0, and q is 2, once the R of Chu Xianing 5aBe OH, the R of another time appearance 5aBe F.
Generally with regard to this section above-claimed cpd, compound can be used as the inhibitor of ionic channel, the sodium channel of preferred voltage-gate and N-type calcium channel.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 inhibitors of NaV1.8 and a kind of TTX-susceptibility ionic channel, for example NaV1.3 or NaV1.7.
V. formula I-B-i compound:
Or its pharmacy acceptable salt,
R wherein 1Be selected from C 1-6Aliphatic group, Cy 1, Cy wherein 1Be 5-7 unit's monocyclic aryl ring or 8-10 unit aryl bicyclic ring, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, or the saturated or undersaturated monocycle of part of 3-12 unit, described ring has 0-3 the heteroatoms that independently is selected from nitrogen, oxygen or sulphur, wherein Cy 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; R wherein 1Randomly on one or more commutable carbon, nitrogen or sulphur atom by z independent occur-R 4Replace, wherein z is 0-5;
X is 0-4;
Y is 0-4;
Each R that occurs 3, R 4And R 5Be 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 randomly and independently by-NR-,-S-,-O-,-CS-,-CO 2-,-OCO-,-CO-,-COCO-,-CONR-,-NRCO-,-NRCO 2-,-SO 2NR-,-NRSO 2-,-CONRNR-,-NRCONR-,-OCONR-,-NRNR-,-NRSO 2NR-,-SO-,-SO 2-,-PO-,-PO 2-,-OP (O) (OR)-or-POR-replaces; Each R that occurs XBe independently selected from-R ' ,=O ,=NR ', halogen ,-NO 2,-CN ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2
Each R that occurs 5aBe optional substituted C 1-6Aliphatic group, halogen ,-OR ' ,-SR ' ,-N (R ') 2,-NR ' COR ' ,-NR ' CON (R ') 2,-NR ' CO 2R ' ,-COR ' ,-CO 2R ' ,-OCOR ' ,-CON (R ') 2,-OCON (R ') 2,-SOR ' ,-SO 2R ' ,-SO 2N (R ') 2,-NR ' SO 2R ' ,-NR ' SO 2N (R ') 2,-COCOR ' ,-COCH 2COR ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2Or-OPO (R ') 2And
Each R that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group; Each R ' that occurs is hydrogen or optional substituted C independently 1-6Aliphatic group, 3-8 unit is saturated, part is unsaturated or complete undersaturated monocycle, described ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur, perhaps 8-12 unit is saturated, part is unsaturated or complete undersaturated second cycle line system, and described second cycle line system has 0-5 heteroatoms that independently is selected from nitrogen, oxygen or sulphur; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance constitutes with their institute's bonded atoms that optional substituted 3-12 unit is saturated, part is unsaturated or complete undersaturated monocycle or two rings, and described ring has 0-4 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.
With regard to above-claimed cpd, in some embodiments,
A) if R 5aBe Me, Cl or OMe, x is 0, then R 1Not Et or Me;
B) if R 5aBe Cl, x is 3, three R that occur 3Be 6-Me, 7-COOEt and 8-Me, then R 1Be not-(CH 2) 2Piperidines-1-base;
C) if R 5aBe Me, x is 1, R 3Be NO 2Or NH 2, R then 1Not Et;
D) if R 5aBe OH, NHMe or N (NO) Me, x is 0, then R 1Be not Et, Me or-CH 2CH=CH 2
E) if R 5aBe NH 2, x is 0, then R 1Be not-COCH 3
F) if R 5aBe Cl or Me, y is 0 or 1, and if y is 1, R 5Be 4-Cl, x is 0, then R 1Not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl, 4-Cl-phenyl, 4-NO 2-phenyl ,-CH 2CH 2NHMe, Et, Me, 4-COOMe-phenyl ,-CH 2Ph, iPr, 2-Me-phenyl, 4-phenyl-phenyl or-CH 2CH=CH 2
With regard to above-claimed cpd, in some other embodiment,
A) R 1Be selected from:
I.Cy 1, Cy wherein 1With the nitrogen-atoms Direct Bonding or by optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace; Perhaps
Ii. optional substituted C 1-4Aliphatic group bonding, wherein this C 1-4One or more MU (methylene unit) in the aliphatic group randomly by-NR-,-O-,-COO-,-OCO-,-NRCO-,-CONR-,-SO 2NR-or-NRSO 2-replace.
With regard to above-claimed cpd, in some embodiments, Cy 1Be:
Figure G2004800119814D00961
In other embodiments, R 1Be-CHR-Cy 1, wherein R is hydrogen or C 1-4Alkyl, Cy 1Be:
In other embodiments, R 1Be optional substituted C 1-4Aliphatic group, and be selected from 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 3Or normal-butyl.
In other embodiments, z is 0-5, R 4Group is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, z is 0-5, R 4Group is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl.
In other embodiments, R 3Be halogen, CN, NO 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-COOR ' ,-NRCOR ' ,-CON (R ') 2,-OCON (R ') 2, COR ' ,-NHCOOR ' ,-SO 2R ' ,-SO 2N (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, R 3Be Cl, Br, F, CF 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3,-CONHCH 2CH 3Perhaps optional substituted group is selected from piperidyl, piperazinyl, morpholino base, phenyl, phenoxy group, benzyl or benzyloxy.
In other embodiments, R 3Be halogen, CN, optional substituted C 1-6Alkyl, OR ', N (R ') 2, CON (R ') 2Or NRCOR '.In other embodiments, R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-CONHCH 3,-CONHCH 2CH 3,-CONH (cyclopropyl) ,-OCH 3,-NH 2,-OCH 2CH 3Or-CN.In other embodiments, R 3Be positioned at the 6-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3In other embodiments, R 3Be positioned at the 7-position of quinazoline ring, be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
In other embodiments, R 3Being positioned at the 6-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.In other embodiments, R 3Being positioned at the 7-position of quinazoline ring, is-CON (R ') 2Or NRCOR '.
In other embodiments, with regard to above-claimed cpd, y is 0-5, and q is 0-2, R 5And R 5aGroup is halogen, CN, NO when existing independently of one another 2,-N (R ') 2,-CH 2N (R ') 2,-OR ' ,-CH 2OR ' ,-SR ' ,-CH 2SR ' ,-NRCOR ' ,-CON (R ') 2,-S (O) 2N (R ') 2,-OCOR ' ,-COR ' ,-CO 2R ' ,-OCON (R ') 2,-NR ' SO 2R ' ,-OP (O) (OR ') 2,-P (O) (OR ') 2,-OP (O) 2OR ' ,-P (O) 2OR ' ,-PO (R ') 2,-OPO (R ') 2Perhaps optional substituted group is selected from C 1-6Aliphatic group, aryl, heteroaryl, cycloaliphatic groups, heterocycle aliphatic group, aryl C 1-6Alkyl, heteroaryl C 1-6Alkyl, cycloaliphatic groups C 1-6Alkyl or heterocycle aliphatic group C 1-6Alkyl.
In other embodiments, y is 0-5, and q is 1 or 2, each R that occurs 5aBe Cl, Br, F, CF independently 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, optional substituted phenoxy group or optional substituted benzyloxy.
In other embodiments, y is 0, R 5aBe F.In other embodiments, y is 0, and q is 1, R 5aBe OR '.In other embodiments, y is 0, and q is 1, R 5aBe OH.In other embodiments, y is 1, R 5aBe OR ', R 5Be F, wherein OR ' is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.In other embodiments, y is 1, R 5aBe OH, R 5Be F, wherein OH is substituted in the 2-position of benzyl ring, and F is substituted in the 6-position of benzyl ring.
Generally with regard to this section above-claimed cpd, compound can be used as the inhibitor of ionic channel, the sodium channel of preferred voltage-gate and N-type calcium channel.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 inhibitors of NaV1.8 and a kind of TTX-susceptibility ionic channel, for example NaV1.3 or NaV1.7.
As above the representative example with compound described herein is listed in the table 2.
Table 2: formula I examples for compounds
Figure G2004800119814D01011
Figure G2004800119814D01021
Figure G2004800119814D01041
Figure G2004800119814D01091
Figure G2004800119814D01131
Figure G2004800119814D01141
Figure G2004800119814D01151
Figure G2004800119814D01211
Figure G2004800119814D01221
Figure G2004800119814D01231
Figure G2004800119814D01241
Figure G2004800119814D01251
Figure G2004800119814D01261
Figure G2004800119814D01271
Figure G2004800119814D01291
Figure G2004800119814D01301
Figure G2004800119814D01321
Figure G2004800119814D01341
Figure G2004800119814D01351
Figure G2004800119814D01361
Figure G2004800119814D01391
Figure G2004800119814D01421
Figure G2004800119814D01431
Figure G2004800119814D01441
Figure G2004800119814D01451
Figure G2004800119814D01471
Figure G2004800119814D01491
Figure G2004800119814D01521
Figure G2004800119814D01541
Figure G2004800119814D01551
Figure G2004800119814D01561
Figure G2004800119814D01581
Figure G2004800119814D01611
Figure G2004800119814D01621
Figure G2004800119814D01651
Figure G2004800119814D01671
Figure G2004800119814D01681
Figure G2004800119814D01691
Figure G2004800119814D01741
Figure G2004800119814D01751
Figure G2004800119814D01761
Figure G2004800119814D01771
Figure G2004800119814D01781
Figure G2004800119814D01791
Figure G2004800119814D01801
Figure G2004800119814D01811
Figure G2004800119814D01831
Figure G2004800119814D01851
Figure G2004800119814D01861
Figure G2004800119814D01891
Figure G2004800119814D01901
Figure G2004800119814D01931
Figure G2004800119814D01941
Figure G2004800119814D01951
Figure G2004800119814D01961
Figure G2004800119814D01971
Figure G2004800119814D01981
Figure G2004800119814D01991
Figure G2004800119814D02031
Figure G2004800119814D02041
Figure G2004800119814D02051
Figure G2004800119814D02061
Figure G2004800119814D02081
Figure G2004800119814D02091
Figure G2004800119814D02101
Figure G2004800119814D02111
Figure G2004800119814D02131
Figure G2004800119814D02141
Figure G2004800119814D02171
Figure G2004800119814D02181
Figure G2004800119814D02211
Figure G2004800119814D02241
Figure G2004800119814D02271
Figure G2004800119814D02281
Figure G2004800119814D02321
Figure G2004800119814D02331
Figure G2004800119814D02341
Figure G2004800119814D02371
Figure G2004800119814D02381
Figure G2004800119814D02411
Figure G2004800119814D02421
Figure G2004800119814D02451
Figure G2004800119814D02501
Figure G2004800119814D02511
Figure G2004800119814D02531
Figure G2004800119814D02561
Figure G2004800119814D02571
Figure G2004800119814D02621
Figure G2004800119814D02631
Figure G2004800119814D02651
Figure G2004800119814D02671
Figure G2004800119814D02691
Figure G2004800119814D02701
Figure G2004800119814D02741
Figure G2004800119814D02751
Figure G2004800119814D02761
Figure G2004800119814D02781
Figure G2004800119814D02791
Figure G2004800119814D02811
Figure G2004800119814D02851
Figure G2004800119814D02871
Figure G2004800119814D02891
Figure G2004800119814D02911
Figure G2004800119814D02941
Figure G2004800119814D02991
Figure G2004800119814D03021
Figure G2004800119814D03031
Figure G2004800119814D03041
Figure G2004800119814D03051
Figure G2004800119814D03081
Figure G2004800119814D03101
Figure G2004800119814D03151
Figure G2004800119814D03161
Figure G2004800119814D03181
Figure G2004800119814D03211
Figure G2004800119814D03231
Figure G2004800119814D03261
Figure G2004800119814D03281
Figure G2004800119814D03291
Figure G2004800119814D03331
Figure G2004800119814D03351
Figure G2004800119814D03371
Figure G2004800119814D03381
Figure G2004800119814D03391
Figure G2004800119814D03421
Figure G2004800119814D03431
Figure G2004800119814D03441
Figure G2004800119814D03451
Figure G2004800119814D03481
Figure G2004800119814D03501
Figure G2004800119814D03511
Figure G2004800119814D03541
Figure G2004800119814D03551
Figure G2004800119814D03571
Figure G2004800119814D03581
Figure G2004800119814D03591
Figure G2004800119814D03601
Figure G2004800119814D03611
Figure G2004800119814D03631
Figure G2004800119814D03671
Figure G2004800119814D03691
Figure G2004800119814D03701
Figure G2004800119814D03731
Figure G2004800119814D03741
Figure G2004800119814D03761
Figure G2004800119814D03791
Figure G2004800119814D03811
Figure G2004800119814D03821
Figure G2004800119814D03831
Figure G2004800119814D03841
Figure G2004800119814D03851
Figure G2004800119814D03881
Figure G2004800119814D03941
Figure G2004800119814D03961
4. universal synthesis method:
The compounds of this invention generally can be prepared by the method that those skilled in the art become known for similar compound, and following generalized flowsheet and preparation embodiment are described.
Following flow process A describes wherein, and X is NR 2The general synthesis condition of formula IA compound.Generally speaking, useful as intermediates iii can be by Benzoyl chloride and anthranilamide condensation and is got.
Flow process A:
(step a) is used K in the reaction of i and ii 2CO 3Under refluxad carry out with ether, under refluxad handle subsequently, obtain intermediate iii with the 5%NaOH aqueous solution.Intermediate iii and POCl 3Reaction generates 4-chlorine compound, i subsequently) and N, accelerine is reaction under refluxad in benzene; Ii) with BBr 3, CH 2Cl 2-78 ℃ of reactions down; Iii) with R 1R 2NH is at THF/CH 2Cl 2In at ambient temperature the reaction, obtain required product IA.
It is synthetic that flow process B describes substituting of formula IA compound:
Figure G2004800119814D04021
(step a) is used triethylamine and 1, and the 4-diox carries out under envrionment conditions, obtains intermediate iii in the reaction of i and ii.(step b) and 0.5M ammonia are 1, and the reactant of the solution in 4-dioxane solution, triethylamine and the bop reagent stirred 16 hours at ambient temperature, obtained intermediate iv with intermediate iii.Iv is under refluxad handled with 5%NaOH solution, obtain intermediate v.With v POCl 3Handle, generate the 4-chlorine compound, subsequently: i) and N, accelerine is reaction under refluxad in benzene; Ii) with BBr 3, CH 2Cl 2,-78 ℃ of reactions; Iii) with R 1R 2NH is at THF/CH 2Cl 2In at ambient temperature the reaction, obtain required product IA.
Flow process C:
Figure G2004800119814D04022
(step a) is used pyridine, obtains intermediate iii in the reaction of i and ii.Iii is under refluxad handled with 5%NaOH solution, obtain intermediate iv.Intermediate iv and POCl 3Reaction generates the 4-chlorine compound, and subsequently: i) and N, accelerine is reaction under refluxad in benzene; Ii) with BBr 3, CH 2Cl 2,-78 ℃ of reactions; Iii) with R 1R 2NH is at THF/CH 2Cl 2In at ambient temperature the reaction, obtain required product IA.
Following flow process D and E describe the synthetic of multiple useful anthranilamide:
Flow process D
(step a) is carried out in the presence of oxammonium hydrochloride, obtains isatin ii in the reaction of i and Chloral Hydrate.Ii is handled with alkaline hydrogen peroxide, and (step b) is shown in flow process D to obtain iii.
Flow process E
Figure G2004800119814D04032
(step a) obtains ii for i and Boc anhydride reaction.Subsequently ii is metallized at low temperatures with butyllithium, with CO 2React, obtain the anthranilic acid (step b) of N-protected.Remove Boc with TFA, obtain anthranilic acid iii, shown in flow process E.
Flow process F
Figure G2004800119814D04033
(step a) obtains ii, shown in flow process F for isatoic anhydride i and ammonium hydroxide aqueous solution reaction.
Flow process G
Figure G2004800119814D04034
(step a) is handled i 24 hours to room temperature at 0 ℃ with AcOH and KOCN in water, with the NaOH reaction, succeeded by the HCl acidifying, obtains intermediate ii subsequently.(step b) is with ii POCl 3Under refluxad handle with triethylamine, obtain intermediate iii.(step c) is with iii R 1R 2NH is at THF/CH 2Cl 2In, handle to room temperature at 0 ℃, obtain intermediate iv.
Flow process H
Figure G2004800119814D04042
Intermediate i and POCl 3(step a) generates 2,4-dichloro compound ii in reaction.Intermediate ii and R 1-NH-R 2And Et 3N is at CH 2Cl 2(step b) obtains amine iii in middle reaction.(step c) generates iv to intermediate iii with containing NH heterocycle, NaH and THF reaction.Intermediate iii and LiHMDS, Pd 2(dba) 3, (step d) obtains diamines v in 2-(dicyclohexyl) phosphino-biphenyl and THF reaction.(step e), generation vi are reacted in 2 of intermediate v and replacement, 5-dimethoxy-tetrahydrofuran in AcOH.Intermediate v and ClCO-CH 2-(CH 2) n-CH 2-Cl, Et 3N and to-dioxs reactions (step f) generates vii.Intermediate iii and cyclic acid anhydride and to-dioxs reactions (step g) generates viii.
Flow process I
Figure G2004800119814D04051
Intermediate i and POCl 3(step a) is used BBr subsequently in reaction 3, CH 2Cl 2Handle down at-78 ℃, generate 4-chlorine compound ii.Intermediate ii and R '-NH-R 2-X (R " ') H and Et 3N is at CH 2Cl 2(step b) obtains iii in middle reaction.Intermediate iii and R ' N (R ") X-SO 2Cl and Et 3N is at CH 2Cl 2(step c) generates iv in middle reaction.Intermediate iii and R '-SO 2Cl and Et 3N is at CH 2Cl 2(step d) generates v in middle reaction.Intermediate iii and R '-CO 2Cl and Et 3N is at CH 2Cl 2In reaction or with phosgene and R ' (R ") (step e) generates vi in the XH reaction.Intermediate iii and R ' COCl, Et 3N is at CH 2Cl 2(step f) generates vii in middle reaction.Intermediate iii and electrophilic reagent are at Et 3N (Organohalogen compounds electrophilic reagent) or NaBH (OAc) 3(step g) obtains viii in reaction under the existence of (aldehyde and ketone electrophilic reagent).
Flow process J
I and ii obtain product iii in methylene dichloride, under microwave radiation, 150 ℃ of reactions down.
Flow process K
Condition: (a) for M=Li:s-BuLi, TMEDA, THF ,-78 ℃; For M=ZnX:i.s-BuLi, TMEDA, THF ,-78 ℃; Ii.ZnCl 2For M=MgX:Mg, THF refluxes. (b) i.RSSR; Ii.H 2O 2(n=1) or KMnO 4(n=2). (c) R 1R 2C=O, THF ,-78 ℃ to room temperature. (d) CO 2, THF ,-78 ℃ to room temperature. (e) for R 1=H:R 2NCO; Other: R 1R 2COCl, THF. (f) i.H 2C=O; Ii.PBr 3Iii.R 1R 2NH. (g) Het-OTf, Ni (acac) 2, PPh 3, MeMgBr, THF, room temperature. and (h) i.B (OMe) 3Ii.ArX (X=halogen), Pd (PPh 3) 4, NaOEt, toluene, 80 ℃. and (i) i.SOCl 2, CH 2Cl 2Ii.R 1Sn (R) 3, Pd (PPh 3) 4, toluene; Iii.R 1MgX, THF. (j) i.SOCl 2, CH 2Cl 2Ii.R 1R 2NH, THF. (k) LiAlH 4, THF.
Flow process L
Figure G2004800119814D04071
Condition: (a) for M=Li:s-BuLi, TMEDA, THF ,-78 ℃; For M=ZnX:i.s-BuLi, TMEDA, THF ,-78 ℃; Ii.ZnCl 2For M=MgX:Mg, THF refluxes. (b) i.RSSR; Ii.H 2O 2(n=1) or KMnO 4(n=2). (c) R 1R 2C=O, THF ,-78 ℃ to room temperature. (d) CO 2, THF ,-78 ℃ to room temperature. (e) for R 1=H:R 2NCO; Other: R 1R 2COCl, THF. (f) i.H 2C=O; Ii.PBr 3Iii.R 1R 2NH. (g) Het-OTf, Ni (acac) 2, PPh 3, MeMgBr, THF, room temperature. and (h) for R 1=aryl: i.B (OMe) 3Ii.ArX (X=halogen), Pd (PPh 3) 4, NaOEt, toluene, 80 ℃; R 1=alkyl: R 1I, THF ,-78 ℃ to room temperature. (i) i.SOCl 2, CH 2Cl 2Ii.R 1Sn (R) 3, Pd (PPh 3) 4, toluene; Iii.R 2MgX, THF. (j) i.SOCl 2, CH 2Cl 2Ii.R 1R 2NH, THF. (k) LiAlH 4, THF. (1) ArXB (OR) 2, Pd (PPh 3) 4, NaOEt, toluene, 80 ℃.
Flow process M
Figure G2004800119814D04081
I is handled with ii, adopt palladium catalytic condition (step a): Pd (dppf) Cl 2, KOAc in DMSO or DMF, 84 ℃, 2-6 hour, obtains intermediate iii.Palladium cross-coupling condition (step b): Pd (dppf) Cl is adopted in the reaction of intermediate iii and intermediate iv 2Or (Ph 3P) 4P d, K 2CO 3, DMF: H 2O (4: 1), microwave radiation, 6 minutes, obtains compound v by 170 ℃.
Flow process N
I is handled down at-78 ℃ with t-BuLi, add solid CO subsequently 2, be warming up to room temperature, obtain carboxylicesters ii.Carboxylicesters among the ii can keep or be used for the peculiar reaction of this functional group.
Flow process O
Figure G2004800119814D04092
I and suitable amine carry out the catalytic cross-coupling of palladium in toluene (80 ℃), obtain ii.
Flow process P
A) phosphorous acid dibenzyl ester, DMAP, DIEA, CCl 4, CH 3CN, 0 ℃ to room temperature; B) TMSBr, CH 2Cl 2, room temperature; C) H 2, Pd/C, MeOH; D) NaOMe, MeOH, room temperature
Figure G2004800119814D04101
Condition: (a) R 4COCl, pyridine, CH 2Cl 2, 0 ℃, room temperature then
Flow process Q
Figure G2004800119814D04102
(step a) uses triethylamine at THF/CH for i and iia or iib reaction 2Cl 2In, at room temperature handle, obtain compound i ii and v respectively.Iii handled in 0 ℃ of THF with NaH (step b) is reacted at 0 ℃ with electrophilic reagent then, obtains compound i v to room temperature.
Although above describe and described some exemplary embodiment, but will be appreciated that The compounds of this invention can use suitable raw material, be prepared according to methods known in the art with this paper.For example, in some embodiments, R wherein 1Be hydrogen, R 2The exemplary embodiment that is the compound described herein of pyrazolyl can be referring to WO 02/22607, WO 02/22604, WO 02/066461, WO 02/22601, WO 02/22603, WO 02/22608, WO 02/022605 or WO 02/22602.
5. purposes, preparation and administration
Pharmaceutically acceptable composition
Just as discussed above, the invention provides such compound, they are the voltage-gated sodium-ion channel and/or the inhibitor of calcium channel, thereby these compounds 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, in another aspect of this invention, provide pharmaceutically acceptable composition, wherein these compositions comprise compound as described herein arbitrarily, randomly comprise pharmaceutically acceptable carrier, auxiliary agent or vehicle.In some embodiments, these compositions randomly further comprise one or more other treatment agent.
Will be appreciated that also 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 voltage-gated sodium-ion channel or the inhibitor of calcium 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, 2-hydroxyl-esilate, 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 mentioned 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.Re minute gton ' s Pharmaceutical Sciences, SixteenthEdition, E.W.Ma room temperature in (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 worthless 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, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, nerve root pain, sciatica, back pain, head or neck pain, seriousness or intractable pain, nociception pain, breakthrough pain, post-operative pain or cancer pain or alleviate the method for its seriousness comprise that the patient to this treatment of needs gives the compound of significant quantity or the pharmaceutically acceptable composition of inclusion compound.In some embodiments, acute, chronic, neuropathic or inflammatory pain of treatment is provided or alleviates the method for its seriousness, comprise that the patient to this treatment of needs gives the compound of significant quantity or the pharmaceutically acceptable composition of inclusion compound.In some other embodiment, the method for the treatment of nerve root pain, sciatica, back pain, head pain or cervical pain or alleviating its seriousness is provided, comprises that the patient to this treatment of needs gives the compound of significant quantity or the pharmaceutically acceptable composition of inclusion compound.In other embodiments, the method for the treatment of seriousness or intractable pain, acute pain, post-operative pain, back pain or cancer pain or alleviating its seriousness is provided, comprises that the patient 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, 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 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, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, nerve root pain, sciatica, back pain, head or neck pain, seriousness or intractable pain, nociception pain, breakthrough pain, post-operative pain or cancer pain 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 situation, infection, the 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 pharmaceutical units 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 injectable formulation according to known technique, for example the water-based of sterile injectable or oiliness suspension.Sterile injectable preparation 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 fixed 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 microemulsion.
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 macromolecule 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 randomly contain opalizer, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, randomly 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 macromolecule 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 randomly contain opalizer, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, randomly 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 general description the 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.In other embodiments, The compounds of this invention can be used as NaV1.8 and a kind of TTX-susceptibility ionic channel, for example double inhibitors of NaV1.3 or NaV1.7.
Also will be appreciated that, 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.Be used in that specific therapy (therapeutical agent or program) combination in the scheme for combining will be considered required therapeutical agent and/or program and the tolerability of the required result of treatment that will reach.Will be appreciated that also used therapy can reach required effect (for example, The compounds of this invention can be used for the treatment of the medicine administration simultaneously of same illness with another kind) to same illness, 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.For example, exemplary other therapeutical agent includes but not limited to: non-OPIOIDS pain killer (indoles, for example R-ETODOLAC, INDOMETHACIN, sulindac, tolmetin; Naphthyl alkane ketone, for example nabumetone; Former times the health class, piroxicam for example; Right-p-aminophenol derivative, paracetamol for example; Propionic acid class, for example fenoprofen, flurbiprofen, Ibuprofen BP/EP, Ketoprofen, Naproxen Base, naproxen sodium, Taisho); Salicylic acid, for example acetylsalicylic acid, choline magnesium three salicylates, diflunisal; Fragrant that acids, for example meclofenamic acid, mefenamic acid; And pyrazoles, for example Phenylbutazone); Or OPIOIDS agonist (narcotic) (for example morphine monomethyl ether, fentanyl, hydromorphone, levorphanol, Pethidine, methadone, morphine, oxycodone, oxymorphone, the third oxygen sweet smell, buprenorphine, butorphanol, Wy-16225, nalbuphine and pentazocine).In addition, can utilize no medicine pain relieving method to combine with the administration of one or more The compounds of this invention.For example, can also utilize narcology (infusion, nerve block in the backbone), neurosurgery (neurolysis of CNS approach), nerve stimulation (transcutaneous electrical neural stimulation, backbone stimulate), physical property (physiatrics, apparatus for correcting, transthermia) or psychology (cognitive approach-hypnosis, biofeedback or behavioral approach) method.Suitable in addition therapeutical agent or method general description are at The Merck Manual, Seventeenth Edition, Ed.Mark H.Beersand Robert Berkow, Merck Research Laboratories, 1999 and the Foodand Drug Administration network address Www.fda.govIn, its full content is quoted at this as a reference.
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 applies 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 randomly further be covered by the top layer of the fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its combination that are fit to, 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 the research of sodium-ion channel in biology and pathology phenomenon; Comparative assessment with new sodium-ion channel inhibitor.
Embodiment
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.
" min " expression of Chu Xianing in an embodiment " minute ", " h " expression " hour ", " rt " expression " room temperature ", " aq. " expression " aqueous solution ".
Embodiment
Synthesizing of exemplary The compounds of this invention
Embodiment 1
Figure G2004800119814D04211
On liquid is housed in the 2L three neck round-bottomed flasks of agitator and reflux exchanger, with anthranilamide 1 (20.0g, 147mmol) and salt of wormwood (28.4g 206mmol) is suspended in the 1L anhydrous diethyl ether, is heated to backflow.Mixture in refluxing slowly add neighbour-anisyl chloride (32.5g, 191mmol).Reflux after 3 hours, make reaction mixture be cooled to room temperature, under reduced pressure remove ether, the gained resistates is filtered, wash with water.Then with the gained solid suspension in 600ml 5%NaOH aqueous solution solution, seethed with excitement 1 hour.Make reaction be cooled to room temperature, with the acetate neutralization, be settled out quinazolinone 2 then.Filter to collect product 2, wash with water, dried overnight in a vacuum, obtain 27g (73%) pure 2.
LC/MS (10-99%) M/Z 253.0 retention time 3.22min; 1H (DMSO) 3.86 (s, 3H), 7.09 (t, 1H), δ 7.18 (d, 1H), δ 7.53 (m, 2H), δ 7.70 (m, 2H), δ 7.80 (m, 1H), δ 8.14 (d, 1H), δ 12.11 (s, 1H); 13C NMR (DMSO) δ 55.75, δ 111.86, and δ 120.89, and δ 120.97, and δ 122.74, and δ 125.75, and δ 126.45, and δ 127.26, and δ 130.41, and δ 132.13, and δ 134.32, and δ 148.97, and δ 152.48, and δ 157.12, and δ 161.35
Figure G2004800119814D04214
In the 1L round-bottomed flask of reflux exchanger was housed, (20.0g 79.3mmol) was suspended in the 500mL dry-out benzene with quinazolinone 2.Add N, (14.4g 119mmol), will be reflected under the nitrogen and reflux 30 minutes accelerine.After being cooled to room temperature, (12.2g 79.3mmol), refluxed reaction mixture other 3 hours then under nitrogen to add phosphoryl chloride.Mixture is cooled to room temperature, is poured on ice, neutralize with saturated sodium bicarbonate aqueous solution.Then solution is extracted four times with toluene, merge organic layer,, filter, be concentrated into red-brown solid in a vacuum through dried over mgso.Gained 4-chloro-quinazoline 3 obtains 20g (93%) 3 through purification by flash chromatography (40% hexane, 60% methylene dichloride), is yellow solid.
LC/MS (40-99%) M/Z 271.4 retention time 2.49min; 1H NMR (CDCl 3) 3.89 (s, 3H),
Figure G2004800119814D04222
7.06 (d, 1H), δ 7.09 (d, 1H), δ 7.45 (m, 1H), δ 7.71 (m, 1H), δ 7.80 (m, 1H), δ 7.95 (m, 1H), δ 8.17 (d, 1H), δ 8.30 (d, 1H); 13C NMR (CDCl 3) δ 56.3 (d), δ 112.15 (d), δ 121.0 (s), δ 122.29 (s), δ 125.97 (s), δ 126.76 (s), δ 127.25 (d), δ 128.71 (d), δ 132.10 (m), δ 135.26 (s), δ 151.16 (s), δ 158.19 (s), δ 161.02 (s), δ 162.58 (s).
Under nitrogen, (5.00g is 18.5mmol) with the 80ml anhydrous methylene chloride to add 4-chloro-quinazoline 3 to the 500mL two neck round-bottomed flasks that addition funnel is housed.Mixture is cooled to-78 ℃, drips the dichloromethane solution of 92ml 1M boron tribromide via addition funnel.Remove cooling bath, will react and at room temperature stir 3 hours.Mixture is cooled to 0 ℃ then, slowly, uses dichloromethane extraction 3 times, merge organic solution,, filter, be concentrated into yellow solid in a vacuum through dried over mgso with the saturated sodium bicarbonate aqueous solution neutralization.Resistates is dissolved in 2: 1 anhydrous THF/CH of 30ml rapidly 2Cl 2, use THF solution (46.3ml, 92.5mmol) processing of 2M dimethylamine then.After 30 minutes, under reduced pressure remove and desolvate, resistates is distributed between methylene dichloride and water, aqueous solution dichloromethane extraction 4 times.Merge organic solution,, filter, be concentrated into orange solids in a vacuum through dried over mgso.Recrystallization from ethanol obtains 2.61g (53%) yellow crystal 4.
LC/MS (10-99%) M/Z 266.0 retention time 2.59min; 1H NMR (DMSO)
Figure G2004800119814D04224
(3.32 s),
Figure G2004800119814D04225
3.45 (s, 6H), δ 6.93 (m, 2H), δ 7.35 (m, 1H), δ 7.46 (m, 1H), δ 7.78 (m, 2H), δ 8.21 (d, 1H), δ 8.43 (d, 1H); 13C NMR (DMSO) δ 41.62,113.77,117.18,118.25,118.97,124.75,126.15,126.51,128.96,132.36,133.11,149.09,159.22,160.74,161.69.
HCl salt:
(1.0g 3.8mmol), 100ml anhydrous diethyl ether, 11ml anhydrous methanol, with the dividing plate sealing, places sound wave processor then, bathes 43 ℃ of temperature to add quinazoline 4 to the 250mL round-bottomed flask.4 fully after the dissolving, and (1.9ml 3.8mmol), causes 5 precipitation immediately to add 2M ether system HCl solution.Remove in a vacuum and desolvate, salt is resuspended in the anhydrous diethyl ether twice, concentrate, dry in a vacuum.Under vacuum, after the dried overnight, obtain 1.13g (98%) 5, be faint yellow solid.
M/Z 266.0 retention time 2.59min; 1H NMR (DMSO) 3.59 (s, 6H), δ 7.02 (m, 1H), δ 7.19 (d, 1H), δ 7.49 (m, 1H), δ 7.64 (m, 1H), δ 7.96 (m, 1H), δ 8.05 (d, 1H), δ 8.20 (d, 1H), δ 8.35 (d, 1H); 13C NMR (DMSO) δ 42.37,112.07,117.19,119.23,121.09,126.15,127.48,130.45,134.01,134.67,155.37,158.61,160.97.
Closing of embodiment 2:2-(2-methoxyl group-phenyl)-7-trifluoromethyl-3H-quinazoline-4-one Become
2-(2-methoxyl group-benzamido)-4-trifluoromethyl-phenylformic acid: with 2-amino-4-trifluoro-benzoic acid (3.84g, 18.73mmol) be dissolved in 30ml anhydrous 1, the 4-diox, succeeded by slow adding neighbour-anisyl chloride (3.3ml, 24.35mmol), be that (7.85ml 56.19mmol), stirred 2 hours under the nitrogen atmosphere room temperature triethylamine then.Under reduced pressure remove and desolvate, organism is distributed between water and Et OAc, regulate pH to 3 with HCl.Separate organic layer, through MgSO 4Drying is filtered, and is concentrated into pale solid.Reclaim 6.35g, yield 100%.LC/MS (10-99) %M/Z 339.9, retention time 3.58 minutes.
2-(2-methoxyl group-benzamido)-4-trifluoromethyl-benzamide: with 2-(2-methoxyl group-benzamido)-4-trifluoromethyl-phenylformic acid (7.04g, 20.77mmol) be suspended in 1 of 0.5M ammonia, 4-dioxane solution (125ml, 62.31mmol) in, (5.78ml 41.54mmol), is bop reagent (12g then succeeded by adding triethylamine, 27.0mmol), at room temperature stirred 16 hours.Product is collected in vacuum filtration, washes with water.With required product on lyophilizer dry 24 hours.Reclaim 3.8g, be white solid.LC/MS (10-99%) M/Z 339.1, retention time 2.93 minutes.
Figure G2004800119814D04241
2-(2-methoxyl group-phenyl)-7-trifluoromethyl-3H-quinazoline-4-one: with 2-(2-methoxyl group-benzamido)-4-trifluoromethyl-benzamide (3.8g, 11.24mmol) be suspended in the 145ml 5%NaOH aqueous solution, refluxed 3 hours down at 120 ℃ then.Reaction is cooled to room temperature, regulates pH 4, cause required product from solution, to be precipitated out.Solid is collected in vacuum filtration, is white solid, and drying is 24 hours on lyophilizer.White solid 2.7g, yield 75%.LC/MS (10-99%) M/Z 321.1, retention time 3.25 minutes.
Synthesizing of 2-(2-methoxyl group-phenyl)-7-methyl-3H-quinazoline-4-one
Figure G2004800119814D04242
N-(2-cyano group-5-methyl-phenyl)-2-methoxyl group-benzamide: (50.0g 378.3mmol) is dissolved in the 1L anhydrous pyridine, is cooled to 0 ℃ with 2-amino-4-methyl benzonitrile.(63.0ml 453.96mmol), makes reaction be warming up to room temperature, stirs 16 hours under nitrogen atmosphere to go through 40 minutes dropping neighbour-anisyl chlorides.Reaction is poured on 2L on ice, and product generates precipitation.Product is collected in vacuum filtration, and dry 3 days, obtain required product, be fine hair shape tawny solid.Reclaim 92.0g, yield 91%.LC/MS (10-99%) M/Z 267.2, retention time 3.34 minutes.
2-(2-methoxyl group-phenyl)-7-methyl-3H-quinazoline-4-one: with N-(2-cyano group-5-methyl-phenyl)-2-methoxyl group-benzamide (47.0g, 176.5mmol) be suspended in the 1L ethanol, succeeded by adding the 6M NaOH aqueous solution (326ml), be 30%H then 2O 2Solution (100ml).To react and reflux 3 hours, be cooled to room temperature, be poured on equal-volume on ice.Solution is adjusted to pH3.5, and product is precipitated out from solution.Required product is collected in vacuum filtration, and drying is 24 hours on lyophilizer.22.4g, yield 48%.LC/MS (10-99%) M/Z 267.0, retention time 2.54 minutes.
5-fluoro-4-methyl-anthranilic acid
2-amino-5-fluoro-4-methyl-phenylformic acid: (76g) is dissolved in 1L water with Chloral Hydrate, adds 1kg Na subsequently 2SO 4, 94.1g H 2The 250ml5%HCl aqueous solution of NOHHCl and 51.3g 4-fluoro-3-monomethylaniline.Suspension is heated to boiling, keeps boiling 1 minute.After being cooled to room temperature, leach solid, with warm water (40 ℃) washed twice.Obtaining 275g after the dried overnight under 60 ℃ of vacuum, need not to be further purified or drying can be used.The 275g crude product slowly poured into 50 ℃ the dense H of 500mL 2SO 4, so that keep temperature to be lower than 75 ℃.After adding is finished, deep purple solution is heated to 85 ℃ reaches 15 minutes.After being cooled to room temperature, solution is poured in the 2L frozen water, placed half an hour.Red solid is filtered, use twice of cold water washing.Subsequently, drying solid under 70 ℃ of vacuum.The mixture of two kinds of regional isomers of yield: 69.9g (counting quantitatively): 5-fluorine and 3-fluoro-3-methyl-isatin, about 55: 45 of ratio from 4-fluoro-3-monomethylaniline.Isatin mixture (69.4g) is dissolved in the 1L 1N NaOH aqueous solution, drips 100ml 30%H subsequently 2O 2The aqueous solution keeps temperature to be lower than 30 ℃.Add finish after, with mixture heating up to 45 ℃, emit until gas and to stop.Solution is cooled to room temperature, filters, use the glacial acetic acid acidifying.Leach the precipitation that is generated, wash with water twice, 45 ℃ air-dry.Yield: 29.4g 5-fluoro-4-methyl anthranilic acid iii.
2-amino-5-trifluoromethyl-phenylformic acid: with 4-(trifluoromethyl) aniline (25g 0.15mol) is dissolved in THF (257ml), use then the Boc acid anhydrides (41g, 0.19mol), Et 3N (19g, 0.19mol) and 4-(dimethylamino) pyridine (0.1g 0.8mmol) handles.Mixture was refluxed 3 hours, remove in a vacuum and desolvate, organic residue is dissolved in EtOAc, dry then with 1M NaOH, 1M HCl washing then, concentrate.Make products therefrom recrystallization from heptane, obtain the 39g end product, be white solid.Solid (0.15mol) is dissolved in THF (350ml), is cooled to-78 ℃ under nitrogen, (1.6M hexane solution, 282ml 0.45mol) dropwise handle to use BuLi then.After 1 hour, solution is warming up to 0 ℃, kept 1.5 hours.Mixture is poured on excessive solid CO 2On, at room temperature stir and spend the night.After 1M HCl distribution, evaporation THF layer is dissolved in EtOAc with resistates, and is with 1M HCl washing, dry then, concentrated.Solid product is developed with hexane, obtained end product, be white solid (15.8g).LC/MS retention time 2.70 minutes, and m/z (obs, M-H)=304.1.At last, Boc cinnamyl o-aminobenzoate (11.3g) is dissolved in CH 2Cl 2(26ml), handle with TFA (21ml).After at room temperature stirring 2 hours, drying solution is dissolved in toluene (100ml) with the gained resistates in a vacuum, is concentrated into dried, repeat dissolving/drying process again twice, obtain required product, be white solid (10.8g), LC/MS retention time 1.2 minutes, and m/z (obs, M-H)=204.0.
2-amino-5-bromo-benzamide: (15g is 0.062mol) with 1M NH with isatoic anhydride 4The OH aqueous solution (340ml) merges, and at room temperature stirs 2 days.Solid collected by filtration product, dry (6.6g) in a vacuum.LC/MS retention time 2.47 minutes, m/z obs=215.2.
In the 500mL three neck round-bottomed flasks that magnetic stirrer and reflux exchanger are housed, to the benzoylene urea 1 that is stirring (10.0g, 61.7mmol) with the disposable adding N of suspension of phosphoryl chloride (20ml), accelerine (7.80ml, 61.7mmol).Suspension was heated 3 hours under refluxing, slowly form light red solution.Under reduced pressure concentrated solution is poured on resistates on the ice (100g).Solution alkalizes 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.Resistates is dissolved in anhydrous THF (75ml), is cooled to 0 ℃.Go through dripping xylidine (67.7ml, 135mmol, 2.0M THF solution) in 30 minutes, stir simultaneously.Then solution was stirred 1 hour down at 0 ℃.Concentrated solution under reduced pressure, resistates with (70% hexane, 30% ethyl acetate) wash-out, obtain 2 (7.90g, 38.1mmol, 62% yields) through the silica gel chromatography purifying, are white solid.
1H NMR(CDCl 3)
Figure G2004800119814D04272
3.43(s，6H)，7.40(t，1H)，7.69(t，1H)，7.78(d，1H)，8.02(d，1H)；M+1(obs)＝208.0；R t＝2.26.
Add 2 (100mg to 5mL microwave reaction container, 0.48mmol), 2-anisole ylboronic acid (96mg, 0.63mmol), four (triphenyl phosphine) palladium (0) (55mg, 0.048mmol), yellow soda ash (1.20ml, 0.48mmol, the 0.40M aqueous solution) with the mixture of acetonitrile (1.20ml).With container sealing, heated 10 minutes down at 170 ℃ via microwave radiation, stir simultaneously.Under reduced pressure concentrate organic moiety, resistates with (80% hexane, 20% ethyl acetate) wash-out, obtains 3 (120mg, 0.43mmol, 89% yields) through the silica gel chromatography purifying, is white solid.
1H NMR(CDCl 3)
Figure G2004800119814D04274
3.32(s，6H)，3. (s，3H)，6.89-7.02(m，2H)，7.28-7.34(m，2H)，7.62(t，1H)，7.75(d，1H)，7.89(d，1H)，7.95(d，1H)；M+1(obs)＝280.2；R t＝2.46.
2-chloro-4-dimethylamino quinazoline-7-carboxylic acid methyl ester: at N 2Down, with stirring 2,4-dioxo-1,2,3,4-tetrahydrochysene-quinazoline-7-carboxylic acid methyl ester (12.2g, 55.4mmol), N, accelerine (14.0ml, 110.8mmol) and POCl 3Suspension (25ml) heated 15 minutes down at 100 ℃.Vapourisation under reduced pressure solution is poured residual oil in the frozen water (800ml) into to doing.Add the 50%NaOH aqueous solution down at 0 ℃, making mixture is strong basicity.Make mixture at CH 2Cl 2With H 2Distribute between the O, the organic moiety vapourisation under reduced pressure is extremely done.Resistates with 70% hexane/30%EtOAc wash-out, obtains the intermediate muriate through the silica gel chromatography purifying, for white solid (5.1g, 19.8mmol).The gained intermediate is dissolved in CH 2Cl 2(100ml).Solution is cooled to 0 ℃, succeeded by adding Et 3N (5.5ml, 39.6mmol) and Dimethylammonium chloride (1.6g, 19.8mmol).Then mixture was stirred 30 minutes down at 0 ℃.Mixture is evaporated to dried, the gained resistates with 70% hexane/30%E tOAc wash-out, obtains required amine via the silica gel chromatography purifying, is white solid (3.3g, 12.4mmol, 11% yield).LC/MS (10-99%) M/Z 268.0, retention time 2.85 minutes.
6-fluoro-N4, N4-dimethyl quinazoline-2, the 4-diamines: (2-chloro-6-fluoro-quinazoline-4-the yl)-dimethyl amine that will stir (50mg, 0.22mmol), two (trimethylsilyl) Lithamide (260 μ L, 0.26mmol, 1.0M hexane solution), Pd 2(dba) 3(20mg, 0.022mmol), 2-(dicyclohexyl) phosphino-biphenyl (19mg, 0.053mmol) with the mixture of THF (1.0ml) in the test tube of sealing via microwave radiation 65 ℃ of heating 1.5 hours down.Add the 1.0N HCl aqueous solution (3.0ml), mixture was at room temperature stirred 30 minutes.Make mixture at H 2Distribute between O and the EtOAc.The organic moiety vapourisation under reduced pressure is extremely done.The gained resistates is used 95%CH via the silica gel chromatography purifying 2Cl 2/ 5%MeOH wash-out obtains required amine, is tawny solid (40mg, 19.4mmol, 88% yield).LC/MS (10-99%) M/Z 206.9, retention time 1.18 minutes.
Figure G2004800119814D04291
1-(4-dimethylamino-6-fluquinconazole quinoline-2-yl)-tetramethyleneimine-2,5-diketone: the 6-fluoro-N4 that will stir, N4-dimethyl quinazoline-2,4-diamines (30.0mg, 0.13mmol), succinyl oxide (12mg, 0.12mmol) with to the mixture of-dioxs (500 μ L) in the sealing test tube via microwave radiation 170 ℃ of heating 20 minutes down.Mixture obtains required succinate via the HPLC purifying, is tfa salt (40mg, 0.10mmol, 76% yield).LC/MS (10-99%) M/Z289.3, retention time 2.01 minutes.
1-(6-fluoro-4-tetramethyleneimine-1-base-quinazoline-2-yl)-pyrrolidin-2-one: the 6-fluoro-4-tetramethyleneimine-1-base-quinazoline that will stir-2-base amine (30.0mg, 0.14mmol), the 4-chlorobutanoylchloride (17 μ L, 0.15mmol), Et 3N (42 μ L, 0.30mmol) with to the mixture of-dioxs (500 μ L) in the sealing test tube via microwave radiation 170 ℃ of heating 20 minutes down.Mixture obtains required lactan via the HPLC purifying, is tfa salt (45mg, 0.11mmol, 81% yield).LC/MS (10-99%) M/Z 301.2, retention time 2.24 minutes.
Figure G2004800119814D04293
1-(4-dimethylamino-6-fluoro-quinazoline-2-yl)-1H-pyrroles-3-formaldehyde: the 6-fluoro-N4 that will stir, N4-dimethyl quinazoline-2,4-diamines (20.0mg, 0.10mmol), 2, (43 μ L, 0.30mmol) mixture with AcOH (500 μ L) heated 30 minutes down at 90 ℃ 5-dimethoxy-3-tetrahydrofuran (THF) aldehyde.Mixture is evaporated to dried, the gained resistates with 70% hexane/30%EtOAc wash-out, obtains required aldehyde via the silica gel chromatography purifying, is white solid (15mg, 0.05mmol, 50% yield).LC/MS (10-99%) M/Z 285.1, retention time 3.23 minutes.
(6-methoxyl group-2-pyrroles-1-base-quinazoline-4-yl)-dimethyl-amine: at N 2Down, (310mg, DMF 4.6mmol) (5.0ml) solution adds NaH (170mg, 4.2mmol, 60% mineral oil) to the pyrroles who is stirring.Mixture was at room temperature stirred 10 minutes.To this solution add (2-chloro-6-methoxyl group quinazoline-4-yl) dimethyl amine (1.0g, 4.2mmol).Mixture was heated 20 minutes down at 220 ℃ via microwave radiation in the sealing test tube.Mixture is evaporated to dried, the gained resistates with 70% hexane/30%EtOAc wash-out, obtains required aldehyde via the silica gel chromatography purifying, is white solid (15mg, 0.05mmol, 50% yield).LC/MS (10-99%) M/Z 269.0, retention time 2.39 minutes.
Figure G2004800119814D04301
[2-(2-chloro-pyrroles-1-yl)-6-methoxyl group quinazoline-4-yl] dimethyl-amine: at N 2Down, to (6-methoxyl group-2-pyrroles-1-base-quinazoline-4-yl) dimethyl-amine that is stirring (25mg, THF 0.09mmol) (2.0ml) solution add N-chloro-succinimide (13mg, 0.09mmol).Solution was at room temperature stirred 17 hours.Mixture obtains required chloro pyrroles via the HPLC purifying, is tfa salt (23mg, 0.06mmol, 62% yield).LC/MS (10-99%) M/Z 303.0, retention time 2.71 minutes.
Figure G2004800119814D04302
2-[4-(4-amino piperidine-1-yl)-7-methyl quinazoline-2-yl]-phenol: at N 2Down, to the 2-that is stirring (4-chloro-7-methyl quinazoline-2-yl)-phenol (100mg, 0.35mmol), Et 3N (72 μ L, 0.52mmol) and CH 2Cl 2The solution adding 4-amino piperidine of (300 μ L) (54 μ L, 0.52mmol).Mixture was at room temperature stirred 2 hours.The mixture vapourisation under reduced pressure is extremely done.Resistates is used 98%CH through the silica gel chromatography purifying 2Cl 2/ 2%MeOH wash-out obtains required amine, is white solid (11mg, 0.31mmol, 89% yield).LC/MS (10-99%) M/Z 349.3, retention time 2.22 minutes.
Figure G2004800119814D04311
Ethyl sulfonic acid 1-[2-(2-hydroxy phenyl)-7-methyl quinazoline-4-yl]-piperidin-4-yl }-acid amides: at N 2Down, to the 2-[4-that is stirring (4-amino piperidine-1-yl)-7-methyl quinazoline-2-yl]-phenol (30mg, 0.09mmol), Et 3N (25 μ L, 0.18mmol) and CH 2Cl 2The solution adding ethyl sulfonyl chloride of (500 μ L) (10 μ L, 0.09mmol).Mixture was at room temperature stirred 3 hours.Mixture obtains required sulphonamide via the HPLC purifying, is tfa salt (33mg, 0.06mmol, 68% yield).LC/MS (10-99%) M/Z 427.3, retention time 2.80 minutes.
3-{1-[2-(2-hydroxy phenyl)-7-methyl quinazoline-4-yl]-piperidin-4-yl }-1,1-dimethyl methyl uride: at N 2Down, to the 2-[4-that is stirring (4-amino piperidine-1-yl)-7-methyl quinazoline-2-yl]-phenol (35mg, 0.11mmol), Et 3N (30 μ L, 0.22mmol) and CH 2Cl 2The solution adding dimethylamino SULPHURYL CHLORIDE of (300 μ L) (12 μ L, 0.11mmol).Mixture was at room temperature stirred 17 hours.Mixture obtains required sulfonylurea via the HPLC purifying, is tfa salt (44mg, 0.08mmol, 71% yield).LC/MS (10-99%) M/Z 442.4, retention time 2.84 minutes.
Figure G2004800119814D04321
1-[2-(2-hydroxy phenyl)-7-methyl quinazoline-4-yl]-piperidin-4-yl }-the carboxylamine isobutyl: at N 2Down, to the 2-[4-that is stirring (4-amino piperidine-1-yl)-7-methyl quinazoline-2-yl]-phenol (30mg, 0.09mmol), Et 3N (25 μ L, 0.18mmol) and CH 2Cl 2The solution adding isobutyl chlorocarbonate of (300 μ L) (12 μ L, 0.09mmol).Mixture was at room temperature stirred 1 hour.Mixture obtains requisite carbamate via the HPLC purifying, is tfa salt (27mg, 0.05mmol, 58% yield).LC/MS (10-99%) M/Z 435.2, retention time 3.21 minutes.
Isobutylamino formic acid 1-[2-(2-hydroxy phenyl)-7-methyl quinazoline-4-yl]-the piperidin-4-yl ester: at N 2Down, to the 1-[2-that is stirring (2-p-methoxy-phenyl)-7-methyl quinazoline-4-yl]-(100mg, THF 0.30mmol) (500 μ L) solution adds phosgene (317 μ L, 0.60mmo l, 20% toluene solution) to piperidines-4-alcohol.Mixture was at room temperature stirred 15 minutes.Go through dripped in 2 minutes isobutylamine (300 μ L, 3.0mmol), succeeded by at room temperature stirring 1 hour.Mixture is evaporated to dried, the gained resistates is used 97%CH via the silica gel chromatography purifying 2Cl 2/ 3%MeOH wash-out obtains the requisite carbamate intermediate, for clarifying oil (90mg, 0.20mmol).At N 2Under-78 ℃, go through carbamate intermediate (90mg, CH 0.20mmol) that 2 fens clockwise is stirring 2Cl 2(15ml) solution drips BBr 3(0.60ml, 0.60mmol, 1.0M CH 2Cl 2Solution).Make mixture be warming up to room temperature then, heated 15 minutes down at 50 ℃ then.Pour mixture into saturated NaHCO 3In the aqueous solution (80ml), organic moiety is evaporated to dried.Resistates obtains requisite carbamate via the HPLC purifying, is tfa salt (66mg, 0.12mmol, 39% yield).LC/MS (10-99%) M/Z 435.3, retention time 3.08 minutes.
N-{1-[2-(2-hydroxyl-phenyl)-7-methyl quinazoline-4-yl]-piperidin-4-yl }-3-methylbutyryl amine: at N 2Down, to the 2-[4-that is stirring (4-amino piperidine-1-yl)-7-methyl quinazoline-2-yl]-phenol (35mg, 0.11mmol), Et 3N (30 μ L, 0.22mmol) and CH 2Cl 2The solution adding isoveryl chloride of (300 μ L) (14 μ L, 0.11mmol).Mixture was at room temperature stirred 17 hours.Mixture obtains required sulphonamide via the HPLC purifying, is tfa salt (37mg, 0.07mmol, 59% yield).LC/MS (10-99%) M/Z 419.3, retention time 2.77 minutes.
Synthesizing of 2-(4-oxyethyl group-quinazoline-2-yl)-phenol
Figure G2004800119814D04332
2-(4-oxyethyl group-quinazoline-2-yl)-phenol: (50mg 0.196mmol) places the microwave tube that agitator arm is housed, and is dissolved in the 0.5ml anhydrous methylene chloride, succeeded by adding the 2ml dehydrated alcohol with 2-(4-chloro-quinazoline-2-yl)-phenol.With the pipe sealing of lid, in the CEM microwave, heated 1 hour down at 160 to 200 ℃.Under reduced pressure remove and desolvate, in DMSO, reclaim organism, through Gilson HPLC purifying.Required compound is concentrated into white solid, is tfa salt.LC/MS (10-99%) M/Z 267.2, retention time 2.57 minutes.
Synthesizing of 2-(4-dimethylamino-quinazoline-2-yl)-6-methyl-phenol
Figure G2004800119814D04341
[2-(2-methoxyl group-3-methyl-phenyl)-quinazoline-4-yl]-dimethyl-amine: under argon atmospher and-78 ℃, to [2-(2-methoxyl group-phenyl)-quinazoline-4-yl]-dimethyl-amine (200mg that is stirring, 0.72mmol) anhydrous THF solution drip 1.6M nBuLi hexane solution (0.671ml, 1.074mmol).After 10 minutes, (0.076ml 1.22mmol), makes reaction be warming up to room temperature to add MeI.After at room temperature 10 minutes, use saturated NH 4Cl aqueous solution quencher reaction distributes between water and EtOAc.Separate organic phase, through MgSO 4Drying is filtered, and is concentrated into xanchromatic oil.Through purification by flash chromatography, with 10%EtOAc/90% hexane wash-out, obtain product, be white solid.Reclaim 146mg, yield 50%.LC/MS (10-99%) M/Z294.0, retention time 3.23 minutes.
Figure G2004800119814D04342
2-(4-dimethylamino-quinazoline-2-yl)-6-methyl-phenol: under-78 ℃ of nitrogen atmosphere, to [2-(2-methoxyl group-phenyl)-quinazoline-4-yl]-dimethyl-amine (54mg, CH 0.184mmol) that is stirring 2Cl 2Solution adds BBr 3(0.92ml, 0.92mmol).Make reaction be warming up to room temperature, heated 4 hours down at 45 ℃.Make reaction be cooled to room temperature, use NaHCO then 3Aqueous solution quencher is until pH 8.Separate organic layer, through MgSO 4Drying is filtered, and is concentrated into yellow solid.Through Gilson HPLC purifying, separate required product, be tfa salt.LC/MS (10-99%) M/Z 280.2, retention time 2.55 minutes.
Synthesizing of 2-(4-dimethylamino-quinazoline-2-yl)-4-morpholine-4-base-phenol
[2-(2-methoxyl group-5-morpholine-4-base-phenyl)-quinazoline-4-yl]-dimethyl-amine: add Pd to the test tube that agitator arm is housed 2(dba) 3(51.1mg, 0.0558mmol), biphenyl-2-base-di-t-butyl-phosphine (67mg, 0.223mmol), NaOtBu (80mg, 0.837mmol) the 2ml anhydrous toluene solution, add 4-bromo-2-(4-dimethylamino-quinazoline-2-yl)-phenol (200mg, 0.558mmol) and morpholine (0.073ml, 0.837mmol).To react with the nut sealing, heating is 16 hours in 100 ℃ of oil baths.Through purification by flash chromatography, with 30%-60%EtOAc/ hexane wash-out, obtain product, be white solid.Reclaim 100mg, 49% yield.LC/MS (10-99%) M/Z 365.0, retention time 2.07 minutes.
Figure G2004800119814D04352
2-(4-dimethylamino-quinazoline-2-yl)-4-morpholine-4-base-phenol: under-78 ℃ of nitrogen atmosphere, to [2-(2-methoxyl group-5-morpholine-4-base-phenyl)-quinazoline-4-yl]-dimethyl-amine (109mg, CH 0.299mmol) that is stirring 2Cl 2Solution adds BBr 3(1.5ml, 1.5mmol).Make reaction be warming up to room temperature, heated 2 hours down at 40 ℃.Use NaHCO 3Aqueous solution quencher reaction is until pH 8.Separate organic layer, through MgSO 4Drying is filtered, and is concentrated into yellow solid.Through Gilson HPLC purifying, separate required product, be tfa salt.LC/MS (10-99%) M/Z 351.4, retention time 1.89 minutes.
Synthesizing of 2-(4-dimethylamino-quinazoline-2-yl)-4-methyl-phenol
Figure G2004800119814D04361
[2-(2-methoxyl group-5-methyl-phenyl)-quinazoline-4-yl]-dimethyl-amine: under argon atmospher and-78 ℃, to [2-(the 5-bromo-2-methoxyl group-phenyl)-quinazoline-4-yl]-dimethyl-amine (200mg that is stirring, 0.558mmol) anhydrous THF solution drip 1.6M nBuLi hexane solution (0.76ml, 1.23mmol).After 10 minutes, (0.054ml 1.23mmol), makes reaction be warming up to room temperature to add Me I.After at room temperature 10 minutes, use saturated NH 4Cl aqueous solution quencher reaction distributes between water and EtOAc.Separate organic phase, through MgSO 4Drying is filtered, and is concentrated into xanchromatic oil.Through purification by flash chromatography, with 30%EtOAc/70% hexane wash-out, obtain product, be white solid.Reclaim 146mg, yield 89%.LC/MS (10-99%) M/Z 294.4, retention time 2.64 minutes.
Figure G2004800119814D04362
2-(4-dimethylamino-quinazoline-2-yl)-4-methyl-phenol: under-78 ℃ of nitrogen atmosphere, to [2-(2-methoxyl group-5-methyl-phenyl)-quinazoline-4-yl]-dimethyl-amine (146mg, CH 0.498mmol) that is stirring 2Cl 2Solution adds BBr 3(2.49ml, 2.49mmol).Make reaction be warming up to room temperature, finish after 2 hours.Use NaHCO 3Aqueous solution quencher reaction is until pH8.Separate organic layer,, filter, be concentrated into yellow solid through dried over mgso.Through the GilsonHPLC purifying, separate required product, be tfa salt.LC/MS (10-99%) M/Z 280.2, retention time 2.65 minutes.
2-(2 '-methylsulfonyl phenyl)-4-dimethylamino quinazoline synthetic
2-(2 '-methylsulfonyl phenyl)-4-dimethylamino quinazoline: add 2-(2 '-bromophenyl)-4-dimethylamino quinazoline (0.020g to the individual chemical microwave reaction container that has agitator arm of 2ml; 61mmol), cupric iodide (I) (0.017g; 91mmol), (0.010g is 97mmol) with 0.5ml DMF for methyl-sulfinic acid sodium 1This mixture was shone 10 minutes down at 180 ℃.After the cooling, add entry and ether, extract.Then the ether layer is passed through diatomite filtration, use about 20%NH then 4OH extracts once more, to remove extra copper.After concentrating, product is dissolved in 50/50DMSO/MeOH solution again.On LC/MS, carry out purifying, obtain tfa salt.LC/MS (10-99%) M/Z 328.3, retention time 3.03 minutes.
2-(2 '-phenylamino)-4-dimethylamino quinazoline synthetic
2-(2 '-phenylamino)-4-dimethylamino quinazoline: under 0 ℃, to 2-(2 '-nitrophenyl)-4-dimethylamino quinazoline (0.530g, acetate 1.80mmol) (10.9ml, 190mmol) solution add zinc powder (1.18g, 18.0mmol).Reaction mixture cured, but after removing ice bath, begin once more to stir 3,4Reaction mixture was at room temperature stirred 3 hours.Add deionized water (approximately 10ml) then, form solution, succeeded by generating precipitation.Then with this solution NaHCO 3(aqueous) transfers to slight alkalinity.With product ethyl acetate extraction 3 times, use MgSO 4Drying is filtered, and concentrates.About 20mg product is dissolved in 50/50DMSO/MeOH solution again,, obtains two-tfa salt through the LC/MS purifying.LC/MS (10-99%) M/Z 265.0, retention time 2.81 minutes.
2-(2 '-ethylmercapto group phenyl)-4-dimethylamino quinazoline synthetic
Figure G2004800119814D04372
2-(2 '-the ethylmercapto group phenyl)-4-dimethylamino quinazoline: in having the microwave reaction container of agitator arm, to 2-(2 '-fluorophenyl)-4-dimethylamino quinazoline (0.020g, 0.0748mmol) N, dinethylformamide (1ml) solution adds salt of wormwood (0.052g, 0.374mmol) and sulfur alcohol (0.055ml, 0.748mmol).This mixture is used microwave irradiation 1.5 hours down at 135 ℃.The gained mixture is filtered, pass through the LC/MS purifying then, obtain tfa salt.LC/MS (10-99%) M/Z 310.2, retention time 3.27 minutes.
2-(2 '-cyano-phenyl)-4-dimethylamino quinazoline synthetic
2-(2 '-cyano-phenyl)-4-dimethylamino quinazoline: add 2-(2 '-bromophenyl)-4-dimethylamino quinazoline (0.010g to round-bottomed flask, 0.0305mmol), potassium cyanide (0.0040g, 0.0609mmol), four (triphenyl phosphine) palladium (0) (0.0018g, 0.00152mmol), cupric iodide (I) (0.00058g, 0.00305mmol) and acetonitrile (0.50ml), being heated to refluxes spends the night 5After being cooled to room temperature, add ethyl acetate, pass through diatomite filtration.Use ammonium hydroxide (about 20%) to extract then, to remove extra copper.After concentrating, product is dissolved in 50/50DMSO/MeOH solution again,, obtains tfa salt through the LC/MS purifying.LC/MS (10-99%) M/Z275.2, retention time 2.85 minutes.
2-(2 '-pseudoallyl phenyl)-4-dimethylamino quinazoline synthetic
Figure G2004800119814D04382
2-(2 '-the pseudoallyl phenyl)-4-dimethylamino quinazoline: in having the microwave container of agitator arm, to 2-(2 '-fluorophenyl)-4-dimethylamino quinazoline (0.040g, 0.150mmol) glycol dimethyl ether (1ml) solution add 0.5M bromination pseudoallyl magnesium solution (0.898ml, 0.449mmol).Sample is used microwave irradiation 5 minutes down at 170 ℃.Add deionized water (approximately 2ml) then.Extract with ether then.After concentrating, product is dissolved in 50/50DMSO/MeOH solution again,, obtains tfa salt through the LC/MS purifying.LC/MS (10-99%) M/Z289.8, retention time 3.23 minutes.
2-(2 '-hydroxy phenyl)-4-dimethylamino-6-methoxyl group quinazoline synthetic
2-(2 '-hydroxy phenyl)-4-dimethylamino-6-methoxyl group quinazoline: add 2-(2 '-acetoxyl group phenyl)-4-dimethylamino-6-bromine quinazoline (0.100g to the microwave reaction container that has agitator arm, 0.259mmol), cupric iodide (I) (0.0245g, 0.129mmol), N, dinethylformamide (0.90ml) and 0.5M sodium methylate (1.04ml, methanol solution 0.518mmol).Sample is used microwave irradiation 20 minutes down at 150 ℃.After the cooling, sample is diluted with ether, pass through diatomite filtration then.Use ammonium hydroxide (about 20%) to extract then, to remove extra copper.After concentrating, product is dissolved in 50/50DMSO/MeOH solution again,, obtains tfa salt through LC/MS purifying (20-99%).Yield=60% (LS/MS) roughly.LC/MS (10-99%) M/Z 296.4, retention time 2.31 minutes.
Synthesizing of 4-fluoro-3-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-benzoic acid methyl ester
Figure G2004800119814D04392
3-bromo-4-fluoro-benzoic acid methyl ester: with 3-bromo-4-fluoro-phenylformic acid (2.5g, 11.42mmol) place agitator arm is housed, with dividing plate sealing with place 100ml round-bottomed flask under the nitrogen atmosphere, be dissolved in anhydrous THF of 9ml and the anhydrous MeOH of 3ml.To the acid solution that stirring drip 2.0M TMS diazomethane diethyl ether solution (6.28ml, 12.56mmol).Analyze according to LC/MS, finish the conversion of acid after 20 minutes to ester.Under reduced pressure remove and desolvate, product need not to be further purified and can use.Reclaim the oil (2.66g, 100% yield) of light color.LC/MS (10-99%) M/Z 234, retention time 3.09 minutes.
4-fluoro-3-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-and benzoic acid methyl ester: add 3-bromo-4-fluorobenzoic acid methyl ester (1.66g to the round-bottomed flask that agitator arm is housed, 7.12mmol), two (tetramethyl ethylene ketone generation) two boron (2.2g, 8.5mmol), potassium acetate (2.1g, 21.3mmol) and [1,1 '-two (diphenyl phosphine) ferrocene] and palladium chloride (II)-methylene dichloride title complex (1: 1) (0.35g, 0.43mmol).To react with the dividing plate sealing, emptying places under the nitrogen atmosphere, succeeded by adding the anhydrous DMSO of 20ml.To be reflected in 80 ℃ of oil baths and heat 2 hours.Make reaction be cooled to room temperature, between ethyl acetate and water, distribute.Separate organic layer, the water layer extracting twice.Merge whole organic layers, through MgSO 4Drying is filtered, and under reduced pressure is concentrated into the oil of black.Product with EtOAc/ hexane 0 to 60% gradient elution, obtains required product through purification by flash chromatography, is white solid (1.48g, 74% yield).LC/MS (10-99%) M/Z 281.4, retention time 2.73 minutes.
(1.5g 3.0mmol) is dissolved in THF (150ml) with quinazoline 1.After being cooled to-78 ℃, and dropping t-BuLi (the 1.7M n-heptane solution, 1.76ml).After stirring 10 minutes under-78 ℃, add CO to solution 2(broken) is warming up to room temperature then, stirs 30 minutes.To react and use H 2O (100ml) quencher is with EtOAc (100ml) dilution.With the organic layer drying, concentrate, through purification by flash chromatography (1%-10%MeOH/DCM), obtain 2 (600mg, 43% yields).
2-(2 '-hydroxy phenyl)-4-dimethylamino-6-morpholino quinazoline synthetic
2-(2 '-hydroxy phenyl)-4-dimethylamino-6-morpholino quinazoline: at N 2Down, dry reaction pipe every nut in having is sequentially added into three (dibenzalacetones), two palladiums (0) (0.012g, 13.0mmol), 2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene (0.024g, 38.8mmol), cesium carbonate (0.097g, 298mmol), toluene (0.25ml), 2-(2 '-acetoxyl group phenyl)-4-dimethylamino-6-bromine quinazoline (0.050g, 129mmo l) and morpholine (23 μ L, 259mmol) 2Then this mixture heating up to 80 ℃ is reached 24 hours.After the cooling, mixture is diluted with ether,, concentrate by diatomite and filtered through silica gel.Product is dissolved in 50/50DMSO/MeOH solution again,, obtains two-tfa salt through the LC/MS purifying.LC/MS (10-99%) M/Z 351.0, retention time 2.75 minutes.
Figure G2004800119814D04411
(0.2g 0.62mmol) is dissolved in CH with quinazoline 1 3CN (5ml).Be cooled to-10 ℃ and (behind the ice/NaCl), add CCl 4, DIEA and DMAP.Stir after 10 minutes, go through the CH that slowly added phosphorous acid dibenzyl ester in 10 minutes 3CN solution (2ml).Continuation was stirred 2 hours down at-10 ℃, at room temperature stirred then 24 hours.Add 0.5M K 2HPO 4Quencher, water (15ml) dilution, with DCM (30ml) extraction, drying concentrates, and through purification by flash chromatography (100%DCM), obtains 2 (168mg, 47% yields), is colourless oil.LC/MS (10-99%) M/Z 586.0, retention time 2.54 minutes.
Under 0 ℃, to quinazoline 2 (0.168g, DCM 0.29mmol) (1.5ml) solution add TMSBr (0.079ml, 0.61mmol).To be reflected at 0 ℃ and stir 1 hour down, at room temperature stir then 1 hour.To react water (3ml) quencher, stir 15 minutes.Water layer with EtOAc (5ml) washing, is used the lyophilizer dried overnight, obtain required product 3, be white foam (0.14g, 100% yield).LC/MS (10-99%) M/Z 406.0, retention time 3.32 minutes.
At room temperature, to quinazoline 3 (0.14g, MeOH 0.36mmol) (3ml) solution add NaOMe (1.44ml, 0.72mmol).To react at room temperature to stir and spend the night.Utilize rotatory evaporator (25 ℃) concentrated reaction mixture, then with resistates water-soluble (75ml), with Et OAc washing (3x50ml).Water lyophilizer drying obtains end product 4 (0.14g, 98% yield), is solid.LC/MS (10-99%) M/Z 406.0, retention time 3.32 minutes.
2-{7-methyl-4-[methyl-(the 5-methyl-[1,3,4] oxadiazole-2-ylmethyls)-amino]-quinazoline-2-yl }-phenol
[2-(2-methoxyl group-phenyl)-7-methyl-quinazoline-4-yl]-(5-methyl-[1,3,4] oxadiazole-2-ylmethyl)-amine: with 4-chloro-2-(2-methoxyl group-phenyl)-7-methyl-quinazoline (400mg, 1.48mmol) be dissolved in the 10ml dry DMF, succeeded by adding C-(5-methyl-[1,3,4] oxadiazole-2-yl)-methylamine oxalate (234mg, 1.48mmol), be then triethylamine (413 μ L, 2.96mmol).Afterreaction was complete in 6 hours, distributed between EtOAc and water.Separate organic phase, through MgSO 4Drying is filtered, and is concentrated into oil.Through purification by flash chromatography (60%EtOAc/40% hexane), obtain required product, be white solid.Reclaim 290mg, yield 56%.LC/MS (10-99%) M/Z 348.4, retention time 2.17 minutes.
[2-(2-methoxyl group-phenyl)-7-methyl-quinazoline-4-yl]-methyl-(5-methyl-[1,3,4] oxadiazole-2-ylmethyl)-amine: under 0 ℃ of nitrogen atmosphere, to the new washed sodium hydride (42mg that is stirring, 1.04mmol) the dry DMF suspension add [2-(2-methoxyl group-phenyl)-7-methyl-quinazoline-4-yl]-(5-methyl-[1,3,4] oxadiazole-2-ylmethyls)-amine (180mg, 0.518mmol, 5ml DMF solution).At 0 ℃ after following 30 minutes, (74 μ L 1.19mmol), make reaction be warming up to room temperature to add MeI.After 1 hour, will react the water quencher, with EtOAc extraction 3 times.Merge organic layer, through MgSO 4Drying is filtered, and is concentrated into xanchromatic oil.Through purification by flash chromatography (50/50 EtOAc/ hexane), obtain required product, be clarifying oil.128mg, yield 66%.LC/MS (10-99%) M/Z 376.1, retention time 2.06 minutes.
2-{7-methyl-4-[methyl-(5-methyl-[1,3,4] oxadiazole-2-ylmethyl)-amino]-quinazoline-2-yl }-phenol: under-78 ℃ of nitrogen atmosphere, to [2-(2-methoxyl group-phenyl)-7-methyl-quinazoline-4-yl]-methyl-(the 5-methyl-[1 that is stirring, 3,4] oxadiazole-2-ylmethyl)-amine (128mg, the anhydrous CH of 7ml 0.341mmol) 2Cl 2Solution drips BBr 3(1.71ml, 1.71mmol).Make reaction be warming up to room temperature, use saturated NaHCO after 3 hours 3Aqueous solution quencher reaction is until pH 8.Separate organic layer, through MgSO 4Drying is filtered, and is concentrated into light yellow oil.Through Gilson HPLC purifying, separating compound is tfa salt.LC/MS (10-99%) M/Z362.3, retention time 2.12 minutes.
At room temperature, to quinazoline (187mg, CH 0.63mmol) 2Cl 2(5ml) solution add pyridine (0.11ml, 1.36mmol).After being cooled to 0 ℃, add Acetyl Chloride 98Min. (50 μ L, CH 0.70mmol) 2Cl 2(5ml) solution continues at room temperature to stir 45 minutes, removes in a vacuum and desolvates.Through silicon-dioxide chromatography (hexane/EtOAc/NEt 3: 2: 1: 0.05), obtain compound 1, be white solid (90mg, 42%).Compound 1:LC/MS (10-99%) m/z=338[M+H] +, room temperature: 3.28 minutes.
Utilize and prepare other compound of Formula I with above-mentioned those similar methods basically.The feature authentication data of these compounds is summarised in the following table 3, and compound number is corresponding to the described compound of table 2.
Table 3: the example features authentication data of formula I compound
Compound # LC_MASS_PLUS
15 308.40
16 306.00
164 320.00
194 389.20
195 404.20
198 302.00，302.20，302.00
202 328.20，328.20，328.00
241 268.30
250 346.00
252 310.00
Compound # LC_MASS_PLUS
Compound # LC_MASS_PLUS
253 344.00
254 319.00
255 333.00
256 348.00
257 319.00
258 289.80
259 249.80，250.40
260 386.20
261 357.00
262 275.20
263 358.00
264 325.00
265 296.60，296.40，296.40
266 345.20
267 310.20，310.00
268 351.00
269 310.00
270 340.10
271 298.10
Compound # LC_MASS_PLUS
272 314.00
273 328.20
274 284.00
275 300.10
276 328.10
277 286.90
278 306.00
279 280.20
280 380.00
281 334.00，334.00
282 336.00
283 351.00
284 336.00，336.00
285 322.00，322.00，322.00，322.00
286 307.00
287 378.00
288 405.00
289 349.00
290 292.00
291 322.00
Compound # LC_MASS_PLUS
292 342.00
293 294.00
294 358.20
295 374.00
296 382.40
297 256.80
298 239.00
299 339.80
300 279.00
301 386.00
302 307.20
303 318.00
304 296.20
Compound # LC_MASS_PLUS
305 278.00
306 291.80
307 239.00
308 289.00
309 270.00
310 402.20
Compound # LC_MASS_PLUS
311 342.00
312 342.00
313 320.20
314 309.00
315 399.00
316 318.00
317 332.00
318 332.00
319 315.00
320 329.00
321 343.00
322 357.00
323 342.00
324 342.00
325 368.00，368.10
326 352.00
327 369.80
328 456.20
329 381.80
330 384.00
Compound # LC_MASS_PLUS
331 395.80
332 322.00，322.20
333 284.00
334 334.00
335 280.00
336 296.00
337 306.00
338 286.80
339 286.80
340 329.40
341 356.20
342 329.40
343 463.20
344 491.60
345 353.20
346 315.80
347 359.00
348 402.20
349 341.80
350 359.80
Compound # LC_MASS_PLUS
351 384.80
352 371.80
353 369.60
354 343.00
355 441.00
356 353.80
Compound # LC_MASS_PLUS
357 314.00
358 320.00
359 323.00
360 289.00
361 322.20
362 400.00
363 386.00
364 390.00
365 306.00
366 385.80
367 370.00
368 374.00
369 320.00
Compound # LC_MASS_PLUS
370 320.00
371 322.00
372 320.00
373 308.00，308.00
374 340.00
375 356.00
376 280.20，280.00
377 300.40，300.00
378 282.00
379 326.20
380 351.20
381 338.20
382 336.20
383 309.20
384 407.40
385 334.20
386 323.40
387 380.20
388 294.00
389 350.00
Compound # LC_MASS_PLUS
390 345.00
391 326.00
392 352.80
393 323.00
394 286.00
395 344.00
396 340.00
397 326.00
398 314.00
399 312.00
400 343.20
401 354.00
402 340.00
403 282.00
404 285.00
405 283.20
406 292.00
407 464.00
408 298.00
Compound # LC_MASS_PLUS
Compound # LC_MASS_PLUS
409 273.00
410 326.20
411 326.20
412 356.00
413 359.20
414 355.00
415 338.00
416 370.00
417 328.00
418 298.20
419 279.80
420 281.80
421 340.90
422 269.30，269.20
423 303.00
424 372.80
425 272.80
426 307.00
427 322.20
428 324.20
Compound # LC_MASS_PLUS
429 284.00，285.00
430 286.00
431 429.00
432 439.00
433 443.00
434 456.00
435 486.00
436 326.20
437 328.00
438 253.00
439 257.00
440 299.20
441 273.00
442 414.40
443 286.00
444 302.20
445 330.00
446 328.20
447 355.40
448 412.00
Compound # LC_MASS_PLUS
449 286.00
450 338.20，338.00
451 352.20
452 267.00
453 326.20
454 284.20
455 309.20
456 399.20
457 312.00
458 340.20
459 302.00
460 316.00
Compound # LC_MASS_PLUS
461 344.00
462 328.00
463 378.00
464 316.00
465 327.80
466 371.80，371.60
467 355.60
Compound # LC_MASS_PLUS
468 356.80
469 359.00
470 435.20
471 368.00
472 344.00
473 282.20
474 281.20
475 355.00
476 302.20
477 316.20
478 344.20
479 328.20
480 378.00
481 316.20
482 282.00
483 286.00
484 328.00
485 324.20
486 353.80
487 377.80
Compound # LC_MASS_PLUS
488 365.00
489 339.80
490 267.00
491 281.00
492 310.20
493 352.20
494 342.00
495 328.00
496 402.20，402.40
497 439.20
498 421.00
499 367.00
500 397.20
501 365.00
502 270.00
508 290.90
516 403.40
517 403.40
518 403.60
519 403.40
Compound # LC_MASS_PLUS
520 408.40
521 409.20
522 432.40
523 432.20
524 431.40
Compound # LC_MASS_PLUS
525 432.40
526 432.40
527 437.40
528 437.40
529 446.40
530 452.40
531 463.00
532 370.00
533 382.20
534 384.20
535 398.20
536 437.40
537 439.40
538 439.40
Compound # LC_MASS_PLUS
539 439.20
540 377.40
541 384.00
542 386.00
543 391.20
544 391.20
545 397.40
546 397.40
547 397.40
548 411.40
549 368.20
550 420.20
551 441.40
552 446.00
553 449.40
554 394.00
555 450.20
556 330.00
557 332.20
558 334.00
Compound # LC_MASS_PLUS
559 346.00
560 348.00
561 372.00
562 383.20
563 383.20
564 383.20
565 383.20
566 387.80
567 388.80
568 403.40
569 412.00
570 412.00
571 412.00
572 349.20
573 361.00
574 375.20
575 389.20
576 411.20
Compound # LC_MASS_PLUS
577 411.20
Compound # LC_MASS_PLUS
586 281.00
587 342.40
588 356.00
589 358.20
590 365.20，365.20
591 369.20，369.20
592 370.00
593 372.40
594 383.20，383.20，383.20，383.20
595 384.00
596 391.20
597 397.40
598 337.80
599 350.00
600 352.00
601 376.00
602 387.20
603 391.80
604 393.00
605 416.00
Compound # LC_MASS_PLUS
606 416.20
607 416.00
608 353.00
609 415.20
610 415.20
611 416.20
612 421.00
613 430.20
614 431.20
615 436.20
616 447.00
617 459.20
618 493.00
619 353.80
620 353.80
621 365.80
622 367.80
623 367.80
624 367.80
625 383.00
Compound # LC_MASS_PLUS
626 409.40
627 421.00
628 423.20
629 423.20
630 423.20
631 429.20，429.00
632 430.00
633 435.20
634 437.00
635 437.40
636 479.20
Compound # LC_MASS_PLUS
637 361.00
638 362.20
639 364.80
640 366.00
641 366.00
642 367.20
643 367.80
644 368.00
Compound # LC_MASS_PLUS
645 370.00
646 375.20
647 375.20
648 375.20
649 375.20
650 375.20
651 381.00
652 381.00
653 381.20
654 381.20
655 381.20
656 388.20
657 395.00
658 395.20
659 418.00
660 352.00
661 365.80
662 365.80
663 385.80
664 404.20
Compound # LC_MASS_PLUS
665 404.00
666 406.00
667 425.20
668 430.20
669 430.20
670 446.00
671 429.40
672 433.20
673 457.20
674 430.00
675 418.20
676 436.20
677 378.00
678 269.80
679 411.20
680 427.20
681 399.80
682 420.20
683 420.00
684 434.20
Compound # LC_MASS_PLUS
685 454.20
686 399.80
687 414.20
688 420.00
Compound # LC_MASS_PLUS
689 432.00
690 367.80，367.80
691 323.00
692 324.00
693 326.00
694 326.00
695 326.00
696 338.00
697 340.00
698 342.00
699 342.00
700 349.00
701 353.20
702 353.00
703 353.00
Compound # LC_MASS_PLUS
704 353.20
705 353.20
706 354.00
707 354.00
708 356.00
709 355.80
710 355.80
711 367.00
712 367.20
713 367.20
714 367.20
715 368.00
716 367.80
717 371.80，373.10
718 375.00
719 381.00
720 382.00
721 382.20
722 383.20
723 385.00
Compound # LC_MASS_PLUS
724 389.20
725 390.00
726 393.20
727 393.20
728 397.20
729 400.20
730 403.40
731 404.20
732 407.40
733 411.20
734 413.20
735 415.40
736 416.20
737 419.00
738 419.20
739 421.00
740 423.20
Compound # LC_MASS_PLUS
741 428.20
742 429.40
Compound # LC_MASS_PLUS
743 430.20
744 431.40
745 431.20
746 441.40
747 446.00
748 450.20
749 432.00
750 470.20
751 352.00
752 352.00
753 352.00
754 374.00
755 373.80
756 374.00
757 378.00
758 378.00
759 378.00
760 416.20
761 429.20
762 432.00
Compound # LC_MASS_PLUS
763 441.40
764 470.20
765 477.00
766 326.00
767 366.00
768 365.80
769 388.20
770 326.00
771 352.20
772 364.20
773 380.80
774 397.20
775 407.40
776 413.20
777 415.20
778 421.00
779 429.20
780 350.00
781 283.80
782 294.00
Compound # LC_MASS_PLUS
783 296.00
784 298.00
785 312.00
786 314.00
787 314.00
788 324.00
789 328.00
790 340.00
791 343.80
792 310.00
Compound # LC_MASS_PLUS
793 347.00
794 347.00
795 351.00
796 373.80
797 326.00
798 326.00
799 326.20
800 338.00
801 372.00
Compound # LC_MASS_PLUS
802 372.00
803 381.80
804 377.20
805 377.20
806 377.20
807 384.00
808 391.00
809 391.20
810 414.40
811 348.00
812 362.00
813 362.00
814 381.80
815 399.80
816 399.80
817 402.00
818 425.80
819 426.00
820 442.00
821 474.20
Compound # LC_MASS_PLUS
822 425.20
823 425.20
824 429.20
825 453.00
826 426.00
827 373.80
828 407.40
829 413.00
830 423.20
831 395.80
832 416.00
833 416.00
834 430.00
835 395.80
836 410.00
837 409.80
838 416.00
839 364.00，364.00
840 439.20
841 319.00
Compound # LC_MASS_PLUS
842 319.80
843 321.80
844 321.80
Compound # LC_MASS_PLUS
845 322.00
846 334.00
847 336.20
848 337.80
849 337.80
850 344.80
851 349.20，349.00
852 349.20
853 349.20
854 350.00
855 350.00
856 352.20
857 353.00
858 352.00
859 352.00
860 363.00
Compound # LC_MASS_PLUS
861 363.00
862 363.00
863 363.20
864 363.80，364.00
865 364.00
866 363.80
867 370.80
868 373.20
869 377.00
870 378.00
871 379.20
872 385.20
873 385.80
874 385.80
875 389.20
876 389.20
877 392.80，393.20，393.30
878 396.20
879 398.20，398.20
880 399.00
Compound # LC_MASS_PLUS
881 284.30
882 412.20
883 417.40
884 417.20
885 432.20
886 417.40
887 419.20
888 357.00
889 364.40
890 371.00
891 348.00，348.20
892 360.20
893 386.20
894 393.20
895 409.00
896 417.40
Compound # LC_MASS_PLUS
897 425.00
898 346.00
899 412.40
Compound # LC_MASS_PLUS
900 426.20
901 427.40
902 443.20
903 455.20
904 489.20
905 350.20
906 350.20
907 362.00
908 364.00
909 364.00
910 364.00
911 378.60
912 405.60
913 419.40
914 419.20
915 425.00
916 431.40
917 433.40
918 433.40
919 475.20
Compound # LC_MASS_PLUS
920 358.20
921 361.00
922 362.00
923 362.00
924 363.20
925 364.00
926 366.00
927 371.20
928 371.40
929 371.20
930 377.20
931 377.20
932 368.00，368.00
933 400.20
934 400.00
935 403.40
936 407.60
937 409.20
938 411.20
939 412.00
Compound # LC_MASS_PLUS
940 415.20
941 417.00
942 419.20
943 424.40
944 425.20
945 426.00
946 427.00
947 427.60
948 437.20
Compound # LC_MASS_PLUS
949 442.20
950 446.00
951 348.00
952 348.00
953 348.00
954 370.00
955 370.00
956 370.00
957 374.00
958 374.20
Compound # LC_MASS_PLUS
959 374.00
960 412.40
961 425.00，425.00
962 430.00
963 437.60
964 440.00
965 466.40
966 473.00
967 364.20，364.00
968 290.20
969 292.00
970 306.20
971 308.60
972 310.00
973 324.20
974 336.00
975 340.00
976 306.60
977 343.00
978 347.00
Compound # LC_MASS_PLUS
979 370.00
980 322.20
981 322.40，322.00
982 356.00
983 368.40
984 368.00
985 378.20
986 405.60
987 409.40
988 416.20
989 420.00
990 423.40
991 427.40
992 429.20
993 431.40
994 435.40
995 439.20
996 445.20
997 447.00
998 466.40
Compound # LC_MASS_PLUS
999 432.40
1000 369.00
Compound # LC_MASS_PLUS
1001 381.00
1002 409.20
1003 431.60
1004 432.40
1005 509.40
1006 384.00
1007 384.00
1008 425.40
1009 445.20
1010 451.20
1011 452.40
1012 495.40
1013 381.00
1014 382.00
1015 411.20
1016 444.40
1017 457.40
Compound # LC_MASS_PLUS
1018 384.00
1019 352.40
1020 368.00
1021 391.20
1022 391.20
1023 328.40
1024 434.40
1025 382.00
1026 358.20
1027 369.20
1028 369.20
1029 383.20
1030 340.20
1031 409.40
1032 420.40
1033 368.00
1034 445.20
1035 330.40
1036 340.00
1037 356.00
Compound # LC_MASS_PLUS
1038 359.80
1039 363.20
1040 367.00
1041 390.00
1042 342.00
1043 342.60
1044 388.40
1045 343.80
1048 455.00
1049 338.00
1050 324.20
1051 433.60
1052 427.00
1053 443.20
1054 398.20
Compound # LC_MASS_PLUS
1055 435.20
1056 415.20
1057 417.40
1058 393.00
Compound # LC_MASS_PLUS
1059 361.00
1060 422.00
1065 385.20
1066 353.10
1067 354.10
1068 367.10
1069 380.90
1070 388.30
1071 353.10
1072 368.10
1073 410.00
1074 383.90
1075 429.10
1083 352.00，351.90，352.30，352.20，352.3 0，352.30，352.00
1084 350.00
1085 363.00
1086 377.00
1087 384.00，384.00
1088 380.00
Compound # LC_MASS_PLUS
1089 362.00
1090 410.00
1091 426.00
1092 370.00
1101 293.00
1102 307.00
1103 334.00
1106 374.10，374.00
1107 379.30
1108 421.10，421.00，421.00
1109 435.50
1110 407.50
1111 399.30
1112 413.30
1113 427.30
1114 391.30
1115 405.50
1116 377.30
1117 441.50，441.00
1118 410.90
Compound # LC_MASS_PLUS
1119 335.90
1120 355.80，355.90
1121 394.90
1122 407.50
1123 343.00，341.90
1124 427.10
1125 396.00
1127 461.30
1128 393.80
Compound # LC_MASS_PLUS
1133 443.00
1134 419.80
1135 453.00
1136 378.00
1137 463.00，463.00
1138 457.00
1141 504.00
1142 420.20
1143 422.20
1144 436.00
Compound # LC_MASS_PLUS
1145 448.20
1146 370.10
1147 457.50
1148 463.10，463.10
1151 435.80
1152 450.00
1153 407.60
1155 518.10
1156 482.00
1157 485.50
1158 432.20
1159 473.10
1160 432.20
1161 468.50
1162 393.80
1163 444.00
1164 450.00
1165 511.00
1166 467.00
1167 363.30
Compound # LC_MASS_PLUS
1168 463.00
1169 482.00
1170 415.00
1171 467.00
1172 511.00
1173 491.00
1174 495.00
1175 365.90
1176 380.30
1179 321.80
1180 560.00
1181 337.20
1182 280.00
1183 259.20
1184 500.20，500.20，500.20
1185 353.00
1186 526.80
1190 350.20
1191 392.00
1192 376.00
Compound # LC_MASS_PLUS
1193 404.20
1194 462.20
Compound # LC_MASS_PLUS
1195 427.20
1196 407.40
1197 391.10
Method:
(A) Micromass MUX LCT 4 passage LC/MS, Waters 60F pump, Gilson 2154 probe automatic samplers, Gilson 849 injection module, 1.5ml/ minute/column flow rate, 10-99%CH 3CN (0.035%TFA)/H 2O (0.05%TFA) gradient, Phenomenex Luna5u C18 post (50x4.60mm), Waters MUX UV-2488 UV detector, Cedex 75ELSD detector.
(B) PESciex API-150-EX LC/MS, Shimadzu LC-8A pump, Gilson 215 automatic samplers, Gilson 819 injection module, 3.0ml/ minute flow velocity, 10-99%CH 3CN (0.035%TFA)/H 2O (0.05%TFA) gradient, Phenomenex Luna 5u C18 post (50x4.60mm), Shimadzu SPD-10A UV/Vis detector, Cedex 75 ELSD detectors.
(C) PESciex API-150-EX LC/MS, Shimadzu LC-8A pump, Gilson 215 automatic samplers, Gilson 819 injection module, 3.0ml/ minute flow velocity, 40-99%CH 3CN (0.035%TFA)/H 2O (0.05%TFA) gradient, Phenomenex Luna 5u C18 post (50x4.60mm), Shimadzu SPD-10A UV/Vis detector, Cedex 75 ELSD detectors.
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
Figure G2004800119814D04631
( Referring to, Gonzalez, J.E., K.Oades, et al. (1999) " Cell-based assays and instrumentation forscreening ion-channel targets " Drug Discov Today4 (9): 431-439).
B) utilize chemical stimulation
Figure G2004800119814D04632
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 MCC2-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 ABSC1 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 to add scheme to exist 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.
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 restoring data.They are mean ratios during the sample spot between 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 (negative control) in the presence of measure.As above calculate response to negative (N) and positive (P) contrast.Compound antagonistic activity A is defined as:
Figure G2004800119814D04643
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 pH 7.4 (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 ℃
ABSC1: 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 the flask with cover of ventilation, 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 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/DiSBAC 2(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 ABSC1，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.At room temperature, cell was in the dark dyeed 30 minutes.
2X DISBAC 2(3) with ABSC1=6 μ M DISBAC 2(3) and 1mM ABSC1: 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 ABSC1 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/ABSC1.At room temperature, in the dark dyeed 30 minutes.
Used apparatus of electro-stimulation and method are as described in the ionic channel measuring method PCT/US 01/21652, and it is quoted at this as a reference.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 integrating 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, pH 7.40,330mOsm
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
ABSC1 storing solution (400X): 200mM ABSC1, 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.To represent to utilize following formula gained ratio as the response of the function of time then:
By calculating initial (R i) and final (R f) ratio, further restoring 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, in the presence of compound (positive control) with required character, 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:
Figure G2004800119814D04672
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 " voltage clamp " pattern assessment Compound I C50.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 serial 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 (0.25x10 -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, 10NaCl, 0.1EGTA, 10Hepes, 2MgCl 2(being buffered to pH 7.34) with KOH.The cell temperature is bathed in (in mM): 140NaCl, 3KCl, 1MgCl 2, 1CaCl 2And 10Hepes).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.
According to these technology, find that representative compounds of the present invention possesses required valtage-gated sodium channel activity and selectivity.
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) " Voltage sensing 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 ( Referring to, Gonzalez, J.E., K.Oades, et al. (1999) " Cell-based assays and instrumentation forscreening ion-channel targets " Drug Discov Today4 (9): 431-439).
Utilize electricity irritation
Figure G2004800119814D04692
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/DiSBAC 2(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)
pH 7.4(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.At room temperature, 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).At room temperature, 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.With solution stirring 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.At room temperature, in the dark dyeed 15 minutes.On the optical readings device, read flat board.
Used apparatus of electro-stimulation and method are as described in the ionic channel measuring method PCT/US 01/21652, and it is quoted at this as a reference.Instrument comprises the dull and stereotyped treater of microtitration, be used for exciting seven dose of tonka bean camphor 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 integrating 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 G2004800119814D04711
By calculating initial (R i) and final (R f) ratio, further restoring 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, in the presence of compound (positive control) with required character, 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:
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 " voltage clamp " pattern assessment Compound I C50.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 serial 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 (19)

1. formula IA-ii compound:
Figure F2004800119814C00011
Or its pharmacy acceptable salt, wherein:
A) by R 1And R 2Be selected from the ring that nitrogen constituted that they connected:
And wherein said ring randomly on one or more commutable carbon or nitrogen-atoms by z independent occur-R 4Replace; Wherein:
B) wherein z is 0-5, R 4Group when existing, is Cl, Br, F, CF independently of one another 3, CH 3,-CH 2CH 3, CN ,-COOH ,-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 2(CH 2) 3CH 3,-SO 2CH (CH 3) 2,-SO 2N (CH 3) 2,-SO 2CH 2CH 3,-C (O) OCH 2CH (CH 3) 2,-C (O) NHCH 2CH (CH 3) 2,-NHCOOCH 3,-C (O) C (CH 3) 3,-COO (CH 2) 2CH 3,-C (O) NHCH (CH 3) 2,-C (O) CH 2CH 3Perhaps be selected from following group: piperidyl, piperazinyl, morpholino base, C 1-4Alkoxyl group, phenyl, phenoxy group, benzyl, benzyloxy ,-CH 2Cyclohexyl, pyridyl ,-CH 2Pyridyl or-CH 2Thiazolyl;
C) wherein x is 1, R 3Be Cl, Br, F, CF 3,-OCF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-NHCOCH (CH 3) 2,-SO 2NH 2,-CONH (cyclopropyl) ,-CONHCH 3Or-CONHCH 2CH 3
D) wherein y is 0-4, R 5Group when existing, is Cl, Br, F, CF independently of one another 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 3,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base ,-OCOCH (CH 3) 2,-OCO (cyclopentyl) ,-COCH 3, phenoxy group or benzyloxy; With
E) R 5aBe Cl, Br, F, CF 3, Me, Et, CN ,-COOH ,-NH 2,-N (CH 3) 2,-N (Et) 2,-N (iPr) 2,-O (CH 2) 2OCH 3,-CONH 2,-COOCH 3,-OH ,-OCH 3,-OCH 2CH 3,-CH 2OH ,-NHCOCH 3,-SO 2NH 2,-SO 2NHC (CH 3) 2,-OCOC (CH 3) 3,-OCOCH 2C (CH 3) 3,-O (CH 2) 2N (CH 3) 2, 4-CH 3-piperazine-1-base, OCOCH (CH 3) 2, OCO (cyclopentyl) ,-COCH 3, phenoxy group or benzyloxy.
2. the compound of claim 1, wherein R 3Be substituted in the 6-position of quinazoline ring, y is 0, and compound has formula III:
3. the compound of claim 1, wherein R 3Be substituted in the 7-position of quinazoline ring, y is 0, and compound has formula IV:
Figure F2004800119814C00022
4. the compound of claim 2, wherein R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
5. the compound of claim 3, wherein R 3Be-Cl ,-CH 3,-CH 2CH 3,-F ,-CF 3,-OCF 3,-OCH 3Or-OCH 2CH 3
6. the compound of claim 1, wherein y is 0, R 5Be F or OH.
7. the compound of claim 1, wherein R 5aBe Cl, F, CF 3, Me, Et ,-OH ,-OCH 3Or-OCH 2CH 3
8. the compound of claim 7, wherein R 5aBe OH.
9. the compound of claim 7, wherein R 5aBe F.
10. be selected from following compound:
Figure F2004800119814C00051
Figure F2004800119814C00071
Figure F2004800119814C00081
Figure F2004800119814C00121
Figure F2004800119814C00141
Figure F2004800119814C00241
Figure F2004800119814C00251
Figure F2004800119814C00261
Figure F2004800119814C00271
Figure F2004800119814C00291
Figure F2004800119814C00301
11. composition comprises each compound and pharmaceutically acceptable carrier, vehicle or thinner of claim 1-10.
12. each compound of claim 1-10 is used for the treatment of following disease, obstacle or illness or alleviates purposes in the medicine of its seriousness in preparation, that described disease, obstacle or illness are selected from is acute, chronic, neuropathic or inflammatory pain, sacroiliitis, migraine, bunch headache, trigeminal neuralgia, herpetic neurodynia, popularity neurodynia, epilepsy or epilepsy, neurodegeneration obstacle, mental disorder, myotony, irregular pulse, dyskinesia, neuroendocrine obstacle, ataxia, multiple sclerosis, irritable bowel syndrome or incontinence.
13. the purposes of claim 12, wherein said mental disorder are anxiety or depression.
14. the purposes of claim 12, wherein this disease, illness or obstacle relate to voltage-gated sodium channel activation or hyperactivity.
15. the purposes of claim 12, wherein this disease, illness or obstacle relate to calcium channel activation or hyperactivity.
16. the purposes of claim 12, wherein this disease, illness or obstacle are acute, chronic, neuropathic or inflammatory pain.
17. the purposes of claim 12, wherein this disease, illness or obstacle are nerve root pain, sciatica, back pain, head pain or cervical pain.
18. the purposes of claim 12, wherein this disease, illness or obstacle are seriousness or intractable pain, acute pain, post-operative pain, back pain or cancer pain.
19. each compound of claim 1-10 is used for suppressing purposes in the active medicine of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9 or CaV2.2 of extracorporeal biology sample in preparation.
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