# Patent

## Title
Quinolone derivative

## Abstract

As a result of extensive studies on NAD(P)H oxidase inhibitors, the present inventors found that a quinolone derivative having, at the 2-position, an alkyl group substituted with a heteroatom or the like has an excellent NAD(P)H oxidase inhibitory activity, and accomplished the present invention. The compound of the present invention has a reactive oxygen species production inhibitory activity based on the NAD(P)H oxidase inhibitory activity, and therefore can be used as an agent for preventing and/or treating diabetes, impaired glucose tolerance, hyperlipidemia, fatty liver, diabetic complications and the like.

## Background
TECHNICAL FIELD
The present invention relates to a medicament, and specifically to a novel quinolone derivative or a salt thereof, which is useful as an agent for preventing and/or treating diabetes.
BACKGROUND ART
Diabetes is a syndrome mainly characterized by chronic continuance of a high concentration of glucose in blood (blood glucose level) and is a disease caused by relative or absolute deficiency of insulin which is a blood glucose-lowering hormone.
The number of diabetic patients throughout the world is currently estimated to be 194,000,000 (2003, adults), accounting for 5.1% of the adult population (3,800,000,000), which corresponds to a diabetic morbidity of one in twenty people. Further, this number is predicted to rise to 333,000,000 by 2025 (Diabetes Atlas, 2003, 2nd edition, p. 15-71).
Further, there is a serious increase in the number of people with impaired glucose tolerance which can be said to be a pre-diabetes state. Impaired glucose tolerance raises a pathogenic risk of hypertension or hyperlipidemia as well as a pathogenic risk of diabetes. The number of people with impaired glucose tolerance in the adult population is already estimated to be 314,000,000, and is said to be increased to 472,000,000 by 2025. Therefore, it is said to the extent that diabetes and impaired glucose tolerance are called the most significant medical problem of the 21st century, there is a great social demand associated with the treatment of this diseases.
In healthy people, saccharides from dietary intake are absorbed by the digestive tract and then transported into blood, resulting in elevation of the blood glucose level. Correspondingly, insulin is secreted from the pancreas, whereby release of glucose from the liver is lowered while increasing glucose uptake into muscle or adipose tissues. Then, the blood glucose level is decreased. As a result, homeostasis of blood glucose is maintained. However, in a diabetic condition, it is caught in chronic dysfunction of the blood glucose control known as postprandial hyperglycemia or fasting hyperglycemia due to incomplete secretion of insulin, or insulin resistance (insufficiency of insulin action).
Chronic duration of a hyperglycemic state leads to an enhancement in the production of reactive oxygen in vivo, which consequently increases oxidative stress to vascular endothelial cells. Indeed, it has been reported that the level of an oxidative stress marker in blood is elevated in diabetic patients. It is considered that oxidative stress stemming from such a hyperglycemic condition is closely correlated with not only the progression of diabetes (hyperglycemic symptom), but also the pathogenesis of microvascular diabetic complications such as diabetic retinopathy, neuropathy, and nephropathy (Non-Patent Citation 1).
Excessive reactive oxygen also acts on lipids in vivo to cause the formation of lipid peroxides such as oxidized LDL, which, in turn, brings about inflammatory reactions including the accumulation of monocytes and macrophages in the vascular endothelium, and macrovascular complications (arteriosclerosis) accompanying the risk of cardiovascular events.
In vivo oxidative stress arises from the excessive production of reactive oxygen species (ROS) such as superoxide anions. NAD(P)H oxidase in neutrophils or phagocytes has been conventionally known as a principle production source of ROS for a long time. Recently, the production of ROS by NAD(P)H oxidase has also been confirmed in several cellular species such as vascular endothelial cells or smooth muscle cells, and the possibility has been pointed to that ROS is implicated in functions of cells and the pathogenesis of diseases in a variety of tissues (Non-Patent Citation 2).
In insulin target cells such as L6 myocytes or 3T3-L1 adipocytes, it has been reported that long-term exposure of ROS to such cells inhibits glucose uptake by insulin stimulation (Non-Patent Citations 3 and 4), and it is believed that oxidative stress induces insulin resistance. Besides, it is believed that ROS produced by chronic hyperglycemia results in dysfunction or apoptosis of pancreatic β cells, consequently lowering insulin secretion (Non-Patent Citation 5).
In diabetic model mice, it has been reported that an expression level of NAD(P)H oxidase is increased in adipose tissues, thus enhancing the production of ROS, and apocynin, an NAD(P)H oxidase inhibitor, inhibits ROS production lower the blood glucose level in diabetes model mice (Non-Patent Citation 6). In addition, it has been reported that diphenyleneiodonium (DPI), another NAD(P)H oxidase inhibitor, promotes glucose uptake into L6 myocytes and improves insulin sensitivity in diabetes model mice (Patent Citation 1).
From these findings, a compound inhibiting the NAD(P)H oxidase activity, based on an inhibitory action of ROS production, is expected to be a drug for improving hyperglycemic symptoms in diabetes through the promotion of glucose uptake in peripheral tissues. Further, with regard to the pancreas or other organs vulnerable to disorders through diabetic hyperglycemia, such a compound also provides a feasibility of a drug having an active protective action via the relief of oxidative stress.
Apocynin, which is an NAD(P)H oxidase inhibitor, has been reported to improve the elevation of triglyceride levels in blood and hepatic tissues in diabetes model mice (Non-Patent Citation 6), and a compound inhibiting an NAD(P)H oxidase activity is also considered to be useful for preventing and treating hyperlipidemia or fatty liver.
Besides, elevation of blood pressure due to a rise of ROS production in vascular walls through the action of NAD(P)H oxidase has been reported in spontaneous hypertension model rats, or hypertension model rats with continuous administration of angiotensin II (Non-Patent Citation 7), and an NAD(P)H oxidase inhibitor is expected to remedy hypertension.
Further, it is considered that a rise of ROS production through the action of NAD(P)H oxidase is involved in the pathogenesis and progression of diabetic complications (such as retinopathy, nephropathy, and neuropathy), peripheral circulatory disturbance, and arteriosclerosis, by the development of vascular endothelial cell disorders and chronic inflammatory reactions (Non-Patent Citation 8), and there is a possibility that the NAD(P)H oxidase inhibitor inhibits these diseases.
Additionally, as diseases associated with an enhancement of ROS production, there are known metabolic syndromes (Non-Patent Citation 5), Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steato-Hepatitis (NASH) (Non-Patent Citation 9), cancer (Non-Patent Citation 10), Alzheimer's type dementia (Non-Patent Citation 11), age-related macular degeneration (Non-Patent Citation 12), neurodegenerative diseases, cerebral stroke, ischemic diseases, arthritis, inflammatory diseases, etc. (Non-Patent Citation 13). The NAD(P)H oxidase inhibitor is expected to ameliorate these diseases.
As the NAD(P)H oxidase inhibitor, bicyclic pyridazine compounds have been reported to be effective for treating diabetes, hypertension, and the like (Patent Citation 2).
Meanwhile, there have been reported Patent Citations 3 through 8, Non-Patent Citation 14, and the like relating to quinolone derivative compounds.
It has been reported in Patent Citation 3 that a compound of the formula (A) exhibits a leucotriene D4 antagonistic action and is effective for allergic diseases. However, there is no disclosure of groups described in R2 of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity.




(In the formula, A represents —CH2CH═CH—, —CH(OH)CH═CH—, —CH(OH)C≡C—, —CH═CHCH2—, or —CH2C≡C—. See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 4 that a compound of the formula (B) exhibits an anti-helicobacter pylori action. However, there is no disclosure of groups described in R2 of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.




(In the formula, A represents —CH(OH)CH═CH—, —CH(OH)C≡C—, —CH═CHCH2—, —(CH2)n—, —CH═CHCH2—, —CH═CHCH═CH—, —COCH2—, or —CH2CH═CH—, and B represents a hydrogen atom, —(CH2)p—CH3, (CH2)q—CO2H, or —CH2CH═C(CH3)CH2CH2CH═C(CH3)—CH3. See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 5 that a wide range of compounds represented by the formula (C) exhibit an anti-helicobacter pylori action. However, there is no disclosure of groups described in R2 of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.




(In the formula, R2 means




See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 6 that a compound of the formula (D) exhibits an anti-helicobacter pylori action. However, there is no disclosure of groups described in R2 of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.




(In the formula, R2 represents C1-10 alkyl, C2-10 alkenyl, (C1-10 alkyl)phenyl, (C2-10 alkenyl)phenyl, C2-10 alkynyl, (C2-10 alkynyl)phenyl, phenyl, naphthyl, thiophenyl, or pyridyl (provided that a cyclic group may be substituted). See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 7 that a wide range of compounds represented by the formula (E) exhibit an inosine monophosphate dehydrogenase (IMPDH) inhibitory activity. However, there is no specific disclosure of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.




(In the formula, R1 represents alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, NR8R9, SR20, cycloalkyl, substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl. See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 8 that 2-(2-heptenyl)-3-methyl-4(1H)-quinolone, 2-(2-cis-heptenyl)-3-methyl-4(1H)-quinolone, and 2-(2-trans-heptenyl)-3-methyl-4(1H)-quinolone exhibit an anti-helicobacter pylori action. However, there is no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.
It has been reported in Patent Citation 9 that a wide range of compounds represented by the formula (F) exhibits a PPAR receptor inhibitory activity. However, there is no specific disclosure of the present invention compound, and no disclosure of an NAD(P)H oxidase inhibitory activity.




(In the formula, Ar I and Ar II represent aryl, heteroaryl, or the like. See the above-referenced document for other symbols in the formula.)
It has been reported in Patent Citation 14 that 3-methyl-2-(5-phenoxypentyl)quinolin-4(1H)-one and 3-ethyl-2-(5-phenoxypentyl)quinolin-4(1H)-one have an NADH-ubiquinone reductase inhibitory action. However, there is no disclosure of an NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.
It has been reported in Patent Citation 15 that 3-methyl-2-[2-(4-phenoxyphenyl)ethyl]quinolin-4(1H)-one has an NADH-ubiquinone reductase inhibitory action. However, there is no disclosure of NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.
A synthesis method of 3-chloro-2-(piperidin-1-ylmethyl)quinolin-4(1H)-one has been reported in Patent Citation 16. However, there is no disclosure of NAD(P)H oxidase inhibitory activity and effectiveness for diabetes.
[Patent Citation 1] Pamphlet of International Publication No. WO2003/087399
[Patent Citation 2] Pamphlet of International Publication No. WO2004/089412
[Patent Citation 3] European Patent Application Laid-open Publication No. 374765
[Patent Citation 4] JP-A-2001-97866
[Patent Citation 5] Pamphlet of International Publication No. WO97/12864
[Patent Citation 6] European Patent Application Laid-open Publication No. 811613
[Patent Citation 7] Pamphlet of International Publication No. WO01/81340
[Patent Citation 8] JP-A-10-279561
[Patent Citation 9] Pamphlet of International Publication No. WO00/064888
[Non-Patent Citation 1] Brownlee, Nature, 2001, Vol. 414, p. 813-820
[Non-Patent Citation 2] Griendling et al., Circulation Research, 2000, Vol. 86, p. 494-501
[Non-Patent Citation 3] Blair et al., The Journal of Biological Chemistry, 1999, Vol. 274, p. 36293-36299
[Non-Patent Citation 4] Rudich et al., Diabetes, 1998, Vol. 47, p. 1562-1569
[Non-Patent Citation 5] Ihara et al., Diabetes, 1999, Vol. 48, p. 927-932
[Non-Patent Citation 6] Furukawa et al., The Journal of Clinical Investigation, 2004, Vol. 114, p. 1752-1761
[Non-Patent Citation 7] Fukui et al., Circulation Research, 1997, Vol. 80, p. 45-51
[Non-Patent Citation 8] Inoguchi et al., Current Drug Targets, 2005, Vol. 6, p. 495-501
[Non-Patent Citation 9] Browning et al., The Journal of Clinical Investigation, 2004, Vol. 114, p. 147-152
[Non-Patent Citation 10] Arbiser et al., Proceedings of the National Academy of Science, 2002, Vol. 99, p. 715-720
[Non-Patent Citation 11] Zhu et al., Brain Research, 2004, Vol. 1000, p. 32-39
[Non-Patent Citation 12] Imamura et al., Proceedings of the National Academy of Science, 2006, Vol. 103, p. 11282-11287
[Non-Patent Citation 13] Droge et al., Physiological Reviews, 2002, Vol. 82, p. 47-95
[Non-Patent Citation 14] Chung et al., Journal of Bioscience, 1989, Vol. 44, p. 609-616
[Non-Patent Citation 15] Chung et al., Journal of Korean Agricultural Chemical Society, 1990, Vol. 33, p. 264-267
[Non-Patent Citation 16] Braun et al., Berichte der Deutschen Chemischen Gesellshaft, 1930, Vol. 63(B), p. 3291-3203
DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
It is an object of the present invention to provide a novel medicament having an NAD(P)H oxidase inhibitory action, in particular a novel compound which is useful as an agent for preventing and/or treating diabetes.
Means for Solving the Problem
As a result of extensive studies on NAD(P)H oxidase inhibitors, the present inventors found that a quinolone derivative having, at the 2-position, an alkyl group substituted with a heteroatom or the like has an excellent NAD(P)H oxidase inhibitory activity, and completed this invention.
Thus, the present invention relates to a compound of the formula (I) or a salt thereof as well as a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof and an excipient:




In formula (I),
R1: lower alkyl, halogen, halogeno-lower alkyl, or cycloalkyl;
R2: —X—Y—R20, —X-a heterocyclic group which may be substituted, or




Ring A: aryl;
R3: the same or different, and lower alkyl, halogen, halogeno-lower alkyl, aryl which may be substituted, a heterocyclic group which may be substituted, —CO2R0, —OR0, or —O-halogeno-lower alkyl;
X: C1-10 alkylene which may be substituted;
Y: *—C(O)N(R7)—, —O—, *—OC(O)—, *—OC(O)N(R7)—, —S—, —S(O)—, —S(O)2—, —N(R8)—, *—N(R7)C(O)—, *—N(R7)C(O)O—, —N(R7)C(O)N(R7)—, or *—N(R7)S(O)2—;
* in Y means a binding point to X;
R7: the same or different, and R0, cycloalkyl, or lower alkylene-cycloalkyl;
R8: the same or different, and R7 or —C(O)R7;
R0: the same or different, and H or lower alkyl;
n: 0, 1, 2, or 3;
s: 0, 1, 2, or 3;
R20: C1-10 alkyl, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-N(R0)2, —W—R0, —W-halogeno-lower alkyl, —W-cycloalkyl which may be substituted, —W-aryl which may be substituted, —W-a heterocyclic group which may be substituted, —W-lower alkylene-cycloalkyl which may be substituted, —W-lower alkylene-aryl which may be substituted, or —W-lower alkylene-a heterocyclic group which may be substituted;
W: *-lower alkylene-C(O)N(R7)—, *-lower alkylene-C(O)—, *-lower alkylene-O—, *-lower alkylene-OC(O)—, *-lower alkylene-OC(O)N(R7)—, *-lower alkylene-O-lower alkylene-O—, *-lower alkylene-S—, *-lower alkylene-S(O)—, *-lower alkylene-S(O)2—, *-lower alkylene-N(R8)—, *-lower alkylene-N(R7)C(O)—, *-lower alkylene-N(R7)C(O)O—, *-lower alkylene-N(R7)C(O)N(R7)—, or *-lower alkylene-N(R7)S(O)2—;
* in W means a binding point to Y;
R4: cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-OR0, —O-lower alkylene-OR0, -J-cycloalkyl which may be substituted, -J-aryl which may be substituted, -J-a heterocyclic group which may be substituted, -J-lower alkylene-cycloalkyl which may be substituted, -J-lower alkylene-aryl which may be substituted, or -J-lower alkylene-a heterocyclic group which may be substituted;
R5: the same or different, and C1-10 alkyl, halogen, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, —CO2R0, —CN, oxo, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-CO2R0, -J-R0, -J-halogeno-lower alkyl, -J-cycloalkyl which may be substituted, -J-aryl which may be substituted, -J-a heterocyclic group which may be substituted, -J-lower alkylene-cycloalkyl which may be substituted, -J-lower alkylene-aryl which may be substituted, or -J-lower alkylene-a heterocyclic group which may be substituted;
J: the same or different, and *—C(O)N(R7)—, —C(O)—, —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, *—N(R7)C(O)—, *—N(R7)C(O)O—, —N(R7)C(O)N(R7)—, *-lower alkylene-C(O)N(R7)—, *-lower alkylene-C(O)—, *-lower alkylene-O—, *-lower alkylene-S—, *-lower alkylene-S(O)—, *-lower alkylene-S(O)2—, *-lower alkylene-N(R8)—, *-lower alkylene-N(R7)C(O)—, *-lower alkylene-N(R7)C(O)O—, *-lower alkylene-N(R7)C(O)N(R7)—, *—O-lower alkylene-C(O)—, —O-lower alkylene-O—, or *—O-lower alkylene-N(R8)—;
* in J means a binding point to ring A;
provided that the following compounds are excluded:

    3-methyl-2-(5-phenoxypentyl)quinolin-4(1H)-one,
    3-ethyl-2-(5-phenoxypentyl)quinolin-4(1H)-one,
    3-methyl-2-[2-(4-phenoxyphenyl)ethyl]quinolin-4(1H)-one,
    3-chloro-2-(piperidin-1-ylmethyl)quinolin-4(1H)-one, and
    5-({4-[(3,4-dihydro-3-methyl-4-oxoquinolin-2-yl)methoxy]phenyl}methyl)thiazolidine-2,4-dione.


In the present specification, the symbols as defined above are used as having the same meaning unless otherwise particularly specified.
In the present specification, the “disease associated with NAD(P)H oxidase” means a “disease that can be treated by the inhibition of NAD(P)H oxidase-mediated ROS production”.
Examples of an embodiment having the “disease associated with NAD(P)H oxidase” include diabetes (types 1 and 2), impaired glucose tolerance, hyperlipidemia, fatty liver, metabolic syndrome, NAFLD, NASH, arteriosclerosis, diabetic complications (retinopathy, nephropathy, neurosis, etc.), peripheral circulatory disturbance, hypertension, cancer, Alzheimer's type dementia, age-related macular degeneration, neurodegenerative diseases, cerebral stroke, ischemic diseases, arthritis, and inflammatory diseases.
Examples of another embodiment having the “disease associated with NAD(P)H oxidase” include diabetes (types 1 and 2), impaired glucose tolerance, hyperlipidemia, fatty liver, metabolic syndrome, NAFLD, NASH, arteriosclerosis, diabetic complications (retinopathy, nephropathy, neurosis, etc), and peripheral circulatory disturbance.
Examples of a further embodiment having the “disease associated with NAD(P)H oxidase” include diabetes (types 1 and 2), glucose tolerance disorder, hyperlipidemia, fatty liver, NAFLD, NASH, and diabetic complications (retinopathy, nephropathy, neurosis, etc.).
Further, the present invention relates to a pharmaceutical composition for preventing and/or treating diseases associated with NAD(P)H oxidase, comprising the compound of the formula (I) or a salt thereof as an active ingredient, that is, an agent for preventing and/or treating diseases associated with NAD(P)H oxidase, comprising the compound of the formula (I) or a salt thereof as an active ingredient.
Further, the present invention relates to use of the compound of the formula (I) or a salt thereof, for the manufacture of a pharmaceutical composition for treating and/or preventing diseases associated with NAD(P)H oxidase.
Further, the present invention relates to a method for preventing and/or treating diseases associated with NAD(P)H oxidase, comprising administering to a patient an effective amount of a compound of the formula (I) or a salt thereof.
Further, the present invention relates to an NAD(P)H oxidase inhibitor comprising the compound of the formula (I) or a salt thereof.
Further, the present invention relates to a method for producing a pharmaceutical composition for preventing or treating diseases associated with NAD(P)H oxidase, comprising mixing a compound of the formula (I) or a salt thereof, and a pharmaceutically acceptable carrier, solvent, or excipient.
Further, the present invention relates to a commercial package, comprising a pharmaceutical composition containing a compound of the formula (I) or a salt thereof; and a description that the compound of the formula (I) or a salt thereof is capable of being used or should be used for treating and/or preventing diseases associated with NAD(P)H oxidase.
Effects of the Invention
The compound of the formula (I) can be used as an agent for preventing and/or treating diseases associated with NAD(P)H oxidase, since it has an NAD(P)H oxidase inhibitory action.
Best Mode For Carrying Out the Invention
Hereinafter, the present invention will be described in detail.
In the definitions of the present specification, the “alkyl”, “alkylene”, and “alkenylene” mean a linear or branched hydrocarbon chain unless otherwise particularly specified.
The “lower alkyl” means alkyl having 1 to 6 carbon atoms (hereinafter, referred to as “C1-6”), and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl groups, and the like. In another embodiment, the lower alkyl is C1-4 alkyl. In yet another embodiment, the lower alkyl is methyl, ethyl, n-propyl, isopropyl, or tert-butyl.
The “lower alkylene” means C1-6 alkylene and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethyl ethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene groups, and the like. In another embodiment, the lower alkylene is C1-5 alkylene. In yet another embodiment, the lower alkylene is methylene, ethylene, trimethylene, tetramethylene, or pentamethylene.
The “lower alkenylene” means linear or branched C2-6 alkenylene, and examples thereof include vinylene, ethylidene, propenylene, butenylene, pentenylene, hexenylene, 1,3-butadienylene, 1,3-pentadienylene groups, and the like. In another embodiment, it is C2-4 alkenylene. In yet embodiment, it is vinylene.
The “halogen” means F, Cl, Br, or I.
The “halogeno-lower alkyl” is lower alkyl substituted with one or more halogens. In another embodiment, the halogeno-lower alkyl is lower alkyl substituted with 1 to 5 halogens. In yet another embodiment, the halogeno-lower alkyl is trifluoromethyl, 3,3,3-trifluoropropyl, or 4,4,4-trifluorobutyl.
The “cycloalkyl” is a C3-10 saturated hydrocarbon ring group which may have a bridge. Examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, adamantyl groups and the like. In another embodiment, the cycloalkyl is C3-8 cycloalkyl. In yet another embodiment, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The “aryl” is a C6-14 monocyclic to tricyclic aromatic hydrocarbon ring group which contains a ring group fused with C5-8 cycloalkene at the double bond site thereof. Examples of the aryl include phenyl, naphthyl, tetrahydronaphthalenyl, indanyl, indenyl, fluorenyl groups, and the like. In another embodiment, the aryl is phenyl, naphthyl, indanyl, or indenyl. In yet another embodiment, the aryl is phenyl.
The “heterocyclic” group means a cyclic group selected from i) a monocyclic 3- to 8-membered, and in another embodiment, 5- to 7-membered monocyclic hetero ring, containing 1 to 4 hetero atoms selected from O, S and N, and ii) a bicyclic to tricyclic hetero ring containing 1 to 5 hetero atoms selected from O, S and N, and formed by ring fusion of the monocyclic hetero ring with one or two rings which are selected from the group consisting of a monocyclic hetero ring, a benzene ring, C5-8 cycloalkane, and C5-8 cycloalkene. The ring atom, S or N, may be oxidized to form an oxide or a dioxide. Further, it may form a bridged ring or a Spiro ring.
Examples of the heterocyclic group includes aziridinyl, azetidyl, pyrrolidinyl, piperidyl, azepanyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, homomorpholinyl, thiomorpholinyl, pyrrolyl, indolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, oxazolidinyl, dihydropyridinyl, benzimidazolyl, quinolyl, quinazolyl, quinoxalinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, carbazolyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, dibenzofuranyl, dihydrobenzofuranyl, benzodioxynyl, chromenyl, isothiazolidinyl, 8-azaspiro[4,5]decanyl, 1-oxa-8-azaspiro[4,5]decanyl, dihydrobenzofuranyl, dihydrobenzodioxynyl, dioxopiperazinyl, etc.
In another embodiment, the heterocyclic group is a monocyclic to bicyclic 5- to 10-membered heterocyclic group.
In yet another embodiment, the heterocyclic group is azetidyl, pyrrolidinyl, piperidyl, azepanyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, homomorpholinyl, thiomorpholinyl, indolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiadiazolyl, oxazolidinyl, dihydropyridinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dibenzofuranyl, dihydrobenzofuranyl, benzodioxynyl, chromenyl, isothiazolidinyl, 8-azaspiro[4,5]decanyl, 1-oxa-8-azaspiro[4,5]decanyl, dihydrobenzofuranyl, or dihydrobenzodioxynyl.
The “saturated heterocyclic” group means that a ring-forming bond in the “heterocyclic” group consists only of single bonds.
Examples of the “saturated heterocyclic” group include azetidyl, pyrrolidinyl, piperidyl, azepanyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, homomorpholinyl, thiomorpholinyl, oxazolidinyl, isothiazolidinyl, 1,4-dioxa-8-azaspiro[4,5]decanyl, 8-azaspiro[4,5]decanyl, 1-oxa-8-azaspiro[4,5]decanyl, and the like.
In another embodiment, the saturated heterocyclic group is azetidyl, pyrrolidinyl, piperidyl, azepanyl, morpholinyl, homomorpholinyl, thiomorpholinyl, oxazolidinyl, or isothiazolidinyl.
In yet another embodiment, the saturated heterocyclic group is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
The “which may be substituted” in the present specification means “not substituted” or “substituted with 1 to 5 substituents”. Further, if there are multiple substituents, the substituents may be the same or different from each other.
The substituents for the “heterocyclic group which may be substituted” in the definition of R2, and the “cycloalkyl which may be substituted”, “aryl which may be substituted” and/or “heterocyclic group which may be substituted” in the definition of R20 include, for example, groups selected from Group G1, and in another embodiment, groups selected from Group G3.
Group G1: C1-10 alkyl, halogen, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, —CO2R0, —CN, oxo, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-CO2R0, -J1-R0, -J1-halogeno-lower alkyl, -J1-cycloalkyl which may be substituted, -J1-aryl which may be substituted, -J1-a heterocyclic group which may be substituted, -J1-lower alkylene-cycloalkyl which may be substituted, -J1-lower alkylene-aryl which may be substituted, and -J1-lower alkylene-a heterocyclic group which may be substituted; wherein
J1: —C(O)N(R7)—*, —C(O)—, —C(O)-lower alkylene-O—*, —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —N(R7)C(O)—*, —N(R7)C(O)O—*, —N(R7)C(O)N(R7)—, —N(R7)S(O)2—*, —N(R7)C(O)-lower alkylene-O—*, -lower alkylene-C(O)N(R0)—*, -lower alkylene-C(O)—*, -lower alkylene-O—*, -lower alkylene-OC(O)—*, -lower alkylene-S—*, -lower alkylene-S(O)—*, -lower alkylene-S(O)2—*, -lower alkylene-N(R8)—*, -lower alkylene-N(R7)C(O)—*, —O-lower alkylene-C(O)—*, —O-lower alkylene-O—, or —O-lower alkylene-N(R8)—*;
wherein * in J1 means a binding point to a remnant of the group in Group G1.
The substituents for the “cycloalkyl which may be substituted”, “aryl which may be substituted”, and/or “heterocyclic group which may be substituted” in Group G1 include, for example, groups selected from Group G2.
Group G2: C1-10 alkyl, halogen, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, —CO2R0, —CN, oxo, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-CO2R0, -J2—R0, -J2-halogeno-lower alkyl, -J2-cycloalkyl which may be substituted, -J2-aryl which may be substituted, -J2-a heterocyclic group which may be substituted, -J2-lower alkylene-cycloalkyl which may be substituted, -J2-lower alkylene-aryl which may be substituted, and -J2-lower alkylene-a heterocyclic group which may be substituted; wherein
J2: —C(O)N(R7)—*, —C(O)—, —C(O)-lower alkylene-O—*, —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —N(R7)C(O)—*, —N(R7)C(O)O—*, —N(R7)C(O)N(R7)—, —N(R7)S(O)2—*, —N(R7)C(O)-lower alkylene-O—*, -lower alkylene-C(O)N(R0)—*, -lower alkylene-C(O)—*, -lower alkylene-O—*, -lower alkylene-OC(O)—*, -lower alkylene-S—*, -lower alkylene-S(O)—*, -lower alkylene-S(O)2—*, -lower alkylene-N(R8)—*, -lower alkylene-N(R7)C(O)—*, —O-lower alkylene-C(O)—*, —O-lower alkylene-O—, or —O—lower alkylene-N(R8)—*;
wherein * in J2 means a binding point to a remnant of the group in Group G2.
The substituents for the “cycloalkyl which may be substituted”, “aryl which may be substituted”, and/or “heterocyclic group which may be substituted” in Group G2 include, for example, lower alkyl, halogen, halogeno-lower alkyl, oxo, —OR7, and —O-halogeno-lower alkyl.
Group G3: lower alkyl, halogen, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, —CO2R0, —CN, oxo, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-CO2R0, lower alkylene-OR0, —C(O)R0, —OR0, —O-lower alkylene-OR0, —N(R7)S(O)2-lower alkyl, —O-halogeno-lower alkyl, —C(O)-cycloalkyl which may be substituted, —O-lower alkylene-cycloalkyl which may be substituted, and —O-lower alkylene-a heterocyclic group which may be substituted.
The substituents for the “cycloalkyl which may be substituted” and/or “heterocyclic group which may be substituted” in Group G3 include, for example, lower alkyl, halogen, halogeno-lower alkyl, oxo, —OR7, —O-halogeno-lower alkyl, and —O-lower alkylene-OR7.
In another embodiment, the substituents for the “heterocyclic group which may be substituted” in the definition of R2, and the “cycloalkyl which may be substituted”, “aryl which may be substituted”, and/or “heterocyclic group which may be substituted” in the definition of R20 include, for example, groups selected from Groups G4 to G26.
Group G4: —NR200R201, wherein
R200: H or lower alkyl;
R201: —C(O)-lower alkyl, —C(O)-(cycloalkyl which may be substituted with lower alkyl or —OR0), —C(O)-lower alkylene-(cycloalkyl which may be substituted with lower alkyl or —OR0, —C(O)-lower alkylene-OR0, —C(O)-lower alkylene-(a saturated heterocyclic group which may be substituted with lower alkyl or —OR0), —C(O)O-lower alkyl, —C(O)N(R0)-lower alkyl, —S(O)2-lower alkyl, or —S(O)2-(cycloalkyl which may be substituted with lower alkyl or —OR0; or
R200 and R201, taken together with N to which they are attached, forms a saturated heterocyclic group which may be substituted with lower alkyl, oxo, or —OR0.
Group G5: a group in which R201 in Group G4 is —C(O)-lower alkyl, —C(O)-(cycloalkyl which may be substituted with lower alkyl or —OR0), —C(O)-lower alkylene-(cycloalkyl which may be substituted with lower alkyl or —OR0, —C(O)-lower alkylene-OR0, or —C(O)-lower alkylene-(a saturated heterocyclic group which may be substituted with lower alkyl or —OR0).
Group G6: a group in which cycloalkyl of R201 in Group G5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the saturated heterocyclic group is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
Group G7: a group in which R201 in Group G4 is —C(O)O-lower alkyl.
Group G8: a group in which R201 in Group G4 is —C(O)N(R0)-lower alkyl.
Group G9: a group in which R201 in Group G4 is —S(O)2-lower alkyl, or —S(O)2-(cycloalkyl which may be substituted with lower alkyl or —OR0.
Group G10: a group in which R200 and R201 in Group G4, taken together with N to which they are attached, form a saturated heterocyclic group which may be substituted with lower alkyl, oxo, or —OR0.
Group G11: H, lower alkyl, halogen, halogeno-lower alkyl, —OR0, —CO2R0, —C(O)R0, and —CN.
Group G12: H, lower alkyl, halogen, halogeno-lower alkyl, and —OR0.
Group G13: lower alkyl, halogen, halogeno-lower alkyl, lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —OR0, —O-lower alkylene-OR0, —O-halogeno-lower alkyl, cycloalkyl which may be substituted with —O-lower alkylene-oxo, and —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group may be substituted with lower alkyl, —OR0, —C(O)-lower alkyl, or —S(O)2-lower alkyl.
Group G14: lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —O-lower alkylene-OR0, and —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which may be substituted with lower alkyl or —OR0.
Group G15:




[In the formula,

    Z1: —C(R0)2— or —O—;
    Z2: a bond, —C(R0)2—, or —C(R0)2C(R0)2—; and
    Z3: —C(R0)2C(R0)2— or —C(O)—.]


Group G16: a group in which Z3 in Group G15 is —C(O)—.
Group G17: lower alkyl, halogen, halogeno-lower alkyl, cyclohexyl which may be substituted with —OR0, lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —OR0, —O-lower alkylene-OR0, —O-halogeno-lower alkyl, and —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group may be substituted with lower alkyl, —OR0, —C(O)-lower alkyl, or —S(O)2-lower alkyl.
Group G18: lower alkylene-a saturated heterocyclic group, and —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which may be substituted with lower alkyl or —OR0.
Group G19: lower alkyl, halogen, halogeno-lower alkyl, lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —OR0, —O-lower alkylene-OR0, —O-halogeno-lower alkyl, and —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group may be substituted with lower alkyl or —OR0.
Group G20: lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —O-lower alkylene-OR0, and —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which may be substituted with lower alkyl or —OR0.
Group G21: —C(O)-lower alkyl, —C(O)-(a saturated heterocyclic group which may be substituted with lower alkyl or —OR0, —C(O)-lower alkylene-OR0, and —C(O)-lower alkylene-(a saturated heterocyclic group which may be substituted with lower alkyl or —OR0.
Group G22: a group in which the saturated heterocyclic group in Group G21 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
Group G23: —C(O)-lower alkyl, —C(O)-(cycloalkyl which may be substituted with lower alkyl or —OR0, —C(O)-lower alkylene-(cycloalkyl which may be substituted with lower alkyl or —OR0, —C(O)-lower alkylene-OR0, —C(O)-lower alkylene-(a saturated heterocyclic group which may be substituted with lower alkyl or —OR0, —C(O)O-lower alkyl, —C(O)N(R0)-lower alkyl, —S(O)2-lower alkyl, and —S(O)2-(cycloalkyl which may be substituted with lower alkyl or —OR0.
Group G24: —C(O)-lower alkyl, —C(O)-(cycloalkyl which may be substituted with lower alkyl or —OR0, —C(O)-lower alkylene-(cycloalkyl which may be substituted with lower alkyl or —OR0, —C(O)-lower alkylene-OR0, and —C(O)-lower alkylene-(a saturated heterocyclic group which may be substituted with lower alkyl or —OR0.
Group G25: a group in which the cycloalkyl in Group G24 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the saturated heterocyclic group is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.
Group G26: —S(O)2-lower alkyl, and —S(O)2-(cycloalkyl which may be substituted with lower alkyl or —OR0.
The substituents for the “C1-10 alkylene which may be substituted” in the definition of X include, for example, halogen and —OR0.
The substituents for the “aryl which may be substituted” and “heterocyclic group which may be substituted” in the definition of R3 include, for example, lower alkyl, halogen, halogeno-lower alkyl, oxo, —OR0, and —O-halogeno-lower alkyl.
The substituents for the “cycloalkyl which may be substituted”, “aryl which may be substituted”, and/or “heterocyclic group which may be substituted” in the definition of R4 and R5 include, for example, groups selected from the Group G2.
Some embodiments of the compound of the formula (I) of the present invention will be described below.
The compound of the formula (I) wherein
R2: —X—Y—R20;
R3: the same or different, and halogen, lower alkyl, halogeno-lower alkyl, —OR0, —O-halogeno-lower alkyl, —CO2R0, aryl which may be substituted, or a heterocyclic group which may be substituted;
Y: —O—, *—OC(O)—, *—OC(O)N(R0)—, —S—, —S(O)—, —S(O)2—, —N(R0)—, —N[C(O)R0]—, *—N(R0)S(O)2—, *—N(R0)C(O)—, *—C(O)N(R0)—, *—N(R0)C(O)O—, or —N(R0)C(O)N(R0)—;
R20: C1-10 alkyl, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, —W—R0, —W-halogeno-lower alkyl, —W-cycloalkyl which may be substituted, —W-aryl which may be substituted, —W-a heterocyclic group which may be substituted, —W-lower alkylene-cycloalkyl which may be substituted, —W-lower alkylene-aryl which may be substituted, or —W-lower alkylene-a heterocyclic group which may be substituted;
W: *-lower alkylene-O—, *-lower alkylene-OC(O)N(R0)—, *-lower alkylene-S—, *-lower alkylene-S(O)—, *-lower alkylene-S(O)2—, *-lower alkylene-N(R0)—, *-lower alkylene-N[C(O)R0]—, *-lower alkylene-N(R0)S(O)2—, *-lower alkylene-C(O)N(R0)—, *-lower alkylene-N(R0)C(O)—, *-lower alkylene-N(R0)C(O)O—, *-lower alkylene-N(R0)C(O)N(R0)—, or *-lower alkylene-O-lower alkylene-O—;
R5: the same or different, and halogen, —CN, C1-10 alkyl, halogeno-lower alkyl, —CO2R0, lower alkylene-CO2R0, —N(R0)C(O)N(R0)2, oxo, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, -J-R0, -J-halogeno-lower alkyl, -J-cycloalkyl which may be substituted, -J-aryl which may be substituted, -J-a heterocyclic group which may be substituted, -J-lower alkylene-cycloalkyl which may be substituted, -J-lower alkylene-aryl which may be substituted, or -J-lower alkylene-a heterocyclic group which may be substituted; and
J: the same or different, and —O—, *-lower alkylene-O—, —O-lower alkylene-O—, *—O-lower alkylene-N(R0)—, *—O-lower alkylene-N[C(O)R0]—, *—O-lower alkylene-C(O)—, —C(O)—, *-lower alkylene-C(O)—, —N(R0)—, —N[C(O)R0]—, *-lower alkylene-N(R0)—, *-lower alkylene-N[C(O)R0]—, *—N(R0)C(O)—, *-lower alkylene-N(R0)C(O)—, *—C(O)N(R0)—, *-lower alkylene-C(O)N(R0)—, —S—, —S(O)—, —S(O)2—, *-lower alkylene-S—, *-lower alkylene-S(O)—, or *-lower alkylene-S(O)2—.
Other embodiments of the compound of formula (I) of the present invention will be described below.
(1) The compound wherein R1 is lower alkyl or halogen. In another embodiment, the compound wherein R1 is lower alkyl. In yet another embodiment, the compound wherein R1 is methyl.
(2) The compound wherein R2 is —X—Y—R20, or —X-a heterocyclic group which may be substituted. In another embodiment, the compound wherein R2 is —X-piperidyl which may be substituted, or —X—Y—R20. In yet another embodiment, the compound wherein R2 is —X-piperidyl which may be substituted. In yet another embodiment, the compound wherein R2 is —X—Y—R20.
(3) The compound wherein Ring A in R2 is phenyl.
(4) The compound wherein X is lower alkylene. In another embodiment, the compound wherein X is C1-4 alkylene. In yet another embodiment, the compound wherein X is —CH2—.
(5) The compound wherein Y is *—C(O)N(R7)—, —O—, *—OC(O)—, *—OC(O)N(R7)—, —S—, —S(O)—, —S(O)2—, —N(R8)—, *—N(R7)C(O)—, or *—N(R7)C(O)O—. In another embodiment, the compound wherein Y is —O—, —S—, —S(O)—, or —S(O)2—. In another embodiment, the compound wherein Y is —O—. In yet another embodiment, the compound wherein Y is —S—, —S(O)—, or —S(O)2—. Here, * means a binding point to X.
(6) The compound wherein R3, which are the same or different from each other, are lower alkyl, halogen, halogeno-lower alkyl, phenyl, pyridyl, pyrimidinyl, piperidyl which may be substituted with oxo, —CO2R0, —OR0, or —O-halogeno-lower alkyl. In another embodiment, the compound wherein R3 are the same or different from each other, and are halogen. In yet another embodiment, the compound wherein R3 are F.
(7) The compound wherein R3 is a substituent at the 6-position.
(8) The compound wherein n is 0 or 1. In another embodiment, the compound wherein n is 0. In yet another embodiment, the compound wherein n is 1.
(9) The compound wherein when R2 is —X-a heterocyclic group which may be substituted, the “heterocyclic group which may be substituted” is 1-substituted piperidin-4-yl.
(10) The compound wherein R20 is cycloalkyl which may be substituted, aryl which may be substituted, or a heterocyclic group which may be substituted. In another embodiment, the compound wherein R20 is cyclohexyl which may be substituted, phenyl which may be substituted, pyridyl which may be substituted, tetrahydroquinolinyl which may be substituted, or tetrahydroisoquinolinyl which may be substituted. In another embodiment, the compound wherein R20 is phenyl which may be substituted, or pyridyl which may be substituted. In another embodiment, the compound wherein R20 is cyclohexyl which may be substituted. In another embodiment, the compound wherein R20 is phenyl which may be substituted. In another embodiment, the compound wherein R20 is pyridyl which may be substituted. In another embodiment, the compound wherein R20 is pyrimidinyl which may be substituted. In yet another embodiment, the compound wherein R20 is tetrahydroquinolinyl which may be substituted, or tetrahydroisoquinolinyl which may be substituted.
(11) The compound wherein when R20 is cycloalkyl which may be substituted, the “cycloalkyl which may be substituted” is 3- or 4-substituted cyclohexyl. In another embodiment, the compound wherein the “cycloalkyl which may be substituted” is 3-substituted cyclohexyl. In another embodiment, the compound wherein the “cycloalkyl which may be substituted” is 4-substituted cyclohexyl.
(12) The compound wherein when R20 is aryl which may be substituted, the “aryl which may be substituted” is 3- and 5-substituted phenyl. In another embodiment, the compound wherein the “aryl which may be substituted” is 3-substituted phenyl. In yet another embodiment, the compound wherein the “aryl which may be substituted” is 4-substituted phenyl.
(13) The compound wherein when R20 is a heterocyclic group which may be substituted, the “heterocyclic group which may be substituted” is pyridin-2-yl which may be substituted. In another embodiment, the compound wherein the “heterocyclic group which may be substituted” is pyridin-3-yl which may be substituted. In yet another embodiment, the compound wherein the “heterocyclic group which may be substituted” is pyridin-4-yl which may be substituted.
(14) The compound wherein when R20 is a heterocyclic group which may be substituted, the “heterocyclic group which may be substituted” is 4-substituted pyridin-2-yl. In another embodiment, the compound wherein the “heterocyclic group which may be substituted” is 2-substituted pyridin-4-yl.
(15) The compound wherein when R20 is a heterocyclic group which may be substituted, the “heterocyclic group which may be substituted” is tetrahydroquinolinyl substituted on a nitrogen atom in the ring, or tetrahydroisoquinolinyl substituted on a nitrogen atom in the ring.
(16) The compound wherein when R20 is a cycloalkyl which may be substituted, a substituent in the “cycloalkyl which may be substituted” is a group selected from Group G1. In another embodiment, the compound wherein a substituent in the “cycloalkyl which may be substituted” is a group selected from Groups G4 to G10.
(17) The compound wherein when R20 is aryl which may be substituted, a substituent in the “aryl which may be substituted” is a group selected from Group G1. In another embodiment, the compound wherein a substituent in the “aryl which may be substituted” is a group selected from Groups G11 to G18. In another embodiment, the compound wherein a substituent in the “aryl which may be substituted” is a group selected from pyrrolidinyl, piperidyl, azepanyl, morpholinyl, homomorpholinyl, and oxazolidinyl, each of which may be substituted with lower alkyl or oxo.
(18) The compound wherein when R20 is a heterocyclic group which may be substituted, a substituent in the “heterocyclic group which may be substituted” is a group selected from Group G1. In another embodiment, the compound wherein a substituent in the “heterocyclic group which may be substituted” is a group selected from Groups G19 to G22.
(19) The compound wherein when R2 is —X-a heterocyclic group which may be substituted, a substituent in the “heterocyclic group which may be substituted” is a group selected from Group G1. In another embodiment, the compound wherein a substituent in the “heterocyclic group which may be substituted” is a group selected from Groups G23 to G26, —C(O)O-lower alkyl, and —C(O)N(R0)-lower alkyl.
(20) The compound which is a combination of any two or more of groups described in the above (1) to (19).
Other embodiments of the compound of formula (I) of the present invention will be described below.
(21) The compound of the formula (I) wherein
R1 is lower alkyl or halogen;
R2 is -lower alkylene-(a heterocyclic group which may be substituted with group(s) selected from Group G1), or -lower alkylene-O—R20;
R3 is halogen;
n is 0 or 1; and
R20 is cycloalkyl which may be substituted with group(s) selected from Group G1, aryl which may be substituted with group(s) selected from Group G1, or a heterocyclic group which may be substituted with group(s) selected from Group G1.
(22) The compound described in (21), wherein
R1 is lower alkyl;
R2 is -lower alkylene-(piperidyl which may be substituted with group(s) selected from Group G1), or -lower alkylene-O—R20; and
R20 is cyclohexyl which may be substituted with group(s) selected from Group G1, phenyl which may be substituted with group(s) selected from Group G1, pyridyl which may be substituted with group(s) selected from Group G1, tetrahydroquinolinyl which may be substituted with group(s) selected from Group G1, or tetrahydroisoquinolinyl which may be substituted with group(s) selected from Group G1.
(23) The compound described in (22), wherein R2 is -lower alkylene-O-(phenyl which may be substituted with group(s) selected from Group G1), or -lower alkylene-O-(pyridyl which may be substituted with group(s) selected from Group G1).
(24) The compound described in (23), wherein R2 is -lower alkylene-O-(phenyl which may be substituted with group(s) selected from Group G1).
(25) The compound described in (24), wherein R2 is




[In the formula, X20 is lower alkylene, R22 is a group selected from Group G1, and R23 is a group selected from Group G11. The same shall apply hereinafter.]
(26) The compound described in (25), wherein R23 is a group selected from Group G12.
(27) The compound described in (26), wherein R22 is a group selected from Group G13.
(28) The compound described in (27), wherein R22 is a group selected from Group G14.
(29) The compound described in (26), wherein R22 is a group selected from Group G15.
(30) The compound described in (29), wherein R22 is a group selected from Group G16.
(31) The compound described in (24), wherein R2 is




[In the formula, R24 is a group selected from Group G1.]
(32) The compound described in (31), wherein R24 is a group selected from Group G17.
(33) The compound described in (32), wherein R24 is a group selected from Group G18.
(34) The compound described in (23), wherein R2 is -lower alkylene-O-(pyridyl which may be substituted with group(s) selected from Group G1).
(35) The compound described in (34), wherein R2 is




[In the formula, R25 is a group selected from Group G1. The same shall apply hereinafter.]
(36) The compound described in (35), wherein R25 is a group selected from Group G19.
(37) The compound described in (36), wherein R25 is a group selected from Group G20.
(38) The compound described in (22), wherein R2 is




[In the formula, R26 is a group selected from Group G4].
(39) The compound described in (38), wherein R26 is a group selected from Group G5.
(40) The compound described in (39), wherein R26 is a group selected from Group G6.
(41) The compound described in (38), wherein R26 is a group selected from Group G7.
(42) The compound described in (38), wherein R26 is a group selected from Group G8.
(43) The compound described in (38), wherein R26 is a group selected from Group G9.
(44) The compound described in (38), wherein R26 is a group selected from Group G10.
(45) The compound described in (22), wherein R2 is




[In the formula, R27 is a group selected from Group G21. The same shall apply hereinafter.]
(46) The compound described in (45), wherein R27 is a group selected from Group G22.
(47) The compound described in (21), wherein R2 is




[In the formula, R28 is a group selected from Group G23. The same shall apply hereinafter.]
(48) The compound described in (47), wherein R28 is a group selected from Group G24.
(49) The compound described in (48), wherein R28 is a group selected from Group G25.
(50) The compound described in (47), wherein R28 is —C(O)O-lower alkyl.
(51) The compound described in (47), wherein R28 is —C(O)N(R0)-lower alkyl.
(52) The compound described in (47), wherein R28 is a group selected from Group G26.
Examples of the specific compounds encompassed by the present invention include the following compounds.

    3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-4(1H)-one,
    N-{trans-4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]cyclohexyl}ethanesulfonamide,
    3-methyl-2-[({4-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-2-yl}oxy)methyl]quinolin-4(1H)-one,
    3-methyl-2-{[3-(3-oxomorpholin-4-yl)phenoxy]methyl}quinolin-4(1H)-one,
    4-{4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]butoxy}benzonitrile,
    2-({4-[4-(2-methoxyethyl)phenoxy]butoxy}methyl)-3-methyl quinolin-4(1H)-one,
    2-({3-[(1-acetylpiperidin-4-yl)methoxy]phenoxy}methyl)-3-methylquinolin-4(1H)-one,
    3-methyl-2-{[3-(2-pyridin-4-ylethoxy)phenoxy]methyl}quinolin-4(1H)-one,
    2-{[3-(3-hydroxy-3-methylbutoxy)phenoxy]methyl}-3-methylquinolin-4(1H)-one,
    6-fluoro-3-methyl-2-({[4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-2-yl]oxy}methyl)quinolin-4(1H)-one,
    2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one,
    6-fluoro-3-methyl-2-({[1-(tetrahydro-2H-pyran-4-ylacetyl)-1,2,3,4-tetrahydroquinolin-7-yl]oxy}methyl)quinolin-4(1H)-one,
    3-methyl-2-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}quinolin-4(1H)-one,
    2-({[4-(3-methoxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one,
    2-[({4-[(4-hydroxy-4-methylpentyl)oxy]pyridin-2-yl}oxy)methyl]-3-methylquinolin-4(1H)-one,
    2-{[3-(4-hydroxypiperidin-1-yl)phenoxy]methyl}-3-methylquinolin-4(1H)-one,
    2-{[3-(4-hydroxy-4-methylpiperidin-1-yl)phenoxy]methyl}-3-methylquinolin-4(1H)-one,
    N-cyclohexyl-N-{2-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]ethyl}tetrahydro-2H-pyrane-4-carboxamide,
    ethyl 4-[2-(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)ethyl]piperidine-1-carboxylate,
    2-{2-[1-(ethylsulfonyl)piperidin-4-yl]ethyl}-3-methylquinolin-4(1H)-one, and
    (3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl(3-phenylpropyl)carbamate.


The compound of formula (I) may in some cases exist in the form of tautomers, geometrical isomers and stereoisomers, depending on the kind of substituents. In the present specification, the compound formula (I) may be described only in one form of isomers, but the present invention includes these isomers as well as isolated forms or mixtures thereof.
Further, the compound of formula (I) may have asymmetric carbon atoms or axial asymmetries in some cases, and correspondingly, it may exist in the form of optical isomers. Isolates or mixtures of optical isomers of the compound of formula (I) are also included in the present invention.
Further, a pharmaceutically acceptable prodrug of the compound of formula (I) is also included in the present invention. As used herein, the “pharmaceutically acceptable prodrug” is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group or the like by solvolysis or under a physiological condition. Examples of the group for forming a prodrug include those as described, for example, in Prog. Med., 5, 2157-2161 (1985) or “Iyakuhin no Kaihatsu (Development of Pharmaceuticals)” (Hirokawa Shoten Ltd., 1990), Vol. 7, “Bunshi Sekkei (Molecular Design)”, pp. 163-198.
In addition, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I). The compound of formula (I) may form an acid addition salt or a salt with a base, depending on the kind of substituents. Specifically, examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, or with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine, ammonium salts, and the like.
Further, the present invention also includes various hydrates or solvates, and crystalline polymorphs of the compound of formula (I) and a salt thereof. Further, compounds labeled with various radioactive or non-radioactive isotopes are also included in the present invention.
(Production Method)
The compound of formula (I) and a salt thereof can be produced by utilizing the characteristics based on the types of its basic skeleton or substituents and by applying various known synthetic methods. It is sometimes effective, in terms of production techniques, that the functional group is replaced by an appropriate protecting group (a group that can be readily converted into the functional group) in the stage of a starting material to intermediate depending on the type of the functional group during the production. Examples of such functional groups include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of such protecting groups include protecting groups described for example in “Protective Groups in Organic Synthesis”, 3rd ed., 1999, edited by Greene and Wuts, or the like. These protecting groups may be appropriately selected and used depending on the reaction conditions. According to such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group, if desired.
In addition, the prodrug of the compound of formula (I) can be produced in the same manner as the case of the protecting groups, by carrying out the reaction after introducing a specific group at the stage of starting materials to intermediates or using the obtained compound of formula (I). The reaction can be carried out by applying methods known to those skilled in the art, such as the usual esterification, amidation, dehydration and the like.
Hereinafter, the representative production processes for the compound of formula (I) will be described. Each of the production processes may also be carried out with reference to References appended to the corresponding description. Further, the production processes of the present invention are not limited to the examples as shown below.
(Production Process 1)




(In the formula, R2a represents R2 or —Xa—Y—R20; and Xa represent C2-10 alkenylene which may be substituted. The same shall apply hereinafter.)
This production process is a method in which the compound of the formula (I) is obtained by debenzylation of compound (1) through hydrogenation thereof.
The hydrogenation reaction can be carried out using a catalyst such as palladium-carbon or platinum oxide, from under normal pressure to under a pressurized hydrogen atmosphere, from under room temperature to under heating. This reaction may also be carried out using cyclohexene or the like as a hydrogen source in place of hydrogen gas. Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tetrahydrofuran (THF), and dioxane; N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetic acid, and water. These materials may be used alone or in any combination thereof.
Further, when R2a is —Xa—Y—R20, reduction of a double bond can also be carried out concurrently with debenzylation under these reaction conditions. Further, when an oxygen or nitrogen atom contained in R2a is protected by a benzyl or benzyloxycarbonyl group, deprotection can also be simultaneously carried out under these reaction conditions.
(Production Process 2)




This production process is a method in which the compound of the formula (I) is obtained by debenzylation of the compound (2) using trifluoroacetic acid (TFA).
The debenzylation reaction can be carried out in the presence of TFA, from under room temperature to under heating. An addition of thioanisole, anisole or the like may be advantageous in some cases for the progress of the reaction, depending on types of compounds. Examples of the solvent used in this reaction include aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, and TFA.
(Production Process 3)




(In the formula, one of J3 and J4 represents —NHR7, and the other represents —C(O)-L1; L1 represents a leaving group or hydroxyl group, and Y1 represents —N(R7)C(O)— or —C(O)N(R7)—. The same shall apply hereinafter.)
This production process is a method in which the compound of the formula (I-a) is obtained by amidation of the compound (3). The leaving group of L1 may be an organosulfonic acid group such as methanesulfonyloxy or p-toluenesulfonyloxy, halogen, or the like. Alternatively, a variety of acid anhydrides may be used as the leaving group.
When L1 is a hydroxyl group, the reaction can be carried out in the presence of a condensing agent such as N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC), 1,1′-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), phosphorus oxychloride/pyridine, or triphenylphosphine/N-bromosuccinimide and, if necessary, also in the presence of an additive (for example, N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), etc.).
When L1 is a leaving group, it may be preferable in some cases to carry out the reaction in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate, or an organic base such as triethylamine, diisopropylethylamine or pyridine.
Examples of the solvent used in this reaction include solvents such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, acetonitrile, ethyl acetate, and pyridine. These materials may be used alone or in any combination thereof. Further, the compounds (3) and (4) are appropriately used in equimolar amounts or in excess amounts, depending on reactions or compounds.
(Production Process 4)




(In the formula, one of J5 and J6 represents —NHR7, and the other represents —OC(O)-L2, or J5 represents —OH, J6 represents —N═C═O; L2 represents a leaving group, and Y2 represents —N(R7)C(O)O— or —OC(O)N(R7)—. The same shall apply hereinafter.)
This production process is a method in which the compound of the formula (I-b) is obtained by carbamation of the compound (5). The leaving group of L2 may be an organosulfonic acid group such as methanesulfonyloxy or p-toluenesulfonyloxy, halogen, or the like. Alternatively, a variety of acid anhydrides may be used as the leaving group.
The carbamation reaction can be carried out using the compound (5) and the compound (6) in equimolar amounts or one of them in an excess amount, from under cooling to under heating. Examples of the solvent used in this reaction include solvents such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, acetonitrile, ethyl acetate, and pyridine. These materials may be used alone or in any combination thereof. Depending on the compounds, it may be preferable in some cases to carry out the reaction in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate, or an organic base such as triethylamine, diisopropylethylamine or pyridine.
(Production Process 5)




This production process is a method in which the compound of the formula (I-c) is obtained by ureation of the compound (7).
The ureation reaction can be carried out using the compounds (7) and (8) in equimolar amounts or one of them in an excess amount, from under cooling to under heating. Examples of the solvent used in this reaction include solvents such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, acetonitrile, and ethyl acetate. These materials may be used alone or in any combination thereof.
(Production Process 6)




(In the formula, L3 represents a leaving group. The same shall apply hereinafter.)
This production process is a method in which the compound of the formula (I-d) is obtained by sulfonamidation of the compound (7). The leaving group of L3 may be a halogen or the like.
The sulfonamidation reaction can be carried out using the compounds (7) and (9) in equimolar amounts or one of them in an excess amount, from under cooling to under heating. Examples of the solvent used in this reaction include solvents such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, acetonitrile, ethyl acetate. These materials may be used alone or in any combination thereof. Depending on the compounds, it may be preferable in some cases to carry out the reaction in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate, or an organic base such as triethylamine, diisopropylethylamine or pyridine.
(Production Process 7)




(In the formula, p represents 1 or 2. The same shall apply hereinafter.)
This production process is a method in which the compound of the formula (I-f) is obtained by oxidation of the compound (I-e).
The oxidation reaction can be carried out using the compound (I-e) and an oxidizing agent (such as m-chloroperbenzoic acid, peracetic acid, or hydrogen peroxide solution) in equimolar amounts or one of them in an excess amount, from under cooling to under heating. Examples of the solvent used in this reaction include solvents such as aromatic hydrocarbons, and halogenated hydrocarbons. These materials may be used alone or in any combination thereof.
Further, various substituents on groups R1, R2 and R3 in formula (I) can be easily converted into other functional groups by using the compound of formula (I) as a starting material and applying reactions described in the following Examples, reactions apparent to those skilled in the art, or modifications thereof. For example, such conversion reactions can be carried out by any combination of processes that can be conventionally employed by those skilled in the art, for example O-alkylation, N-alkylation, acylation, oxidation, reduction, hydrolysis, amidation, and the like.
(Production of Starting Compounds)
The starting compounds in the above-mentioned production processes can be produced, for example, by the following methods, methods described in the following Production Examples, known methods, or modifications thereof.
(Starting Material Synthesis 1)




(In the formula, R2b represents lower alkyl or —CO2R, R represents lower alkyl, and Bn represents a benzyl group. The same shall apply hereinafter.)
The compound (12) can be obtained by dehydration, condensation and cyclization of the compound (10) and the compound (11). This reaction is carried out using the compound (10) and the compound (11) in the presence of an acid such as acetic acid, hydrochloric acid, or sulfuric acid, usually stirring under heating in a solvent such as aromatic hydrocarbon.
The compound (13) can be obtained by benzylation of the compound (12). The benzylation is carried out using the compound (12) and a benzylating agent such as benzyl bromide in the presence of a base, in a solvent such as ethers, aromatic hydrocarbons, halogenated hydrocarbons, or DMF, usually stirring from under cooling to under heating. Examples of the base include an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate, or an organic base such as triethylamine, N,N-diisopropylethylamine or pyridine.
(Starting Material Synthesis 2)




(In the formula, Me represents a methyl group, and L4 represents a leaving group. The same shall apply hereinafter.)
The compound (14) can be obtained by oxidation of the compound (13-a). The oxidation is carried out using an oxidizing agent such as m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide solution, in a solvent such as aromatic hydrocarbons, or halogenated hydrocarbons, usually stirring from under cooling to under heating.
The compound (15) can be obtained by rearrangement reaction of the compound (14). The rearrangement reaction is carried out using the compound (14) and an excess of acetic anhydride, without a solvent or in a solvent such as aromatic hydrocarbons, halogenated hydrocarbons, or ethers, stirring from under room temperature to under heating.
The compound (16) can be obtained by hydrolysis of the compound (15). The hydrolysis is carried out in the presence of an alkali such as sodium hydroxide or potassium hydroxide, in a solvent such as alcohols, ethers or water, usually stirring from under room temperature to under heating.
The compound (17) can be obtained by functional group transformation reaction of the compound (16). The leaving group of L4 may be an organosulfonic acid group such as methanesulfonyloxy or p-toluenesulfonyloxy, halogen, or the like. The functional group transformation reaction is carried out using a sulfonylating agent such as methane sulfonyl chloride or p-toluene sulfonyl chloride, or a halogenating agent such as thionyl chloride, in a solvent such as aromatic hydrocarbons, halogenated hydrocarbons, or ethers, usually stirring from under cooling to under room temperature. It may be advantageous in some cases for smooth progress of the reaction to carry out the reaction in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate, or an organic base such as triethylamine, N,N-diisopropylethylamine or pyridine.
(Starting Material Synthesis 3)




The compound (18) can be obtained by reduction of the compound (13-b) into an aldehyde. The reduction is carried out using a reducing agent such as diisobutylaluminum hydride, in a solvent such as aromatic hydrocarbons or ethers, usually stirring from under cooling.
The compound (16) can be obtained by reduction of the compound (18). The reduction is carried out using a reducing agent such as sodium borohydride, in a solvent such as alcohols, usually stirring from under cooling to under room temperature.
The compound (16) can also be obtained by carrying out the reduction reaction of the compound (13-b) under reaction conditions such as room temperature.
(Starting Material Synthesis 4)




(In the formula, Y2 represents —O—, —S—, or —N(R7)—. The same shall apply hereinafter.)
The compound (1-a) can be obtained by reaction of the compound (17) with the compound (19). This reaction is carried out using the compound (17) and the compound (19) in equivalent amounts or one of them in an excess amount, in the presence of a base, from under cooling to under heating at reflux, preferably at 0° C. to 80° C. usually stirring for 0.1 hour to 5 days, in a reaction-inert solvent. There is no particular limit to the solvent that can be used herein. Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, and a mixture thereof. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene and n-butyllithium, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, or potassium tert-butoxide. It may be advantageous in some cases to carry out the reaction in the presence of a phase-transfer catalyst such as tetra-n-butylammonium chloride.
(Starting Material Synthesis 5)




The compound (1-b) can be obtained by reaction of the compound (16) with the compound (20). The leaving group of L5 may be an organosulfonic acid group such as methanesulfonyloxy or p-toluenesulfonyloxy, halogen, or the like. The reaction conditions are the same as in “Starting material synthesis 4”.
(Starting Material Synthesis 6)




(In the formula, Rx represents a remnant of a Wittig reagent, A− represents a counter anion, and Xb represents C1-8 alkylene. The same shall apply hereinafter.)
The compound (1-c) can be obtained by Wittig reaction of the compound (18) with the compound (21). This reaction is carried out using the compound (18) and compound (21) in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride, n-butyllithium, or lithium hexamethyldisilazide, in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMA, NMP, dimethylsulfoxide (DMSO), or acetonitrile, usually stirring from under cooling to under heating.
(Starting Material Synthesis 7)




(In the formula, L6 represents halogen, R2c represents —Xc-aryl which may be substituted, —Xc-a heterocyclic group which may be substituted, or —Xd—Y—R20; and Xc represents a bond or Xd and Xd represent C1-8 alkylene which may be substituted. The same shall apply hereinafter.)
The compound (23) can be obtained by Arbuzov reaction of the compound (17-a) with the compound (22). This reaction is carried out using the compound (17-a) and an excess of the compound (22), stirring under heating, without a solvent or in a solvent such as aromatic hydrocarbons or ethers.
The compound (1-d) can be obtained by Horner-Emmons reaction of the compound (23) with the compound (24). This reaction is carried out using the compound (23) and compound (24) in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride, n-butyllithium, or lithium hexamethyldisilazide, in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMA, NMP, DMSO, or acetonitrile, usually stirring from under cooling to under heating.
(Starting Material Synthesis 8)




The compound (1-e) can be obtained by reductive amination of the compound (18) and the compound (24). This reaction is carried out using the compound (18) and the compound (24) in equivalent amounts or one of them in an excess amount, from under room temperature to under heating, stirring from under cooling, in a solvent such as halogenated hydrocarbons, aromatic hydrocarbons, or esters (such as ethyl acetate), ethers, alcohols, acetic acid, in the presence of a reducing agent such as sodium borohydride, sodium triacetoxy borohydride.
The compound of the formula (I) is isolated and purified as its free compound, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorph thereof. The pharmaceutically acceptable salt of the compound of the formula (I) can also be prepared in accordance with a conventional method for a salt formation reaction.
Isolation and purification are carried out by employing common chemical operations such as extraction, fractional crystallization, and various types of fraction chromatography.
Various isomers can be prepared by selecting an appropriate starting compound, or can be separated by making use of the difference in the physicochemical properties between isomers. For example, the optical isomer can be derived into an optically pure isomer by means of general optical resolution methods of racemic forms (for example, fractional crystallization for inducing diastereomers with optically active bases or acids, chromatography using a chiral column, etc., and the like). In addition, the isomers can also be prepared from an appropriate optically active starting compound.
(Pharmacological Test)
The pharmacological activity of the compound of the formula (I) was confirmed by the following tests.
Test 1: Inhibitory Activity on ROS Production Derived from NADPH Oxidase
This activity was measured by using Human Umbilical Vein Endothelial Cells (HUVECs). The test method is as follows.
3×104 cells/well (100 μL) of HUVECs were seeded into a 96-well plate coated with collagen. The culture medium was MCDB131 medium containing 10% fetal bovine serum, 2 mM glutamine, 100 U/mL penicillin, 100 U/mL streptomycin, and 10 ng/mL recombinant human basic-FGF. On the next day, the culture medium was removed by an aspirator, and 100 μL/well of phosphate buffered saline containing 25 mM glucose, 200 μM NADPH, 0.2% nitrotetrazolium blue, and test compounds followed by culturing at 37° C. Nitrotetrazolium blue reacts with intracellularly produced ROS and turns into a water-insoluble blue pigment. After 2 hours, the supernatant was discarded, and the wells were washed three times with phosphate buffered physiological saline. Then, 100 μL/well of 90% DMSO water containing 0.04M sodium hydroxide was added to each well to completely dissolve the pigment, and an absorbance at a wavelength of 715 nm was measured. By taking an absorbance with no addition of a test compound as A, an absorbance with no addition of a test compound as B, and an absorbance with addition of glucose, NADPH and a test compound as C, ROS production inhibitory rate was calculated according to the following equation.

Inhibition rate (%)=(A−B)/(A−C)×100

Table 1 shows the results obtained upon addition of 1.0 μM test compound. Abbreviation “Ex” in the table represents Example Compound No. which will follow, and abbreviation “Inh” represents an ROS production inhibition rate. It was confirmed that the compounds of the formula (I) of the present invention have an excellent ROS production inhibitory activity.









TABLE 1






Ex
Inh(%)(1.0 μM)


















2
91.9 ± 5.2



4
84.7 ± 2.1



6
79.9 ± 1.2



8
91.5 ± 4.7



9
88.7 ± 1.5



19
99.1 ± 0.0



49
90.8 ± 5.2



50
80.5 ± 2.5



55
57.3 ± 2.3



98
101.5 ± 1.9 



127
85.3 ± 2.9



128
77.7 ± 3.9



166
84.3 ± 2.4



180
69.5 ± 1.3



198
97.5 ± 6.1



199
93.1 ± 1.1



228
66.3 ± 2.1



276
118.2 ± 4.0 



279
98.9 ± 1.0



283
61.6 ± 1.7



284
64.2 ± 0.1



285
67.3 ± 0.1



291
118.8 ± 0.4 









Test 2: Oral Glucose Tolerance Test Using Mice
This test is intended to evaluate an inhibitory action of a test compound on elevation of the blood glucose level after glucose loading, using mice. A test method is described hereinafter.
Male ICR or C57BL/6 J mice (6 weeks old, available from CLEA JAPAN, Inc.) pre-bred for one week were fasted overnight and used as test animals. A test compound was suspended in 10% PEG-60 Hydrogenated Castor Oil (HCO-60) aqueous solution, and was orally administered (3 mg/kg) to animals 5 minutes prior to oral glucose loading (2 g/kg). The control group was given a 10% HCO-60 aqueous solution. According to the following equation, a blood glucose-lowering rate (%) at 30 minutes after glucose loading was calculated for the test compound-treated group relative to the control group. An increase in the blood glucose level of the test compound-treated group and an increase in the blood glucose level of the control group were taken as A and B, respectively.

Blood glucose-lowering rate (%)=100−[(A/B)×100]

As a result, it was confirmed that the compound of the formula (I) of this invention has an excellent blood glucose-lowering action. Compounds of Examples 2, 4, 8, 141, 153, 186, 188, and 284 exhibited a blood glucose-lowering rate of 70 to 105%. For example, the compounds of Examples 2, 8, 188, and 248 exhibited a blood glucose-lowering rate of 93%, 70%, 105%, and 89%, respectively.
As a result of the above respective tests, it was confirmed that the compound of the formula (I) has an ROS production inhibitory activity based on the NAD(P)H oxidase inhibitory action, and possess an excellent blood glucose-lowering action. Therefore, the compound of the formula (I) can be used as an agent for preventing and/or treating diseases associated with NAD(P)H oxidase.
A preparation containing one or two or more kinds of the compound of formula (I) or a salt thereof as an active ingredient can be prepared in accordance with a generally used method, using a pharmaceutical carrier, excipient, or the like, that is usually used in the art.
The administration can be carried out by oral administration via tablets, pills, capsules, granules, powders, liquid preparations, or the like, or parenteral administration via injections such as intraarticular injection, intravenous injection, intramuscular injection, or the like, as well as suppositories, eye drops, eye ointments, percutaneous liquid preparations, ointments, percutaneous patches, transmucosal liquid preparations, transmucosal patches, inhalations, and the like.
As solid compositions for oral administration according to the present invention, tablets, powders, granules, or the like are used. In such a solid composition, one or two or more kinds of active ingredients are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and/or magnesium aluminometasilicate. According to a conventional method, the composition may contain inert additives such as a lubricant such as magnesium stearate, a disintegrator such as sodium carboxymethyl starch, a stabilizing agent, and a solubilizing aid. As occasion demands, the tablets or the pills may be coated with a film of a sugar coating, or a gastric or enteric coating agent.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and contain a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, the liquid composition may contain an adjuvant such as a solubilizing agent, a moistening agent, and a suspending agent, a sweetener, a flavor, an aromatic, and a preservative.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The aqueous solvent includes, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (Japanese Pharmacopeia), and the like. Such a composition may further contain a tonicity agent, a preservative, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. These are sterilized, for example, by filtration through a bacteria-retaining filter, blend of a sterilizing agent, or irradiation. In addition, these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to use.
External preparations include ointments, plasters, creams, jellies, adhesive skin patches, sprays, lotions, eye drops, eye ointments, and the like. The external preparation contains generally used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, and the like. Examples of the ointment or lotion bases include polyethylene glycol, propylene glycol, white Vaseline, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like.
Transmucosal preparations such as inhalations and transnasal preparations are used in a solid, liquid or semi-solid form and may be prepared in accordance with a conventionally known method. For example, a known excipient, and also a pH-adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or blowing may be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, it may be in a form such as a pressurized aerosol spray or the like which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.
In oral administration, the daily dose is generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg, per body weight, administered in one portion or in 2 to 4 divided portions. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.
The compounds of formula (I) can be used in combination with various agents for treating or preventing for the diseases for which the aforementioned compounds of formula (I) are considered to be effective. The combined preparation may be administered simultaneously, or separately and continuously, or at a desired time interval. The preparations to be co-administered may be a blend, or may be prepared individually.


EXAMPLES
Hereinafter, production processes of compounds of the formula (I) will be described in more detail with reference to Examples. The present invention compounds are not limited to compounds described in the following Examples. In addition, production processes of starting compounds are shown in Production Examples.
Production Example 1
To a solution of 4-bromoaniline (25 g) and diethyl 2-methyl-3-oxo succinate (30 mL) in benzene (300 mL) was added dropwise acetic acid (3.3 mL) at room temperature, followed by refluxing using a Dean-Stark reflux apparatus for 12 hours. After the reaction mixture was concentrated under reduced pressure, the residue was gradually added dropwise to 100 mL of diphenyl ether which had been previously heated to 270° C., followed by stirring at the same temperature for 1 hour. The reaction mixture was allowed to cool to room temperature, and hexane was added thereto. The precipitated solid was collected by filtration to obtain ethyl 6-bromo-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (19 g).
Production Example 2
To a solution of ethyl 3-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.1 g) in DMF (30 mL) were added benzyl bromide (0.57 mL) and potassium carbonate (720 mg) at room temperature, followed by stirring for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=85/15) to obtain ethyl 4-(benzyloxy)-3-chloroquinoline-2-carboxylate (1.24 g).
Production Example 3
To an ice-cold solution of 4-(benzyloxy)-2,3,6-trimethylquinoline (1.36 g) in chloroform (25 mL) was added m-chloroperbenzoic acid (75%, 1.35 g), and the mixture was stirred for 4.5 hours. A 1M aqueous sodium hydroxide solution (10 mL) and water (10 mL) were added to the reaction mixture, followed by extraction with chloroform (20 mL). The organic layer was washed sequentially with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to obtain 4-(benzyloxy)-2,3,6-trimethylquinoline-1-oxide (1.20 g).
Production Example 4
4-(Benzyloxy)-2,3,6-trimethylquinoline-1-oxide (1.18 g) was dissolved in acetic anhydride (32 mL), followed by stirring at room temperature for 2 hours. After the solvent was evaporated under reduced pressure, water (50 mL) was added to the residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methyl acetate (1.25 g).
Production Example 5
To a mixture of 4-benzyloxy-2,3-dimethylquinoline-1-oxide (21.2 g), potassium carbonate (20.9 g), and acetonitrile (400 mL) was added p-toluenesulfonyl chloride (18.8 g), followed by stirring at room temperature for 12 hours. Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Water (500 mL) was added to the residue, followed by twice extractions with ethyl acetate (500 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain p-toluenesulfonic acid [4-(benzyloxy)-3-methylquinolin-2-yl]methyl ester (13.4 g).
Production Example 6
To a solution of [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methyl acetate (1.20 g) in THF-methanol (1:3, 24 mL) was added a 1M aqueous sodium hydroxide solution (5.5 mL), followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and water was then added to the residue. The precipitated solid was collected by filtration, washed with water, and dried to obtain [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methanol (900 mg).
Production Example 7
Ethyl 4-(benzyloxy)-6-bromo-3-methylquinoline-2-carboxylate (2.37 g) was dissolved in THF (30 mL) and toluene (30 mL). A solution of 1M diisobutylaluminum hydride in toluene (7.10 mL) was gradually added dropwise to this solution at −78° C., followed by stirring at the same temperature for 3 hours. The reaction mixture was warmed to about 0° C., and water was added thereto, followed by stirring overnight. The precipitated insolubles were removed by filtration through Celite, and then the filtrate was concentrated. The resulting residue was dissolved in ethyl acetate, and powdered with gradual addition of hexane to obtain 4-(benzyloxy)-6-bromo-3-methylquinoline-2-carboxyaldehyde (1.76 g).
Production Example 8
4-(Benzyloxy)-6-bromo-3-methylquinoline-2-carboxyaldehyde (3.23 g) was dissolved in THF (50 mL) and ethanol (50 mL), and sodium borohydride (410 mg) was gradually added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was ice-cooled, and water was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the precipitated solid was collected by filtration. The resulting solid was suspended in ethanol, stirred for a while, and collected by filtration to obtain [4-(benzyloxy)-6-bromo-3-methylquinolin-2-yl]methanol (3.20 g).
Production Example 9
To a solution of ethyl 4-(benzyloxy)-8-methoxy-3-methylquinoline-2-carboxylate (1.95 g) in toluene (30 mL) was added dropwise a solution of diisobutylaluminum hydride in toluene (0.99M, 6.1 mL) at room temperature under nitrogen flow, followed by stirring. After 1 hour and 2 hours, a solution of diisobutylaluminum hydride in toluene (0.99M, each 6.1 mL) was added thereto, followed by stirring for 3 hours. Water was added to the reaction mixture to stop the reaction, and then anhydrous sodium sulfate was added thereto, followed by stirring. Insolubles were removed by filtration through Celite. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/50 ̃ethyl acetate, then chloroform ̃chloroform/methanol=95/5) to obtain [4-(benzyloxy)-8-methoxy-3-methylquinolin-2-yl]methanol (551 mg).
Production Example 10
[4-(Benzyloxy)-6-fluoro-3-methylquinolin-2-yl]methanol (4.02 g) was dissolved in THF (50 mL) and toluene (50 mL), and 10 drops of pyridine were added thereto. Thionyl chloride (1.50 mL) was gradually added dropwise thereto under ice-cooling, and the reaction mixture was stirred at the same temperature for 1 hour, and further stirred at room temperature for 1 hour. After the precipitated solid was collected by filtration, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were gradually added with stirring to the filtrate under ice-cooling. After the foaming became stable, the organic layer was separated, washed sequentially with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 4-(benzyloxy)-2-(chloromethyl)-6-fluoro-3-methylquinoline (3.85 g).
Production Example 11
To a solution of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (5.0 g) in THF (50 mL) was added anhydrous lithium bromide (15 g), followed by heating under reflux for 3 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Water was added to the residue, followed by stirring, and the resulting solid was collected by filtration. This solid was dried under vacuum at 60° C. to obtain 5.73 g of 4-(benzyloxy)-2-(bromomethyl)-3-methylquinoline as a white solid.
Production Example 12
A mixture of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (1.00 g) and triethyl phosphite (3.84 g) was stirred at 150° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=98/2) to obtain diethyl {[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}phosphonate (1.12 g).
Production Example 13
To a solution of 4-(benzyloxy)-2-[4-(benzyloxy)-1-buten-1-yl]-3-methylquinoline (2.57 g) in ethanol (26 mL) were added cyclohexene (13 mL) and 20% palladium hydroxide-activated carbon powder (1.5 g), followed by stirring under reflux for 2 hours. The catalyst was removed by filtration, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=93/7) to obtain 2-(4-hydroxybutyl)-3-methylquinolin-4(1H)-one (1.10 g).
Production Example 14
A mixture of 4-(benzyloxy)-3-methylquinoline-2-carboxyaldehyde (570 mg), n-heptylamine (240 mg), sodium triacetoxy borohydride (530 mg), acetic acid (0.1 mL), and 1,2-dichloroethane (15 mL) was stirred at room temperature for 14.5 hours. Water (15 mL) was added to the reaction mixture, followed by extraction with chloroform (30 mL). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain N-{[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}heptane-1-amine (740 mg).
Production Example 15
To a solution of N-benzyl-1-[4-(benzyloxy)-3-methylquinolin-2-yl]methaneamine (2.21 g) in ethyl acetate (50 mL) was added a 4M hydrogen chloride-ethyl acetate solution (4 mL), and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether, and dried to obtain a solid (1.10 g). This solid (1.00 g) was dissolved in a mixed solvent of ethanol-THF-water (10:5:1, 32 mL), and 10% palladium-activated carbon (400 mg) was added thereto, followed by stirring at room temperature under hydrogen atmosphere for 3 hours. To reaction mixture were added water (10 mL) and 10% palladium-activated carbon (400 mg), followed by stirring at room temperature under hydrogen atmosphere for 6 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol (1:1, 10 mL), and a 4M hydrogen chloride-ethyl acetate solution (2 mL) was added thereto. The solvent was evaporated under reduced pressure and the resulting residue was dried to obtain 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (560 mg).
Production Example 16
To a solution of N-{[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}heptane-1-amine (153 mg) in pyridine (5 mL) was added acetic anhydride (0.06 mL), followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and water (10 mL) and 1M hydrochloric acid (10 mL) were added to the residue, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-{[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}-N-heptylacetamide (158 mg).
Production Example 17
1-Heptanethiol (250 mg) was dissolved in methanol (5 mL), to which a solution of 28% sodium methoxide in methanol (0.37 mL) was then added, followed by stirring at room temperature for 15 minutes. The reaction mixture was added to a solution of p-toluenesulfonic acid [4-(benzyloxy)-3-methylquinolin-2-yl]methyl ester (464 mg) in methanol-THF (1:1, 10 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and water (100 mL) was added to the resulting residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 4-(benzyloxy)-2-[(heptylsulfanyl)methyl]-3-methylquinoline (380 mg).
Production Example 18
To a solution of 4-(benzyloxy)-2-[(heptylsulfanyl)methyl]-3-methylquinoline (106 mg) in dichloromethane (5 mL) was added m-chloroperbenzoic acid (75%, 68 mg) at −30° C., followed by stirring for 5 hours while warming to room temperature. A 0.2M aqueous sodium hydroxide solution (20 mL) was added to the reaction mixture, followed by extraction with chloroform (50 mL). The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 4-(benzyloxy)-2-[(heptylsulfinyl)methyl]-3-methylquinoline (75 mg).
Production Example 19
A solution of 1-(4-bromobutoxy)-4-fluorobenzene (2.56 g) and triphenylphosphine (2.72 g) in toluene (10 mL) was heated under reflux for 24 hours. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and dried to obtain [4-(4-fluorophenoxy]butyl]triphenylphosphonium bromide (2.06 g).
Production Example 20
60% Sodium hydride (160 mg) was added to DMSO (20 mL), followed by stirring at 40° C. for 1 hour, and [4-(4-fluorophenoxy)butyl]triphenylphosphonium bromide (2.00 g) was added thereto. The reaction mixture was stirred at 40° C. for 1.5 hours, and then 4-(benzyloxy)-3-methylquinoline-2-carboxyaldehyde (910 mg) was added thereto, followed by stirring at room temperature for 3 hours. Water (100 mL) was added to the reaction mixture, followed by extraction with diethyl ether (100 mL). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 4-(benzyloxy)-2-[5-(4-fluorophenoxy)pent-1-en-1-yl]-3-methylquinoline (816 mg) as an E/Z mixture.
Production Example 21
1-Heptanol (470 mg) was dissolved in THF (10 mL), and potassium tert-butoxide (450 mg) was added thereto, followed by stirring at room temperature for 30 minutes. 4-(Benzyloxy)-2-[(chloromethyl)-3-methylquinoline (1.00 g) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 4-(benzyloxy)-2-[(heptyloxy)methyl]-3-methylquinoline (1.13 g).
Production Example 22
To a solution of [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (105 mg) in THF (3 mL) was added pentylisocyanate (45 mg), followed by stirring at room temperature for 1 hour. Pentylisocyanate (20 mg) was further added to the reaction mixture, followed by stirring at room temperature for 16 hours. Methanol (2 mL) was added to the reaction mixture, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to obtain [4-(benzyloxy)-3-methylquinolin-2-yl]methylpentylcarbamate (150 mg).
Production Example 23
A mixture of ethyl 3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}-5-hydroxybenzoate (2.10 g), 4-(bromomethyl)tetrahydro-2H-pyrane (2.29 g), potassium carbonate (0.98 g), and DMF (40 mL) was stirred at 80° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, and then water was added to the residue, followed by extraction with ethyl acetate (150 mL). The organic layer was washed sequentially with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain ethyl 3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate (2.50 g).
Production Example 24
To a solution of {[4-(2,2-dimethylpropoxy)butoxy]methyl}benzene (1.50 g) in acetic acid (30 mL) was added 10% palladium-activated carbon (500 mg), followed by stirring under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to obtain 4-(2,2-dimethylpropoxy)butan-1-ol (267 mg).
Production Example 25
To a solution of diethyl {[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}phosphonate (1.85 g) in THF (40 mL) was added lithium hexamethyldisilazide (1.0M hexane solution, 4.76 mL) at 5 to 6° C. under nitrogen atmosphere, followed by stirring at the same temperature for 30 minutes. A solution of tetrahydrofuran-2-ol (675 mg) in THF (10 mL) was added to the reaction mixture, followed by stirring at the same temperature for 5 hours. Water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1-1/1) to obtain (4E)-5-[4-(benzyloxy)-3-methylquinolin-2-yl]penten-1-ol (427 mg).
Production Example 26
2,3,5-trichloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (214 mg) and [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (222 mg) were dissolved in DMF (5 mL), and 60% sodium hydride (40 mg) was added thereto, followed by stirring at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (80 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-2-({[3,5-dichloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-2-yl]oxy}methyl)-3-methylquinoline (250 mg).
Production Example 27
To a solution of ethyl (2E,4E)-5-(2,3-dihydro-1,4-benzodioxin-6-yl)penta-2,4-dienoate (5.00 g) in ethanol (100 mL) was added 10% palladium-activated carbon (1.0 g), followed by stirring at room temperature under hydrogen atmosphere (4 atm.) for 5 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=85/15) to obtain ethyl 5-(2,3-dihydro-1,4-benzodioxin-6-yl)pentanoate (2.94 g).
Production Example 28
To a suspension of lithium aluminum hydride (418 mg) in anhydrous THF (25 mL) was added dropwise under ice-cooling a solution of ethyl 5-(2,3-dihydro-1,4-benzodioxin-6-yl)pentanoate (2.91 g) in anhydrous THF (10 mL) under nitrogen atmosphere. The mixture was stirred under ice-cooling for 30 minutes, and then a saturated aqueous sodium sulfate solution was added dropwise thereto, followed by stirring at room temperature for 1 hour. Ethyl acetate was added thereto, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=65/35) to obtain 5-(2,3-dihydro-1,4-benzodioxin-6-yl)pentan-1-ol (2.17 g).
Production Example 29
4-Fluorophenol (500 mg) and benzyl 4-bromobutyl ether (1.1 g) were dissolved in DMF (20 mL), and potassium carbonate (1.0 g) was added thereto at room temperature, followed by stirring at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain 1-[4-(benzyloxy)butoxy]-4-fluorobenzene (851 mg).
Production Example 30
Under reaction conditions as described in J. Org. Chem. 1997, 62, 1560, {[4-(vinyloxy)butoxy]methyl}benzene was obtained using 4-(benzyloxy)butan-1-ol as a starting material. That is, 1,10-phenanthroline (1.00 g) and palladium(II) acetate (2.50 g) were added to a mixture of ethyl vinyl ether (25 mL) and dichloromethane (15 mL), followed by stirring for 15 minutes, and then 4-(benzyloxy)butan-1-ol (5.00 g) was added thereto, followed by stirring at room temperature for 60 hours. The reaction mixture was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=95/5) to obtain {[4-(vinyloxy)butoxy]methyl}benzene (3.24 g).
Production Example 31
To a solution of {[4-(vinyloxy)butoxy]methyl}benzene (3.16 g) in diethyl ether (63 mL) was added diethyl zinc (1.0M, hexane solution) (30.6 mL) under nitrogen atmosphere, and a solution of diiodomethane (8.49 g) in diethyl ether (13 mL) was added dropwise thereto. The reaction liquid was stirred under reflux for 1 hour, followed by stirring at room temperature for 12 hours. A saturated aqueous ammonium acetate solution (80 mL) was added to the reaction liquid, followed by extraction with diethyl ether (400 mL). The organic layer was washed sequentially with a saturated aqueous ammonium acetate solution and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=95/5) to obtain {[4-(cyclopropyloxy)butoxy]methyl}benzene (2.41 g).
Production Example 32
To a solution of 2-(tetrahydro-2H-pyran-4-yl)ethyl p-toluenesulfonate (465 mg) in DMF (5 mL) were added 2,4-dihydroxypyridine (363 mg) and potassium carbonate (339 mg), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and water (50 mL) was added thereto, followed by extraction with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/chloroform=0/100 ̃10/90) to obtain 4-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-2-ol (160 mg) as a major product, and 2-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-4-ol (Production Example 347) (43 mg) as a minor product.
Production Example 33
4-(cyclopropyloxy)butan-1-ol (400 mg) was dissolved in a mixture of DMSO (3.5 mL), dichloromethane (10 mL), and triethylamine (2.14 mL), and a solution of a sulfur trioxide pyridine complex (1.47 g) in DMSO (3.5 mL) added dropwise thereto under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour, and then poured into water (20 mL). The mixture was extracted with diethyl ether (200 mL), the organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20) to obtain 4-(cyclopropyloxy)butanal (233 mg).
Production Example 34
To a solution of 4-(benzyloxy)butan-1-ol (3.00 g), 6-(trifluoromethyl)pyrimidin-4-ol (3.00 g), and triphenylphosphine (5.25 g) in THF (30 mL) was added diisopropyl azodicarboxylate (4.05 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 4-[4-(benzyloxy)butoxy]-6-(trifluoromethyl)pyrimidine (2.83 g).
Production Example 35
8-{[3-(Benzyloxy)phenoxy]methyl}-1,4-dioxaspiro[4.5]decane (817 mg) was dissolved in a mixed solvent of ethanol (15 mL) and THF (15 mL), and cyclohexene (4.67 mL) and 20% palladium hydroxide-activated carbon (218 mg) were added thereto, followed by heating under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, the catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-95/5) to obtain 3-(1,4-dioxaspiro[4.5]dec-8-ylmethoxy)phenol (567 mg).
Production Example 36
1-(3-Phenylpropanoyl)piperazine hydrochloride (1.0 g) was dissolved in acetonitrile, and 1,1′-carbonyldiimidazole (950 mg) was added thereto at room temperature, followed by stirring at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to obtain 1-(1H-imidazol-1-ylcarbonyl)-4-(3-phenylpropanoyl)piperazine (1.13 g).
Production Example 37
To a solution of 1-(1H-imidazol-1-ylcarbonyl)-4-(3-phenylpropanoyl)piperazine (1.03 g) in acetonitrile (20 mL) was added dropwise methyl iodide (1.40 mL) and triethylamine (2.20 mL) at room temperature, followed by stirring at 60° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, and then [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (300 mg) was added thereto, followed by dropwise addition of triethylamine (0.50 mL) and stirring at 70° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain [4-(benzyloxy)-3-methylquinolin-2-yl]methyl 4-(3-phenylpropanoyl)piperazine-1-carboxylate (405 mg).
Production Example 38
Diethyl malonate (597 mg) was dissolved in THF (6 mL) under nitrogen atmosphere, and 60% sodium hydride (150 mg) was added thereto under ice-cooling, followed by stirring for 20 minutes. A solution of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (1.11 g) in THF (5 mL) was added thereto, followed by stirring at 50° C. for 9 hours. The reaction mixture was allowed to cool to room temperature, and water (30 mL) was added thereto, followed by extraction with ethyl acetate (300 mL). The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=95/5) to obtain {[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}diethyl malonate (1.08 g).
Production Example 39
To a solution of {[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}diethyl malonate (1.04 g) in THF (5 mL) were added a solution of potassium hydroxide (555 mg) in water (0.60 mL) and methanol (4 mL), followed by stirring at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and then neutralized with 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was heated at 130° C. for 2 hours and then purified by silica gel column chromatography (eluent: chloroform/methanol=98/2) to obtain 3-[4-(benzyloxy)-3-methylquinolin-2-yl]propionic acid (230 mg).
Production Example 40
3-[4-(Benzyloxy)-3-methylquinolin-2-yl]propionic acid (213 mg) and 1-hydroxybenzotriazole hydrate (107 mg) were dissolved in DMF (4 mL). 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 3-phenylpropylamine (134 mg), and N,N-diisopropylethylamine (0.14 mL) were added thereto, and the mixture was stirred at room temperature for 72 hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200 mL). The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1) to obtain 3-[4-(benzyloxy)-3-methylquinolin-2-yl]-N-(3-phenylpropyl)propanamide (90 mg).
Production Example 41
3-Sulfanylphenol (250 mg) was dissolved in methanol (5 mL), and a 28% sodium methoxide-methanol solution (0.5 mL) was added thereto, followed by stirring at room temperature for 10 minutes. 4-(Bromomethyl)tetrahydro-2H-pyrane (410 mg) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and then water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried. The solvent was evaporated under reduced pressure, and the residue was washed with hexane to obtain 3-[(tetrahydro-2H-pyran-4-ylmethyl)sulfanyl]phenol (265 mg).
Production Example 42
To a solution of 1,4-dioxaspiro[4.5]dec-8-ylmethanol (946 mg), 3-(benzyloxy)phenol (1 g), and triphenylphosphine (1.57 g) in THF (15 mL) was added azodicarboxylate diethyl (944 μL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction liquid was concentrated under reduced pressure, benzene was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=92/8-85/15) to obtain 8-{[3-(benzyloxy)phenoxy]methyl}-1,4-dioxaspiro[4.5]decane (846 mg).
Production Example 43
To an ice-cold solution of 4-[(3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}phenoxy)methyl]piperidine-1-carbamic acid tert-butyl ester (735 mg) in ethyl acetate-ethanol (3:1, 20 mL) was added a 4M hydrogen chloride-ethyl acetate solution (15 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then a 5% aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 4-(benzyloxy)-3-methyl-2-{[3-(piperidin-4-ylmethoxy)phenoxy]methyl}quinoline (545 mg).
Production Example 44
4-{[3-(Benzyloxy)phenoxy]methyl}piperidine hydrochloride (1.5 g) was dissolved in chloroform (30 mL), and diisopropyl ethylamine (3.13 mL) and methanesulfonyl chloride (0.52 mL) were added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was powdered and purified from chloroform/hexane to obtain 4-{[3-(benzyloxy)phenoxy]methyl}-1-(methylsulfonyl)piperidine (1.508 g).
Production Example 45
To a solution of (3-hydroxyphenoxy)acetic acid (246 mg) in DMF (10 mL) were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (336 mg), 1H-benzotriazol-1-ol hydrate (268 mg) and morpholine (153 μL) at room temperature, followed by overnight stirring at room temperature. The solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-95/5) to obtain 3-(2-(morpholin-4-yl)-2-oxoethoxy)phenol (305 mg).
Production Example 46
4-(Benzyloxy)-6-bromo-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (500 mg) was dissolved in DMSO (30 mL) and ethanol (10 mL), and palladium(II) acetate (60 mg), 1,3-bis(diphenylphosphino)propane (230 mg), and triethylamine (0.19 mL) were added thereto at room temperature, followed by stirring under carbon monoxide atmosphere at 80° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=60/40) to obtain ethyl 4-(benzyloxy)-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline-6-carboxylate (257 mg).
Production Example 47
To a solution of 4-(benzyloxy)-6-bromo-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (300 mg) in dioxane (10 mL) were added pyridin-3-yl boric acid (135 mg), tetrakis(triphenylphosphine)palladium(0) (65 mg), and a 1M aqueous sodium carbonate solution (1.60 mL), followed by stirring at 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added thereto, followed by extraction with chloroform (50 mL). The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=15/85) to obtain 4-(benzyloxy)-3-methyl-6-(pyridin-3-yl)-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (265 mg).
Production Example 48
To a solution of 4-(benzyloxy)-6-bromo-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (400 mg) in dioxane (10 mL) were added piperidin-2-one (90 mg), tris(dibenzylideneacetone)dipalladium(0) (35 mg), cesium carbonate (360 mg), and (9,9-dimethyl-9H-xanthen-4,5-diyl)bis(diphenylphosphine) (65 mg), and the mixture was stirred at 100° C. for 30 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=97/3) to obtain 1-[4-(benzyloxy)-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-6-yl]piperidin-2-one (328 mg).
Production Example 49
To a solution of 3-(1,4-dioxaspiro[4.5]dec-8-ylmethoxy)phenol (536 mg) in acetone (9.6 mL) was added 1M hydrochloric acid (9.6 mL), followed by stirring at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and then water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4-[(3-hydroxyphenoxy)methyl]cyclohexanone (446 mg).
Production Example 50
To a solution of tetrahydro-2H-pyran-4-yl methanol (1.00 g) and 2,6-difluoropyridine (1.19 g) in DMF (10 mL) was added 60% sodium hydride (410 mg), and the mixture was stirred at 80° C. for 8 hours. Water (50 mL) was added dropwise to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20) to obtain 2-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (1.36 g).
Production Example 51
To a solution of 1-(benzyloxy)-3-bromobenzene (1.00 g) in 1,2-dimethoxyethane (15 mL) were added tris(dibenzylideneacetone)dipalladium(0) (180 mg), 2′-[dicyclohexylphosphino]-N,N-dimethylbiphenyl-2-amine (150 mg), piperidine (500 μL), and tripotassium phosphate (2.5 g) at room temperature, and the mixture was stirred at 110° C. for 21 hours. After the reaction mixture was cooled to room temperature, insolubles were separated by filtration and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-85/15) to obtain 1-[3-(benzyloxy)phenyl]piperidine (722 mg).
Production Example 52
To an ice-cold solution of 2-(tetrahydro-2H-pyran-4-yl)ethanol (1.00 g) in pyridine (6.5 mL) was added p-toluenesulfonyl chloride (1.5 g), followed by stirring at the same temperature for 30 minutes, and at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and then diluted aqueous hydrochloric acid (20 mL) was added to the residue, followed by twice extractions with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20-50/50) to obtain p-toluenesulfonic acid 2-(tetrahydro-2H-pyran-4-yl)ethyl ester (450 mg).
Production Example 53
1-[3-(Benzyloxy)phenoxy]acetone (1.77 g) was dissolved in THF (20 mL), and, a solution of 0.97M methyl magnesium bromide in THF (9.0 mL) was added dropwise thereto with cooling in an ice bath under nitrogen flow. The reaction mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-85/15) to obtain 1-[3-(benzyloxy)phenoxy]-2-methylpropan-2-ol (997 mg).
Production Example 54
Palladium(II) chloride (112 mg) and copper(I) chloride (628 mg) were added to DMF-water (7:1, 8 mL), followed by stirring at room temperature under oxygen atmosphere for 1 hour. A solution of 1-(benzyloxy)-3-(pent-4-en-1-yloxy)benzene (1.70 g) in DMF (7 mL) was added dropwise to the reaction mixture, followed by vigorous stirring at room temperature for 2 hours. 0.5M Hydrochloric acid (60 mL) was added to the reaction mixture, followed by extraction with diethyl ether (100 mL). The organic layer was washed sequentially with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain 5-[3-(benzyloxy)phenoxy]pentan-2-one (1.65 g).
Production Example 55
A mixture of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (200 mg), 1-hexanoylpiperazin (130 mg), potassium carbonate (111 mg), and DMF (6 mL) was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 4-(benzyloxy)-2-[(4-hexanoylpiperazin-1-yl)methyl]-3-methylquinoline (241 mg).
Production Example 56
To a solution of [4-(benzyloxy)-8-methoxy-3-methylquinolin-2-yl]methanol (250 mg) in THF (10 mL) were added 3-(tetrahydro-2H-pyran-4-ylmethoxy)phenol (185 mg) and 1,1-(azodicarbonyl)dipiperidine (245 mg), followed by dropwise addition of tributylphosphine (0.24 mL) at room temperature and stirring. After 1 hour, tributyl phosphine (0.24 mL) was added thereto, followed by stirring for 12 hours. Ethyl acetate was added to the reaction mixture, and then insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography twice (eluent for the first round: hexane/ethyl acetate=80/20 ̃67/33 ̃60/40, eluent for the second round: chloroform ̃chloroform/methanol=95/5), and also by thin layer silica gel chromatography (developer: chloroform/methanol=95/5) to obtain 4-(benzyloxy)-8-methoxy-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (340 mg).
Production Example 57
A mixture of 3-bromo-5-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (300 mg), copper(II) sulfate pentahydrate (130 mg), bronze (100 mg), sodium hydroxide (700 mg), and water (5 mL) was stirred in an autoclave at 210° C. for 6 hours. The reaction mixture was cooled to room temperature, followed by addition of methanol, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure and extracted with chloroform. The aqueous layer was neutralized by addition of 1M hydrochloric acid (3.5 mL), followed by extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-ol (137 mg).
Production Example 58
To a mixture of (2-fluoropyridin-4-yl)methanol (300 mg), triethylamine (239 mg), and dichloromethane (24 mL) was added anhydrous trifluoromethanesulfonic acid (666 mg) under ice-cooling, followed by stirring at the same temperature for 1 hour. (Tetrahydro-2H-pyran-4-yl)methanol (1.37 g) was added to the reaction liquid at room temperature, followed by stirring at the same temperature for 8 hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, followed by extraction with chloroform (30 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/1) to obtain 2-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethoxy)methyl]pyridine (132 mg).
Production Example 59
To a mixture of magnesium (35 mg) and THF (1.5 mL) was added one grain of iodine under nitrogen flow, followed by warming in an oil bath at 50° C. A solution of 1-(benzyloxy)-4-(2-bromoethyl)benzene (400 mg) in THF (3 mL) was added dropwise to the mixture over 20 minutes, and then the reaction liquid was heated under reflux for 4 hours. The reaction liquid was ice-cooled, and a solution of cyclobutanone (100 mg) in THF (4 mL) was added dropwise over 15 minutes, followed by stirring at room temperature for another 6 hours. The reaction liquid was adjusted to an acidic pH by adding 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9:1-1/1) to obtain 1-{2-[4-(benzyloxy)phenyl]ethyl}cyclobutanol (80 mg).
Production Example 60
To a solution of 3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}-2,2-dimethylpropan-1-ol (500 mg) in THF (10 mL) was added dropwise a solution of n-butyl lithium in hexane (1.55M, 1.1 mL) at an internal temperature of −20° C. under nitrogen flow, followed by stirring at the same temperature for 15 minutes. Morpholine-4-carbonylchloride (0.2 mL) was added to the reaction mixture, followed by stirring for 3 hours while warming to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0 ̃50/50), and the solvent was evaporated under reduced pressure. The resulting residue was dried under vacuum at room temperature to obtain 459 mg of 3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}-2,2-dimethylpropylmorpholine-4-carboxylate as a yellow solid.
Production Example 61
To a mixture of magnesium (120 mg) and THF (1.5 mL) was added 1,4-dibromobutane (0.2 mL) at room temperature under nitrogen flow, followed by stirring for 1 hour. The reaction solution was ice-cooled, and a solution of ethyl 3-[4-(benzyloxy)phenyl]propanoate (400 mg) in THF (3 mL) was added dropwise thereto while maintaining an internal temperature of 10° C. or less. The reaction mixture was stirred under ice-cooling for 3 hours, and allowed to stand overnight at room temperature. The reaction liquid was ice-cooled and was adjusted to an acidic pH by adding 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/3-1/1) to obtain 1-{2-[4-(benzyloxy)phenyl]ethyl}cyclopentanol (145 mg).
Production Example 62
To a solution of 2-(benzyloxy)-5-bromopyridine (600 mg) in DMF (12 mL) were added 3-buten-2-one (400 mg), tris(dibenzylidene acetone) dipalladium(0) (74 mg), triethylamine (460 mg), and tris(o-tolyl)phosphine (70 mg) at room temperature under nitrogen flow, and the mixture was stirred at 100° C. for 24 hours. The reaction liquid was allowed to cool, and insolubles were filtered through Celite. Water was added to the filtrate, followed by three times extractions with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-3/2) to obtain (3E)-4-[6-(benzyloxy)pyridin-3-yl]but-3-en-2-one (220 mg).
Production Example 63
1-(trans-4-{[4-(Benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)-3-ethylurea was obtained from trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexaneamine, in the same manner as in Example 15 which will follow.
Production Example 64
N-(trans-4-{[4-(Benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)ethanesulfonamide was obtained from trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexaneamine, in the same manner as in Example 16 which will follow.
Production Example 65
To a solution of trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexaneamine (300 mg) in dichloromethane (5 mL) were added 4-bromo butanoic acid chloride (0.11 mL) and triethylamine (0.15 mL) under ice-cooling, followed by stirring at the same temperature for 45 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in THF, and 60% sodium hydride (50 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, followed by stirring for another 15 hours while heating it in an oil bath at 60° C. 60% sodium hydride (50 mg) was added to the reaction mixture, followed by stirring for 4 hours while heating it in an oil bath at 60° C. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0 ̃95/5). The solvent was evaporated under reduced pressure, and the residue was then dried under vacuum at room temperature to obtain 161 mg of 1-(trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)pyrrolidin-2-one as a yellow oily substance.
Production Example 66
To a mixed solution (10 mL) of N-(trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)cyclopentanecarboxamide (260 mg) in THF-DMF (1:1) was added 60% sodium hydride (45 mg) under ice-cooling, followed by stirring at the same temperature. Methyl iodide (0.055 mL) was added thereto, followed by stirring at room temperature for 3.5 hours. The reaction mixture was ice-cooled, and 60% sodium hydride (45 mg) and methyl iodide (0.055 mL) were added thereto, followed by stirring at room temperature for another 17 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0 ̃50/50), and the solvent was evaporated under reduced pressure. The residue was dried under vacuum at room temperature to obtain 93 mg of N-(trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)-N-methylcyclopentanecarboxamide as a colorless viscous substance.
Production Example 67
4-(Benzyloxy)-2-{[(5-bromopyrimidin-2-yl)oxy]methyl}-3-methylquinoline (1.5 g) was suspended in a mixed solvent (40 mL) of DMF-methanol (1:1), and triethylamine (1 mL) and dichlorobis(triphenylphosphine)palladium(II) (1.2 g) were added thereto, followed by stirring at 100° C. under a carbon monoxide atmosphere (1.0 MPa) for 5 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0 ̃50/50). The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue which was then warmed to be dissolved. Hexane was added to this solution, followed by stirring at room temperature, and the resulting solid was collected by filtration and dried under vacuum at room temperature to obtain 1.034 g of methyl 2-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}pyrimidine-5-carboxylate as a pale yellow solid.
Production Example 68
2-{[4-(Benzyloxy)-3-methylquinolin-2-yl]methoxy}pyrimidine-5-carboxylic acid was obtained from methyl 2-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}pyrimidine-5-carboxylate, in the same manner as in Example 20 which will follow.
Production Example 69
To a solution of 3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}-5-methoxyphenol (104 mg) and pyridine (52 mg) in dichloromethane (4 mL) was gradually added a solution of anhydrous trifluoroacetic acid (110 mg) in dichloromethane (1 mL) under ice-cooling, followed by stirring under the same conditions for 30 minutes, and at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1 ̃1/1) to obtain 3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}-5-methoxyphenyltrifluoromethanesulfonate (130 mg).
Compounds of Production Examples 70 to 565 shown in the following Tables were produced in the same manner as in Production Examples 1 to 69. Structures, Production methods and physicochemical data of Production Example Compounds are shown in Tables 2 to 96.
Example 1
4-(Benzyloxy)-2-[5-(4-fluorophenoxy)pent-1-en-1-yl]-3-methylquinoline (E/Z mixture, 810 mg) was dissolved in ethanol-THF (1:1, 20 mL), and 10% palladium-activated carbon (200 mg) was added thereto. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2-[5-(4-fluorophenoxy)pentyl]-3-methylquinolin-4(1H)-one (572 mg).
Example 2
To a solution of 4-(benzyloxy)-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (330 mg) in ethanol-THF (1:1, 10 mL) was added 10% palladium-activated carbon (80 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-4(1H)-one (207 mg).
Example 3
To a solution of 1-[2-(4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}phenyl)ethyl]cyclopentanol (128 mg) in ethanol-THF (1:1, 4 mL) was added 10% palladium-activated carbon (30 mg) under nitrogen atmosphere, followed by stirring at room temperature under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=92/8). The resulting solid was washed with ether and dried to obtain 2-({4-[2-(1-hydroxycyclopentyl)ethyl]phenoxy}methyl)-3-methylquinolin-4(1H)-one (51 mg) as a crystal.
Example 4
To a solution of 4-[(2-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}pyridin-4-yl)oxy]-2-methyl butan-2-ol (1.33 g) in ethanol-THF (1:4, 45 mL) was added 10% palladium-activated carbon (300 mg) under nitrogen atmosphere. The mixture was placed under hydrogen atmosphere, and then stirred at room temperature for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=97/3) to obtain 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (783 mg) as a crystal.
Example 5
To a solution of ethyl (trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)carbamate (153 mg) in ethanol-THF (1:1, 6 mL) was added 5% Pd—BaSO4 (70 mg) under nitrogen atmosphere, followed by stirring at room temperature under hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5). The resulting solid was washed with ethyl acetate and dried to obtain ethyl {trans-4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl]methoxy]cyclohexyl}carbamate (88 mg) as a crystal.
Example 6
N-(trans-4-{[4-(Benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)ethanesulfonamide (315 mg) was subjected to debenzylation under the same reaction conditions as in Example 5, and then purified by silica gel column chromatography (eluent: chloroform/methanol=97/3) to obtain N-{trans-4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]cyclohexyl}ethanesulfonamide (168 mg) as a crystal.
Example 7
1-(trans-4-{[4-(Benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)pyrrolidin-2-one (158 mg) was subjected to debenzylation under the same reaction conditions as in Example 5, and then purified by silica gel column chromatography (eluent: chloroform/methanol=97/3) to obtain 3-methyl-2-({[trans-4-(2-oxopyrrolidin-1-yl)cyclohexyl]oxy}methyl)quinolin-4(1H)-one (72 mg) as a crystal.
Example 8
4-(Benzyloxy)-3-methyl-2-[({4-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-2-yl}oxy)methyl]quinoline (1.7 g) was subjected to debenzylation under the same reaction conditions as in Example 5, and then purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=100/0 ̃50/50) to obtain 3-methyl-2-[({4-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-2-yl}oxy)methyl]quinolin-4(1H)-one (1.34 g) as a crystal.
Example 9
4-(3-{[4-(Benzyloxy)-3-methylquinolin-2-yl]methoxy}phenyl)morpholine-3-one (160 mg) was subjected to debenzylation under the same reaction conditions as in Example 5, and then purified by thin layer silica gel chromatography (developer: chloroform/methanol=15/1) to obtain 3-methyl-2-{[3-(3-oxomorpholin-4-yl)phenoxy]methyl}quinolin-4(1H)-one (96 mg) as a crystal.
Example 10
4-(3-{[4-(Benzyloxy)-3-methylquinolin-2-yl]methoxy}-5-morpholin-4-ylphenoxy)-2-methylbutan-2-ol (510 mg) was subjected to debenzylation under the same reaction conditions as in Example 5, and then was purified by silica gel column chromatography (eluent: chloroform/methanol=90/10) to obtain 2-{[3-(3-hydroxy-3-methylbutoxy)-5-morpholin-4-ylphenoxy]methyl}-3-methylquinolin-4(1H)-one (279 mg) as a crystal.
Example 11
To a mixture of benzyl 4-{(E)-2-[4-(benzyloxy)-3-methylquinolin-2-yl]vinyl}piperidine-1-carboxylate (978 mg), THF (6 mL) and ethanol (6 mL) was added 10% palladium-activated carbon (200 mg) under nitrogen atmosphere. The mixture was stirred at room temperature under hydrogen atmosphere of 3 atms, for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Fuji Silysia Chemical Ltd., NH, eluent: chloroform/methanol=97/3 ̃92/8), and the solvent was evaporated. The residue was washed with ether, and collected by filtration to obtain 3-methyl-2-(2-piperidin-4-ylethyl)quinolin-4(1H)-one (490 mg).
Example 12
To a solution of 4-(benzyloxy)-2-[(heptylsulfanyl)methyl]-3-methylquinoline (150 mg) in trifluoroacetic acid (5 mL) was added thioanisole (150 mg), followed by stirring at room temperature for 16 hours. The reaction mixture was added dropwise to an ice-cold aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2-[(heptylsulfanyl)methyl]-3-methylquinolin-4(1H)-one (110 mg).
Example 13
To an ice-cold solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in pyridine (5 mL) was added heptanoic acid chloride (110 mg), and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure, and then water (40 mL) was added to the residue. The resulting solid was collected by filtration, washed with water, and dried. This solid was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]heptanamide (127 mg).
Example 14
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in pyridine (8 mL) was added pentyl chloroformate (100 mg), followed by stirring at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: chloroform/methanol) to obtain pentyl [(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]carbamate (104 mg).
Example 15
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in chloroform (5 mL) were sequentially added triethylamine (0.26 mL) and pentyl isocyanate (0.09 mL), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 1-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]-3-pentylurea (117 mg).
Example 16
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (212 mg) in pyridine-DMF (8:1, 9 mL) was added hexanesulfonyl chloride (180 mg) under ice-cooling, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]hexane-1-sulfonamide (56 mg).
Example 17
Sodium hydride (60%, 173 mg) was added to DMSO (20 mL), followed by stirring at room temperature for 1 hour. [(3-Benzyloxy)propyl]triphenylphosphonium bromide (2.13 g) was added to this mixture, followed by stirring at room temperature for 1.5 hours. 4-(Benzyloxy)-3-methylquinoline-2-carboxyaldehyde (1.00 g) was added to the reaction mixture, followed by stirring for 1.5 hours. Water (80 mL) was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with saturated brine and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to give an oily substance. To this oily substance were added ethanol (10 mL), THF (5 mL), and 10% palladium-activated carbon (200 mg), followed by stirring under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1). The resulting solid was washed with diethyl ether to obtain 2-[4-(benzyloxy)butyl]-3-methylquinolin-4(1H)-one (490 mg).
Example 18
To a solution of [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (400 mg) in THF (8 mL) was added (5-indanyl)isocyanate (498 mg), and the mixture was stirred at 40° C. for 15 hours. Methanol (2 mL) was added to the reaction liquid to stop the reaction. Ethanol (10 mL) and 10% palladium-activated carbon (200 mg) were added to this mixture. The mixture was stirred at room temperature under hydrogen atmosphere for 30 minutes. The catalyst was removed by filtration, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=98/2) to obtain (3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl(2,3-dihydro-1H-inden-5-yl)carbamate (356 mg).
Example 19
To a solution of 2-[(heptylsulfanyl)methyl]-3-methylquinolin-4(1H)-one (110 mg) in chloroform (5 mL) was added m-chloroperbenzoic acid (75%, 200 mg) at room temperature, and the mixture was stirred for 5 hours. A 0.2M aqueous sodium hydroxide solution (20 mL) was added to the reaction mixture, followed by extraction with chloroform (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting powder was washed with diethyl ether and dried to obtain 2-[(heptylsulfonyl)methyl]-3-methylquinolin-4(1H)-one (70 mg).
Example 20
To ethyl 4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]-2-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate (110 mg) were added ethanol (3 mL) and a 0.5M aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to a pH of 7 by adding 1M hydrochloric acid under ice-cooling. The resulting solid was collected by filtration, washed with water, and dried to obtain 4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]-2-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid (100 mg).
Example 21
4-[(3-Methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]-2-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid (67 mg) and 1-hydroxybenzotriazole hydrate (25 mg) were dissolved in DMF (1.3 mL). To this solution were sequentially added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (33 mg) and morpholine (15 mg), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution (5 mL) to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=15/1) to obtain 3-methyl-2-{[4-(morpholin-4-ylcarbonyl)-3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-4(1H)-one (73 mg).
Example 22
To a solution of 3-[(3-methyl-4-oxo-1,4-dihydropyridin-2-yl)methoxy]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzonitrile (100 mg) in DMF (2 mL) were added sodium azide (18 mg) and ammonium chloride (15 mg), followed by stirring at 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 1M aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was adjusted to a pH of 2 by adding 1M hydrochloric acid, followed by extraction with chloroform and a mixed solvent of chloroform-methanol (5:1). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (developer: chloroform/methanol=6/1) and washed with ethyl acetate to obtain 3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1H-tetrazol-5-yl)phenoxy]methyl}quinolin-4(1H)-one (37 mg).
Example 23
To an ice-cold suspension of ethyl 3-methyl-4-oxo-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}-1,4-dihydroquinoline-6-benzoate (158 mg) in ethanol (5.0 mL)-THF (3.0 mL) was added dropwise a 4M aqueous potassium hydroxide solution (0.18 mL), and the mixture was stirred at 65° C. for 15 hours. The reaction mixture was ice-cooled, and adjusted to a pH of 7 by adding 1M hydrochloric acid. The resulting solid was collected by filtration, washed with water, and dried to obtain 3-methyl-4-oxo-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}-1,4-dihydroquinoline-6-benzoic acid (103 mg).
Compounds of Examples 24 to 301 shown in the following Tables were produced using respective corresponding starting materials, in the same manner as in Examples 1 to 23. Structures of respective Example Compounds are shown in Tables 97 to 122, and Production methods and the physicochemical data of the compounds are shown in Tables 123 to 179.
In addition, structures of other compounds of the present invention are shown in Table 180. These compounds can be easily synthesized according to the above-mentioned production methods, methods described in Examples, and methods apparent to those skilled in the art, or modifications thereof.
The following abbreviations are used in Tables below.
PEx: Production Example numbers, Ex: Example numbers, Syn: Example numbers in which the corresponding compounds were produced using the same method, PSyn: Production Example numbers in which the corresponding compounds were produced using the same method, No: compound number, mp: melting point, dec.: decomposition, Str: Structural formula, DATA: physicochemical data, EI+: m/z values in mass analysis (ionization method EI, representing (M)+ when not specified), CI+: m/z values in mass analysis (ionization method CI, representing (M+H)+ when not specified), FAB+: m/z values in mass analysis (ionization method FAB, representing (M+H)+ when not specified), ESI+: m/z values in mass analysis (ionization method ESI, representing (M+H)+ when not specified), ESI−: m/z values in mass analysis (ionization method ESI, representing (M−H)− when not specified), NMR1: δ(ppm) in 1H NMR in DMSO-d6), NMRI+TFA: δ(ppm) in 1H NMR in DMSO-d6) (trifluoroacetic acid-D added), NMR2: δ(ppm) in 1H NMR in CDCl3), NMR3: δ(ppm) in 1H NMR in CD3OD), s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), q: quadruplet (spectrum), br: broad (spectrum) (e.g., br s), Me: methyl, Bn: benzyl. Further, HCl in the Structural formula represents hydrochloride, and the numeral before HCl represents a molar ratio. For example, 2HCl means dihydrochloride.










TABLE 2





PEx
PSyn
Str
DATA


















1
1




ESI+: 310, 312


 


70
1




ESI−: 260


 


71
1




EI+: 249


 


2
2




NMR1: 1.38(3H, t, J = 7.2 Hz), 4.47(2H, q, J = 7.2 Hz), 5.39(2H, s), 7.38-7.49(3H, m), 7.56- 7.62(2H, m), 7.71- 7.78(1H, m), 7.86-7.93(1H, m), 8.11(2H, d, J = 8.4 Hz)


 


72
2




EI+: 339


 


73
2




FAB+: 294



















TABLE 3





PEx
PSyn
Str
DATA


















74
2




FAB+: 292


 


75
2




FAB+: 340


 


76
2




EI+: 277


 


77
2




ESI+: 400, 402


 


78
2




ESI+: 352


 


3
3




ESI+: 294



















TABLE 4





PEx
PSyn
Str
DATA


















79
3




ESI+: 310


 


80
3




FAB+: 308


 


4
4




FAB+: 336


 


81
4




FAB+: 350


 


82
4




ESI+: 352


 


5
5




NMR2: 2.38(3H, s), 2.41(3H, s), 5.03(2H, s), 5.37(2H, s), 7.26(2H, d, J = 8.2 Hz), 7.37- 7.54(6H, m), 7.62-7.69(1H, m), 7.80(2H, d, J = 8.3 Hz), 7.95- 8.03(2H, m)



















TABLE 5





PEx
PSyn
Str
DATA


















6
6




FAB+: 294


 


83
6




FAB+: 308


 


84
6




FAB+: 310


 


7
7




ESI+: 356, 358


 


85
7




ESI+: 296


 


86
7




ESI+: 298, 300


 


87
7




EI+: 295



















TABLE 6





PEx
PSyn
Str
DATA


















8
8




ESI+: 358, 360


 


88
8




NMR1: 2.38(3H, s), 4.74(2H, d, J = 4.8 Hz), 5.11(2H, s), 5.29(1H, t, J = 4.8 Hz), 7.37- 7.48(3H, m), 7.50-7.56(2H, m), 7.70(1H, dd, J = 8.8, 2.0 Hz), 7.91(1H, d, J = 2.0 Hz), 8.01(1H, d, J = 8.8 Hz)


 


89
8




ESI+: 298


 


90
8




NMR1: 4.83(2H, s), 5.30(2H, s), 5.37(1H, br s), 7.37-7.49(3H, m), 7.55-7.61(2H, m), 7.61- 7.68(1H, m), 7.77-7.85(1H, m), 8.01-8.10(2H, m)


 


91
8




ESI+: 298


 


9
9




ESI+: 310



















TABLE 7





PEx
PSyn
Str
DATA







10
10




NMR1: 2.46(3H, s), 4.99(2H, s), 5.13(2H, s), 7.37-7.48(3H, m), 7.51-7.57(2H, m), 7.61-7.69(2H, m), 8.07(1H, dd, J = 8.8, 5.6 Hz)


 


92
10




FAB+: 312


 


93
10




NMR1: 5.06(2H, s), 5.34(2H, s), 7.38-7.49(3H, m), 7.57-7.62(2H, m), 7.67-7.73(1H, m), 7.82- 7.89(1H, m), 8.04-8.10(2H, m)


 


94
10




EI+: 325


 


95
10




FAB+: 328


 


96
10




NMR1: 2.46(3H, s), 4.99(2H, s), 5.14(2H, s), 7.37-7.48(3H, m), 7.48-7.57(2H, m), 7.74(1H, dd, J = 9.2, 2.4 Hz), 7.94(1H, d, J = 2.4 Hz), 8.01(1H, d, J = 9.2 Hz)



















TABLE 8





PEx
PSyn
Str
DATA


















97
10




NMR1: 2.47(3H, s), 4.98(2H, s), 5.14(2H, s), 7.38-7.48(3H, m), 7.49-7.55(2H, m), 7.85(1H, dd, J = 9.2, 2.4 Hz), 7.94(1H, d, J = 9.2 Hz), 8.08(1H, d, J = 2.4 Hz)


 


11
11




ESI+: 342, 344


 


12
12




ESI+: 400


 


98
12




ESI+: 418


 


13
13




ESI+: 232


 


99
2




ESI+: 322



















TABLE 9





PEx
PSyn
Str
DATA


















100
14




FAB+: 413


 


101
14




FAB+: 369


 


15
15




NMR1: 2.11(3H, s), 4.20- 4.26(2H, m), 7.31-7.36(1H, m), 7.64-7.70(2H, m), 8.12(1H, d, J = 7.9 Hz), 8.73(3H, br s), 8.85(1H, br s), 12.53(1H, br s)


 


14
14




FAB+: 377


 


102
16




FAB+: 455


 


16
16




FAB+: 419



















TABLE 10





PEx
PSyn
Str
DATA


















103
14




FAB+: 411


 


104
14




FAB+: 441


 


105
14




FAB+: 397


 


17
17




FAB+: 394


 


18
18




FAB+: 410


 


19
19




ESI+: 429



















TABLE 11





PEx
PSyn
Str
DATA


















20
20




FAB+: 428


 


106
19




ESI+: 379


 


107
20




ESI+: 378


 


21
21




FAB+: 378


 


108
19




ESI+: 455


 


109
20




ESI+: 454



















TABLE 12





PEx
PSyn
Str
DATA


















110
19




ESI+: 447


 


111
20




FAB+: 446


 


112
20




ESI+: 464


 


113
20




ESI+: 464


 


22
22




FAB+: 393


 


114
23




CI+: 235


 


115
24




CI+: 145



















TABLE 13





PEx
PSyn
Str
DATA


















116
21




FAB+: 406


 


25
25




ESI+: 334


 


117
26




ESI+: 435


 


118
25




EI+: 260


 


27
27




EI+: 264


 


28
28




EI+: 222


 


119
21




ESI+: 484



















TABLE 14





PEx
PSyn
Str
DATA







120
21




ESI+: 429


 


121
21




FAB+: 352


 


122
22




FAB+: 437


 


123
21




ESI+: 428


 


124
29




CI+: 291


 


125
24




CI+: 201


 


126
21




ESI+: 462


 


127
21




FAB+: 453



















TABLE 15





PEx
PSyn
Str
DATA


















128
29




EI+: 314


 


129
24




EI+: 224


 


130
21




ESI+: 486


 


29
29




ESI+: 275


 


131
24




NMR2: 1.70-1.81(2H, m), 1.81- 1.93(2H, m), 3.73(2H, dd, J = 6.4, 6.4 Hz), 3.97(2H, dd, J = 6.4, 6.4 Hz), 6.83(2H, dd, J = 9.2, 4.4 Hz), 6.96(2H, dd, J = 9.2, 9.2 Hz)


 


132
21




ESI+: 446


 


133
21




ESI+: 498


 


134
29




CI+: 249



















TABLE 16





PEx
PSyn
Str
DATA







135
24




CI+: 159


 


136
21




FAB+: 420


 


137
21




FAB+: 436


 


138
29




NMR2: 1.17(6H, s), 1.64- 1.70(4H, m), 1.78(2H, t, J = 7.2 Hz), 3.18(3H, s), 3.40- 3.44(2H, m), 3.45-3.51(4H, m), 4.50(2H, s), 7.26-7.35(5H, m)


 


139
24




CI+: 191


 


140
21




FAB+: 452


 


141
29




EI+: 276


 


142
24




CI+: 187



















TABLE 17





PEx
PSyn
Str
DATA







143
21




FAB+: 448


 


144
21




FAB+: 408


 


145
29




ESI+: 364


 


146
24




NMR2: 1.45(9H, s), 1.47- 1.57(2H, m), 1.63-1.74(4H, m), 1.78-1.88(2H, m), 2.05(1H, br s), 3.03-3.14(2H, m), 3.43- 3.50(1H, m), 3.48-3.54(2H, m), 3.62-3.68(2H, m), 3.71-3.80(2H, m)


 


147
21




ESI+: 535


 


148
29




ESI+: 342


 


149
24




ESI+: 252



















TABLE 18





PEx
PSyn
Str
DATA


















150
21




ESI+: 513


 


30
30




CI+: 207


 


31
31




CI+: 221


 


151
24




CI+: 131


 


152
21




ESI+: 392


 


153
29




NMR2: 0.89(9H, s), 1.63- 1.70(4H, m), 3.04(2H, s), 3.42(2H, t, J = 6.1 Hz), 3.50(2H, t, J = 6.3 Hz), 4.51(2H, s), 7.25- 7.35(5H, m)


 


24
24




CI+: 161


 


154
21




FAB+: 422



















TABLE 19





PEx
PSyn
Str
DATA







155
21




FAB+: 372


 


156
21




FAB+: 428


 


157
22




FAB+: 469


 


158
22
 


 
FAB+: 511


 


159
22




FAB+: 495, 497


 


160
22




FAB+: 441



















TABLE 20





PEx
PSyn
Str
DATA







161
22




FAB+: 491


 


162
22




FAB+: 445


 


163
22




ESI+: 499


 


164
32




EI+: 220


 


165
21
 


 
FAB+: 482


 


166
32




FAB+: 209



















TABLE 21





PEx
PSyn
Str
DATA







167
21




FAB+: 470


 


168
21
 


 
ESI+: 442


 


169
32




EI+: 210


 


170
21




FAB+: 472


 


 33
33




CI+: 129


 


171
25




ESI+: 374


 


172
22




ESI+: 441



















TABLE 22





PEx
PSyn
Str
DATA







173
14




ESI+: 420


 


174
26
 


 
ESI+: 442


 


175
30




FAB+: 221


 


176
31




CI+: 235


 


177
24




CI+: 145


 


178
21




ESI+: 406


 


179
23




FAB+: 456


 


180
21




ESI+: 461



















TABLE 23





PEx
PSyn
Str
DATA







181
21




FAB+: 500


 


182
21




ESI+: 500


 


183
21




FAB+: 444


 


 23
23
 


 
FAB+: 542


 


184
21




FAB+: 444



















TABLE 24





PEx
PSyn
Str
DATA







185
23
 


 
FAB+: 542


 


186
21




FAB+: 408


 


187
23




FAB+: 506


 


188
25




ESI+: 466


 


 34
34




FAB+: 327


 


189
35




CI+: 237



















TABLE 25





PEx
PSyn
Str
DATA







190
33




CI+: 235


 


191
25
 


 
ESI+: 480


 


192
21




FAB+: 444


 


193
23




FAB+: 542


 


 36
36




NMR2: 2.66 (2H, dd, J = 7.2, 7.2 Hz), 3.00 (2H, dd, J = 7.2, 7.2 Hz), 3.35-3.42 (2H, m), 3.42-3.49 (2H, m), 3.51-3.60 (2H, m), 3.66-3.76 (2H, m), 7.09-7.13 (1H, m), 7.15-7.19 (1H, m), 7.19-7.36 (5H, m), 7.86 (1H, s)



















TABLE 26





PEx
PSyn
Str
DATA







 37
37




ESI+: 524


 


194
34




FAB+: 375


 


195
24




FAB+: 285


 


196
21
 


 
FAB+: 546


 


197
36




NMR2: 0.81-0.87 (2H, m), 1.00-1.07 (2H, m), 1.69-1.78 (1H, m), 3.55-3.73 (4H, m), 3.70-3.91 (4H, m), 7.13 (1H, s), 7.22 (1H, s), 7.91 (1H,s)


 


198
37




ESI+: 460



















TABLE 27





PEx
PSyn
Str
DATA







199
21
 


 
FAB+: 442


 


200
21




NMR2: 0.90 (3H, t, J = 7.2 Hz), 1.26-1.40 (2H, m), 1.45-1.52 (2H, m), 1.86-1.95 (2H, m), 2.48 (3H, s), 3.39 (2H, t, J = 6.9 Hz), 3.51 (2H, t, J = 6.3 Hz), 3.67 (2H, t, J = 6.3 Hz), 4.82 (2H, s), 5.09 (2H, s), 7.40-7.56 (6H, m), 7.60-7.70 (1H, m), 8.02-8.12 (2H, m)


 


 38
38




ESI+: 422


 


 39
39




ESI+: 322


 


 40
40




ESI+: 439



















TABLE 28





PEx
PSyn
Str
DATA







201
21




FAB+: 390


 


202
23




FAB+: 488


 


203
32




EI+: 226


 


204
21
 


 
FAB+: 488


 


205
32




NMR2: 1.38-1.52 (2H, m), 1.71-1.78 (2H, m), 1.98-2.10 (1H, m), 2.27 (3H, s), 3.44 (2H, td, J = 11.9, 1.3 Hz), 3.76 (2H, d, J = 6.5 Hz), 4.01 (2H, dd, J = 10.4, 3.2 Hz), 4.69 (1H, s), 6.21 (1H, t, J = 2.2 Hz), 6.25 (1H, s), 6.31 (1H, s)



















TABLE 29





PEx
PSyn
Str
DATA







206
21
 


 
ESI+: 484


 


207
21




FAB+: 373


 


208
23




FAB+: 471


 


209
23




FAB+: 471


 


210
32




EI+: 238



















TABLE 30





PEx
PSyn
Str
DATA







211
21




ESI+: 500


 


212
32




EI+: 224


 


213
21




FAB+: 486


 


214
32




EI+: 251


 


215
21
 


 
ESI+: 513



















TABLE 31





PEx
PSyn
Str
DATA







216
32




ESI−: 249


 


217
21




ESI+: 512


 


 41
41




EI+: 224


 


218
21




FAB+: 486


 


219
21




ESI+: 488


 


220
21
 


 
ESI+: 548, 550



















TABLE 32





PEx
PSyn
Str
DATA







221
42




FAB+: 398


 


222
43




FAB+: 298


 


223
16




FAB+: 340


 


224
35




EI+: 249


 


225
21
 


 
FAB+: 511


 


226
21




ESI+: 462



















TABLE 33





PEx
PSyn
Str
DATA







227
21




ESI+: 484


 


228
21




FAB+: 500


 


229
21




ESI+: 504, 506


 


 44
44




FAB+: 376


 


230
35




FAB+: 286


 


231
21
 


 
FAB+: 547



















TABLE 34





PEx
PSyn
Str
DATA


















232
32




ESI−: 232


 


233
21




ESI−: 493


 


234
42




FAB+: 347


 


235
35




FAB+: 257


 


236
21




ESI+: 518


 


237
42




ESI+: 314



















TABLE 35





PEx
PSyn
Str
DATA


















238
35




FAB+: 224


 


239
21




FAB+: 485


 


45
45




CI+: 238


 


240
21




ESI+: 499


 


46
46




ESI+: 542


 


241
21




FAB+: 365


 


47
47




ESI+: 547



















TABLE 36





PEx
PSyn
Str
DATA


















242
16




ESI+: 407


 


243
42




CI+: 313


 


244
35




EI+: 222


 


245
21




ESI+: 484


 


246
42




NMR2: 1.87-1.99 (2H, m), 2.22 (2H, t, J = 8.1), 3.44 (2H, t, J = 7.0), 3.53 (2H, t, J = 5.5), 4.06 (2H, t, J = 5.5 Hz), 5.09 (2H, s), 6.55 (1H, d, J = 2.0 Hz), 6.60- 6.62 (2H, m), 7.16-7.20 (1H, m), 7.31-7.46 (5H, m)


 


247
35




CI+: 222



















TABLE 37





PEx
PSyn
Str
DATA


















248
21




ESI+: 483


 


249
21




ESI+: 490, 492


 


250
23




NMR2: 1.27-1.42 (2H, m), 1.62- 1.70 (2H, m), 1.79-1.94 (1H, m), 3.34 (2H, d, J = 6.5 Hz), 3.40 (2H, ddd, J = 11.9, 11.6, 2.2 Hz), 3.54 (2H, dd, J = 4.7, 4.2 Hz), 3.74 (2H, dd, J = 4.9, 4.1 Hz), 3.98 (2H, dd, J = 9.0, 3.6 Hz)


 


251
42




NMR2: 1.24-1.40 (2H, m), 1.63- 1.71 (2H, m), 1.82-1.95 (1H, m), 3.34-3.44 (4H, m), 3.77 (2H, dd, J = 4.7, 4.7 Hz), 3.97 (2H, dd, J = 11.3, 4.5 Hz), 4.09 (2H, dd, J = 5.2, 4.5 Hz), 5.04 (2H, s), 6.51−6.61 (3H, m), 7.71 (1H, dd, J = 8.4, 8.1 Hz), 7.30-7.46 (5H, m)


 


252
35




ESI−: 251



















TABLE 38





PEx
PSyn
Str
DATA


















253
21




ESI+: 514


 


254
17




ESI+: 388


 


255
23




ESI+: 486


 


256
42




EI+: 298


 


257
35




EI+: 208


 


258
21




FAB+: 470


 


259
16




EI+: 235



















TABLE 39





PEx
PSyn
Str
DATA


















260
21




FAB+: 497


 


261
45




EI+: 221


 


262
21




FAB+: 483


 


263
21




FAB+: 498


 


264
32




ESI−: 225


 


265
21




ESI−: 486



















TABLE 40





PEx
PSyn
Str
DATA


















266
47




ESI+: 548


 


267
42




EI+: 305


 


268
35




EI+: 215


 


269
21




ESI+: 477


 


270
42




NMR2: 1.22-1.35 (2H, m), 1.35- l.47 (2H, m), 1.47-1.58 (1H, m), 1.58-1.68 (2H, m), 1.74-1.84 (2H, m), 3.38 (2H, td, J = 11.6, 1.7 Hz), 3.87-4.01 (4H, m), 5.01 (2H, s), 6.49-6.60 (3H, m), 7.17 (1H, dd, J = 8.5, 8.5 Hz), 7.28- 7.49 (5H, m)



















TABLE 41





PEx
PSyn
Str
DATA


















271
35




NMR2: 1.23-1.36 (2H, m), 1.36- 1.46 (2H, m), 1.46-1.57 (1H, m), 1.60-1.68 (2H, m), 1.75-1.84 (2H, m), 3.39 (2H, td, J = 12.2, 1.9 Hz), 3.92 (2H, dd, J = 6.9, 6.7 Hz), 3.97 (2H, dd, J = 10.9, 3.7 Hz), 4.92 (1H, s), 6.37-6.43 (2H, m), 6.46-6.50 (1H, m), 7.12 (1H, dd, J = 8.2, 7.7 Hz)


 


272
21




ESI+: 498


 


273
42




EI+: 305


 


274
35




ESI+: 216


 


275
21




ESI+: 477


 


48
48




ESI+: 567



















TABLE 42





PEx
PSyn
Str
DATA


















276
21




ESI+: 532


 


42
42




FAB+: 355


 


35
35




EI+: 264


 


49
49




EI+: 220


 


277
21




ESI+: 482


 


278
42




EI+: 305


 


279
35




ESI+: 216



















TABLE 43





PEx
PSyn
Str
DATA


















280
21




ESI+: 477


 


281
21




ESI+: 479


 


282
50




CI+: 296


 


26
26




ESI+: 539


 


283
32




ESI+: 210


 


284
21




ESI+: 471



















TABLE 44





PEx
PSyn
Str
DATA


















285
21




FAB+: 503


 


57
57




ESI+: 210


 


286
21




FAB+: 489


 


287
51




EI+: 323


 


288
35




EI+: 233


 


289
21




ESI+: 495



















TABLE 45





PEx
PSyn
Str
DATA


















290
16




ESI+: 172


 


291
21




ESI+: 451


 


292
21




ESI+: 471


 


293
51




EI+: 341


 


294
35




EI+: 251


 


295
21




ESI+: 513


 


51
51




EI+: 267



















TABLE 46





PEx
PSyn
Str
DATA


















296
35




ESI+: 178


 


297
21




ESI+: 439


 


298
21




ESI+: 441


 


299
35




EI+: 307


 


300
21




ESI+: 569


 


43
43




ESI+: 469



















TABLE 47





PEx
PSyn
Str
DATA


















301
16




ESI+: 274


 


302
31




ESI+: 288


 


303
35




NMR1: 0-0.06 (2H, m), 0.33- 0.40 (2H, m), 0.64-0.77 (1H, m), 1.12-l.25 (1H, m), l.25-l.37 (1H, m), l.37 (2H, dd, J = 14.8, 7.2 Hz), 1.61-1.69 (1H, m), 1.69- 1.77 (1H, m), 2.36 (2H, dd, J = 7.6, 7.2 Hz), 2.89-3.01 (1H, m), 3.08-3.19 (1H, m), 3.63- 3.73 (2H, m), 3.85-3.96 (1H, m), 4.73 (1H, d, J = 4.0 Hz)


 


304
21




ESI+: 477


 


305
23




EI+: 286


 


306
35




EI+: 196



















TABLE 48





PEx
PSyn
Str
DATA


















307
21




ESI+: 458


 


308
16




EI+: 247


 


309
21




ESI+: 509


 


50
50




EI+: 211


 


310
26




ESI+: 471


 


311
16




ESI+: 304



















TABLE 49





PEx
PSyn
Str
DATA







312
24




ESI+: 214


 


313
21




ESI+: 493


 


314
16




ESI+: 318


 


315
24




ESI+: 228


 


316
21




ESI+: 507


 


317
16




EI+: 213



















TABLE 50





PEx
PSyn
Str
DATA







318
21




ESI+: 475


 


319
42




FAB+: 384


 


320
35




FAB+: 294


 


321
43




ESI+: 284


 


322
16




EI+: 325


 


323
35




EI+: 235


 


324
21




ESI+: 497



















TABLE 51





PEx
PSyn
Str
DATA







325
16




ESI+: 396


 


326
35




EI+: 305


 


327
21




ESI+: 567


 


328
16




ESI+: 410


 


329
35




EI+: 319


 


330
21




ESI+: 581



















TABLE 52





PEx
PSyn
Str
DATA







331
21




ESI+: 515


 


332
21




ESI+: 585


 


333
21




ESI+: 599


 


334
21




ESI+: 489


 


335
21




NMR1: 2.04(3H, s), 2.44(3H, s), 3.06-3.13(2H, m), 3.13-3.20(2H, m), 3.51-3.60(4H, m), 5.13(2H, s), 5.34(2H, s), 6.52-6.61(2H, m), 6.66-6.71(1H, m), 7.14(1H, dd, J = 8.4, 8.4 Hz), 7.38-7.47(3H, m), 7.50-7.57(2H, m), 7.61- 7.70(2H, m), 8.10(1H, dd, J = 10.0, 5.2 Hz)



















TABLE 53





PEx
PSyn
Str
DATA







336
21




ESI+: 476


 


52
52




NMR2: 1.14-1.30(2H, m), 1.43- 1.53(2H, m), 1.54-1.71(3H, m), 2.46(3H, s), 3.26-3.37(2H, m), 3.86-3.94(2H, m), 4.08(2H, t, J = 6.3 Hz), 7.35(2H, d, J = 8.2 Hz), 7.80(2H, d, J = 8.2 Hz)


 


32
32




ESI+: 224


 


337
21




ESI+: 485


 


338
42




EI+: 256


 


53
53




EI+: 272



















TABLE 54





PEx
PSyn
Str
DATA







339
35




EI+: 182


 


340
21




ESI+: 462


 


341
21




ESI+: 503


 


342
16




ESI+: 276


 


343
21




ESI+: 555


 


344
51




ESI+: 282



















TABLE 55





PEx
PSyn
Str
DATA







345
35




ESI+: 192


 


346
21




ESI+: 471


 


347
32




ESI−: 222


 


348
21




ESI+: 485


 


349
32




FAB+: 198


 


350
21




ESI+: 459


 


351
42




EI+: 268



















TABLE 56





PEx
PSyn
Str
DATA







54
54




EI+: 284


 


352
53




EI+: 300


 


353
24




EI+: 210


 


354
21




ESI+: 472


 


355
21




ESI+: 490


 


356
16




FAB+: 262


 


357
21




ESI+: 541



















TABLE 57





PEx
PSyn
Str
DATA







358
16




FAB+: 276


 


359
21




ESI+: 555


 


360
16




FAB+: 262


 


361
21




ESI+: 541


 


362
16




FAB+: 276


 


363
21




ESI+: 555



















TABLE 58





PEx
PSyn
Str
DATA







364
16




FAB+: 262


 


365
21




ESI+: 541


 


366
16




EI+: 275


 


367
21




ESI+: 555


 


368
16




FAB+: 262


 


369
21




ESI+: 541



















TABLE 59





PEx
PSyn
Str
DATA







370
16




ESI+: 276


 


371
21




ESI+: 555


 


372
16




FAB+: 262


 


373
21




ESI+: 541


 


374
52




CI+: 301


 


375
32




EI+: 328


 


376
35




EI+: 238



















TABLE 60





PEx
PSyn
Str
DATA







377
21




ESI+: 500


 


378
52




EI+: 270


 


379
32




EI+: 209


 


380
21




ESI+: 471


 


381
21




ESI+: 435


 


382
32




ESI+: 212



















TABLE 61





PEx
PSyn
Str
DATA







383
33




NMR2: 1.33(6H, s), 2.04(2H, t, J = 6.1 Hz), 3.91(1H, br s), 4.29(2H, t, J = 6.6 Hz), 7.03(1H, dd, J = 5.6, 2.5 Hz), 7.49(1H, d, J = 2.5 Hz), 8.59(1H, d, J = 5.6 Hz), 10.04(1H, s)


 


384
25




ESI+: 455


 


385
32




ESI+: 237


 


386
21




ESI+: 498


 


387
45




ESI−: 249


 


388
21




ESI−: 510



















TABLE 62





PEx
PSyn
Str
DATA







389
32




ESI+: 184


 


390
21




ESI+: 445


 


391
32




ESI+: 240


 


392
21




ESI+: 501


 


393
32




NMR2: 1.36-1.54(2H, m), 1.49(9H, s), 1.70-1.81(2H, m), 2.05(1H, m), 2.79(2H, t, J = 6 Hz), 3.44(2H, ddd, J = 11.7, 11.7, 1.7 Hz), 3.62(2H, br s), 3.78(2H, d, J = 6.5 Hz), 3.96- 4.06(2H, m), 4.50(2H, s), 6.66(1H, d, J = 2 Hz), 6.74(1H, dd, J = 8.5, 2 Hz), 7.01(1H, d, J = 8.5 Hz)


 


394
43




ESI+: 248



















TABLE 63





PEx
PSyn
Str
DATA







395
55




ESI+: 509


 


55
55




ESI+: 446


 


396
26




CI+: 143


 


397
21




ESI+: 404


 


398
32




ESI+: 240


 


399
21




ESI+: 501


 


400
49




ESI+: 457



















TABLE 64





PEx
PSyn
Str
DATA







401
52




CI+: 271


 


402
32




EI+: 298


 


403
35




NMR2: 1.50-1.63(2H, m), 1.73- 1.87(1H, m), 2.05-2.l9(6H, m), 4.19(2H, t, J = 5.9 Hz), 5.73(1H, s), 6.40(1H, m), 6.48(2H, m), 7.14(1H, m)


 


404
21




ESI+: 470


 


405
32




ESI+: 224


 


406
33




NMR2: 1.41-1.54(2H, m), 1.72- 1.81(2H, m), 2.05-2.18(1H, m), 3.40-3.51(2H, m), 3.93(2H, d, J = 6.5 Hz), 4.04(2H, dd, J = 11.6, 4.3 Hz), 7.01(1H, dd, J = 5.6, 2.6 Hz), 7.46(1H, d, J = 2.5 Hz), 8.59(1H, d, J = 5.6 Hz), 10.04 (1H, s)



















TABLE 65





PEx
PSyn
Str
DATA







407
25




ESI+: 467


 


56
56




ESI+: 500


 


408
51




ESI+: 284


 


409
35




ESI+: 194


 


410
21




ESI+: 455


 


411
32




ESI+: 212


 


412
21




ESI+: 473



















TABLE 66





PEx
PSyn
Str
DATA







413
29




ESI+: 286, 288


 


414
57




ESI+: 224


 


415
21




ESI+: 485


 


416
53




ESI+: 473


 


417
32




FAB+: 168


 


418
21




ESI+: 429


 


419
53




ESI+: 445



















TABLE 67





PEx
PSyn
Str
DATA







420
32




ESI+: 196


 


421
21




ESI+: 457


 


422
21




ESI+: 512


 


423
32




ESI+: 260, 262


 


424
57




ESI+: 198


 


425
21




ESI+: 459


 


426
66




EI+: 342


 


427
35




EI+: 252



















TABLE 68





PEx
PSyn
Str
DATA







428
21




ESI+: 514


 


429
32




EI+: 287


 


430
43




ESI+: 188


 


431
51




EI+: 369


 


432
35




EI+: 279


 


433
21




ESI+: 541


 


434
52




FAB+: 273



















TABLE 69





PEx
PSyn
Str
DATA







435
32




EI+: 301


 


436
43




ESI+: 202


 


437
51




EI+: 383


 


438
35




EI+: 293


 


439
21




ESI+: 555


 


440
52




EI+: 256


 


441
32




FAB+: 196


 


442
21




ESI+: 457



















TABLE 70





PEx
PSyn
Str
DATA







443
32




EI+: 276, 278


 


444
26




NMR2: 1.30(6H, s), 1.97(2H, t, J = 6.3 Hz), 4.12(2H, t, J = 6.3 Hz), 4.70(1H, m), 5.01(2H, s), 6.46(1H, m), 6.69(1H, m), 6.76(1H, m), 7.38(5H, m)


 


445
51




EI+: 371


 


446
35




EI+: 281


 


447
21




FAB+: 543



















TABLE 71





PEx
PSyn
Str
DATA







448
32




NMR2: 1.32(6H, s), 1.98(2H, t, J = 6.0 Hz), 3.76(3H, s), 4.15(2H, t, J = 6.0 Hz), 5.97- 6.02(1H, m), 6.02−6.08(2H, m)


 


449
21




ESI+: 488


 


450
51




EI+: 283


 


451
35




EI+: 193


 


452
21




ESI+: 455



















TABLE 72





PEx
PSyn
Str
DATA







453
51




NMR2: 1.29(3H, s), 1.56(1H, s), 1.64-1.81(4H, m), 3.14-3.22(2H, m), 3.30-3.37(2H, m), 5.04(2H, s), 6.46(1H, dd, J = 1.6, 7.5 Hz), 6.56-6.60(2H, m), 7.16(1H, t, J = 8.6 Hz), 7.29-7.45(5H, m)


 


454
35




EI+: 207


 


455
21




FAB+: 469


 


456
20




NMR2: 1.44-1.57(2H, m), 1.66- 1.74(2H, m), 3.39-3.54(3H, m), 3.92−4.01(2H, m), 5.12(2H, s), 5.58(1H, dd, J = 11.9, 9.5 Hz), 6.32(1H, d, J = 11.7 Hz), 7.10(1H, d, J = 8.8 Hz), 7.20(1H, dd, J = 8.6, 2.9 Hz), 7.29-7.46(5H, m), 8.37(1H, d, J = 3.2 Hz) ESI+: 296



















TABLE 73





PEx
PSyn
Str
DATA


















457
20




NMR2: 1.46-1.66(2H, m), 1.68- 1.77(2H, m), 2.34-2.48(1H, m), 3.42-3.52(2H, m), 3.98-4.05(2H, m), 5.11(2H, s), 6.42(1H, d, J = 16.0 Hz), 6.52(1H, dd, J = 16.0, 6.3 Hz), 7.17-7.50(7H, m), 8.30- 8.33(1H, m) ESI+: 296


 


458
35




ESI+: 208


 


459
21




ESI+: 469


 


58
58




ESI+: 226


 


460
26




ESI+: 485



















TABLE 74





PEx
PSyn
Str
DATA


















59
59




NMR2: l.51-1.65(2H, m), 1.72- l.83(1H, m), l.87-1.94(2H, m), 1.97-2.16(4H, m), 2.62-2.70(2H, m), 5.05(2H, s), 6.91(2H, d, J = 8.3 Hz), 7.14(2H, d, J = 8.7 Hz), 7.31-7.47(5H, m)


 


461
35




ESI−: 191


 


462
21




ESI+: 454


 


463
21




ESI+: 362


 


464
21




EI+: 365


 


60
60




ESI+: 479



















TABLE 75





PEx
PSyn
Str
DATA


















465
21




ESI+: 406


 


466
16




NMR2: 1.40-1.57(2H, m), 1.52- 1.63(2H, m), 1.69-1.79(2H, m), 1.78-1.86(4H, m), 1.85-199(2H, m), 2.91(1H, q, J = 8.1 Hz), 3.08-3.34(2H, m), 3.74-3.90(1H, m), 3.88-4.01(1H, m), 4.06- 4.23(1H, m)


 


467
21




ESI+: 459


 


468
21




ESI+: 449


 


469
21




FAB+: 364



















TABLE 76





PEx
PSyn
Str
DATA


















470
60




ESI+: 477


 


471
20




NMR2: 1.46-1.66(4H, m), 2.68- 2.81(1H, m), 3.38-3.48(2H, m), 3.92−4.00(2H, m), 5.39(2H, s), 5.52(1H, dd, J = 11.6, 10.0 Hz), 6.27(1H, d, J = 11.6 Hz), 6.80(1H, d, J = 8.6 Hz), 7.28- 7.43(3H, m), 7.43-7.50(3H, m), 8.09(1H, d, J = 2.3 Hz)


 


472
20




NMR2: 1.53-1.62(2H, m), 1.66- 1.74(2H, m), 2.29-2.43(1H, m), 3.42-3.51(2H, m), 3.98-4.04(2H, m), 5.37(2H, s), 6.05(1H, dd, J = 16.0, 6.7 Hz), 6.32(1H, d, J = 16.2 Hz), 6.77(1H, d, J = 8.6 Hz), 7.29-7.42(3H, m), 7.43- 7.48(2H, m), 7.66(1H, dd, J = 8.7, 3.0 Hz), 8.08(1H, d, J = 2.5 Hz)


 


473
35




ESI+: 208



















TABLE 77





PEx
PSyn
Str
DATA


















474
21




ESI+: 469


 


475
33




NMR2: 0.68-0.85(2H, m), 0.89- 1.05(2H, m), 1.49-1.72(2H, m), 1.68-1.84(1H, m), 1.88-2.06(2H, m), 2.45-2.63(1H, m), 2.80- 3.17(1H, m), 3.07-3.46(1H, m), 3.92−4.50(2H, m), 9.70(1H, s)


 


476
25




ESI+: 427


 


477
36




NMR2: 1.50-1.66(2H, m), 1.71- 1.83(2H, m), 1.77-1.94(4H, m), 2.91(1H, q, J = 8.7 Hz), 3.53- 3.71(6H, m), 3.67-3.80(2H, m), 7.14(1H, s), 7.22(1H, s), 7.92(1H, s)


 


478
37




ESI+: 488



















TABLE 78





PEx
PSyn
Str
DATA


















479
36




NMR2: 1.28-1.41(1H, m), 1.35- 1.46(1H, m), 1.59-1.73(2H, m), 1.81-2.02(1 H, m), 3.33-3.46(2H, m), 3.34(2H, dd, J = 6.6, 6.6 Hz), 3.93-4.06(2H, m), 6.12−6.25(1H, m), 7.10(1H, s), 7.36(1H, s), 8.16(1H, s)


 


480
22




ESI+: 421


 


481
21




ESI+: 364


 


482
16




ESI+: 250


 


483
21




ESI+: 511



















TABLE 79





PEx
PSyn
Str
DATA







484
16




ESI+: 248


 


485
21




ESI+: 509


 


486
53




ESI+: 525


 


487
20




NMR2: 1.47-1.72(4H, m), 2.75-  2.88(1H, m), 3.36-3.48(2H, m), 3.92-4.00(2H, m), 5.08(2H, s), 5.40(1H, dd, J = 11.7, 10.3 Hz), 6.32(1H, d, J = 11.7 Hz), 6.95(2H, d, J = 8.9 Hz), 7.18(2H, d, J = 8.9 Hz), 7.28- 7.47(5H, m)


 


488
35




NMR2: 1.24-1.37(2H, m), 1.44-  1.69(5H, m), 2.56(2H, dd, J = 8.0, 7.6 Hz), 3.32-3.40(2H, m), 3.96(2H, dd, J = 11.4, 4.2 Hz), 4.65(1H, s), 6.75(2H, d, J = 8.5 Hz), 7.04(2H, d, J = 8.5 Hz)



















TABLE 80





PEx
PSyn
Str
DATA


















489
21




ESI+: 468


 


61
61




NMR2: 1.71-1.88(6H, m), 1.88- 2.06(4H, m), 2.82-2.89(2H, m), 5.19(2H, s), 7.05(2H, d, J = 8.8 Hz), 7.28(2H, d, J = 8.4 Hz), 7.43-7.61(5H, m)


 


490
35




NMR2: 1.56-1.74(6H, m), 1.74- 1.91(4H, m), 2.65-2.74(2H, m), 6.75(2H, d, J = 8.3 Hz), 7.08(2H, d, J = 8.3 Hz)


 


491
21




ESI+: 468


 


492
52




FAB+: 259


 


493
26




ESI+: 366



















TABLE 81





PEx
PSyn
Str
DATA







494
21




NMR2: 2.46(3H, s), 5.10(2H, s), 5.66(2H, s), 6.86(1H, d, J = 7.6 Hz), 6.88-6.94(1H, m), 7.37-7.47(3H, m), 7.48-7.52(2H, m), 7.51-7.55(1H, m), 7.60(1H, ddd, J = 9.2, 7.2, 2.4 Hz), 7.63-7.70(1H, m), 8.04-8.08(1H, m), 8.08-8.15(1H, m), 8.17-8.22(1H, m)


 


495
26




ESI+: 405


 


496
25




NMR2: 1.42-1.55(11H, m), 1.82- 1.91(2H, m), 2.40(3H, s), 2.41-2.49(1H, m), 2.74-2.90(2H, m), 4.06-4.30(2H,  m), 5.05(2H, s), 6.81(1H, dd, J = 15.4, 1.2 Hz), 7.04(1H, dd, J = 15.5, 6.8 Hz), 7.37-7.47(4H, m), 7.49-7.53(2H, m),  7.59-7.64(1H, m), 7.97-8.05(2H, m) ESI+: 459



















TABLE 82





PEx
PSyn
Str
DATA







497
43




NMR1: 1.64-1.82(2H, m), 1.97- 2.08(2H, m), 2.44(3H, s), 2.65- 2.78(1H, m), 2.90-3.08(2H, m), 3.27-3.36(2H, m), 5.29(2H, s), 6.93(1H, d, J = 15.9 Hz), 7.17(1H, dd, J = 15.5, 5.6 Hz), 7.38-7.50(3H, m), 7.53-7.59(2H, m), 7.66-7.76(1H, m), 7.87- 7.97(1H, m), 8.12(IH, d, J = 8.1 Hz), 8.31-8.43(1H, m),  8.63-8.79(1H, m), 8.79-8.94(1H, m) ESI+: 359


 


498
16




ESI+: 441


 


499
16




ESI+: 471



















TABLE 83





PEx
PSyn
Str
DATA


















62
62




NMR2: 2.38(3H, s), 5.42(2H, s), 6.64(1H, d, J = 16.1 Hz), 6.85(1H, d, J = 8.8 Hz), 7.28- 7.42(3H, m), 7.43-7.51(3H, m), 7.82(1H, dd, J = 8.6, 2.5 Hz), 8.31(1H, d, J = 2.5 Hz)


 


500
35




NMR2: 2.14(3H, s), 2.61- 2.73(4H, m), 6.54(1H, d, J = 9.4 Hz), 7.17(1H, d, J = 2.4 Hz), 7.35(1H, dd, J = 9.3, 2.4 Hz) ESI+: 166


 


501
21




ESI+: 427


 


502
53




ESI+: 443


 


503
16




ESI+: 441



















TABLE 84





PEx
PSyn
Str
DATA


















504
16




ESI+: 431


 


505
21




ESI+: 477


 


506
43




ESI+: 377


 


63
63




ESI+: 448


 


64
64




ESI+: 469



















TABLE 85





PEx
PSyn
Str
DATA


















65
65




ESI+: 445


 


507
25




ESI+: 493


 


508
16




ESI+: 473


 


509
66




ESI+: 463


 


510
26




ESI+: 458



















TABLE 86





PEx
PSyn
Str
DATA







511
21




FAB+: 405


 


512
16




FAB+: 517


 


513
25




ESI+: 507


 


514
16




ESI+: 457


 


515
53




ESI+: 473


 


516
26




ESI+: 436, 438



















TABLE 87





PEx
PSyn
Str
DATA


















67
67




ESI+: 416


 


68
68




ESI+: 402


 


517
45




ESI+: 469


 


518
45




ESI+: 523


 


519
45




ESI+: 455



















TABLE 88





PEx
PSyn
Str
DATA


















66
66




ESI+: 487


 


520
51




NMR2: 2.10-2.20(2H, m), 2.61(2H, t, J = 8.2 Hz), 3.84(2H, t, J = 7.1 Hz), 5.08(2H, s), 6.75- 6.79(1H, m), 7.13-7.17(1H, m), 7.24-7.47(7H, m) ESI+: 268


 


521
35




ESI+: 178


 


522
21




ESI+: 439


 


523
51




ESI+: 282


 


524
35




ESI+: 192



















TABLE 89





PEx
PSyn
Str
DATA







525
21




ESI+: 453


 


526
51




ESI+: 296


 


527
35




ESI+: 206


 


528
21




ESI+: 467


 


529
37




ESI+: 393


 


530
36




NMR2: 1.27(6H, s), 1.64- 1.88(2H, m), 1.76-1.87(2H, m), 1 .84-2.05(2H, m), 1.87-2.50(2H, m), 3.37-3.57(2H, m), 3.57- 3.71(1H, m), 3.68-3.82(3H, m), 7.10(1H, s), 7.19(1H, s),  7.86(1H, s)



















TABLE 90





PEx
PSyn
Str
DATA







531
37




ESI+: 493


 


532
36




NMR2: 1.68-1.81(2H, m), 1.81- 1.97(2H, m), 3.38(3H, s), 3.40- 3.53(2H, m), 3.47-3.58(1H, m), 3.65-3.81(2H, m), 7.10(1H, s), 7.19(1H, s), 7.86(1H, s)


 


533
37




ESI+: 421


 


534
36




NMR2: 1.19(6H, s), 1.66- 1.79(2H, m), 1.80(2H, t, J = 7.2 Hz), 1.83-1.96(2H, m), 3.19(3H, s), 3.47(2H, ddd, J = 13.2, 7.8, 3.9 Hz), 3.56(2H, t, J = 7.2 Hz), 3.57-3.65(1H, m), 3.75(2H, ddd, J = 12.6, 7.8, 3.3 Hz), 7.09(1H, s), 7.19(1H, s), 7.86(1H, s)


 


535
37




ESI+: 507



















TABLE 91





PEx
PSyn
Str
DATA


















536
21




ESI+: 434, 436


 


537
51




ESI+: 441


 


538
21




ESI+: 402


 


69
69




ESI+: 534


 


539
51




ESI+: 485



















TABLE 92





PEx
PSyn
Str
DATA







540
16




ESI+: 487


 


541
16




ESI+: 459


 


542
16




ESI+: 459


 


543
16




ESI+: 503


 


544
16




ESI+: 489



















TABLE 93





PEx
PSyn
Str
DATA







545
16




ESI+: 477


 


546
65




ESI+: 481


 


547
21




ESI+: 452, 454


 


548
51




ESI+: 473


 


549
36




NMR2: 1.70-1.86(2H, m), 1.91- 2.05(2H, m), 2.09(3H, s), 3.52(2H, ddd, J = 12.9, 7.8, 3.9 Hz), 3.80(2H, ddd, J = 12.9, 7.5, 3.9 Hz), 4.99-5.11(1H, m), 7.11(1H, s), 7.17-7.22(1H, m), 7.87(1H, s)



















TABLE 94





PEx
PSyn
Str
DATA


















550
37




ESI+: 449


 


551
6




ESI+: 407


 


552
21




ESI+: 386


 


553
69




ESI+: 518


 


554
51




ESI+: 469



















TABLE 95





PEx
PSyn
Str
DATA


















555
66




ESI+: 435


 


556
25




ESI+: 445


 


557
64




ESI+: 481


 


558
51




ESI+: 483


 


559
51




ESI+: 298


 


560
35




ESI+: 208



















TABLE 96





PEx
PSyn
Str
DATA


















561
21




ESI+: 469


 


562
21




ESI+: 487


 


563
55




ESI+: 462


 


564
43




ESI+: 362


 


565
16




ESI+: 446

















TABLE 97





Ex
Str
















1






 


24






 


25






 


26






 


27






 


28






 


29






 


30






 


31






 


32






 


2






 


33





















TABLE 98





Ex
Str







34






 


35






 


36






 


37






 


38






 


39






 


40






 


41






 


42






 


43






 


44






 


45






 


46






 


47





















TABLE 99





Ex
Str







48






 


49






 


50






 


51






 


52






 


53






 


54






 


55






 


56






 


57






 


58






 


59






 


60






 


61





















TABLE 100





Ex
Str







62






 


63






 


64






 


65






 


66






 


67






 


68






 


69






 


70






 


71






 


72






 


73






 


74





















TABLE 101





Ex
Str







75






 


76






 


77






 


78






 


79






 


80






 


81






 


82






 


83






 


84






 


85





















TABLE 102





Ex
Str
















86






 


87






 


88






 


89






 


90






 


91






 


92






 


93






 


94






 


95






 


96





















TABLE 103





Ex
Str
















97






 


98






 


99






 


100






 


101






 


102






 


103






 


104






 


105






 


106






 


107






 


108






 


109





















TABLE 104





Ex
Str
















110






 


111






 


112






 


113






 


114






 


115






 


116






 


117






 


118






 


119






 


120






 


121





















TABLE 105





Ex
Str







122






 


123






 


124






 


125






 


126






 


127






 


128






 


129






 


130






 


131






 


132






 


133





















TABLE 106





Ex
Str
















134






 


135






 


136






 


137






 


138






 


139






 


140






 


141






 


142






 


143






 


144





















TABLE 107





Ex
Str
















145






 


146






 


147






 


148






 


149






 


150






 


151






 


152






 


153






 


154






 


155






 


156






 


157





















TABLE 108





Ex
Str
















158






 


159






 


160






 


161






 


162






 


163






 


164






 


165






 


166






 


167






 


168






 


169






 


170





















TABLE 109





Ex
Str







171






 


172






 


173






 


174






 


175






 


176






 


177






 


178






 


179






 


180






 


181






 


182






 


183





















TABLE 110





Ex
Str







184






 


185






 


186






 


187






 


188






 


189






 


190






 


191






 


192






 


193






 


194






 


195





















TABLE 111





Ex
Str







 


196






 


197






 


198






 


199






 


200






 


201






 


202






 


203






 


204






 


205






 


206





















TABLE 112





Ex
Str







207






 


208






 


209






 


210






 


211






 


212






 


213






 


214






 


215






 


216






 


217






 


218





















TABLE 113





Ex
Str







219






 


220






 


221






 


222






 


223






 


224






 


225






 


226






 


227






 


228





















TABLE 114





Ex
Str







229






 


230






 


231






 


232






 


233






 


234






 


235






 


236






 


237






 


238






 


239





















TABLE 115





Ex
Str







240






 


241






 


242






 


243






 


244






 


245






 


246






 


247






 


248






 


249






 


250





















TABLE 116





Ex
Str
















251






 


252






 


253






 


254






 


255






 


256






 


257






 


258






 


259






 


3






 


4





















TABLE 117





Ex
Str
















5






 


6






 


7






 


8






 


9






 


10






 


11






 


260






 


12






 


261






 


262





















TABLE 118





Ex
Str
















263






 


264






 


265






 


266






 


267






 


268






 


269






 


13






 


270






 


271






 


272





















TABLE 119





Ex
Str
















273






 


274






 


275






 


14






 


276






 


277






 


15






 


278






 


16






 


279






 


17






 


18





















TABLE 120





Ex
Str
















280






 


281






 


282






 


283






 


284






 


285






 


286






 


287






 


288






 


289






 


290






 


291





















TABLE 121





Ex
Str
















292






 


293






 


294






 


295






 


19






 


296






 


297






 


20






 


298






 


299





















TABLE 122





Ex
Str
















21






 


300






 


301






 


22






 


23






















TABLE 123





Ex
Syn
DATA

















1
1
NMR1: 1.47-1.57(2H, m), 1.64-1.81(4H, m), 2.00(3H, s), 2.71(2H, t, J = 8.0 Hz),




3.95(2H, t, J = 6.4 Hz), 6.89-6.94(2H, m), 7.05-7.12(2H, m), 7.21-7.26(1H, m),




7.48(1H, d, J = 8.1 Hz), 7.54-7.59(1H, m), 8.05(1H, d, J = 7.1 Hz), 11.33(1H, s)




FAB+: 340


24
1
NMR1: 1.54-1.72(4H, m), 1.99(3H, s), 2.70(2H, t, J = 7.3 Hz), 3.23(3H, s),




3.40-3.50(6H, m), 7.21-7.26(1H, m), 7.47-7.51(1H, m), 7.54-7.60(1H, m), 8.03-8.07(1H,




m), 11.32(1H, s)




FAB+: 290


25
1
NMR1: 1.24(3H, t, J = 6.8 Hz), 1.45-1.60(2H, m), 1.64-1.76(2H, m), 1.72-1.83(2H,




m), 2.00(3H, s), 2.71(2H, dd, J = 8.0, 8.0 Hz), 3.95(2H, q, J = 6.8 Hz), 3.96(2H, dd,




J = 6.0, 6.0 Hz), 6.79-6.89(2H, m), 6.89-6.98(2H, m), 7.23(1H, dd, J = 7.2, 7.2 Hz),




7.49(1H, d, J = 8.0 Hz), 7.57(1H, td, J = 7.2, 1.2 Hz), 8.05(1H, d, J = 7.2 Hz),




11.33(1H, s)




FAB+: 366


26
1
NMR1: 1.47-1.57(2H, m), 1.65-1.82(4H, m), 2.00(3H, s), 2.71(2H, t, J = 7.6 Hz),




4.03(2H, t, J = 6.4 Hz), 6.95-7.02(1H, m), 7.13-7.29(2H, m), 7.48(1H, d, J = 8.0 Hz),




7.53-7.58(1H, m), 8.05(1H, d, J = 7.1 Hz), 11.33(1H, s)




FAB+: 358


27
1
NMR1: 1.48-1.58(2H, m), 1.62-1.72(2H, m), 1.74-1.83(2H, m), 2.01(3H, s),




2.80(2H, t, J = 7.8 Hz), 4.04(2H, t, J = 6.7 Hz), 6.96-7.02(1H, m), 7.14-7.29(3H,




m), 7.46-7.53(1H, m), 7.88(1H, d, J = 7.9 Hz), 11.29(1H, s)




FAB+: 376


















TABLE 124





Ex
Syn
DATA







28
1
NMR1: 1.46-1.58(2H, m), 1.63-1.75(2H, m), 1.72-1.84(2H, m), 2.00(3H, s),




2.71(2H, dd, J = 7.2, 7.2 Hz), 4.03(2H, dd, J = 6.8, 6.8 Hz), 6.94-7.04(1H, m),




7.17(1H, td, J = 10.0, 5.2 Hz), 7.25(1H, ddd, J = 11.6, 8.8, 2.8 Hz), 7.48(1H, td, J = 8.8,




2.8 Hz), 7.57(1H, dd, J = 9.2, 5.2 Hz), 7.68(1H, dd, J = 9.2, 2.8 Hz), 11.50(1H,




br s)




FAB+: 376




mp: 201-203° C.


29
1
NMR1: 1.46-1.57(2H, m), 1.64-1.75(2H, m), 1.75-1.84(2H, m), 2.00(3H, s),




2.66-2.75(2H, m), 4.08(2H, t, J = 6.5 Hz), 7.08(2H, d, J = 8.8 Hz), 7.21-7.26(1H, m),




7.46-7.50(1H, m), 7.54-7.59(1H, m), 7.74(2H, d, J = 8.8 Hz), 8.02-8.07(1H, m),




11.32(1H, s)




FAB+: 347


30
1
NMR1: 0.35-0.44(4H, m), 1.33-1.43(2H, m), 1.49-1.68(4H, m), 1.99(3H, s),




2.64-2.70(2H, m), 3.18-3.24(1H, m), 3.42(2H, t, J = 6.4 Hz), 7.20-7.26(1H, m),




7.47-7.51(1H, m), 7.54-7.59(1H, m), 8.02-8.07(1H, m), 11.32(1H, s)




FAB+: 286


31
1
NMR1: 1.22-1.35(2H, m), 1.60-1.68(2H, m), 1.89-2.02(4H, m), 2.85-3.00(4H, m),




3.27-3.38(2H, m), 3.75(2H, d, J = 6.5 Hz), 3.83-3.90(2H, m), 6.75-6.86(3H, m),




7.16-7.27(2H, m), 7.47-7.52(1H, m), 7.55-7.61(1H, m), 8.03-8.08(1H, m), 11.37(1H,




s)




FAB+: 378


32
1
NMR1: 1.46-1.56(2H, m), 1.64-1.76(2H, m), 1.76-1.87(2H, m), 2.00(3H, s),




2.66-2.75(2H, m), 4.45(2H, t, J = 6.5 Hz), 7.20-7.27(1H, m), 7.44-7.51(2H, m),




7.53-7.60(1H, m), 8.02-8.08(1H, m), 8.98(1H, s), 11.32(1H, s)




FAB+: 392




mp: 173-175° C.


















TABLE 125





Ex
Syn
DATA

















2
2
NMR1: 1.25-1.37(2H, m), 1.66(2H, d, J = 12.7 Hz), 1.92-2.03(1H, m), 2.05(3H, s),




3.26-3.36(2H, m), 3.80(2H, d, J = 6.4 Hz), 3.80-3.90(2H, m), 5.16(2H, s),




6.56-6.61(1H, m), 6.66-6.70(2H, m), 7.19-7.32(2H, m), 7.58-7.67(2H, m), 8.09(1H, d, J = 8.0 Hz),




11.59(1H, s)




FAB+: 380




mp: 200-202° C.


33
2
NMR1: 2.15(3H, s), 2.96-3.03(2H, m), 3.23-3.33(2H, m), 3.73(2H, s),




4.38-4.45(2H, m), 5.60(2H, br s), 6.90(2H, d, J = 8.6 Hz), 7.19(2H, d, J = 8.6 Hz),




7.33-7.38(1H, m), 7.65-7.70(2H, m), 8.14(1H, d, J = 7.9 Hz), 9.73(2H, br s)




FAB+: 323


34
2
NMR1: 0.86(3H, t, J = 6.9 Hz), 1.21-1.37(8H, m), 1.65-1.74(2H, m), 2.13(3H, s),




3.00-3.10(2H, m), 4.35(2H, t, J = 5.9 Hz), 5.87(2H, br s), 7.31-7.37(1H, m),




7.61-7.70(2H, m), 8.12(1H, d, J = 7.7 Hz), 9.50(2H, br s)




FAB+: 287


35
2
NMR1: 1.95(3H, s), 1.96(3H, s), 2.75(2H, t, J = 7.4 Hz), 3.43(2H, t, J = 7.6 Hz),




3.70(3H, s), 4.66(2H, s), 6.83(2H, d, J = 8.6 Hz), 7.08(2H, d, J = 8.6 Hz), 7.28(1H,




t, J = 7.9 Hz), 7.57-7.67(2H, m), 8.07(1H, d, J = 7.8 Hz), 11.08(1H, br s)




FAB+: 365


36
2
NMR1: 0.79(3H, t, J = 7.0 Hz), 1.08-1.26(10H, m), 1.92-2.03(3H, m),




2.07-2.14(3H, m), 3.14-3.28(2H, m), 4.60-4.68(2H, m), 7.27(1H, t, J = 6.4 Hz),




7.55-7.80(2H, m), 8.07(1H, d, J = 7.8 Hz) 11.06(1H, br s)




FAB+: 329


37
2
NMR1: 1.60-1.76(4H, m), 2.12(3H, s), 2.61(2H, t, J = 7.1 Hz), 3.03-3.15(2H, m),




4.35(2H, t, J = 5.9 Hz), 5.25(2H, br s), 7.15-7.36(6H, m), 7.62-7.70(2H, m),




8.12(1H, d, J = 7.9 Hz), 9.49(2H, br s)




FAB+: 321


















TABLE 126





Ex
Syn
DATA







38
2
NMR1: 1.56-1.75(4H, m), 2.12(3H, s), 2.54(2H, t, J = 7.2 Hz), 3.03-3.12(2H, m),




3.71(3H, s), 4.35(2H, t, J = 5.7 Hz), 5.46(2H, br s), 6.83(2H, d, J = 8.5 Hz),




7.12(2H, d, J = 8.6 Hz), 7.31-7.37(1H, m), 7.62-7.71(2H, m), 8.12(1H, d, J = 7.9 Hz),




9.48(2H, br s)




FAB+: 351


39
2
NMR1: 2.02(2H, quint, J = 7.7 Hz), 2.12(3H, s), 2.70(2H, t, J = 7.7 Hz),




3.02-3.11(2H, m), 4.37(2H, t, J = 5.7 Hz), 5.50(2H, br s), 7.16-7.37(6H, m),




7.62-7.71(2H, m), 8.12(1H, d, J = 7.8 Hz), 9.61(2H, br s)




FAB+: 307


40
2
NMR1: 0.83(3H, t, J = 6.9 Hz), 1.19-1.35(8H, m), 1.54-1.62(2H, m), 2.00(3H, s),




3.51(2H, t, J = 6.5 Hz), 4.56(2H, s), 7.26(1H, t, J = 7.3 Hz), 7.56-7.61(1H, m),




7.66(1H, d, J = 8.4 Hz), 8.07(1H, d, J = 8.1 Hz), 11.32(1H, s)




FAB+: 288


41
2
NMR1: 0.85(3H, t, J = 7.2 Hz), 1.15-1.30(4H, m), 1.35-1.45(2H, m), 2.02(3H, s),




2.99(2H, q, J = 6.3 Hz), 5.06(2H, s), 7.25-7.36(2H, m), 7.55-7.64(2H, m), 8.07(1H,




d, J = 7.8 Hz), 11.57(1H, s)




FAB+: 303


42
2
NMR1: 0.08-0.14(2H, m), 0.38-0.45(2H, m), 0.89-0.99(1H, m), 1.50-1.67(4H, m),




2.00(3H, s), 3.16(2H, d, J = 6.8 Hz), 3.36(2H, t, J = 6.2 Hz), 3.53(2H, t, J = 6.4 Hz),




4.57(2H, s), 7.24-7.30(1H, m), 7.55-7.62(1H, m), 7.67(1H, d, J = 8.3 Hz), 8.07(1H,




d, J = 8.1 Hz), 11.32(1H, s)




FAB+: 316


43
2
NMR1: 1.27-1.37(2H, m), 1.46-1.55(2H, m), 1.55-1.64(2H, m), 1.99(3H, s),




2.43(2H, t, J = 7.5 Hz), 3.50(2H, t, J = 6.5 Hz), 4.18(4H, s), 4.55(2H, s),




6.56-6.60(1H, m), 6.62-6.65(1H, m), 6.68-6.72(1H, m), 7.24-7.30(1H, m), 7.56-7.62(1H,




m), 7.64-7.69(1H, m), 8.05-8.10(1H, m), 11.31(1H, s)




FAB+: 394




mp: 135-137° C.


















TABLE 127





Ex
Syn
DATA







44
2
NMR1: 1.70-1.86(4H, m), 2.01(3H, s), 3.60(2H, t, J = 6 Hz), 4.06(2H, t, J = 6 Hz),




4.59(2H, s), 7.24-7.36(3H, m), 7.56-7.62(1H, m), 7.64-7.69(1H, m), 8.05-8.10(1H,




m), 8.12-8.16(1H, m), 8.24-8.28(1H, m), 11.33(1H, s)




FAB+: 339


45
2
NMR1: 0.77-0.87(3H, m), 1.30-1.68(6H, m), 2.00(3H, s), 2.87-2.95(2H, m),




3.50-3.60(2H, m), 3.90-3.97(2H, m), 4.57(2H, s), 7.02-7.10(1H, m), 7.27(1H, t, J = 7.8 Hz),




7.56-7.62(1H, m), 7.66(1H, d, J = 8.2 Hz), 8.07(1H, d, J = 8.2 Hz), 11.31(1H, s)




FAB+: 347


46
2
NMR1: 1.44-1.52(2H, m), 1.58-1.67(2H, m), 2.00(3H, s), 3.40(2H, q, J = 5.2 Hz),




3.53(2H, t, J = 6.5 Hz), 4.40(1H, t, J = 5.0 Hz), 4.56(2H, s), 7.24-7.30(1H, m),




7.56-7.62(1H, m), 7.66(1H, d, J = 8.1 Hz), 8.06-8.10(1H, m), 11.32(1H, s)




FAB+: 262


47
2
NMR1: 1.70-1.83(4H, m), 2.01(3H, s), 3.59(2H, t, J = 6.0 Hz), 3.97(2H, t, J = 6.0 Hz),




4.59(2H, s), 6.86-6.92(3H, m), 7.22-7.30(3H, m), 7.56-7.62(1H, m), 7.66(1H,




d, J = 8.2 Hz), 8.06-8.10(1H, m), 11.33(1H, s)




FAB+: 338


48
2
NMR1: 1.50-1.72(6H, m), 2.00(3H, s), 2.18-2.32(2H, m), 3.34-3.40(4H, m),




3.53(2H, t, J = 6.4 Hz), 4.56(2H, s), 7.24-7.29(1H, m), 7.56-7.62(1H, m), 7.66(1H,




d, J = 8.2 Hz), 8.05-8.09(1H, m), 11.32(1H, s)




FAB+: 372


49
2
NMR1: 1.70-1.86(4H, m), 2.01(3H, s), 3.59(2H, t, J = 6.0 Hz), 4.08(2H, t, J = 6.4 Hz),




4.59(2H, s), 7.06(2H, d, J = 8.6 Hz), 7.27(1H, t, J = 7.4 Hz), 7.56-7.68(2H, m),




7.72(2H, d, J = 8.6 Hz), 8.08(1H, d, J = 8.4 Hz), 11.34(1H, s)




FAB+: 363


















TABLE 128





Ex
Syn
DATA







50
2
NMR1: 1.70-1.82(4H, m), 2.01(3H, s), 2.70(2H, t, J = 7.0 Hz), 3.22(3H, s),




3.46(2H, t, J = 7.0 Hz), 3.58(2H, t, J = 6.0 Hz), 3.93(2H, t, J = 6.2 Hz), 4.58(2H, s),




6.79(2H, d, J = 8.6 Hz), 7.08(2H, d, J = 8.6 Hz), 7.24-7.30(1H, m), 7.57-7.62(1H,




m), 7.66(1H, d, J = 8.2 Hz), 8.06-8.10(1H, m), 11.33(1H, s)




FAB+: 396


51
2
NMR1: 1.66-1.84(4H, m), 2.00(3H, s), 3.58(2H, dd, J = 6.0, 6.0 Hz), 3.94(2H, dd, J = 6.0,




6.0 Hz), 4.59(2H, br s), 6.90(2H, dd, J = 8.8, 4.4 Hz), 7.07(2H, dd, J = 8.8,




8.8 Hz), 7.23-7.31(1H, m), 7.55-7.63(1H, m), 87.67(1H, d, J = 8.0 Hz),




8.05-8.11(1H, m), 11.36(1H, br s)




FAB+: 356


52
2
NMR1: 1.38(6H, s), 1.67-1.82(4H, m), 2.01(3H, s), 2.96(2H, s), 3.56(2H, dd, J = 5.2,




5.2 Hz), 3.97(2H, dd, J = 5.2, 5.2 Hz), 4.58(2H, s), 6.67(1H, dd, J = 8.0, 6.4 Hz),




6.71-6.78(2H, m), 7.23-7.31(1H, m), 7.55-7.63(1H, m), 7.67(1H, d, J = 8.0 Hz),




8.08(1H, d, J = 8.0 Hz), 11.33(1H, s)




FAB+: 408




mp: 139-140° C.


53
2
NMR1: −0.02-0.02(2H, m), 0.32-0.38(2H, m), 0.62-0.72(1H, m), 1.35(2H, q, J = 6.8 Hz),




1.53-1.66(4H, m), 2.00(3H, s), 3.33-3.39(2H, m), 3.53(2H, t, J = 6.4 Hz),




4.56(2H, s), 7.24-7.28(1H, m), 7.56-7.61(1H, m), 7.66(1H, d, J = 8.2 Hz),




8.06-8.09(1H, m), 11.31(1H, s)




FAB+: 330




mp: 155-157° C.


54
2
NMR1: 1.19(3H, s), 1.54-1.69(4H, m), 2.00(3H, s), 3.38(2H, s), 3.43(2H, t, J = 6.0 Hz),




3.54(2H, t, J = 6.4 Hz), 4.16(2H, d, J = 5.4 Hz), 4.33(2H, d, J = 5.5 Hz),




4.57(2H, s), 7.24-7.29(1H, m), 7.56-7.62(1H, m), 7.66(1H, d, J = 8.2 Hz),




8.06-8.10(1H, m), 11.33(1H, s)




FAB+: 346


















TABLE 129





Ex
Syn
DATA







55
2
NMR1: 1.06(6H, s), 1.50-1.67(6H, m), 2.00(3H, s), 3.04(3H, s), 3.34-3.40(4H, m),




3.53(2H, t, J = 6.4 Hz), 4.56(2H, s), 7.27(1H, t, J = 7.0 Hz), 7.56-7.62(1H, m),




7.66(1H, d, J = 8.2 Hz), 8.08(1H, d, J = 8.2 Hz), 11.32(1H, s)




FAB+: 362


56
2
NMR1: 1.52-1.67(4H, m), 2.00(3H, s), 2.43-2.56(2H, m), 3.40(2H, t, J = 6.0 Hz),




3.50-3.58(4H, m), 4.56(2H, s), 7.24-7.29(1H, m), 7.56-7.62(1H, m), 7.67(1H, d, J = 8.3 Hz),




8.08(1H, d, J = 7.9 Hz), 11.32(1H, s)




FAB+: 358


57
2
NMR1: 1.08(9H, s), 1.44-1.52(2H, m), 1.58-1.66(2H, m), 2.00(3H, s),




3.25-3.31(2H, m), 3.52(2H, t, J = 6.6 Hz), 4.56(2H, s), 7.24-7.29(1H, m), 7.56-7.61(1H,




m), 7.67(1H, d, J = 8.2 Hz), 8.07(1H, d, J = 7.2 Hz), 11.32(1H, s)




FAB+: 318


58
2
NMR1: 1.19-1.33(2H, m), 1.38(9H, s), 1.47-1.59(2H, m), 1.58-1.69(2H, m),




1.65-1.79(2H, m), 2.00(3H, s), 2.88-3.08(2H, m), 3.32-3.44(3H, m), 3.47-3.64(4H, m),




4.56(2H, s), 7.22-7.31(1H, m), 7.59(1H, ddd, J = 6.8, 6.8, 1.6 Hz), 7.67(1H, d, J = 8.0 Hz),




8.08(1H, dd, J = 8.0, 1.6 Hz), 11.32(1H, s)




ESI+: 445


59
2
NMR1: 1.68-1.84(4H, m), 2.01(3H, s), 3.06(4H, dd, J = 4.8, 4.8 Hz), 3.59(2H, dd, J = 6.4,




6.4 Hz), 3.70(4H, dd, J = 4.8, 4.8 Hz), 3.94(2H, dd, J = 6.4, 6.4 Hz), 4.59(2H,




s), 6.35(1H, dd, J = 9.2, 2.0 Hz), 6.41(1H, dd, J = 2.0, 2.0 Hz), 6.49(1H, dd, J = 9.2,




2.0 Hz), 7.08(1H, dd, J = 8.4, 8.4 Hz), 7.23-7.31(1H, m), 7.55-7.63(1H, m),




7.67(1H, d, J = 8.4 Hz), 8.08(1H, dd, J = 8.4, 1.2 Hz), 11.34(1H, br s)




ESI+: 423


















TABLE 130





Ex
Syn
DATA







60
2
NMR1: 0.34-0.42(4H, m), 1.49-1.65(4H, m), 2.00(3H, s), 3.17-3.22(1H, m),




3.41(2H, t, J = 6 Hz), 3.52(2H, t, J = 6 Hz), 4.56(2H, s), 7.24-7.29(1H, m),




7.56-7.62(1H, m), 7.64-7.69(1H, m), 8.05-8.10(1H, m), 11.31(1H, s)




FAB+: 302


61
2
NMR1: 0.83(9H, s), 1.54-1.67(4H, m), 2.00(3H, s), 2.98(2H, s), 3.33-3.38(2H, m),




3.54(2H, t, J = 6.5 Hz), 4.56(2H, s), 7.26(1H, t, J = 7.2H), 7.56-7.61(1H, m),




7.66(1H, d, J = 8.2 Hz), 8.07(1H, d, J = 7.0 Hz), 11.30(1H, s)




FAB+: 332


62
2
NMR1: 0.92(3H, t, J = 7.5 Hz), 1.37-1.47(2H, m), 1.64-1.72(2H, m), 2.05(3H, s),




3.95(2H, t, J = 6.5 Hz), 5.15(2H, s), 6.55-6.59(1H, m), 6.65-6.69(2H, m),




7.17-7.31(2H, m), 7.58-7.66(2H, m), 8.09(1H, d, J = 7.6 Hz), 11.57(1H, s)




FAB+: 338


63
2
NMR1: 0.85(3H, t, J = 7.2 Hz), 1.18-1.35(4H, m), 1.44-1.61(2H, m), 2.08(3H, s),




2.43-2.56(2H, m), 5.20(2H, s), 7.10(2H, d, J = 8.0 Hz), 7.25-7.32(1H, m), 7.37(2H,




d, J = 8.0 Hz), 7.58(1H, d, J = 8.0 Hz), 7.60-7.66(1H, m), 8.09(1H, d, J = 8.0 Hz),




9.75(1H, s), 11.68(1H, s)




ESI+: 379




mp: 215-216° C.


64
2
NMR1: 0.85(3H, t, J = 7.2 Hz), 1.16-1.33(10H, m), 1.45-1.58(2H, m), 2.08(3H, s),




2.44-2.56(2H, m), 5.20(2H, s), 7.09(2H, d, J = 8.0 Hz), 7.24-7.32(1H, m), 7.37(2H,




d, J = 8.0 Hz), 7.58(1H, d, J = 8.0 Hz), 7.60-7.67(1H, m), 8.09(1H, d, J = 8.0 Hz),




9.75(1H, s), 11.68(1H, s)




ESI+: 421


65
2
NMR1: 2.01(3H, s), 2.74(2H, dd, J = 6.4, 6.4 Hz), 3.19-3.30(2H, m), 5.05(2H, s),




7.16-7.22(1H, m), 7.28(1H, dd, J = 7.2, 7.2 Hz), 7.38-7.48(1H, m), 7.49(1H, s),




7.50(1H, d, J = 8.4 Hz), 7.56(1H, d, J = 7.2 Hz), 7.58-7.66(1H, m), 8.08(1H, d, J = 8.4 Hz),




11.58(1H, br s)




ESI+: 405, 407


















TABLE 131





Ex
Syn
DATA







66
2
NMR1: 1.16(3H, s), 1.17(3H, s), 2.08(3H, s), 2.82(1H, qq, J = 6.8, 6.8 Hz),




5.20(2H, s), 7.16(2H, d, J = 8.8 Hz), 7.29(1H, dd, J = 7.2, 7.2 Hz), 7.39(2H, d, J = 8.8 Hz),




7.58(1H, d, J = 8.0 Hz), 7.60-7.67(1H, m), 8.09(1H, d, J = 8.0 Hz),




9.75(1H, s), 11.67(1H, s)




FAB+: 351




mp: 254-256° C.


67
2
NMR1: 1.88-1.97(2H, m), 2.05(3H, m), 2.35-2.46(2H, m), 4.04(2H, t, J = 6.2 Hz),




5.16(2H, s), 6.58-6.62(1H, m), 6.68-6.72(2H, m), 7.21-7.32(2H, m), 7.58-7.67(2H,




m), 8.09(1H, d, J = 8.0 Hz), 11.60(1H, s)




FAB+: 392


68
2
NMR1: 0.83(3H, t, J = 7 Hz), 1.43-1.53(2H, m), 2.05(3H, s), 2.75(2H, t, J = 7 Hz),




3.32(2H, t, J = 7 Hz), 3.52(2H, t, J = 7 Hz), 5.15(2H, s), 7.02(2H, d, J = 8 Hz),




7.20(2H, d, J = 8 Hz), 7.26-7.32(1H, m), 7.58-7.68(2H, m), 8.07-8.12(1H, m),




11.59(1H, s)




FAB+: 352


69
2
NMR1: 1.16(6H, s), 1.90(2H, t, J = 7.2 Hz), 2.06(3H, s), 3.10(3H, s), 4.01(2H, t, J = 7.1 Hz),




5.17(2H, s), 6.56-6.60(1H, m), 6.66-6.70(2H, m), 7.19-7.33(2H, m),




7.59-7.67(2H, m), 8.09(1H, d, J = 7.9 Hz), 11.58(1H, s)




FAB+: 382


70
2
NMR1: 1.18(3H, t, J = 7.2 Hz), 2.03(3H, s), 2.41-2.48(4H, m), 3.36-3.45(4H, m),




3.60(2H, s), 4.04(2H, q, J = 7.2 Hz), 7.21-7.29(1H, m), 7.58(1H, ddd, J = 6.8, 6.8,




1.6 Hz), 7.67(1H, d, J = 8.4 Hz), 8.07(1H, dd, J = 8.4, 1.6 Hz), 11.18(1H, s)




FAB+: 330


71
2
NMR1: 1.30(3H, t, J = 7.0 Hz), 1.73-1.85(4H, m), 2.01(3H, s), 2.71-2.80(2H, m),




3.94-4.03(4H, m), 6.43-6.51(3H, m), 7.14(1H, t, J = 8.0 Hz), 7.21-7.26(1H, m),




7.48-7.52(1H, m), 7.55-7.60(1H, m), 8.03-8.07(1H, m), 11.36(1H, s)




FAB+: 352


















TABLE 132





Ex
Syn
DATA







72
2
NMR1: 0.35-0.43(4H, m), 1.29-1.38(2H, m), 1.43-1.52(2H, m), 1.54-1.63(2H, m),




2.00(3H, s), 3.16-3.22(1H, m), 3.39(2H, t, J = 6.7 Hz), 3.51(2H, t, J = 6.7 Hz),




4.56(2H, s), 7.23-7.30(1H, m), 7.56-7.62(1H, m), 7.64-7.69(1H, m), 8.05-8.10(1H,




m), 11.32(1H, s)




FAB+: 316


73
2
NMR1: 1.36(3H, s), 2.06(3H, s), 4.04(2H, s), 4.30(2H, d, J = 5.7 Hz), 4.48(2H, d, J = 5.7 Hz),




5.17(2H, s), 6.64(1H, dd, J = 2.0, 8.1 Hz), 6.69-6.77(2H, m),




7.22-7.32(2H, m), 7.59-7.67(2H, m), 8.09(1H, d, J = 7.6 Hz), 11.58(1H, s)




FAB+: 366


74
2
NMR1: 0.86(3H, t, J = 7.0 Hz), 1.19-1.34(4H, m), 1.38-1.56(4H, m), 1.81-1.96(2H,




m), 2.01(3H, s), 2.29(2H, t, J = 7.0 Hz), 3.00-3.10(1H, m), 3.14-3.24(1H, m),




3.64-3.75(2H, m), 3.86-3.96(1H, m), 4.63(2H, s), 7.24-7.30(1H, m), 7.57-7.62(1H, m),




7.65-7.69(1H, m), 8.05-8.10(1H, m), 11.27(1H, s)




FAB+: 371


75
2
NMR1: 2.11(3H, s), 5.37(2H, s), 7.25-7.34(2H, m), 7.57-7.68(6H, m), 8.03(1H, d, J = 8.9 Hz),




8.10-8.14(3H, m), 11.68(1H, s)




FAB+: 410


76
2
NMR1: 2.10(3H, s), 5.34(2H, s), 7.07(1H, s), 7.30(1H, t, J = 8.1 Hz), 7.60-7.70(7H,




m), 7.84(1H, d, J = 9.1 Hz), 8.10-8.13(3H, m), 11.63(1H, s)




FAB+: 410


77
2
NMR1: 1.27-1.40(2H, m), 1.31(3H, t, J = 7.2 Hz), 1.67(2H, d, J = 12.8 Hz),




1.95-2.05(1H, m), 2.07(3H, s), 3.28-3.36(2H, m), 3.85-3.91(4H, m), 4.31(2H, q, J = 7.0 Hz),




6.99(1H, t, J = 2.4 Hz), 7.11-7.13(1H, m), 7.24-7.32(2H, m), 7.60-7.68(2H, m),




8.09(1H, d, J = 7.8 Hz), 11.56(1H, s)




FAB+: 452


















TABLE 133





Ex
Syn
DATA







78
2
NMR1: 1.28(3H, t, J = 6.8 Hz), 1.34-1.44(2H, m), 1.70(2H, d, J = 12.8 Hz),




1.92-2.05(1H, m), 2.07(3H, s), 3.32(2H, t, J = 11.6 Hz), 3.85-3.92(4H, m), 4.21(2H, q, J = 6.8 Hz),




5.25(2H, s), 6.75(1H, dd, J = 2.4, 8.8 Hz), 6.80(1H, d, J = 2.4 Hz),




7.25-7.36(1H, m), 7.60-7.65(2H, m), 7.72(1H, d, J = 8.0 Hz), 8.10(1H, d, J = 7.6 Hz),




11.58(1H, s)




FAB+: 452


79
2
NMR1: 1.23-1.36(2H, m), 1.64(2H, d, J = 12.9 Hz), 1.90-2.04(1H, m), 2.05(3H, s),




3.25-3.32(2H, m), 3.82-3.92(4H, m), 5.25(2H, s), 7.18(1H, t, J = 8.3 Hz),




7.27-7.31(1H, m), 7.38(1H, t, J = 11.0 Hz), 7.58-7.66(2H, m), 8.09(1H, d, J = 7.9 Hz),




11.69(1H, s)




FAB+: 416


80
2
NMR1: 1.25-1.37(2H, m), 1.66(2H, d, J = 12.7 Hz), 1.90-2.03(1H, m), 2.05(3H, s),




3.27-3.35(4H, m), 3.60(3H, s), 3.81(2H, d, J = 6.5 Hz), 3.87(2H, dd, J = 2.9, 11.4 Hz),




5.14(2H, s), 6.50(1H, s), 6.60(2H, d, J = 1.5 Hz), 7.26-7.31(1H, m),




7.57-7.67(2H, m), 8.04(1H, d, J = 7.6 Hz), 11.61(1H, s)




FAB+: 452


81
2
NMR1: 2.04(3H, s), 2.62(2H, t, J = 8.0 Hz), 2.81(2H, t, J = 8.0 Hz), 3.22-3.41(4H,




m), 3.38-3.53(4H, m), 5.16(2H, s), 7.12-7.20(1H, m), 7.19-7.33(5H, m), 7.57(1H, d,




J = 8.0 Hz), 7.61(1H, ddd, J = 8.0, 8.0, 1.2 Hz), 8.08(1H, d, J = 8.0 Hz), 11.65(1H,




br s)




ESI+: 434


82
2
NMR1: 2.05(3H, s), 3.03(2H, t, J = 6.8 Hz), 4.62(2H, t, J = 6.8 Hz), 5.16(2H, s),




7.05(2H, d, J = 8.5 Hz), 7.26-7.32(3H, m), 7.48(1H, s), 7.59-7.67(2H, m), 8.09(1H,




d, J = 8.2 Hz), 8.99(1H, s), 11.59(1H, s)




FAB+: 456


83
2
NMR1: 0.66-0.78(4H, m), 1.88-2.02(1H, m), 2.05(3H, s), 3.33-3.44(2H, m),




3.37-3.58(4H, m), 3.60-3.80(2H, m), 5.17(2H, s), 7.24-7.33(1H, m), 7.58(1H, d, J = 8.0 Hz),




7.62(1H, ddd, J = 8.0, 8.0, 1.6 Hz), 8.08(1H, d, J = 8.0 Hz), 11.62(1H, s)




ESI+: 370


















TABLE 134





Ex
Syn
DATA







84
2
NMR1: 1.04(3H, t, J = 7.3 Hz), 2.06(3H, s), 3.05-3.13(2H, m), 5.11(2H, s),




6.13-6.19(1H, m), 6.63(1H, dd, J = 2.2, 8.2 Hz), 6.90-6.95(1H, m), 7.15(1H, t, J = 8.2 Hz),




7.24-7.31(2H, m), 7.56-7.66(2H, m), 8.07-8.11(1H, m), 8.51(1H, s)




FAB+: 352


85
2
NMR1: 0.82(3H, t, J = 7.3 Hz), 1.20-1.30(2H, m), 1.36-1.44(2H, m), 1.76-1.85(2H,




m), 2.00(3H, s), 3.27-3.34(2H, m), 3.42(2H, t, J = 6.2 Hz), 3.57(2H, t, J = 6.4 Hz),




4.57(2H, s), 7.27(1H, t, J = 6.9 Hz), 7.55-7.64(1H, m), 7.67(1H, d, J = 8.2 Hz),




8.08(1H, d, J = 7.2 Hz), 11.34(1H, s)




FAB+: 304


86
2
NMR1: 1.60-1.70(2H, m), 2.00(3H, s), 2.41-2.55(4H, m), 2.87-2.95(2H, m),




3.02-3.09(2H, m), 7.11-7.29(6H, m), 7.48(1H, d, J = 8.2 Hz), 7.52-7.58(1H, m),




7.94-7.99(1H, m), 8.04(1H, d, J = 8.2 Hz), 11.41(1H, s)




FAB+: 349




mp: 260-264° C.


87
2
NMR1: 1.23-1.37(2H, m), 1.61-1.69(2H, m), 1.90-2.02(1H, m), 2.06(3H, s),




3.26-3.35(2H, m), 3.80(2H, d, J = 6.5 Hz), 3.84-3.90(2H, m), 5.23(2H, s), 6.52-6.57(1H,




m), 6.91(1H, dd, J = 2.9, 7.2 Hz), 7.12-7.18(1H, m), 7.27-7.32(1H, m),




7.58-7.65(2H, m), 8.04(1H, d, J = 7.8 Hz), 11.70(1H, s)




FAB+: 398


88
2
NMR1: 1.25-1.38(2H, m), 1.61-1.70(2H, m), 1.95-2.05(1H, m), 2.05(3H, s),




3.28-3.36(2H, m), 3.82-3.94(4H, m), 5.16(2H, s), 6.62-6.68(1H, m), 6.92(1H, dd, J = 2.9,




7.3 Hz), 7.13-7.20(1H, m), 7.26-7.32(1H, m), 7.59-7.67(2H, m), 8.09(1H, d, J = 7.9 Hz),




11.57(1H, s)




FAB+: 398


















TABLE 135





Ex
Syn
DATA







89
2
NMR1: 1.21-1.38(2H, m), 1.65(2H, d, J = 12.5 Hz), 1.90-2.00(1H, m), 2.05(3H, s),




2.26(3H, s), 3.25-3.35(2H, m), 3.80(2H, d, J = 6.4 Hz), 3.83-3.92(2H, m), 5.13(2H,




s), 6.42(1H, s), 6.49(1H, s), 6.53(1H, s), 7.26-7.33(1H, m), 7.58-7.69(2H, m),




8.10(1H, d, J = 7.9 Hz), 11.57(1H, s)




FAB+: 394


90
2
NMR1: 1.25-1.37(2H, m), 1.60-1.67(2H, m), 1.94-2.04(1H, m), 2.05(3H, s),




3.27-3.36(2H, m), 3.83-3.90(2H, m), 4.11(2H, d, J = 6.6 Hz), 5.23(2H, s), 6.54(1H, d, J = 2.2 Hz),




6.74(1H, dd, J = 2.3, 5.9 Hz), 7.26-7.34(1H, m), 7.61-7.64(2H, m), 8.01(1H,




d, J = 5.9 Hz), 8.09(1H, d, J = 8.1 Hz), 11.61(1H, s)




FAB+: 381


91
2
NMR1: 1.17-1.30(2H, m), 1.85-1.44(2H, m), 1.92-2.02(1H, m), 2.04(3H, s),




3.16-3.26(2H, m), 3.72(2H, d, J = 7.3 Hz), 3.80-3.86(2H, m), 5.13(2H, s), 6.02-6.07(2H,




m), 7.27-7.32(1H, m), 7.56-7.66(2H, m), 8.09(1H, d, J = 7.8 Hz), 10.62(1H, s)




FAB+: 381


92
2
NMR1: 1.25-1.35(2H, m), 1.62-1.68(2H, m), 1.90-2.04(1H, m), 2.05(3H, s),




3.26-3.37(2H, m), 3.72(3H, s), 3.80(2H, d, J = 6.5 Hz), 3.83-3.90(2H, m), 5.14(2H, s),




6.14-6.17(1H, m), 6.26-6.31(2H, m), 7.26-7.31(1H, m), 7.59-7.67(2H, m),




8.07-8.12(1H, m), 11.61(1H, s)




FAB+: 410


93
2
NMR1: 1.23-1.36(2H, m), 1.60-1.67(2H, m), 1.88-2.00(1H, m), 2.04(3H, s),




3.27-3.30(2H, m), 3.75(2H, d, J = 6.4 Hz), 3.83-3.90(2H, m), 5.09(2H, s), 5.99(1H, t, J = 2.0 Hz),




6.09(1H, t, J = 2.1 Hz), 6.14(1H, t, J = 2.2 Hz), 7.26-7.32(1H, m),




7.59-7.67(2H, m), 8.07-8.12(1H, m), 9.50(1H, s), 11.55(1H, s)




FAB+: 396


















TABLE 136





Ex
Syn
DATA







94
2
NMR1: 1.27-1.39(2H, m), 1.64-1.71(2H, m), 1.95-2.05(1H, m), 2.06(3H, s),




3.27-3.37(2H, m), 3.84-3.91(4H, m), 5.20(2H, s), 6.83-6.86(1H, m), 7.10-7.12(1H, m),




7.20-7.22(1H, m), 7.27-7.32(1H, m), 7.39(1H, s), 7.58-7.67(2H, m), 7.96(1H, s),




8.09(1H, d, J = 7.8 Hz), 11.59(1H, s)




FAB+: 423


95
2
NMR1: 1.26-1.44(2H, m), 1.68(2H, d, J = 12.7 Hz), 1.93-2.05(1H, m), 2.07(3H, s),




2.58(3H, s), 3.28-2.27(2H, m), 3.83-3.97(4H, m), 5.25(2H, s), 6.98(1H, s), 7.14(1H,




s), 7.26(1H, s), 7.27-7.34(1H, m), 7.58-7.70(2H, m), 8.10(1H, d, J = 8.0 Hz),




11.60(1H, s)




FAB+: 422


96
2
NMR1: 1.31(2H, dddd, J = 12.8, 12.8, 12.8, 4.4 Hz), 1.57-1.73(2H, m),




1.88-2.04(1H, m), 2.06(3H, s), 3.21-3.43(2H, m), 3.82(2H, d, J = 5.6 Hz), 3.87(2H, dd, J = 11.6,




3.6 Hz), 5.17(2H, s), 6.53-6.63(1H, m), 6.64-6.73(2H, m), 7.22(1H, dd, J = 8.4,




8.4 Hz), 7.54(1H, ddd, J = 8.4, 8.4, 2.8 Hz), 7.68-7.81(1H, m), 7.74(1H, s),




11.73(1H, br s)




FAB+: 398


97
2
NMR1: 1.31(2H, dddd, J = 12.8, 12.8, 12.8, 4.0 Hz), 1.66(2H, d, J = 12.8 Hz),




1.89-2.02(1H, m), 2.06(3H, s), 3.24-3.41(2H, m), 3.82(2H, d, J = 6.0 Hz), 3.83-3.93(2H,




m), 5.16(2H, s), 6.55-6.63(1H, m), 6.63-6.73(2H, m), 7.23(1H, dd, J = 8.8, 8.8 Hz),




7.66(1H, d, J = 8.8 Hz), 7.77(1H, dd, J = 8.8, 2.0 Hz), 8.18(1H, d, J = 2.0 Hz),




11.75(1H, s)




FAB+: 458, 460


98
2
NMR1: 1.05-1.13(1H, m), 1.18-1.26(1H, m), 1.76(2H, t, J = 17.5 Hz),




1.96-2.02(1H, m), 1.99(3H, s), 2.05(3H, s), 2.52-2.56(1H, m), 3.02(1H, t, J = 11.7 Hz),




3.82-3.84(3H, m), 4.39(1H, d, J = 13.1 Hz), 5.16(2H, s), 6.59(1H, dd, J = 8.1, 1.8 Hz),




6.67-6.89(2H, m), 7.20-7.24(1H, m), 7.27-7.31(1H, m), 7.60-7.66(2H, m),




8.10(1H, d, J = 7.9 Hz), 11.59(1H, s)




ESI+: 421


















TABLE 137





Ex
Syn
DATA

















99
2
NMR1: 2.05(3H, s), 5.10(2H, s), 5.16(2H, s), 6.66-6.72(2H, m), 6.78(1H, t, J = 2.3 Hz),




7.22-7.45(7H, m), 7.60-7.66(2H, m), 8.10(1H, d, J = 7.6 Hz), 11.59(1H, s)




ESI+: 372


100
2
NMR1: 1.25-1.37(2H, m), 1.62-1.70(2H, m), 1.91-2.02(1H, m), 2.04(3H, s),




2.40(3H, s), 3.27-3.36(2H, m), 3.80-3.90(4H, m), 5.14(2H, s), 6.56-6.66(1H, m),




6.65-6.70(2H, m), 7.19-7.25(1H, m), 7.45(1H, dd, J = 2.0, 8.5 Hz), 7.56(1H, d, J = 8.4 Hz),




7.89(1H, s), 11.51(1H, s)




FAB+: 394


101
2
NMR1: 1.25-1.37(2H, m), 1.62-1.70(2H, m), 1.90-2.02(1H, m), 2.06(3H, s),




3.28-3.35(2H, m), 3.80-3.90(7H, m), 5.15(2H, s), 6.56-6.60(1H, m), 6.65-6.70(2H, m),




7.19-7.30(2H, m), 7.49(1H, d, J = 3.0 Hz), 7.62(1H, d, J = 9.0 Hz), 11.58(1H, s)




FAB+: 410


102
2
NMR1: 1.32(2H, dddd, J = 12.0, 12.0, 12.0, 4.0 Hz), 1.60-1.72(2H, m),




1.90-2.04(1H, m), 2.06(3H, s), 3.24-3.39(2H, m), 3.82(2H, d, J = 6.8 Hz), 3.83-3.93(2H,




m), 5.17(2H, s), 6.55-6.63(1H, m), 6.63-6.73(2H, m), 7.23(1H, dd, J = 8.4, 8.4 Hz),




7.66(1H, dd, J = 8.4, 2.0 Hz), 7.73(1H, d, J = 8.4 Hz), 8.03(1H, d, J = 2.0 Hz),




11.75(1H, s)




ESI+: 414, 416


103
2
NMR1: 1.29-1.37(2H, m), 1.85-1.87(3H, m), 2.06(3H, s), 2.71(2H, t, J = 11.2 Hz),




2.85(3H, s), 3.59(2H, d, J = 11.7 Hz), 3.86(2H, d, J = 5.9 Hz), 5.17(2H, s), 6.59(1H,




d, J = 7.2 Hz), 6.68-6.70(2H, m), 7.20-7.30(2H, m), 7.59-7.67(2H, m), 8.10(1H, d, J = 8.1 Hz),




11.69(1H, s)




ESI+: 457


104
2
NMR1: 1.71-1.80(2H, m), 2.05(3H, s), 2.02-2.14(3H, m), 3.05-3.08(2H, m),




3.15-3.18(2H, m), 3.88(2H, d, J = 6.1 Hz), 5.16(2H, s), 6.59-6.61(1H, m), 6.69-6.70(2H,




m), 7.21-7.31(2H, m), 7.60-7.66(2H, m), 8.10(1H, d, J = 7.8 Hz), 11.59(1H, s)




ESI+: 428


















TABLE 138





Ex
Syn
DATA







105
2
NMR1: 2.06(3H, s), 2.46(4H, br s), 2.68(2H, br s), 3.57(4H, br s), 4.08(2H, t, J = 5.4 Hz),




5.17(2H, s), 6.58-6.61(1H, m), 6.68-6.70(2H, m), 7.22(1H, t, J = 8.2 Hz),




7.27-7.31(1H, m), 7.60-7.67(2H, m), 8.10(1H, d, J = 7.9 Hz), 11.62(1H, s)




FAB+: 395


106
2
NMR1: 2.06(3H, s), 3.45(4H, br s), 3.56(4H, br s), 4.82(2H, s), 5.15(2H, s),




6.59(1H, dd, J = 2.2, 8.2 Hz), 6.68-6.72(2H, m), 7.23(1H, t, J = 8.2 Hz),




7.27-7.31(1H, m), 7.60-7.65(2H, m), 8.10(1H, d, J = 7.8 Hz), 11.64(1H, s)




ESI+: 409


107
2
NMR1: 1.36(3H, t, J = 6.8 Hz), 1.62-1.71(2H, m), 1.89-2.04(1H, m), 2.07(3H, s),




3.27-3.36(4H, m), 3.82(2H, d, J = 6.8 Hz), 3.84-3.91(2H, m), 4.35(2H, q, J = 6.8 Hz),




5.18(2H, s), 5.56-6.63(1H, m), 6.65-6.70(1H, m), 6.69(1H, d, J = 2.0 Hz),




7.23(1H, dd, J = 8.4, 8.4 Hz), 7.75(1H, d, J = 8.4 Hz), 8.13(1H, dd, J = 8.8, 2.0 Hz),




8.72(1H, d, J = 2.0 Hz), 11.88(1H, br s)




ESI+: 452


108
2
NMR1: 1.27-1.38(4H, m), 1.53-1.62(2H, m), 2.00(3H, s), 3.36(2H, s), 3.51(2H, t, J = 6.7 Hz),




4.56(2H, s), 7.24-7.29(1H, m), 7.56-7.61(1H, m), 7.67(1H, d, J = 8.0 Hz),




8.07(1H, dd, J = 1.2, 8.2 Hz)




FAB+: 275


109
2
NMR1: 1.32(2H, dddd, J = 12.4, 12.4, 12.4, 4.0 Hz), 1.61-1.73(2H, m),




1.90-2.04(1H, m), 2.09(3H, s), 3.25-3.41(2H, m), 3.83(2H, d, J = 6.4 Hz), 3.83-3.94(2H,




m), 5.20(2H, s), 6.56-6.63(1H, m), 6.66-6.75(2H, m), 7.23(1H, dd, J = 8.4, 8.4 Hz),




7.52(1H, dd, J = 8.4, 5.2 Hz), 7.80(1H, d, J = 8.4 Hz), 8.03(1H, dd, J = 8.4, 2.0 Hz),




8.11-8.18(1H, m), 8.38(1H, d, J = 2.0 Hz), 8.59(1H, d, J = 4.0 Hz), 8.95(1H, br s),




11.72(1H, s)




ESI+: 457


















TABLE 139





Ex
Syn
DATA







110
2
NMR1: 1.25-1.44(4H, m), 1.54-1.63(2H, m), 1.77(3H, s), 2.00(3H, s), 3.00(2H, q, J = 6.0 Hz),




3.51(2H, t, J = 6.5 Hz), 4.56(2H, s), 7.27(1H, t, J = 7.8 Hz), 7.59(1H, t, J = 7.0 Hz),




7.67(1H, d, J = 8.3 Hz), 7.75-7.80(1H, s), 8.08(1H, d, J = 8.0 Hz),




11.32(1H, s)




FAB+: 317


111
2
NMR1: 1.16-1.26(2H, m), 1.58-1.68(5H, m), 2.05(3H, s), 3.25-3.30(2H, m),




3.82(2H, dd, J = 3.1, 11.2 Hz), 4.00(2H, t, J = 6.2 Hz), 5.16(2H, s), 6.57-6.59(1H, m),




6.67-6.68(2H, m), 7.22(1H, t, J = 8.5 Hz), 7.27-7.31(1H, m), 7.60-7.66(2H, m),




8.09(1H, d, J = 7.9 Hz), 11.59(1H, s)




ESI+: 394


112
2
NMR1: 1.86-1.94(2H, m), 2.06(3H, s), 2.21(2H, t, J = 8.1 Hz), 3.43(2H, t, J = 7.0 Hz),




3.53(2H, t, J = 5.5 Hz), 4.07(2H, t, J = 5.5 Hz), 5.17(2H, s), 6.58-6.61(1H, m),




6.69-6.71(2H, m), 7.21-7.25(1H, m), 7.27-7.31(1H, m), 7.60-7.66(2H, m), 8.10(1H,




d, J = 7.6 Hz), 11.61(1H, s)




ESI+: 393


113
2
NMR1: 1.31(2H, dddd, J = 12.0, 12.0, 12.0, 4.0 Hz), 1.60-1.72(2H, m),




1.90-2.06(1H, m), 3.23-3.40(2H, m), 3.83(2H, d, J = 6.4 Hz), 3.83-3.92(2H, m), 5.31(2H,




s), 6.56-6.64(1H, m), 6.64-6.74(2H, m), 7.23(1H, dd, J = 8.4, 8.4 Hz), 7.41(1H, dd,




J = 7.6, 7.6 Hz), 7.67-7.76(1H, m), 7.79(1H, d, J = 8.4 Hz), 8.15(1H, d, J = 8.4 Hz),




12.22(1H, s)




FAB+: 400, 402


114
2
NMR1: 1.11-1.25(2H, m), 1.55(2H, d, J = 12.9 Hz), 1.72-1.85(1H, m), 2.06(3H, s),




3.20-3.33(4H, m), 3.66-3.72(2H, m), 3.77-3.86(2H, m), 4.05-4.12(2H, m), 5.16(2H,




s), 6.59(1H, d, J = 9.2 Hz), 6.65-6.74(2H, m), 7.23(1H, t, J = 8.7 Hz), 7.26-7.32(1H,




m), 7.58-7.69(2H, m), 8.09(1H, d, J = 7.8 Hz), 11.61(1H, s)




ESI+: 424


















TABLE 140





Ex
Syn
DATA







115
2
NMR1: 1.26-1.35(2H, m), 1.64-1.67(2H, m), 1.93-1.97(1H, m), 2.04(3H, s),




3.30-3.34(2H, m), 3.77(2H, d, J = 6.4 Hz), 3.85-3.87(2H, m), 5.11(2H, s), 6.90(2H, d, J = 9.0 Hz),




7.03(2H, d, J = 9.2 Hz), 7.26-7.30(1H, m), 7.58-7.67(2H, m), 8.09(1H, d, J = 7.8 Hz),




11.56(1H, s)




ESI+: 380


116
2
NMR1: 1.19-1.29(2H, m), 1.56-1.60(2H, m), 2.00-2.03(1H, m), 2.06(3H, s),




2.24(2H, d, J = 7.1 Hz), 3.27-3.32(2H, m), 3.82(2H, dd, J = 2.6, 11.3 Hz), 5.15(2H,




s), 6.79(1H, dd, J = 2.0, 8.1 Hz), 7.16(1H, d, J = 8.1 Hz), 7.22-7.31(2H, m), 7.50(1H,




br s), 7.59-7.67(2H, m), 8.10(1H, d, J = 8.1 Hz), 9.95(1H, s), 11.62(1H, s)




ESI+: 407


117
2
NMR1: 2.05(3H, s), 3.43-3.46(6H, m), 3.50-3.53(2H, m), 3.71(2H, s), 5.16(2H, s),




6.88(1H, d, J = 7.7 Hz), 6.98-6.99(2H, m), 7.26-7.31(2H, m), 7.59-7.67(2H, m),




8.10(1H, d, J = 8.1 Hz), 11.61(1H, s)




ESI+: 393


118
2
NMR1: 1.25-1.38(8H, m), 1.62-1.70(2H, m), 1.91-2.03(1H, m), 3.05-3.13(1H, m),




3.27-3.36(2H, m), 3.78-3.90(4H, m), 5.13(2H, s), 6.56-6.60(1H, m), 6.65-6.69(2H,




m), 7.19-7.29(2H, m), 7.56-7.64(2H, m), 8.07(1H, d, J = 8.4 Hz), 11.51(1H, s)




FAB+: 408


119
2
NMR1: 1.24-1.37(2H, m), 1.65(2H, d, J = 11.0 Hz), 1.90-2.10(4H, m),




3.26-3.39(2H, m), 3.77-3.93(4H, m), 5.13-5.22(2H, m), 6.48(1H, d, J = 10.9 Hz),




6.55(1H, s), 6.60(1H, d, J = 10.8 Hz), 7.27-7.33(1H, m), 7.59-7.69(2H, m),




8.10(1H, d, J = 8.0 Hz), 11.60(1H, br s)




ESI+: 398


120
2
NMR1: 1.32(2H, dddd, J = 12.0, 12.0, 12.0, 4.4 Hz), 1.61-1.72(2H, m),




1.91-2.05(1H, m), 2.09(3H, s), 3.26-3.37(2H, m), 3.83(2H, d, J = 6.4 Hz), 3.83-3.92(2H,




m), 5.20(2H, s), 6.56-6.63(1H, m), 6.66-6.75(2H, m), 7.23(1H, dd, J = 8.4, 8.4 Hz),




7.82(1H, d, J = 8.4 Hz), 8.08(1H, dd, J = 8.4, 2.4 Hz), 8.44(1H, d, J = 2.4 Hz),




9.20(3H, s), 11.74(1H, s)




ESI+: 458


















TABLE 141





Ex
Syn
DATA







121
2
NMR1: 2.05(3H, s), 3.05(2H, t, J = 6.6 Hz), 4.21(2H, t, J = 6.6 Hz), 5.15(2H, s),




6.58-6.60(1H, m), 6.68-6.70(2H, m), 7.22(1H, t, J = 8.4 Hz), 7.27-7.35(2H, m),




7.60-7.65(2H, m), 7.75(1H, d, J = 7.8 Hz), 8.10(1H, d, J = 7.7 Hz), 8.43-8.45(1H, m),




8.54(1H, d, J = 1.8 Hz), 11.58(1H, s)




ESI+: 387


122
2
NMR1: 1.08-1.21(2H, m), 1.29-1.38(2H, m), 1.41-1.53(1H, m), 1.57(2H, d, J = 13.1 Hz),




1.66-1.77(2H, m), 2.05(3H, s), 3.26(2H, t, J = 11.5 Hz), 3.83(2H, dd, J = 11.2,




3.6 Hz), 3.94(2H, dd, J = 6.5, 6.4 Hz), 5.16(2H, s), 6.58(1H, d, J = 9.2 Hz),




6.34-6.71(2H, m), 7.21(1H, dd, J = 8.6, 8.5 Hz), 7.29(1H, ddd, J = 8.1, 7.9, 1.4 Hz),




7.57-7.69(2H, m), 8.10(1H, d, J = 7.9 Hz), 11.58(1H, s)




ESI+: 408


123
2
NMR1: 2.05(3H, s), 3.18(2H, t, J = 6.6 Hz), 4.36(2H, t, J = 6.6 Hz), 5.15(2H, s),




6.58-6.60(1H, m), 6.67-6.69(2H, m), 7.20-7.31(3H, m), 7.36(1H, d, J = 7.8 Hz),




7.59-7.66(2H, m), 7.72(1H, dt, J = 1.9, 7.6 Hz), 8.09-8.11(1H, m), 8.50-8.52(1H,




m), 11.58(1H, s)




ESI+: 387


124
2
NMR1: 1.31(2H, dddd, J = 11.6, 11.6, 11.6, 4.0 Hz), 1.60-1.71(2H, m),




1.81-1.95(4H, m), 1.93-2.04(1H, m), 2.05(3H, s), 2.41(2H, dd, J = 5.6, 5.6 Hz),




3.25-3.38(1H, m), 3.65(2H, dd, J = 5.6, 5.6 Hz), 3.82(2H, d, J = 6.4 Hz), 3.83-3.92(2H,




m), 5.17(2H, s), 6.55-6.63(1H, m), 6.64-6.73(2H, m), 7.22(1H, dd, J = 8.4, 8.4 Hz),




7.54(1H, dd, J = 8.4, 2.4 Hz), 7.64(1H, d, J = 8.4 Hz), 7.91(1H, d, J = 2.4 Hz),




8.31(1H, s), 11.63(1H, s)




ESI+: 477


125
2
NMR1: 1.18(2H, dddd, J = 12.8, 12.8, 12.8, 4.0 Hz), 1.50-1.61(2H, m),




1.71-1.84(1H, m), 2.06(3H, s), 3.20-3.28(2H, m), 3.30(2H, d, J = 6.4 Hz), 3.64-3.73(2H,




m), 3.77-3.87(2H, m), 4.04-4.13(2H, m), 5.17(2H, s), 6.56-6.64(1H, m),




6.65-6.73(2H, m), 7.23(1H, dd, J = 8.8, 8.8 Hz), 7.54(1H, ddd, J = 8.8, 8.8, 2.4 Hz),




7.74(1H, ddd, J = 8.8, 8.8, 3.2 Hz), 7.74(1H, d, J = 3.6 Hz), 11.76(1H, br s)




ESI+: 442


















TABLE 142





Ex
Syn
DATA







126
2
NMR1: 1.44-1.54(2H, m), 2.06(3H, s), 2.06-2.10(2H, m), 2.22-2.26(3H, m),




2.38-2.46(2H, m), 3.90(2H, d, J = 6.4 Hz), 5.17(2H, s), 6.59-6.62(1H, m), 6.68-6.71(2H,




m), 7.21-7.31(2H, m), 7.60-7.66(2H, m), 8.10(1H, d, J = 7.9 Hz), 11.60(1H, s)




ESI+: 392


127
2
NMR1: 2.05(3H, s), 3.06(2H, t, J = 6.5 Hz), 4.24(2H, t, J = 6.5 Hz), 5.15(2H, s),




6.58-6.61(1H, m), 6.68-6.70(2H, m), 7.20-7.24(1H, m), 7.27-7.31(1H, m), 7.34(2H,




d, J = 5.7 Hz), 7.60-7.65(2H, m), 8.10(1H, d, J = 7.9 Hz), 8.49(2H, d, J = 4.6 Hz),




11.58(1H, s)




ESI+: 387


128
2
NMR1: 0.88(3H, t, J = 7.6 Hz), 1.18-1.34(4H, m), 1.36-1.58(4H, m), 1.80-1.90(1H,




m), 1.89-1.98(1H, m), 2.01(3H, s), 2.29(2H, dd, J = 8.0, 8.0 Hz), 2.98-3.10(1H, m),




3.13-3.25(1H, m), 3.61-3.77(2H, m), 3.85-3.99(1H, m), 4.64(2H, s), 7.53(1H, ddd, J = 8.8,




8.8, 3.2 Hz), 7.71(1H, dd, J = 8.8, 3.2 Hz), 7.78(1H, dd, J = 8.8, 5.3 Hz),




11.40(1H, s)




ESI+: 389


129
2
NMR1: 0.29-0.45(4H, m), 1.26-1.39(2H, m), 1.41-1.53(2H, m), 1.52-1.66(2H, m),




2.00(2H, s), 3.15-3.24(2H, m), 3.39(2H, t), 3.52(2H, t), 4.57(2H, s), 7.52(1H, ddd),




7.71(1H, dd), 7.78(1H, s), 11.47(1H, s)




ESI+: 334


130
2
NMR1: 1.22-1.36(2H, m), 1.59-1.68(2H, m), 1.93-2.05(1H, m), 2.06(3H, s),




3.27-3.36(2H. m), 3.82-3.93(4H, m), 5.38(2H, s), 6.49(1H, d, J = 2.0 Hz), 6.67(1H, dd, J = 2.0,




5.9 Hz), 7.24-7.32(1H, m), 7.58-7.65(2H, m), 8.01(1H, d, J = 5.9 Hz),




8.09(1H, d, J = 8.0 Hz), 11.60(1H, s)




ESI+: 381


131
2
NMR1: 2.06(3H, s), 2.44-2.47(4H, m), 2.67(2H, t, J = 5.8 Hz), 3.57-3.58(4H, m),




4.07(2H, t, J = 5.7 Hz), 5.17(2H, s), 6.58-6.61(1H, m), 6.67-6.70(2H, m), 7.22(1H,




t, J = 8.2 Hz), 7.53(1H, dt, J = 3.2, 8.4 Hz), 7.71-7.77(2H, m), 11.8(1H, br s)




ESI+: 413


















TABLE 143





Ex
Syn
DATA







132
2
NMR1: 1.30-1.35(2H, m), 1.65-1.68(2H, m), 2.00-2.03(1H, m), 2.07(3H, s),




3.29-3.35(2H, m), 3.85-3.89(2H, m), 3.92(2H, d, J = 6.5 Hz), 5.27(2H, s), 7.19-7.21(1H,




m), 7.56(1H, dt, J = 2.9, 9.2 Hz), 7.71-7.76(2H, m), 7.99(1H, d, J = 2.4 Hz),




8.07(1H, d, J = 2.3 Hz), 11.8(1H, s)




ESI+: 399


133
2
NMR1: 1.59(4H, t, J = 5.4 Hz), 1.66(2H, t, J = 6.9 Hz), 1.87(2H, sept., J = 7.7 Hz),




2.06(3H, s), 3.16-3.23(4H, m), 3.72(2H, t, J = 6.7 Hz), 5.14(2H, s), 6.48(1H, dd, J = 2.0,




7.9 Hz), 6.56-6.62(2H, m), 7.13(1H, t, J = 8.2 Hz), 7.26-7.31(1H, m),




7.59-7.67(2H, m), 8.09(1H, d, J = 7.5 Hz), 11.6(1H, br s)




ESI+: 405


134
2
NMR1: 0.85(3H, t, J = 7.2 Hz), 1.13-1.33(4H, m), 1.38-1.52(2H, m), 2.00(3H, s),




2.03(2H, t, J = 7.6 Hz), 3.77(1H, dd, J = 10.0, 3.6 Hz), 3.96-4.10(1H, m), 4.04(1H,




d, J = 10.0 Hz), 4.32(1H, dd, J = 10.0, 7.2 Hz), 4.40-4.52(1H, m), 4.59(2H, s),




7.54(1H, ddd, J = 8.8, 8.8, 3.2 Hz), 7.71(1H, dd, J = 8.8, 3.2 Hz), 7.77(1H, dd, J = 8.8,




4.4 Hz), 11.49(1H, s)




ESI+: 361


135
2
NMR1: 1.27-1.38(2H, m), 1.65-1.68(2H, m), 1.97-2.03(1H, m), 2.07(3H, s),




3.29-3.35(2H, m), 3.87(2H, dd, J = 2.9, 11.2 Hz), 3.92(2H, d, J = 6.4 Hz), 5.26(2H, s),




7.20(1H, t, J = 2.3 Hz), 7.27-7.32(1H, m), 7.60-7.66(2H, m), 7.98(1H, d, J = 2.3 Hz),




8.07(1H, d, J = 2.3 Hz), 8.09(1H, d, J = 8.1 Hz), 11.6(1H, s)




ESI+: 381


136
2
NMR1: 1.44-1.51(2H, m), 1.87(2H, m), 2.06(3H, s), 2.84-2.89(2H, m), 3.25(3H, s),




3.42-3.56(7H, m), 5.14(2H, s), 6.49(1H, dd, J = 2.0, 8.1 Hz), 6.57-6.59(1H, m),




6.63(1H, m), 7.12(1H, t, J = 8.2 Hz), 7.26-7.30(1H, m), 7.59-7.67(2H, m), 8.09(1H,




d, J = 7.7 Hz), 11.6(1H, s)




ESI+: 423


















TABLE 144





Ex
Syn
DATA







137
2
NMR1: 1.52-1.59(6H, m), 2.06(3H, s), 3.11-3.15(4H, m), 5.14(2H, s), 6.48(1H, dd,




J = 2.1, 8.1 Hz), 6.56(1H, d, J = 8.2 Hz), 6.60-6.61(1H, m), 7.13(1H, t, J = 8.2 Hz),




7.29(1H, t, J = 7.2 Hz), 7.59-7.67(2H, m), 8.09(1H, d, J = 8.1 Hz), 11.6(1H, s)




ESI+: 349


138
2
NMR1: 2.06(3H, s), 3.09-3.12(4H, m), 3.71-3.74(4H, m), 5.15(2H, s),




6.54-6.61(2H, m), 6.63-6.65(1H, m), 7.17(1H, t, J = 8.2 Hz), 7.27-7.31(1H, m),




7.59-7.66(2H, m), 8.09(1H, d, J = 7.8 Hz), 11.6(1H, s)




ESI+: 351


139
2
NMR1: 1.06-1.19(2H, m), 1.62-1.70(2H, m), 1.72-1.84(1H, m), 2.05(3H, s),




2.40-2.50(2H, m), 2.90-2.97(2H, m), 3.77(2H, d, J = 6.4 Hz), 5.16(2H, s), 6.55-6.59(1H,




m), 6.65-6.69(2H, m), 7.18-7.32(2H, m), 7.59-7.67(2H, m), 8.09(1H, d, J = 7.8 Hz),




11.50(1H, s)




FAB+: 379


140
2
NMR1: 0.00-0.09(2H, m), 0.29-0.45(2H, m), 0.63-0.78(1H, m), 1.31-1.43(2H, m),




1.38-1.49(1H, m), 1.47-1.62(1H, m), 1.80-2.00(2H, m), 2.01(3H, s), 2.38(2H, dd, J = 8.0,




8.0 Hz), 2.98-3.12(1H, m), 3.14-3.29(1H, m), 3.63-3.79(2H, m),




3.86-4.00(1H, m), 4.64(2H, s), 7.53(1H, ddd, J = 8.8, 8.8, 3.2 Hz), 7.71(1H, dd, J = 8.8,




3.2 Hz), 7.78(1H, dd, J = 8.8, 4.4 Hz), 11.40(1H, s)




ESI+: 387


141
2
NMR1: 1.15(6H, s), 1.82(2H, t, J = 7.0 Hz), 2.05(3H, s), 4.07(2H, t, J = 7.0 Hz),




4.36(1H, s), 5.16(2H, s), 6.58(1H, dd, J = 1.8, 8.1 Hz), 6.66-6.68(2H, m), 7.22(1H, t,




J = 8.7 Hz), 7.28(1H, m), 7.59-7.66(2H, m), 8.09(1H, d, J = 7.8 Hz), 11.6(1H, s)




ESI+: 368


















TABLE 145





Ex
Syn
DATA







142
2
NMR1: 0.82-0.88(3H, m), 1.27(4H, m), 2.05(3H, s), 2.36(2H, t, J = 7.6 Hz),




2.74(1H, t, J = 5.8 Hz), 2.84(1H, t, J = 5.7 Hz), 3.35(2H, s), 3.64(2H, t, J = 5.8 Hz),




4.55(2H, d, J = 18.2 Hz), 5.15(2H, s), 6.94(2H, s), 7.13-7.16(1H, m), 7.28(1H, t, J = 6.8 Hz),




7.59-7.67(2H, m), 8.10(1H, d, J = 7.7 Hz), 11.6(1H, s)




ESI+: 419


143
2
NMR1: 1.14-1.27(2H, m), 1.50-1.58(2H, m), 1.82-1.93(1H, m), 2.07(3H, s),




3.17-3.25(2H, m), 3.78-3.84(2H, m), 4.01(2H, d, J = 6.6 Hz), 5.39(2H, s), 6.40(1H, d, J = 7.8 Hz),




6.51(1H, d, J = 7.8 Hz), 7.25-7.29(1H, m), 7.57-7.68(3H, m), 7.08(1H, d,




J = 7.6 Hz), 11.53(1H, s)




FAB+: 381




mp: 221-223° C.


144
2
NMR1: 1.35-1.66(6H, m), 1.82-1.99(2H, m), 2.01(3H, s), 2.80-2.95(1H, m),




2.98-3.14(1H, m), 3.18-3.34(1H, m), 3.39(2H, dd, J = 12.0, 2.2 Hz), 3.67-3.75(1H, m),




3.75-3.88(3H, m), 3.87-4.01(1H, m), 4.64(2H, s), 7.52(1H, ddd, J = 8.8, 8.8, 2.8 Hz),




7.71(1H, dd, J = 10.0, 2.8 Hz), 7.79(1H, dd, J = 8.8, 4.8 Hz), 11.44(1H, br s)




ESI+: 403


145
2
NMR1: 1.19(2H, ddd, J = 24.0, 12.0, 4.4 Hz), 1.37-1.55(2H, m), 1.51-1.62(2H, m),




1.80-1.98(3H, m), 2.01(3H, s), 2.25(2H, d, J = 7.2 Hz), 3.00-3.11(1H, m),




3.15-3.25(1H, m), 3.22-3.31(3H, m), 3.64-3.75(1H, m), 3.75-3.84(2H, m), 3.88-3.99(1H,




m), 4.64(2H, s), 7.53(1H, ddd, J = 8.8, 8.8, 3.2 Hz), 7.71(1H, dd, J = 8.8, 2.8 Hz),




7.78(1H, dd, J = 8.8, 4.4 Hz), 11.39(1H, s)




ESI+: 417


146
2
NMR1: 0.85(3H, t, J = 7.1 Hz), 0.97-1.10(2H, m), 1.21-1.28(4H, m), 1.44-1.50(2H,




m), 1.71(2H, t, J = 15.2 Hz), 1.87(1H, m), 2.01(3H, s), 2.25(2H, t, J = 7.7 Hz),




2.50(1H, m), 2.95(1H, t, J = 11.3 Hz), 3.36(2H, m), 3.83(1H, d, J = 13.4 Hz),




4.37(1H, d, J = 13.0 Hz), 4.56(2H, s), 7.25-7.29(1H, m), 7.57-7.67(2H, m),




8.07-8.09(1H, m), 11.4(1H, s)




ESI+: 385


















TABLE 146





Ex
Syn
DATA







147
2
NMR1: 1.45-1.60(2H, m), 1.84-1.97(2H, m), 2.01(3H, s), 2.06(3H, s),




3.19-3.35(2H, m), 3.63(1H, m), 3.82(1H, m), 4.60(1H, m), 5.16(2H, s), 6.64(1H, dd, J = 1.8,




8.1 Hz), 6.69(1H, dd, J = 2.0, 8.2 Hz), 6.72(1H, t, J = 2.3 Hz), 7.23(1H, t, J = 8.2 Hz),




7.28(1H, ddd, J = 1.9, 6.2, 8.0 Hz), 7.59-7.65(2H, m), 8.08-8.10(1H, m),




11.6(1H, s)




ESI+: 407


148
2
NMR1: 1.49-1.63(6H, m), 1.96(2H, m), 2.05(3H, s), 2.91(1H, m), 3.21-3.41(4H,




m), 3.82-3.85(4H, m), 4.61(1H, m), 5.16(2H, s), 6.65(1H, dd, J = 1.8, 8.0 Hz),




6.67(1H, dd, J = 2.1, 8.0 Hz), 6.72(1H, t, J = 2.3 Hz), 7.23(1H, t, J = 8.1 Hz),




7.28(1H, ddd, J = 2.0, 6.0, 8.2 Hz), 7.61-7.63(2H, m), 8.09(1H, d, J = 7.9 Hz),




11.6(1H, s)




ESI+: 477


149
2
NMR1: 1.19(2H, dq, J = 4.3, 12.7 Hz), 1.40-1.59(4H, m), 1.91(3H, m), 2.05(3H, s),




2.26(2H, d, J = 6.3 Hz), 3.20-3.40(4H, m), 3.60-3.82(4H, m), 4.60(1H, m), 5.16(2H,




s), 6.63(1H, dd, J = 1.7, 8.1 Hz), 6.69(1H, dd, J = 2.0, 8.0 Hz), 6.72(1H, t, J = 2.1 Hz),




7.23(1H, t, J = 8.2 Hz), 7.29(1H, ddd, J = 1.9, 5.9, 8.0 Hz), 7.59-7.65(2H, m),




8.09(1H, d, J = 7.8 Hz), 11.6(1H, s)




ESI+: 491


150
2
NMR1: 1.47(1H, m), 1.59(1H, m), 1.84-1.93(2H, m), 2.01(3H, s), 2.05(3H, s),




3.17-3.22(1H, m), 3.28-3.35(1H, m), 3.64(1H, m), 3.82(1H, m), 4.60(1H, m), 5.17(2H,




s), 6.64(1H, dd, J = 1.9, 8.2 Hz), 6.69(1H, dd, J = 2.1, 8.0 Hz), 6.73(1H, t, J = 2.3 Hz),




7.23(1H, t, J = 8.2 Hz), 7.55(1H, dt, J = 3.0, 8.7 Hz), 7.71-7.76(2H, m), 11.7(1H, s)




ESI+: 425


151
2
NMR1: 1.49-1.64(6H, m), 1.89(2H, m), 2.06(3H, s), 2.89(1H, m), 3.34-3.41(4H,




m), 3.75-3.89(4H, m), 4.62(1H, m), 5.17(2H, s), 6.63-6.72(3H, m), 7.24(1H, t, J = 8.2 Hz),




7.55(1H, dt, J = 3.0, 8.5 Hz), 7.71-7.76(2H, m), 11.7(1H, s)




ESI+: 495


















TABLE 147





Ex
Syn
DATA







152
2
NMR1: 1.19(2H, dq, J = 4.4, 12.0 Hz), 1.45-1.59(4H, m), 1.88-1.98(3H, m),




2.06(3H, s), 2.26(2H, d, J = 6.5 Hz), 3.18-3.36(4H, m), 3.69-3.89(4H, m), 4.61(1H,




m), 5.17(2H, s), 6.63-6.72(3H, m), 7.23(1H, t, J = 8.2 Hz), 7.54(1H, dt, J = 3.0, 8.6 Hz),




7.71-7.76(2H, m), 11.7(1H, s)




ESI+: 509


153
2
NMR1: 1.31(2H, dddd, J = 12.4, 12.4, 12.4, 4.4 Hz), 1.58-1.71(2H, m),




1.92-2.06(1H, m), 2.06(3H, s), 3.23-3.42(1H, m), 3.86(2H, dd, J = 11.6, 3.6 Hz),




3.91(2H, d, J = 6.8 Hz), 5.39(2H, s), 6.49(1H, d, J = 2.0 Hz), 6.67(2H, dd, J = 5.6,




2.0 Hz), 7.54(1H, ddd, J = 8.4, 8.4, 8.4, Hz), 7.67-7.77(1H, m), 7.72(1H, d, J = 8.4 Hz),




8.01(1H, d, J = 6.4 Hz), 11.75(1H, s)




ESI+: 399


154
2
NMR1: 2.04(3H, s), 2.06(3H, s), 3.05-3.14(2H, m), 3.14-3.22(2H, m),




3.51-3.63(4H, m), 5.17(2H, s), 6.57(1H, dd, J = 8.4, 2.0 Hz), 6.62(1H, dd, J = 8.4, 2.0 Hz),




6.64-6.69(1H, m), 7.18(1H, dd, J = 8.4, 8.4 Hz), 7.54(1H, ddd, J = 8.4, 8.4, 2.8 Hz),




7.73(1H, dd, J = 8.8, 2.8 Hz), 7.76(1H, dd, J = 8.8, 4.8 Hz), 11.76(1H, br s)




ESI+: 410


155
2
NMR1: 1.16(6H, s), 1.82(2H, t, J = 7.2 Hz), 2.06(3H, s), 4.07(2H, t, J = 6.8 Hz),




4.37(1H, s), 5.18(2H, s), 6.58(1H, dd, J = 1.2, 8.0 Hz), 6.67(2H, m), 7.20-7.24(1H,




m), 7.52-7.57(1H, m), 7.71-7.77(2H, m), 11.7(1H, s)




ESI+: 386


156
2
NMR1: 1;19(6H, s), 2.06(3H, s), 3.70(2H, s), 4.61(1H, s), 5.18(2H, s), 6.59(1H, m),




6.69(2H, m), 7.22(1H, t, J = 8.3 Hz), 7.52-7.57(1H, m), 7.71-7.77(2H, m), 11.7(1H,




s)




ESI+: 372


















TABLE 148





Ex
Syn
DATA







157
2
NMR1: 1.12-1.31(2H, m), 1.60(2H, d, J = 12.4 Hz), 1.61-1.76(3H, m), 2.06(3H, s),




3.27(2H, ddd, J = 12.0, 12.0, 2.0 Hz), 3.82(2H, dd, J = 11.2, 3.2 Hz), 4.09(2H, dd, J = 6.0,




6.0 Hz), 5.39(2H, s), 6.49(1H, d, J = 2.0 Hz), 6.66(1H, dd, J = 6.0, 2.0 Hz),




7.54(1H, ddd, J = 8.4, 8.4, 3.2 Hz), 7.67-7.75(1H, m), 7.72(1H, d, J = 8.4 Hz),




8.00(1H, d, J = 5.6 Hz), 11.76(1H, s)




ESI+: 413


158
2
NMR1: 1.16-1.25(2H, m), 1.57(2H, d, J = 12.8 Hz), 1.95(1H, m), 2.05(3H, s),




2.33(2H, d, J = 6.8 Hz), 2.75(1H, t, J = 5.9 Hz), 2.84(1H, t, J = 5.8 Hz),




3.23-3.28(2H, m), 3.65(2H, m), 3.80(2H, m), 4.54(1H, s), 4.60(1H, s), 5.16(2H, s),




6.94(2H, m), 7.15(1H, m), 7.51-7.57(1H, m), 7.71-7.78(2H, m), 11.7(1H, s)




ESI+: 465


159
2
NMR1: 1.78-1.93(4H, m), 2.06(3H, s), 2.34-2.43(2H, m), 3.55-3.64(2H, m),




5.18(2H, s), 6.88-6.95(1H, m), 7.00(1H, dd, J = 8.4, 2.4 Hz), 7.04-7.09(1H, m),




7.34(1H, dd, J = 8.4, 8.4 Hz), 7.55(1H, ddd, J = 8.4, 8.4, 2.8 Hz), 7.68-7.79(1H, m),




7.71-7.76(1H, m), 11.76(1H, br s)




ESI+: 381


160
2
NMR2: 1.30-1.42(2H, m), 1.58-1.81(5H, m), 2.16(3H, s), 3.34-3.44(2H, m),




3.92-4.00(2H, m), 4.34(2H, t, J = 6.2 Hz), 5.17(2H, s), 6.30(1H, d, J = 2.2 Hz), 6.61(1H,




dd, J = 5.8, 2.2 Hz), 7.31-7.40(2H, m), 7.59(1H, ddd, J = 7, 7, 1 Hz), 8.04(1H, d, J = 5.8 Hz),




8.39(1H, d, J = 8 Hz), 8.92(1H, s)




ESI+: 395


161
2
NMR1: 1.10(6H, s), 1.43-1.51(2H, m), 1.69-1.80(2H, m), 2.06(3H, s), 3.95(2H, t, J = 6.4 Hz),




4.17(1H, s), 5.16(2H, s), 6.57(1H, d, J = 8.1 Hz), 6.64-6.69(2H, m),




7.22(1H, dd, J = 8.1, 8.1 Hz), 7.26-7.32(1H, m), 7.58-7.68(2H, m), 8.09(1H, d, J = 8.2 Hz),




11.59(1H, s)




ESI+: 382


















TABLE 149





Ex
Syn
DATA







162
2
NMR1: 1.10(6H, s), 1.43-1.51(2H, m), 1.69-1.80(2H, m), 2.06(3H, s), 3.95(2H, t, J = 6.3 Hz),




4.17(1H, s), 5.17(2H, s), 6.58(1H, d, J = 8.4 Hz), 6.65-6.70(2H, m),




7.22(1H, dd, J = 9.1, 8.4 Hz), 7.51-7.59(1H, m), 7.70-7.79(2H, m), 11.74(1H, s)




ESI+: 400


163
2
NMR1: 1.52-1.54(2H, m), 1.63(2H, dq, J = 4.3, 13.3 Hz), 1.79-1.85(2H, m),




2.97(3H, s), 2.66(2H, t, J = 6.9 Hz), 3.06-3.14(1H, m), 3.21-3.26(2H, m), 3.66(2H,




t, J = 5.9 Hz), 3.81-3.84(2H, m), 5.19(2H, s), 6.97(1H, d, J = 8.2 Hz), 7.00-7.09(1H,




m), 7.20(1H, t, J = 8.2 Hz), 7.54(1H, dt, J = 2.9, 8.4 Hz), 7.68-7.75(2H, m), 11.8(1H,




s)




ESI+: 451


164
2
NMR1: 1.03-1.17(2H, m), 1.54(2H, d, J = 12.6 Hz), 1.78-1.85(2H, m),




1.95-2.01(1H, m), 2.07(3H, s), 2.43(2H, d, J = 6.8 Hz), 2.65(2H, t, J = 7.0 Hz),




3.23-3.32(2H, m), 3.64-3.67(2H, m), 3.75-3.80(2H, m), 5.19(2H, s), 6.96(1H, d, J = 8.3 Hz),




7.08(1H, br s), 7.18(1H, t, J = 8.1 Hz), 7.55(1H, dt, J = 2.6, 8.4 Hz),




7.69-7.75(2H, m), 11.8(1H, s)




ESI+: 465


165
2
NMR1: 1.50-1.54(2H, m), 1.57-1.68(2H, dq, J = 4.2, 13.4 Hz), 1.81-1.89(2H, m),




2.05(3H, s), 2.64(2H, t, J = 6.6 Hz), 3.05-3.12(1H, m), 3.13-3.24(2H, m), 3.68(2H,




t, J = 6.3 Hz), 3.78-3.81(2H, m), 5.17(2H, s), 6.90(1H, dd, J = 2.4, 8.3 Hz), 7.15(1H,




d, J = 8.5 Hz), 7.17(1H, br s), 7.51-7.56(1H, m), 7.70-7.78(2H, m), 11.8(1H, s)




ESI+: 451


166
2
NMR1: 0.94-1.12(2H, m), 1.48(2H, d, J = 12.2 Hz), 1.83(2H, sept, J = 6.4 Hz),




1.87-1.99(1H, m), 2.05(3H, s), 2.37(2H, d, J = 6.8 Hz), 2.62(2H, t, J = 6.6 Hz), 3.22(2H,




t, J = 10.9 Hz), 3.65(2H, t, J = 6.4 Hz), 3.71-3.75(2H, m), 5.18(2H, s), 6.87(1H, dd,




J = 2.4, 8.3 Hz), 7.13(1H, d, J = 8.5 Hz), 7.19(1H, br s), 7.53(1H, dt, J = 3.2, 8.6 Hz),




7.70-7.76(2H, m), 11.7(1H, s)




ESI+: 465


















TABLE 150





Ex
Syn
DATA

















167
2
NMR1: 1.53-1.64(4H, m), 2.05(3H, s), 2.67-2.71(1H, m), 2.78-2.81(1H, m),




2.93-2.99(1H, m), 3.37-3.43(2H, m), 3.64-3.67(1H, m), 3.72-3.75(1H, m), 3.84-3.87(2H,




m), 4.59(1H, s), 4.72(1H, s), 5.16(2H, s), 6.91-6.99(2H, m), 7.13(1H, d, J = 8.4 Hz),




7.54(1H, dt, J = 2.8, 8.6 Hz), 7.72(1H, dd, J = 2.8, 9.5 Hz), 7.75(1H, dd, J = 4.6,




9.1 Hz), 11.7(1H, s)




ESI+: 451


168
2
NMR1: 1.14-1.26(2H, m), 1.58(2H, d, J = 12.8 Hz), 1.87-2.01(1H, m), 2.04(3H, s),




2.33(2H, d, J = 6.8 Hz), 2.67-2.70(1H, m), 2.76-2.80(1H, m), 3.23-3.30(2H, m),




3.65-3.68(2H, m), 3.76-3.83(2H, m), 4.60(1H, s), 4.65(1H, s), 5.16(2H, s),




6.91-6.99(2H, m), 7.13(1H, d, J = 8.4 Hz), 7.52-7.57(1H, m), 7.71-7.77(2H, m), 11.7(1H,




s)




ESI+: 465




mp: 179-182° C.


169
2
NMR1: 1.51-1.60(4H, m), 2.07(3H, s), 2.74-2.84(2H, m), 2.89-3.01(1H, m),




3.19-3.26(2H, m), 3.37-3.43(2H, m), 3.65-3.85(4H, m), 4.53(1H, s), 4.64(1H, s),




6.83-6.85(1H, m), 6.97-7.07(1H, m), 7.17-7.25(1H, m), 7.52-7.60(1H, m), 7.69-7.75(2H,




m), 11.8(1H, s)




ESI+: 451


170
2
NMR1: 1.12-1.24(2H, m), 1.51-1.58(2H, m), 1.84-1.98(1H, m), 2.06(3H, s),




2.32(2H, t, J = 6.5 Hz), 2.73-2.82(2H, m), 3.18-3.31(2H, m), 3.64-3.67(2H, m),




3.73-3.80(2H, m), 4.53-4.58(2H, m), 5.19(2H, s), 6.82-6.85(1H, m), 6.97-7.05(1H,




m), 7.17-7.24(1H, m), 7.52-7.58(1H, m), 7.67-7.75(2H, m), 11.8(1H, s)




ESI+: 465


171
2
NMR1: 1.51-1.63(4H, m), 2.05(3H, s), 2.74-2.85(2H, m), 2.91-3.01(1H, m),




3.40(2H, t, J = 11.0 Hz), 3.61-3.68(1H, m), 3.71-3.75(1H, m), 3.83-3.86(2H, m),




4.54(1H, s), 4.67(1H, s), 5.16(2H, s), 6.94-6.96(2H, m), 7.14-7.19(1H, m), 7.54(1H,




dt, J = 3.0, 8.4 Hz), 7.72(1H, dd, J = 3.0, 9.6 Hz), 7.75(1H, dd, J = 4.6, 9.2 Hz),




11.7(1H,




FAB+: 451


















TABLE 151





Ex
Syn
DATA

















172
2
NMR1: 1.43-1.47(2H, m), 1.54-1.62(2H, m), 1.85(2H, t, J = 7.0 Hz), 2.06(3H, s),




3.56(2H, dt, J = 4.0, 10.8 Hz), 3.63(2H, dt, J = 2.4, 10.6 Hz), 4.11(2H, t, J = 7.0 Hz),




4.43(1H, s), 5.16(2H, s), 6.56-6.59(1H, m), 6.66-.669(2H, m), 7.22(1H, t, J = 8.4 Hz),




7.27-7.31(1H, m), 7.59-7.67(2H, m), 8.07-8.10(1H, m), 11.6(1H, s)




ESI+: 410


173
2
NMR1: 1.30-1.41(1H, m), 1.44-1.64(2H, m), 1.77-1.86(1H, m), 1.95-2.05(1H, m),




2.06(3H, s), 3.21-3.40(2H, m), 3.70-3.87(2H, m), 3.93(2H, J = 6.7 Hz), 5.38(2H, s),




6.49(1H, d, J = 2.1 Hz), 6.67(1H, dd, J = 6.0, 2.3 Hz), 7.25-7.31(1H, m),




7.60-7.63(2H, m), 8.01(1H, d, J = 5.9 Hz), 8.08(1H, d, J = 7.9 Hz), 11.60(1H, s)




ESI+: 381


174
2
NMR1: 1.95-2.04(1H, m), 2.07(3H, s), 2.23-2.33(1H, m), 2.58-2.77(4H, m),




5.23(2H, s), 7.08-7.13(2H, m), 7.19(1H, t, J = 2.1 Hz), 7.27-7.31(1H, m), 7.42(1H, t,




J = 8.0 Hz), 7.59-7.67(2H, m), 8.10(1H, d, J = 7.9 Hz), 11.61(1H, s)




ESI+: 345


175
2
NMR1: 1.14(6H, s), 1.81(2H, t, J = 7.2 Hz), 1.96(3H, s), 2.96-3.12(4H, m), 4.12(2H,




t, J = 7.2 Hz), 4.41(1H, s), 6.82(1H, dd, J = 5.6, 2.4 Hz), 6.85(1H, d, J = 2.3 Hz),




7.21-7.27(1H, m), 7.51(1H, d, J = 7.8 Hz), 7.55-7.60(1H, m), 8.05(1H, d, J = 8.2 Hz),




8.32(1H, d, J = 5.8 Hz), 11.47(1H, s)




ESI+: 367


176
2
NMR1: 1.36-1.47(2H, m), 1.46-1.55(2H, m), 1.52-1.64(2H, m), 2.06(3H, s),




3.29-3.38(2H, m), 3.35-3.45(2H, m), 4.92(2H, s), 5.37(2H, s), 6.45(1H, d, J = 2.4 Hz),




6.66(1H, dd, J = 6.0, 2.4 Hz), 7.22-7.33(1H, m), 7.61(2H, d, J = 4.0 Hz), 8.01(1H,




d, J = 5.6 Hz), 8.09(1H, d, J = 8.4 Hz), 11.64(1H, s)




ESI+: 408


















TABLE 152





Ex
Syn
DATA

















177
2
NMR1: 1.07-1.21(2H, m), 1.38-1.47(2H, m), 1.45-1.57(1H, m), 1.53-1.64(2H, m),




1.93(3H, s), 3.18-3.26(2H, m), 3.25-3.31(2H, m), 3.75-3.87(2H, m), 5.19(2H, s),




6.56(1H, dd, J = 6.8, 2.0 Hz), 6.85(1H, d, J = 2.0 Hz), 7.29(1H, ddd, J = 8.4, 6.8, 1.6 Hz),




7.55-7.60(1H, m), 7.59-7.65(1H, m), 7.73(1H, d, J = 7.6 Hz), 8.08(1H, d, J = 8.4 Hz),




8.61(1H, dd, J = 5.6, 5.6 Hz), 11.53(1H, s)




ESI+: 422


178
2
NMR1: 1.94(2H, q, J = 6.8 Hz), 2.06(3H, s), 3.24(3H, s), 3.44(2H, t, J = 6.8 Hz),




4.09(2H, t, J = 6.8 Hz), 5.38(2H, s), 6.48(1H, d, J = 2.4 Hz), 6.67(1H, dd, J = 6.0,




2.4 Hz), 7.28(1H, ddd, J = 8.0, 6.0, 2.4 Hz), 7.58-7.65(2H, m), 8.01(1H, d, J = 6.0 Hz),




8.07-8.12(1H, m), 11.60(1H, br s)




ESI+: 355


179
2
NMR1: 1.44(2H, d, J = 12.7 Hz), 1.53-1.61(2H, m), 1.86(2H, t, J = 7.0 Hz),




2.06(3H, s), 3.54-3.64(4H, m), 4.20(2H, t, J = 7.1 Hz), 4.47(1H, s), 5.38(2H, s),




6.49(1H, d, J = 2.1 Hz), 6.65(1H, dd, J = 2.2, 5.9 Hz), 7.26-7.30(1H, m),




7.60-7.62(2H, m), 8.00(1H, d, J = 5.8 Hz), 8.08(1H, d, J = 7.8 Hz), 11.6(1H, s)




ESI+: 411




mp: 189-190° C.


180
2
NMR2: 1.40-1.52(2H, m), 1.73-1.81(2H, m), 2.07(1H, m), 2.13(3H, s), 2.90(2H, t, J = 6 Hz),




2.99(2H, t, J = 6 Hz), 3.45(2H, ddd, J = 11.7, 11.7, 2 Hz), 3.76(2H, s),




3.80(2H, d, J = 6 Hz), 3.81(2H, s), 3.99-4.07(2H, m), 6.72(1H, d, J = 2.2 Hz),




6.75(1H, dd, J = 8, 2.2 Hz), 6.96(1H, d, J = 8 Hz), 7.23-7.33(2H, m), 7.53(1H, ddd, J = 7,




7, 1.5 Hz), 8.39(1H, dd, J = 7, 1.5 Hz), 9.61(1H, s)




ESI+: 419


















TABLE 153





Ex
Syn
DATA

















181
2
NMR1: 0.86(3H, t, J = 6.8 Hz), 1.20-1.32(4H, m), 1.44-1.52(2H, m), 2.03(3H, s),




2.25-2.31(2H, m), 2.40-2.48(4H, m), 3.45-3.51(4H, m), 3.60(2H, s), 7.23-7.28(1H,




m), 7.56-7.61(1H, m), 7.65-7.70(1H, m), 8.05-8.08(1H, m), 11.21(1H, s)




ESI+: 356




mp: 171-173° C.


182
2
NMR1: 0.33-0.40(4H, m), 0.43-0.46(4H, m), 2.01(3H, s), 3.19-3.25(1H, m),




3.35(2H, s), 3.38(2H, s), 4.57(2H, s), 7.24-7.29(1H, m), 7.57-7.66(2H, m),




8.06-8.09(1H, m), 11.35(1H, s)




ESI+: 314




mp: 125-127° C.


183
2
NMR1: 1.45-1.52(1H, m), 1.56-1.64(1H, m), 1.95-2.04(6H, m), 2.05(3H, s),




3.43(1H, br s), 4.06(2H, t, J = 7.2 Hz), 5.17(2H, s), 5.57(1H, dd, J = 2.0, 7.6 Hz),




6.66-6.68(2H, m), 7.19-7.24(1H, m), 7.27-7.31(1H, m), 7.59-7.67(2H, m),




8.08-8.10(1H, m), 11.6(1H, s)




ESI+: 380


184
2
NMR1: 1.21-1.36(2H, m), 1.57-1.67(2H, m), 1.89-2.05(4H, m), 2.96-3.14(4H, m),




3.26-3.35(2H, m), 3.81-3.90(4H, m), 6.79-6.88(2H, m), 7.20-7.28(1H, m), 7.50(1H,




d, J = 8.0 Hz), 7.54-7.61(1H, m), 8.05(1H, d, J = 8.4 Hz), 8.33(1H, d, J = 5.5 Hz),




11.47(1H, s)




ESI+: 379




mp: 212-215° C.


185
2
NMR1: 1.25-1.37(2H, m), 1.62-1.72(2H, m), 1.98(1H, m), 2.04(3H, s),




3.27-3.37(2H, m), 3.82(2H, d, J = 6 Hz), 3.83-3.90(2H, m), 4.00(3H, s), 5.26(2H, s),




6.57(1H, dd, J = 8.2 Hz), 6.62-6.68(2H, m), 7.18-7.27(3H, m), 7.66(1H, m),




10.91(1H, s)




ESI+: 410


















TABLE 154





Ex
Syn
DATA

















186
2
NMR1: 1.15(6H, s), 1.91(2H, t, J = 7.6 Hz), 2.06(3H, s), 3.10(3H, s), 4.10(2H, t, J = 7.6 Hz),




5.38(2H, s), 6.50(1H, d, J = 2.0 Hz), 6.57(1H, dd, J = 6.0, 2.0 Hz),




7.28(1H, ddd, J = 8.0, 6.0, 2.0 Hz), 7.57-7.66(2H, m), 8.01(1H, d, J = 6.0 Hz),




8.06-8.12(1H, m), 11.59(1H, s)




ESI+: 383


187
2
NMR1: 1.13-1.30(2H, m), 1.55-1.77(5H, m), 2.06(3H, s), 3.28(2H, ddd, J = 11.9,




11.8, 2.0 Hz), 3.83(2H, dd, J = 11.3, 4.0 Hz), 4.10(2H, t, J = 6.5 Hz), 5.26(2H, s),




7.20(1H, dd, J = 2.4, 2.4 Hz), 7.27-7.34(1H, m), 7.59-7.66(2H, m), 7.98(1H, d, J = 2.3 Hz),




8.06(1H, d, J = 2.4 Hz), 8.10(1H, d, J = 8.3 Hz), 11.63(1H, s)




ESI+: 395


188
2
NMR1: 1.09(6H, s), 1.42-1.48(2H, m), 1.70-1.79(2H, m), 2.06(3H, s), 4.01-4.06(2H,




m), 4.20(1H, s), 5.38(2H, s), 6.47(1H, d, J = 2.0 Hz), 6.65(1H, dd, J = 2.4, 6.0 Hz),




7.25-7.30(1H, m), 7.58-7.64(2H, m), 8.00(1H, d, J = 6.0 Hz), 8.08(1H, d, J = 8.0 Hz),




11.62(1H, s)




ESI+: 383


189
2
NMR1: 1.18(6H, s), 2.06(3H, s), 3.79(2H, s), 4.69(1H, s), 5.38(2H, s), 6.48(1H, d, J = 2.0 Hz),




6.68(1H, dd, J = 2.0, 6.0 Hz), 7.26-7.31(1H, m), 7.58-7.66(2H, m),




8.01(1H, d, J = 6.0 Hz), 8.08(1H, d, J = 8.4 Hz), 11.61(1H, s)




ESI+: 355


190
2
NMR1: 1.35(3H, s), 2.06(3H, s), 4.14(2H, s), 4.30(2H, d, J = 6.0 Hz), 4.46(2H, d, J = 6.0 Hz),




5.39(2H, s), 6.55(1H, d, J = 2.4 Hz), 6.72(1H, dd, J = 6.0, 2.4 Hz),




7.28(1H, ddd, J = 8.4, 5.2, 3.2 Hz), 7.57-7.66(2H, m), 8.03(1H, d, J = 6.0 Hz),




8.06-8.12(1H, m), 11.61(1H, s)




ESI+: 367


















TABLE 155





Ex
Syn
DATA

















191
2
NMR1: 1.20(3H, t, J = 7.2 Hz), 2.06(3H, s), 3.09-3.17(4H, m), 3.44-3.53(4H, m),




4.06(2H, q, J = 7.2 Hz), 5.15(2H, s), 6.57(1H, dd, J = 8.0, 2.4 Hz), 6.61(1H, dd, J = 8.0,




2.4 Hz), 6.66(1H, dd, J = 2.4, 2.4 Hz), 7.17(1H, dd, J = 8.0, 8.0 Hz), 7.29(1H,




ddd, J = 8.0, 6.4, 1.6 Hz), 7.63(1H, dddd, J = 8.0, 8.0, 8.0, 1.6 Hz), 7.60-7.68(1H,




m), 8.09(1H, dd, J = 8.0, 1.2 Hz), 11.59(1H, s)




ESI+: 422




mp: >234° C.(dec.)


192
2
NMR1: 1.16(6H, s), 1.85(2H, t, J = 7.1 Hz), 2.07(3H, s), 4.16(2H, t, J = 7.2 Hz),




4.42(1H, s), 5.27(2H, s), 7.20(1H, dd, J = 2.4, 2.3 Hz), 7.26-7.34(1H, m),




7.59-7.67(2H, m), 7.97(1H, d, J = 2.3 Hz), 8.06(1H, d, J = 2.4 Hz), 8.10(1H, d, J = 8.0 Hz),




11.63(1H, br s)




ESI+: 369


193
2
NMR1: 1.52-1.59(2H, m), 1.66-1.70(2H, m), 1.94(2H, t, J = 7.0 Hz), 2.06(3H, s),




3.11(3H, s), 3.49-3.59(4H, m), 4.00(2H, t, J = 7.0 Hz), 5.17(2H, s), 6.55-6.60(1H,




m), 6.66-6.69(2H, m), 7.20-7.25(1H, m), 7.27-7.31(1H, m), 7.59-7.66(2H, m),




8.07-8.10(1H, m), 11.6(1H, s)




FAB+: 424


194
2
NMR1: 1.10(6H, s), 1.44-1.52(2H, m), 1.62(2H, t, J = 7.2 Hz), 1.84-1.92(2H, m),




2.03(3H, s), 2.85-2.92(2H, m), 3.40-3.44(1H, m), 3.47-3.52(2H, m), 3.53(2H, t, J = 7.1 Hz),




4.12(1H, s), 5.14(2H, s), 6.48(1H, dd, J = 2.1, 8.0 Hz), 6.58(1H, dd, J = 2.0,




8.2 Hz), 6.61-6.63(1H, m), 7.13(1H, t, J = 8.2 Hz), 7.26-7.31(1H, m),




7.59-7.66(2H, m), 8.07-8.10(1H, m), 11.6(1H, s)




FAB+: 451




mp: 160-163° C.


















TABLE 156





Ex
Syn
DATA

















195
2
NMR1: 1.10(6H, s), 1.41-1.54(2H, m), 1.68(2H, t, J = 7.2 Hz), 1.83-1.92(2H, m),




2.05(3H, s), 2.86-2.92(2H, m), 3.07(3H, s), 3.42-3.45(1H, m), 3.45-3.51(2H, m),




3.47(2H, t, J = 7.3 Hz), 5.14(2H, s), 6.48(1H, dd, J = 2.0, 8.0 Hz), 6.57-6.60(1H, m),




6.61-6.63(1H, m), 7.13(1H, t, J = 8.0 Hz), 7.26-7.31(1H, m), 7.59-7.66(2H, m),




8.08-8.09(1H, m), 11.6(1H, s)




FAB+: 465


196
2
NMR1: 2.01-2.02(5H, m), 3.05-3.14(1H, m), 4.02(2H, t, J = 6.4 Hz), 4.33(2H, t, J = 6.0 Hz),




4.62-4.67(2H, m), 5.37(2H, s), 6.46(1H, d, J = 2.2 Hz), 6.61-6.65(1H, dd, J = 2.3,




5.9 Hz), 7.25-7.31(1H, m), 7.60-7.63(2H, m), 8.00(1H, d, J = 5.9 Hz), 8.08(1H,




d, J = 8.0 Hz), 11.60(1H, s)




ESI+: 367


197
2
NMR1: 1.15(6H, s), 1.81(2H, t, J = 7.3 Hz), 2.05(3H, s), 3.72(3H, s), 4.04(2H, t, J = 7.2 Hz),




4.36(1H, s), 5.14(2H, s), 6.15(1H, dd, J = 2.1, 2.1 Hz), 6.25-6.30(2H, m),




7.26-7.32(1H, m), 7.58-7.67(2H, m), 8.10(1H, d, J = 8.1 Hz), 11.58(1H, s)




ESI+: 398


198
2
NMR1: 1.37-1.48(2H, m), 1.73-1.82(2H, m), 2.05(3H, s), 2.79-2.87(2H, m),




3.48-3.56(2H, m), 3.56-3.65(1H, m), 4.66(1H, d, J = 4.0 Hz), 5.14(2H, s), 6.47(1H, dd, J = 2.2,




8.1 Hz), 6.57(1H, dd, J = 2.1, 8.2 Hz), 6.60-6.63(1H, m), 7.12(1H, t, J = 8.2 Hz),




7.25-7.30(1H, m), 7.58-7.67(2H, m), 8.09(1H, dd, J = 1.2, 8.2 Hz),




11.60(1H, s)




ESI+: 365


199
2
NMR1: 1.13(3H, s), 1.49-1.55(4H, m), 2.06(3H, s), 3.08-3.16(2H, m),




3.26-3.32(2H, m), 4.27(1H, s), 5.14(2H, s), 6.46(1H, d, J = 2.1, 8.0 Hz), 6.55-6.59(1H,




m), 6.59-6.62(1H, m), 7.11(1H, t, J = 8.2 Hz), 7.26-7.30(1H, m), 7.58-7.67(2H, m),




8.09(1H, dd, J = 1.2, 8.2 Hz), 11.57(1H, s)




ESI+: 379


















TABLE 157





Ex
Syn
DATA

















200
2
NMR1: 1.09-1.22(2H, m), 1.36-1.51(1H, m), 1.52-1.64(4H, m), 2.06(3H, s),




2.65-2.74(2H, m), 3.18-3.27(2H, m), 3.82(2H, dd, J = 11.0, 3.9 Hz), 5.24(2H, s),




7.24(1H, d, J = 8.5 Hz), 7.27-7.32(1H, m), 7.46(1H, dd, J = 8.5, 2.9 Hz),




7.59-7.66(2H, m), 8.09(1H, d, J = 8.2 Hz), 8.34(1H, d, J = 2.9 Hz), 11.59(1H, br s)




ESI+: 379


201
2
NMR1: 1.16-1.28(2H, m), 1.55-1.62(2H, m), 1.79-1.90(1H, m), 2.06(3H, s),




3.25-3.38(4H, m), 3.80-3.86(2H, m), 4.50(2H, s), 5.41(2H, s), 6.89(1H, s), 6.98(1H, d, J = 5.6 Hz),




7.25-7.31(1H, m), 7.58-7.65(2H, m), 8.08(1H, d, J = 8.0 Hz), 8.16(1H, d,




J = 4.8 Hz), 11.61(1H, s)




FAB+: 395


202
2
NMR1: 1.38-1.53(1H, m), 1.56-1.67(1H, m), 1.67-1.76(2H, m), 1.90-1.98(4H, m),




2.05(3H, s), 2.50-2.60(2H, m), 4.90(1H, s), 5.15(2H, s), 7.01(2H, d, J = 8.6 Hz),




7.17(2H, d, J = 6.6 Hz), 7.26-7.31(1H, m), 7.59-7.68(2H, m), 8.09(1H, dd, J = 8.0,




1.0 Hz), 11.60(1H, br s)




FAB+: 364


203
2
NMR1: 1.17-1.37(5H, m), 1.46-1.51(1H, m), 1.66-1.75(2H, m), 1.90-1.98(2H, m),




2.00(3H, s), 33.6-3.48(1H, m), 4.58(2H, s), 7.24-7.28(1H, m), 7.55-7.64(1H, m),




7.66-7.68(1H, m), 8.05-8.09(1H, m), 11.3(1H, s)




FAB+: 272


204
2
NMR1: 0.89(6H, s), 2.01(3H, s), 3.19-3.50(10H, m), 3.84(2H, s), 4.57(2H, s),




7.23-7.31(1H, m), 7.58-7.60(2H, m), 8.06-8.08(1H, m), 11.3(1H, s)




FAB+: 389




mp: 155-157° C.


205
2
NMR1: 1.13-1.26(1H, m), 1.26-1.50(7H, m), 1.50-1.63(2H, m), 1.72(2H, t, J = 7.0 Hz),




1.98(3H, s), 3.67(2H, t, J = 7.1 Hz), 4.20(1H, s), 4.57(2H, s), 7.23-7.30(1H, m),




7.56-7.63(1H, m), 7.68(1H, d, J = 8.2 Hz), 8.08(1H, dd, J = 8.0, 1.3 Hz), 11.34(1H,




s)




FAB+: 316




mp: 125-127° C.


















TABLE 158





Ex
Syn
DATA

















206
2
NMR1: 1.37-1.69(8H, m), 1.67-1.80(2H, m), 1.81-1.97(2H, m), 2.01(3H, s),




2.98(1H, q, J = 7.2 Hz), 3.02-3.12(1H, m), 3.18-3.28(1H, m), 3.64-3.74(1H, m),




3.74-3.84(1H, m), 3.87-3.97(1H, m), 4.63(2H, s), 7.27(1H, ddd, J = 8.0, 6.8, 1.2 Hz),




7.60(1H, ddd, J = 8.0, 6.8, 1.2 Hz), 7.68(1H, d, J = 8.0 Hz), 8.08(1H, dd, J = 8.0,




1.2 Hz), 11.25(1H, s)




FAB+: 369


207
2
NMR1: 0.52-0.56(4H, m), 2.00(3H, s), 3.19(4H, br s), 3.40(4H, br s), 3.40(2H, s),




3.98(2H, s), 4.59(2H, s), 7.27(1H, t, J = 8.0 Hz), 7.57-7.65(2H, m), 8.07(1H, d, J = 8.0 Hz),




11.3(1H, s)




FAB+: 387


208
2
NMR1: 1.08-1.23(2H, m), 1.37-1.53(3H, m), 1.56-1.65(2H, m), 2.06(3H, s),




2.52-2.59(2H, m), 3.19-3.28(2H, m), 3.82(2H, dd, J = 10.4, 3.3 Hz), 5.37(2H, s),




6.90(1H, d, J = 8.2 Hz), 7.24-7.31(1H, m), 7.56-7.66(3H, m), 8.04(1H, d, J = 2.3 Hz),




8.09(1H, d, J = 8.1 Hz), 11.60(1H, br s)




ESI+: 379


209
2
NMR1: 0.58-0.78(4H, m), 0.94-1.23(2H, m), 1.49-1.61(2H, m), 1.54-1.67(1H, m),




1.68-1.90(2H, m), 1.92-2.04(1H, m), 2.00(3H, s), 2.50-2.63(1H, m), 2.63-2.77(2H,




m), 2.98-3.15(1H, m), 4.18-4.45(2H, m), 7.24(1H, ddd, J = 8.0, 6.4, 1.2 Hz),




7.50(1H, d, J = 8.0 Hz), 7.57(1H, ddd, J = 8.0, 6.4, 1.2 Hz), 8.05(1H, dd, J = 8.0,




1.2 Hz), 11.36(1H, s)




ESI+: 339




mp: 222-224° C.


210
2
NMR1: 1.42-1.56(2H, m), 1.54-1.69(4H, m), 1.68-1.81(2H, m), 2.04(3H, s),




2.96(1H, q, J = 8.0 Hz), 3.31-3.46(4H, m), 3.41-3.57(4H, m), 5.17(2H, s), 7.28(1H,




ddd, J = 8.0, 6.8, 1.2 Hz), 7.57(1H, d, J = 8.0 Hz), 7.62(1H, ddd, J = 8.0, 6.8, 1.2 Hz),




8.08(1H, dd, J = 8.0, 1.2 Hz), 11.61(1H, br s)




ESI+: 398


















TABLE 159





Ex
Syn
DATA

















211
2
NMR1: 1.02-1.21(2H, m), 1.44-1.58(2H, m), 1.56-1.71(1H, m), 2.03(3H, s),




2.91(2H, dd, J = 6.0, 6.0 Hz), 3.17-3.28(2H, m), 3.76-3.88(2H, m), 5.07(2H, s),




7.28(1H, ddd, J = 8.0, 6.8, 1.2 Hz), 7.36-7.43(1H, m), 7.56(1H, d, J = 8.0 Hz),




7.61(1H, ddd, J = 8.0, 6.8, 1.2 Hz), 8.08(1H, dd, J = 8.0, 1.2 Hz), 11.56(1H, br s)




ESI+: 331


212
2
NMR1: 1.47-1.57(2H, m), 1.91-1.95(2H, m), 2.01(3H, s), 3.32-3.38(2H, m),




3.62-3.70(1H, m), 3.81-3.86(2H, m), 4.62(2H, s), 7.26(1H, t, J = 7.0 Hz), 7.57-7.61(1H,




m), 7.67(1H, d, J = 8.3 Hz), 8.07(1H, d, J = 8.2 Hz), 11.2(1H, s)




ESI+: 274




mp: 194-196° C.


213
2
NMR1: 1.17(6H, d, J = 8.1 Hz), 2.04(3H, s), 2.50-2.54(2H, m), 1.76-2.85(2H, m),




3.65-3.73(2H, m), 4.56(1H, s), 4.64(1H, s), 4.84(1H, d, J = 8.5 Hz), 5.15(2H, s),




6.93-6.96(2H, m), 7.13-7.17(1H, m), 7.27-7.31(1H, m), 7.58-7.66(2H, m), 8.09(1H,




d, J = 7.8 Hz), 11.5(1H, s)




ESI+: 421




mp: 135-138° C.


214
2
NMR1: 1.09(6H, s), 1.56-1.64(2H, m), 2.05(3H, s), 2.39-2.44(2H, m),




2.71-2.78(1H, m), 2.82-2.90(1H, m), 3.63-3.68(2H, m), 4.00-4.06(1H, m), 4.53(1H, s),




4.60(1H, s), 5.16(2H, s), 6.94(2H, br s), 7.14-7.18(1H, m), 7.26-7.30(1H, m),




7.59-7.66(2H, m), 8.09(1H, d, J = 7.9 Hz), 11.5(1H, s)




ESI+: 435


215
2
NMR1: 1.09-1.22(2H, m), 1.37-1.52(3H, m), 1.55-1.64(2H, m), 2.05(3H, s),




2.51-2.58(2H, m), 3.18-3.28(2H, m), 3.82(2H, dd, J = 11.0, 3.7 Hz), 5.14(2H, s),




7.01(2H, d, J = 8.6 Hz), 7.16(2H, d, J = 8.6 Hz), 7.25-7.31(1H, m), 7.57-7.67(2H,




m), 8.09(1H, d, J = 8.0 Hz), 11.55(1H, br s)




ESI+: 378


















TABLE 160





Ex
Syn
DATA

















216
2
NMR1: 1.12(6H, s), 1.74(2H, t, J = 6.8 Hz), 1.99(3H, s), 3.66(2H, t, J = 6.8 Hz),




4.38(1H, br s), 4.57(2H, s), 7.27(1H, dd, J = 7.2, 7.2 Hz), 7.55-7.63(1H, m),




7.67(1H, d, J = 8.4 Hz), 8.08(1H, d, J = 8.4 Hz), 11.31(1H, br s)




ESI+: 276


217
2
NMR1: 2.07(3H, s), 5.41(2H, s), 6.97(1H, d, J = 8.0 Hz), 7.06(1H, dd, J = 7.2,




5.2 Hz), 7.24-7.31(1H, m), 7.57-7.65(2H, m), 7.74-7.81(1H, m), 8.09(1H, d, J = 8.0 Hz),




8.20-8.25(1H, m), 11.59(1H, br s)




ESI+: 267


218
2
NMR1: 1.40-1.53(4H, m), 1.52-1.63(2H, m), 1.98(3H, s), 3.24-3.36(2H, m),




3.40-3.50(2H, m), 4.39(2H, s), 4.71(2H, s), 7.27(1H, ddd, J = 8.4, 6.8, 1.6 Hz), 7.60(1H,




ddd, J = 8.4, 6.8, 1.6 Hz), 7.62-7.66(1H, m), 8.08(1H, dd, J = 8.4, 1.6 Hz),




11.70(1H, br s)




ESI+: 315


219
2
NMR1: 0.08-0.14(2H, m), 0.40-0.48(2H, m), 0.83-1.22(3H, m), 1.51-1.66(3H, m),




1.72-1.84(2H, m), 2.09(3H, s), 2.24(2H, d, J = 6.7 Hz), 2.47-2.59(1H, m),




2.77-2.86(2H, m), 2.93-3.04(1H, m), 3.84(1H, d, J = 13.5 Hz), 4.40(1H, d, J = 12.7 Hz),




7.34-7.42(1H, m), 7.63-7.72(2H, m), 8.17(1H, d, J = 8.1 Hz), 12.36(1H, br s)




ESI+: 353


220
2
NMR1: 0.93-1.16(2H, m), 1.45-1.67(7H, m), 1.73-1.87(2H, m), 2.10(3H, s),




2.47-2.58(1H, m), 2.77-2.92(3H, m), 2.95-3.07(1H, m), 3.33-3.43(2H, m), 3.80-3.87(2H,




m), 3.99(1H, d, J = 13.2 Hz), 4.40(1H, d, J = 11.6 Hz), 7.34-7.41(1H, m),




7.63-7.72(2H, m), 8.17(1H, d, J = 8.1 Hz), 12.36(1H, br s)




ESI+: 383


221
2
NMR1: 1.13(6H, s), 1.56-1.64(2H, m), 2.06(3H, s), 2.54-2.62(2H, m), 4.25(1H, s),




5.37(2H, s), 6.89(1H, d, J = 8.6 Hz), 7.25-7.31(1H, m), 7.57-7.65(3H, m), 8.03(1H,




d, J = 2.2 Hz), 8.09(1H, d, J = 7.8 Hz), 11.59(1H, br s)




ESI+: 353


















TABLE 161





Ex
Syn
DATA

















222
2
NMR1: 0.49-0.56(2H, m), 0.73-0.80(2H, m), 1.01-1.19(2H, m), 1.22(3H, s),




1.53-1.68(3H, m), 1.75-1.85(2H, m), 2.12(3H, s), 2.69-2.90(4H, m), 4.21-4. 32(2H, m),




7.36-7.45(1H, m), 7.67-7.74(2H, m), 8.19(1H, d, J = 8.2 Hz), 12.55(1H, br s)




ESI+: 353


223
2
NMR1: 0.97-1.23(2H, m), 1.52-1.68(3H, m), 1.74-1.83(2H, m), 3.13(3H, s),




2.57(1H, t, J = 13.1 Hz), 2.81-2.91(2H, m), 2.96(1H, t, J = 12.3 Hz), 3.28(3H, s),




3.7-3.83(1H, m), 4.03(1H, d, J = 14.0 Hz), 4.10(1H, d, J = 13.7 Hz), 4.34(1H, d, J = 13.0 Hz),




7.40-7.48(1H, m), 7.69-7.79(2H, m), 8.22(1H, d, J = 8.2 Hz), 12.8(1H, br




s)




ESI+: 343


224
2
NMR1: 0.96(3H, t, J = 7.2 Hz), 1.10-1.21(2H, m), 1.26-1.40(2H, m), 1.84(2H, d, J = 10.8 Hz),




2.03(2H, d, J = 10.5 Hz), 2.09(3H, s), 2.98(2H, q, J = 7.1 Hz),




3.30-3.38(1H, m), 3.38-3.48(1H, m), 4.70(2H, s), 7.41(1H, t, J = 7.4 Hz), 7.71(1H, t, J = 7.3 Hz),




7.87(1H, d, J = 8.1 Hz), 8.20(1H, d, J = 8.1 Hz), 12.2(1H, s)




ESI+: 358




mp: >270° C.(dec.)


225
2
NMR1 + TFA: 1.20-1.30(2H, m), 1.39-1.50(4H, m), 1.56-1.63(4H, m),




1.69-1.74(2H, m), 1.83-1.87(2H, m), 2.11-2.13(2H, m), 2.32(3H, s), 2.50-2.53(1H, m),




3.52-3.58(2H, m), 4.95(2H, s), 7.62(1H, d, J = 7.5 Hz), 7.74(1H, t, J = 7.6 Hz),




7.96(1H, t, J = 7.2 Hz), 8.26(1H, d, J = 8.6 Hz), 8.45(1H, d, J = 8.2 Hz)




ESI+: 383


226
2
NMR1: 1.17(3H, t, J = 7.0 Hz), 1.28-1.41(2H, m), 1.47-1.64(4H, m), 2.00(3H, s),




2.13(2H, d, J = 12.0 Hz), 2.68(3H, s), 3.33-3.42(1H, m), 3.82(1H, br s), 4.01(2H, q,




J = 7.0 Hz), 4.60(2H, s), 7.24-7.28(1H, m), 7.56-7.62(1H, m), 7.68(1H, d, J = 8.3 Hz),




8.05-8. 08(1H, m), 11.2(1H, s)




ESI+: 373


















TABLE 162





Ex
Syn
DATA

















227
2
NMR1: 2.03(3H, s), 5.21(2H, s), 7.27-7.39(3H, m), 7.63(2H, d, J = 3.2 Hz),




7.69-7.74(2H, m), 8.08(1H, d, J = 8.4 Hz), 11.74(1H, s)




ESI+: 368


228
2
NMR1: 1.10-1.72(14H, m), 2.00(3H, d, J = 10.7 Hz), 2.75-2.90(1H, m), 3.14(1H, t,




J = 2.8 Hz), 3.35-3.85(8H, m), 4.61(2H, d, J = 6.8 Hz), 7.27(1H, t, J = 7.5 Hz),




7.57-7.71(2H, m), 8.08(1H, d, J = 8.1 Hz)




ESI+: 427


229
2
NMR1: 0.91-1.27(9H, m), 1.47-1.65(5H, m), 1.69-1.87(2H, m), 1.99(3H, s),




2.25-2.38(2H, m), 2.64-2.75(2H, m), 2.92-3.09(1H, m), 3.80-3.95(1H, m), 4.21(1H, s),




4.32-4. 47(1H, m), 7.23(1H, dd, J = 7.4, 7.2 Hz), 7.48(1H, d, J = 8.2 Hz), 7.56(1H, dd,




J = 7.5, 7.2 Hz), 8.05(1H, d, J = 7.9 Hz), 11.29(1H, s)




ESI+: 385


230
2
NMR1: 1.53(4H, br s), 1.69(2H, br s), 1.89(2H, br s), 2.10(3H, s), 4.16-4.27(1H,




m), 5.52(2H, s), 7.24-7.32(1H, m), 7.60-7.62(2H, m), 8.08(1H, d, J = 8.0 Hz),




8.43(1H, d, J = 7.0 Hz), 9.02(2H, s), 11.7(1H, s)




ESI+: 379




mp: >231° C.(dec.)


231
2
NMR1: 1.44(8H, br s), 1.59(4H, br s), 2.10(3H, s), 3.36(2H, br s), 3.59(2H, br s),




5.51(2H, s), 7.25-7.31(1H, m), 7.61-7.62(2H, m), 8.09(1H, d, J = 8.1 Hz), 8.74(2H,




s), 11.7(1H, s)




ESI+: 433


232
2
NMR1: 0.23(2H, d, J = 4.6 Hz), 0.45(2H, d, J = 8.0 Hz), 0.97-1.09(1H, m),




2.10(3H, s), 3.15(2H, t, J = 6.2 Hz), 5.53(2H, s), 7.24-7.33(1H, m), 7.61-7.62(2H,




m), 8.09(1H, d, J = 8.1 Hz), 8.69-8.78(1H, m), 9.05(2H, s), 11.7(1H, s)




ESI+: 365




mp: >265° C.(dec.)


















TABLE 163





Ex
Syn
DATA

















233
2
NMR1: 1.33-1.75(10H, m), 1.93-2.00(2H, m), 2.00(3H, s), 2.01(3H, s),




2.11-2.14(2H, m), 2.89-3.00(2H, m), 3.34-3.41(1H, m), 3.72-3.81(1H, m), 4.23-4.29(1H,




m), 4.60(2H, s), 7.26(1H, t, J = 7.6 Hz), 7.59(1H, t, J = 7.4 Hz), 7.67(1H, t, J = 7.2 Hz),




8.07(1H, d, J = 7.8 Hz), 11.2(1H, s)




ESI+: 397


234
2
NMR1: 2.00-2.11(5H, m), 2.45-2.54(2H, m), 3.82(2H, t, J = 7.1 Hz), 5.18(2H, s),




6.89(1H, dd, J = 7.9, 2.2 Hz), 7.22-7.36(3H, m), 7.50(1H, dd, J = 2.2, 2.1 Hz),




7.57-7.68(2H, m), 8.09(1H, d, J = 8.1 Hz), 11.58(1H, br s)




ESI+: 349


235
2
NMR1: 1.77-1.92(4H, m), 2.06(3H, s), 2.36-2.42(2H, m), 3.56-3.62(2H, m),




5.16(2H, s), 6.92(1H, d, J = 7.8 Hz), 6.99(1H, dd, J = 8.3, 2.6 Hz), 7.06(1H, dd, J = 2.3,




2.1 Hz), 7.26-7.36(2H, m), 7.58-7.67(2H, m), 8.10(1H, d, J = 8.1 Hz), 11.58(1H,




br s)




ESI+: 363


236
2
NMR1: 1.65-1.77(6H, m), 2.06(3H, s), 2.56-2.62(2H, m), 3.67-3.73(2H, m),




5.17(2H, s), 6.85(1H, d, J = 7.7 Hz), 6.95-7.01(2H, m), 7.24-7.37(2H, m),




7.57-7.68(2H, m), 8.09(1H, d, J = 8.2 Hz), 11.57(1H, s)




ESI+: 377


237
2
NMR1: 2.04(3H, s), 3.33-3.44(4H, m), 3.51-3.61(4H, m), 5.16(2H, s), 7.28(1H,




ddd, J = 8.0, 6.8, 1.6 Hz), 7.57(1H, d, J = 8.0 Hz), 7.62(1H, ddd, J = 8.0, 6.8, 1.6 Hz),




8.08(1H, d, J = 8.0 Hz), 11.57(1H, br s)




ESI+: 303


238
2
NMR1: 1.08(6H, s), 1.29-1.43(2H, m), 1.60(2H, t, J = 6.8 Hz), 1.73-1.84(2H, m),




2.03(3H, s), 3.08-3.21(2H, m), 3.40-3.48(1H, m), 3.50(2H, t, J = 6.8 Hz),




3.61-3.71(2H, m), 4.14(1H, s), 5.12(2H, s), 7.28(1H, ddd, J = 8.0, 7.2, 1.6 Hz), 7.57(1H,




d, J = 8.0 Hz), 7.61(1H, ddd, J = 8.0, 7.2, 1.6 Hz), 8.05-8. 11(1H, m), 11.56(1H, br s)




ESI+: 403


















TABLE 164





Ex
Syn
DATA

















239
2
NMR1: 1.30-1.42(2H, m), 1.74-1.85(2H, m), 2.03(3H, s), 3.07-3.20(2H, m),




3.24(3H, s), 3.28-3.42(1H, m), 3.60-3.72(2H, m), 5.12(2H, s), 7.28(1H, ddd, J = 8.0,




6.8, 1.6 Hz), 7.57(1H, d, J = 8.0 Hz), 7.61(1H, ddd, J = 8.0, 6.8, 1.6 Hz),




8.05-8. 10(1H, m), 11.60(1H, br s)




ESI+: 331


240
2
NMR1: 1.09(6H, s), 1.30-1.42(2H, m), 1.67(2H, t, J = 7.6 Hz), 1.73-1.84(2H, m),




2.03(3H, s), 3.06(3H, s), 3.08-3.21(2H, m), 3.25-3.37(1H, m), 3.45(2H, t, J = 7.6 Hz),




3.60-3.72(2H, m), 5.12(2H, s), 7.28(1H, ddd, J = 8.0, 6.4, 1.2 Hz), 7.57(1H, d, J = 8.0 Hz),




7.61(1H, ddd, J = 8.0, 6.4, 1.2 Hz), 8.08(1H, d, J = 8.0 Hz), 11.56(1H, s)




ESI+: 417


241
2
NMR1: 2.07(3H, s), 4.02-4. 09(2H, m), 4.40-4.47(2H, m), 5.19(2H, s), 6.90(1H, dd, J = 8.3,




2.2 Hz), 7.18(1H, dd, J = 8.3, 1.7 Hz), 7.26-7.32(1H, m), 7.32-7.40(2H, m),




7.58-7.67(2H, m), 8.09(1H, d, J = 8.0 Hz), 11.59(1H, s)




ESI+: 351


242
2
NMR1: 2.06(3H, s), 3.69-3.75(2H, m), 3.76(3H, s), 3.93-3.99(2H, m), 4.19(2H, s),




5.16(2H, s), 6.61-6. 67(2H, m), 6.78(1H, dd, J = 2.0, 2.0 Hz), 7.25-7.33(1H, m),




7.58-7.68(2H, m), 8.10(1H, d, J = 7.9 Hz), 11.61(1H, br s)




ESI+: 395


243
2
NMR1: 1.05-1.14(2H, m), 1.14-1.24(2H, m), 1.30-1.39(2H, m), 1.42-1.49(2H, m),




1.49-1.59(2H, m), 1.62-1.69(2H, m), 1.77-1.82(2H, m), 1.99(3H, s), 2.02-2.13(5H,




m), 3.37-3.42(1H, m), 3.49-3.56(1H, m), 4.59(2H, s), 7.26(1H, t, J = 8.0 Hz),




7.57-7.61(2H, m), 7.68(1H, d, J = 8.3 Hz), 8.07(1H, d, J = 8.0 Hz), 11.2(1H, s)




ESI+: 397


















TABLE 165





Ex
Syn
DATA







244
2
NMR1: 0.07-0.11(2H, m), 0.37-0.43(2H, m), 0.89-0.96(1H, m), 1.15-1.24(2H, m),




1.30-1.39(2H, m), 1.79-1.82(2H, m), 1.93(2H, d, J = 7.0 Hz), 2.00(3H, s),




2.04-2.07(2H, m), 3.37-3.43(1H, m), 3.49-3.56(1H, m), 4.59(2H, s), 7.26(1H, t, J = 7.9 Hz),




7.52(1H, d, J = 7.7 Hz), 7.56-7.61(1H, m), 7.68(1H, d, J = 8.3 Hz), 8.07(1H, d,




J = 8.1 Hz), 11.2(1H, s)




ESI+: 369


245
2
NMR1: 0.44-0.47(2H, m), 0.89-0.92(2H, m), 1.22(3H, s), 1.29-1.35(4H, m),




1.69-1.80(2H, m), 2.00(3H, s), 2.02-2.12(2H, m), 3.32-3.42(1H, m), 3.51-3.63(1H, m),




4.60(2H, s), 7.07(1H, d, J = 7.9 Hz), 7.24-7.29(1H, m), 7.56-7.61(1H, m), 7.68(1H,




d, J = 8.3 Hz), 8.07(1H, d, J = 8.1 Hz), 11.2(1H, s)




ESI+: 369


246
2
NMR1: 1.10-1.24(4H, m), 1.29-1.38(2H, m), 1.48-1.51(2H, m), 1.78-1.81(2H, m),




1.81-1.90(1H, m), 1.96(2H, d, J = 7.1 Hz), 2.00(3H, s), 2.03-2.06(2H, m),




3.20-3.29(2H, m), 3.37-3.43(1H, m), 3.48-3.58(1H, m), 3.77-3.81(2H, m), 4.59(2H, s),




7.26(1H, t, J = 7.1 Hz), 7.56-7.61(1H, m), 7.64-7.69(2H, m), 8.07(1H, d, J = 8.2 Hz),




11.2(1H, s)




ESI+: 413


247
2
NMR1: 1.15-1.24(2H, m), 1.30-1.39(2H, m), 1.54-1.58(4H, m), 1.77-1.80(2H, m),




2.04(3H, s), 2.98-2.32(3H, m), 3.23-3.34(4H, m), 3.82-3.85(2H, m), 4.65(2H, s),




7.33(1H, t, J = 7.4 Hz), 7.58-7.66(2H, m), 7.77(1H, d, J = 8.3 Hz), 8.13(1H, d, J = 7.9 Hz),




11.7(1H, s)




ESI+: 399


248
2
NMR1: 1.12(6H, s), 1.12-1.25(2H, m), 1.31-1.40(2H, m), 1.80-1.83(2H, m),




2.00(3H, s), 2.04-2.06(2H, m), 2.16(2H, s), 3.38-3.44(1H, m), 3.55-3.58(1H, m),




4.59(2H, s), 4.81(1H, s), 7.26(1H, t, J = 7.8 Hz), 7.56-7.61(1H, m), 7.67-7.73(2H,




m), 8.06-8.08(1H, m), 11.2(1H, s)




ESI+: 387


















TABLE 166





Ex
Syn
DATA







249
2
NMR1: 1.33-1.42(2H, m), 1.49-1.58(2H, m), 1.80-1.83(2H, m), 2.00(3H, s),




2.09-2.12(2H, m), 2.16-2.22(2H, m), 3.14(2H, t, J = 7.7 Hz), 3.19(2H, t, J = 6.7 Hz),




3.23-3.25(1H, m), 3.30-3.40(1H, m), 4.60(2H, s), 7.27(1H, t, J = 7.3 Hz), 7.59(1H,




t, J = 7.4 Hz), 7.67(1H, d, J = 8.3 Hz), 8.07(1H, d, J = 8.0 Hz), 11.2(1H, s)




ESI+: 391


250
2
NMR1: 2.06(3H, s), 3.74(2H, dd, J = 5.6, 4.0 Hz), 3.97(2H, dd, J = 5.6, 4.0 Hz),




4.21(2H, s), 5.19(2H, s), 7.01-7.07(2H, m), 7.21(1H, dd, J = 2.0, 2.0 Hz), 7.38(1H,




dd, J = 8.0, 8.0 Hz), 7.55(1H, ddd, J = 8.0, 8.0, 2.8 Hz), 7.73(1H, dd, J = 9.6, 2.8 Hz),




7.75(1H, dd, J = 9.6, 4.8 Hz), 11.76(1H, br s)




FAB+: 383


251
2
NMR1: 1.20-1.36(2H, m), 1.62-1.77(2H, m), 2.03(3H, s), 2.97-3.17(2H, m),




3.58-3.68(1H, m), 3.67-3.78(2H, m), 4.71(1H, d, J = 4.0 Hz), 5.12(2H, s), 7.28(1H, ddd,




J = 8.0, 6.8, 1.2 Hz), 7.57(1H, d, J = 8.0 Hz), 7.61(1H, d, J = 8.0, 8.0, 1.2 Hz),




8.08(1H, d, J = 8.0 Hz), 11.57(1H, s)




ESI+: 317


252
2
NMR1: 2.06(3H, s), 2.31(3H, s), 3.68-3.74(2H, m), 3.93-3.99(2H, m), 4.19(2H, s),




5.15(2H, s), 6.85-6.90(2H, m), 6.97-7.02(1H, m), 7.25-7.32(1H, m), 7.58-7.67(2H,




m), 8.10(1H, d, J = 7.8 Hz), 11.57(1H, br s)




ESI+: 379


253
2
NMR1: 1.52(2H, m), 1.72-1.92(1H, m), 2.04(3H, s), 2.81-2.93(3H, m), 3.13(2H, d,




J = 6.8 Hz), 3.15-3.26(2H, m), 3.69-3.87(2H, m), 5.12(2H, s), 7.28(1H, ddd, J = 8.0,




7.2, 1.6 Hz), 7.56(1H, d, J = 8.0 Hz), 7.61(1H, ddd, J = 8.0, 8.0, 1.6 Hz), 8.08(1H,




d, J = 8.0 Hz), 11.55(1H, s)




ESI+: 345


254
2
NMR1: 0.63-0.75(4H, m), 0.96-1.27(2H, m), 1.52-2.05(6H, m), 2.00(3H, s),




2.49-2.75(3H, m), 3.01-3.14(1H, m), 4.18-4.43(2H, m), 7.45-7.52(1H, m), 7.55-7.60(1H,




m), 7.65-7.71(1H, m), 11.47(1H, s)




ESI+: 357


















TABLE 167





Ex
Syn
DATA

















255
2
NMR1: 0.90-0.92(4H, m), 1.28-1.38(4H, m), 1.92-1.95(2H, m), 2.00(3H, s),




2.03-2.06(2H, m), 2.50-2.53(1H, m), 3.15-3.16(1H, m), 3.34-3.42(1H, m), 4.58(2H, s),




6.99(1H, d, J = 7.7 Hz), 7.26(1H, t, J = 7.5 Hz), 7.59(1H, t, J = 8.0 Hz), 7.67(1H, d,




J = 8.3 Hz), 8.07(1H, d, J = 8.0 Hz), 11.2(1H, s)




ESI+: 391


256
2
NMR1: 1.42(6H, s), 2.06(3H, s), 3.70-3.74(2H, m), 3.93-3.98(2H, m), 5.18(2H, s),




7.00(1H, dd, J = 7.8, 1.7 Hz), 7.03(1H, dd, J = 8.2, 2.5 Hz), 7.15(1H, dd, J = 2.3,




2.2 Hz), 7.27-7.32(1H, m), 7.37(1H, dd, J = 8.1, 8.1 Hz), 7.59-7.67(2H, m), 8.10(1H,




d, J = 8.3 Hz), 11.62(1H, br s)




ESI+: 393


257
2
NMR1: 2.06(3H, s), 2.78-2.85(2H, m), 3.75-3.89(6H, m), 5.17(2H, s), 6.87(1H, d, J = 8.4 Hz),




6.97-7.03(2H, m), 7.26-7.38(2H, m), 7.59-7.68(2H, m), 8.10(1H, d, J = 7.6 Hz),




11.65(1H, br s)




ESI+: 379


258
2
NMR1: 2.06(3H, s), 2.78-2.84(2H, m), 3.76-3.87(6H, m), 5.18(2H, s),




6.85-6.90(1H, m), 6.98-7.03(2H, m), 7.31-7.37(1H, m), 7.55(1H, ddd, J = 8.8, 8.6, 3.0 Hz),




7.70-7.78(2H, m), 11.78(1H, br s)




ESI+: 397


259
2
NMR1: 0.83-0.88(6H, m), 1.90-2.00(1H, m), 1.93(3H, s), 2.16-2.21(2H, m),




3.15-3.41(2H, m), 3.63-3.71(2H, m), 4.09-4.21(2H, m), 4.68(2H, s), 7.24-7.29(1H, m),




7.57-7.61(2H, m), 8.06(1H, d, J = 8.0 Hz), 11.27(1H, s)




ESI+: 356


3
3
NMR1: 1.36-1.61(6H, m), 1.67-1.75(4H, m), 2.05(3H, s), 2.58-2.66(2H, m),




4.07(1H, s), 5.14(2H, s), 7.00(2H, d, J = 8.6 Hz), 7.15(2H, d, J = 8.6 Hz),




7.26-7.31(1H, m), 7.58-7.68(2H, m), 8.09(1H, dd, J = 7.8, 1.6 Hz), 11.54(1H, br s)




ESI+: 378




mp: 200-202° C.


















TABLE 168





Ex
Syn
DATA







4
4
NMR1: 1.15(6H, s), 1.83(2H, t, J = 7.1 Hz), 2.06(3H, s), 4.15(2H, t, J = 7.1 Hz),




4.40(1H, s), 5.38(2H, s), 6.49(1H, d, J = 2.1 Hz), 6.65(1H, dd, J = 2.1, 5.8 Hz),




7.26-7.31(1H, m), 7.58-7.65(2H, m), 8.00(1H, d, J = 5.8 Hz), 8.09(1H, d, J = 7.9 Hz),




11.6(1H, s)




ESI+: 369




mp: 127-130° C.


5
5
NMR1: 1.14(3H, t, J = 7.1 Hz), 1.16-1.24(2H, m), 1.25-1.37(2H, m), 1.79-1.84(2H,




m), 1.99(3H, s), 2.01-2.06(2H, m), 3.25-3.29(2H, m), 3.95(2H, q, J = 7.1 Hz),




4.59(2H, s), 7.00(1H, d, J = 7.7 Hz), 7.27(1H, m), 7.57-7.61(1H, m), 7.67(1H, d, J = 8.2 Hz),




8.07(1H, dd, J = 1.4, 8.2 Hz), 11.2(1H, s)




ESI+: 359




mp: 268-271° C.


6
6
NMR1: 1.18(3H, t, J = 7.3 Hz), 1.23-1.39(4H, m), 1.85-1.90(2H, m), 1.99(3H, s),




2.02-2.06(2H, m), 2.98(2H, q, J = 7.3 Hz), 3.04-3.13(1H, m), 3.34-3.40(1H, m),




4.58(2H, s), 7.01(1H, d, J = 7.7 Hz), 7.24-7.28(1H, m), 7.57-7.61(1H, m), 7.67(1H,




d, J = 8.2 Hz), 8.06-8.08(1H, m), 11.2(1H, s)




ESI+: 379




mp: 245-247° C.


7
7
NMR1: 1.12-1.63(6H, m), 1.76-1.95(2H, m), 2.00(3H, s), 2.11-2.14(2H, m),




2.18(2H, t, J = 8.2 Hz), 3.26(2H, t, J = 7.1 Hz), 3.35-3.43(1H, m), 3.69-3.77(1H, m),




4.61(2H, s), 7.25-7.28(1H, m), 7.57-7.61(1H, m), 7.68(1H, d, J = 8.3 Hz),




8.06-8.08(1H, m), 11.2(1H, s)




ESI+: 355




mp: 216-217° C.


















TABLE 169





Ex
Syn
DATA

















8
8
NMR2: 1.31-1.43(2H, m), 1.58-1.69(2H, m), 1.72-1.84(3H, m), 2.25(3H, s),




3.40(2H, ddd, J = 12, 12, 2 Hz), 3.94-4.01(2H, m), 4.06(2H, t, J = 6 Hz), 5.50(2H,




s), 6.35(1H, d, J = 2 Hz), 6.59(1H, dd, J = 6, 2 Hz), 7.24-7.32(2H, m), 7.55(1H, m),




8.03(1H, d, J = 6 Hz), 8.38(1H, d, J = 7.5 Hz), 9.89(1H, br s)




ESI+: 395




mp: 137-138° C.


9
9
NMR1: 0.06(3H, s), 3.72-3.76(2H, m), 3.95-4.00(2H, m), 4.21(2H, s), 5.18(2H, s),




7.02-7.07(2H, m), 7.21(1H, dd, J = 2.0, 2.0 Hz), 7.27-7.32(1H, m), 7.38(1H, dd, J = 8.2,




8.0 Hz), 7.59-7.67(2H, m), 8.10(1H, d, J = 8.0 Hz), 11.62(1H, br s)




ESI+: 365




mp: 221-223° C.


10
10
NMR1: 1.15(6H, s), 1.80(2H, t, J = 7.2 Hz), 2.05(3H, s), 3.07-3.10(4H, m),




3.69-3.72(4H, m), 4.03(2H, t, J = 7.2 Hz), 4.35(1H, s), 5.12(2H, s), 6.12(1H, t, J = 2.0 Hz),




6.17(1H, t, J = 1.9 Hz), 6.24(1H, t, J = 2.0 Hz), 7.26-7.31(1H, m),




7.59-7.66(2H, m), 8.06-8.10(1H, m), 11.6(1H, s)




FAB+: 453




mp: 189-190° C.


11
11
NMR1: 1.00-1.13(2H, m), 1.32-1.45(1H, m), 1.45-1.57(2H, m), 1.62-1.72(2H, m),




1.98(3H, s), 2.44(2H, t, J = 12.1 Hz), 2.63-2.71(2H, m), 2.88-2.97(2H, m), 7.23(1H,




dd, J = 7.5, 7.2 Hz), 7.49(1H, d, J = 8.1 Hz), 7.54-7.59(1H, m), 8.04(1H, d, J = 8.2 Hz),




11.32(1H, br s)




FAB+: 271


260
11
NMR1: 0.88-1.03(2H, m), 1.21-1.39(3H, m), 1.52-1.70(4H, m), 1.99(3H, s),




2.34-2.45(2H, m), 2.61-2.71(2H, m), 2.83-2.92(2H, m), 7.23(1H, ddd, J = 7.6, 7.6, 0.9 Hz),




7.49(1H, d, J = 8.1 Hz), 7.56(1H, ddd, J = 7.6, 7.6, 1.2 Hz), 8.04(1H, d, J = 8.3 Hz),




11.28(1H, br s)




FAB+: 285


















TABLE 170





Ex
Syn
DATA

















12
12
NMR1: 0.82(3H, t, J = 7.0 Hz), 1.13-1.32(8H, m), 1.46-1.55(2H, m), 2.04(3H, s),




2.57(2H, t, J = 7.4 Hz), 3.81(2H, s), 7.23-7.28(1H, m), 7.52(1H, d, J = 7.9 Hz),




7.53-7.62(1H, m), 7.85(1H, dd, J = 1.4, 8.1 Hz), 11.49(1H, s)




FAB+: 304


261
12
NMR1: 0.86(3H, t, J = 7.0 Hz), 1.20-1.46(8H, m), 1.65-1.75(2H, m), 2.03(3H, s),




2.80-2.98(2H, m), 4.12(1H, d, J = 13.2 Hz), 4.27(1H, d, J = 13.2 Hz), 7.28(1H, t, J = 7.0 Hz),




7.51(1H, d, J = 8.1 Hz), 7.58-7.63(1H, m), 8.06-8.09(1H, m), 11.58(1H, s)




FAB+: 320


262
12
NMR1: 2.09(3H, s), 5.22(2H, s), 6.95(2H, d, J = 7.6 Hz), 7.00(2H, d, J = 7.6 Hz),




7.09(1H, dd, J = 7.6, 7.6 Hz), 7.26-7.32(1H, m), 7.36(2H, dd, J = 7.6, 7.6 Hz),




7.45-7.56(2H, m), 7.59(1H, d, J = 7.6 Hz), 7.60-7.68(1H, m), 8.10(1H, d, J = 8.8 Hz),




9.90(1H, s), 11.70(1H, s)




FAB+: 401


263
12
NMR1: 2.08(3H, s), 3.43(3H, s), 5.21(2H, s), 7.23(2H, d, J = 8.4 Hz), 7.26-7.34(1H,




m), 7.45(1H, d, J = 8.4 Hz), 7.58(2H, d, J = 8.4 Hz), 7.60-7.66(1H, m), 8.09(1H, d,




J = 8.4 Hz), 9.87(1H, s), 11.68(1H, s)




ESI+: 355


264
12
NMR1: 2.08(3H, s), 5.25(2H, s), 7.29(1H, dd, J = 7.2, 7.2 Hz), 7.58(2H, d, J = 8.0 Hz),




7.60-7.69(2H, m), 7.65(2H, s), 8.10(1H, d, J = 8.0 Hz), 10.27(1H, s),




11.69(1H, s)




FAB+: 409


265
12
NMR1: 2.07(3H, s), 3.14(2H, qq, J = 8.4, 8.4 Hz), 4.48(2H, t, J = 8.4 Hz), 5.17(2H,




s), 6.67(1H, d, J = 8.4 Hz), 7.08-7.19(1H, m), 7.24-7.32(1H, m), 7.35(1H, br s),




7.58(1H, d, J = 8.4 Hz), 7.59-7.67(1H, m), 8.05-8.12(1H, m), 9.60(1H, s), 11.66(1H,




s)




ESI+: 351


















TABLE 171





Ex
Syn
DATA

















266
12
NMR1: 1.15-1.29(2H, m), 1.63-1.71(3H, m), 2.08(3H, s), 2.91(2H, d, J = 6.4 Hz),




3.15-3.23(2H, m), 3.29-3.32(2H, m), 3.78-3.84(2H, m), 5.20(2H, s), 6.90-6.98(2H,




m), 7.03-7.05(1H, m), 7.25-7.32(2H, m), 7.59-7.66(2H, m), 8.09(1H, d, J = 7.6 Hz),




11.57(1H, s)




FAB+: 396


267
12
NMR1: 1.24-1.39(2H, m), 1.66(2H, d, J = 11.0 Hz), 1.93-2.04(1H, m), 2.06(3H, s),




3.27-3.38(2H, m), 3.83-3.95(4H, m), 5.24(2H, s), 7.03-7.06(1H, m), 7.11(1H, s),




7.24(1H, s), 7.27-7.33(1H, m), 7.60-7.68(2H, m), 8.10(1H, d, J = 8.0 Hz), 11.58(1H,




s)




ESI+: 405


268
12
NMR1: 1.20-1.32(2H, m), 1.58-1.65(2H, m), 1.90-1.95(4H, m), 3.26-3.36(2H, m),




3.72(2H, d, J = 6.4 Hz), 3.83-3.89(2H, m), 4.26(2H, s), 6.83(1H, dd, J = 2.2, 8.2 Hz),




6.90-6.92(1H, m), 6.98(1H, d, J = 7.9 Hz), 7.20-7.28(2H, m), 7.48(1H, d, J = 8.2 Hz),




7.56-7.62(1H, m), 8.05(1H, d, J = 7.2 Hz), 11.53(1H, s)




FAB+: 396


269
12
NMR1: 1.16-1.29(2H, m), 1.47-1.55(2H, m), 1.81-1.92(1H, m), 2.06(3H, s),




3.16-3.24(2H, m), 3.77-3.84(2H, m), 4.10(2H, d, J = 6.6 Hz), 5.48(2H, s), 7.26-7.32(1H,




s), 7.56-7.65(2H, m), 8.08(1H, d, J = 7.6 Hz), 8.13(1H, s), 11.62(1H, s)




FAB+: 449


13
13
NMR1: 0.83(3H, t, J = 6.9 Hz), 1.19-1.28(6H, m), 1.45-1.55(2H, m), 1.98(3H, s),




2.14(2H, t, J = 7.5 Hz), 4.32(2H, d, J = 5.2 Hz), 7.24-7.29(1H, m), 7.55-7.61(2H, m),




8.07(1H, d, J = 8.4 Hz), 8.25-8.30(1H, m), 11.57(1H, s)




FAB+: 301


















TABLE 172





Ex
Syn
DATA







270
13
NMR1: 0.97-1.31(2H, m), 1.43-1.68(4H, m), 1.68-1.88(2H, m), 1.88-2.04(1H, m),




2.05(3H, s), 2.41-2.63(1H, m), 2.80-2.94(1H, m), 2.95-3.11(1H, m), 3.25-3.47(2H,




m), 3.84(4H, d, J = 5.6 Hz), 4.00(1H, d, J = 12.4 Hz), 4.42(1H, d, J = 12.4 Hz),




5.16(2H, s), 6.53-6.62(1H, m), 6.63-6.74(2H, m), 7.22(1H, dd, J = 8.8, 8.8 Hz),




7.25-7.35(1H, m), 7.57-7.69(2H, m), 8.09(1H, d, J = 8.0 Hz), 11.58(1H, s)




ESI+: 491


271
13
NMR1: 0.95-1.21(8H, m), 1.50-1.66(3H, m), 1.73-1.81(2H, m), 1.99(3H, s),




2.44(2H, s), 2.50-2.59(1H, m), 2.65-2.74(2H, m), 2.99(1H, t, J = 12.4 Hz), 3.99(1H,




d, J = 13.5 Hz), 4.45(1H, d, J = 12.4 Hz), 4.92(1H, s), 7.23(1H, dd, J = 7.6, 7.5 Hz),




7.49(1H, d, J = 8.2 Hz), 7.34-7.60(1H, m), 8.05(1H, d, J = 7.9 Hz), 11.32(1H, s)




ESI+: 371




mp: 203-205° C.


272
13
NMR1: 0.94-1.12(2H, m), 1.51-1.66(3H, m), 1.66-1.81(3H, m), 1.81-1.96(1H,




m), 2.00-2.22(7H, m), 2.46-2.60(1H, m), 2.80-2.97(3H, m), 3.26-3.38(1H, m),




3.69(1H, d, J = 13.5 Hz), 4.36(1H, d, J = 13.5 Hz), 7.39-7.47(1H, m),




7.69-7.78(2H, m), 8.21(1H, d, J = 8.5 Hz), 12.77(1H, br s)




ESI+: 353


273
13
NMR1: 1.68(5H, m), 1.72-1.84(2H, m), 1.84-1.96(1H, m), 2.14(3H, s), 2.24(2H,




d, J = 6.9 Hz), 2.47-2.58(1H, m), 2.82-2.92(2H, m), 2.99(1H, t, J = 12.4 Hz),




3.23-3.33(2H, m), 3.77-3.84(3H, m), 4.41(1H, d, J = 12.9 Hz), 7.42-7.47(1H, m),




7.70-7.80(2H, m), 8.23(1H, d, J = 8.1 Hz), 12.90(1H, br s)




ESI+: 397


















TABLE 173





Ex
Syn
DATA

















274
13
NMR1: 0.61-0.74(4H, m), 0.79-1.19(2H, m), 1.27-1.40(2H, m), 1.45-1.60(1H,




m), 1.60-1.80(4H, m), 1.88-1.97(1H, m), 1.99(3H, s), 2.62-2.73(2H, m),




2.94-3.10(1H, m), 3.26-3.34(1H, m), 4.12-4.42(2H, m), 7.23(1H, dd, J = 7.5, 7.5 Hz),




7.49(1H, d, J = 8.0 Hz), 7.56(1H, dd, J = 7.5, 7.5 Hz), 8.05(1H, d, J = 8.0 Hz),




11.29(1H, br s)




ESI+: 353


275
13
NMR1: 0.82-1.10(2H, m), 1.15(6H, s), 1.26-1.38(2H, m), 1.45-1.59(1H, m),




1.59-1.75(4H, m), 1.99(3H, s), 2.42(2H, s), 2.62-2.72(2H, m), 2.89-3.00(1H, m),




3.95(1H, d, J = 13.2 Hz), 4.42(1H, d, J = 12.8 Hz), 4.90(1H, s), 7.23(1H, dd, J = 7.5,




7.5 Hz), 7.49(1H, d, J = 8.2 Hz), 7.56(1H, dd, J = 7.7, 7.4 Hz), 8.05(1H, d, J = 8.1 Hz),




11.32(1H, s)




ESI+: 385


14
14
NMR1: 0.60-0.90(3H, m), 1.00-1.35(4H, m), 1.50-1.60(2H, m), 1.99(3H, s),




3.98(2H, t, J = 6.5 Hz), 4.27(2H, t, J = 5.4 Hz), 7.23-7.28(1H, m), 7.55-7.65(3H, m),




8.06(1H, d, J = 7.6 Hz), 11.25(1H, s)




FAB+: 303


276
14
NMR1: 0.99-1.14(2H, m), 1.17(3H, t, J = 7.0 Hz), 1.45-1.60(3H, m),




1.69-1.80(2H, m), 1.99(3H, s), 2.63-2.88(4H, m), 3.91-4.07(4H, m), 7.23(1H, dd, J = 7.6,




7.4 Hz), 7.48(1H, d, J = 8.2 Hz), 7.54-7.59(1H, m), 8.04(1H, d, J = 8.1 Hz),




11.31(1H, br s)




ESI+: 343




mp: 211-213° C.


277
14
NMR1: 0.89-1.04(2H, m), 1.16(3H, t, J = 7.0 Hz), 1.26-1.37(2H, m),




1.37-1.52(1H, m), 1.58-1.71(4H, m), 1.99(3H, s), 2.61-2.80(4H, m), 3.90-4.05(4H, m),




7.24(1H, dd, J = 7.7, 7.5 Hz), 7.49(1H, d, J = 8.4 Hz), 7.57(1H, dd, J = 7.7, 7.5 Hz),




8.05(1H, d, J = 7.9 Hz), 11.32(1H, br s)




ESI+: 357


















TABLE 174





Ex
Syn
DATA

















15
15
NMR1: 0.85(3H, t, J = 7.2 Hz), 1.18-1.42(6H, m), 2.01(3H, s), 3.00(2H, q, J = 6.0 Hz),




4.28(2H, d, J = 5.7 Hz), 6.06(1H, t, J = 5.8 Hz), 6.28-6.35(1H, m),




7.22-7.28(1H, m), 7.55-7.61(2H, m), 8.06(1H, d, J = 8.0 Hz), 11.28(1H, s)




FAB+: 302


278
15
NMR1: 1.00(3H, t, J = 7.6 Hz), 1.05-1.21(2H, m), 1.70(2H, d, J = 13.2 Hz),




1.81-1.95(1H, m), 2.06(3H, s), 2.64(2H, dd, J = 11.6, 11.6 Hz), 3.03(2H, qd, J = 7.6,




7.6 Hz), 3.82(2H, d, J = 6.8 Hz), 3.90-4.03(2H, m), 5.16(2H, s), 6.40(1H, dd, J = 5.6,




5.6 Hz), 6.58(1H, d, J = 8.0 Hz), 6.62-6.73(2H, m), 7.22(1H, dd, J = 8.0, 8.0 Hz),




7.25-7.34(1H, m), 7.63(1H, dd, J = 8.0, 8.0 Hz), 7.64(1H, s), 8.10(1H, d, J = 8.0 Hz),




11.58(1H, s)




ESI+: 450


16
16
NMR1: 0.81(3H, t, J = 7.1 Hz), 1.10-1.32(6H, m), 1.56-1.66(2H, m), 2.04(3H, s),




3.00-3.06(2H, m), 4.24(2H, s), 7.25-7.30(1H, m), 7.56-7.65(3H, m), 8.07(1H, d,




J = 7.9 Hz), 11.34(1H, s)




FAB+: 337


279
16
NMR1: 1.12-1.28(5H, m), 1.39-1.53(1H, m), 1.53-1.64(2H, m), 1.78-1.88(2H,




m), 1.99(3H, s), 2.64-2.74(2H, m), 2.74-2.84(2H, m), 3.02(2H, q, J = 7.4 Hz),




3.56-3.65(2H, m), 7.23(1H, dd, J = 7.6, 7.3 Hz), 7.49(1H, d, J = 8.3 Hz),




7.54-7.60(1H, m), 8.05(1H, d, J = 8.3 Hz), 11.32(1H, br s)




ESI+: 363




mp: 225-228° C.


17
17
NMR1: 1.60-1.75(4H, m), 1.99(3H, s), 2.70(2H, t, J = 7.8 Hz), 3.47(2H, t, J = 5.8 Hz),




4.45(2H, s), 7.21-7.36(6H, m), 7.48(1H, d, J = 8.0 Hz), 7.54-7.60(1H, m),




8.06(1H, dd, J = 1.3, 8.1 Hz) 11.33(1H, s)




FAB+: 322


18
18
NMR1: 1.94-2.03(2H, m), 2.08(3H, s), 2.75-2.84(4H, m), 5.19(2H, s),




7.09-7.14(1H, m), 7.18-7.24(1H, m), 7.26-7.32(1H, m), 7.36(1H, s), 7.55-7.66(2H, m),




8.06-8.12(1H, m), 9.71(1H, s), 11.67(1H, s)




FAB+: 349


















TABLE 175





Ex
Syn
DATA







280
18
NMR1: 2.09(3H, s), 5.25(2H, s), 7.27-7.32(1H, m), 7.55-7.72(6H, m), 8.09(1H,




d, J = 8.0 Hz), 10.31(1H, s), 11.69(1H, s)




FAB+: 377




mp: 254-257° C.


281
18
NMR1: 0.92(3H, t, J = 7.3 Hz), 1.36-1.47(2H, m), 1.64-1.71(2H, m), 2.07(3H, s),




3.90(2H, t, J = 6.4 Hz), 5.18(2H, s), 6.84-6.86(2H, m), 7.26-7.40(3H, m),




7.56-7.65(2H, m), 8.08(1H, d, J = 7.5 Hz), 9.65(1H, s), 11.66(1H, s)




FAB+: 381


282
18
NMR1: 2.09(3H, s), 5.24(2H, s), 7.26-7.32(1H, m), 7.35(1H, d, J = 7.7 Hz),




7.47(1H, t, J = 8.2 Hz), 7.56-7.68(3H, m), 7.94(1H, s), 8.09(1H, d, J = 7.3 Hz),




10.20(1H, s), 11.68(1H, s)




FAB+: 409


283
18
NMR1: 2.04(3H, s), 2.27(3H, s), 4.18(2H, d, J = 6.2 Hz), 5.10(2H, s),




7.02-7.08(3H, m), 7.19(1H, t, J = 7.2 Hz), 7.25-7.31(1H, m), 7.54-7.64(2H, m), 7.89(1H, t,




J = 6.0 Hz), 8.07(1H, d, J = 8.0 Hz), 11.59(1H, s)




FAB+: 337




mp: 240-243° C.


284
18
NMR1: 1.64-1.75(2H, m), 2.03(3H, s), 2.54-2.60(2H, m), 2.96-3.06(2H, m),




5.07(2H, s), 7.10-7.21(3H, m), 7.23-7.31(3H, m), 7.40-7.45(1H, m), 7.55-7.64(2H,




m), 8.07(1H, d, J = 7.7 Hz), 11.59(1H, s)




FAB+: 351


285
18
NMR1: 2.07(3H, s), 3.89(2H, s), 5.19(2H, s), 6.88(1H, d, J = 7.6 Hz),




7.15-7.40(9H, m), 7.55-7.65(2H, m), 8.09(1H, dd, J = 1.2, 8.1 Hz), 9.80(1H, s), 11.65(1H,




s)




FAB+: 399


286
18
NMR1: 1.30(3H, t, J = 7.0 Hz), 2.08(3H, s), 3.96(2H, q, J = 7.0 Hz), 5.20(2H, s),




6.55-6.60(1H, m), 6.99-7.06(1H, m), 7.10-7.20(2H, m), 7.26-7.32(1H, m),




7.55-7.66(2H, m), 8.06-8.12(1H, m), 9.83(1H, s), 11.67(1H, s)




FAB+: 353


















TABLE 176





Ex
Syn
DATA







287
18
NMR1: 1.25(9H, s), 2.08(3H, s), 5.20(2H, s), 7.26-7.33(3H, m), 7.34-7.42(2H,




m), 7.56-7.66(2H, m), 8.07-8.12(1H, m), 9.76(1H, s), 11.69(1H, s)




FAB+: 365


288
18
NMR1: 0.84-0.90(3H, m), 1.23-1.44(6H, m), 1.63-1.71(2H, m), 2.07(3H, s),




3.87-3.92(2H, m), 5.18(2H, s), 6.83-6.88(2H, m), 7.26-7.40(3H, m),




7.56-7.66(2H, m), 8.07-8.11(1H, m), 8.65(1H, s), 11.66(1H, s)




FAB+: 409


289
18
NMR1: 1.14(3H, t, J = 7.5 Hz), 2.02(3H, s), 2.51-2.57(2H, m), 2.65-2.72(2H, m),




3.17-3.25(2H, m), 5.06(2H, s), 7.09(4H, s), 7.25-7.31(1H, m), 7.40-7.46(1H, m),




7.54-7.65(2H, m), 8.05-8.11(1H, m), 11.58(1H, s)




FAB+: 365


290
18
NMR1: 2.06(3H, s), 5.19(2H, s), 6.63-6.68(1H, m), 6.99-7.04(2H, m),




7.12-7.18(1H, m), 7.19-7.32(4H, m), 7.36-7.43(2H, m), 7.54-7.65(2H, m), 8.06-8.11(1H,




m), 9.99(1H, s), 11.68(1H, s)




FAB+: 401




mp: 194-197° C.


291
18
NMR1: 0.76-0.92(2H, m), 1.05-1.24(3H, m), 1.30-1.42(1H, m), 1.55-1.70(5H,




m), 2.03(3H, s), 2.85(2H, t, J = 6.3 Hz), 5.05(2H, s), 7.24-7.30(1H, m), 7.34(1H,




t, J = 5.8 Hz), 7.54-7.64(2H, m), 8.07(1H, d, J = 7.1 Hz), 11.56(1H, s)




FAB+: 329


292
18
NMR1: 2.08(3H, s), 5.23(2H, s), 7.26-7.35(3H, m), 7.55-7.66(4H, m),




8.07-8.12(1H, m), 10.09(1H, s), 11.69(1H, s)




FAB+: 393


293
18
NMR1: 2.09(3H, s), 5.25(2H, s), 7.26-7.32(1H, m), 7.34-7.40(1H, m),




7.51-7.74(4H, m), 7.93(1H, s), 8.07-8.12(1H, m), 10.26(1H, s), 11.70(1H, s)




FAB+: 377


















TABLE 177





Ex
Syn
DATA

















294
18
NMR1: 2.02(3H, s), 2.66(2H, t, J = 7.1 Hz), 3.19(2H, q, J = 6.6 Hz), 3.70(3H, s),




5.06(2H, s), 6.82(2H, d, J = 8.4 Hz), 7.10(2H, d, J = 8.4 Hz), 7.28(1H, t, J = 6.7 Hz),




7.41(1H, t, J = 5.6 Hz), 7.55-7.64(2H, m), 8.08(1H, d, J = 7.8 Hz), 11.58(1H,




s)




FAB+: 367


295
18
NMR1: 2.07(3H, s), 4.16-4.24(4H, m), 5.18(2H, s), 6.76(1H, d, J = 8.7 Hz),




6.86-6.92(1H, m), 7.06(1H, s), 7.29(1H, t, J = 7.7 Hz), 7.56-7.65(2H, m), 8.09(1H, d,




J = 8.0 Hz), 9.66(1H, s), 11.67(1H, s)




FAB+: 367


19
19
NMR1: 0.86(3H, t, J = 7.1 Hz), 1.19-1.45(8H, m), 1.68-1.78(2H, m), 2.08(3H, s),




3.23-3.29(2H, m), 4.63(2H, s), 7.26-7.32(1H, m), 7.54(1H, d, J = 8.1 Hz),




7.60-7.66(1H, m), 8.06-8.10(1H, m), 11.59(1H, s)




FAB+: 336




mp: >310° C.(dec.)


296
19
NMR1: 1.23-1.35(2H, m), 1.59-1.66(2H, m), 1.93-2.05(1H, m), 2.08(3H, s),




3.18-3.26(2H, m), 3.30-3.33(2H, m), 3.71-3.77(2H, m), 5.32(2H, s),




7.27-7.32(1H, m), 7.46-7.51(1H, m), 7.54-7.58(1H, m), 7.60-7.67(4H, m), 8.10(1H, d, J = 7.8 Hz),




11.60(1H, s)




FAB+: 428


297
19
NMR1: 1.20-1.33(2H, m), 1.57-1.67(5H, m), 1.88-2.00(1H, m), 3.27-3.37(2H,




m), 3.77(2H, d, J = 6.4 Hz), 3.83-3.90(2H, m), 4.80(2H, s), 7.22-7.40(4H, m),




7.46-7.57(2H, m), 7.60-7.65(1H, m), 8.05(1H, d, J = 6.9 Hz), 11.51(1H, s)




FAB+: 428


20
20
NMR1: 1.30-1.41(2H, m), 1.69(2H, d, J = 11.1 Hz), 1.95-2.05(1H, m), 2.07(3H,




s), 3.27-3.33(2H, m), 3.83-3.92(4H, m), 5.25(2H, s), 6.72-6.80(2H, m),




7.27-7.32(1H, m), 7.60-7.65(2H, m), 7.72(1H, d, J = 8.7 Hz), 8.10(1H, d, J = 8.1 Hz),




11.63(1H, s), 12.21(1H, s)




FAB+: 424


















TABLE 178





Ex
Syn
DATA

















298
20
NMR1: 1.27-1.39(2H, m), 1.67(2H, d, J = 15.2 Hz), 1.90-2.03(1H, m), 2.07(3H,




s), 3.22-3.38(2H, m), 3.86-3.91(4H, m), 5.24(2H, s), 6.93-6.95(1H, m),




7.10-7.12(1H, m), 7.24-7.32(2H, m), 7.59-7.68(2H, m), 8.09(1H, d, J = 7.6 Hz),




11.56(1H, s), 13.01(1H, br s)




FAB+: 424


299
20
NMR1: 1.24-1.36(2H, m), 1.62-1.69(2H, m), 1.90-2.00(1H, m), 2.05(3H, s),




3.20-3.40(4H, m), 3.79-3.90(4H, m), 5.14(2H, s), 6.50(1H, s), 6.57-6.62(2H, m),




7.26-7.32(1H, m), 7.59-7.67(2H, m), 8.09(1H, d, J = 7.8 Hz), 11.59(1H, s)




FAB+: 438


21
21
NMR1: 1.22-1.38(2H, m), 1.56-1.69(2H, m), 1.90-2.03(1H, m), 2.07(3H, s),




3.13(2H, s), 3.26-3.72(8H, m), 3.80-3.95(4H, m), 5.21(2H, s), 6.73-6.77(1H, m),




6.78-6.82(1H, m), 7.16(1H, d, J = 8.2 Hz), 7.27-7.33(1H, m), 7.59-7.67(2H, m),




8.10(1H, d, J = 8.2 Hz), 11.63(1H, s)




ESI+: 493


300
21
NMR1: 1.25-1.45(4H, m), 1.45-1.70(6H, m), 1.92-2.03(1H, m), 2.05(3H, s),




3.16-3.23(2H, m), 3.28-3.34(2H, m), 3.50-3.60(2H, m), 3.83-3.90(4H, m),




5.20(2H, s), 6.53(1H, s), 6.65(1H, s), 6.74(1H, t, J = 2.2 Hz), 7.26-7.32(1H, m),




7.60-7.66(2H, m), 8.09(1H, d, J = 7.8 Hz), 11.56(1H, s)




FAB+: 491


301
21
NMR1: 1.25-1.65(10H, m), 1.88-2.00(1H, m), 2.07(3H, s), 3.07-3.12(2H, m),




3.25-3.35(2H, m), 3.40-3.70(2H, m), 3.86-3.90(4H, m), 5.20(2H, s), 6.72(1H,




dd, J = 2.3, 8.3 Hz), 6.78(1H, d, J = 2.1 Hz), 7.11(1H, d, J = 8.2 Hz), 7.25-7.33(1H,




m), 7.62-7.65(2H, m), 8.10(1H, d, J = 7.9 Hz), 11.61(1H, s)




FAB+: 491


















TABLE 179





Ex
Syn
DATA







22
22
NMR1: 1.27-1.43(2H, m), 1.70(2H, d, J = 11.1 Hz), 1.95-2.07(1H, m), 2.09(3H,




s), 3.27-3.45(2H, m), 3.84-3.93(4H, m), 5.22(2H, s), 6.59(1H, t, J = 2.4 Hz),




7.22(1H, s), 7.26-7.32(1H, m), 7.35(1H, s), 7.59-7.65(1H, m), 7.69(1H, d, J = 8.1 Hz),




8.10(1H, d, J = 8.1 Hz), 11.63(1H, s)




ESI+: 448


23
23
NMR1: 1.31(2H, dddd, J = 12.4, 12.4, 12.4, 4.4 Hz), 1.60-1.72(2H, m),




1.90-2.03(1H, m), 2.07(3H, s), 3.26-3.34(2H, m), 3.83(2H, d, J = 6.4 Hz), 3.83-3.92(2H,




m), 5.17(2H, s), 6.56-6.63(1H, m), 6.65-6.73(2H, m), 7.23(1H, dd, J = 8.4, 8.4 Hz),




7.72(1H, d, J = 8.4 Hz), 8.11(1H, dd, J = 8.4, 1.6 Hz), 8.71(1H, d, J = 1.6 Hz),




11.83(1H, s), 12.98(1H, br s)




FAB+: 424

















TABLE 180





No
Str
















1






 


2






 


3






 


4






 


5






 


6






 


7






 


8






 


9






 


10






 


11













INDUSTRIAL APPLICABILITY
Since the compound which is an active ingredient of the medicament of the present invention has an NAD(P)H oxidase inhibitory action and a superior reactive oxygen species production inhibitory action based thereon, the pharmaceutical composition according to the present invention can be used as an agent for treating and/or preventing diseases associated with NAD(P)H oxidase.

## Claims

1. A compound of the formula (I) or a salt thereof:



wherein:
R1: lower alkyl or halogen;
R2: —X—Y—R20, —X-a heterocyclic group which may be substituted, or




Ring A: aryl;
R3: lower alkyl, halogen, halogeno-lower alkyl, aryl which may be substituted, a heterocyclic group which may be substituted, —CO2R0, —OR0, or —O-halogeno-lower alkyl, wherein R3s can be the same or different from one another, when n is 2 or 3;
X: C1-10 alkylene which may be substituted;
Y: *—C(O)N(R7)—, —O—, *—OC(O)—, *—OC(O)N(R7)—, —S—, —S(O)—, —S(O)2—, —N(R8)—, *—N(R7)C(O)—, *—N(R7)C(O)O—, —N(R7)C(O)N(R7)—, or *—N(R7)S(O)2—; wherein
* in Y means a binding point to X;
R7: the same or different, and R0, cycloalkyl, or lower alkylene-cycloalkyl;
R8: the same or different, and R7 or —C(O)R7;
R0: the same or different, and H or lower alkyl;
n: 0, 1, 2, or 3;
s: 0, 1, 2, or 3;
R20: C1-10 alkyl, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower)alkylene-N(R0)2, —W—R0, —W—halogeno-lower alkyl, —W-cycloalkyl which may be substituted, —W-aryl which may be substituted, —W-a heterocyclic group which may be substituted, —W-lower alkylene-cycloalkyl which may be substituted, —W-lower alkylene-aryl which may be substituted, or —W-lower alkylene-a heterocyclic group which may be substituted;
W: *-lower alkylene-C(O)N(R7)—, *-lower alkylene-C(O)—, *-lower alkylene-O—, *-lower alkylene-OC(O)—, *-lower alkylene-OC(O)N(R7)—, *-lower alkylene-O-lower alkylene-O—, *-lower alkylene-S—, *-lower alkylene-S(O)—, *-lower alkylene-S(O)2—, *-lower alkylene-N(R8)-, *-lower alkylene-N(R7)C(O)—, *-lower alkylene-N(R7)C(O)O—, *-lower alkylene-N(R7)C(O)N(R7)—, or *-lower alkylene-N(R7)S(O)2—; wherein
* in W means a binding point to Y;
R4: cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-OR0, —O-lower alkylene-OR0, -J-cycloalkyl which may be substituted, -J-aryl which may be substituted, -J-a heterocyclic group which may be substituted, -J-lower alkylene-cycloalkyl which may be substituted, -J-lower alkylene-aryl which may be substituted, or -J-lower alkylene-a heterocyclic group which may be substituted;
R5: C1-10 alkyl, halogen, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, —CO2R0, —CN, oxo, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-CO2R0, -J-R0, -J-halogeno-lower alkyl, -J-cycloalkyl which may be substituted, -J-aryl which may be substituted, -J-a heterocyclic group which may be substituted, -J-lower alkylene-cycloalkyl which may be substituted, -J-lower alkylene-aryl which may be substituted, or -J-lower alkylene-a heterocyclic group which may be substituted, wherein R5s can be the same or different from one another, when s is 2 or 3; and
J: the same or different, and *—C(O)N(R7)—, —C(O)—, —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, *—N(R7)C(O)—, *—N(R7)C(O)O—, —N(R7)C(O)N(R7)—, *-lower alkylene-C(O)N(R7)—, *-lower alkylene-C(O)—, *-lower alkylene-O—, *-lower alkylene-S—, *-lower alkylene-S(O)—, *-lower alkylene-S(O)2—, *-lower alkylene-N(R8)—, *-lower alkylene-N(R7)C(O)—, *-lower alkylene-N(R7)C(O)O—, *-lower alkylene-N(R7)C(O)N(R7)—, *—O-lower alkylene-C(O)—, —O-lower alkylene-O—, or *—O-lower alkylene-N(R8)—; wherein
* in J means a binding point to ring A;
provided that the following compounds are excluded:
3-methyl-2-(5-phenoxypentyl)quinolin-4(1H)-one,
3-ethyl-2-(5-phenoxypentyl)quinolin-4(1H)-one,
3-methyl-2-[2-(4-phenoxypheny)ethyl]quinolin-4(1H)-one,
3-chloro-2-(piperidin-1-ylmethyl)quinolin-4(1H)-one, and
5-({4-[(3,4-dihydro-3-methyl-4-oxoquinolin-2-yl) methoxy]phenyl}methyl)thiazolidine-2,4-dione.

2. The compound or a salt thereof according to claim 1, wherein
R1: lower alkyl or halogen;
R2: -lower alkylene-(a heterocyclic group which may be substituted with group(s) selected from Group G1), or -lower alkylene-O—R20;
R3: halogen;
n: 0 or 1;
R20: : cycloalkyl which may be substituted with at least one group selected from Group G1, aryl which may be substituted with at least one group selected from Group G1, or a heterocyclic group which may be substituted with at least one group selected from Group G1; wherein
Group G1: C1-10 alkyl, halogen, halogeno-lower alkyl, cycloalkyl which may be substituted, aryl which may be substituted, a heterocyclic group which may be substituted, —CO2R0, —CN, oxo, lower alkylene-cycloalkyl which may be substituted, lower alkylene-aryl which may be substituted, lower alkylene-a heterocyclic group which may be substituted, lower alkylene-CO2R0, -J1-R0, -J1-halogeno-lower alkyl, -J1-cycloalkyl which may be substituted, -J1-aryl which may be substituted, -J1-a heterocyclic group which may be substituted, -J1-lower alkylene-cycloalkyl which may be substituted, -J1-lower alkylene-aryl which may be substituted, and -J1-lower alkylene-a heterocyclic group which may be substituted; and
J1: —C(O)N(R7)—*, —C(O)—, —C(O)-lower alkylene-O—*, —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —N(R7)C(O)—*, —N(R7)C(O)O—*, —N(R7)C(O)N(R7)—, —N(R7)S(O)2—*, —N(R7)C(O)-lower alkylene-O—*, -lower)alkylene-C(O)N(R0)—*, -lower alkylene-C(O)—*, -lower alkylene-O—*, -lower alkylene-OC(O)—*, -lower alkylene-S—*, -lower alkylene-S(O)—*, -lower alkylene-S(O)2—*, -lower alkylene-N(R8)—*, -lower alkylene-N(R7)C(O)—*, —O-lower alkylene-C(O)—*, —O-lower alkylene-O—, or —O-lower alkylene-N(R8)—*; wherein
* in J1 means a binding point to a remnant of the group in Group G1.

3. The compound or a salt thereof according to claim 2, wherein
R1: lower alkyl;
R2: -lower alkylene-(piperidyl which may be substituted with at least one group selected from Group G1), or -lower alkylene-O—R20; and
R20: a cyclohexyl which may be substituted with at least one group selected from Group G1, phenyl which may be substituted with at least one group selected from Group G1, pyridyl which may be substituted with at least one group selected from Group G1, tetrahydroquinolinyl which may be substituted with at least one group selected from Group G1, or tetrahydroisoquinolinyl which may be substituted with at least one group selected from Group G1.

4. The compound or a salt thereof according to claim 3, wherein R2 is -lower alkylene-O-(phenyl which may be substituted with at least one group selected from Group G1), or -lower alkylene-O-(pyridyl which may be substituted with at least one group selected from Group G1).

5. The compound or a salt thereof according to claim 4, wherein R2 is -lower alkylene-O-(phenyl which may be substituted with at least one group selected from Group G1).

6. The compound or a salt thereof according to claim 5, wherein R2 is



wherein:
X20: lower alkylene;
R22: a group selected from Group G1; and
R23: H, lower alkyl, halogen, halogeno-lower alkyl, —OR0, —CO2R0, —C(O)R0, or —CN.

7. The compound or a salt thereof according to claim 6, wherein R23 is H, lower alkyl, halogen, halogeno-lower alkyl, or —OR0.

8. The compound or a salt thereof according to claim 7, wherein R22 is lower alkyl, halogen, halogeno-lower alkyl, lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —OR0, —O-lower alkylene-OR0, —O-halogeno-lower alkyl, cycloalkyl which may be substituted with —O-lower alkylene-oxo, or —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group may be substituted with lower alkyl, —OR0, —C(O)-lower alkyl, or —S(O)2-lower alkyl.

9. The compound or a salt thereof according to claim 8, wherein R22 is lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —O-lower alkylene-OR0, or —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which may be substituted with lower alkyl or —OR0.

10. The compound or a salt thereof according to claim 7, wherein R22 is



wherein:
Z1: —C(R0)2—or —O—;
Z2: a bond,)—C(R0)2—, or) —C(R0)2C(R0)2—; and
Z3:))—C(R0)2C(R0)2—or —C(O)—.

11. The compound or a salt thereof according to claim 5, wherein R2 is



wherein:
X20: lower alkylene; and
R24: a group selected from Group G1.

12. The compound or a salt thereof according to claim 11, wherein R24 is lower alkyl, halogen, halogeno-lower alkyl, cyclohexyl which may be substituted with —OR0, lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —OR0, —O-lower alkylene-OR0, —O-halogeno-lower alkyl, or —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group may be substituted with a lower alkyl, —OR0, —C(O)-lower alkyl, or —S(O)2-lower alkyl.

13. The compound or a salt thereof according to claim 12, wherein R24 is lower alkylene-a saturated heterocyclic group, or —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which may be substituted with a lower alkyl or —OR0.

14. The compound or a salt thereof according to claim 4, wherein R2 is -lower alkylene-O-(pyridyl which may be substituted with at least one group selected from Group G1).

15. The compound or a salt thereof according to claim 14, wherein R2 is



wherein:
X20: lower alkylene; and
R25: a group selected from Group G1.

16. The compound or a salt thereof according to claim 15, wherein R25 is lower alkyl, halogen, halogeno-lower alkyl, lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —OR0, —O-lower alkylene-OR0, —O-halogeno-lower alkyl, or —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group may be substituted with lower alkyl or —OR0.

17. The compound or a salt thereof according to claim 16, wherein R25 is lower alkylene-a saturated heterocyclic group, lower alkylene-OR0, —O-lower alkylene-OR0, or —O-lower alkylene-a saturated heterocyclic group; provided that the saturated heterocyclic group is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which may be substituted with lower alkyl or —OR0.

18. The compound or a salt thereof according to claim 1, which is selected from the following group:
3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-4(1H)-one;
N-{trans-4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]cyclohexyl}ethanesulfonamide;
3-methyl-2-[({4-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-2-yl}oxy)methyl]quinolin-4(1H)-one;
3-methyl-2-{[3-(3-oxomorpholin-4-yl)phenoxy]methyl}quinolin-4(1H)-one;
4-{4-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]butoxy}benzonitrile;
2-({4-[4-(2-methoxyethyl)phenoxy]butoxy}methyl)-3-methylquinolin-4(1H)-one;
2-({3-[(1-acetylpiperidin-4-yl)methoxy]phenoxy}methyl)-3-methylquinolin-4(1H)-one;
3-methyl-2-{[3-(2-pyridin-4-ylethoxy)phenoxy]methyl}quinolin-4(1H)-one;
2-{[3-(3-hydroxy-3-methylbutoxy)phenoxy]methyl}-3-methylquinolin-4(1H)-one;
6-fluoro-3-methyl-2-({[4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-2-yl]oxy}methyl)quinolin-4(1H)-one;
2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one;
6-fluoro-3-methyl-2-({[1-(tetrahydro-2H-pyran-4-ylacetyl)-1,2,3,4-tetrahydroquinolin-7-yl]oxy}methyl)quinolin-4(1H)-one;
3-methyl-2-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}quinolin-4(1H)-one;
2-({[4-(3-methoxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one;
2-[({4-[(4-hydroxy-4-methylpentyl)oxy]pyridin-2-yl}oxy)methyl]-3-methylquinolin-4(1H)-one;
2-{[3-(4-hydroxypiperidin-1-yl)phenoxy]methyl}-3-methylquinolin-4(1H)-one;
2-{[3-(4-hydroxy-4-methylpiperidin-1-yl)phenoxy]methyl}-3-methylquinolin-4(1H)-one;
N-cyclohexyl-N-{2-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]ethyl}tetrahydro-2H-pyrane-4-carboxamide;
ethyl 4-[2-(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)ethyl]piperidine-1-carboxylate;
2-{2-[1-(ethylsulfonyl)piperidin-4-yl]ethyl}-3-methylquinolin-4(1H)-one; and
(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl (3-phenylpropyl)carbamate.

19. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

20. A compound of the formula 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one or a salt thereof.

21. A method for treating a disease associated with NAD(P)H oxidase, comprising administering to a patient in need thereof an effective amount of a compound or a salt thereof according to claim 20, wherein the disease is selected from the group consisting of diabetes types 1 and 2, impaired glucose tolerance, hyperlipidemia, fatty liver and diabetic complications.