Patent Grant
7078405
This application is the national phase under 35 U.S.C. § 371 of PCT International Application No. PCT/JP02/01098 which has an International filing date of Feb. 8, 2002, which designated the United States of America.
The present invention relates to a novel compound having corticotropin-releasing-factor receptor antagonistic activity, a salt thereof and a hydrate of them, a process for preparing its and its medical use.
Corticotropin-releasing-factor (hereinafter, referred to as “CRF”) is a neuropeptide comprising 41 amino acids, and isolated from sheep hypothalamus (Science, 213, 1394 (1981)) and, then, its presence was confirmed in a rat (Proc. Natl. Acad. Sci. USA, 80, 4851 (1983)) and a human being (EMBO J. 5, 775 (1983)). CRF is the most abundant in pituitary gland and hypothalamus and is widely distributed in a brain such as cerebral cortex, cerebellum and the like. In addition, in a peripheral tissue, CRF is confirmed to be present in placenta, adrenal gland, lung, lever, pancreas and digestive tract (J. Clin. Endocrinol. Metab., 65, 176 (1987), J. Clin. Endocrinol. Metab., 67, 768 (1988), Regul. Pept., 18, 173 (1987), peptides, 5 (Suppl. 1), 71 (1984)). Two subtypes CRF1 and CRF2 are present in a CRF receptor, and a CRF1 receptor is reported to be distributed at a large amount in cerebral cortex, cerebellum, olfactory bulb, pituitary gland, almond nucleus and the like. Recently, two subtypes CRF2α and CRF2β were confirmed to be present in a CRF2 receptor, and it was found that a CRF2α receptor is distributed in hypothalamus, septal area and choroid plexus at a large amount and a CRF2β is distributed in a peripheral tissue such as skeletal muscle and in a cerebrovascular part in central tissue (J. Neuroscience, 15 (10) 6340 (1995); Endocrinology, 137, 72 (1996); BBA, 1352, 129 (1997)). Since each receptor is distributed differently, it is suggested that its role is also different. CRF is produced in and secrete from hypothalamus and promotes the release of adrenocorticotropic hormone (ACTH) by stress (Recent Prog. Horm. Res., 39, 245(1983)). CRF serves as a neurotransmitter or a neuromodulator also in a brain and integrates electrophysiology to stress, autonomic nerve and action, in addition to a role to incretion (Brain Res. Rev., 15, 71, (1990); Pharmacol. Rev., 43, 425 (1991)).
Currently, CRF is thought to be involved in a variety of diseases and there are reports as follows:
CRF in a cerebrospinal liquid in a depression patient is at a higher value as compared with a healthy man (Am. J. Psychiatry, 144(7), 873 (1987)). A CRF-mRNA level in hypothalamus in a depression patient is a higher value as compared with a healthy man (Am. J. Psychiatry, 152, 1372 (1995)). A CRF receptor is decreased in a cerebral cortex of a person who commits suicide (Arch. Gen. Psychiatry, 45, 577 (1988)). A rise of ACTH in a plasma is small in a depression patient upon administration of CRF (N. Engl. J. Med., 314, 1329 (1986)). CRF in a cerebrospinal liquid of a certain anxiety patient such as compulsion disorder, posttraumatic stress disorder, teulett syndrome etc. is a higher value as compared with a healthy man (Arch. Gen. Psychiatry, 51, 794 (1994); Am. J. Psychiatry, 154, 624 (1997); Biol. Psychiatry, 39, 776 (1996)). A rise of ACTH in a plasma is small in a panic disorder patient upon administration of a CRF (Am. J. Psychiatry, 143, 896 (1986)). An anxiety behavior is recognized when CRF is administered in a brain of an experimental animal (Brain Res., 574, 70 (1992); J. Neurosci., 10 (1), 176 (1992)). In addition, many anxiety behavior are recognized in a CRF overexpressing mouse as compared with a normal animal (J. Neurosci., 14 (5), 2579 (1994)). CRF ceruleus is decreased by administration of an anti-anxiety agent (J. Pharmaco. Exp. Ther., 258, 349 (1991)). In addition, α-helical CRF (9–41) of a peptidic CRF antagonist exerts an anti-anxiety behavior in an animal model (Brain Res., 509, 80 (1990); Regulatory Peptize, 18, 37 (1987); J. Neurosci., 14 (5), 2579 (1994)). α-Helical CRF (9–41) of a peptidic CRF antagonist inhibits an abnormal behavior due to abstinence of dependency drug such as alcohol and cocaine (Psychopharmacology, 103, 227 (1991)). CRF suppresses a sexual behavior of a rat (Nature, 305, 232 (1983)). CRF is thought to be involved in sleep disorder because it reduces rat's sleep (Pharmacol. Biochem. Behav., 26, 699 (1987)). α-Helical CRF (9–41) of a peptidic CRF antagonist inhibits disorder of a brain and brain wave abnormality due to brain ischemia and activation of NMDA receptor (Brain Res., 545, 339 (1991), Brain Res. 656, 405 (1994)). CRF awakens abrainwave and induces convulsion (Brain Res., 278, 332 (1983)). CRF in a cerebrospinal liquid of a schizophrenia patient is a higher value as compared with a healthy man (Am. J. Psychiatry, 144(7), 873 (1987)). CRF in a cerebral cortex in an Alzheimer's disease, Parkinson's disease or progressive supranuclear palsy is reduced (Neurology, 37, 905 (1987)). CRF in a Huntington disease ganglion is reduced (Brain Res., 437, 355 (1987), Neurology, 37, 905 (1987)). In addition, it has been found that administration of CRF in a rat enhances learning and memory (Nature, 378, 384 (1995); Neuroendocrinology, 57, 1071 (1993)). CRF in a cerebrospinal liquid in an amyotrophic lateral sclerosis patient. In a CRF overexpressing mouse, oversecretion of ACTH and adrenal gland steroid hormone occurs and abnormality similar to Cushing syndrome such as muscular atrophy, alopecia and infertility (Endocrinology, 130(6), 3378 (1992)). CRF in a cerebrospinal liquid in an anorexia nervosa patient is a higher value as compared with a healthy man, and a rise of ACTH in a plasma is small in an anorexia nervosa upon administration of CRF (J. Clin. Endocrinol. Metab., 62, 319 (1986)). CRF suppresses eating in an experimental animal (Neuropharmacology, 22 (3A), 337 (1983)). In addition, α-helical CRF (9–41) of a peptidic CRF antagonist improved decrease in eating in an animal model due to stress load (Brain Res. Bull., 17 (3), 285 (1986)). CRF suppressed weight gain in a hereditary obesity animal (Physiol. Behav., 45, 565 (1989)). It is suggested that the lowness of a CRF value and obesity syndrome are related (Endocrinology, 130, 1931 (1992)). It is suggested that eating inhibition and weight loss action of a serotonine reuptake inhibiting agent is via release of CRF (Pharmacol. Rev., 43, 425 (1991)). CRF acts on centralness and peripherallness, weakens constriction of a stomach and reduces stomach excretion ability (Regulatory Peptides, 21, 173 (1983); Am. J. Physiol., 253, G241 (1987)) In addition, α-helical CRF (9–41) of a peptidic CRF antagonist has the recovery action on the functional decrease of stomach due to abdominal operation (Am. J. Physiol., 262, G616 (1992)). CRF promotes secretion of bicarbonate ions in stomach, decreases gastric acid secretion, and at the same time, inhibits coldconstraint stress ulcer (Am. J. Physiol., 258, G152 (1990)). In addition, ulcer is increased in a non-constraint animal by CRF administration (Life Sci., 45, 907 (1989)). CRF suppresses small intestine transport, promotes large intestine transport and induces defecation. In addition, α-helical CRF (9–41) of a peptidic CRF antagonist has the inhibitory action on decrease in gastric acid secretion, decrease in stomach excretion, decrease in small intestine transport and asthenia in large intestine (Gastroenterology, 95, 1510 (1988)).
26) In a healthy man, mental stress increases a gas and bellyache due to anxiety and gastrectasis and CRF reduces a threshold of uncomfort (Gastroenterol., 109, 1772 (1995); Neurogastroenterol. Mot., 8, 9 (1996)). In an irritable bowel syndrome patient, large intestine movement is excessively exasperated by administration of CRF as compared with a healthy man (Gut., 42, 845 (1998)). Administration of CRF increases blood pressure, heart rate and body temperature. In addition, α-helical CRF (9–41) of a peptidic CRF antagonist inhibits elevation of blood pressure, heart rate and body temperature (J. Physiol., 460, 221 (1993)). In an inflammatory part of an experimental animal and a joint liquid of a rheumatoid arthritis patient, production of CRF is locally increased (Science, 254, 421(1991); J. Clin. Invest., 90, 2555 (1992); J. Immunol., 151, 1587 (1993)). CRF induces degranulation of a mast cell and exasperates vessel permeability (Endocrinology, 139(1), 403 (1998); J. Parmacol. Exp. Ther., 288 3), 1349 (1999)). Also in an autoimmune thyroiditis patient, CRF is detected (Am. J. Pathol., 145, 1159 (1994)). When CRF is administered to an experimental autoimmune cerebrospinal meningitis rat, progression of symptom of palsy and the like was remarkably inhibited (J. Immunol., 158, 5751 (1997)). In a system for culturing pituitary gland adenocarcinoma of an acromegaly patient, urocortin (analogue of CRF) increased secretion of a growth hormone (Endocri, J., 44, 627 (1997)). In addition, CRF stimulates secretion of cytokin such as interleukin 1 and interleukin2 (J. Neuroimmunol., 23, 256(1989); Neurosci. Lett., 120, 151(1990)). Activity of natural killer cell and increase of T lymphocyte are decreased by administration of CRF and load of stress. α-Helical CRF(9–41) of a peptidic CRF antagonist improves decrease in the function of immune cells due to administration of CRF and stress load (Endocrinology, 128(3), 1329 (1991)). Breathing is remarkably increased by administration of CRF (Eur. J. Pharmacol., 182, 405 (1990)). In an advanced aged patient equipped with a long term artificial inhaler, animus of breathing and insomnia were recognized by administration of CRF (Acta Endcrinol. Copenh., 127, 200 (1992)).
From the above study reports, a CRF antagonist can be expected to exert the excellent effects in treating or preventing depression and depressive symptom including great depression, monostotic depression, recurrent depression, infant tyrannism by depression and postpartum depression, mania, anxiety, generalized anxiety disorder, panic disorder, phobia, compulsive disorder, posttraumatic stress disorder, Tourette syndrome, autism, emotional disorder, sentimental disorder, bipolar disorder, cyclothymia, schizophrenia, Alzheimer's disease, Alzheimer-type senile dementia, neurodegenerative disease such as Parkinson's disease and Huntington's disease, multi-infarct dementia, senile dementia, neurotic anorexia, appetite asthenia and other diet disorder, obesity, diabetes, alcohol dependence, pharmacophilia to cocaine, heroin, benzodiazepine etc., drug or alcohol withdrawal, sleep disorder, insomnia, migraine, stress headache, myotonic headache, ischemic neuropathy, excitation toxic neuropathy, cerebral apoplexy, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular convulsion, chronic fatigue syndrome, mental social growth failure, epilepsy, head trauma, spinal trauma, graphospasm, spasmodic torticollis, muscular convulsion, neck-shoulder-arm syndrome, primary glaucoma, Meniere syndrome, autonomic imbalance, alopecia, neurosis including cardioneurosis, intestinal neurosis and bladder neurosis, peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, coprostasis, postoperational ileus, gastrointestinal function abnormality associated with stress and neural vomiting, hypertension, cardiovascular disorder including neural angina, tachycardia, congestive cardioplegia, hyperpnea syndrome, bronchial asthma, apnea syndrome, infant sudden death syndrome, inflammatory disorder (for example, rheumatoid arthritis, bone arthritis, lumbago etc.), pain, allergic disease (for example, atopic dermatis, eczema, urticaria, psoriasis etc.), impotence, climacteric disorder, fertilization disorder, infertility, cancer, immune function abnormality upon infection with HIV, immune function abnormality by stress, hemorrhagic stress, Cushing syndrome, thyroid function disorder, encephalomyelitis, acromegaly, incontinence, osteoporosis etc. There is a report on a CRF antagonist, for example, a peptide-type CRF receptor antagonist in which a part of an amino acid sequence of a human being or other mammal is altered or deleted, and it is reported that the antagonist shows the ACTH release inhibitory action and anti-anxiety action of the antagonist (Science, 224, 889 (1984), J. Pharmacol. Exp. Ther., 269, 564 (1994), Brain Research Reviews, 15, 71 (1990)). However, it must be said that, from a viewpoint of pharmacokinetics such as the chemical stability in vivo, the bioavailability and the transferability to brain, the utility value thereof as a medicament is low.
On the other hand, regarding a non-peptide type CRF antagonist, there is the following report:
1) a compound represented by the formula:
(wherein R1 represents NR4R5 etc.; R2 represents a C1-6 alkyl group etc.; R3 represents a C1-6 alkyl group etc.; R4 represents a C1-16 alkyl group etc.; R5 represents a C1-6 alkyl group etc.; and Ar represents phenyl etc.), a stereoisomer thereof, or pharmaceutically acceptable acid addition salts thereof (WO97/29109);
2) a compound represented by the formula:
(wherein a broken line represents a single or double bond; A represents CR7 etc.; B represents NR1R2 etc.; J and K are the same as or different from each other and each represents nitrogen atom etc.; D and E are the same as or different from each other and each represents nitrogen atom etc.; G denotes nitrogen atom etc.; R1 represetns a C1-6 alkyl group etc.; R2 represents a C1–C12 alkyl group etc.; and R7 represents hydrogen atom etc.) or a pharmacologically acceptable salt thereof (WO98/08847);
3) an anilinopyrimidine compound described in WO95/10506, a pyrazolopyrimidine compound described in WO95/34563, a pyrazole compound described in WO94/13661, a pyrazole and pyrazolopyrimidine compound described in WO94/13643, aminopyrazole described in WO94/18644, a pyrazolopyrimidine compound described in WO94/13677, a pyrrolopyrimidine compound described in WO94/13676, a thiazole compound described in EP-659747, EP-611766, an anilinopyrimidine compound described in J. Med. Chem., 39, 4358 (1996), an anilinotriazine compound described in ibid. 39, 3454 (1996), a thienopyrimidine compound described in WO97/29110 and the like; and
4) as an imidazo[1,2-a]pyrazine compound, there is, for example, a compound described in EP0068378 and, as an imidazo[1,2-b]pyridazine compound, there is, for example, a compound described in EP0353902.
As described above, there is desired the provision of a CRF receptor antagonist which is useful as a medicament. However, a medicament which shows the excellent CRF receptor antagonism, and satisfies the pharmacological activity, the dose, the safety etc. as a medicament and effectively acts clinically has not been found. That is, an object of the present invention is to search and find such the excellent CRF receptor antagonist.
In view of the above-mentioned circumstances, the present inventors studied intensively and, as a result, they have succeeded in synthesizing a novel compound (hereinafter, referred to as “the compound (I)” in some cases) represented by the following formula:
(wherein R1 denotes a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C1-6 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, or a group represented by —NR1aR1b (R1a and R1b are the same as or different from each other and each denotes a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group or a C1-7 aliphatic acyl group), —CO—NR1aR1b (R1a and R1b have the same meanings as defined above, respectively), —CO-A1 (A1 denotes a C1-6 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group), -G1-A2 (G1 denotes —O—CO—, S, SO or SO2; and A2 denotes a C1-6 alkyl group or a C2-6 alkenyl group) or —SO2—NR1aR1b (R1a and R1b have the same meanings as defined above, respectively), and further, the R1 may be substituted with at least one group selected from a halogen atom, a cyano group, a C1-6 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C1-6 alkoxy group, a C1-6 alkenyloxy group, a C1-6 alkylthio group and a C2-6 alkenylthio group;
R2 denotes:
(a) a halogen atom, a cyano group, a nitro group, a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C3-8 cycloalkyl C1-6 alkyl group, a C3-8 cycloalkyl C2-6 alkenyl group, a C1-10 alkoxy group, a C2-6 alkenyloxy group, a C1-10 alkoxy C1-10 alkyl group, a C1-6 alkoxy C2-8 alkenyl group, a C2-6 alkenyloxy C1-6 alkyl group, a C2-6 alkenyloxy C2-6 alkenyl group, a group represented by —NR2aR2b (R2a and R2b are independent of each other and each denotes a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-6 alkynyl group, a C1-6 hydroxyalkyl group, a C1-6alkyl group substituted with a 5- to 14-membered non-aromatic heterocyclic group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkoxy C1-6 alkyl group, a C1-6 alkylthio C1-6 alkyl group, an aminocarbonyl C1-6 alkyl group, a heteroarylcarbonyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl C1-6 alkyl group, a heteroaryl C1-6 alkyl group, an aryl C1-6 alkyl group, an aryl group, a 5- to 14-membered heterocyclic group, a C1-6 alkoxycarbonyl group or a C2-6 alkenyloxycarbonyl group), —CO—NR2aR2b (R2a and R2b have the same meanings as defined above, respectively), —CO-A3 (A3 denotes a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C1-6 alkoxy group, a C2-8 alkenyloxy group, an aryl group or a heteroaryl group), —O—C(O)-A4 (A4 denotes a C1-6 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group) or -G2-A5 (G2 denotes S, SO or SO2; and A5 denotes a C1-6 alkyl group or a C2-6 alkenyl group), or a 5- to 14-membered non-aromatic heterocyclic group, or
(b) may be bound together with R1 to form a cycle, and further,
in the case of (a) or (b), R2 may be substituted with at least one group selected from a halogen atom, a hydroxyl group, a cyano group, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C1-6 alkylthio group, a C2-6 alkenylthio group, —NR2aR2b (R2a and R2b have the same meanings as defined above, respectively), an aryl group and a heteroaryl group;
R3 denotes a C6-14 aromatic hydrocarbon cyclic group or a 5- to 14-membered aromatic heterocyclic group, each of which may have a substituent; and
X, Y and Z are independent of each other and each denotes (a) N or (b) CR4 (wherein R4 (aa) denotes a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally halogenated C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, —NR1aR1b (wherein R4a and R4b are independent of each other and each denotes a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-6 alkynyl group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C1-6 alkoxy C1-6 alkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl C1-6 alkyl group, a heteroaryl C1-6 alkyl group, an aryl C1-6 alkyl group, an aryl group, a 5 to 14-membered heterocyclic group, a C1-6 alkoxycarbonyl group or a C2-6 alkenyloxycarbonyl group) or -G3-A6 (wherein G3 denotes S, SO or SO2; A6 denotes a C1-6 alkyl group or a C2-6 alkenyl group) or (bb) R4s, or R2 and R4 may be bound together to form a ring); in this case, at least two of X, Y and Z denote CR4 (R4 has the same meaning as defined above),
provided that, in the above definition, compounds in the following cases (1) to (4) are excluded:
(1) the case where R1 and R2 are a methyl group, X, Y and Z are CH, and R3 is a 2,4-dichlorophenyl group,
(2) the case where R2 is a trifluoromethyl group, R2 is a fluorine atom or a bromine atom, X is N, Y is ═C(CH3)—, Z is CH, and R3 is a phenyl group,
(3) the case where R1 is a trifluoromethyl group, R2 is an ethoxycarbonyl group or an amide group, X is N, Y is ═C(CH3)—, Z is CH, and R3 is a 3-chlorophenyl group, and
(4) the case where R1 is a hydrogen atom, R2 is a 4-morpholinylmethyl group, X is N, Y is ═CR′— (R′ denotes a phenyl group), Z is CH, and R3 is a phenyl group), a salt thereof or a hydrate of them. Further, they have surprisingly found that the compound has an excellent CFR antagonism. Thus, they have completed the present invention.
That is, the present invention relates to:
(1) a compound represented by the above formula (I) or a salt thereof; (2) the compound described in the above (1) or a salt thereof, wherein R1 is a C1-6 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, a C1-6 alkylsulfinyl group or a C1-6 alkylsulfonyl group; (3) the compound described in the above (1) or a salt thereof, wherein R1 is a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a methoxy group, an ethoxy group, a n-propyloxy group, an iso-propyloxy group, a methylthio group, an ethylthio group, a n-propylthio group, an iso-propylthio group, a methylsulfinyl group, an ethylsulfinyl group, a methylsulfonyl group or an ethylsulfonyl group; (4) the compound described in the above (1) or a salt thereof, wherein R1 is -G4-CH3 (wherein G4 denotes a single bond, CH2, O or S); (5) the compound described in the above (1) or a salt thereof, wherein R2 denotes a C1-6alkyl group, C1-6alkoxy C1-6alkyl group, a C1-6alkylsulfonyl group, a C2-6alkenylsulfonyl group or —NR2aR2b (R2a and R2b have the same meanings as defined above), each of which may be substituted; (6) the compound described in the above (1) or a salt thereof, wherein R2 is —NR2aaR2bb (wherein R2aa and R2bb are independent of each other and each denotes a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-6 alkynyl group, a C1-6 alkyl group substituted with a 5- to 14-membered non-aromatic heterocyclic group, a C1-8 alkoxy group, a C1-8 alkoxy C1-8 alkyl group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C3-8 cycloalkyl group, a C3-8cycloalkyl C1-6alkyl group or a 5- to 14-membered heterocyclic group, and further, the R2aa and R2bb are independent of each other and each may be substituted with a halogen atom); (7) the compound described in the above (1) or a salt thereof, wherein R2 is a di(C1-6 alkyl)amino group; (8) the compound described in the above (1) or a salt thereof, wherein R3 is a phenyl group or a pyridyl group, each of which may be substituted; (9) the compound described in the above (1) or a salt thereof, wherein R3 is a phenyl group or a pyridyl group, each of which may be substituted with 1 to 4 group(s) selected from a halogen atom, a C1-6 alkyl group, a halogeno-C1-6 alkyl group, a C1-6 alkoxy group, a halogeno-C1-6 alkoxy group, a C1-6 alkylthio group and a 5- to 8-membered aromatic heterocyclic group; (10) the compound described in the above (1) or a salt thereof, wherein R3 is a phenyl group or a pyridyl group, each of which may be substituted with 1 to 3 group(s) selected from a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, a methylthio group and a pyrrolyl group; (11) the compound described in the above (1) or a salt thereof, wherein any one of X, Y and Z is N, and remaining two are CR4′ (wherein R4′ denotes a hydrogen atom, a halogen atom, a cyano group, a C1-6alkyl group or a C1-6alkoxy group); (12) the compound described in the above (1) or a salt thereof, wherein X and Y are CR4′ (wherein R4 has the same meaning as defined above); and Z is N; (13) the compound described in the above (1) or a salt thereof, wherein X, Y and Z are a group represented by CR4′ (wherein R4′ has the same meaning as defined above); (14) the compound described in any one of the above (11) to (13) or a salt thereof, wherein R4 is a hydrogen atom, a halogen atom, a methyl group, an ethyl group, a methoxy group or an ethoxy group; (15) the compound described in any one of the above (11) to (12) or a salt thereof, wherein R4′ is a hydrogen atom; (16) the compound described in the above (1) which is represented by the following formula:
(wherein X′ and Z′ are independent of each other and each denotes N or CH (in this case, at least one of X′ and Z′ denotes CH); and G4, R2 and R3 have the same meanings as defined above) or a salt thereof; (17) the compound described in the above (16) or a salt thereof, wherein R2 is —NR2aaR2bb (wherein R2aa and R2bb are independent of each other and each denotes a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-6 alkynyl group, a C1-6 alkyl group which may be substituted with a 5- to 14-membered non-aromatic heterocyclic group, a C1-8 alkoxy group, a C1-8 alkoxy C1-8 alkyl group, a C1-6 alkylsulfinyl group, a C1-6 alkylsulfonyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl C1-6 alkyl group or a 5- to 14-membered heterocyclic group, and further, the R2aa and R2bb are independent of each other and each may be substituted with a halogen atom) (18) the compound described in the above (16) or a salt thereof, wherein R2 is a di(C1-6 alkyl)amino group; (19) the compound described in the above (16) or a salt thereof, wherein R3 is a phenyl group or a pyridyl group, each of which may be substituted; (20) the compound described in the above (16) or a salt thereof, wherein R3 is a phenyl group or a pyridyl group, each of which may be substituted with 1 to 4 group(s) selected from a halogen group, a C1-6alkyl group, a halogeno-C1-6alkyl group, a halogeno-C1-6alkoxy group, a C1-6alkoxy group, a C1-6alkylthio group and a 5- to 8-membered aromatic heterocyclic group; (21) the compound described in the above (1) which is represented by the following formula:
(wherein Z′ denotes N or CH; the ring M denotes a benzene ring which may further have a substituent; and G4, R2a and R2b have the same meanings as defined above) or a salt thereof; (22) the compound described in the above (21) or a salt thereof, wherein R2a and R2b are independent of each other and each represents a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-6 alkynyl group, a C1-6 alkyl group which may be substituted with a 5- to 14-membered non-aromatic heterocyclic group, a C1-8 alkoxy C1-8 alkyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkyl C1-6 alkyl group, and further, each of which may be substituted with a halogen atom; (23) the compound described in the above (21) or a salt thereof, wherein R2a and R2b are a C1-6 alkyl group; (24) the compound described in the above (21) or a salt thereof, wherein the ring M is a benzene ring which may be further substituted with 1 to 3 group(s) selected from a halogen atom, a C1-6alkyl group, a C1-6alkoxy group, a halogeno-C1-6alkyl group and a halogeno-C1-6alkoxy group; (25) the compound described in the above (1) or a salt thereof, wherein the compound is
4-[3-[di(cyclopropylmethyl)amino]-2-(methylsulfanyl)imidazo[1,2-a]pyrazin-8-yl]-3-methoxybenzonitrile,
The meanings of symbols, terms and the like described in the present specification will be explained below and the present invention will be explained in detail.
In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present invention includes all isomers such as geometrical isomer, optical isomer based on an asymmetrical carbon, stereoisomer, tautomer and the like which occur structurally and an isomer mixture and is not limited to the description of the formula for convenience, and may be any one of isomer or a mixture. Therefore, an asymmetrical carbon atom may be present in the molecule and an optically active compound and a racemic compound may be present in the present compound, but the present invention is not limited to them and includes any one. In addition, a crystal polymorphism may be present but is not limiting, but any crystal form may be single or a crystal form mixture, or an anhydride or hydrate. Further, so-called metabolite which is produced by degradation of the present compound in vivo is included in the scope of the present invention.
As used herein, ‘neural degenerative disease’ means acute degenerative disease or chronic degenerative disease, specifically, means neural disorder derived from subarachnoidal hemorrhage, cerebrovascular disorder acute phase and the like, Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, spinal cerebellar degenerative disease and the like. As used herein, ‘diet disorder’ means appetite sthenia, cibophobia and the like. As used herein, ‘cardiovascular disorder’ means neural angina and the like. As used herein, ‘inflammatory disorder’ menas, for example, rheumatoid arthritis, bone arthritis, lumbago and the like. ‘Allergy disease’ denotes, for example, atopic dermatis, eczema, urticaria, psoriasis and the like.
The “halogen atom” in the present specification denotes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like, preferably a fluorine atom, a chlorine atom, and a bromine atom.
The “C1-6 alkyl group” used in the present specification denotes an alkyl group having a carbon number of 1 to 6, and preferably, a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, an n-hexyl group, a 1-methyl-2-ethylpropyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1-propylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, and the like may be proposed.
The “n-” in the present specification denotes normal, “sec-” denotes secondary, and “tert-” denotes tertiary, respectively.
The “C2-6 alkenyl group” used in the present specification denotes an alkenyl group having a carbon number of 2 to 6, and examples of the preferable group include a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, an isopenyl group, a 2-methyl-1-propenyl group, a 3-methyl-1-propenyl group, a 2-methyl-2-propenyl group, a 3-methyl-2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-pentenyl group, a 1-hexenyl group, a 1,3-hexanedienyl group, a 1,6-hexanedienyl group, and the like.
The “C2-6 alkynyl group” used in the present specification denotes an alkynyl group having a carbon number of 2 to 6, and preferable examples of the group include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 3-methyl-1-propynyl group, a 1-ethynyl-2-propynyl group, a 2-methyl-3-propynyl group, a 1-pentynyl group, a 1-hexynyl group, a 1,3-hexanediyneyl group, a 1,6-hexanediyneyl group, and the like.
The “C3-8 cycloalkyl group” in the present specification denotes a cycloalkyl group formed by 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl and the like. Examples of the C3-8 cycloalkenyl group in the present specification include a 2-cyclopropen-1-yl group, a 3-cyclopropenyl group, a 1-cyclobutenyl group, a 4-cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, and the like.
The “C1-6 alkoxy group” used in the present specification denotes an alkoxy group having a carbon number of 1 to 6, such as a methoxy group, an ethoxy group, a n-propoxy group, an iso-propoxy group, a sec-propoxy group, an n-butoxy group, an iso-butoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentyloxy group, an iso-pentyloxy group, a sec-pentyloxy group, a n-hexoxy group, an iso-hexoxy group, a 1,1-dimethylpropyloxy group, a 1,2-dimethylpropoxy group, a 2,2-dimethylpropyloxy group, a 2-ethylpropoxy group, a 1-methyl-2-ethylpropoxy group, a 1-ethyl-2-methylpropoxy group, a 1,1,2-trimethylpropoxy group, a 1,1,2-trimethylpropoxy group, a 1,1-dimethylbutoxy group, a 1,2-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2,3-dimethylbutyloxy group, a 1,3-dimethylbutyloxy group, a 2-ethylbutoxy group, a 1,3-dimethylbutoxy group, a 2-methylpentoxy group, a 3-methylpentoxy group, a hexyloxy group, and the like.
The “C2-6 alkenyloxy group” used in the present specification denotes an alkenyloxy group having a carbon number of 2 to 6, such as a vinyloxy group, an allyloxy group, a 1-propenyloxy group, a 2-propenyloxy group, an isopropenyloxy group, a 2-methyl-1-propenyloxy group, a 3-methyl-1-propenyloxy group, a 2-methyl-2-propenyloxy group, a 3-methyl-2-propenyloxy group, a 1-butenyloxy group, a 2-butenyloxy group, a 3-butenyloxy group, a 1-pentenyloxy group, a 1-hexenyloxy group, a 1,3-hexanedienyloxy group, a 1,6-hexanedienyl group, and the like.
The “C1-6 alkylthio group” used in the present specification denotes an alkylthio group having a carbon number of 1 to 6. For example, a methylthio group, an ethylthio group, a n-propylthio group, an iso-propylthio group, a n-butylthio group, an iso-butylthio group, a sec-butylthio group, a tert-butylthio group, a n-pentylthio group, a 1,1-dimethylpropylthio group, a 1,2-dimethylpropylthio group, a 2,2-dimethylpropylthio group, a 1-ethylpropylthio group, a 2-ethylpropylthio group, a n-hexyl group, a 1-methyl-2-ethylpropylthio group, a 1-ethyl-2-methylpropylthio group, a 1,1,2-trimethylpropylthio group, a 1-propylpropylthio group, a 1-methylbutylthio group, a 2-methylbutylthio group, a 1,1-dimethylbutylthio group, a 1,2-dimethylbutylthio group, a 2,2-dimethylbutylthio group, a 1,3-dimethylbutylthio group, a 2,3-dimethylbutylthio group, a 2-ethylbutylthio group, a 2-methylpentylthio group, a 3-methylpentylthio group, and the like may be proposed.
The “a C2-6 alkenylthio group” used in the present specification denotes an alkenylthio group having a carbon number of 2 to 6. For example, a vinylthio group, an allylthio group, a 1-propenylthio group, a 2-propenylthio group, an isopropenylthio group, a 2-methyl-1-propenylthio group, a 3-methyl-1-propenylthio group, a 2-methyl-2-propenylthio group, a 3-methyl-2-propenylthio group, a 1-butenylthio group, a 2-butenylthio group, a 3-butenylthio group, a 1-pentenylthio group, a 1-hexenylthio group, a 1,3-hexanedienylthio group, a 1,6-hexanedienylthio group, and the like may be proposed.
The C6-14 aromatic hydrocarbon cyclic group in the “C6-14 aromatic hydrocarbon cyclic group optionally having a substituent” used in the present specification refers to an aromatic hydrocarbon cyclic group having a carbon number of 6 to 14, and includes a fused ring such as a dicyclic group, a tricyclic group and the like in addition to a monocyclic group. Preferable examples of the group include a phenyl group, an indenyl group, a 1-naphthyl group, a 2-naphthyl group, an azulenyl group, a heptalenyl group, biphenyl group, an indacenyl group, an acenaphthyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group, an anthracenyl group, a cyclopentacyclooctenyl group, a benzocyclooctenyl and the like.
The “allyl” and “aryl group” used in the present specification denote have the same meanings as the C6-14 aromatic hydrocarbon cyclic group.
The 5- to 14-membered aromatic heterocyclic group in the “5- to 14-membered aromatic heterocyclic group optionally having a substituent” used in the present specification refers to a monocyclic, dicyclic or tricyclic 5- to 14-membered aromatic heterocyclic group containing at least one hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the group include, as the nitrogen-containing aromatic heterocyclic group, a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a tetrazolyl group, a benzotriazolyl group, a pyrazolyl group, an imidazolyl group, a benzimidazolyl group, an indolyl group, an isoindolyl group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizyl group, a phthalazyl group, a naphthyridinyl group, a quinoxalyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, an imidazotriazinyl group, a pyrazinopyridazinyl group, an acridinyl group, a phenanthridinyl group, a carbazolyl group, a carbazolinyl group, a pyrimidinyl group, a phenanthrolinyl group, a phenacinyl group, an imidazopyridinyl group, an imidazopyrimidinyl group, a pyrazolopyridinyl group, a pyrazolopyridinyl group, and the like; as the sulfur-containing aromatic heterocyclic group, a thienyl group, a benzothienyl group, and the like; as the oxygen-containing aromatic heterocyclic group, a furyl group, a pyranyl group, a cyclopentapyranyl group, a benzofuryl group, an isobenzofuryl group, and the like; as the aromatic heterocyclic group containing two or more different hetero atoms, a thiazolyl group, an isothiazolyl group, a benzothiazolyl group, a benzthiadiazolyl group, a phenothiazinyl group, an isoxazolyl group, a furazanyl group, a phenoxazinyl group, an oxazolyl group, an isoxazolyl group, a benzoxazolyl group, oxadiazolyl group, a pyrazolooxazolyl group, an imidazothiazolyl group, a thienofuranyl group, a furopyrrolyl group, a pridoxazinyl group, and the like.
The “heteroaryl” and “heteroaryl group” used in the present specification have the same meanings as the 5- to 14-membered aromatic heterocyclic group.
The “5- to 14-membered non-aromatic heterocyclic group” used in the present specification refers to a a saturated or unsaturated, monocyclic, dicyclic or tricyclic 5- to 14-membered non-aromatic heterocyclic group having aromatic property and containing at least one hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the group include a pyrrolidinyl group, a pyrrolyl group, a piperidinyl group, a piperazinyl group, an imidazolyl group, a pyrazolidyl group, an imidazolidyl group, a morpholyl group, a pyranyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolinyl group, a dihydrofuryl group, a dihydropyranyl group, an imidazolinyl group, an oxazolinyl group, and the like. In addition, the group includes groups derived from a pyridone ring, and groups derived from a non-aromatic fused ring (e.g. phthalimide ring, succinimide ring etc.).
The “5- to 14-membered heterocyclic group” used in the present specification denotes a 5- to 14-membered aromatic or non-aromatic heterocyclic group, and the meaning of each word is as defined above.
The “C2-7 aliphatic acyl group” denotes an atomic entity obtained by removing a OH group from a carboxyl group of a C2-7 aliphatic saturated carboxylic acid or C2-7 aliphatic unsaturated carboxylic acid, and the preferable examples of the group include an acetyl group, a propionyl group, a butyroyl group, and the like.
The “C1-6 alkylsulfinyl group” used in the present specification denotes a sulfinyl group to which the above-mentioned C1-6 alkyl group is bound, and examples thereof include a methylmethylsulfinyl group, an ethylsulfinyl group, a n-propylsulfinyl group, an iso-propylsulfinyl group, and the like.
The “C1-6 alkylsulfonyl group” used in the present specification denotes a sulfonyl group to which the above-mentioned C1-6 alkyl group is bound, and examples thereof include a methylmethylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group, an iso-propylsulfonyl group, and the like.
The “C3-8 cycloalkyl C1-6 alkyl group” and “C3-8 cycloalkyl C2-6 alkenyl group” used in the present specification denote a C1-6 alkyl group (examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, etc.) and a C2-6 alkenyl group (examples of the alkenyl group include a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, etc.), each of which may be substituted with the above-mentioned C3-8 cycloalkyl group (e.g. cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclheptyl group, cyclooctyl group, etc.). Preferable examples thereof are not particularly limited, but include a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropyl n-propyl group, a cyclobutylmethyl group, a cyclobutylethyl group and the like, and a cyclopropylvinyl group, a cyclopropylallyl group and the like, respectively.
The “C1-10 alkoxy C1-10 alkyl group” and “C1-10 alkoxy C2-8 alkenyl group” used in the present specification denote a C1-1, alkyl group (examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a 1,1-dimethylpropyl group, etc.) and a C2-8 alkenyl group (examples of the alkenyl group include a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, etc.), each of which may be substituted with an alkoxy group having a carbon number of 1 to 10 (examples of the alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an iso-propoxy group, etc.).
The “C2-6 alkenyloxy C1-6 alkyl group” and “C2-6 alkenyloxy C2-6 alkenyl group” used in the present specification denote a C1-6 alkyl group (examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a 1,1-dimethylpropyl group, etc.) and a C2-6 alkenyl group (examples of the alkenyl group include a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, etc.), each of which may be substituted with the above-mentioned C2-6 alkenyloxy group (examples of the alkenyloxy group include a vinyloxy group, an allyloxy group, a 1-propenyloxy group, a 2-propenyloxy group, an isopropenyloxy group, a 2-methyl-1-propenyloxy group, etc.).
The “a C1-6 hydroxyalkyl group” used in the present specification denotes a C1-6 alkyl group (examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a 1,1-dimethylpropyl group, etc.) optionally substituted with at least one hydroxyl group, and preferable examples thereof are not particularly limited, but include more preferably a C1-6 alkyl group substituted with one hydroxyl group, such as a hydroxymethyl group, a 2-hydroxy-1-ethyl group, a 2-hydroxy-1-propyl group and the like.
The “C1-6 alkyl group substituted with a 5- to 14-membered non-aromatic heterocyclic group” used in the present specification denotes a C1-6 alkyl group substituted with the above-mentioned 5- to 14-membered non-aromatic heterocyclic group (e.g. pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinyl group, imidazolyl group, pyrazolidyl group, imidazolidyl group, morpholyl group, tetrahydrofuryl group, pyranyl group, tetrahydropyranyl group, pyrrolinyl group, dihydrofuryl group, dihydropyranyl group, imidazolinyl group, oxazolinyl group, pyridone-yl group, phthalimide-yl group, succinimide-yl group etc.) at an arbitrary position. Preferable examples thereof are not particularly limited, but more preferable examples thereof include a methyl group, an ethyl group, a n-propyl group, an iso-butyl group, an n-butyl group and a tert-butyl group, each of which are substituted with a pyrrolidinyl group, a pyrrolyl group, a piperidinyl group, a piperazinyl group, an imidazolyl group, a pyrazolidyl group, an imidazolidyl group, a morpholyl group, a tetrahydrofuryl group, a pyranyl group or a tetrahydropyranyl group.
The “C1-6 alkylthio C1-6 alkyl group” used in the present specification denotes a C1-6 alkyl group (examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a 1,1-dimethylpropyl group, etc.) substituted with the above-mentioned C1-6 alkylthio group (e.g. methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, etc.) at an arbitrary position.
The “aminocarbonyl C1-6 alkyl group” used in the present specification denotes a C1-6 alkyl group (examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a 1,1-dimethylpropyl group, etc.) substituted with a group represented by the formula —CONH2 at an arbitral position.
The “heteroarylcarbonyl group” used in the present specification denotes a carbonyl group to which the above-mentioned heteroaryl group (e.g. pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolizyl group, phthalazyl group, naphthyridinyl group, quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinyl group, perimidinyl group, phenanthrolinyl group, phenacinyl group, imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl group, pyrazolopyridinyl group, thienyl group, benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group, isobenzofuryl group, thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, isoxazolyl group, benzoxazolyl group, oxadiazolyl group, pyrazoloxazolyl group, imidazothiazolyl group, thienofuranyl group, furopyrrolylcarbonyl group or oxazinyl carbonyl group) is bound. Preferable examples thereof are not particularly limited, but more preferable examples thereof include a carbonyl group to which a monocyclic heteroaryl group (pyrrolyl group, thienyl group, furyl group, imidazolyl group, pyrazolyl group, thiazolyl group, pyridyl group, etc.) is bound.
The “heteroaryl C1-6 alkyl group” used in the present specification denotes a C1-6 alkyl group substituted with the above-mentioned heteroaryl group at an arbitrary position. Preferable examples thereof are not particularly limited, but more preferable examples thereof include a C1-6 alkyl group (example of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a 1,1-dimethylpropyl group, etc.) to which a pyrrolyl group, a thienyl group, a furyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group or a pyridyl group is bound.
The “aryl C1-6 alkyl group” used in the present specification denotes a C1-6 alkyl group substituted with the above-mentioned aryl group (e.g. phenyl group, naphthyl group, etc,) at an arbitrary position, and is preferably a C1-6 alkyl group substituted with a phenyl group, more preferably a benzyl group, a phenyl ethyl group, or the like.
The “C1-6 alkoxycarbonyl group” used in the present specification denotes a carbonyl group to which a C1-6 alkoxy group is bound. Preferable examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an iso-propoxycarbonyl group, and the like. The “C2-6alkenyloxycarbonyl group” denotes a carbonyl group to which a C2-6 alkenyloxy group is bound. Preferable examples thereof-include a vinyloxycarbonyl group, an allyloxycarbonyl group, a 1-propenyloxycarbonyl group, a 2-propenyloxycarbonyl group, an isopropenyloxycarbonyl group, a 2-methyl-1-propenyloxycarbonyl group and the like.
The “halogeno-C1-6 alkyl group” used in the present specification denotes a C1-6 alkyl group (examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, etc.) substituted with at least one halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom, etc.) at an arbitrary position. Preferable examples thereof are not particularly limited, but more preferable examples thereof include a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group and tert-butyl group, each of which are substituted with 1 to 4 atom(s) selected from a fluorine atom, a chlorine atom and a bromine atom (e.g. trifluoromethyl group etc.).
The “halogeno-C1-6 alkoxy group” used in the present specification denotes a C1-6 alkoxy group (examples of the alkyl group include a methoxy group, an ethoxy group, a n-propoxy group, an iso-propoxy group, etc.) substituted with at least one halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom, etc.) at an arbitrary position. Preferable examples thereof are not particularly limited, but more preferable examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, an iso-propoxy group, a n-butoxy group, an iso-butoxy group, a sec-butoxy group and a tert-butoxy group, each of which are substituted with 1 to 4 atom(s) selected from a fluorine atom and a chlorine atom (e.g. trifluoromethoxy group etc.).
In the present specification, R1, R2 and R3 are the same as or different from each other and each may have a substituent. Preferable examples of the substituent include (1) a halogen atom, (2) a hydroxyl group, (3) a nitro group, (4) a cyano group, (5) a carboxyl group, (6) a C1-6 alkyloxycarbonyl group, and (7) the formula—S(O)rR13 (wherein r denotes an integer of 0, 1 or 2; and R13 denotes (a) a hydrogen atom, (b) a C1-6 alkyl group, (c) the formula —NR14R15 (wherein R14 and R15 are the same as or different from each other and each denotes a hydrogen atom, a C1-6 alkyl group optionally substituted with an optionally substituted aryl group, a C1-4 alkylacyl group, an optionally substituted aryl C1-4 alkyl group, an optionally substituted heteroaryl C1-4 alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group), (d) an optionally substituted aryl C1-4 alkyl group, (e) an optionally substituted aryl group, (f) an optionally substituted heteroaryl C1-4 alkyl group, or (g) an optionally substituted heteroaryl group, (h) —NR16R17 (wherein R16 and R17 are the same as or different from each other and each denotes a hydrogen atom, a C1-6 alkyl group or a C1-4 alkylacyl group), (i) a C1-6 alkyl group, (j) a C1-6 alkoxy group, (k) a C3-8 cycloalkyl group optionally substituted with a C1-4 alkyl group, (1) a C1-4 alkoxy C1-6 alkyl group, (m) a saturated 3- to 8-membered heterocyclic ring optionally substituted with a C1-4 alkyl group, (n) an optionally substituted aryl group, (o) an optionally substituted heteroaryl group, (p) a C2-6 alkenyl group, (q) a C2-8 alkynyl group, (r) a C2-6 alkenyloxy group, and the like).
The meanings of groups expressed as R1, R2, R3, X, Y and X in the formula of Compound (I) of the present invention are as defined above.
Preferable examples of each group are not particularly limited, but more preferable examples in the case of R1 include a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, -G1-A2 (wherein G1 and A2 have the same meanings as defined above) and the like, most preferably a C1-6 alkyl group (e.g. methyl group, ethyl group, etc,), C1-6 alkoxy group (e.g, methoxy group, ethoxy group, etc.), a C1-6alkylthio group (e.g. methylthio group, ethylthio group, etc.) and the like.
More preferable examples in R2 include a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-8 cycloalkyl C1-6 alkyl group, a C3-8 cycloalkyl C2-6 alkenyl group, a C1-10 alkoxy C1-10 alkyl group, a C1-6 alkoxy C2-8 alkenyl group, a C2-6 alkenyloxy C1-6 alkyl group, a C2-6 alkenyloxy C2-6 alkenyl group, —NR2aR2b (R2a and R2b have the same meanings as defined above) and the like, most preferably —NR2aR2b (R2a and R2b have the same meanings as those defined above).
More preferable examples in R3 include a phenyl group optionally having a substituent, and a 5- or 6-membered aromatic heterocyclic group (e.g. pyrrolyl group, imidazolyl group, pyrazolyl group, thienyl group, furyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazyl group, pyrimidyl and pyrazyl group) optionally having a substituent, and most preferable examples include a phenyl group and a pyridyl group, each of which may have a substituent. In addition, more preferable examples of the substituent include groups selected from a halogen atom (fluorine atom, chlorine atom, bromine atom or iodine atom), a hydroxyl group, a nitro group, a cyano group, a carboxyl group, a C1-6 alkyloxycarbonyl group, —S(O)rR13 (wherein r denotes an integer of 0, 1 or 2; and R13 denotes (a) a hydrogen atom, (b) a C1-6 alkyl group, (c) the formula —NR14R15 (wherein R14 and R15 are the same as or different from each other and each denotes a hydrogen atom, a C1-6 alkyl group optionally substituted with an optionally substituted aryl group, a C1-4 alkylacyl group, an optionally substituted aryl C1-4 alkyl group, an optionally substituted heteroaryl C1-4 alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group), (d) an optionally substituted aryl C1-4 alkyl group, (e) an optionally substituted aryl group, (f) an optionally substituted heteroaryl C1-4 alkyl group or (g) an optionally substituted heteroaryl group), —NR16R17 (wherein R16 and R17 are the same as or different from each other and each denotes a hydrogen atom, a C1-6 alkyl group or a C1-4 alkylacyl group), a C1-6 alkyl group (e.g. methyl group, ethyl group, n-propyl group, iso-propyl group, etc.), a C1-6 alkoxy group (e.g. methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, etc.), a C1-6 alkylthio group (e.g. methylthio group, ethylthio group, etc.), a C1-4 alkoxy C1-6 alkyl group (e.g. methoxymethyl group etc.) a halogeno-C1-6 alkyl group (e.g. trifluoromethyl group etc.), a halogeno-C1-6 alkoxy group (e.g. trifluoromethoxy group etc.), and the like, and more preferable examples include groups selected from a halogen atom, a cyano group, a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno-C1-6 alkyl group, a halogeno-C1-6 alkoxy group, a monoalkylamino group, a dialkylamino group and the like. More specifically, most preferable examples in R3 include a phenyl group and a pyridyl group, each of which may be substituted with 1, 2 or 3 group(s) selected from a halogen atom (fluorine atom, chlorine atom or bromine atom), a cyano group, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a methylthio group, an ethylthio group, a trifluoromethyl group, a trifluoromethoxy group, a methylamino group and a dimethyl group.
In addition, a possible combination of X, Y and Z is not particularly limited as far as at least two denote CR4 (R4 has the same meaning as defined above) at the same time.
The preferable examples of the Compound (I) relating to the present invention are not particularly limited. More preferable examples thereof include a compound represented by formula:
(wherein X′ and Z′ are independent of each other and each denotes N or CH (in this case, at least one of X′ and Z′ denote CH); and G4, R2 and R3 have the same meanings as defined above each) or a salt thereof, further preferable examples thereof include a compound (hereinafter, referred to as “Compound (III)” in some cases) represented by the formula:
(wherein Z″ denotes N or CH, the ring M denotes a benzene ring optionally further having a substituent; and G4, R2a and R2b have the same meanings as defined above each) or a salt thereof, and most preferable examples include Compound (III) wherein R2a and R2b are independent of each other and each denotes a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-6 alkynyl group, a C1-6 alkyl group substituted with a 5- to 14-membered non-aromatic heterocyclic group, a C1-8 alkoxy C1-8 alkyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkyl C1-6alkyl group, and respective groups may be further substituted, independently, with a halogen atom, and the ring M is a benzene ring optionally substituted with 1 to 3 group (s) selected from a halogen atom, a C1-6 alkyl group, a halogeno-C1-6 alkyl group, a halogeno-C1-6 alkoxy group and a C1-6 alkoxy group.
The “salt” used in the present specification is not particularly limited as far as it forms a salt with the compound of the present invention and is pharmacologically acceptable, and preferable examples of the salt include a hydrogen halide salt (e.g. hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), an inorganic acid salt (e.g. sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), an organic carboxylic acid salt (e.g. acetate, trifluoroacetate, oxalate, maleate, tartrate, fumarate, citrate, etc.), an organic sulfonic acid salt (e.g. methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), an amino acid salt (e.g. aspartate, glutamate, etc.), a quaternary amine salt, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (magnesium salt, calcium salt, etc.) and the like, and more preferable examples of the “pharmacologically acceptable salt” include hydrochloride, oxalate, trifluoroacetate and the like.
A representative process for preparing the compound represented by the aforementioned formula (I) relating to the present invention will be shown below. In the following process schemes, R1, R2a, R2b, X, Y and Z have the same meanings as defined above; R5 and R6 have the same meaning as R4, and are independently defined; R denotes a hydrocarbon group; R′ and R″ are independent of each other and each denotes alkyl, alkenyl or alkynyl; Rs denotes a C1-6 alkyl group or the like; Rg and Rh denote a hydrocarbon group; Ar denotes an aryl or heteroaryl group; T denotes a halogen atom (particularly preferable are a chlorine atom, a bromine atom and an iodine atom); T′ denotes a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom, etc.); Ts denotes a halogen atom or the like; a symbol represented by Pro denotes a protecting group; and a symbol represented by Lev represents a halogen atom or a leaving group (e.g. trifluoromethanesulfonyl group etc.). The “room temperature” described below refers to around 0 to 40° C.
Step A: An imidazo[1,2-a]pyrazine derivative (3) can be obtained by reacting an aminopyrazine derivative (1) and an α-chloro-β-ketoester derivative (2) at 0 to 200° C. in a solvent or without a solvent. The solvent to be used is different depending on starting materials, regents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferably, acetic acid, toluene, xylene, methanol, ethanol, ethylene glycol monomethyl ether, N,N-dimethylformamide and the like can be used alone or by mixing them.
Step B: An imidazo[1,2-a]pyrazine-3-carboxylic acid ester derivative (5) substituted with an aryl group at the 8-position can be obtained by reacting an imidazo[1,2-a]pyrazine-3-carboxylic acid ester derivative (3) with an aryl-metal compound (4 in the formula) such as an aryltin compound and an arylboronic acid compound at 0 to 250° C. using a palladium or nickel metal complex in the presence or absence of a base in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, regents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples of the solvent include benzene, toluene, xylene, anisole, N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, n-butanol, ethanol, methanol, N-methyl-2-pyridone, water and the like. In addition, the base to be used is different depending on starting raw materials, a solvent to be used, and the like, and is not particularly limited as far as it does not inhibit a reaction. Preferable examples of the base include potassium carbonate, sodium carbonate, cesium fluoride, potassium fluoride, sodium bicarbonate, barium hydroxide, triethylamine and the like. Examples of the palladium or nickel metal complex to be used include Pd(PPh3)4, Pd(OAc)2/PPh3, PdCl2, PdCl2(dppf), Ni(dpp)2Cl2, Cl2 and the like.
Step C: An imidazo[1,2-a]pyrazine-3-carboxylic acid derivative (6) can be obtained by hydrolyzing an imidazo[1,2-a]pyrazine-3-carboxylic acid ester derivative (5) at 0 to 200° C. in the presence of a base in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, regents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferably, ethanol, methanol, n-butanol, t-butanol, tetrahydrofuran, dioxane, water and the like can be used alone or as a mixed solvent. The base to be used is different depending on starting raw materials, a solvent to be used, and the like, and is not particularly limited as far as it does not inhibit a reaction. Preferable examples of the base include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and potassium t-butoxide.
Steps D, E, F: An imidazo[1,2-a]pyrazine-3-carboxylic acid derivative (6) is reacted with an aziding agent such as diphenylphosphorylazide (DPPA) at −70 to 250° C. in the presence or absence of a base in a solvent or without a solvent to obtain an acid azide derivative (7), this acid azide derivative is heated to a temperature of 0 to 250° C. to cause a rearrangement reaction such as Curtius rearrangement reaction, producing isocianate (8) in situ, which can be reacted with tert-butanol or the like to obtain 3-amino-imidazo[1,2-a]pyrazine derivative (9) protected with a carbamate group such as tert-butoxycarbonyl (Boc) and the like. The solvent to be used is different depending on starting raw materials, regents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferably, benzene, toluene, xylene, diphenyl ether, t-butanol, tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide and the like can be used alone or as a mixed solvent. Examples of the base to be used include triethylamine, diisopropylethylamine, 4-(dimethylamino)pyridine, and pyridine.
On the other hand, acid azide derivative (7) can be also prepared by derivatizing an imidazo[1,2-a]pyrazine-3-carboxylic acid derivative (6) into acid chloride or mixed acid anhydride, and aziding the (6) with a aziding agent (e.g. sodium azide, trimethylsilylazide, etc.).
Alternatively, a 3-amino-imidazo[1,2-a]pyrazine derivative (9) may be prepared from Hofmman rearrangement reaction or Schmidt rearrangement reaction.
Step G: An imidazo[1,2-a]pyrazine derivative (10) can be obtained by reacting a 3-amino-imidazo[1,2-a]pyrazine derivative (9) with a carbonyl derivative such as diethyl ketone or an aldehyde derivative such as propionaldehyde at −10 to 150° C. in the presence of a reducing agent. When this step is performed in the presence or absence of an acid in a solvent or without a solvent, and in the presence or absence or an inorganic salt, the better results can be obtained. The solvent to be used is different depending on starting raw materials, regents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substance to some extent. Preferable examples include tetrahydrofuran, diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, water and the like, and these can be used alone or as a mixed solvent. In addition, the acid to be used is different depending on starting raw materials, a solvent to be used, and the like, and is not particularly limited as far as it does not inhibit a reaction. Preferable examples include acetic acid, sulfuric acid and the like. In addition, an inorganic salt to be used is different depending on starting raw materials, a solvent to be used, and the like, and is not particularly limited as far as it does not inhibit a reaction. Preferable examples include sodium sulfate, magnesium sulfate and the like. In addition, examples of a reducing agent to be used include sodium triacetoxyborohydride, sodium borohydride, and sodium cyanotrihydridoborate.
Alternatively, an imidazo[1,2-a]pyrazine derivative (10) can be also obtained by reacting a 3-amino-imidazo[1,2-a]pyrazine derivative (9) with an alkylating agent (alkyl halide etc.) containing a leaving group such as halide, an acylating agent such as acid chloride and acid anhydride or sulfonic acid chloride such as p-toluenesulfonic acid chloride and the like at −70 to 200° C. in the presence or absence of a base in a solvent or without a solvent. The solvent to be used is different depending on the starting raw material, regents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide and the like. In addition, examples of the base to be used include sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, pyridine, triethylamine and the like.
Step H: An imidazo[1,2-a]pyrazine derivative (11) can be obtained by reacting an imidazo[1,2-a]pyrazine derivative (10) at −70 to 200° C. in the presence or absence of a deprotecting agent in a solvent or without a solvent, to deprotect a protecting group such as a tert-butoxycarbonyl group (Boc) and the like. The solvent to be used is different depending on starting raw materials, regents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include ethyl acetate, tetrahydrofuran, diethyl ether, dioxane, acetonitrile, dichloromethane, chloroform, nitromethane, phenol, anisole, thiophenol and the like. Examples of the deprotecting agent to be used include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, iodotrimethylsilane, aluminum (III) chloride, trimethylsilyl triflate and the like. When a protecting group other than Boc (e.g. Fmoc, Troc etc.) is used, it is enough to use a deprotecting agent and a reaction suitable for the protecting group.
Step I: An imidazo[1,2-a]pyrazine derivative (I) of the present invention can be prepared as in the aforementioned step G.
Step A: A deprotected derivative (12) can be obtained by subjecting a dicyclic nitrogen-containing heterocyclic derivative (9) having a protected amino group at the 3-position and having a fused imidazole ring, to the same reaction as that of step H in Producing Process 1.
Step B: A dicyclic nitrogen-containing heterocyclic derivative (I) having a fused imidazole ring, which is a compound of the present invention, can be prepared by subjecting an amine derivative (12) to the same reaction as that of the step G in Producing Process 1 to introduce a substituent therein.
In the present process, first, Compound (13) can be prepared by subjecting Compound (3) to the same reaction as that of the step C in Producing Process 1 (step A). Compound (16) can be prepared by subjecting the Compound (13) obtained in step A to the same rearrangement reactions as those of steps D, E, F in Producing Process 1 (steps B, C and D). Compound (17) can be prepared by subjecting Compound (16) to the same reaction as that of the step G in Producing Process 1 (step E). Compound (18) can be prepared by subjecting Compound (17) to the same reaction as that of the step H in Producing Process 1 (step F). Compound (19) can be prepared by subjecting Compound (18) to the same reaction as that of the step I in Producing Process 1 (step G). Finally, Compound (19) can be subjected to the same reaction as that of the step B in Producing Process 1 to prepare the Compound (I) of the present invention (step H).
In the formula, Lev has the same meaning as defined above. In the present Producing Process, first, Compound (17) can be prepared by subjecting Compound (16) to the same deprotecting reaction as that of the step H in Producing Process 1 (step A). Finally, Compound (17) can be subjected to the same substituent introducing reaction as that of the step I in Producing Process 1 to prepare the Compound (I) relating to the present invention.
In the formula, Lev has the same meaning as defined above. In the present Producing Process, derivatives ((9), (10) or (11)) with an aryl group introduced at the 8-position can be prepared by subjecting Compound (16), (17) or (18) to the same coupling reaction as that of the step B in Producing Process 1, corresponding to respective starting raw materials.
Step A: A halogenated 2-aminopyrazine derivative (22) can be obtained by reacting a 2-aminopyradine derivative (21) in the formula with a halogenating agent (e.g, N-chlorosuccinimide etc.) at 0 to 200° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples of the solvent include acetic acid, toluene, xylene, methanol, ethanol, diethyl ether, ethylene glycol monomethyl ether, N,N-dimethylformamide, dichloromethane, chloroform, carbon tetrachloride and the like, and these solvents can be used alone or by mixing them. As the halogenating agent, for example, chlorine, bromine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and the like can be used. However, the carbon atom to which R4 is bound is halogenated in some cases, depending on the halogenating conditions.
Step B: An imidazo[1,2-a]pyrazine derivative (5′) can be obtained by subjecting a 2-aminopyrazine derivative (22) and an α-chloro-β-ketoester derivative (2) to the same reaction as that of the step A in Producing Process 1.
The derivative (5′) in the present Producing Process 6 can be subjected to the same reaction as that using the derivative (5) in Producing Process 1 to prepare the Compound (I) of the present invention.
Step A: A 2-aminopyrazine acid derivative (24) can be prepared by subjecting a pyrazine-2-carboxylic acid derivative (23) to a rearrangement reaction such as Curtius rearrangement reaction and the like shown in steps D, E and F in a process 1.
Step B: A halogenated 2-aminopyrazine derivative (25) can be obtained by reacting a 2-aminopyrazine derivative (24) with a halogenating agent at a temperature between −70 and 200° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it is does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples of the solvent include acetic acid, toluene, xylene, pyridine, pyrimidine, 4-(dimethylamino)pyridine, methanol, ethanol, diethyl ether, ethylene glycol monomethyl ether, N,N-dimethylformamide, dichloromethane, chloroform, carbon tetrachloride and the like, and these solvents can be used alone or by mixing them. As the halogenated agent, for examples, chlorine, bromine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and the like can be used.
Step C: An imidazo[1,2-a]pyrazine derivative (3) can be prepared by subjecting an aminopyrazine derivative (25) and an α-chloro-β-ketoester derivative (2) to the same reaction as that of the step A in Producing Process 1.
The derivative (3) in the present Producing Process 7 can be subjected to the same reaction as the reaction using the derivative (3) in Producing Process 1 to prepare the Compound (I) of the present invention.
Step A: An imidazo[1,2-a]pyrazine derivative (28) can be prepared by reacting an aminopyrazine derivative (27) and an α-halogenoketone derivative (26) at between 0° C. and 200° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents, and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetic acid, toluene, xylene, methanol, ethanol, ethylene glycol monomethyl ether, N,N-dimethylformamide and the like, and these solvents can be used alone or by mixing them.
Step B: A 3-nitro-imidazo[1,2-a]pyrazine derivative (29) can be obtained by reacting a pyrazolo[1,5-a]pyrimidine derivative (28) with a nitrating agent at between −20° C. and 200° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetic anhydride, acetic acid, sulfuric acid, trifluoroacetic anhydride, trifluoroacetic acid, acetonitrile acid and the like. Examples of the nitrating agent include copper nitrate trihydrate, nitric acid, fuming nitric acid, NaNO3, NH4+NO3−, NO2BF4 and the like.
Step C: A 3-amino-imidazo[1,2-a]pyrazine derivative (30) can be obtained by reacting a 3-nitro-imidazo[1,2-a]pyrazine derivative (29) with a metal (powder) in the presence or absence of an acid in a solvent or without a solvent. The reaction temperature in the present step is usually between −10° C. and 150° C. Examples of the acid to be used include acetic acid, hydrochloric acid, sulfuric acid and the like. The solvent to be used is different depending on starting material, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples of the solvent include methanol, ethanol, n-butanol, water and the like, and these can be used alone or as a mixed solvent. In addition, examples of the metal (powder) to be used include Zn, Fe, SnCl2, NiCl2 and the like.
Alternatively, a 3-amino-imidazo[1,2-a]pyrazine derivative (30) may be prepared alos by subjecting a 3-nitro-imidazo[1,2-a]pyrazine derivative (4) to a hydrogenating reaction at between 0° C. and 200° C. and at a pressure of hydrogen of 1 to 100 atm in hydrogen atmosphere using a metal catalyst in the presence or absence of an acid in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include methanol, ethanol, propanol, butanol, tetrahydrofuran, dioxane, ethyl acetate, acetone, N,N-dimethylformamide and the like. Examples of the acid to be used include acetic acid, hydrochloric acid and the like. Examples of the metal catalysis to be used include Pd—C, PtO2, Pt—C, Raney-Ni and the like. Alternatively, the hydrogenating reaction in this alternative method may be also performed by generating hydrogen in situ by heating ammonium formate etc. in a solvent.
The derivative (30) in the present process 8 can be subjected to the same reaction as the reaction using the derivative (12) in the above-mentioned Producing Process 2 to prepare the Compound (I) of the present invention.
Step A: A 3-formyl compound (32) can be prepared by subjecting an imidazo[1,2-a]pyrazine derivative (31) to a reaction with phosphorus oxychloride under the conditions of Vilsmeier reaction. The present reaction is usually performed at a temperature of 0° C. to 200° C. in a solvent such as N,N-dimethylformamide and the like. Alternatively, a 3-formyl derivative (32) may be prepared by reacting an imidazo[1,2-a]pyrazine derivative (31) with dichloromethyl methyl ether in the presence of Lewis acid in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples of the solvent include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like, and these can be used alone or by mixing them. Examples of Lewis acid to be used include titanium tetrachloride, aluminum chloride, tin chloride and the like.
Step B: A secondary alcohol derivative (34) can be prepared by reacting a 3-formyl-imidazo[1,2-a]pyrazine derivative (32) with Grignard regent or an organic metal reagent (33) such as an alkyllithium reagent and the like. The present reaction is usually performed at between −100° C. and 100° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include diethyl ether, tetrahydrofuran, n-hexane, toluene and the like, and these can be used alone or by mixing them.
Step C: An ether derivative (36) can be prepared by reacting a secondary alcohol derivative (34) and an alkyl halide derivative (35) at between 0 and 200° C. in the presence of a base in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include diethyl ether, tetrahydrofuran, n-hexane, toluene, N,N-dimethylformamide, acetone and the like, and these can be used alone or by mixing them. The base to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include sodium hydride, potassium hydride, potassium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide and the like, and these can be used alone or by mixing them.
Step D: Compound (36) can be subjected to the same reaction as that of the step B in the above Producing Process 1 to prepare Compound (I) of the present invention.
Step A: A carbonyl derivative (37) can be prepared by reacting a secondary alcohol derivative (34) with an oxidizing agent such as manganese(IV) oxide and the like in solvent or without a solvent. The present reaction is usually performed at between −100° C. and 150° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetone, dichloromethane, n-hexane, toluene and the like, and these can be used alone or by mixing them. The oxidizing agent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited, but preferable examples thereof include manganese dichloride, Jones oxidizing regent, Kiliani regent, pyridinium dichromate, pyridinium chlorochromate, potassium dichromate and the like, and these maybe used alone or by mixing them. In addition, the oxidizing reaction in this step is not limited to a metal oxidizing agent, but may be performed under the oxidizing reaction conditions such as Swern oxidation and the like.
Step B: A derivative (I)C can be prepared by subjecting Compound (37) to the same reaction as that of the step B in Producing Process 1.
Step C: An olefin derivative (I)O can be prepared by treating a carbonyl derivative of the formula (I)C with Wittig regent or Horner-Emmons regent (38a) (Wittig reaction or Horner-Emmons reaction). The present reaction is usually performed in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include tetrahydrofuran, diethyl ether, dichloromethane, n-hexane, toluene and the like, and these may be used alone or by mixing them. Alternatively, an olefin derivative (I)O can be prepared by Reformatsky reaction or the like. In addition, in the present step, a carbonyl derivative (I)C can be reacted with a hydroxylamine derivative or its salt derivative such as hydrochloride and the like (38b) to prepare an oxime derivative. The reaction is usually performed at a temperature between 0° C. and 150° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include tetrahydrofuran, diethyl ether, ethanol, methanol, n-propanol, water and the like, and these may be used alone or by mixing them.
Step D: An alkyl derivative (I) of the present invention can be prepared by subjecting an olefin derivative (I)O to a hydrogenating reaction in the presence or absence of an acid in the presence of a metal catalyst such as Pd—C and the like in a solvent or without a solvent. The present reaction is usually performed at a temperature of 0° C. to 200° C. in hydrogen atmosphere at a hydrogen pressure of 1 atm to 100 atm. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include methanol, ethanol, propanol, butanol, ethyl acetate, dioxane, tetrahydrofuran, diethyl ether, N,N-dimethylformamide, n-hexane, toluene and the like, and these may be used alone or by mixing them. Examples of the acid to be used include acetic acid, hydrochloric acid and the like. Examples of the metal catalyst to be used include Pd—C, PtO2, Pt—C, Raney-Ni and the like. Alternatively, an objective compound may be obtained by generating hydrogen in situ by heating ammonium formate etc. in a solvent such as methanol.
Step A: Alkyl(alkylsulfanyl)methaneimido thioate (40) can be prepared by first reacting a 6-membered nitrogen-containing heterocyclic ring having an amino group (39) with a base at a temperature of 0° C. to 100° C. in a solvent or without a solvent, allowing to stand for a little while, reacting with carbon disulfide at a temperature of 0° C. to 100° C., further, adding a base at a temperature of 0° C. to 100° C., and subjecting to a reaction with alkyl halide (compound represented by RSTS in the formula) at a temperature of 0° C. to 100° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include N,N-dimethylformamide, methanol, ethanol, ethylene glycol monomethyl ether, toluene, water and the like, and these may be used alone or by mixing them. Examples of the base to be used include preferably sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like.
Step B: A dicyclic nitrogen-containing heterocyclic ring (42) which has an ester group at the 3-position and is fused with an imidazole ring, can be prepared by reacting alkyl(alkylsulfanyl)methaneimido thioate (40) with halogenoacetic acid ester (41) at a temperature of 0° C. to 200° C. in a solvent or without a solvent, then, cooling the reaction mixture to a room temperature, and treating the mixture with a base such as triethylamine and the like. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting materials to some extent. Preferable examples include N,N-dimethylformamide, methanol, ethanol, ethylene glycol monomethyl ether, toluene and the like, and these can be used alone or by mixing them. Examples of the base to be used include triethylamine, pyridine, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like.
When T″ in the formula is a halogen atom in Compounds 39 and 42 in the present Producing Process 11, the compounds can be derived into a derivative with an aryl group or the like introduced therein by performing the same coupling reaction as that of the step B in the above Producing Process 1. Alternatively, a derivative (42) can be prepared by subjecting to the same reaction as the reaction treating the derivative (5) in the above Producing Process 1.
Step A: A 3-aminopyridazine derivative (44) can be prepared by reacting a 3-oxo-alkyl cyanide derivative (43) with hydrazine at a temperature of 0° C. to 200° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetic acid, toluene, xylene, methanol, ethanol, ethylene glycol monomethyl ether, N,N-dimethylformamide, water and the like, and these can be used alone or by mixing them. Hydrazine may be also used as a corresponding salt such as hydrazine monohydrochloride and the like in the reaction.
Step B: An imidazo[1,2-b]pyridazine derivative (45) can be prepared by reacting a 3-aminopyridazine derivative (44) and an α-chloro-β-ketoester derivative (2) at a temperature of 0° C. to 200° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include toluene, xylene, methanol, ethanol, ethylene glycol monomethyl ether, N,N-dimethylformamide, dimethyl sulfoxide and the like, and these can be used alone or by mixing them.
Step C: An imidazo[1,2-b]pyridazine-3-carboxylic acid derivative (46) can be prepared by subjecting an imidazo[1,2-b]pyridazine-3-carboxylic acid ester derivative (45) or the like to a hydrolyzing reaction at a temperature of 0° C. to 200° C. in the presence of a base in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include ethanol, methanol, n-butanol, tert-butanol, tetrahydrofuran, dioxane, water and the like, and these can be used alone or as a mixed solvent. Examples of the base to be used include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium t-butoxide and the like.
Steps D, E, F: A 3-aminoimidazo[1,2-b]pyridazine derivative (49) protected with a carbamate group (e.g. tert-butoxycarbonyl (Boc) etc.) can be prepared by reacting an imidazo[1,2-b]pyridazine-3-carboxylic acid derivative (46) with a aziding agent (e.g. diphenylphosphorylazide etc.) at a temperature of −70° C. to 250° C. in the presence or absence of a base in a solvent or without a solvent to prepare an acid azide derivative (47), then, subjecting the acid azide derivative to a rearrangement reaction such as Curtius rearrangement reaction and the like by heating to 0 to 250° C., to generate isocyanate (48) in situ and, further, reacting this with tert-butanol or the like. The solvent to be used is different depending on starting materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include benzene, toluene, xylene, diphenyl ether, tert-butanol, tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide and the like, and these may be used alone or as a mixed solvent. Examples of the base to be used include triethylamine, diisopropylethylamine, 4-(dimethylamino)pyridine, and pyridine.
Besides, as another method of a process for preparing an acid azide derivative (47), the derivative may be prepared by deriving an imidazo[1,2-b]pyridazine3-carboxylic acid derivative (46) into acid chloride or mixed acid anhydride and, then, subjecting the derivative to a reaction with an aziding agent (e.g. sodium azide, trimethylsilylazide etc.). In addition, as another method for preparing a 3-amino-imidazo [1,2-b]pyridazine derivative (49), there are processes using Hofmann rearrangement reaction and Schmidt rearrangement reaction.
Step G: A 3-amino-imidazo[1,2-b]pyridazine derivative (50) can be prepared by subjecting a protected imidazo[1,2-b]pyridazine derivative (49) to a deprotecting reaction at a temperature of −70 to 200° C. in the presence or absence of a deprotecting agent in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include ethyl acetate, tetrahydrofuran, diethyl ether, dioxane, acetonitrile, dichloromethane, chloroform, nitoromethane, phenol, anisole, thiophenol and the like. In addition, examples of the deprotecting agent to be used include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, iodotrimethylsilane, aluminum (III) chloride, trimethylsilyl triflate and the like. In addition, when a protecting group other than Boc (e.g. Fmoc, Troc, etc.) is used as a protecting group for Compound (49), the compound is deprotected by a deprotecting agent and a reaction which are suitable for each protecting group.
Step H: An imidazo[1,2-b]pyridazine derivative (I) of the present invention can be obtained by reacting a 3-aminoimidazo[1,2-b]pyridazine derivative (50) with a carbonyl derivative (e.g. diethyl ketone) or an aldehyde derivative (e.g. propionaldehyde) in the presence or absence of an acid and in the presence or absence of an inorganic salt in a solvent or without a solvent, to form an imine derivative in the reaction system and, then, adding a reducing agent at a temperature of −10 to 150° C. to react them. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include tetrahydrofuran, diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, water and the like, and these can be used alone or as a mixed solvent. Examples of the acid to be used include acetic acid, sulfuric acid and the like. Examples of the inorganic salt to be used include sodium sulfate, magnesium sulfate and the like. Examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium borohydride, sodium cyanotrihydroborohydride and the like.
As another method regarding the present step, an imidazo[1,2-b]pyridazine derivative (I) can be prepared by reacting a 3-amino-imidazo[1,2-b]pyridazine derivative (50) with an alkylating agent containing a leaving group such as halide (e.g. alkyl halide etc.), an acylating agent (e.g. acid chloride, acid anhydride, etc.) or sulfonic acid chloride (e.g. tosylate chloride etc.) at a temperature of −70° C. to 200° C. in the presence or absence of a base in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide and the like. Examples of the base to be used include sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, pyridine, triethylamine and the like.
Step A: An aminopyridazine derivative (52) can be prepared by treating a 3-amino-6-chloropyridazine (51) with a halogenating agent, which is subjected to a halogenating reaction. The present reaction is usually performed in the presence or absence of a base in a solvent or without a solvent, and a reaction temperature is usually 0 to 200° C. The halogenating agent to be used is different depending on starting raw materials, a solvent to be used, and the like, and is not particularly limited as far as it does not inhibit a reaction. Preferable examples include bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, tetrabutylammonium tribromide and the like. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, methanol, ethanol, dichloromethane, acetic acid, carbon tetrachloride, water and the like. Examples of the base to be used include potassium carbonate, sodium carbonate, calcium carbonate, sodium bicarbonate and the like.
Step B: An aminopyridazine derivative (53) substituted with an aryl group at the 4-position can be prepared by subjecting an aminopyridazine derivative (52) to the same reaction as that of the step B in the above Producing Process 1.
Step C: A 3-aminopyridazine derivative (54) can be prepared by subjecting a 3-amino-4-aryl-6-chloropyridazine derivative (53) to a catalytic hydrogenating reaction. Such the catalytic hydrogenating reaction is usually performed in the presence or absence of a base and in the presence of a metal regent such as Pd—C and the like in a solvent or without a solvent, a hydrogen pressure is usually 1 to 100 atm, and a reaction temperature is usually 0 to 200° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include methanol, ethanol, propanol, butanol, ethyl acetate, dioxane, tetrahydrofuran, diethyl ether, N,N-dimethylformamide, n-hexane, toluene, acetic acid and the like, and these can be used alone or by mixing them. Examples of the base to be used include sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like. Examples of the metal regent to be used include Pd—C, PtO2, Pt—C, Raney-Ni and the like.
As another process regarding this step, a 3-aminopyridazine derivative (54) may be prepared by generating hydrogen in situ by heating a hydrogen source such as ammonium formate and the like in a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetic acid, methanol, ethanol, n-propanol and the like. Examples of the hydrogen source to be used include NaH2PO2, HCO2NH4, HCO2NH(CH2)3 and the like.
Step D: An imidazo[1,2-b]pyridazine derivative (55) can be prepared by reacting an aminopyridazine derivative (54) and an α-chloro-β-ketoester derivative (2) at a temperature of 0 to 200° C. in a solvent or without a solvent. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetic acid, toluene, xylene, methanol, ethanol, ethylene glycol monomethyl ether, N,N-dimethylformamide and the like, and these can be used alone or by mixing them.
Finally, the imidazo[1,2-b]pyridazine derivative (55) prepared by the present process can be subjected to the same reaction treating the imidazo[1,2-b]pyridazine derivative (45) in the above Producing Process 12, to prepare the compound of the present invention.
Step A: A nitrogen-containing heterocyclic derivative (I)L can be prepared by subjecting a dicyclic nitrogen-containing heterocyclic derivative (I)S to an oxidizing reaction, and converting a substituted sulfide group which binds to the 2-position of (I)S , into a leaving group (e.g. substituted sulfonyl group etc.). The oxidizing reaction is usually performed in a solvent or without a solvent, and a reaction temperature is −70 to 150° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include toluene, xylene, methanol, ethanol, tetrahydrofuran, ethylene glycol monomethyl ether, dichloromethane, chloroform and the like, and these can be used alone or by mixing them. Examples of the oxidizing agent to be used include meta-chloroperbenzoic acid, oxone and the like.
Step B: This step is for converting a dicyclic nitrogen-containing heterocyclic derivative (I)L having a leaving group (e.g. halogen atom, trifluoromethanesulfonyl group, etc.) into a dicyclic nitrogen-containing heterocyclic derivative (I)n to which a desired substituent Rn binds. As the reaction, a nucleophilic reaction using alkoxide, a metal cyan compound and the like, a coupling reaction using a Pd catalyst can be used. The number of a substituent to be introduced is not limited to one, and a derivative in which two or more substituents are introduced can be easily prepared.
Step A: A monocyclic nitrogen-containing heterocyclic derivative (58) substituted with an amino group of the above ethanolamine derivative at the 2-position can be prepared by reacting a monocyclic nitrogen-containing heterocyclic derivative (56) substituted with a halogen atom at the 2-position with the ethanolamine derivative (57). The reaction is performed in the presence or absence of a base and in a solvent or without a solvent, and a reaction temperature is usually 0 to 250° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include toluene, xylene, tetrahydrofuran, ethylene glycol dimethyl ether, N,N-dimethylformamide, 1,4-dioxane and the like, and these can be used alone or by mixing them. Examples of the base to be used include triethylamine, pyridine, 4-(dimethylamino)pyridine and the like.
Step B: A monocyclic nitrogen-containing heterocyclic derivative (59) substituted with halogen at the 3-position can be prepared by subjecting a monocyclic nitrogen-containing heterocyclic derivative (58) substituted with an amino group at the 2-position to a halogenating reaction. The halogenating reaction is usually performed by treating with a halogenating agent in a solvent or without a solvent, and a reaction temperature is usually 0 to 200° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetic acid, toluene, xylene, methanol, ethanol, diethyl ether, ethylene glycol monomethyl ether, N,N-dimethylformamide, dichloromethane, chloroform, carbon tetrachloride and the like, and these can be used alone or by mixing them. As the halogenating agent, for example, chlorine, bromine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and the like can be used.
Step C: A derivative (61) in which a dihydroimidazole ring is formed can be prepared by subjecting a monocyclic nitrogen-containing heterocyclic derivative (59) to a halogenating reaction, followed by cyclizing reaction. The reaction is usually performed in a solvent or without a solvent, and a reaction temperature is usually 0 to 200° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetic acid, toluene, xylene, tetrahydrofuran, ethylene glycol momomethyl ether, N,N-dimethylformamide, dichloromethane, chloroform, carbon tetrachloride and the like, and these can be used alone or by mixing them. As the halogenating agent, for example, chlorine, bromine, iodine, thionyl chloride, thionyl bromide and the like can be used.
Step D: A nitrogen-containing heterocyclic derivative (62) having an imidazole ring can be prepared by reacting a dicyclic nitrogen-containing heterocyclic derivative (61) having a dihydroimidazole ring with an oxidizing agent or an aromatizing agent. The reaction is usually performed in a solvent, and a reaction temperature is usually 0 to 250° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetone, dichloromethane, n-hexane, toluene, xylene, 1-methyl-2-pyrrolidinone and the like, and these can be used alone by mixing them. The oxidizing agent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited, but preferable examples include manganese (IV) oxide, pyridinium dichromate, pyridinium chlorochromate, potassium dichromate and the like, and these can be used alone or by mixing them. Examples of the aromatizing agent include 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, air oxidizing and the like.
Step E: An aldehyde compound (63) can be prepared by subjecting the nitrogen-containing heterocyclic derivative (62) having an imidazole ring to the same reaction as that of the step A in Producing Process 9.
Step F: The carboxylic acid compound (64) can be prepared by reacting an aldehyde compound (63) and an oxidizing agent. The reaction is usually performed in a solvent or without a solvent, and a reaction temperature is usually −10 to 200° C. The solvent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. Preferable examples include acetone, dichloromethane, n-hexane, toluene, xylene, acetonitrile, water and the like, and these can be used alone or by mixing them. The oxidizing agent to be used is different depending on starting raw materials, reagents and the like, and is not particularly limited, but preferable examples include potassium permanganate, silver oxide, activated manganese (IV) oxide, pyridinium dichromate, sodium chlorate and the like, and these can be used alone or by mixing them. The above derivative (64) can be subjected to the same reaction as that treating the derivative (13) in the above Producing Process 2 to prepare Compound (I) of the present invention.
The foregoing are representative examples of a process for preparing the Compound (I) of the present invention, but raw material compounds and various reagents in preparing the present compound may form a salt or a hydrate, and any of a salt and a hydrate is different depending on starting raw materials, a solvent to be used, and the like, and is not particularly limited as far as it does not inhibit a reaction. The solvent to be used is also different depending on starting raw materials, reagents and the like, and it goes without saying that the solvent is not particularly limited as far as it does not inhibit a reaction and dissolves starting substances to some extent. When Compound (I) of the present invention is obtained as a free compound, it can be converted into a salt which may be formed by the Compound (I), according to the conventional method. In addition, various isomers (e.g. geometrical isomer, optical isomer based on asymmetric carbon, rotamer, stereo isomer, tautomer, etc.) obtained for Compound (I) of the present invention can be purified and isolated by using the conventional separating means, for example, recrystallization, diastereomer salt method, enzyme dissolution method, a variety of chromatographies (e.g. thin layer chromatography, column chromatography, gas chromatography, etc.) and the like.
A compound represented by the aforementioned formula (I) of the present invention, a salt thereof or a hydrate of them can be used as it is, or can be formulated into preparations by mixing with a known per se pharmaceutically acceptable carrier, according to the conventional method. Examples of a preferable dosage form include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, cataplasms, lotions and the like. For formulation into preparations, fillers, binders, disintegrating agents, lubricants, coloring agents, flavoring agents and, if necessary, stabilizer, emulsifying agents, absorption promoting agents, surfactants, pH adjusting agents, preservatives and antioxidants which are normally used can be employed, and can be formulated into preparations by incorporating components which are used as a raw material for general pharmaceutical preparations, according to the conventional method.
Examples of these components include animal and vegetable oils such as soybean oil, beef tallow, synthetic glyceride and the like; hydrocarbons such as liquid paraffin, squalane, solid paraffin and the like; ester oils such as octyldodecyl myristate, isopropyl myristate and the like; higher alcohols such as cetostearyl alcohol, behenyl alcohol and the like; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymer and the like; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silisic anhydride, aluminum magnesium silicate, and aluminum silicate; purified water. As an filler, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like are used; as a binder, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl celulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymer, meglumine, calcium citrate, dextrin, pectin and the like are used; as a disintegrating agent, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, calcium carboxymethyl celluose and the like are used; as a lubricant, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like are used; as a coloring agent, any colorants may be used as far as they are permitted to add to medicaments; as a flavoring agent, cocoa powder, 1-menthol, aromatic powder, mentha oil, Borneo camphor, powdered cinnamon bark and the like are used; as an antioxidant, those which are permitted to add to medicaments, such as ascorbic acid, α-tocopherol and the like are used.
An oral preparation is formulated into powders, fine granules, granules, tablets, coated tablets, capsules or the like according to the conventional method after a filler and, if necessary, a binder, a disintegrating agent, a lubricant, a colorant and a flavoring agent are added to the compound of the present invention or a salt thereof.
In the case of tablets and granules, of course, they may be subjected to sugar coating, gelatin coating and, if necessary, other suitable coating.
In the case of solutions such as syrups, injections, eye drops and the like, a pH adjusting agent, a dissolving agent, an isotonic and the like and, if necessary, a solublizer, a stabilizer, a buffer, a suspending agent, an antioxidant and the like are added, which is formulated into a preparation according to the conventional method. In the case of the solutions, they can be formulated into freeze-dried materials, and injections can be administered intravenously, subcutaneously or intramuscularly. Preferable examples of the suspending agent include methylcellulose, Polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like; preferable examples of the solubilizer include polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate and the like; preferable examples of the stabilizer include sodium sulfite, sodium metasulfite, ether and the like; and preferable examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.
In the case of an external preparation, a process for preparing it is not particularly limited, but it can be prepared by the conventional method. As the base raw material to be used, various raw materials which are normally used for medicaments, quasi-drugs, cosmetics and the like can be used, and examples thereof include raw materials such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and purified water and, if necessary, a pH adjusting agent, an antioxidant, a chelating agent, a preservative, an antifungal agent, a colorant and a perfume can be added. Further, if necessary, ingredients such as an ingredient having the differentiation inducing activity, a blood flow promoter, a sterilizer, an anti-inflammatory, a cell activating agent, vitamins, an amino acid, a humectant, a keratin dissolving agent and the like may be also incorporated.
A pharmaceutical preparation containing Compound (I) of the present invention, a salt or a hydrate of them as an active ingredient is useful for treating or preventing a mammal (e.g. human, mouse, rat, guinea pig, rabbit, dog, horse, monkey, etc.), in particular, treating or preventing human. A dose of a pharmaceutical of the present invention is different depending on an extent of symptom, age, sex, weight, dosage form, a kind of a salt, a difference in sensitivity to a drug, a specific kind of diseases, and the like and, in the case of human, usually, in the case of an adult, about 30 μg to 10 g, preferably 100 μg to 500 mg, more preferably 100 μg to 100 mg is orally administered, or about 1 to 3000 μg/kg, preferably 3 to 1000 μg/kg is administered by injection, per day once or a few times.
According to the present invention, novel compounds having the CRF receptor antagonism, a pharmacologically acceptable salt thereof and hydrates thereof can be provided. The compound of the present invention, a pharmacologically acceptable salt thereof or hydrates thereof have an excellent antagonism to a CRF receptor, are low toxic, highly safe and highly useful as a drug. The compounds of the present invention are useful as an agent for treating or preventing diseases to which CRF and/or its receptor relate. In particular, they are useful as an agent for treating or preventing depression, depressive symptom (great depression, monostotic depression, recurrent depression, infant tyrannism by depression, postpartum depression etc.), mania, anxiety, generalized anxiety disorder, panic disorder, phobia, compulsive disorder, posttraumatic stress disorder, Tourette syndrome, autism, emotional disorder, sentimental disorder, bipolar disorder, cyclothymia, schizophrenia, peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, coprostasis, postoperational ileus, gastrointestinal function abnormality associated with stress, neural vomiting etc.
The following Reference Examples, Examples and Experimental Examples are merely illustrative, and compounds of the present invention are not limited by the following embodiments in any case. A person skilled in the art can implement the present invention at maximum by variously altering not only the following Examples but also claims of the present specification, and such the alterations are included in claims of the present specification.
3-Chloro-2-aminopyrazine (2.1 g, 16.2 mmol) and methyl 2-chloro-3-oxopentanoate (6.7 mL, 48.6 mmol) were mixed, and heated under stirring at 170° C. for 2 hours. After being allowed to cool, the unnecessary materials were filtered off and washed with ethyl acetate, and then filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (0.99 g) as white crystals.
1H NMR (400 MHz, CDCl3) δ 1.37 (t, J=7.6 Hz, 3H), 3.18 (q, J=7.6 Hz, 2H), 4.03 (s, 3H), 7.87 (d, J=4.6 Hz, 1H), 9.14 (d, J=4.6 Hz, 1H).
3-(2,4-Dichlorophenyl)-2-pyrazinamine (1.43 g, 6.0 mmol) was dissolved in chloroform (9 mL), N-chlorosuccinimide (0.96 g, 7.2 mmol) was added thereto, and the mixture was stirred by heating under reflux for 4 hours. After being allowed to cool, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (1.54 g) as yellow crystals.
1H NMR (400 MHz, CDCl3) δ 4.55 (br s, 2H), 7.38 (d, J=8.2 Hz, 1H), 7.41 (dd, J=1.8, 8.2 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 8.10 (s, 1H).
3-Bromo-5-methyl-2-pyrazineamine (3.5 g, 18.6 mmol) and methyl 2-chloro-3-oxopentanoate (6.7 mL, 48.6 mmol) were mixed, and the mixture was heated under stirring at 130° C. for 1 hour. After being allowed to cool, the unnecessary materials were filtered off and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (0.32 g) as pale yellow crystals.
1H NMR (400 MHz, CDCl3) δ 1.35 (t, J=7.5 Hz, 3H), 2.56 (s, 3H), 3.15 (q, J=7.5 Hz, 2H), 4.01 (s, 3H), 8.98 (s, 1H).
8-Chloro-2-ethylimidazo[1,2-a]pyrazine (600 mg, 3.3 mmol) was dissolved in N,N-dimethylformamide (3.3 mL), phosphorus oxychloride (1.2 mL, 13.2 mmol) was added dropwise at room temperature, and the mixture was heated under stirring at 90° C. for 2 hours. After being allowed to cool, the reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give the title compound (472 mg) as white crystals.
1H NMR (400 MHZ, CDCl3) δ 1.49 (t, J=7.5 Hz, 3H), 3.18 (q, J=7.5 Hz, 2H), 7.97 (d, J=4.4 Hz, 1H), 9.31 (d, J=4.4 Hz, 1H), 10.18 (s, 1H).
8-Chloro-2-ethylimidazo[1,2-a]pyrazine-3-carbaldehyde (146 mg, 0.70 mmol) was dissolved in tetrahydrofuran (1.4 mL), then a 0.90M propylmagnesium bromide solution in tetrahydrofuran (1.6 mL, 1.4 mmol) was added thereto under ice-cooling, and the mixture was stirred for 30 minutes. An aqueous saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting alcohol compound was used in the next reaction without purification.
The resulting 1-(8-chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanol was dissolved in N,N-dimethylformamide (2.2 mL), then iodoethane (0.079 mL, 0.99 mmol) and sodium hydride (65% in oil; 49 mg, 1.32 mmol) were added thereto under ice-cooling, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (55 mg) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 0.88–0.96 (m, 3H), 1.12–1.17 (m, 3H), 1.18–1.37 (m, 4H), 1.39–1.52 (m, 1H), 1.69–1.81 (m, 1H), 1.97–2.07 (m, 1H), 2.75–2.89 (m, 2H), 3.18–3.27 (m, 1H), 3.33–3.42 (m, 1H), 4.70–4.76 (m, 1H), 7.60 (d, J=4.6 Hz, 1H). 8.35 (d, J=4.6 Hz, 1H).
8-Chloro-2-ethylimidazo[1,2-a]pyrazine-3-carbaldehyde (328 mg, 1.6 mmol) was dissolved in tetrahydrofuran (3.2 mL), then a 0.90M propylmagnesium bromide solution in tetrahydrofuran (4.4 mL, 4.0 mmol) was added thereto under ice-cooling, and the mixture was stirred for 30 minutes. An aqueous saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting 1-(8-chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanol was used in the next reaction without purification.
The resulting 1-(8-chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanol was dissolved in ethyl acetate (4 mL) and methylene chloride (1 mL), then activated manganese (IV) oxide (3 g) was added thereto, and the mixture was heated under stirring at 60° C. for 5 hours. After being allowed to cool, the reaction mixture was filtered and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (226 mg) as white crystals.
1H NMR (400 MHz, CDCl3) δ 1.06 (t, J=7.3 Hz, 3H), 1.49 (t, J=7.5 Hz, 3H), 1.84 (tq, J=7.3, 7.3 Hz, 2H), 2.97 (t, J=7.3 Hz, 2H), 3.23 (q, J=7.5 Hz, 2H), 7.88 (d, J=4.6 Hz, 1H), 9.53 (d, J=4.6 Hz, 1H).
1-Triphenylphosphoranilidene-2-propanone (49.08 g, 0.225 mol) was added to a solution of 2,4-dimethylbenzaldehyde (15.08 g, 0.112 mol) in dichloromethane (100 mL), and the mixture was heated at 60° C. for 20 hours. The reaction mixture was evaporated as it was. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (18.32 g, 94%).
1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 2.37 (s, 3H), 2.42 (s, 3H), 6.62 (d, J=16.1 Hz, 1H), 7.00–7.08 (m, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.79 (d, J=16.1 Hz, 1H).
Ammonium chloride (6.84 g, 0.126 mol) and potassium cyanide (13.68 g, 0.210 mol) were added to a mixed solution (100 mL) of a 15% aqueous solution of (E)-4-(2,4-dimethylphenyl)-3-butene-2-one (18.32 g, 0.105 mol) and N,N-dimethylformamide, and the mixture was heated under reflux for 6 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (10.13 g, 48%).
1H NMR (400 MHz, CDCl3) δ 2.20 (s, 3H), 2.30 (s, 3H), 2.33 (s, 3H), 2.87 (dd, J=5.2, 18.0 Hz, 1H), 3.16 (dd, J=8.9, 18.0 Hz, 1H), 4.44 (dd, J=5.2, 8.9 Hz, 1H), 7.01 (s, 1H), 7.04 (d, J=7.9 Hz, 1H), 7.27 (d, J=10.3 Hz, 1H).
Sodium bicarbonate (13.0 g, 155 mmol) and bromine (4.0 mL, 78 mmol) were added to a solution of 3-amino-6-chloropyridazine (10.0 g, 78 mmol) in methanol (150 mL) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was filtered, and the solvent was evaporated. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous sodium thiosulfate solution, an aqueous saturated sodium bicarbonate solution and a brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (8.6 g, 53%) as tan crystals.
1H NMR (400 MHz, CDCl3) δ 5.35 (br s, 2H), 7.54 (s, 1H).
Ethanol (8 mL), a 2M aqueous sodium carbonate solution (4 mL), 2,4-dimethylbenzeneboric acid (650 mg, 4.3 mmol) and tetrakistriphenylphosphine palladium complex (456 mg, 0.39 mmol) were added to a solution of 3-amino-4-bromo-6-chloropyridazine (822 mg, 3.9 mmol) in toluene (40 mL), and the mixture was heated at 100° C. for 2 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (759 mg, 82%) as a pale brown powder.
1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 2.37 (s, 3H), 5.03 (br s, 2H), 7.03 (d, J=7.7 Hz, 1H), 7.07 (s, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.15 (s, 1H).
10% Pd—C (759 mg, 50 wt %) and ammonium formate (1.23 g, 19 mmol) were added to a solution of 6-chloro-4-(2,4-dimethylphenyl)-3-pyridazineamine (759 mg, 3.2 mmol) in methanol (40 mL), and the mixture was heated under reflux for 1 hour. The reaction solution was filtered through Celite, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (640 mg, 99%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 2.13 (s, 3H), 2.37 (s, 3H), 4.89 (br s, 2H), 7.03 (d, J=4.6 Hz, 1H), 7.04 (d, J=7.1 Hz, 1H), 7.11 (d, J=7.7 Hz, 1H), 7.14 (s, 1H), 8.63 (d, J=4.6 Hz, 1H).
Methyl 2-chloro-3-oxopentanoate (5 mL) was added to 4-(2,4-dimethylphenyl)-3-pyridazineamine (640 mg, 3.2 mmol), and the mixture was heated at 155° C. for 30 minutes. Water was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: N-hexane=1:3) to give the title compound (373 mg, 37%) as a brown oil.
1H NMR (400 MHz, CDCl3) δ 1.29 (t, J=7.5 Hz, 3H), 2.21 (s, 3H), 2.38 (s, 3H), 3.11 (q, J=7.5 Hz, 2H), 4.01 (s, 3H), 7.06 (d, J=4.6 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.16 (s, 1H), 7.28 (d, J=7.7 Hz, 1H), 8.55 (d, J=4.6 Hz, 1H).
3-Bromo-5-methyl-2-pyridineamine (5.0 g) was dissolved in N,N-dimethylformamide (30 mL), and a 20M aqueous sodium hydroxide solution (1.35 mL) was added thereto slowly at room temperature. After stirred at room temperature for 30 minutes, carbon disulfide (2.4 mL) was added thereto, and the mixture was further stirred for 30 minutes. Thereafter, a 20M aqueous sodium hydroxide solution (1.35 mL) was added thereto slowly at room temperature, which was stirred for 2 hours. Then, methyl iodide (7.7 g) was added thereto, followed by stirring overnight. Ice was added to the resulting mixture, which was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated. The resulting methyl N-(3-bromo-5-methyl-2-pyridyl)-(methylsulfanyl)methaneimidothioate was subjected to the next reaction without purification.
Ethyl bromoacetate (5.4 g) was added to methyl N-(3-bromo-5-methyl-2-pyridyl)(methylsulfanyl)methaneimidothioate, and the mixture was stirred at 60° C. for 4 hours. After cooled to room temperature, triethylamine was added to treat the material, and water was further added thereto. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by column chromatography (ethyl acetate:n-hexane=1:9) to give 8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-carboxylic acid ethyl ester (2.4 g) as a white powder.
1H NMR (400 MHz, CDCl3) δ 1.46 (t, J=7.2 Hz, 3H), 2.37 (s, 3H), 2.73 (s, 3H), 4.44 (q, J=7.2 Hz, 2H), 7.49 (d, J=1.6 Hz, 1H), 9.07 (d, J=2.4 Hz, 1H).
8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-carboxylic acid ethyl ester (1.33 g) was dissolved in ethanol (50 mL), then a 5N aqueous sodium hydroxide solution (3 mL) was added thereto, and the mixture was stirred under reflux for 1 hour. Ice was added to the reaction mixture, then 2N hydrochloric acid (8 mL) was further added thereto, and as a result, the precipitates were obtained. The resulting precipitates were collected by filtration, washed with water, and dried under reduced pressure to give 8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridine-3-carboxylic acid (1.1 g) as a white powder.
1H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 3H), 2.48 (s, 3H), 7.77 (s, 1H), 9.02 (s, 1H), 13.4 (br s, 1H).
8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridine-3-carboxylic acid (500 mg) was dissolved in a mixture of tert-butyl alcohol (15 mL) and toluene (50 mL), then diphenylphospholylazide (500 mg) and triethylamine (206 mg) were added thereto. After the mixture was heated at 70° C. for 2 hours, it was stirred for 2 hours by heating under reflux. After cooled to room temperature, the reaction mixture was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give tert-butyl N-[8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]carbamate (0.85 g) as a white powder.
1H NMR (400 MHz, CDCl3) δ 1.50 (br s, 9H), 2.33 (s, 3H), 2.60 (s, 3H), 6.18 (br s, 1H), 7.32 (s, 1H), 7.61 (s, 1H).
tert-Butyl N-[8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]carbamate (123 mg) was dissolved in N,N-dimethylformamide (10 mL), then sodium hydride (65% in oil; 15 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 minutes. Iodopropane (67 mg) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The extracted organic layers were combined, dried over anhydrous magnesium sulfate and evaporated, to give the title compound (133 mg) as a brown oil.
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 3H), 1.31 (br s, 9H), 1.45–1.60 (m, 2H), 2.33 (s, 3H), 2.60 (s, 3H), 3.50–3.63 (m, 2H), 7.31 (s, 1H), 7.44 (s, 1H).
tert-Butyl N-[8-bromo-6-methyl-2-(methysulfanyl)imidazo[1,2-a]pyridin-3-yl]-N-propylcarbamate was dissolved in ethyl acetate (5 mL), then a 4N hydrochloric acid-ethyl acetate solution (10 mL) was added thereto at room temperature, and the mixture was stirred at room temperature for 20 hours. Under ice-cooling, a 5N aqueous sodium hydroxide solution was added to neutralize the solution, which was extracted with ethyl acetate. The organic layers were combined, which was dried over anhydrous magnesium sulfate, and evaporated, to give the title compound (103 mg) as a yellow amorphous.
1H NMR (400 MHz, CDCl3) δ 1.01 (t, J=7.6 Hz, 3H), 1.57–1.63 (m, 2H), 2.32 (s, 3H), 2.54 (s, 3H), 2.95–3.00 (m, 2H), 7.24 (s, 1H), 7.71 (s, 1H).
N-[8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N-propylamine (103 mg) and propionaldehyde (57 mg) were dissolved in tetrahydrofuran (1.2 mL), then 3M sulfuric acid (0.24 mL) was added thereto, follwed by adding sodium borohydride (24 mg) under ice-cooling, and then the mixture was stirred for 3 hours. Water was added to the reaction mixture, which was neutralized with a 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give the title compound (79 mg) as a white powder.
1H NMR (400 MHz, CDCl3) δ 0.85 (t, J=7.2 Hz, 6H), 1.33–1.40 (m, 4H), 2.31 (s, 3H), 2.62 (s, 3H), 3.00–3.10 (m, 4H), 7.23 (s, 1H), 7.81 (s, 1H).
A 20N aqueous sodium hydroxide solution (11.3 mL) was added to a solution of 3-methoxy-2-pyrazineamine (28.3 g) in N,N-dimethylformamide (230 mL) at room temperature. After stirred for 1 hour, carbon disulfide (20.4 mL) was added thereto, followed by further stirring for 1 hour. A 20N aqueous sodium hydroxide solution (11.3 mL) was added thereto at room temperature, and the mixture was stirred for 1 hour. Thereafter, methyl iodide (28.2 mL) was added thereto, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, which was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (19.1 g) as yellow crystals.
1H NMR (400 MHz, DMSO-d6) δ 2.58 (s, 6H), 3.99 (s, 3H), 7.83 (d, J=2.9 Hz, 1H), 7.91 (d, J=2.9 Hz, 1H).
Ethyl bromoacetate (18.5 mL) and iso-dipropylethylamine (29 mL) were added to a solution of methyl N-(3-methoxy-2-pyrazinyl)-(methylsulfanyl)methaneimidothioate (19.1 g) in acetonitrile (42 mL), and the mixture was heated under stirring at 100° C. for 14 hours. After the reaction mixture was cooled to room temperature, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was washed with n-hexane to give the title compound (10.7 g) as pale yellow crystals.
1H NMR (400 MHz, CDCl3) δ 1.47 (t, J=7.1 Hz, 3H), 2.74 (s, 3H), −4.19 (s, 3H), 4.46 (q, J=7.1 Hz, 2H), 7.55 (d, J=4.6 Hz, 1H), 8.72 (d, J=4.6 Hz, 1H).
Phosphorus oxychloride (75 mL) was added to ethyl 8-methoxy-2-(methylsulfanyl)imidazo[1,2-a]pyrazine-3-carboxylate (10.7 g), and the mixture was heated under stirring at 130° C. for 8 hours. The resulting reaction mixture was cooled to room temperature, and poured on ice. Then, the residue was collected by filtration and washed with ethanol and water, and dried under reduced pressure to give the title compound (7.6 g) as pale yellow crystals.
1H NMR (400 MHz, CDCl3) δ 1.48 (t, J=7.1 Hz, 3H), 2.76 (s, 3H), 4.48 (q, J=7.1 Hz, 2H), 7.85 (d, J=4.7 Hz, 1H), 9.07 (d, J=4.7 Hz, 1H).
Ethyl 8-chloro-2-(methylsulfanyl)imidazo[1,2-a]pyrazine-3-carboxylate (2.0 g) was dissolved in tetrahydrofuran (36 mL) and ethanol (9 mL), then a 2N aqueous sodium hydroxide solution (9 mL) was added thereto, and the mixture was stirred at room temperature. Under ice-cooling, 1N hydrochloric acid (19 mL) was added thereto, then the solvent was ebaporated. The resulting crude 8-chloro-2-(methylsulfanyl)imidazo[1,2-a]pyrazine-3-carboxylic acid was used in the next reaction without purification.
The resulting crude 8-chloro-2-(methylsulfanyl)imidazo[1,2-a]pyrazine-3-carboxylic acid was dissolved in toluene (71 mL), then tert-butyl alcohol (14 mL), triethylamine (1.1 mL) and diphenylphospholylazide (1.7 mL) were added thereto, and the mixture was heated at 100° C. for 4 hours. After completion of the reaction, it was evaporated, which was added with water, extracted with ethyl acetate, and washed with water. After that, it was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (880 mg) as pale red crystals.
H NMR (400 MHz, CDCl3) δ 1.51 (br s, 9H), 2.69 (s, 3H), 6.25 (br s, 1H), 7.70 (d, J=4.6 Hz, 1H), 7.77 (d, J=4.6 Hz, 1H).
According to the same manner as that of Reference Examples 16 and 17, tert-butyl N-[8-chloro-2-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]carbamate was used to give the title compound as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 1.01 (t, J=7.3 Hz, 3H), 1.59 (ddq, J=7.1, 7.1, 7.3 Hz, 2H), 2.64 (s, 3H), 3.05 (ddd, J=7.1, 7.1, 7.1 Hz, 2H), 3.30 (t, J=7.1 Hz, 1H), 7.62 (d, J=4.6 Hz, 1H), 7.82 (d, J=4.6 Hz, 1H).
According to the same manner as that of Reference Example 18, N-[8-chloro-2-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N,N-dipropylamine was used to give the title compound as pale yellow crystals.
1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.36 (ddq, J=7.5, 7.5, 7.5 Hz, 4H), 2.71 (s, 3H), 3.08 (dd, J=7.5, 7.5 Hz, 4H), 7.62 (d, J=4.6 Hz, 1H), 7.92 (d, J=4.6 Hz, 1H).
4-Bromo-6-chloro-3-pyridazineamine (12 g) and 4-methoxy-2-methylphenylboronic acid (10.5 g) were dissolved in a mixed solvent of toluene (240 mL) and ethanol (45 mL), then tetrakistriphenylphosphine palladium complex (6.7 g) and a 2M aqueous sodium carbonate solution (24 mL) were added thereto, and the mixture was heated under stirring at 100° C. for 12 hours. After completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4) to give the title compound (7.89 g) as brown crystals.
1H NMR (400 MHz, CDCl3) δ 2.18 (s, 3H), 3.85 (s, 3H), 5.43 (br s, 2H), 6.82–6.90 (m, 2H), 7.08 (d, J=8.2 Hz, 1H), 7.14 (s, 1H).
10% Pd—C (hydrous product; 7.89 g) and ammonium formate (11.96 g) were added to a solution of 6-chloro-4-(4-methoxy-2-methylphenyl)-3-pyridazineamine (7.89 g) in methanol (100 mL), and the mixture was heated under reflux for 1.5 hours. The reaction mixture was filtered through Celite, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:ethanol=10:1) to give the title compound (6.16 g) as white crystals.
1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 3.83 (s, 3H), 4.89 (br s, 2H), 6.80–6.90 (m, 2H), 7.02 (d, J=4.6 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 8.62 (d, J=4.8 Hz, 1H).
A 20N aqueous sodium hydroxide solution (1.43 mL) was added to a solution of 4-(4-methoxy-2-methylphenyl)-3-pyridazineamine (6.16 g) in N,N-dimethylformamide (60 mL) at room temperature. After stirred for 1 hour, carbon disulfide (3.45 mL) was added thereto, and the mixture was further stirred for 1 hour. In addition, a 20N aqueous sodium hydroxide solution (1.43 mL) was added thereto at room temperature. Methyl iodide (3.57 mL) was added thereto, followed by stirring for 1 hour. Water was added to the reaction mixture, which was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:nhexane=2:1) to give the title compound (1.25 g) as a brown oil.
1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 2.35 (s, 6H), 3.83 (s, 3H), 6.72–6.84 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 7.32 (d, J=4.6 Hz, 1H), 8.97 (d, J=4.6 Hz, 1H).
Ethyl bromoacetate (0.87 mL) and i-Pr2EtN (1.36 mL) were added to a solution of methyl N-[4-(4-methoxy-2-methylphenyl)-3-pyridazinyl]-(methylsulfanyl)methaneimidothioate (1.25 g) in acetonitrile (10 mL), and the mixture was heated under stirring at 100° C. for 14 hours. The reaction mixture was cooled to room temperature, which was added with water, extracted with ethyl acetate, and washed with water. After that, it was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (628 mg) as a red brown oil.
1H NMR (400 MHz, CDCl3) δ 1.38 (t, J=7.1 Hz, 3H), 2.10 (s, 3H), 2.72 (s, 3H), 3.85 (s, 3H), 4.33 (q, J=7.1 Hz, 2H), 6.79–6.95 (m, 2H), 7.13 (d, J=8.8 Hz, 1H), 7.39 (d, J=4.7 Hz, 1H), 8.53 (br s, 1H).
4,6-Dichloropyrimidine (5.0 g) and 2-amino-1-butanol (6.5 mL) were heated under reflux in 1,4-dioxane (26 mL) for 1 hour. The reaction mixture was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (5.6 g) as a pale orange oil.
1H NMR (400 MHz, CDCl3) δ0.98 (t, J=7.2 Hz, 3H), 1.52–1.64 (m, 2H), 2.58 (br s, 1H), 3.66 (dd, J=10.8, 5.2 Hz, 1H), 3.77 (dd, J=10.8, 3.6 Hz, 1H), 3.85 (br s, 1H), 5.42 (br s, 1H), 6.40 (s, 1H), 8.30 (s, 1H).
2-[(6-Chloro-4-pyrimidinyl)amino]-1-butanol was dissolved in ethanol (110 mL), which was sequentially added with a 5N aqueous sodium hydroxide solution (5.5 mL) and Pd—C (hydrous product; 0.55 g), and hydrogenation was performed under hydrogen atmosphere at a normal temperature and a normal pressure. After completion of the reaction, Pd—C was filtered off, and the solvent was evaporated. The resulting residue was extracted with dichloromethane-methanol, and the solvent was removed to give the title compound (4.3 g) as white crystals.
1H NMR (400 MHz, CDCl3) δ 0.99 (t, J=7.6 Hz, 3H), 1.52–1.64 (m, 2H), 2.46 (br s, 1H), 3.66 (dd, J=11.2, 6.0 Hz, 1H), 3.77 (dd, J=11.2, 3.6 Hz, 1H), 3.88 (br s, 1H), 5.16 (br s, 1H), 6.38 (d, J=6.0 Hz, 1H), 8.11 (d, J=6.0 Hz, 1H), 8.51 (s, 1H).
2-(4-Prymidinylamino)-1-butanol (4.2 g) was dissolved in acetic acid (42 mL), and bromine (1.5 mL) was added dropwise at a normal temperature. After stirred for 1 day at the same temperature, the solution was neutralized with a 5N aqueous sodium hydroxide solution and extracted with ethyl acetate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1.1) to give the title compound (4.4 g) as white crystals.
1H NMR (400 MHz, CDCl3) δ 1.01 (t, J=7.6 Hz, 3H), 1.58–1.81 (m, 2H), 3.72 (dd, J=10.8, 5.6 Hz, 1H), 3.82 (dd, J=10.8, 3.6 Hz, 1H), 4.12–4.20 (m, 1H), 5.56 (br s, 1H), 8.30 (s, 1H), 8.45 (s, 1H).
2-[(5-Bromo-4-pyrimidinyl)amino]-1-butanol (3.3 g) was dissolved in xylene (27 mL), then thionyl chloride (4.9 mL) was added thereto, and the mixture was heated under stirring at 100° C. for 1 day. The precipitated crystals were collected by filtration and suspended in a 1M aqueous sodium carbonate solution. This mixture was extracted with dichloromethane to give the crude title compound (3.0 g) as an orange oil. This title compound was used in the next reaction without purification.
1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=7.6 Hz, 3H), 1.55–1.67 (m, 1H), 1.79–1.91 (m, 1H), 3.82 (dd, J=11.2, 8.0 Hz, 1H), 4.21–4.30 (m, 2H), 7.62 (s, 1H), 7.77 (s, 1H).
8-Bromo-2-ethyl-2,3-dihydroimidazo[1,2-c]pyrimidine (3.0 g) was dissolved in toluene (60 mL), then activated manganese(IV) dioxide (3.5 g) was added thereto, and the mixture was heated under stirring at 90° C. for 1 day. Manganese(IV) oxide was filtered off through Celite, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (1.3 g) as white crystals.
1H NMR (400 MHz, CDCl3) δ 1.36 (t, J=7.6 Hz, 3H), 2.84–2.99 (m, 2H), 7.49 (s, 1H), 8.08 (s, 1H), 8.89 (s, 1H).
8-Bromo-2-ethylimidazo[1,2-c]pyrimidine (1.0 g) was added to a mixture of phosphorus oxychloride (1.2 mL) and N,N-dimethylformamide (4.4 mL) at room temperature. The mixture was heated under stirring as it was at 80° C. for 1 day. After cooled to room temperature, it was poured slowly on ice. The material was extracted with ethyl acetate and washed with water, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (0.5 g) as white crystals.
1H NMR (400 MHz, CDCl3) δ 1.47 (t, J=7.6 Hz, 3H), 3.15 (q, J=7.6 Hz, 2H), 8.41 (s, 1H), 10.11 (s, 1H), 10.16 (s, 1H).
8-Bromo-2-ethylimidazo[1,2-c)pyrimidine-3-carbaldehyde was reacted in the same manner as that of Reference Example 5 to give the title compound as white crystals.
1H NMR (400 MHz, CDCl3) δ 0.95 (t, J=7.2 Hz, 3H), 1.22–1.36 (m, 1H), 1.31 (t, J=7.6 Hz, 3H), 1.41–1.54 (m, 1H), 1.771.87 (m, 1H), 2.01–2.11 (m, 1H), 2.70–2.82 (m, 2H), 5.22 (t, J=7.2 Hz, 1H), 8.10 (s, 1H), 9.38 (s, 1H).
1-(8-Bromo-2-ethylimidazo[1,2-c]pyrimidin-3-yl)-1-buthanol was reacted in the same manner as that of Reference Example 5 to give the title compound as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 0.92 (t, J=7.2 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H), 1.18–1.30 (m, 1H), 1.33 (t, J=7.6 Hz, 3H), 1.38–1.50 (m, 1H), 1.71–1.81 (m, 1H), 1.99–2.09 (m, 1H), 2.73–2.88 (m, 2H), 3.22–3.43 (m, 2H), 4.73 (t, J=7.2 Hz, 1H), 8.08 (s, 1H), 9.28 (s, 1H).
8-Chloro-2-ethylimidazo[1,2-a]pyrazine-3-carboxyilic methyl ester (0.92 g, 3.8 mmol) synthesized in Reference Example 1 was dissolved in a mixed solvent of toluene (32 mL) and methanol (8 mL), then 2,4-dichlorobenzeneboronic acid (1.49 g, 7.8 mmol) and tetrakistriphenylphosphine palladium complex (230 mg, 0.2 mmol) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was allowed to cool, and purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (1.03 g) as a pale yellow crystals.
1H NMR (400 MHz, CDCl3) δ 1.31 (t, J=7.5 Hz, 3H), 3.14 (q, J=7.5 Hz, 2H), 4.03 (s, 3H), 7.41 (dd, J=2.0, 8.2 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 8.20 (d, J=4.6 Hz, 1H), 9.23 (d, J=4.6 Hz, 1H).
8-(2,4-Dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1.03 g, 2.9 mmol) was dissolved in ethanol (11 mL), then a 2N aqueous sodium hydroxide solution (3.7 mL, 7.3 mmol) was added thereto, and the mixture was stirred for 1 hour by heating under reflux. After completion of the reaction, the material was cooled to an ice temperature, which was added with 2N hydrochloric acid (7.3 mL) to adjust pH to 5. The resulting reaction mixture was extracted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting 8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazine-3-carboxylic acid was used in the next reaction without purification.
The resulting 8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazine-3-carboxylic acid was dissolved in tert-butyl alcohol (15 mL), then diphenylphosphorylazide (0.69 mL, 3.2 mmol) and triethylamine (0.49 mL, 3.5 mmol) were added thereto, and the mixture was stirred for 2 hours by heating under reflux. After being cooled to room temperature, the reaction mixture was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (0.85 g) as a white amorphous.
1H NMR (400 MHz, CDCl3) δ 1.29 (t, J=7.5 Hz, 3H), 1.54 (br s, 9H), 2.81 (q, J=7.5 Hz, 2H), 6.20 (br s, 1H), 7.39 (dd, J=2.0, 8.2 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.86 (d, J=4.5 Hz, 1H), 8.02 (d, J=4.5 Hz, 1H).
tert-Butyl N-[8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]carbamate (200 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (1.6 mL), then sodium hydride (65% in oil; 27 mg, 0.74 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. Iodopropane (0.062 mL, 0.64 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The extracted organic layers were combined, which was dried over anhydrous magnesium sulfate and evaporated. The resulting tert-butyl N-[8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N-propylcarbamate was subjected to the next reaction without purification.
tert-Butyl N-[8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N-propylcarbamate was dissolved in ethyl acetate (1 mL), then a 4N hydrochloric acid-ethyl acetate solution (1.9 mL, 7.4 mmol) was added thereto at room temperature, and the mixture was stirred at room temperature for 20 hours. Under ice-cooling, a 5N aqueous sodium hydroxide solution was added thereto, which was extracted with ethyl acetate. The organic layers were combined, which was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:4) to give the title compound (151 mg) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 1.00–1.07 (m, 3H), 1.30 (t, J=7.5 Hz, 3H), 1.56–1.69 (m, 2H), 2.81 (q, J=7.5 Hz, 2H), 2.99–3.08 (m, 2H), 7.38 (dd, J=2.0, 8.2 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.94 (d, J=4.5 Hz, 1H), 7.97 (d, J=4.5 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) δ 0.79–0.87 (m, 6H), 1.21 (t, J=7.5 Hz, 3H), 1.32–1.44 (m, 4H), 2.78 (q, J=7.5 Hz, 2H), 3.05–3.13 (m, 4H), 7.66 (dd, J=2.0, 8.2 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 8.29 (d, J=4.2 Hz, 1H), 8.59 (d, J=4.2 Hz, 1H).
5-Chloro-3-(2,4-dichlorophenyl)-2-pyrazineamine (1.1 g, 4.0 mmol) and methyl 2-chloro-3-oxopentanoate (5.7 mL) were mixed, and the mixture was heated under stirring at 170° C. 3 hours. After being allowed to cool, the reaction mixture was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), and the resulting residue was washed with hexane to give the title compound (0.56 g) as pale yellow crystals.
1H NMR (400 MHz, CDCl3) δ 1.30 (t, J=7.5 Hz, 3H), 3.12 (q, J=7.5 Hz, 2H), 4.04 (s, 3H), 7.42 (dd, J=2.0, 8.2 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 9.34 (s, 1H).
By using 6-chloro-8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazine-3-caboxylic acid methyl ester, the title compound was obtained as a yellow oil according to the same manner as that of Example 2.
1H NMR (400 MHz, CDCl3) δ 1.29 (t, J=7.5 Hz, 3H), 1.54 (br s, 9H), 2.80 (q, J=7.5 Hz, 2H), 6.17 (br s, 1H), 7.40 (dd, J=2.0, 8.2 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.93 (s, 1H).
By using tert-butyl N-[6-chloro-8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]carbamate, the title compound was obtained as a red brawn oil according to the same manner as that of Example 3.
1H NMR (400 MHz, CDCl3) δ 1.00–1.07 (m, 3H), 1.30 (t, J=7.5 Hz, 3H), 1.56–1.70 (m, 2H), 2.80 (q, J=7.5 Hz, 2H), 2.98–3.08 (m, 2H), 7.38 (dd, J=2.0, 8.2 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 8.02 (s, 1H).
By using N-[6-chloro-8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N-propylamine, the title compound was obtained as pale yellow crystals according to the same manner as that of Example 3.
1H NMR (400 MHz, CDCl3) δ 0.87–0.94 (m, 6H), 1.29 (t, J=7.5 Hz, 3H), 1.37–1.49 (m, 4H), 2.78 (q, J=7.5 Hz, 2H), 3.03–3.11 (m, 4H), 7.38 (dd, J=2.0, 8.2 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 8.08 (s, 1H).
8-Bromo-2-ethyl-6-methylimidazo[1,2-a]pyrazine-3-carboxylic acid methyl ester (0.30 g, 1.0 mmol) was dissolved in a mixed solvent of toluene (5.6 mL) and methanol (1.4 mL). Then 2,4-dichlorobenzeneboronic acid (0.382 g, 2.0 mmol) and tetrakistriphenylphosphine palladium complex (116 mg, 0.1 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After the reaction mixture was allowed to cool, the solvent was removed. Then the residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give the title compound (391 mg) as white crystals.
1H NMR (400 MHz, CDCl3) δ 1.29 (t, J=7.5 Hz, 3H), 2.65 (s, 3H), 3.11 (q, J=7.5 Hz, 2H), 4.02 (s, 3H), 7.41 (dd, J=2.0, 8.2 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 9.08 (s, 1H).
According to the processes of Examples 1 to 4, the following compounds of Examples 10 to 12 were synthesized.
White Amorphous
1H NMR (400 MHz, CDCl3) δ 1.28 (t, J=7.5 Hz, 3H), 1.55 (br s, 9H), 2.58 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 6.14 (br s, 1H), 7.38 (dd, J=2.0, 8.2 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.67 (s, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 1.00–1.07 (m, 3H), 1.29 (t, J=7.5 Hz, 3H), 1.56–1.69 (m, 2H), 2.57 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 2.98–3.06 (m, 2H), 7.37 (dd, J=2.0, 8.2 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.78 (s, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.89–0.96 (m, 6H), 1.40–1.55 (m, 7H), 2.74 (s, 3H), 3.03–3.15 (m, 6H), 7.52 (dd, J=2.0, 8.2 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 8.04 (s, 1H).
8-(2,4-Dichlorophenyl)-2-methylimidazo[1,2-a]pyrazine (0.10 g, 0.36 mmol) was dissolved in acetonitrile (0.36 mL), then nitronium tetrafluoroborate (72 mg, 0.54 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give 8-(2,4-dichlorphenyl)-2-methyl-3-nitroimidazo[1,2-a]pyrazine (1.54 g) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 2.92 (s, 3H), 7.47 (dd, J=2.0, 8.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 8.48 (d, J=4.6 Hz, 1H), 9.36 (d, J=4.6 Hz, 1H).
8-(2,4-Dichlorophenyl)-2-methyl-3-nitroimidazo[1,2-a]pyrazine (25 mg, 0.077 mmol) was dissolved in ethanol (0.36 mL), then acetic acid (0.5 mL) and iron powders (22 mg) were added thereto, and the mixture was stirred for 1 hour by heating under reflux. After the reaction mixture was allowed to cool, the solvent was evaporated and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=4:1) to give 8-(2,4-dichlorophenyl)-2-methylimidazo[1,2-a]pyrazin-3-amine (8 mg) as yellow crystals.
1H NMR (400 MHz, CDCl3) δ 2.47 (s, 3H), 3.23 (br s, 2H), 7.39 (dd, J=2.0, 8.2 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.39 (d, J=4.4 Hz, 1H), 7.96 (d, J=4.4 Hz, 1H).
According to the processes of Examples 1 to 4, the following compounds of Examples 15 to 109 were synthesized.
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88–0.95 (m, 6H), 1.40–1.53 (m, 4H), 2.73 (s, 3H), 3.10–3.17 (m, 4H), 7.51 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.65 (s, 1H), 8.24 (br s, 1H), 8.34 (br s, 1H).
Orange Crystals
1H NMR (400 MHz, CDCl3) δ 1.02 (t, J=7.2 Hz, 6H), 1.44–1.60 (m, 4H), 2.45 (s, 3H), 2.85 (br s, 1H), 2.92–3.00 (m, 1H), 7.39 (dd, J=2.0, 8.4 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H), 7.97 (d, J=4.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, DMSO-d6) δ 0.80–0.88 (m, 6H), 1.19 (t, J=7.5 Hz, 3H), 1.34–1.47 (m, 4H), 1.94 (s, 6H), 2.33 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.07–3.15 (m, 4H), 7.04 (s, 2H), 8.24 (br s, 1H), 8.57 (br s, 1H).
Orange Crystals
1H NMR (400 MHz, DMSO-d6) δ 0.87–0.97 (m, 6H), 1.20 (t, J=7.5 Hz, 3H), 1.44–1.60 (m, 4H), 2.82 (q, J=7.5 Hz, 2H), 3.16–3.28 (m, 1H), 7.67 (dd, J=2.0, 8.2 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 8.07 (d, J=4.9 Hz, 1H), 8.57 (d, J=4.9 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87–0.95 (m, 3H), 1.09 (t, J=7.1 Hz, 3H), 1.29–1.50 (m, 4H), 1.47 (t, J=7.7 Hz, 3H), 3.09 (q, J=7.7 Hz, 2H), 3.15–3.22 (m, 2H), 3.24 (q, J=7.1 Hz, 2H), 7.53 (dd, J=2.0, 8.2 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 8.29 (d, J=4.6 Hz, 1H), 8.38 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.98–1.05 (m, 6H), 1.25 (t, J=7.5 Hz, 3H), 1.44–1.61 (m, 4H), 2.02 (s, 6H), 2.32 (s, 3H), 2.75 (q, J=7.5 Hz, 2H), 3.07–3.15 (m, 4H), 6.94 (s, 2H), 7.90 (d, J=4.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, DMSO-d6) δ 0.78–0.88 (m, 6H), 1.26 (t, J=7.5 Hz, 3H), 1.33–1.47 (m, 4H), 2.82 (q, J=7.5 Hz, 2H), 3.06–3.15 (m, 4H), 3.82 (s, 3H), 3.89 (s, 3H), 6.78 (dd, J=2.3, 8.6 Hz, 1H), 6.81 (d, J=2.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 8.24 (br s, 1H), 8.54 (br s, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.85–0.93 (m, 6H), 1.25 (t, J=7.5 Hz, 3H), 1.38–1.49 (m, 4H), 2.06 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.02–3.11 (m, 4H), 3.69 (s, 3H), 3.84 (s, 3H), 6.44 (d, J=1.8 Hz, 1H), 6.45 (d, J=1.8 Hz, 1H), 7.90 (d, J=4.6 Hz, 1H), 7.98 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, DMSO-d6) δ 0.80–0.88 (m, 6H), 1.22 (t, J=7.5 Hz, 3H), 1.35–1.47 (m, 4H), 2.80 (q, J=7.5 Hz, 2H), 3.07–3.16 (m, 4H), 3.68 (s, 6H), 3.89 (s, 3H), 6.44 (s, 2H), 8.30 (br s, 1H), 8.60 (br s, 1H).
White Amorphous
1H NMR (400 MHz, DMSO-d6) δ 0.77–0.89 (m, 6H), 1.20 (t, J=7.3 Hz, 3H), 1.32–1.47 (m, 4H), 1.97 (s, 6H), 2.77 (q, J=7.3 Hz, 2H), 3.05–3.17 (m, 4H), 3.80 (s, 3H), 6.80 (s, 2H), 8.19 (br s, 1H), 8.56 (br s, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, DMSO-d6) δ 0.80–0.88 (m, 6H), 1.23 (t, J=7.5 Hz, 3H), 1.34–1.47 (m, 4H), 2.29 (s, 3H), 2.80 (q, J=7.5 Hz, 2H), 3.06–3.14 (m, 4H), 3.84 (s, 3H), 6.98 (dd, J=2.6, 8.4 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 8.20 (d, J=4.8 Hz, 1H), 8.54 (d, J=4.8 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.86–0.94 (m, 6H), 1.34 (t, J=7.5 Hz, 3H), 1.38–1.52 (m, 4H), 2.87 (q, J=7.5 Hz, 2H), 3.05–3.13 (m, 4H), 3.88 (s, 3H), 6.98 (dd, J=2.6, 8.6 Hz, 1H), 7.10 (d, J=2.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 8.02 (d, J=4.0 Hz, 1H), 8.08 (d, J=4.0 Hz, 1H).
1H NMR (400 MHz, CDCl3) δ 0.86–0.93 (m, 6H), 1.29 (t, J=7.5 Hz, 3H), 1.37–1.48 (m, 4H), 2.76 (q, J=7.5 Hz, 2H), 3.02–3.09 (m, 4H), 3.82 (s, 3H), 7.04 (d, J=2.0 Hz, 1H), 7.07 (dd, J=2.0, 8.1 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 8.02 (s, 1H).
Pale Yellow Crystals
Hereinafter, compounds were synthesized in the same process as that of Example 1 or a similar process.
Yellow Crystals
1H NMR (400 MHZ, DMSO-d6) δ 0.79–0.88 (m, 6H), 1.22 (t, J=7.5 Hz, 3H), 1.34–1.47 (m, 4H), 2.42 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 3.06–3.15 (m, 4H), 3.66 (s, 6H), 6.72 (s, 2H), 8.31 (br s, 1H), 8.60 (br s, 1H).
Orange Crystals
1H NMR (400 MHz, CDCl3) δ 0.84–0.92 (m, 6H), 1.35–1.46 (m, 4H), 1.40 (t, J=7.5 Hz, 3H), 2.84 (q, J=7.5 Hz, 2H), 3.03–3.11 (m, 4H), 7.50 (d, J=8.5 Hz, 2H), 7.89 (d, J=4.4 Hz, 1H), 7.99 (d, J=4.4 Hz, 1H), 8.71 (d, J=8.5 Hz, 2H).
Orange Crystals
1H NMR (400 MHZ, CDCl3) δ 0.86–0.94 (m, 6H), 1.38–1.52 (m, 4H), 1.45 (t, J=7.5 Hz, 3H), 2.94 (q, J=7.5 Hz, 2H), 3.09–3.17 (m, 4H), 3.94 (s, 3H), 7.18 (d, J=9.2 Hz, 2H), 8.09 (s, 2H), 8.96 (d, J=9.2 Hz, 2H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88–0.97 (m, 6H), 1.39 (t, J=7.5 Hz, 3H), 1.43–1.55 (m, 4H), 2.16 (s, 3H), 2.41 (s, 3H), 2.99 (q, J=7.5 Hz, 2H), 3.08–3.17 (m, 4H), 3.84 (s, 3H), 6.78 (s,1H), 6.80 (s, 1H), 8.20 (d, J=4.9 Hz, 1H), 8.24 (d, J=4.9 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.10–0.00 (m, 2H), 0.27–0.38 (m, 2H), 0.75–0.85 (m, 1H), 0.92–0.99 (m, 6H), 1.25 (t, J=7.5 Hz, 3H), 1.59–1.72 (m, 1H), 2.01 (s, 3H), 2.36 (s, 3H), 2.77 (q, J=7.5 Hz, 2H), 2.79–3.05 (m, 4H), 3.69 (s, 3H), 6.68 (s, 1H), 6.73 (s, 1H), 7.90 (d, J=4.6 Hz, 1H), 8.08 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.86–0.93 (m, 6H), 1.23 (t, J=7.5 Hz, 3H), 1.36–1.50 (m, 4H), 2.07 (s, 3H), 2.36 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 3.01–3.08 (m, 4H), 3.70 (s, 3H), 3.94 (s, 3H), 6.69 (s, 1H), 6.74 (s, 1H), 7.55 (s, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.4 Hz, 6H), 1.31 (t, J=7.6 Hz, 3H), 1.37–1.47 (m, 4H), 2.78 (q, J=7.6 Hz, 2H), 3.03–3.09 (m, 4H), 3.99 (s, 3H), 3.99 (s, 3H), 6.47 (d, J=8.2 Hz, 1H), 7.90 (d, J=4.4 Hz, 1H), 7.96 (d, J=4.4 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.4 Hz, 6H), 1.32 (t, J=7.5 Hz, 3H), 1.48–1.58 (m, 4H), 2.53 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 3.05–3.11 (m, 4H), 3.99 (s, 3H), 6.69 (d, J=8.5 Hz, 1H), 7.89 (d, J=4.6 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.99 (d, J=4.6 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ0.89 (t, J=7.4 Hz, 6H), 1.31 (t, J=7.5 Hz, 3H), 1.38–1.48 (m, 4H), 2.40 (s, 3H), 2.77 (q, J=7.5 Hz, 2H), 3.04–3.09 (m, 4H), 3.14 (s, 6H), 6.44 (s, 1H), 7.85 (d, J=4.6 Hz, 1H), 7.93 (d, J=4.6 Hz, 1H), 8.65 (s, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J=7.4 Hz, 6H), 1.26 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 4H), 2.07 (s, 3H), 2.28 (s, 3H), 2.55 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 3.06–3.11 (m, 4H), 6.96 (s, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.4 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.37–1.47 (m, 4H), 2.35 (s, 3H), 2.80 (q, J=7.6 Hz, 2H), 3.06–3.10 (m, 4H), 7.30 (dd, J=7.8, 4.6 Hz, 1H), 7.64–7.68 (m, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.06 (d, J=4.4 Hz, 1H), 8.58–8.62 (m, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J=7.4 Hz, 6H), 1.26 (t, J=7.5 Hz, 3H), 1.38–1.48 (m, 4H), 2.05 (s, 3H), 2.22 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 3.06–3.11 (m, 4H), 3.95 (s, 3H), 6.52 (s, 1H), 7.90 (d, J=4.6 Hz, 1H), 8.03 (d, J=4.6 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.3 Hz, 6H), 1.31 (t, J=7.5 Hz, 3H), 1.38–1.48 (m, 4H), 2.27 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 3.04–3.10 (m, 4H), 5.97 (s, 2H), 6.79 (s, 1H), 7.16 (s, 1H), 7.86 (d, J=4.4 Hz, 1H), 7.98 (d, J=4.4 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.4 Hz, 6H), 1.31 (t, J=7.5 Hz, 3H), 1.37–1.48 (m, 4H), 2.21 (s, 3H), 2.33 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 3.04–3.10 (m, 4H), 3.87 (s, 3H), 6.76 (s, 1H), 7.41 (s, 1H), 7.86 (d, J=4.6 Hz, 1H), 7.97 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 2H), 1.55–1.68 (m, 1H), 2.80 (q, J=7.2 Hz, 2H), 2.94 (d, J=6.8 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 7.40 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.07 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 405 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.36 (d, J=8.4 Hz, 2H), 0.76–0.92 (m, 1H), 0.91 (t, J=7.6 Hz, 3H), 1.30 (t, J=7.6 Hz, 3H), 1.43–1.48 (m, 2H), 2.80 (q, J=8.0 Hz, 2H), 2.96 (d, J=6.8 Hz, 2H), 3.16 (t, J=7.2 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.93 (d, J=4.8 Hz, 1H), 8.13 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 403 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J=7.6 Hz, 3H), 1.30 (t, J=7.6 Hz, 3H), 1.40–1.50 (m, 2H), 1.72–1.78 (m, 1H), 1.80–1.86 (m, 1H), 2.81 (q, J=7.6 Hz, 2H), 3.09 (dd, J=7.6, 7.6 Hz, 2H), 3.30 (t, J=7.2 Hz, 2H), 4.45 (t, J=6.0 Hz, 1H) 4.57 (t, J=5.6 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.95 (d, J=4.8 Hz, 1H), 8.05 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 409 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.37 (br d, J=6.8 Hz, 2H), 0.74–0.88 (m, 1H), 0.97 (d, J=6.4 Hz, 6H), 1.32 (t, J=7.6 Hz, 3H), 1.60–1.72 (m, 1H), 2.83 (q, J=7.6 Hz, 2H), 2.95 (d, J=7.2 Hz, 2H), 3.02 (d, J=6.8 Hz, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.95 (d, J=4.4 Hz, 1H), 8.17 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 417 MH+
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.95 (d, J=6.8 Hz, 12H), 1.29 (t, J=7.2 Hz, 3H), 1.56–1.64 (m, 2H), 2.80 (q, J=7.6 Hz, 2H), 2.89 (d, J=6.4 Hz, 4H), 7.38 (dd, J=8.0, 2.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.93 (d, J=4.8 Hz, 1H), 8.07 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 419 MH+
MS (FAB) m/z 363 MH+
MS (FAB) m/z 391 MH+
MS (FAB) m/z 419 MH+
MS (FAB) m/z 453 MH+
MS (FAB) m/z 459 MH+
MS (FAB) m/z 443 MH+
MS (FAB) m/z 433 MH30
MS (FAB) m/z 451 MH+
MS (FAB) m/z 433 MH30
MS (FAB) m/z 459 MH+
MS (FAB) m/z 367 MH+
MS (FAB) m/z 395 MH+
MS (FAB) m/z 423 MH+
MS (FAB) m/z 457 MH+
MS (FAB) m/z 463 MH+
MS (FAB) m/z 447 MH+
MS (FAB) m/z 437 MH+
MS (FAB) m/z 455 MH+
MS (FAB) m/z 437 MH+
MS (FAB) m/z 463 MH+
MS (FAB) m/z 477 MH+
MS (FAB) m/z 421 MH+
MS (FAB) m/z 423 MH+
MS (FAB) m/z 473 MH+
MS (FAB) m/z 377 MH+
MS (FAB) m/z 405 MH+
MS (FAB) m/z 433 MH+
MS (FAB) m/z 473 MH+
MS (FAB) m/z 447 MH+
MS (FAB) m/z 465 MH+
MS (FAB) m/z 447 MH+
MS (FAB) m/z 487 MH+
MS (FAB) m/z 432 MH+
MS (FAB) m/z 419 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.2 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.47–1.38 (m, 4H), 2.78 (q, J=7.6 Hz, 2H), 3.06 (dd, J=7.2, 8.8 Hz, 4H), 3.02 (s, 3H), 7.05 (d, J=2.0 Hz, 1H), 7.08 (dd, J=2.0, 8.4 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.90 (d, J=4.4 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H).
Orange Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 6H), 1.29 (t, J=7.2 Hz, 3H), 1.47–1.38 (m, 4H), 2.80 (q, J=8.0 Hz, 2H), 3.06 (dd, J=7.6, 7.6 Hz, 4H), 7.53 (ddd, J=0.4, 2.0, 8.4 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.93 (dd, J=0.4, 4.8 Hz, 1H), 8.05 (dd, J=0.4, 4.8 Hz, 1H).
Orange Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 6H), 1.29 (t, J=7.2 Hz, 3H), 1.46–1.38 (m, 2H), 2.79 (q, J=7.2 Hz, 2H), 3.08 (dd, J=7.2, 7.2 Hz, 4H), 7.57 (s, 1H), 7.57 (dd, J=0.8, 2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H) 8.05 (dd, J=0.4, 4.4 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.6 Hz, 6H), 1.32 (t, J=7.2 Hz, 3H), 1.45–1.38 (m, 4H), 2.81 (q, J=7.6 Hz, 2H), 3.07 (dd, J=7.6, 7.6 Hz, 4H), 7.43 (dd, J=2.0, 10.0 Hz, 1H), 7.45 (ddd, J=0.4, 1.6, 7.6 Hz, 1H), 7.86 (dd, J=7.2, 8.0 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.04 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H), 1.46–1.40 (m, 2H), 2.80 (q, J=7.6 Hz, 2H) 3.07 (t, J=7.6 Hz, 4H), 6.98 (dd, J=2.8, 8.8 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.01 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.84 (t, J=7.6 Hz, 3H), 0.95 (t, J=7.6 Hz, 3H), 1.08 (d, J=6.0 Hz, 3H), 1.30 (t, J=7.6 Hz, 3H), 1.30–1.44 (m, 2H), 1.74–1.62 (m, 2H), 2.79 (q, J=7.2 Hz, 2H), 3.18–3.04 (m, 3H), 7.38 (dd, J=2.0, 8.4 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.02–0.0 (m, 2H), 0.25–0.29 (m, 2H), 0.70–0.60 (m, 1H), 0.95 (t, J=7.2 Hz, 3H), 1.06 (m, 3H), 1.31 (t, J=7.6 Hz, 3H), 1.67 (m, 2H), 2.79 (q, J=7.6 Hz, 2H), 3.04–2.94 (m, 2H), 3.20 (br s, 1H), 7.39 (dd, J=2.0, 8.4 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.14 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.84 (t, J=6.8 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.02–1.12 (m, 3H), 1.31 (t, J=7.6 Hz, 3H), 1.20–1.46 (m, 4H), 1.64–1.78 (m, 2H), 2.80 (q, J=7.6 Hz, 2H), 3.02–3.20 (m, 3H), 7.39 (dd, J=2.0, 8.4 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.92–0.80 (m, 6H), 1.01 (t, J=7.2 Hz, 3H), 1.09 (dd, J=6.8, 9.8 Hz, 3H), 1.31 (t, J=7.6 Hz, 3H), 1.30–1.46 (m, 2H), 1.62–1.82 (m, 2H), 2.78–2.90 (m, 3H), 2.92–3.12 (m, 2H), 7.39 (dd, J=2.0, 8.4 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.06 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.23–0.10 (m, 1H), 0.00–0.12 (m, 1H), 0.18–0.32 (m, 1H), 0.28–0.40 (m, 1H), 0.67–0.73 (m, 1H), 1.34 (t, J=7.6 Hz, 3H), 1.90–2.02 (m, 1H), 2.00–2.24 (m, 1H), 2.46–2.55 (m, 1H), 2.56–2.72 (m, 1H), 2.81 (q, J=7.6 Hz, 2H), 2.86–3.12 (m, 4H), 4.00–4.10 (m, 1H), 7.41 (dd, J=2.0, 8.4 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.98 (d, J=4.4 Hz, 1H), 8.22–8.14 (m, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 3H), 1.28–1.40 (m, 2H), 1.36 (t, J=7.6 Hz, 3H), 1.90–2.20 (m, 2H), 2.503.02 (m, 6H), 3.01–3.21 (m, 2H), 3.96–4.03 (m, 1H), 7.42 (dd, J=2.0, 8.4 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 8.01–8.06 (m, 1H), 8.15 (d, J=4.4 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.94 (d, J=6.8 Hz, 12H), 1.25 (t, J=7.6 Hz, 3H), 1.58–1.65 (m, 2H), 2.40 (s, 3H), 2.79 (q, J=7.6 Hz, 2H), 2.87 (d, J=6.8 Hz, 4H), 3.70 (s, 6H), 6.50 (s, 2H), 7.92 (d, J=4.8 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H).
Yellow Oil
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.95 (d, J=6.4 Hz, 12H), 1.26 (t, J=7.6 Hz, 3H), 1.56–1.68 (m, 2H), 2.03 (s, 3H), 2.36 (s, 3H), 2.79 (q, J=7.6 Hz, 2H), 2.89 (d, J=6.8 Hz, 4H), 3.70 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.06 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.95 (d, J=7.6 Hz, 12H), 1.25 (t, J=7.6 Hz, 3H), 1.58–1.65 (m, 2H), 2.03 (s, 6H), 2.32 (s, 3H), 2.79 (q, J=7.2 Hz, 2H), 2.90 (d, J=6.8 Hz, 4H), 6.94 (s, 2H), 7.91 (d, J=4.8 Hz, 1H), 8.07 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H), 1.31 (t, J=7.2 Hz, 3H), 1.25–1.42 (m, 4H), 1.58–1.65 (m, 1H), 2.81 (q, J=7.2 Hz, 2H), 2.93 (d, J=7.2 Hz, 2H), 3.06 (d, J=6.8 Hz, 2H), 3.86 (s, 3H), 6.94 (dd, J=2.8, 8.8 Hz, 1H), 7.08 (d, J=2.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 3H), 0.95 (d, J=6.8 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H), 1.24–1.46 (m, 4H), 1.48–1.67 (m, 1H), 2.03 (s, 6H), 2.32 (s, 3H), 2.78 (q, J=7.8 Hz, 2H), 2.94 (d, J=7.2 Hz, 2H), 3.07 (t, J=6.8 Hz, 2H), 6.94 (s, 2H), 7.92 (d, J=4.4 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H), 1.26 (t, J=7.6 Hz, 3H), 1.25–1.42 (m, 4H), 1.58–1.68 (m, 1H), 2.40 (s, 3H), 2.79 (q, J=7.6 Hz, 2H), 2.91 (d, J=7.2 Hz, 2H), 3.05 (t, J=7.2.Hz, 2H), 3.70 (s, 6H), 6.50 (d, J=0.8 Hz, 2H), 7.93 (d, J=4.0 Hz, 1H), 7.99 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H), 1.26 (t, J=7.6 Hz, 3H), 1.20–1.41 (m, 4H), 1.59–1.68 (m, 1H), 2.03 (s, 3H), 2.37 (s, 3H), 2.79 (q, J=7.6 Hz, 2H), 2.92 (d, J=6.8 Hz, 2H), 3.06 (t, J=7.6 Hz, 2H), 3.71 (s, 3H), 6.69 (s, 1H), 6.74 (d, J=0.8 Hz, 1H), 7.93 (d, J=4.8 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.05–0.04 (m, 2H), 0.36–0.42 (m, 2H), 0.76–0.96 (m, 1H), 0.94 (d, J=6.8 Hz, 6H), 1.33 (t, J=7.2 Hz, 3H), 1.60–1.70 (m, 1H), 2.83 (q, J=7.6 Hz, 2H), 2.94 (d, J=7.2 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 3.88 (s, 3H), 6.96 (dd, J=2.4, 8.4 Hz, 1H), 7.09 (d, J=2.8 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.13 (d, J=4.4 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.12–0.02 (m, 2H), 0.29–0.40 (m, 2H), 0.73–0.85 (m, 1H), 0.95 (d, J=6.8 Hz, 6H), 1.29 (t, J=7.2 Hz, 3H), 1.63–1.70 (m, 1H), 2.41 (s, 3H), 2.90–2.75 (m, 1H), 2.92 (d, J=6.8 Hz, 2H), 3.00 (d, J=7.2 Hz, 2H), 3.72 (s, 6H), 6.51 (s, 2H), 7.94–8.04 (m, 1H), 8.08–8.13 (m, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ0.88 (t, J=7.2 Hz, 6H), 1.361–146 (m, 7H), 2.85 (q, J=7.6 Hz, 2H), 3.05–3.09 (m, 4H), 7.51 (d, J=8.8 Hz, 2H), 8.44 (s, 1H), 8.78 (d, J=8.8 Hz, 2H).
Orange Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 4H), 2.78 (q, J=7.6 Hz, 2H), 3.04–3.09 (m, 4H), 7.38 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 8.08 (s, 1H).
Orange Oil
1H NMR (400 MHz, CDCl3) δ0.90 (t, J=7.6 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 4H), 2.81 (q, J=7.6 Hz, 2H), 3.05–3.11 (m, 4H), 7.40 (dd, J=8.4, 2.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.50 (s, 1H).
Colorless Crystals
1H NMR (400 MHz, CDCl3) δ0.89 (t, J=7.6 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 2H), 1.54–1.68 (m, 1H), 2.79 (q, J=7.6 Hz, 2H), 2.92 (d, J=7.2 Hz, 2H), 2.99–3.04 (m, 2H), 7.38 (dd, J=8.4, 2.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 8.18 (s, 1H).
Orange Oil
1H NMR (400 MHz, CDCl3) δ0.90 (t, J=7.6 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 4H), 2.79 (q, J=7.6 Hz, 2H), 3.03–3.09 (m, 4H), 7.38 (dd, J=8.4, 2.0 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 8.17 (s, 1H).
Colorless Crystals
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.6 Hz, 6H), 1.31 (d, J=6.8 Hz, 6H), 1.38–1.48 (m, 4H), 3.05–3.10 (m, 4H), 3.14–3.22 (m, 1H), 7.39 (dd, J=8.4, 2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 6H), 1.28 (dd, J=6.8 Hz, 3.2 Hz, 6H), 1.38–1.48 (m, 4H), 2.05 (s, 3H), 2.38 (s, 3H), 3.05–3.10 (m, 4H), 3.12–3.20 (m, 1H), 3.72 (s, 3H), 6.71 (s, 1H), 6.75 (s, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.00 (d, J=4.4 Hz, 1H).
By performing a coupling reaction in the same manner as that of Example 1 using 1-(8-chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)butyl ethyl ether obtained in Reference Example 5, the title compound could be obtained as a pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 0.92–0.98 (m, 3H), 1.15–1.37 (m, 7H), 1.42–1.56 (m, 1H), 1.76–1.88 (m, 1H), 2.03–2.15 (m, 1H), 2.72–2.88 (m, 2H), 3.24–3.33 (m, 1H), 3.35–3.46 (m, 1H), 4.75–4.81 (m, 1H), 7.40 (dd, J=2.0, 8.4 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.92 (d, J=4.6 Hz, 1H), 8.42 (d, J=4.6 Hz, 1H).
According to the process of Example 110, the following compounds of Examples 111 to 114 were synthesized.
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.91–0.98 (m, 3H), 1.15–1.34 (m, 7H), 1.41–1.55 (m, 1H), 1.76–1.88 (m, 1H), 2.02 (s, 3H), 2.04–2.15 (m, 1H), 2.37 (s, 3H), 2.70–2.82 (m, 2H), 3.21–3.44 (m, 2H), 3.69 (s, 3H), 4.72–4.78 (m, 1H), 6.68 (s, 1H), 6.74 (s, 1H), 7.89 (d, J=4.6 Hz, 1H), 8.34 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.89–0.98 (m, 3H), 1.13–1.35 (m, 7H), 1.40–1.55 (m, 1H), 1.74–1.86 (m, 1H), 2.02–2.14 (m, 1H), 2.40 (s, 3H), 2.68–2.83 (m, 2H), 3.24–3.43 (m, 2H), 3.69 (s, 3H), 3.70 (s, 3H), 4.70–4.77 (m, 1H), 6.50 (s, 2H), 7.89 (d, J=4.8 Hz, 1H), 8.31 (d, J=4.8 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90–0.98 (m, 3H), 1.19 (t, J=7.0 Hz, 3H), 1.22–1.36 (m, 4H), 1.40–1.55 (m, 1H), 1.77–1.88 (m, 1H), 2.03–2.15 (m, 1H), 2.72–2.87 (m, 2H), 3.29 (dq, J=9.3, 7.0 Hz, 1H), 3.39 (dq, J=9.3, 7.0 Hz, 1H), 3.87 (s, 3H), 4.73–4.80 (m, 1H), 6.95 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.90 (d, J=4.6 Hz, 1H), 8.37 (d, J=4.6 Hz, 1H).
1-(8-Chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanone (226 mg, 0.90 mmol) and 4,6-dimethyl-2-methoxybenzeneboronic acid (198 mg, 1.1 mmol) were dissolved in a mixed solvent of 1,2-dimethoxyethane (4.5 mL) and water (0.75 mL). Barium hydroxide octahydrate (347 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium complex (79 mg, 0.068 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was filtered and washed with ethyl acetate. Then, the filtrates were combined and washed with a 1N aqueous sodium hydroxide solution. It was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give 1-[2-ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-1-butanone (245 mg) as a white amorphous.
The resulting 1-[2-ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-1-butanone (220 mg, 0.63 mmol) was dissolved in tetrahydrofuran (2 mL), then a 0.90M propylmagnesium bromide solution in tetrahydrofuran (3.6 mL, 3.2 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 2 hours. An aqueous saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=6:5) to give the title compound (150 mg) as white crystals.
1H NMR (400 MHz, CDCl3) δ 0.87–0.96 (m, 6H), 1.18–1.45 (m, 4H), 1.25 (t, J=7.5 Hz, 3H), 1.90–2.12 (m, 4H), 2.02 (s, 3H) 2.37 (s, 3H), 2.82 (q, J=7.5 Hz, 2H), 3.68 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.81 (d, J=4.9 Hz, 1H), 8.75 (d, J=4.9 Hz, 1H).
4-[2-Ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-4-heptanol (115 mg, 0.29 mmol) and triethylamine (0.48 mL, 3.5 mmol) were dissolved in methylene chloride (3 mL), then methanesulfonyl chloride (0.13 mL, 1.7 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (111 mg) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 0.87–0.93 (m, 3H), 1.12 (t, J=7.4 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.24–1.36 (m, 2H), 2.04 (s, 3H), 2.33 (dq, J=7.5, 7.4 Hz, 2H), 2.37 (s, 3H), 2.38–2.44 (m, 2H), 2.74 (q, J=7.5 Hz, 2H), 3.70 (s, 3H), 5.71 (t, J=7.5 Hz, 1H), 6.68 (s, 1H), 6.74 (s, 1H), 7.81 (d, J=4.6 Hz, 1H), 7.88 (d, J=4.6 Hz, 1H).
2-[2-Ethyl-3-[(Z)-1-propyl-1-butenyl]imidazo[1,2-a]pyrazin-8-yl]-3,5-dimethylphenyl methyl ether (41 mg, 0.12 mmol) was dissolved in ethanol (1.5 mL), then 10% palladium-carbon (50% hydrous product; 120 mg) was added thereto, and the mixture was heated under stirring at 45° C. for 4 hours at a normal pressure under hydrogen atmosphere. The mixture was further stirred at room temperature for 15 hours. The reaction mixture was filtered and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (25 mg) as white crystals.
1H NMR (400 MHz, CDCl3) δ 0.84–0.92 (m, 6H), 1.04–1.33 (m, 4H), 1.23 (t, J=7.5 Hz, 3H), 1.71–1.91 (m, 4H), 2.01 (s, 3H), 2.36 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.05–3.15 (m, 1H), 3.69 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.87 (d, J=4.8 Hz, 1H), 7.92 (d, J=4.8 Hz, 1H).
According to the processes of Examples 116 and 117, compounds of Examples 118 to 120 were synthesized.
Orange Oil
1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=7.5 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.92 (d, J=7.0 Hz, 3H), 2.04 (s, 3H), 2.37 (s, 3H), 2.47 (q, J=7.5 Hz, 2H), 2.73 (q, J=7.5 Hz, 2H), 3.70 (s, 3H), 5.76 (q, J=7.0 Hz, 1H), 6.68 (s, 1H), 6.74 (s, 1H), 7.79 (d, J=4.6 Hz, 1H), 7.88 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.79–0.87 (m, 6H), 1.23 (t, J=7.5 Hz, 3H), 1.82–1.94 (m, 4H), 2.01 (s, 3H), 2.37 (s, 3H), 2.77 (q, J=7.5 Hz, 2H), 2.87–2.97 (m, 1H), 3.69 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.87 (d, J=4.8 Hz, 1H), 7.92 (d, J=4.8 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ0.78–0.86 (m, 6H), 1.29 (t, J=7.5 Hz, 3H), 1.82–1.92 (m, 4H), 2.79 (q, J=7.5 Hz, 2H), 2.872–197 (m, 1H), 3.81 (s, 3H), 3.87 (s, 3H), 6.60–6.67 (m, 2H), 7.64–7.68 (m, 1H), 7.85 (d, J=4.6 Hz, 1H), 7.88 (d, J=4.6 Hz, 1H).
Acetic acid (5 mL) and hydrazine monohydrate (2.52 g, 0.05 mol) were added to a solution of 1-(2,4-dimethylphenyl)-3-oxobutyl cyanide (10.13 g, 0.05 mol) in ethanol (100 mL), and the mixture was heated under reflux for 8 hours. The reaction mixture was evaporated as it was. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give 4-(2,4-dimethylphenyl)-6-methyl-3-pyridazinamine as a crude product.
Methyl 2-chloro-3-oxopentanoate (7 mL) was added to a solution of the resulting 4-(2,4-dimethylphenyl)-6-methyl-3-pyridazinamine in N,N-dimethylformamide (60 mL), and the mixture was heated at 140° C. for 6 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid methyl ester as a crude product.
A 5N aqueous sodium hydroxide solution (20 mL) was added to a solution of the resulting 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazin-3-carboxylic acid methyl ester in ethanol (100 mL), and the mixture was heated under reflux for 3 hours. The reaction mixture was evaporated as it was. Water was added thereto, which was extracted with ethyl acetate. 5N Hydrochloric acid (pH=1) was added to the aqueous layer, and the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid as a crude compound (2.8 g).
Triethylamine (20 mL), tert-butyl alcohol (30 mL) and diphenylphospholylazide (1.95 mL, 9.05 mmol) were added to a solution of the resulting 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (2.8 g, 9.05 mmol) in toluene (40 mL), and the mixture was heated at 140° C. for 6 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give tert-butyl N-[8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazin-3-yl]carbamate as a crude compound.
4N hydrochloric acid/ethyl acetate (30 mL) was added to a solution of the resulting tert-butyl N-[8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazin-3-yl]carbamate in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 14 hours. The mixture was neutralized by adding 5N aqueous sodium hydroxide solution under ice-cooling, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazin-3-amine as a crude product.
Propionaldehyde (3.26 mL, 45.25 mmol) was added to a solution of the resulting 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazin-3-amine (9.05 mmol) in dichloromethane (60 mL), and the mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (5.75 g, 27.15 mmol) was gradually added thereto, then acetic acid (1 mL) was further added dropwise, and the mixture was stirred for 5 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give the title compound (8.8 mg) as a pale green oil.
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.3 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H), 1.31–1.44 (m, 4H), 2.24 (s, 3H), 2.37 (s, 3H), 2.57 (s, 3H), 2.75 (q, J=7.6 Hz, 2H), 3.20 (t, J=7.4 Hz, 4H), 6.65 (s, 1H), 7.09 (d, J=7.7 Hz, 1H), 7.13 (s, 1H), 7.28 (d, J=7.7 Hz, 1H).
MS (ESI) m/z 365 MH+
A 5N aqueous sodium hydroxide solution (0.603 mL, 3.0 mmol) was added to a solution of methyl 8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazine-3-carboxylate (373 mg, 1.20 mmol) in ethanol (15 mL), and the mixture was heated under reflux for 1 hour. 5N hydrochloric acid (0.603 mL) was added thereto under ice-cooling and the solvent was evaporated, to give 8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazine-3-carboxylic acid as a crude compound.
Triethylamine (0.202 mL, 1.4 mmol), t-butyl alcohol (5 mL) and diphenylphospholylazide (0.26 mL, 1.2 mmol) were added to a solution of the crude 8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazine-3-carboxylic acid (1.206 mmol) in toluene (10 mL), and the mixture was heated at 90° C. for 1 hour and 110° C. for 4 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give crude tert-butyl N-[8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazin-3-yl]carbamate.
4N hydrochloric acid/ethyl acetate (15 mL) was added to a solution of the crude tert-butyl N-[8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazin-3-yl]carbamate in ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 hours. The mixture was neutralized by adding a 5N aqueous sodium hydroxide solution under ice-cooling, and extracted with ethyl acetate. It was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give crude 8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazin-3-amine.
Propionaldehyde (0.435 mL, 6.0 mmol) and 3M sulfuric acid (2.01 mL, 6.0 mmol) were added to a solution of the crude 8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazin-3-amine (1.2 mmol) in tetrahydrofuran (10 mL) under ice-cooling, and sodium borohydride (182 mg, 4.8 mmol) was gradually added at the same temperature. After heating under stirring for 30 minutes, it was stirred at room temperature for 20 minutes, and neutralized by adding a 5N aqueous sodium hydroxide solution under ice-cooling. Water was added thereto, which was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:15) to give the title compound (42 mg, 10% (4 steps)) as yellow crystals.
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.4 Hz, 6H), 1.28 (t, J=7.5 Hz, 3H), 1.32–1.46 (m, 4H), 2.25 (s, 3H), 2.38 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 3.20 (t, J=7.5 Hz, 4H), 6.79 (br s, 1H), 7.10 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 7.32 (d, J=7.9 Hz, 1H), 8.26 (d, J=4.4 Hz, 1H).
Hereinafter, compounds of Examples 123 to 126 were synthesized in the same manner as that of Example 122.
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.3 Hz, 6H), 1.31 (t, J=7.6 Hz, 3H), 1.32–1.44 (m, 4H), 2.80 (q, J=7.5 Hz, 2H), 3.19 (t, J=7.5 Hz, 4H), 3.83 (s, 3H), 3.87 (s, 3H), 6.59 (d, J=2.4 Hz, 1H), 6.66 (dd, J=2.4, 8.6 Hz, 1H), 7.16 (d, J=4.8 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H), 8.23 (d, J=5.1 Hz, 1H).
MS (ESI) m/z 383 MH+
Orange Crystals
1H NMR (400 MHz, CDCl3) δ 1.01 (d, J=6.8 Hz, 6H), 1.34 (t, J=7.6 Hz, 3H), 1.75–1.88 (m, 1H), 2.84–2.95 (m, 2H), 3.07 (d, J=6.8 Hz, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.59 (d, J=2.2 Hz, 1H), 6.65 (dd, J=2.4, 8.6 Hz, 1H), 7.07 (d, J=4.6 Hz, 1H), 7.94 (br s, 1H), 8.24 (d, J=3.7 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.02–0.06 (m, 2H), 0.34–0.44 (m, 2H), 0.84–1.00 (m, 1H), 1.02 (d, J=6.6 Hz, 6H), 1.43 (t, J=7.6 Hz, 3H), 1.63–1.76 (m, 1H), 2.95 (q, J=7.5 Hz, 2H), 3.17 (t, J=7.7 Hz, 4H), 3.93 (s, 3H), 3.97 (s, 3H), 6.69 (d, J=2.4 Hz, 1H), 6.76 (dd, J=2.4, 8.6 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.32 (d, J=4.8 Hz, 1H).
MS (ESI) m/z 409 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.4 Hz, 6H), 1.28 (t, J=7.6 Hz, 3H), 1.33–1.45 (m, 4H), 2.29 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 3.20 (t, J=7.5 Hz, 4H), 3.85 (s, 3H), 6.79 (br s, 1H), 6.82–6.90 (m, 2H), 7.39 (d, J=8.2 Hz, 1H), 8.26 (d, J=4.2 Hz, 1H).
MS (ESI) m/z 367 MH+
N-[8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (50 mg) was dissolved in a mixed solvent of 1,2-dimethoxyethane (6 mL) and water (1 mL). 2,4-Dichlorobenzeneboronic acid (53 mg), barium hydroxide octahydrate (88 mg) and tetrakistriphenylphosphine palladium complex (16 mg) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give N-[8-(2,4-dichlorophenyl)-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (43 mg) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.38–1.44 (m, 4H), 2.36 (s, 3H), 2.50 (s, 3H), 3.02–3.18 (m, 4H), 6.99 (d, J=2.0 Hz, 1H), 7.32 (dd, J=2.4, 8.8 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H).
Hereinafter, according to the process of Example 127, compounds of Examples of 128 and 129 were synthesized.
Colorless Oil
1HNMR (400 MHz, CDCl3) δ0.89 (t, J=7.6 Hz, 6H), 1.35–1.46 (m, 4H), 2.59 (s, 3H), 3.08–3.12 (m, 4H), 7.38 (ddd, J=8.4, 2.0, 0.4 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.73 (dd, J=8.4, 0.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.01 (d, J=4.4 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 6H), 0.93 (d, J=6.4 Hz, 6H), 1.37–1.47 (m, 2H), 1.54–1.62 (m, 1H), 2.59 (s, 3H), 2.98 (d, J=7.2 Hz, 2H), 3.02–3.08 (m, 2H), 7.39 (dd, J=8.4, 2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.95 (d, J=4.4 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H).
Hereinafter, according to the process of Example 4, compounds of Examples of 130 to 187 were synthesized.
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 4H), 2.09 (s, 3H), 2.78 (q, J=7.6 Hz, 2H), 3.07 (dd, J=6.4, 8.0 Hz, 4H), 7.64–7.67 (m, 1H), 7.80 (br s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.94–7.97 (m, 1H), 8.08 (d, J=4.4 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 4H), 2.80 (q, J=7.6 Hz, 2H), 3.08 (dd, J=6.4, 8.0 Hz, 4H), 7.64–7.67 (m, 1H), 7.79–7.80 (m, 1H), 7.81–7.84 (m, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.08 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 6H), 1.28 (d, J=6.8 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 4H), 2.80 (q, J=7.6 Hz, 2H), 2.94 (hept., J=6.8 Hz, 1H), 3.07 (dd, J=6.4, 8.0 Hz, 4H), 7.28 (d, J=1.6, 8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.6 Hz, 6H), 1.24 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 4H), 2.38 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 3.07 (dd, J=6.4, 8.0 Hz, 4H), 3.70 (s, 3H), 6.78 (s, 1H), 7.12 (s, 1H), 7.90 (d, J=4.8 Hz, 1H), 8.02 (d, J=4.8 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 6H), 1.24 (t, J=7.6 Hz, 3H), 1.37–1.47 (m, 4H), 2.08 (s, 3H), 2.34 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 3.07 (dd, J=6.4, 8.0 Hz, 4H), 7.05 (s, 1H), 7.34 (s, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.2 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.37–1.47 (m, 4H), 2.35 (s, 3H), 2.37 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 3.07 (dd, J=6.4, 8.0 Hz, 4H), 7.09–7.14 (m, 2H), 7.53 (d, J=7.6 Hz, 1H), 7.87 (d, J=4.4 Hz, 1H), 7.98 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H), 1.37–1.47 (m, 4H), 2.34 (s, 3H), 2.79 (q, J=7.6 Hz, 2H), 3.07 (dd, J=6.0, 7.2 Hz, 4H), 7.29 (dd, J=2.0, 8.0 Hz, 1H), 7.30–7.32 (m, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.90 (d, J=4.8 Hz, 1H), 8.02 (d, J=4.8 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.6 Hz, 6H), 1.24 (t, J=7.2 Hz, 3H), 1.38–1.48 (m, 4H), 2.38 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 3.06 (t, J=7.6 Hz, 4H), 3.71 (s, 3H), 6.74 (s, 1H), 6.94 (s, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.01 (d, J=4.4 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 6H), 1.29 (t, J=7.2 Hz, 3H), 1.38–1.48 (m, 4H), 2.40 (s, 3H), 2.79 (q, J=7.2 Hz, 2H), 3.07 (t, J=7.6 Hz, 4H), 7.22–7.25 (m, 1H), 7.54–7.56 (m, 2H)), 7.92 (d, J=4.4 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H), 1.37–1.47 (m, 4H), 2.07 (s, 3H), 2.34 (s, 3H), 2.78 (q, J=7.6 Hz, 2H), 3.08 (t, J=7.6 Hz, 4H), 7.02 (s, 1H), 7.16 (s, 1H), 7.92 (d, J=4.8 Hz, 1H), 8.04 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.35 (d, J=8.0 Hz, 2H), 0.76–0.90 (m, 1H), 1.30 (t, J=7.6 Hz, 3H), 2.79 (q, J=7.6 Hz, 2H), 3.04 (d, J=7.2 Hz, 2H), 3.26 (s, 3H), 3.30–3.42 (m, 4H), 7.39 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.19 (d, J=4.4 Hz, 1H).
MS (FAB) m/z 365 MH+
MS (FAB) m/z 407 MH+
MS (FAB) m/z 421 MH+
MS (FAB) m/z 434 MH+
MS (FAB) m/z 421 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.36 (br s, 2H) 0.78–0.85 (m, 1H), 0.90 (t, J=7.6 Hz, 3H), 0.97 (d, J=7.8 Hz, 3H), 1.10–1.21 (m, 1H), 1.33 (t, J=7.6 Hz, 3H), 1.401–151 (m, 1H), 1.51–1.60 (m, 1H), 2.84 (q, J=7.6 Hz, 2H), 2.88–2.89 (m, 3H), 3.17 (dd, J=6.4, 6.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.96 (d, J=4.4 Hz, 1H), 8.18 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H), 0.96 (d, J=6.8 Hz, 3H), 1.04–1.16 (m, 1H), 1.30–1.44 (m, 1H), 1.46–1.64 (m, 2H), 2.81 (q, J=7.6 Hz, 2H), 2.84–2.96 (m, 3H), 3.04 (dd, J=6.0, 6.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.10 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.36 (br s, 2H), 0.72–0.82 (m, 1H), 1.30 (t, J=7.6 Hz, 3H), 1.56–1.72 (m, 2H), 1.74–1.96 (m, 4H), 2.24–2.34 (m, 1H), 2.79 (q, J=7.6 Hz, 2H), 2.94 (d, J=7.2 Hz, 2H), 3.20 (d, J=7.6 Hz, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.09 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.42 (q, J=7.2 Hz, 2H), 1.54–1.66 (m, 2H), 1.72–1.94 (m, 4H), 2.22–2.34 (m, 1H), 2.79 (q, J=7.6 Hz, 2H), 3.06 (t, J=7.4 Hz, 2H), 3.14 (d, J=7.2 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 3H), 1.30 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 2H), 1.50–1.78 (m, 4H), 2.80 (q, J=7.6 Hz, 2H), 3.09 (dd, J=7.6, 7.6 Hz, 2H), 3.17 (t, J=7.6 Hz, 2H), 4.37 (t, J=6.0 Hz, 1H), 4.48 (t, J=6.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 3H), 1.30 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 2H), 1.50–1.78 (m, 4H), 2.80 (q, J=7.6 Hz, 2H), 3.09 (dd, J=7.6, 7.6 Hz, 2H), 3.17 (t, J=7.6 Hz, 2H), 4.37 (t, J=6.0 Hz, 1H), 4.48 (t, J=6.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.38 (d, J=8.0 Hz,2H), 0.74–0.84 (m, 1H), 1.31 (t, J=7.6 Hz, 3H), 1.50–1.60 (m, 2H), 1.64–1.82 (m, 2H), 2.81 (q, J=7.6 Hz, 2H), 2.97 (d, J=6.8 Hz, 2H), 3.26 (t, J=7.6 Hz, 2H), 4.38 (t, J=5.6 Hz, 1H), 4.50 (t, J=5.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.11 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.95 (t, J=6.8 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H), 1.50–1.76 (m, 5H), 2.80 (q, J=7.6 Hz, 2H), 2.94 (d, J=7.2 Hz, 2H), 3.13 (dd, J=8.0, 8.0 Hz, 2H), 4.367 (t, J=6.0 Hz, 1H), 4.48 (t, J=6.0 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.05 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.03 (br s, 4H), 0.36 (d, J=7.6 Hz, 4H), 0.74–0.86 (m, 2H), 1.30 (t, J=7.6 Hz, 3H), 2.80 (q, J=7.6 Hz, 2H), 3.03 (d, J=6.4 Hz, 4H), 7.38 (t, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.20 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.83 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.6 Hz, 3H), 1.50–2.08 (m, 6H), 2.74 (q, J=7.6 Hz, 2H), 3.68–3.98 (m, 2H), 4.48 (t, J=5.7 Hz, 1H), 4.60 (t, J=5.7 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.79 (d, J=4.4 Hz, 1H), 8.09 (d, J=4.8 Hz, 1H).
MS (ESI) m/z 437 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.94 (t, J=7.6 Hz, 3H), 1.31 (t, J=7.6 Hz, 3H), 1.48 (q, J=7.2 Hz, 2H), 2.46 (br s, 2H), 2.79 (q, J=7.6 Hz, 2H), 3.14 (t, J=7.6 Hz, 2H), 3.47 (t, J=6.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 8.01 (d, J=4.4 Hz, 1H), 8.22 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.40 (br s, 2H) 0.78–0.88 (m, 1H), 1.31 (t, J=7.6 Hz, 3H), 2.40–2.56 (m, 1H) 2.80 (q, J=7.6 Hz, 2H), 2.96–3.04 (m, 2H), 3.46–3.58 (m, 2H) 7.39 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 8.00 (d, J=4.4 Hz, 1H), 8.28 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.6 Hz, 3H), 1.32–1.20 (m, 4H), 1.54–1.66 (m, 2H), 1.74–1.92 (m, 4H), 2.22–2.32 (m, 1H), 2.79 (q, J=7.6 Hz, 2H), 3.09 (t, J=7.6 Hz, 2H), 3.13 (d, J=7.2 Hz, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.01 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.01 (br s, 2H), 0.36 (d, J=8.0 Hz, 2H), 0.76–0.88 (m, 1H), 0.89 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.6 Hz, 3H), 1.32–1.44 (m, 4H), 2.81 (q, J=7.6 Hz, 2H), 2.96 (d, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H), 8.12 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H), 1.24–1.46 (m, 4H), 1.56–1.70 (m, 1H), 2.39 (s, 3H), 2.78 (q, J=7.6 Hz, 2H), 2.92 (d, J=7.2 Hz, 2H), 3.06 (t, J=7.2 Hz, 2H), 3.71 (s, 3H), 6.75 (s, 1H), 6.95 (s, 1H), 7.92 (d, J=4.8 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 429 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 4H), 0.36 (br s, 4H) 0.74–0.88 (m, 2H), 1.26 (t, J=7.6 Hz, 3H), 2.39 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 2.94–3.10 (m, 4H), 3.71 (s, 3H), 6.74 (s, 1H), 6.95 (s, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.15 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 425 MH+
Yellow Oil
MS (ESI) m/z 421 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.03 (br s, 4H), 0.37 (d, J=7.6 Hz, 4H), 0.76–0.88 (m, 2H), 1.31 (m, J=7.6 Hz, 3H), 2.81 (q, J=8.0 Hz, 2H), 3.03 (d, J=6.8 Hz, 4H), 3.86 (s, 3H), 6.95 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 411 MH+
Yellow Oil
MS (ESI) m/z 405 MH+
Yellow Oil
MS (ESI) m/z 441 MH+
Yellow Oil
1H NMR (400 MHZ, CDCl3) δ 0.00 (br s, 2H), 0.33 (br s, 2H), 0.74–0.86 (m, 1H), 0.87 (t, J=7.6 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H), 1.06–1.18 (m, 1H), 1.25 (t, J=7.6 Hz, 3H), 1.381–1.60 (m, 2H), 2.41 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 2.82–3.18 (m, 4H), 3.69 (s, 6H), 6.50 (s, 2H), 7.90 (d, J=4.8 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.05 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 437 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.35 (br s, 2H), 0.74–0.84 (m, 1H), 0.87 (t, J=7.6 Hz, 3H), 0.93 (d, J=7.4 Hz, 3H), 1.08–1.18 (m, 1H), 1.31 (t, J=7.6 Hz, 3H), 1.36–1.60 (m, 2H), 2.81 (q, J=7.6 Hz, 2H), 2.84–3.18 (m, 4H), 3.86 (s, 3H), 6.94 (d, J=8.8 Hz, 1H), 7.07 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.10 (d, J=4.8 Hz, 1H).
MS (ESI) m/z 427 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.01 (br s, 2H), 0.33 (br s, 2H), 0.74–0.84 (m, 1H), 0.87 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.06–1.16 (m, 1H), 1.25 (t, J=7.6 Hz, 3H), 1.40–1.60 (m, 2H), 2.01 (s, 1H), 2.37 (s, 3H), 2.77 (q, J=7.2 Hz, 2H), 2.80–3.18 (m, 4H), 3.69 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.90 (d, J=4.4 Hz, 1H), 8.07 (d, J=4.8 Hz, 1H).
MS (ESI) m/z 421 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.01 (br s, 2H), 0.34 (d, J=7.8 Hz, 2H), 0.74–0.84 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.6 Hz, 3H), 1.40–1.50 (m, 2H), 3.39 (s, 3H), 2.77 (q, J=7.2 Hz, 2H), 2.86–3.02 (m, 2H), 3.15 (dd, J=7.6, 7.6 Hz, 2H), 3.71 (s, 3H), 6.74 (s, 1H), 6.94 (s, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.09 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 413 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.36 (br s, 2H), 0.78–0.88 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.6 Hz, 3H), 1.40–1.50 (m, 2H), 2.41 (s, 3H), 2.77 (q, J=7.2 Hz, 2H), 2.94 (d, J=6.8 Hz, 2H), 3.15 (t, J=7.2 Hz, 2H), 3.70 (s, 6H), 6.51 (s, 2H), 7.91 (d, J=4.8 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
MS (FAB) m/z 409 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.36 (d, J=8.1 Hz, 2H), 0.76–0.86 (m, 1H), 0.91 (t, J=7.6 Hz, 3H), 1.31 (t, J=7.6 Hz, 3H), 1.38–1.48 (m, 2H), 2.81 (q, J=7.6 Hz, 2H), 2.96 (d, J=6.8 Hz, 2H), 3.16 (t, J=7.2 Hz, 2H), 3.87 (s, 3H), 6.95 (dd, J=2.4, 8.8 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.09 (d, J=4.4 Hz, 1H).
MS (FAB) m/z 399 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 2H), 0.36 (d, J=8.4 Hz, 2H), 0.80–0.90 (m, 1H), 0.95 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.6 Hz, 3H), 1.42–1.52 (m, 2H), 2.04 (s, 3H), 2.39 (s, 3H), 2.79 (q, J=7.2 Hz, 2H), 2.88–3.06 (m, 2H), 3.18 (t, J=7.2 Hz, 2H), 3.71 (s, 3H), 6.71 (s, 1H), 6.76 (s, 1H), 7.93 (d, J=4.8 Hz, 1H), 8.08 (d, J=4.8 Hz, 1H).
MS (FAB) m/z 393 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.95 (d, J=6.4 Hz, 6H), 1.27 (t, J=7.6 Hz, 3H), 1.52–1.66 (m, 2H), 2.40 (s, 3H), 2.82 (q, J=7.6 Hz, 2H), 2.89 (d, J=6.8 Hz, 4H), 3.73 (s, 3H), 6.76 (s, 1H), 6.95 (s, 1H), 7.96 (d, J=4.4 Hz, 1H), 8.10 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.10–0.05 (m, 2H), 0.32–0.24 (m, 2H), 0.78–0.92 (m, 1H), 1.01 (d, J=6.4 Hz, 6H), 1.34 (t, J=7.2 Hz, 3H), 1.64–1.76 (m, 1H), 2.45 (s, 3H), 2.45 (s, 3H), 2.89 (q, J=7.2 Hz, 2H), 2.89–3.04 (m, 2H), 3.06 (d, J=8.8 Hz, 2H), 3.79 (s, 3H), 6.82 (s, 1H), 7.01 (s, 1H), 8.05 (br s, 1H), 8.22 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.6 Hz, 3H), 1.30 (t, J=7.6 Hz, 3H), 1.45 (q, J=7.6 Hz, 2H), 1.72–1.86 (m, 2H), 2.80 (q, J=7.6 Hz, 2H), 3.09 (t, J=7.6 Hz, 2H), 3.30 (t, J=7.2 Hz, 2H), 3.86 (s, 3H), 4.45 (t, J=5.6 Hz, 1H), 4.56 (t, J=5.6 Hz, 1H), 6.98 (dd, J=2.4, 8.0 Hz, 1H), 7.27 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.92 (d, J=4.8 Hz, 1H), 7.99 (d, J=4.4 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.6 Hz, 3H), 1.40–1.50 (m, 2H), 1.72–1.86 (m, 2H), 2.38 (s, 3H), 2.78 (q, J=7.2 Hz, 2H), 3.08 (t, J=7.6 Hz, 2H), 3.29 (t, J=7.6 Hz, 2H), 3.71 (s, 3H), 4.45 (t, J=5.6 Hz, 1H), 4.56 (t, J=5.6 Hz, 1H), 6.74 (s, 1H), 6.94 (s, 1H), 7.93 (d, J=4.4 Hz, 1H), 7.99 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 4H), 0.33 (d, J=7.6 Hz, 4H), 0.72–0.82 (m, 2H), 1.28 (t, J=7.2 Hz, 3H), 2.77 (q, J=7.6 Hz, 2H), 3.01 (d, J=7.2 Hz, 4H), 7.53 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.90 (d, J=4.8 Hz, 1H), 8.16 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 4H), 0.33 (d, J=8.4 Hz, 4H), 0.76–0.86 (m, 2H), 1.25 (t, J=7.6 Hz, 3H), 2.37 (s, 3H), 2.76 (t, J=7.6 Hz, 2H), 2.92–3.12 (m, 4H), 3.69 (s, 3H) 6.77 (s, 1H), 7.11 (s, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.14 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 4H), 0.33 (d, J=7.6 Hz, 4H), 0.72–0.84 (m, 2H), 1.28 (t, J=7.6 Hz, 3H), 2.76 (q, J=7.6 Hz, 2H), 3.01 (d, J=7.2 Hz, 4H), 3.83 (s, 3H), 6.96 (dd, J=2.4, 8.4 Hz, 1H), 7.23 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.88 (d, J=4.8 Hz, 1H), 8.13 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 455 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 4H), 0.34 (d, J=7.4 Hz, 4H), 0.76–0.86 (m, 2H), 1.25 (t, J=7.6 Hz, 3H), 2.76 (q, J=7.6 Hz, 2H), 2.96–3.08 (m, 4H), 3.71 (s, 3H), 6.92 (d, J=1.6 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.91 (d, J=4.8 Hz, 1H), 8.16 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.40–0.40 (m, 4H), 0.38 (d, J=8.0 Hz, 4H), 0.78–0.88 (m, 2H), 1.30 (t, J=7.6 Hz, 3H), 2.07 (s, 3H), 2.35 (s, 3H), 2.89 (q, J=7.6 Hz, 2H), 2.98–3.16 (m, 4H), 7.10 (s, 1H), 7.35 (s, 1H), 8.35 (d, J=4.8 Hz, 1H), 8.40 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.30–0.40 (m, 2H), 0.36–0.46 (m, 2H), 0.82–0.92 (m, 1H), 1.01 (t, J=7.2 Hz, 3H), 1.38 (t, J=7.6 Hz, 3H), 1.54–1.62 (m, 2H), 2.16 (s, 3H), 2.43 (s, 3H), 2.98 (q, J=7.6 Hz, 2H), 3.00–3.16 (m, 2H), 3.25 (t, J=7.2 Hz, 2H), 7.18 (s, 1H), 7.44 (s, 1H), 8.40 (d, J=4.4 Hz, 1H), 8.42 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.95 (d, J=6.8 Hz, 12H), 1.29 (t, J=7.6 Hz, 3H), 1.56–1.64 (m, 2H), 2.80 (q, J=8.0 Hz, 2H), 2.99 (d, J=6.4 Hz, 4H), 7.55 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.11 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 4H), 0.32 (d, J=7.6 Hz, 4H), 0.70–0.82 (m, 2H), 1.30 (t, J=7.6 Hz, 3H), 2.02 (s, 6H), 2.77 (q, J=7.6 Hz, 2H), 2.99 (d, J=7.2 Hz, 4H), 3.74 (s, 3H), 5.91 (s, 2H), 6.94 (s, 1H), 8.82 (s, 1H), 7.89 (d, J=4.4 Hz, 1H), 8.13 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00 (br s, 4H), 0.32 (d, J=7.2 Hz, 4H), 1.72–1.80 (m, 2H), 1.29 (t, J=7.6 Hz, 3H), 2.75 (q, J=7.2 Hz, 2H), 2.97 (d, J=6.8 Hz, 4H), 3.73 (s, 3H), 4.20 (br s, 2H), 6.41 (s, 1H), 7.62 (s, 1H), 7.83 (d, J=4.4 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 426 MH+
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.30–0.36 (m, 4H), 0.72–0.82 (m, 2H), 1.27 (t, J=7.6 Hz, 3H), 2.76 (q, J=7.6 Hz, 2H), 3.01 (d, J=6.8 Hz, 4H), 7.24 (dd, J=2.0, 7.6 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.90 (d, J=4.4 Hz, 1H), 8.17 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.28–0.38 (m, 4H), 0.70–0.82 (m, 2H), 1.26 (t, J=7.6 Hz, 3H), 2.76 (q, J=7.6 Hz, 2H), 3.00 (d, J=7.2 Hz, 4H), 7.62 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.19 (d, J=4.4 Hz, 1H).
Hereinafter, compounds of Example 188 to Example 195 were synthesized in the same manner as that of Example 8.
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.3 Hz, 6H), 1.29 (t, J=7.5 Hz, 3H), 1.43 (ddq, J=7.3, 7.3, 7.3 Hz, 4H), 2.76 (q, J=7.5 Hz, 2H), 3.05 (dd, J=7.3, 7.3 Hz, 4H), 3.98 (s, 3H), 7.38 (dd, J=2.0, 8.2 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.61 (s, 1H), 7.78 (d, J=8.2 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.3 Hz, 6H), 1.24 (t, J=7.5 Hz, 3H), 1.44 (ddq, J=7.3, 7.3, 7.3 Hz, 4H), 2.05 (s, 3H), 2.35 (s, 3H), 2.75 (q, J=7.5 Hz, 2H), 3.06 (dd, J=7.3, 7.3 Hz, 4H), 3.69 (s, 3H), 6.66 (s, 1H), 6.72 (s, 1H), 8.01 (s, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.06–0.08 (m, 4H), 0.31–0.43 (m, 4H), 0.78–0.90 (m, 2H), 1.25 (t, J=7.5 Hz, 3H), 2.03 (s, 3H), 2.35 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 2.92–3.11 (m, 4H), 3.68 (s, 3H), 6.66 (s, 1H), 6.73 (s, 1H), 8.16 (s, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.11–0.03 (m, 2H), 0.28–0.42 (m, 2H), 0.77–0.86 (m, 1H), 0.92 (t, J=7.3 Hz, 3H), 1.24 (t, J=7.5 Hz, 3H), 1.45 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.04 (s, 3H), 2.35 (s, 3H), 2.75 (q, J=7.5 Hz, 2H), 2.86–3.03 (m, 2H), 3.14 (dd, J=7.3, 7.3 Hz, 2H), 3.68 (s, 3H), 6.66 (s, 1H), 6.72 (s, 1H), 8.09 (s, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.09–0.05 (m, 2H), 0.31–0.44 (m, 2H), 0.77–0.88 (m, 1H), 1.25 (t, J=7.5 Hz, 3H), 1.74–1.90 (m, 2H), 2.04 (s, 3H), 2.36 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 2.88–3.05 (m, 2H), 3.32–3.40 (m, 2H), 3.68 (s, 3H), 4.44–4.50 (m, 1H), 4.56–4.62 (m, 1H), 6.67 (s, 1H), 6.73 (s, 1H), 8.07 (s, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.03–0.08 (m, 2H), 0.35–0.45 (m, 2H), 0.76–0.87 (m, 1H), 1.31 (t, J=7.5 Hz, 3H), 1.72–1.88 (m, 2H), 2.80 (q, J=7.5 Hz, 2H), 2.93–3.00 (m, 2H), 3.33–3.41 (m, 2H), 3.86 (s, 3H), 4.43–4.49 (m, 1H), 4.55–4.62 (m, 1H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 8.10 (s, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J=7.3 Hz, 3H), 1.30 (t, J=7.5 Hz, 3H), 1.45 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 1.72–1.88 (m, 2H), 2.79 (q, J=7.5 Hz, 2H), 3.08 (dd, J=7.3, 7.3 Hz, 2H), 3.25–3.33 (m, 2H), 3.86 (s, 3H), 4.42–4.48 (m, 1H), 4.53–4.60 (m, 1H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 8.02 (s, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.98–1.05 (m, 6H), 1.30 (t, J=7.5 Hz, 3H), 1.42–1.54 (m, 4H), 2.78 (q, J=7.5 Hz, 2H), 2.86 (br s, 1H), 2.91–3.00 (m, 1H), 3.86 (s, 3H), 6.93 (dd, J=2.6, 8.6 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.97 (s, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.3 Hz, 6H), 1.41 (ddq, J=7.3, 7.3, 7.3 Hz, 4H), 2.60 (s, 3H), 3.10 (dd, J=7.3, 7.3 Hz, 4H), 3.88 (s, 3H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 7.98 (d, J=4.4 Hz, 1H).
Hereinafter, compounds of Examples 197 to 260 were synthesized in the same manners as in Example 196.
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.3 Hz, 6H), 1.41 (ddq, J=7.3, 7.3, 7.3 Hz, 4H), 2.04 (s, 3H), 2.38 (s, 3H), 2.53 (s, 3H), 3.10 (dd, J=7.3, 7.3 Hz, 4H), 3.70 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.91 (d, J=4.6 Hz, 1H), 7.96 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.84–0.97 (m, 9H), 1.37–1.48 (m, 2H), 1.52–1.68 (m, 1H), 2.04 (s, 3H), 2.38 (s, 3H), 2.53 (s, 3H), 2.91–3.10 (m, 4H), 3.70 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.92 (d, J=4.6 Hz, 1H), 7.98 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.5 Hz, 3H), 0.93 (d, J=6.8 Hz, 6H), 1.43 (ddq, J=7.5, 7.5, 7.5 Hz, 2H), 1.58 (tqq, J=7.1, 6.8, 6.8 Hz, 1H), 2.60 (s, 3H), 2.98 (d, J=7.1 Hz, 2H), 3.05 (dd, J=7.5, 7.5 Hz, 2H), 3.88 (s, 3H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.93 (d, J=4.6 Hz, 1H), 7.99 (d, J=4.6 Hz, 1H).
Yellow Green Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.3 Hz, 6H), 1.41 (ddq, J=7.3, 7.3, 7.3 Hz, 4H), 2.42 (s, 3H), 2.53 (s, 3H), 3.09 (dd, J=7.3, 7.3 Hz, 4H), 3.71 (s, 6H), 6.50 (s, 2H), 7.92 (d, J=4.6 Hz, 1H), 7.93 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.3 Hz, 6H), 1.40 (ddq, J=7.3, 7.3, 7.3 Hz, 4H), 2.60 (s, 3H), 3.09 (dd, J=7.3, 7.3 Hz, 4H), 3.83 (s, 3H), 3.88 (s, 3H), 6.62 (dd, J=2.2, 9.0 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.90 (d, J=4.6 Hz, 1H), 7.92 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.5 Hz, 6H), 1.42 (ddq, J=7.5, 7.5, 7.5 Hz, 4H), 2.08 (s, 3H), 2.54 (s, 3H), 3.11 (dd, J=7.5, 7.5 Hz, 4H), 3.69 (s, 3H), 3.86 (s, 3H), 6.44 (s, 1H), 6.46 (s, 1H), 7.91 (d, J=4.6 Hz, 1H), 7.96 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.06–0.06 (m, 4H), 0.22–0.36 (m, 4H), 0.75–0.85 (m, 2H), 2.03 (s, 3H), 2.38 (s, 3H), 2.53 (s, 3H), 2.97–3.12 (m, 4H), 3.69 (s, 3H), 6.68 (s, 1H), 6.75 (s, 1H), 7.92 (d, J=4.6 Hz, 1H), 8.12 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.02–0.06 (m, 4H), 0.26–0.35 (m, 4H), 0.72–0.83 (m, 2H), 2.61 (s, 3H), 3.00–3.07 (m, 4H), 3.88 (s, 3H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.93 (d, J=4.6 Hz, 1H), 8.15 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.15–0.00 (m, 2H), 0.20–0.34 (m, 2H), 0.72–0.84 (m, 1H), 0.91 (t, J=7.3 Hz, 3H), 1.42 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.03 (s, 3H), 2.38 (s, 3H), 2.53 (s, 3H), 2.90–3.04 (m, 2H), 3.18 (dd, J=7.3, 7.3 Hz, 2H), 3.69 (s, 3H), 6.69 (s, 1H), 6.74 (s, 1H), 7.92 (d, J=4.6 Hz, 1H), 8.05 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.05–0.03 (m, 2H), 0.28–0.35 (m, 2H), 0.71–0.82 (m, 1H), 0.90 (t, J=7.3 Hz, 3H), 1.40 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.60 (s, 3H), 2.94–3.01 (m, 2H), 3.18 (dd, J=7.3, 7.3 Hz, 2H), 3.88 (s, 3H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.93 (d, J=4.6 Hz, 1H), 8.07 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.13–0.02 (m, 2H), 0.32–0.48 (m, 2H), 0.74–0.85 (m, 1H), 1.71–1.87 (m, 2H), 2.03 (s, 3H), 2.39 (s, 3H), 2.54 (s, 3H), 2.91–3.07 (m, 2H), 3.35–3.45 (m, 2H), 3.69 (s, 3H), 4.46–4.50 (m, 1H), 4.56–4.62 (m, 1H), 6.69 (s, 1H), 6.75 (s, 1H), 7.93 (d, J=4.6 Hz, 1H), 8.01 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.05–0.05 (m, 2H), 0.28–0.38 (m, 2H), 0.72–0.85 (m, 1H), 1.68–1.85 (m, 2H), 2.61 (s, 3H), 2.96–3.02 (m, 2H), 3.35–3.46 (m, 2H), 3.88 (s, 3H), 4.43–4.48 (m, 1H), 4.54–4.60 (m, 1H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.94 (d, J=4.6 Hz, 1H), 8.04 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.06–0.08 (m, 4H), 0.24–0.38 (m, 4H), 0.73–0.86 (m, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 3.00–3.08 (m, 4H), 3.70 (s, 6H), 6.50 (s, 2H), 7.93 (d, J=4.5 Hz, 1H), 8.10 (d, J=4.5 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.07–0.00 (m, 2H), 0.27–0.34 (m, 2H), 0.73–0.84 (m, 1H), 0.91 (t, J=7.5 Hz, 3H), 1.41 (ddq, J=7.5, 7.5, 7.5 Hz, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 2.93–3.00 (m, 2H), 3.18 (dd, J=7.5, 7.5 Hz, 2H), 3.70 (s, 3H), 6.50 (s, 2H), 7.92 (d, J=4.6 Hz, 1H), 8.02 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.06–0.03 (m, 2H), 0.28–0.37 (m, 2H), 0.74–0.85 (m, 1H), 1.70–1.86 (m, 2H), 2.42 (s, 3H), 2.54 (s, 3H), 2.95–3.01 (m, 2H), 3.36–3.45 (m, 2H), 3.70 (s, 3H), 4.43–4.49 (m, 1H), 4.55–4.61 (m, 1H), 6.51 (s, 2H), 7.94 (d, J=4.6 Hz, 1H), 7.99 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.13–0.02 (m, 2H), 0.22–0.37 (m, 2H), 0.73–0.84 (m, 1H), 1.71–1.87 (m, 2H), 2.41 (s, 3H), 2.54 (s, 3H), 2.92–3.06 (m, 2H), 3.37–3.46 (m, 2H), 3.72 (s, 3H), 4.43–4.50 (m, 1H), 4.56–4.62 (m, 1H), 6.75 (s, 1H), 6.95 (s, 2H), 7.95 (d, J=4.6 Hz, 1H), 8.04 (d, J=4.6 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.06–0.03 (m, 2H), 0.28–0.37 (m, 2H), 0.73–0.85 (m, 1H), 1.69–1.85 (m, 2H), 2.61 (s, 3H), 2.97–3.02 (m, 2H), 3.37–3.45 (m, 2H), 3.87 (s, 3H), 4.42–4.48 (m, 1H), 4.54–4.61 (m, 1H), 6.99 (dd, J=2.6, 8.6 Hz, 1H), 7.27 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.94 (d, J=4.6 Hz, 1H), 8.04 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.03–0.06 (m, 4H), 0.26–0.36 (m, 4H), 0.73–0.86 (m, 2H), 2.54 (s, 3H), 3.00–3.08 (m, 4H), 3.70 (s, 6H), 3.88 (s, 3H), 6.25 (s, 2H), 7.92 (d, J=4.6 Hz, 1H), 8.09 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.08–0.06 (m, 4H), 0.23–0.36 (m, 4H), 0.73–0.85 (m, 2H), 2.41 (s, 3H), 2.54 (s, 3H), 2.98–3.12 (m, 4H), 3.71 (s, 3H), 6.75 (s, 1H), 6.95 (s, 2H), 7.94 (d, J=4.6 Hz, 1H), 8.15 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.11–0.01 (m, 2H), 0.25–0.35 (m, 2H), 0.73–0.85 (m, 1H), 0.94 (d, J=6.6 Hz, 6H), 1.61 (tqq, J=7.0, 6.6, 6.6 Hz, 1H), 2.54 (s, 3H), 2.89–2.96 (m, 2H), 3.03 (d, J=7.0 Hz, 2H), 3.70 (s, 6H), 3.88 (s, 3H), 6.25 (s, 2H), 7.91 (d, J=4.6 Hz, 1H), 8.04 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.11–0.02 (m, 2H), 0.25–0.34 (m, 2H), 0.72–0.82 (m, 1H), 0.94 (d, J=6.8 Hz, 6H), 1.61 (tqq, J=7.0, 6.8, 6.8 Hz, 1H), 2.42 (s, 3H), 2.53 (s, 3H), 2.39–2.45 (m, 2H), 3.03 (d, J=7.0 Hz, 2H), 3.70 (s, 6H), 6.50 (s, 2H), 7.92 (d, J=4.6 Hz, 1H), 8.04 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ −0.20–0.02 (m, 2H), 0.18–0.35 (m, 2H), 0.73–0.84 (m, 1H), 0.95 (d, J=6.6 Hz, 6H), 1.62 (tqq, J=7.0, 6.6, 6.6 Hz, 1H), 2.03 (s, 3H), 2.38 (s, 3H), 2.53 (s, 3H), 2.86–3.01 (m, 2H), 3.03 (d, J=7.0 Hz, 2H), 3.69 (s, 3H), 6.69 (s, 1H), 6.74 (s, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.07 (d, J=4.4 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.08–0.00 (m, 2H), 0.28–0.36 (m, 2H), 0.72–0.83 (m, 1H), 0.94 (d, J=6.6 Hz, 6H), 1.59 (tqq, J=6.8, 6.6, 6.6 Hz, 1H), 2.60 (s, 3H), 2.91–2.97 (m, 2H), 3.04 (d, J=6.8 Hz, 2H), 3.88 (s, 3H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.93 (d, J=4.6 Hz, 1H), 8.09 (d, J=4.6 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.12–0.06 (m, 2H), 0.21–0.28 (m, 2H), 0.72–0.84 (m, 1H), 0.92 (t, J=7.3 Hz, 3H), 1.42 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.06 (s, 6H), 2.54 (s, 3H), 2.95–3.02 (m, 2H), 3.19 (dd, J=7.3, 7.3 Hz, 2H), 3.84 (s, 3H), 6.68 (s, 2H), 7.91 (d, J=4.6 Hz, 1H), 8.07 (d, J=4.6 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.02 (m, 2H), 0.26–0.34 (m, 2H), 0.72–0.83 (m, 1H), 0.90 (t, J=7.3 Hz, 3H), 1.40 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.39 (s, 3H), 2.61 (s, 3H), 2.94–3.00 (m, 2H), 3.18 (dd, J=7.3, 7.3 Hz, 2H), 3.86 (s, 3H), 6.86 (d, J=9.2 Hz, 1H), 6.87 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.89 (d, J=4.4 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.03–0.04 (m, 2H), 0.29–0.37 (m, 2H), 0.71–0.82 (m, 1H), 0.90 (t, J=7.3 Hz, 3H), 1.39 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.43 (s, 3H), 2.59 (s, 3H), 2.93–2.99 (m, 2H), 3.17 (dd, J=7.3, 7.3 Hz, 2H), 3.83 (s, 3H), 6.88 (s, 1H), 6.90 (d, J=7.7 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.02 (d, J=4.4 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.06 (m, 2H), 0.27–0.38 (m, 2H), 0.71–0.82 (m, 1H), 0.90 (t, J=7.5 Hz, 3H), 1.39 (ddq, J=7.5, 7.5, 7.5 Hz, 2H), 2.59 (s, 3H), 2.93–3.01 (m, 2H), 3.17 (dd, J=7.5, 7.5 Hz, 2H), 3.83 (s, 3H), 7.06 (d, J=1.8 Hz, 1H), 7.08 (dd, J=1.8, 8.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.05 (d, J=4.4 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.03–0.04 (m, 2H), 0.29–0.36 (m, 2H), 0.71–0.82 (m, 1H), 0.89 (t, J=7.3 Hz, 3H), 1.39 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.60 (s, 3H), 2.93–2.99 (m, 2H), 3.17 (dd, J=7.3, 7.3 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 6.62 (s, 1H), 6.63 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.91 (d, J=4.6 Hz, 1H), 8.01 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.05–0.02 (m, 2H), 0.27–0.34 (m, 2H), 0.72–0.83 (m, 1H), 0.91 (t, J=7.3 Hz, 3H), 1.40 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.41 (s, 3H), 2.59 (s, 3H), 2.95–3.00 (m, 2H), 3.18 (dd, J=7.3, 7.3 Hz, 2H), 7.61 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.94 (d, J=4.6 Hz, 1H), 8.11 (d, J=4.4 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.99–1.06 (m, 6H), 1.44–1.64 (m, 4H), 2.54 (s, 3H), 3.00–3.10 (m, 1H), 3.13 (br s, 1H), 3.87 (s, 3H), 6.94 (dd, J=2.6, 8.6 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.86 (d, J=4.6 Hz, 1H), 7.92 (d, J=4.6 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.95–1.07 (m, 6H), 1.44–1.63 (m, 4H), 2.03 (s, 3H), 2.37 (s, 3H), 2.47 (s, 3H), 3.00–3.10 (m, 1H), 3.13 (br s, 1H), 3.68 (s, 3H), 6.68 (s, 1H), 6.74 (s, 1H), 7.84 (d, J=4.6 Hz, 1H), 7.91 (d, J=4.6 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.05–0.02 (m, 2H), 0.27–0.34 (m, 2H), 0.72–0.83 (m, 1H), 0.90 (t, J=7.3 Hz, 3H), 1.40 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.24 (s, 3H), 2.62 (s, 3H), 2.95–3.00 (m, 2H), 3.18 (dd, J=7.3, 7.3 Hz, 2H), 6.03 (s, 2H), 6.80 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.89 (d, J=4.6 Hz, 1H), 8.04 (d, J=4.6 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.05–0.02 (m, 2H), 0.27–0.34 (m, 2H), 0.72–0.83 (m, 1H), 0.90 (t, J=7.5 Hz, 3H), 1.40 (ddq, J=7.5, 7.5, 7.5 Hz, 2H), 2.18 (s, 3H), 2.61 (s, 3H), 2.95–3.00 (m, 2H), 3.17 (dd, J=7.5, 7.5 Hz, 2H), 4.32 (br s, 4H), 6.84 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.89 (d, J=4.4 Hz, 1H), 8.04 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.02–0.02 (m, 2H), 0.30–0.34 (m, 2H), 0.72–0.84 (m, 1H), 0.91 (t, J=7.6 Hz, 3H), 1.34–1.44 (m, 2H), 2.59 (s, 3H), 2.98 (m, 1H), 3.18 (t, J=7.6 Hz, 2H), 3.88 (s, 3H), 7.27 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H), 8.08 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.00–0.02 (m, 4H), 0.26–0.32 (m, 4H), 0.70–0.80 (m, 2H), 2.57 (s, 3), 3.01 (d, J=7.2 Hz, 4H), 3.84 (s, 3H), 7.24 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.13 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.24–0.34 (m, 4H), 0.74–0.84 (m, 2H), 2.57 (s, 3H), 0.36 (d, J=6.8 Hz, 4H) 3.93 (s, 3H), 7.18 (dd, J=2.4, 8.8 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H), 8.16 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.24–0.34 (m, 4H), 0.68–0.80 (m, 2H),2.59 (s, 3H), 3.01 (d, J=7.2 Hz, 4H), 3.79 (s, 3H), 3.85 (s, 3H), 6.59 (s, 1H), 6.61 (dd, J=2.0, 8.0 Hz, 1H), 7.71 (dd, J=2.0, 7.6 Hz, 1H), 7.89 (d, J=4.4 Hz, 1H), 8.06 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.06 (m, 4H), 0.24–0.36 (m, 4H), 0.68–0.80 (m, 2H), 2.57 (s, 3H), 3.01 (d, J=6.8 Hz, 4H), 3.80 (s, 3H), 7.03 (s, 1H), 7.06 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.90 (d, J=4.4 Hz, 1H), 8.11 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.22–0.32 (m, 4H), 0.70–0.82 (m, 2H), 2.36 (s, 3H), 2.60 (s, 3H), 3.02 (d, J=6.8 Hz, 4H), 3.85 (s, 3H), 6.82–6.86 (m, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.89 (d, J=4.4 Hz, 1H), 8.10 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.24–0.32 (m, 4H), 0.68–0.80 (m, 2H), 2.41 (s, 3H), 2.57 (s, 3H), 3.00 (d, J=6.8 Hz, 4H), 3.79 (s, 3H), 6.85 (s, 1H), 6.88 (d, J=7.6 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.90 (d, J=4.4 Hz, 1H), 8.07 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.22–0.34 (m, 4H), 0.70–0.82 (m, 2H), 2.59 (s, 3H), 3.03 (d, J=6.8 Hz, 4H) 7.27 (d, J=7.6 Hz, 1H), 7.41 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.18 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.24–0.32 (m, 4H), 0.72–0.80 (m, 2H), 2.59 (s, 3H), 3.03 (d, J=6.8 Hz, 4H), 7.38 (dd, J.=2.0, 8.4 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.17 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.26–0.30 (m, 4H), 0.70–0.80 (m, 2H), 2.51 (s, 3H), 3.03 (d, J=6.8 Hz, 4H), 3.86 (s, 3H), 6.98 (dd, J=2.4, 8.8 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.92 (d, J=4.4 Hz, 1H), 8.15 (d, J=4.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.03–0.05 (m, 2H), 0.33–0.41 (m, 2H), 0.78–0.88 (m, 1H), 2.18 (t, J=5.3 Hz, 1H), 2.62 (s, 3H) 3.03–3.08 (m, 2H), 3.43 (t, J=5.3 Hz, 2H), 3.59 (dt, J=5.3, 5.3 Hz, 2H), 3.88 (s, 3H), 6.95 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.96 (d, J=4.6 Hz, 1H), 8.04 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHZ, CDCl3) δ −0.04–0.04 (m, 2H), 0.26–0.36 (m, 2H), 0.72–0.82 (m, 1H), 1.64–1.94 (m, 6H), 2.24–2.34 (m, 1H), 2.63 (s, 3H), 2.98 (d, J=7.2 Hz, 2H), 3.24 (d, J=7.0 Hz, 2H), 3.89 (s, 3H), 6.96 (dd, J=2.8, 8.8 Hz, 1H), 7.10 (d, J=2.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.06 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.02 (m, 4H), 0.28–0.34 (m, 2H), 0.70–0.82 (m, 1H), 1.26 (t, J=7.6 Hz, 3H), 2.76 (q, J=7.6 Hz, 2H), 2.98 (d, J=7.2 Hz, 4H), 3.81 (s, 3H), 7.22 (d, J=2.0 Hz, 1H), 7.32 (dd, J=2.0, 8.4 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.88 (d, J=4.4 Hz, 1H), 8.12 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 4H), 0.24–0.32 (m, 4H), 0.72–0.82 (m, 2H), 2.40 (s, 3H), 2.62 (s, 3H), 3.01 (d, J=7.2 Hz, 4H), 3.13 (s, 6H), 6.43 (s, 1H), 7.86 (d, J=4.4 Hz, 1H), 8.05 (d, J=4.4 Hz, 1H), 8.70 (s, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.02–0.02 (m, 4H), 0.28–0.36 (m, 2H), 0.76–0.86 (m, 1H), 1.66–2.74 (m, 2H), 2.06 (s, 3H), 2.55 (t, J=7.2 Hz, 2H), 2.63 (s, 3H), 2.99 (d, J=7.2 Hz, 2H), 3.37 (t, J=7.0 Hz, 2H), 3.89 (s, 3H), 6.96 (dd, J=2.4, 8.8 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.96 (d, J=4.8 Hz, 1H), 8.06 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 426 MH+
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.09–0.07 (m, 2H), 0.17–0.33 (m, 2H), 0.60–0.71 (m, 1H), 1.49–1.63 (m, 4H), 2.62 (s, 3H), 3.00–3.09 (m, 2H), 3.32–3.46 (m, 4H), 3.88 (s, 3H), 3.87–4.03 (m, 1H), 6.95 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.94 (d, J=4.6 Hz, 1H), 8.08 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.03–0.05 (m, 2H), 0.34–0.42 (m, 2H), 0.78–0.88 (m, 1H), 1.16 (d, J=6.2 Hz, 3H), 2.62 (s, 3H), 2.92 (dd, J=9.7, 13.8 Hz, 1H), 2.97–3.13 (m, 2H), 3.50 (dd, J=3.4, 13.8 Hz, 1H), 3.73 (ddq, J=3.4, 9.7, 6.2 Hz, 1H), 3.88 (s, 3H), 6.95 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.96 (d, J=4.6 Hz, 1H), 8.01 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.05–0.07 (m, 2H), 0.32–0.44 (m, 2H), 0.78–0.90 (m, 1H), 1.17 (d, J=6.2 Hz, 3H), 2.62 (s, 3H), 2.93 (dd, J=9.9, 13.0 Hz, 1H), 2.97–3.04 (m, 1H), 3.06–3.13 (m, 1H), 3.50 (dd, J=3.6, 13.0 Hz, 1H), 3.74 (ddq, J=3.6, 9.9, 6.2 Hz, 1H), 7.28 (dd, J=2.6, 8.4 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.98 (d, J=4.6 Hz, 1H), 8.07 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.08–0.05 (m, 2H), 0.17–0.32 (m, 2H), 0.61–0.71 (m, 1H), 1.45–1.61 (m, 4H), 2.62 (s, 3H), 3.02–3.08 (m, 2H), 3.33–3.46 (m, 4H), 3.89–4.03 (m, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.43 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.96 (d, J=4.6 Hz, 1H), 8.13 (d, J=4.6 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.06–0.03 (m, 4H), 0.23–0.32 (m, 4H), 0.74–0.86 (m, 2H), 2.05 (s, 3H), 2.18 (s, 3H), 2.55 (s, 3H), 3.02–3.08 (m, 4H), 3.12 (s, 6H), 6.30 (s, 1H), 7.91 (d, J=4.6 Hz, 1H), 8.13 (d, J=4.6 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 2H), 0.34–0.46 (m, 2H), 0.80–0.90 (m, 2H), 2.58 (s, 3H), 3.04 (d, J=7.2 Hz, 2H), 3.92 (s, 2H), 5.54 (br s, 1H), 7.00 (br s, 1H), 7.26 (s, 1H), 7.41 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.99 (d, J=4.4 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.10–0.78 (m, 10H), 1.10–1.25 (m, 3H), 2.52–2.58 (m, 1H), 2.60 (s, 3H), 3.04–3.10 (m, 1H), 3.22–3.28 (m, 1H), 7.28 (dd, J=2.4, 8.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.23 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 497 MH+
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.01–0.08 (m, 4H), 0.27–0.36 (m, 4H), 0.71–0.82 (m, 2H), 2.60 (s, 3H), 2.99–3.07 (m, 4H), 3.83 (s, 3H), 7.21 (d, J=1.8 Hz, 1H), 7.24 (dd, J=1.8, 8.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.93 (d, J=4.4 Hz, 1H), 8.13 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00–0.52 (m, 4H), 0.96–1.08 (m, 2H), 2.48 (s, 3H), 3.45 (dd, J=7.2, 13.6 Hz, 1H), 4.10 (dd, J=7.2, 13.6 Hz, 1H), 6.25 (s, 1H), 6.33 (s, 1H), 7.14 (s, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.89 (d, J=4.4 Hz, 1H), 8.01 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.02–0.04 (m, 2H), 0.26–0.32 (m, 2H), 0.72–0.80 (m, 1H), 2.59 (s, 3H), 3.06 (d, J=7.2 Hz, 2H), 4.30 (s, 2H), 6.07 (s, 1H), 6.20 (s, 2H), 7.20–7.26 (m, 1H), 7.29 (s, 1H), 7.40 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.88 (d, J=4.4 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 2H), 0.30–0.36 (m, 2H), 1.78–1.86 (m, 1H), 2.61 (s, 3H), 3.03 (d, J=7.2 Hz, 2H), 3.37 (t, J=6.0 Hz, 2H), 3.64 (t, J=6.0 Hz, 2H), 7.28 (dd, J=2.4, 8.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.98 (d, J=4.4 Hz, 1H), 8.27 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.02–0.04 (m, 2H), 0.30–0.36 (m, 2H), 1.76–1.82 (m, 1H), 1.66–1.74 (m, 4H), 2.38–2.48 (m, 4H), 2.51 (t, J=7.2 Hz, 2H), 2.61 (s, 3H), 3.03 (q, J=6.8 Hz, 2H), 3.39 (t, J=7.2 Hz, 2H), 7.24–7.30 (m, 1H), 7.43 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H), 8.20 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 2H), 0.28–0.34 (m, 2H), 0.72–0.82 (m, 1H), 2.28 (br s, 4H), −2.38 (t, J=6.4 Hz, 2H), 2.60 (s, 3H), 3.01 (d, J=7.2 Hz, 2H), 3.36 (br s, 2H), 3.47 (t, J=4.4 Hz, 4H), 7.27 (dd, J=2.4, 8.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 2H), 7.77 (d, J=8.4-Hz, 1H), 7.95 (d, J=4.4 Hz, 1H), 8.19 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.02–0.04 (m, 2H), 0.32–0.38 (m, 2H), 0.72–0.82 (m, 1H), 2.68 (s, 3H), 3.00 (d, J=6.8 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 4.26 (t, J=6.0 Hz, 2H), 6.29 (dd, J=1.6, 1.6 Hz, 1H), 7.30–7.34 (m, 2H), 7.48 (d, J=1.6 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.65 (d, J=4.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.91 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.04–0.04 (m, 2H), 0.32–0.40 (m, 2H), 0.72–0.82 (m, 1H), 2.67 (s, 3H), 2.99 (d, J=6.8 Hz, 2H), 3.70 (t, J=6.0 Hz, 2H), 4.05 (t, J=6.0 Hz, 2H), 6.88 (s, 1H), 7.11 (s, 1H), 7.30–7.34 (m, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.45 (s, 1H), 7.59 (d, J=4.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00–0.07 (m, 4H), 0.28–0.35 (m, 4H), 0.71–0.82 (m, 2H), 2.62 (s, 3H), 2.98–3.05 (m, 4H), 3.05 (s, 6H), 3.86 (s, 3H), 6.36 (d, J=2.4 Hz, 1H), 6.44 (dd, J=2.4, 8.6 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.89 (d, J=4.6 Hz, 1H), 8.03 (d, J=4.6 Hz, 1H).
m-chloroperbenzoic acid (148 mg) was added to N-[8-(2-chloro-4-methoxyphenyl)-2-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylmethyl-N-propylamine (166 mg) and dichloromethane (2 mL) at room temperature, and the mixture was stirred for 20 minutes. An aqueous sodium thiosulfate solution and an aqueous sodium bicarbonate solution were added thereto, which was extracted with ethyl acetate and evaporated. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (21 mg) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 0.02–0.07 (m, 2H), 0.31–0.42 (m, 2H), 0.76–0.97 (m, 4H), 1.42–1.54 (m, 2H), 3.02–3.12 (m, 2H), 3.04 (s, 3H), 3.22–3.36 (m, 2H), 3.89 (s, 3H), 6.95 (dd, J=2.6, 8.8 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 8.03 (d, J=4.6 Hz, 1H), 8.16 (d, J=4.6 Hz, 1H).
The mixture produced in the above-mentioned Example 261 was separated and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (130 mg) as a Pale yellow oil.
1H NMR (400 MHz, CDCl3) δ −0.03–0.04 (m, 2H), 0.27–0.34 (m, 2H), 0.72–0.83 (m, 1H), 3.07–3.12 (m, 2H), 3.27 (dd, J=7.3, 7.3 Hz, 2H), 3.30 (s, 3H), 3.89 (s, 3H), 6.96 (dd, J=2.6, 8.6 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 8.08 (d, J=4.6 Hz, 1H), 8.27 (d, J=4.6 Hz, 1H).
Hereinafter, the compound Example 263 was synthesized in the same manner as that of Example 261.
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.02–0.09 (m, 2H), 0.31–0.43 (m, 2H), 0.79–0.89 (m, 1H), 0.91–0.97 (m, 3H), 1.41–1.54 (m, 2H), 2.47 (s, 3H), 3.03 (s, 3H), 3.04–3.13 (m, 2H), 3.12 (s, 3H), 3.23–3.37 (m, 2H), 7.87–7.96 (m, 3H), 8.06 (d, J=4.6 Hz, 1H) 8.21 (d, J=4.4 Hz, 1H).
1H NMR (400 MHz, CDCl3) δ −0.02–0.07 (m, 4H), 0.28–0.37 (m, 4H), 0.71–0.82 (m, 2H), 2.59 (s, 3H), 3.00–3.08 (m, 4H), 3.85 (s, 3H), 7.30 (d, J=1.5 Hz, 1H), 7.41 (dd, J=1.5, 7.9 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.95 (d, J=4.4 Hz, 1H), 8.17 (d, J=4.4 Hz, 1H).
The compound of Example 265 was synthesized in the same manner as that of Example 264.
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.00–0.10 (m, 4H), 0.28–0.38 (m, 4H), 0.71–0.82 (m, 2H), 1.99–2.10 (m, 4H), 2.63 (s, 3H), 2.98–3.07 (m, 4H), 3.33–3.43 (m, 4H), 3.86 (s, 3H), 6.21 (d, J=2.0 Hz, 1H), 6.30 (dd, J=2.0, 8.6 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.89 (d, J=4.6 Hz, 1H), 8.02 (d, J=4.6 Hz, 1H).
Hereinafter, compounds of Example 266 to Example 269 were synthesized in the same manner as that of Example 110.
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.91–1.00 (m, 3H), 1.17–1.35 (m, 7H), 1.42–1.57 (m, 1H), 1.73–1.85 (m, 1H), 2.01–2.15 (m, 1H), 2.05 (s, 3H), 2.36 (s, 3H), 2–69–2.81 (m, 2H), 3.23–3.45 (m, 2H), 3.68 (s, 3H), 4.70–4.75 (m, 1H), 6.67 (s, 1H), 6.73 (s, 1H), 8.43 (s, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.91–0.97 (m, 3H), 1.19 (t, J=7.2 Hz, 3H), 1.21–1.33 (m, 1H), 1.40–1.52 (m, 1H), 1.77–1.89 (m, 1H), 1.99–2.10 (m, 1H), 2.59 (s, 3H), 3.30 (dq, J=7.2, 9.3 Hz, 1H), 3.42 (dq, J=7.2, 9.3 Hz, 1H), 3.88 (s, 3H), 4.84–4.90 (m, 1H), 6.94 (dd, J=2.4, 8.6 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.92 (d, J=4.8 Hz, 1H), 8.34 (d, J=4.8 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.90–0.98 (m, 3H), 1.15–1.34 (m, 4H), 1.40–1.53 (m, 1H), 1.77–1.89 (m, 1H), 1.95–2.11 (m, 1H), 2.04 (br s, 3H), 2.38 (s, 3H), 2.52 (s, 3H), 3.23–3.47 (m, 2H), 3.70 (s, 3H), 4.84–4.91 (m, 1H), 6.69 (s, 1H), 6.74 (s, 1H), 7.91 (d, J=4.6 Hz, 1H), 8.31 (d, J=4.6 Hz, 1H).
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.91–0.98 (m, 3H), 1.19 (t, J=7.0 Hz, 3H), 1.21–1.34 (m, 1H), 1.39–1.53 (m, 1H), 1.77–1.88 (m, 1H), 1.99–2.10 (m, 1H), 2.58 (s, 3H), 3.30 (dq, J=9.3, 7.0 Hz, 1H), 3.43 (dq, J=9.3, 7.0 Hz, 1H), 4.83–4.89 (m, 1H), 7.39 (dd, J=2.0, 8.2 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.94 (d, J=4.6 Hz, 1H), 8.37 (d, J=4.6 Hz, 1H).
1-[8-(2-Chloro-4-methoxyphenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-1-butanone (60 mg) was dissolved in a mixed solvent of ethanol (0.34 mL) and water (0.28 mL), then O-methylhydroxylamine hydrochloride (71 mg) was added thereto, and the mixture was heated under reflux for 6 hours. The reaction solution was cooled and water was added thereto. It was extracted with ethyl acetate and evaporated. The resulting crude isomer mixture was separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to give the isomer 1 (31 mg) having a greater Rf value on TLC and the isomer 2 (13 mg) having a smaller Rf value on TLC were as a colorless oil each.
1H NMR (400 MHz, CDCl3) δ 0.93–1.00 (m, 3H), 1.32 (t, J=7.5 Hz, 3H), 1.53–1.65 (m, 2H), 2.77–2.83 (m, 2H), 2.91 (q, J=7.5 Hz, 2H), 3.87 (s, 3H), 4.06 (s, 3H), 6.95 (dd, J=2.4, 8.6 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 8.00 (d, J=4.6 Hz, 1H), 8.68 (d, J=4.6 Hz, 1H).
1H NMR (400 MHz, CDCl3) δ 0.94 (t, J=7.3 Hz, 3H), 1.30 (t, J=7.5 Hz, 3H), 1.51 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.66 (dd, J=7.3, 7.3 Hz, 2H), 2.82 (q, J=7.5 Hz, 2H), 3.87 (s, 3H), 3.93 (s, 3H), 6.96 (dd, J=2.6, 8.6 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 7.56 (d, J=4.6 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.98 (d, J=4.6 Hz, 1H).
Hereinafter, compounds of Examples 271 and 272 were synthesized in the same manner as that of Example 270.
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.96–1.02 (m, 3H), 1.33 (t, J=7.5 Hz, 3H), 1.57–1.68 (m, 2H), 2.82–2.89 (m, 2H), 2.92 (q, J=7.5 Hz, 2H), 3.87 (s, 3H), 6.95 (dd, J=2.4, 8.4 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.98 (d, J=4.6 Hz, 1H), 8.59 (d, J=4.6 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.95 (t, J=7.3 Hz, 3H), 1.31 (t, J=7.5 Hz, 3H), 1.52 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.67 (dd, J=7.3, 7.3 Hz, 2H), 2.84 (q, J=7.5 Hz, 2H), 3.87 (s, 3H), 6.95 (dd, J=2.4, 8.2 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.67 (d, J=4.6 Hz, 1H), 7.99 (d, J=4.6 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.98–1.04 (m, 3H), 1.61–1.72 (m, 2H), 2.04 (s, 3H), 2.39 (s, 3H), 2.58 (s, 3H), 2.93–2.99 (m, 2H), 3.68 (s, 3H), 4.05 (s, 3H), 6.68 (s, 1H), 6.75 (s, 1H), 8.03 (d, J=4.8 Hz, 1H), 9.08 (d, J=4.8 Hz, 1H).
Colorless Oil
1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=7.3 Hz, 3H), 1.49 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.06 (s, 3H), 2.39 (s, 3H), 2.56 (s, 3H), 2.81 (dd, J=7.3, 7.3 Hz, 2H), 3.70 (s, 3H), 3.95 (s, 3H), 6.70 (s, 1H), 6.76 (s, 1H), 7.52 (d, J=4.6 Hz, 1H), 7.99 (d, J=4.6 Hz, 1H).
A 28% sodium methoxide solution (5 mL) was added to N[8-(2-chloro-4-methoxyphenyl)-2-(methylsulfonyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylmethyl-N-propylamine (80 mg), and the mixture was stirred for 6 hours by heating under ref lux. After cooled to room temperature, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (23 mg) as a pale yellow oil.
1H NMR (400 MHz, CDCl3) δ −0.06–0.03 (m, 2H), 0.26–0.35 (m, 2H), 0.72–0.83 (m, 1H), 0.90 (t, J=7.3 Hz, 3H), 1.39 (ddq, J=7.3, 7.3, 7.3 Hz, 2H), 2.87–2.92 (m, 2H), 3.08 (dd, J=7.3, 7.3 Hz, 2H), 3.88 (s, 3H), 4.03 (s, 3H), 6.95 (dd, J=2.6, 8.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.96 (d, J=4.4 Hz, 1H), 8.06 (d, J=4.4 Hz, 1H).
The compound of Example 274 was synthesized in the same manner as that of Example 273.
Pale Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.14–0.01 (m, 2H), 0.19–0.24 (m, 2H), 0.72–0.84 (m, 1H), 0.85–0.93 (m, 3H), 1.35–1.47 (m, 2H), 2.02 (s, 3H), 2.39 (s, 3H), 2.80–2.97 (m, 2H), 3.03–3.11 (m, 2H), 3.71 (s, 3H), 3.96 (s, 3H), 6.69 (s, 1H), 6.75 (s, 1H), 7.95 (d, J=4.6 Hz, 1H), 8.03 (d, J=4.6 Hz, 1H).
Hereinafter, compounds of Example 275 to Example 293 were synthesized in the same manner as that of Example 121.
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.4 Hz, 6H), 1.30 (t, J=7.5 Hz, 3H), 1.32–1.44 (m, 4H), 2.41 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 3.19 (t, J=7.4 Hz, 4H), 3.83 (s, 3H), 6.86 (s, 1H), 6.93 (dt, J=0.73, 7.9 Hz, 1H), 7.12 (d, J=4.6 Hz, 1H), 7.82 (d, J=7.3 Hz, 1H), 8.24 (d, J=4.8 Hz, 1H).
MS (ESI) m/z 367 MH+
Orange Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.4 Hz, 6H), 1.26 (t, J=7.5 Hz, 3H), 1.36–1.56 (m, 4H), 2.34 (s, 3H), 2.79 (q, J=7.1 Hz, 2H), 3.15–3.28 (m, 1H), 3.58 (s, 1H), 3.75 (s, 3H), 6.79 (s, 1H), 6.85 (dd, J=0.73, 7.9 Hz, 1H), 6.95 (d, J=4.6 Hz, 1H), 7.71 (d, J=6.6 Hz, 1H), 8.15 (d, J=3.8 Hz, 1H).
MS (ESI) m/z 353 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.4 Hz, 6H), 1.24 (t, J=7.5 Hz, 3H), 1.34–1.46 (m, 4H), 2.73 (q, J=7.5 Hz, 2H), 3.18 (t, J=7.4 Hz, 4H), 4.00 (s, 3H), 6.64 (s, 1H), 7.36 (dd, J=2.1, 8.3 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H).
MS (ESI) m/z 421 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.3 Hz, 3H), 0.92 (d, J=6.6 Hz, 6H), 1.28 (t, J=7.5 Hz, 3H), 1.33–1.46 (m, 2H), 1.53–1.66 (m, 1H), 2.29 (s, 3H), 2.80 (q, J=7.5 Hz, 2H), 3.05 (d, J=7.1 Hz, 2H), 3.17 (t, J=7.4 Hz, 2H), 3.84 (s, 3H), 6.78 (d, J=4.6 Hz, 1H), 6.80–6.92 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 8.25 (d, J=4.6 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.4 Hz, 6H), 1.32 (t, J=7.5 Hz, 3H), 1.30–1.42 (m, 4H), 2.79 (q, J=7.5 Hz, 2H), 3.18 (t, J=7.5 Hz, 4H), 3.98 (s, 3H), 4.00 (s, 3H), 6.51 (d, J=8.4 Hz, 1H), 7.32 (d, J=4.8 Hz, 1H), 8.24 (d, J=4.8 Hz, 1H), 8.64 (d, J=8.2 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.4 Hz, 6H), 1.27 (t, J=7.6 Hz, 3H), 1.32–1.44 (m, 4H), 2.53 (s, 3H), 2.61 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 3.20 (t, J=7.4 Hz, 4H), 6.80 (d, J=4.8 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 8.28 (d, J=4.8 Hz, 1H).
MS (ESI) m/z 352 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.3 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.33–1.45 (m, 4H), 2.45 (s, 3H), 2.80 (q, J=7.5 Hz, 2H), 3.20 (t, J=7.5 Hz, 4H), 3.97 (s, 3H), 6.69 (d, J=8.4 Hz, 1H), 6.81 (d, J=3.1 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 8.28 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 368 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.3 Hz, 6H), 1.20–1.30 (m, 3H), 1.33–1.46 (m, 4H), 2.05 (s, 3H), 2.37 (s, 3H), 2.66–2.88 (m, 2H), 3.20 (dd, J=6.4, 7.9 Hz, 4H), 3.70 (s, 3H), 6.69 (s, 1H), 6.77 (s, 2H), 8.26 (br s, 1H).
MS (ESI) m/z 381 MH+
Pale Brown oil
1H NMR (400 MHZ, CDCl3) δ 0.87 (t, J=7.3 Hz, 6H), 1.36 (t, J=7.5 Hz, 3H), 1.32–1.44 (m, 4H), 2.85 (q, J=7.6 Hz, 2H), 3.20 (t, J=7.5 Hz, 4H), 7.04 (d, J=4.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 8.14 (d, J=8.6 Hz, 2H), 8.31 (d, J=4.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.4 Hz, 6H), 1.26 (t, J=7.1 Hz, 3H), 1.33–1.46 (m, 4H), 2.08 (s, 3H), 2.68–2.90 (m, 2H), 3.20 (dt, J=0.8, 7.3 Hz, 4H), 3.70 (s, 3H), 3.84 (s, 3H), 6.43 (d, J=1.8 Hz, 1H), 6.47 (d, J=2.2 Hz, 1H), 6.80 (br s, 1H), 8.26 (br s, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.3 Hz, 6H), 1.29 (t, J=7.6 Hz, 3H), 1.34–1.46 (m, 4H), 2.81 (q, J=7.3 Hz, 2H), 3.20 (t, J=7.5 Hz, 4H), 3.86 (s, 3H), 6.95 (dd, J=2.5, 8.7 Hz, 1H), 7.03 (d, J=4.2 Hz, 1H), 7.07 (d, J=2.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 8.29 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 387 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.4 Hz, 6H), 1.24 (t, J=7.5 Hz, 3H), 1.33–1.46 (m, 4H), 2.06 (s, 6H), 2.78 (q, J=7.2 Hz, 2H), 3.21 (t, J=7.6 Hz, 4H), 3.82 (s, 3H), 6.70 (s, 2H), 6.74 (br s, 1H), 8.28 (br s, 1H).
MS (ESI) m/z 381 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.4 Hz, 6H), 1.23 (t, J=7.5 Hz, 3H), 1.33–1.46 (m, 4H), 2.03 (s, 6H), 2.33 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.21 (t, J=7.5 Hz, 4H), 6.72 (d, J=4.2 Hz, 1H), 6.97 (s, 2H), 8.27 (d, J=4.4 Hz, 1H).
MS (ESI) m/z 365 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.18–0.04 (m, 4H), 0.18–0.34 (m, 4H), 0.76–0.92 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 2.02 (s, 6H), 2.33 (s, 3H), 2.76–2.90 (m, 2H), 3.18 (d, J=6.8 Hz, 4H), 6.72 (br s, 1H), 6.97 (s, 2H), 8.26 (br s, 1H).
MS (ESI) m/z 389 MH+
Pale Green Crystals
1H NMR (400 MHz, CDCl3) δ −0.18–0.00 (m, 4H), 0.20–0.36 (m, 4H), 0.76–0.92 (m, 2H), 1.20–1.36 (m, 3H), 2.04 (s, 3H), 2.38 (s, 3H), 2.74–2.96 (m, 2H), 3.09–3.26 (m, 4H), 3.70 (s, 3H), 6.69 (s, 1H), 6.77 (s, 1H), 6.80 (br s, 1H), 8.26 (br s, 1H).
MS (ESI) m/z 405 MH+
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ −0.21–0.03 (m, 2H), 0.19–0.35 (m, 2H), 0.75–0.91 (m, 1H), 0.90 (t, J=7.3 Hz, 3H), 1.191.35 (m, 3H), 1.36–1.49 (m, 2H), 2.05 (s, 3H), 2.37 (s, 3H), 2.71–2.99 (m, 2H), 3.10 (d, J=6.8 Hz, 2H), 3.26 (dt, J=1.6, 7.3 Hz, 2H), 3.71 (s, 3H), 6.70 (s, 1H), 6.77 (s, 3H), 6.85 (br s, 1H), 8.29 (br s, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ0.81 (t, J=7.3 Hz, 3H), 0.85 (dd, J=1.8, 6.8 Hz, 6H), 1.18 (t, J=7.3 Hz, 3H), 1.26–1.38 (m, 2H), 1.48–1.62 (m, 1H), 1.99 (s, 3H), 2.31 (s, 3H), 2.63–2.82 (m, 2H), 2.98 (d, J=7.1 Hz, 2H), 3.10 (t, J=7.3 Hz, 2H), 3.64 (s, 3H), 6.62 (s, 1H), 6.70 (s, 1H), 6.75 (br s, 1H), 8.21 (br s, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.21–0.03 (m, 2H), 0.19–0.37 (m, 2H), 0.75–0.91 (m, 1H), 1.26 (t, J=7.5 Hz, 3H), 1.69–1.91 (m, 2H), 2.04 (s, 3H), 2.37 (s, 3H), 2.71–2.89 (m, 2H), 3.12 (d, J=6.8 Hz, 2H), 3.40–3.54 (m, 2H), 3.70 (s, 3H), 4.51 (t, J=5.9 Hz, 1H), 4.62 (t, J=5.9 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 6.83 (br s, 1H), 8.26 (d, J=4.6 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.3 Hz, 3H), 1.20–1.30 (m, 3H), 1.34–1.48 (m, 2H), 1.66–1.85 (m, 2H), 2.05 (s, 3H), 2.37 (s, 3H), 2.68–2.88 (m, 2H), 3.21 (t, J=7.4 Hz, 2H), 3.41 (t, J=7.1 Hz, 2H), 3.70 (s, 3H), 4.48 (t, J=5.7 Hz, 1H), 4.60 (t, J=5.7 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 6.84 (br s, 1H), 8.28 (br s, 1H).
A 5N aqueous sodium hydroxide solution (0.88 mL) was added to a solution of ethyl 8-(4-methoxy-2-methylphenyl)-2-(methylsulfanyl)imidazo[1,2-b]pyridazine-3-carboxylate (628 mg) in ethanol (20 mL), and the mixture was heated under reflux for 1 hour. After ice-cooling, 5N hydrochloric acid (0.88 mL) was added thereto, then the solvent was evaporated. The resulting crude 8-(4-methoxy-2-methylphenyl)-2-(methylsulfanyl)imidazo[1,2-b]pyridazine-3-carboxylic acid was used in the next reaction without purification.
The resulting 8-(4-methoxy-2-methylphenyl)-2-(methylsulfanyl)imidazo[1,2-b]pyridazine-3-carboxylic acid was dissolved in toluene (10 mL), then tert-butyl alcohol (10 mL), triethylamine (0.49 mL) and diphenylphosphorylazide (0.38 mL) were added thereto, and the mixture was heated at 100° C. for 4 hours. After completion of the reaction, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting Boc compound was dissolved in ethyl acetate (10 mL) without purification, then a 4N hydrochloric acid-ethyl acetate solution (15 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, a 5N aqueous sodium hydroxide solution was added thereto, which was neutralized and extracted with ethyl acetate. The material was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (73 mg) as a brown oil.
1HNMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 2.55 (s, 3H), 3.85 (s, 3H), 6.80–6.96 (m, 3H), 7.37 (d, J=8.8 Hz, 1H), 8.42 (d, J=4.6 Hz, 1H).
8-(4-Methoxy-2-methylphenyl)-2-(methylsulfanyl)imidazo[1,2-b]pyridazin-3-amine obtained in Example 294 was alkylated at its amino group in the same manner as that of Example 4 to give the title compound as an orange oil.
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.3 Hz, 6H), 1.36–1.48 (m, 4H), 2.31 (s, 3H), 2.56 (s, 3H), 3.23 (t, J=7.6 Hz, 4H), 3.86 (s, 3H), 6.78 (d, J=4.8 Hz, 1H), 6.80–6.92 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 8.26 (d, J=4.6 Hz, 1H).
Hereinafter, the compound Example 296 was synthesized in the same manner as that of Example 295.
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.11–0.01 (m, 4H), 0.23–0.34 (m, 4H), 0.85–0.99 (m, 2H), 2.28 (s, 3H), 2.59 (s, 3H), 3.20 (d, J=6.8 Hz, 4H), 3.86 (s, 3H), 6.81 (d, J=4.8 Hz, 1H), 6.83–6.90 (m, 2H), 7.42 (d, J=8.4 Hz, 1H), 8.27 (d, J=4.6 Hz, 1H).
Hereinafter, compounds of Examples 297 to 371 were synthesized in the same manner as that of Example 127.
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 6H), 1.38–1.44 (m, 4H), 2.52 (s, 3H), 3.00–3.20 (m, 4H), 6.82 (dd, J=6.8, 6.8 Hz, 1H), 7.14 (d, J=6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H9, 7.62 (d, J=8.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.38–1.45 (m, 4H), 2.03 (s, 3H), 2.38 (s, 3H), 2.46 (s, 3H), 3.00–3.20 (m, 4H), 3.68 (s, 3H), 6.67 (s, 1H), 6.75 (s, 1H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 6.95 (dd, J=1.6, 6.8 Hz, 1H), 8.07 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 6H), 1.38–1.45 (m, 4H), 2.52 (s, 3H), 3.00–3.20 (m, 4H), 3.85 (s, 3H), 6.81 (dd, J=6.8, 6.8 Hz, 1H), 6.90 (dd, J=2.4, 8.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.14 (dd, J=1.2, 6.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 8.09 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 1.06 (d, J=6.8 Hz, 6H), 1.80–1.90 (m, 1H), 2.46 (s, 3H), 2.76–2.96 (m, 2H), 3.30 (br s, 1H), 6.85 (dd, J=7.2, 7.2 Hz, 1H), 7.11 (dd, J=1.2, 2.7 Hz, 1H), 7.33 (dd, J=2.0, 8.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 8.00 (dd, J=1.2, 6.4 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 3H), 0.92 (d, J=6.8 Hz, 6H), 1.35–1.50 (m, 2H), 1.55–1.63 (m, 1H), 2.52 (s, 3H), 2.90–3.10 (m, 4H), 6.83 (dd, J=7.2, 7.2 Hz, 1H), 7.14 (dd, J=1.2, 6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.14 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.15–0.10 (m, 2H), 0.15–0.40 (m, 2H), 0.75–0.85 (m, 1H), 0.93 (d, J=6.8 Hz, 6H), 1.53–1.68 (m, 1H), 2.86–3.22 (m, 4H), 6.82 (dd, J=6.8, 6.8 Hz, 1H), 7.13 (dd, J=1.2, 6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 8.23 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=7.2 Hz, 3H), 0.92 (d, J=6.4 Hz, 6H), 1.24–1.41 (m, 4H), 1.50–1.65 (m, 1H), 2.52 (s, 3H), 2.80–3.10 (m, 4H), 6.83 (dd, J=6.8, 6.8 Hz, 1H), 7.14 (dd, J=1.2, 6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 8.13 (dd, J=1.2, 7.2 Hz, 1H).
Greenish Brown Oil
1H NMR (400 MHz, CDCl3) δ 0.92 (d, J=6.8 Hz, 6H), 1.50–1.65 (m, 1H), 2.52 (s, 3H) 2.80–3.45 (m, 6H), 6.83 (dd, J=7.2, 6.8 Hz, 1H), 7.14 (dd, J=1.2, 7.2 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 8.24 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 6H), 1.35–1.43 (m, 4H), 2.56 (s, 3H), 3.00–3.20 (m, 4H), 3.96 (s, 3H), 3.97 (s, 3H), 6.45 (d, J=8.0 Hz, 1H), 6.80 (dd, J=6.8, 7.2 Hz, 1H), 7.39 (dd, J=1.2, 7.2 Hz, 1H), 8.03 (dd, J=1.2, 6.4 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.39–1.46 (m, 4H), 2.41 (s, 3H), 2.47 (s, 3H), 3.00–3.20 (m, 4H), 3.71 (s, 6H), 6.51 (s, 2H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 7.02 (dd, J=1.2, 6.8 Hz, 1H), 8.04 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.94 (d, J=6.8 Hz, 6H), 1.50–1.65 (m, 1H), 1.70–1.90 (m, 2H), 2.53 (s, 3H), 2.82–3.38 (m, 4H), 4.43 (t, J=6.0 Hz, 1H), 4.54 (t, J=5.5 Hz, 1H), 6.85 (dd, J=6.8, 6.8 Hz, 1H), 7.15 (dd, J=1.2, 6.8 Hz, 1H), 7.35 (dd, J=2.8, 8.0 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 8.10 (dd, J=1.2, 6.8 Hz, 1H).
Green Oil
1H NMR (400 MHz, CDCl3) δ 0.93 (d, J=6.8 Hz, 6H), 1.40–1.80 (m, 5H), 2.82–3.22 (m, 4H), 4.34 (t, J=5.6 Hz, 1H), 4.46 (t, J=6.0 Hz, 1H), 6.84 (dd, J=6.8, 6.8 Hz, 1H), 7.15 (dd, J=1.2, 6.8 Hz, 1H), 7.34 (dd, J=2.0, 8.4 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.11 (dd, J=1.2, 6.8 Hz, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 6H), 1.37–1.44 (m, 4H), 2.54 (s, 3H), 3.00–3.20 (m, 4H), 3.80 (s, 3H), 3.87 (s, 3H), 6.60–6.63 (m, 2H), 6.79 (dd, J=7.2, 7.2 Hz, 1H), 7.75 (br d, J=8.0 Hz, 1H), 8.03 (br d, J=6.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 6H), 1.30–1.50 (m, 4H), 2.47 (s, 3H), 2.52 (s, 3H), 2.60 (s, 3H), 6.81 (dd, J=6.8, 6.8 Hz, 1H), 6.97 (dd, J=1.6, 6.8 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 8.11 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.10–0.10 (m, 2H), 0.24–0.38 (m, 2H), 0.72–0.83 (m, 1H), 0.89 (t, J=7.6 Hz, 3H), 1.35–1.43 (m, 2H), 2.52 (s, 3H), 2.98 (br d, J=6.8 Hz, 2H), 3.05–3.30 (m, 2H), 6.82 (dd, J=7.2, 7.2 Hz, 1H), 7.13 (br d, J=6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.21 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.2 Hz, 3H), 1.36–1.50 (m, 2H), 1.70–1.90 (m, 2H), 2.53 (s, 3H), 3.04–3.18 (m, 2H), 3.20–3.42 (m, 2H), 4.44 (t, J=6.0 Hz, 1H), 4.56 (t, J=6.0 Hz, 1H), 6.84 (dd, J=6.8 Hz, 1H), 7.15 (dd, J=1.2, 7.2 Hz, 1H), 7.33 (dd, J=1.6, 8.4 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 8.08 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 3H), 1.30–1.43 (m, 2H), 1.50–1.63 (m, 2H), 1.70–1.90 (m, 4H), 2.22–2.36 (m, 1H), 2.52 (s, 3H), 2.90–3.35 (m, 4H), 6.81 (dd, J=6.8 Hz, 1H) 7.12 (dd, J=1.2, 6.8 Hz, 1H), 7.33 (dd, J=2.4, 8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 8.09 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.30–1.50 (m, 4H), 2.41 (s, 3H), 2.53 (s, 3H), 3.00–3.20 (m, 4H), 3.98 (s, 3H), 6.65 (d, J=8.4 Hz, 1H), 6.80 (dd, J=8.0, 8.0 Hz, 1H), 6.96 (dd, J=2.0, 6.8 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 8.09 (dd, J=2.0, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 3H), 1.35–1.80 (m, 6H), 2.53 (s, 3H), 3.02–3.25 (m, 4H), 4.35 (t, J=6.0 Hz, 1H), 4.47 (t, J=6.4 Hz, 1H), 6.84 (dd, J=6.8 Hz, 1H), 7.15 (dd, J=1.2, 6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.0 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.09 (dd, J=1.6, 6.8 Hz, 1H).
Pale Green Crystals
1H NMR (400 MHz, CDCl3) δ −0.10–0.10 (m, 2H), 0.20–0.40 (m, 2H), 0.75–0.90 (m, 1H), 1.70–1.90 (m, 2H), 2.41 (s, 3H), 2.48 (s, 3H), 2.98 (br d, J=6.8 Hz, 2H), 3.20–3.60 (m, 2H), 3.70 (s, 3H), 4.45 (t, J=5.2 Hz, 1H), 4.57 (t, J=5.6 Hz, 1H), 6.51 (s, 2H), 6.80 (dd, J=6.8, 6.8 Hz, 1H), 7.02 (dd, J=1.2, 7.2 Hz, 1H), 8.07 (dd, J=1.2, 6.8 Hz, 1H).
Pale Gray Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 3H), 1.30–1.50 (m, 2H), 1.70–1.83 (m, 2H), 2.42 (s, 3H), 2.47 (s, 3H), 3.05–3.12 (m, 2H), 3.22–3.60 (m, 2H), 3.71 (s, 6H), 4.44 (t, J=5.6 Hz, 1H), 4.56 (t, J=6.0 Hz, 1H), 6.51 (s, 2H), 6.80 (dd, J=6.8, 6.8 Hz, 1H), 7.03 (br d, J=6.8 Hz, 1H), 7.99 (br d, J=6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.10–1.00 (m, 2H), 0.25–0.40 (m, 2H), 0.75–0.85 (m, 1H), 1.72–1.82 (m, 2H), 2.53 (s, 3H), 2.99 (br d, J=7.2 Hz, 2H), 3.20–3.60 (m, 2H), 4.45 (t, J=6.6 Hz, 1H), 4.57 (t, J=5.6 Hz, 1H), 6.84 (dd, J=6.8, 6.8 Hz, 1H), 7.15 (dd, J=1.2, 6.8 Hz, 1H), 7.34 (dd, J=2.0, 8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 8.16 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 3H), 1.30–1.60 (m,4H), 1.70–1.90 (m, 2H), 3.10–3.30 (m,4H), 3.60–3.90 (m, 3H), 6.83 (dd, J=7.2, 7.2 Hz, 1H), 7.15 (dd, J=2.0, 7.2 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 8.25 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.94 (d, J=6.4 Hz, 1H), 1.50–1.60 (m, 1H), 1.70–1.85 (m, 2H), 2.42 (s, 3H), 2.48 (s, 3H),2.90–3.08 (m, 2H), 3.10–3.40 (m, 2H), 3.71 (s, 6H), 4.43 (t, J=6.0 Hz, 1H), 4.55 (t, J=6.0 Hz, 1H), 6.51 (s, 2H), 6.81 (dd, J=6.8, 6.8 Hz, 1H), 7.03 (d, J=6.0 Hz, 1H), 8.03 (br d, J=6.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.35–1.45 (m, 4H), 2.06 (s, 3H), 2.47 (s, 3H), 3.00–3.20 (m, 4H), 3,67 (s, 3H), 3.85 (s, 3H), 6.43 (d, J=2.4 Hz, 1H), 6.47 (d, J=2.0 Hz, 1H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 6.94 (dd, J=1.2, 6.4 Hz, 1H), 8.07 (dd, J=1.2, 8.0 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=7.6 Hz, 6H), 1.05 (t, J=6.8 Hz, 3H), 1.35–1.43 (m, 4H), 2.40 (s, 3H), 2.47 (s, 3H), 3.00–3.20 (m, 4H), 3.72 (s, 3H), 3.91–4.05 (m, 2H), 6.50 (br s, 2H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 7.03 (dd, J=1.2, 6.8 Hz, 1H), 8.04 (dd, J=1.2, 6.8 Hz, 1H).
Pale Green Crystals
1H NMR (400 MHz, CDCl3) δ 1.70–1.89 (m, 4H), 2.42 (s, 3H), 2.49 (s, 3H), 3.20–3.40 (m, 4H), 3.71 (s, 6H), 4.44 (t, J=5.6 Hz, 1H), 4.56 (t, J=5.6 Hz, 1H), 6.51 (s, 2H), 6.83 (dd, J=6.8, 6.8 Hz, 1H), 7.05 (dd, J=1.2, 5.6 Hz, 1H), 7.97 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.35–1.45 (m, 4H), 2.39 (s, 3H), 2.46 (s, 3H), 3.05–3.20 (m 4H), 3.70 (s, 3H), 6.73 (s, 3H), 6.80 (dd, J=7.2, 7.2 Hz, 1H), 6.95 (br s, 1H), 6.99 (dd, J=1.2, 5.6 Hz, 1H), 8.09 (br d, J=6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.35–1.42 (m, 4H), 2.02 (s, 6H), 2.34 (s, 3H), 2.45 (s, 3H), 3.05–3.20 (m, 4H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 6.88 (dd, J=1.2, 6.8 Hz, 1H), 6.96 (s, 2H), 8.09 (dd, J=1.2, 6.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 6H), 1.35–1.45 (m, 4H), 2.42 (s, 3H), 2.53 (s, 3H), 3.00–3.20 (m, 4H), 3.80 (s, 3H), 6.76–6.90 (m, 3H), 7.22 (dd, J=1.6, 7.2 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 8.04 (dd, J=1.6, 6.8 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.31 (t, J=7.6 Hz, 3H), 1.30–1.50 (m, 4H), 2.47 (s, 3H), 2.70 (q, J=7.6 Hz, 2H), 3.02–3.18 (m, 4H), 3.72 (s, 6H), 6.53 (s, 2H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 7.03 (br d, J=6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.10–0.06 (m, 2H), 0.22–0.40 (m, 2H), 0.75–0.86 (m, 1H), 0.89 (t, J=7.2 Hz, 1H), 1.32–1.50 (m, 2H), 2.41 (s, 3H), 2.47 (s, 3H), 2.97 (br d, J=6.8 Hz, 2H), 3.10–3.30 (m, 2H), 3.70 (s, 6H), 6.51 (s, 2H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 7.02 (br d, J=6.4 Hz, 1H), 8.12 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.10–0.15 (m, 4H), 0.20–0.40 (m, 4H), 0.75–0.85 (m, 2H), 2.41 (s, 3H), 2.48 (s, 3H), 3.00–3.10 (m, 4H), 3.70 (s, 6H), 6.51 (s, 2H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 7.02 (dd, J=1.2, 6.4 Hz, 1H), 8.20 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.10–0.10 (m, 4H), 0.20–0.30 (m, 4H), 0.75–0.85 (m, 2H), 2.02 (s, 3H), 2.38 (s, 3H), 2.46 (s, 3H), 3.00–3.10 (m, 4H), 3.68 (s, 3H), 6.68 (br s, 1H), 6.75–6.81 (m, 2H), 6.95 (dd, J=1.2, 6.4 Hz, 1H), 8.23 (dd, J=1.2, 6.8 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 6H), 1.30–1.50 (m, 4H), 2.49 (s, 3H), 3.00–3.20 (m, 4H), 3.74 (s, 3H), 3.84 (s, 3H), 6.36–6.40 (m, 2H), 6.79 (dd, J=7.2, 7.2 Hz, 1H), 7.04 (br d, J=6.8 Hz, 1H), 8.07 (dd, J=1.2, 6.8 Hz, 1H).
Pale Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 6H), 1.35–1.43 (m, 4H), 2.53 (s, 3H), 3.00–3.17 (m, 4H), 3.81 (s, 3H), 6.80 (dd, J=6.8, 6.8 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 7.05 (dd, J=1.6, 8.0 Hz, 1H), 7.72 (dd, J=1.2, 8.4 Hz, 1H), 8.06 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 6H), 1.35–1.45 (m, 4H), 2,47 (s, 3H), 3.03–3.16 (m, 4H), 3.71 (s, 6H), 3.87 (s, 3H), 6.26 (s, 2H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 7.01 (dd, J=1.6, 6.8 Hz, 1H), 8.04 (dd, 1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.91 (t, J=7.6 Hz, 3H), 1.41–1.50 (m, 2H), 2.17 (t, J=2.4 Hz, 1H), 2.52 (s, 3H), 3.20–3.30 (m, 2H), 3.92 (d, J=2.8 Hz, 2H), 6.84 (dd, 7.2, 7.2 Hz, 1H), 7.16 (dd, J=1.2, 6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 8.17 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.6 Hz, 6H), 1.35–1.43 (m, 4H), 2.62 (s, 3H), 3.00–3.18 (m, 4H), 3.87 (s, 3H), 6.81 (dd, J=6.8, 6.8 Hz, 1H), 7.00–7.02 (m, 2H), 7.20 (dd, J=1.6, 7.2 Hz, 1H), 8.03–8.08 (m, 3H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.94 (t, J=7.6 Hz, 3H), 1.63–1.72 (m, 2H), 2.43 (br s, 6H), 3.55–3.63 (m, 1H), 3.73 (s, 6H), 6.02–6.03 (m, 1H), 6.29–6.31 (m, 1H), 6.53 (s, 2H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 7.08–7.13 (m, 2H), 7.71 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 3H), 1.35–1.46 (m, 2H), 1.72 (t, J=2.4 Hz, 3H), 3.20–3.30 (m, 2H), 3.81 (q, J=2.4 Hz, 2H), 6.83 (dd, J=6.8, 6.8 Hz, 1H), 7.14 (dd, J=1.2, 6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 8,17 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ0.88 (t, J=7.2 Hz, 6H), 1.35–1.45 (m, 4H), 2.47 (s, 3H), 3.03–3.20 (m, 4H), 3.71 (s, 3H), 6.81 (dd, J=6.8, 6.8 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.97 (dd, J=1.2, 6.8 Hz, 1H), 7.14 (d, J=1.6 Hz, 1H), 8.11 (dd, J=1.6, 6.8 Hz, 1H).
Green Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H), 1.32–1.48 (m, 2H), 2.52 (s, 3H), 3.10–3.25 (m, 4H), 6.82 (dd, J=6.8, 6.8 Hz, 1H), 7.14 (dd, J=1.2, 6.8 Hz, 1H), 7.33 (dd, J=2.0, 8.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.12 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 6H), 1.35–1.44 (m, 4H), 2.24 (s, 3H), 2.52 (s, 3H), 3.05–3.18 (m, 4H), 3.85 (s, 3H), 6.77–6.86 (m, 3H), 6.95 (dd, J=1.6, 7.2 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 8.08 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.2 Hz, 3H), 1.30–1.45 (m, 2H), 1.50–1.60 (m, 2H), 1.60–1.90 (m, 4H), 2.22–2.80 (m, 1H), 2.41 (s, 3H), 2.47 (s, 3H), 3.00–3.25 (m, 4H), 3.70 (s, 3H), 6.51 (s, 2H), 6.77 (dd, J=6.8, 6.8 Hz, 1H), 7.01 (dd, J=1.2, 6.8 Hz, 1H), 8.02 (dd, J=1.2, 6.8 Hz, 1H).
Tan Oil
1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.2 Hz, 3H), 1.40–1.50 (m, 2H), 2.19 (t, J=1.6 Hz, 1H), 2.42 (s, 3H), 2.47 (s, 3H), 2.20–2.31 (m, 2H), 3.70 (s, 6H), 3.91 (d, J=1.6 Hz, 2H), 6.51 (s, 2H), 6.81 (dd, J=6.8, 6.8 Hz, 1H), 7.04 (br d, J=7.2 Hz, 1H), 8.08 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.35–1.45 (m, 4H), 2.46 (s, 3H), 3.02–3.18 (m, 4H), 6.79 (dd, J=7.2, 7.2 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 7.50–7.60 (m, 2H), 7.77 (br s, 1H), 8.12 (dd, J=1.2, 6.8 Hz, 1H).
Pale Green Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 6H), 1.35–1.47 (m, 4H), 2.47 (s, 3H), 3.04–3.16 (m, 4H), 3.71 (s, 6H), 6.68 (s, 2H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 6.99 (dd, J=1.2, 6.8 Hz, 1H), 8.06 (dd, J=0.8, 6.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.6 Hz, 3H), 1.35–1.45 (m, 2H), 1.50–1.90 (m, 6H), 2.22–2.40 (m, 1H), 2.47 (s, 3H), 3.00–3.20 (m, 4H), 3.70 (s, 6H), 6.68 (s, 2H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 6.99 (br d, J=6.8 Hz, 1H), 8.03 (d, J=6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.25–1.45 (m, 4H), 2.46 (s, 3H), 3.04–3.20 (m, 4H), 3.90 (s, 3H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 7.12 (dd, J=2.4, 6.8 Hz, 1H), 7.25–7.29 (m, 1H), 7.50 (d, J=8.8 Hz, 1H), 8.10 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.35–1.43 (m, 4H), 2.10 (s, 3H), 2.52 (s, 3H), 3.02–3.18 (m, 4H), 6.01 (br s, 2H), 6.73–6.80 (m, 2H), 6.88–6.97 (m, 2H), 8.08 (dd, J=2.0, 6.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ0.86 (t, J=7.2 Hz, 3H), 1.25–1.37 (m, 4H), 1.60–1.90 (m, 4H), 2.22–2.38 (m, 1H), 2.41 (s, 3H); 2.47 (s, 3H), 3.00–3.25 (m, 4H), 3.70 (s, 6H), 6.50 (s, 2H), 6.75–6.80 (m, 1H), 7.01 (br d, J=6.8 Hz, 1H), 8.01 (dd, J=2.0, 8.4 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=6.8 Hz, 3H), 1.50–1.90 (m, 6H), 2.22–2.40 (m, 1H), 2.41 (s, 3H), 2.47 (s, 3H), 3.08–3.24 (m, 4H), 3.70 (s, 6H), 6.51 (s, 2H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 7.01 (br d, J=6.8 Hz, 1H), 8.02 (br d, J=6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 6H), 1.35–1.45 (m, 4H), 2.52 (s, 3H), 3.03–3.18 (m, 4H), 2.52 (s, 3H), 3.03–3.18 (m, 4H), 6.83 (dd, 7.2, 7.2 Hz, 1H), 7.15 (dd, J=1.2, 6.8 Hz, 1H), 7.22 (br d, J=7.2 Hz, 1H), 7.39 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 8.13 (dd, J=1.2, 7.2 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.18–0.12 (m, 2H), 0.20–0.40 (m, 2H), 0.70–0.85 (m, 1H), 1.50–1.85 (m, 6H), 2.22–2.38 (m, 1H), 2.41 (s, 3H), 2.47 (s, 3H), 2.90–3.00 (m, 2H), 3.10–3.35 (m, 2H), 3.70 (s, 6H), 6.51 (s, 2H), 6.77 (dd, J=6.8, 6.8 Hz, 1H), 7.01 (dd, J=1.2, 6.8 Hz, 1H), 8.09 (dd, J=1.2, 7.2 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.38–1.45 (m, 4H), 2.06 (s, 3H), 2.52 (s, 3H), 3.02–3.20 (m, 4H), 4.25–4.36 (m, 4H), 6.76–6.80 (m, 2H), 6.89–6.96 (m, 2H), 8.08 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 1.50–1.85 (m, 8H), 2.30–2.40 (m, 1H), 2.41 (s, 3H), 2.48 (s, 3H), 3.00–3.40 (m, 4H), 3.70 (s, 6H), 4.43 (t, J=6.0 Hz, 1H), 4.55 (t, J=6.0 Hz, 1H), 6.51 (s, 2H), 6.80 (dd, J=6.8, 6.8 Hz, 1H), 7.03 (dd, J=1.2, 6.8 Hz, 1H), 7.97 (dd, J=1.2, 6.8 Hz, 1H).
Orange Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.35–1.45 (m, 4H), 2.24 (s, 3H), 2.53 (s, 3H), 3.00–3.20 (m, 4H), 3.12 (s, 6H), 6.45 (s, 1H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 6.95 (dd, J=1.2, 6.0 Hz, 1H), 8.07 (d, J=6.8 Hz, 1H), 8.15 (s, 1H).
Yellow Crystals
1H NMR (400 MHz, CDCl3) δ 0.84 (t, J=7.2 Hz, 3H), 1.22–1.40 (m, 4H), 1.50–1.70 (m, 2H), 2.42 (s, 3H), 2.48 (s, 3H), 2.95–3.05 (m, 1H), 3.22–3.42 (m, 4H), 3.71 (s, 6H), 3.89–4.05 (m, 2H), 6.51 (s, 2H), 6.79 (dd. J=6.8, 6.8 Hz, 1H), 7.03 (br d, J=6.8 Hz, 1H), 8.03 (dd, 1.2, 6.4 Hz, 1H).
Brown Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 3H), 1.32–1.43 (m, 2H), 1.50–1.90 (m, 6H), 2.23 (s, 3H), 2.21–2.36 (m, 1H), 2.53 (s, 3H), 2.95–3.30 (m, 4H), 3.13 (s, 6H), 6.45 (s, 1H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 6.95 (dd, J=1.2, 6.8 Hz, 1H), 8.05 (dd, J=1.2, 6.8 Hz, 1H), 8.15 (s, 1H).
Brown Oil
1H NMR (400 MHz, CDCl3) δ 1.50–1.85 (m, 8H), 2.23 (s, 3H), 2.25–2.38 (m, 1H), 2.54 (s, 3H), 3.00–3.40 (m, 4H), 3.13 (s, 6H), 4.44 (t, J=6.0 Hz, 1H), 4.55 (t, J=6.0 Hz, 1H), 6.45 (s, 1H), 6.80 (dd, J=6.8, 6.8 Hz, 1H), 6.97 (dd, J=1.2, 7.2 Hz, 1H), 8.00 (dd, J=1.2, 6.8 Hz, 1H), 8.15 (s, 1H).
Brown Oil
1H NMR (400 MHz, CDCl3) δ −0.15–0.12 (m, 4H), 0.18–0.40 (m, 4H), 0.75–0.85 (m, 2H), 2.22 (s, 3H), 2.52 (s, 3H), 2.95–3.20 (m, 4H), 3.12 (s, 6H), 6.46 (s, 1H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 6.96 (dd, J=1.2, 6.8 Hz, 1H), 8.16 (s, 1H), 8.24 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.2 Hz, 6H), 1.35–1.45 (m, 4H), 2.00 (s, 3H), 2.18 (s, 3H), 2.47 (s, 3H), 3.00–3.20 (m, 4H), 3.11 (s, 6H), 6.31 (s, 1H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 6.88 (dd, J=1.2, 6.8 Hz, 1H), 8.08 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=7.2 Hz, 3H), 0.98 (t, J=7.2 Hz, 3H), 1.23–1.40 (m, 4H), 2.24 (s, 3H), 2.53 (s, 3H), 3.12 (s, 6H), 3.13–3.25 (m, 4H), 6.46 (s, 1H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 6.95 (dd, J=1.2, 6.8 Hz, 1H), 8.07 (dd, J=1.6, 6.8 Hz, 1H), 8.16 (s, 1H).
Brown Oil
1H NMR (400 MHz, CDCl3) δ 0.85 (t, J=7.4 Hz, 3H), 1.23–1.40 (m, 2H), 1.45–1.70 (m, 4H), 2.24 (s, 3H), 2.54 (s, 3H), 2.95–3.07 (m, 1H), 3.13 (s, 6H), 3.25–3.42 (m, 4H), 3.87–4.03 (m, 2H), 6.46 (s, 1H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 6.96 (dd, J=1.6, 6.4 Hz, 1H), 8.07 (dd, J=1.6, 6.8 Hz, 1H), 8.16 (s, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H), 1.38–1.44 (m, 4H), 2.39 (s, 3H), 2.54 (s, 3H), 3.02–3.18 (m, 4H), 3.12 (s, 6H), 6.44 (d, J=8.4 Hz, 1H), 6.77 (dd, J=7.2, 7.2 Hz, 1H), 6.94 (dd, J=1.2, 6.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 8.05 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.85 (t, J=7.4 Hz, 3H), 1.20–1.40 (m, 2H), 1.40–1.80 (m, 4H), 2.53 (s, 3H), 2.95–3.05 (m, 1H), 3.25–3.43 (m, 4H), 3.84–4.05 (m, 2H), 6.83 (dd, J=7.2, 7.2 Hz, 1H), 7.15 (dd, J=1.2, 7.2 Hz, 1H), 7.34 (dd, J=2.4, 8.4 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 8.11 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 1.25–2.02 (m, 10H), 2.10–2.20 (m, 1H), 2.41 (s, 3H), 2.49 (s, 3H), 3.05–3.10 (m, 1H), 3.20–3.40 (m, 2H), 3.69 (s, 3H), 3.71 (s, 3H), 3.90–4.00 (m, 2H), 6.51 (s, 2H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 7.03 (br d, J=6.8 Hz, 1H), 7.99 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Amorphous
1H NMR (400 MHz, CDCl3) δ −0.20–0.10 (m, 1H), −0.50–0.08 (m, 1H), 0.12–0.20 (m, 1H), 0.25–0.35 (m, 1H), 1.40–1.70 (m, 4H), 2.41 (s, 3H), 2.49 (s, 3H), 2.97–3.10 (m, 2H), 3.30–3.45 (m, 3H), 3.69 (s, 3H), 3.72 (s, 3H), 3.85–3.92 (m, 1H), 3.95–4.02 (m, 1H), 6.51 (s, 2H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 7.03 (dd, J=1.2, 6.8 Hz, 1H), 8.13 (dd, J=1.2, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.85 (t, J=7.2 Hz, 3H), 1.20–1.40 (m, 2H), 1.40–1.75 (m, 4H), 2.05 (s, 3H), 2.49 (s, 3H), 2.95–3.10 (m, 1H), 3.22–3.45 (m 3H), 3.68 (s, 3H), 3.85 (s, 3H), 3.85–4.05 (m, 2H), 6.43 (d, J=2.4 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 6.96 (dd, J=1.6, 7.2 Hz, 1H), 8.06 (dd, J=1.6, 6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ −0.30–0.08 (m, 1H), −0.02–0.10 (m, 1H), 0.15–0.40 (m, 2H), 0.60–0.75 (m, 1H), 1.40–1.70 (m, 4H), 2.03–2.08 (m, 3H), 2.49 (s, 3H), 2.95–3.12 (m, 2H), 3.30–3.45 (m, 3H), 3.66–3.69 (m, 3H), 3.85 (s, 3H), 3.80–3.92 (m, 1H), 3.95–4.02 (m, 1H), 6.44 (br s, 1H), 6.47 (br s, 1H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 6.96 (br d, J=6.8 Hz, 1H), 8.16 (br d, J=6.8 Hz, 1H).
Brown Crystals
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J=7.6 Hz, 3H), 1.35–1.57 (m, 3H), 1.70–1.95 (m, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 3.00–3.35 (m, 5H), 3.50–3.90 (m, 8H), 6.51 (br s, 2H), 6.79 (dd, J=6.8, 6.8 Hz, 1H), 7.02 (dd, J=1.2, 6.8 Hz, 1H), 8.14 (dd, J=1.2, 6.8 Hz, 1H).
Brown Crystals
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=8.0 Hz, 3H), 1.35–1.50 (m, 2H), 1.60–1.95 (m, 2H), 2.10–2.30 (m, 1H), 2.42 (s, 3H), 2.48 (s, 3H), 2.90–3.10 (m, 4H), 3.60–3.84 (m, 10H), 6.51 (br s, 2H), 6.80 (dd, J=6.8, 6.8 Hz, 1H), 7.03 (br d, J=6.8 Hz, 1H), 7.93–8.02 (m, 1H).
Yellow Oil
1H NMR (400 MHz, CDCl3) δ 0.86 (t, J=6.8 Hz, 3H), 1.22–1.42 (m, 1H), 1.65–1.90 (m, 4H), 2.05 (s, 3H), 2.24–2.36 (m, 1H), 2.48 (s, 3H), 2.94–3.32 (m, 4H), 3.67 (s, 3H), 3.85 (s, 3H), 6.43 (d, J=2.0 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 6.78 (dd, J=6.8, 6.8 Hz, 1H), 6.93 (br d, J=6.8 Hz, 1H), 8.03 (br d, J=6.8 Hz, 1H).
Yellow Oil
1H NMR (400 MHZ, CDCl3) δ 0.86 (t, J=7.2 Hz, 3H), 1.20–1.45 (m, 4H), 1.65–1.90 (m, 4H), 2.02 (s, 3H), 2.20–2.35 (s, 1H), 2.38 (s, 3H), 2.47 (s, 3H), 2.95–3.35 (m, 4H), 3.68 (s, 3H), 6.67 (br s, 1H), 6.75–6.80 (m, 2H), 6.95 (dd, J=1.2, 6.8 Hz, 1H), 8.04 (dd, J=1.2, 6.4 Hz, 1H).
Ethyl bromo-2-(methylsulfanyl)imidazo[1,2-a]pyridine-3-carboxylate (840 mg) was dissolved in tetrahydrofuran (30 mL), then a 1M solution of diisobutyl aluminum hydride in toluene (10 mL) was added dropwise at −70° C., and the temperature was raised to room temperature. An aqueous ammonium chloride solution was added to the reaction mixture at 0° C. After the temeperature was raised to room temperature, it was extracted with ethyl acetate. The resulting [8-bromo-2-(methylsulfanyl) imidazo[1,2-a]pyridin-3-yl]methanol was used in the next reaction without purification.
The resulting [8-bromo-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]methanol (640 mg) was dissolved in acetone (50 mL), then activated manganese (IV) oxide (4 g) was added thereto, and the mixture was stirred overnight. Manganese (IV) oxide was filtered off through Celite, and the filtrate was evaporated. The resulting residue was purified by column chromatography using silica gel (ethyl acetate:n-hexane=1:10), to give 8-bromo-3-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridine (120 mg) as a brown oil.
The resulting 8-bromo-3-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridine was reacted in the same manner as that of Example 4 to give the title compound as white crystals.
1H NMR (400 MHz, CDCl3) δ2.50 (s, 3H), 2.52 (s, 3H), 6.91 (dd, J=7.2 Hz, 1H), 7.17 (dd, J=1.2, 6.8 Hz, 1H), 7.34 (dd, J=2.0, 8.4 Hz, 1H), 7.52–7.57 (m, 2H), 7.83 (d, J=6.8 Hz, 1H).
The compound of Example 373 was synthesized in the same manner as that of Example 1.
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.95 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.6 Hz, 3H), 1.22–1.35 (m, 1H), 1.29 (t, J=7.2 Hz, 3H), 1.42–1.52 (m, 1H), 1.77–1.85 (m, 1H), 2.05–2.15 (m, 1H), 2.73–2.84 (m, 2H), 3.30–3.48 (m, 2H), 4.77 (t, J=7.2 Hz, 1H), 7.39 (dd, J=8.4, 2.0 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.97 (br s, 1H), 9.39 (br s, 1H).
Hereinafter, compounds of Examples 374 to 376 were synthesized in the same manner as that of Example 373.
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.95 (t, J=7.2 Hz, 3H), 1.14–1.36 (m, 1H), 1.19 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.41–1.54 (m, 1H), 1.77–1.88 (m, 1H), 2.06–2.16 (m, 1H), 2.07 (s, 3H), 2.37 (s, 3H), 2.68–2.80 (m, 2H), 3.27–3.44 (m, 2H), 3.70 (s, 3H), 4.75 (t, J=7.2 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.78 (br s, 1H), 9.32 (br s, 1H).
(b) Isomer 2 having a smaller Rf value on TLC
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.94 (t, J=7.2 Hz, 3H), 1.14–1.34 (m, 1H), 1.20 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.41–1.54 (m, 1H), 1.78–1.88 (m, 1H), 2.06–2.16 (m, 1H), 2.07 (s, 3H), 2.38 (s, 3H), 2.68–2.84 (m, 2H), 3.30–3.44 (m, 2H), 3.71 (s, 3H), 4.75 (t, J=7.2 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.78 (br s, 1H), 9.34 (br s, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.94 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H), 1.22–1.35 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.42–1.52 (m, 1H), 1.78–1.88 (m, 1H), 2.05–2.15 (m, 1H), 2.71–2.82 (m, 2H), 3.29–3.45 (m, 2H), 3.86 (s, 3H), 4.76 (t, J=7.2 Hz, 1H), 6.94 (dd, J=8.4, 2.8 Hz, 1H), 7.08 (d, J=2.8 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 9.34 (s, 1H).
White Crystals
1H NMR (400 MHz, CDCl3) δ 0.94 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H), 1.26–1.38 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.42–1.52 (m, 1H), 1.78–1.88 (m, 1H), 2.05–2.15 (m, 1H), 2.42 (s, 3H), 2.70–2.81 (m, 2H), 3.29–3.46 (m, 2H), 3.97 (s, 3H), 4.77 (t, J=7.2 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 9.34 (s, 1H).
Among the above-mentioned Examples, particularly preferable compounds are N-(2-ethyhl-8-mesitylimidazo[1,2-a]pyrazin-3-yl)-N,N-dipropylamine hydrochloride, N-(2-ethyl-8-mesitylimidazo[1,2-a]pyrazin-3-yl)-N-(1-ethylpropyl)amine, N-[8-(2-chloro-4-methoxyphenyl)-2-ethylimdazo[1,2-a]pyrazin-3-yl]-N,N-dipropylamine hydrochloride, N-cyclopropylmethyl-N-[8-(2,4-dichloropheyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N-isobutylamine, N-[8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N-propyl-N-tetrahydro-3-thiophenylamine, N3,N3-dipropyl-2-isopropyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-amine, N-[2-ethyl-8-(6-methyl-1,3-benzodioxol-5-yl)imidazo[1,2-a]pyrazin-3-yl]-N,N-dipropylamine, N-[2-ethyl-8-(4-methoxy-2,5-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-N,N-dipropylamine, N-cyclopropylmethyl-N-[8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N-(2-methoxyethyl)amine hydrochloride, N-[8-(2-chloro-4-methoxyphenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N,N-dicyclopropylmethylamine, N-8-[5-chloro-4-(2,5-dimethyl-1H-1-pyrroyl)-2-methoxyphenyl]-2-ethylimidazo[1,2-a]pyrazin-3-yl-N,N-dicyclopropylmethylamine, N-[8-(2,4-dichlorophenyl)-2-ethyl-6-methylimidazo[1,2-a]pyrazin-3-yl]-N,N-dipropylamine hydrochloride, N3,N3-dipropyl-5-bromo-8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-amine, 8-(2,4-dichlorophenyl)-3-(dipropylamino)-2-ethylimidazo[1,2-a]pyrazin-6-yl cyanide, N-[8-(2,4-dichlorophenyl)-2-ethyl-6-methoxyimidazo[1,2-a]pyrazin-3-yl]-N,N-dipropylamine, N-[6-chloro-2-ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-N,N-dipropylamine, N3,N3-dipropyl-8-(2,4-dichlorophenyl)-2-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-amine,
The present compounds were evaluated for the ability to bind to a corticotrophin releasing hormone receptor (CRFR) and the adenylate cyclase activity inhibitory ability. Each test procedures and the results-are as follows:
(1) Preparation of CRFR expressing cell: As an experiment material for the CRFR binding experiment, a membrane fraction of a cell which expressed highly human CRFR 1. CRFR expressing cell was prepared as follows. The full length gene of CRFR1 was obtained by a PCT method using human brain (QuickClone™ Clontech) as cDNA library. The resulting DNA fragment was inserted into a cloning vector to confirm the base sequence. A cDNA having the correct base sequence was ligated to an expression vector (pcDNA3.1™, Invitrogen). A gene was inserted into Hek 283 cell and grown in a cell culturing solution containing G418 (1 mg/ml) to obtain a resistance cell, into which a CRFR 1 expression vector was cloned by a limitation diluting method. A clone having the high binding ability of membrane and sauvagine per unit protein was finally selected from cloned cells by a binding experiment shown by the method shown below, which was used for an experiment.
(2) Preparation of a membrane fraction: G418 resistant cells into which a gene for CRFR 1 was introduced were collected, and cell rupture was performed by an ultrasound generator with a sonicate buffer (D-PBS-10 mM MgCl2, 2 mM EGTA). A suspension after ultrasound rupture was centrifuged (46,000×g, 10 minutes), the sediment thereof was further resuspended with a sonicate buffer, and the same procedures were related. Finally, the sediment was suspended inabinding buffer (D-PBS-10 mMMgCl2, 2 mM EGTA, 1.5% BSA, 0.15 mM bacitracin, 1× protease inhibitor cocktail (COMPLETE™, Boehringer), to adjust the protein concentration at 1.6 mg/ml, which was used as a membrane fraction. (3) Binding experiment: Binding experiment with sauvagine was performed using a 96-well plate and SPA™ (Amersham pharmacia). An experiment was according to the specification of SPA beads. 40 mg of a membrane fraction protein, 0.5 mg of beads and 40 pM 125]-sauvagine (Amersham pharmacia) were allowed to stand at room temperature for two hours in the presence a test compound, centrifuged (1,000×g, 5 minutes), and then the radioactivity of each well was measured with TopCount™ (Packard).
(4) Calculation of the binding ability: The radioactivity as the non-specific binding when 1,000-fold excessive amount of non-radioactive sauvagine was added was substacted from each value, the radioactivity where no test material is added is regarded as 100% (control), and each value is shown by % (% of control). The concentration showing 50% in % (% of control) was obtained from a graph where the concentration test material is plotted on an abscissa axis and %(% of control) is plotted on a coordinate axis and IC50 value was calculated.
(1) Test procedures: AtT-20 cell is a cell strain derived from mouse pytuitari gland tumor, it is known that the intracellular adenyrate cyclase system is activated in response to corticotrophin release hormone (CRF), to produce cyclic AMP (cAMP), releasing adrenocortical hormone(ACTH) (Biochem. Piophys. Res. Com. 106. 1364–1371, 1982). In this experiment, the cell (1×105) suspended in D-MEM medium (0.1% FPS), seeded on a 96-well plate, a phosphodiesterase inhibitor (IBMX, Calbiochem) was added to the final concentration of 1 mM, which was cultured at 37° C. for 30 minutes. A diluted test compound solution and CRF (30 nM) were added, which was further cultured at 37° C. for 10 minutes, cells were collected by centrifugation (500×g, 5 minutes), cells were lysed with a lysis buffer (Amersham Pharmacia), and an amount of intracellular cAMP produced was quantitated using the ELISA method. For ELISA, cAMP EIA system (BIOTRAK™ Amersham Pharmacia) was used. (2) Calculation of adenyrate cyclase activity inhibitory ability: Treatment of the resulting data was carried out as follows. An amount of cAMP produced by a cell to which 30 nM CRF was added is regarded as 100% (control) and a value of each sample is expressed as % (% of control). The concentration showing 50% in % (% of control) was obtained from a graph where the concentration of a test material is plotted on an abscissa axis and % (% of control) is plotted on a coordinate and IC50 value was calculated.
In Test Example 1, the compounds of the present invention exhibited an excellent binding ability to CRFR, and IC50 values thereof were 10 to 5000 nM. Further, in Test Example 2, the compounds of the present invention exhibited an excellent inhibitory activity to the adenylate cyclase by CRF.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2001-032637 | Feb 2001 | JP | national |
| 2001-133208 | Apr 2001 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP02/01098 | 2/8/2002 | WO | 00 | 6/25/2003 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO02/062800 | 8/15/2002 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20040082781 A1 | Apr 2004 | US |
