HETEROAROMATIC DERIVATIVES HAVING SEROTONIN RECEPTOR BINDING ACTIVITY
20230143664 · 2023-05-11
Assignee
Inventors
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
A61K31/4439
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
A61K31/4709
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61K31/438
HUMAN NECESSITIES
A61K31/435
HUMAN NECESSITIES
A61K31/4535
HUMAN NECESSITIES
A61K31/4545
HUMAN NECESSITIES
A61P25/14
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
A61K31/501
HUMAN NECESSITIES
A61K31/437
HUMAN NECESSITIES
C07D491/056
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
A61P25/28
HUMAN NECESSITIES
A61K31/444
HUMAN NECESSITIES
A61K31/496
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
C07D413/12
CHEMISTRY; METALLURGY
A61K31/454
HUMAN NECESSITIES
International classification
A61K31/438
HUMAN NECESSITIES
A61K31/444
HUMAN NECESSITIES
Abstract
Provided are compounds having a serotonin 5-HT2A receptor inverse agonism, pharmaceutically acceptable salts thereof, and a composition comprising them,
A composition comprising the compounds of Formula (I):
##STR00001## or pharmaceutically acceptable salts thereof, wherein: R.sup.1 is substituted or unsubstituted aromatic heterocyclyl or the like; R.sup.2 is each independently a hydrogen atom or the like; R.sup.3 is each independently a hydrogen atom or the like; n is 1 or 2; R.sup.4 is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl or the like; L is —NR.sup.8— or the like; R.sup.8 is a hydrogen atom or the like; R.sup.8 is each independently a hydrogen atom or the like; R.sup.8 is each independently a hydrogen atom or the like; p is 1 or 2; and R.sup.7 is a group represented by Formula:
##STR00002## wherein R.sup.9 is substituted or unsubstituted alkyloxy or the like; R.sup.10 is a hydrogen atom or the like; R.sup.11 is halogen or the like; and m is 0 or 1.
Claims
1. A composition for serotonin 5-HT2A receptor inverse agonism comprising a compound represented by Formula (I): ##STR00274## wherein R.sup.1 is substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl; R.sup.2 is each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R.sup.3 is each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; n is 1 or 2; R.sup.4 is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl; L is —NR.sup.8—, —O—, or a single bond; R.sup.8 is a hydrogen atom or substituted or unsubstituted alkyl; R.sup.5 is each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R.sup.6 is each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; p is 1 or 2; R.sup.7 is a group represented by Formula: ##STR00275## wherein R.sup.9 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkyl; R.sup.10 is a hydrogen atom, hydroxy, halogen or substituted or unsubstituted alkyl; or R.sup.9 and R.sup.10 are taken together to form a substituted or unsubstituted non-aromatic heterocycle; R.sup.11 is halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; m is 0 or 1, provided that the following compounds (i) and (ii) are excluded: (i) a compound wherein L is a single bond, and R.sup.1 is substituted or unsubstituted furyl, or substituted or unsubstituted thienyl; (ii) a compound wherein L is —NR.sup.8—, and R.sup.1 is substituted or unsubstituted 2,3-dihydrobenzofuryl; or a pharmaceutically acceptable salt thereof.
2. The composition for serotonin 5-HT2A receptor inverse agonism according to claim 1, comprising a compound wherein R.sup.1 is substituted or unsubstituted aromatic heterocyclyl; L is —NR.sup.8—, or —O—, or a pharmaceutically acceptable salt thereof.
3. A compound represented by Formula (II): ##STR00276## wherein R.sup.1 is substituted or unsubstituted aromatic heterocyclyl; R.sup.2 is each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R.sup.3 is each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; n is 1 or 2; R.sup.4 is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl; R.sup.8 is a hydrogen atom or substituted or unsubstituted alkyl; R.sup.5 is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R.sup.6 is a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R.sup.7 is a group represented by Formula: ##STR00277## wherein R.sup.9 is substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkyl; R.sup.10 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; or R.sup.9 and R.sup.10 are taken together to form a substituted or unsubstituted non-aromatic heterocycle; R.sup.11 is halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; m is 0 or 1; provided that the following compounds are excluded: ##STR00278## or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3, wherein R.sup.1 is substituted or unsubstituted aromatic nitrogen-containing heterocyclyl, or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 3, wherein R.sup.1 is substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclyl, or substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclyl, or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 3, wherein R.sup.2 and R.sup.3 are hydrogen atoms, or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 3, wherein n is 1, or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 3, wherein R.sup.4 is substituted or unsubstituted 4 to 7-membered non-aromatic nitrogen-containing heterocyclyl, or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 3, wherein R.sup.4 is substituted or unsubstituted piperidinyl, or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 3, wherein R.sup.4 is a group represented by Formula: ##STR00279## wherein R.sup.20 is a hydrogen atom or substituted or unsubstituted alkyl; R.sup.22 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; R.sup.23 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; or R.sup.22 and R.sup.23 are taken together with the carbon atom to which they are bonded to form a substituted or unsubstituted non-aromatic carbocycle, or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 10, wherein R.sup.4 is a group represented by Formula: ##STR00280## R.sup.21, R.sup.22 and R.sup.23 have the same meaning as claim 10, or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 10, wherein R.sup.22 is halogen or substituted or unsubstituted alkyl; R.sup.23 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; or R.sup.22 and R.sup.23 are taken together with the carbon atom to which they are bonded to form a substituted or unsubstituted non-aromatic carbocycle, or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 3, wherein R.sup.8 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 3, wherein R.sup.5 and R.sup.6 are hydrogen atoms, or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 3, wherein R.sup.7 is a group represented by Formula: ##STR00281## wherein R.sup.9 is substituted or unsubstituted alkyloxy, or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 3, wherein the compound is selected from the group consisting of compounds I-008, I-027, I-047, I-095 I-102, I-112, I-114, I-115, I-124, I-126, I-129, I-133, I-134, I-138, I-139, I-140, I-141, I-144 and I-145 or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising the compound according to claim 3, or a pharmaceutically acceptable salt thereof.
18. The pharmaceutical composition according to claim 17, wherein the composition is a serotonin 5-HT2A receptor inverse agonist.
19. A method for treating and/or preventing a disease related to serotonin 5-HT2A receptor comprising administering the compound according to claim 3, or a pharmaceutically acceptable salt thereof.
Description
MODE FOR CARRYING OUT THE INVENTION
[0525] Terms used in this description are explained below. Each term, unless otherwise indicated, has the same meaning when it is used alone or together with other terms.
[0526] The term of “consisting of” means having only components.
[0527] The term of “comprising” means not restricting with components and not excluding undescribed factors.
[0528] Hereinafter, the present invention is described with reference to embodiments. It should be understood that, throughout the present description, the expression of a singular form includes the concept of its plural form unless specified otherwise. Accordingly, it should be understood that an article in singular form (for example, in the English language, “a,” “an,” and “the”) includes the concept of its plural form unless specified otherwise.
[0529] Furthermore, it should be understood that the terms used herein are used in a meaning normally used in the art unless specified otherwise. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the field to which the present invention pertains. If there is a contradiction, the present description (including definitions) precedes.
[0530] The term “halogen” includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A fluorine atom and a chlorine atom are especially preferable.
[0531] The term “alkyl” includes a C1 to C15, preferably C1 to C10, more preferably C1 to C6 and further preferably C1 to C4 linear or branched hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, see-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.
[0532] Preferred embodiments of “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.
[0533] As the alkyl moiety of alkyloxy in R.sup.9, C2-C4 alkyl is preferable. Examples include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
[0534] The term “haloalkyl” means the above alkyl substituted with one or more halogen(s). When substituted with two or more halogens, the halogens may be the same or different. Examples include fluoromethyl, difluoromethyl, trifluoromethyl and chlorofluoromethyl.
[0535] The term “alkenyl” includes a C2 to C15, preferably a C2 to C10, more preferably a C2 to C6 and further preferably a C2 to C4 linear or branched hydrocarbon group having one or more double bond(s) at any position(s). Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.
[0536] Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl, and butenyl. More preferred embodiments include vinyl and n-propenyl.
[0537] The term “alkynyl” includes a C2 to C10, preferably a C2 to C8, more preferably a C2 to C6 and further preferably a C2 to C4 linear or branched hydrocarbon group having one or more triple bond(s) at any position(s). Furthermore, it may have double bond(s) at any position(s). Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl.
[0538] Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl, and pentynyl. More preferred embodiments include ethynyl and propynyl.
[0539] The term “aromatic carbocyclyl” means a cyclic aromatic hydrocarbon group which is monocyclic or polycyclic having two or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl.
[0540] Preferred embodiments of the “aromatic carbocyclyl” include phenyl.
[0541] The term “aromatic carbocycle” means a ring derived from the above “aromatic carbocyclyl”.
[0542] The term “non-aromatic carbocyclyl” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group, which is monocyclic or polycyclic having two or more rings. The “non-aromatic carbocyclyl” which is polycyclic having two or more rings includes a fused ring group wherein a non-aromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”.
[0543] In addition, examples of the “non-aromatic carbocyclyl” also include a group having a bridge or a group to form a spiro ring as follows:
##STR00065##
[0544] The non-aromatic carbocyclyl which is monocyclic is preferably C3 to C16, more preferably C3 to C12 and further preferably C4 to C8 carbocyclyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
[0545] The non-aromatic carbocyclyl which is polycyclic having two or more rings is preferably C8 to C20, more preferably C8 to C16 carbocyclyl. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.
[0546] The term “non-aromatic carbocycle” means a ring derived from the above “non-aromatic carbocyclyl”.
[0547] The term “aromatic heterocyclyl” means an aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N.
[0548] The aromatic heterocyclyl, which is polycyclic having two or more rings, includes a fused ring group wherein an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”, the bond may be held in any ring.
[0549] The aromatic heterocyclyl, which is monocyclic, is preferably a 5- to 8-membered ring and more preferably a 5- to 6-membered ring. Examples of the 5-membered aromatic heterocyclyl include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of the 6-membered aromatic heterocyclyl include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl. The aromatic heterocyclyl, which is bicyclic, is preferably a 8- to 10-membered ring and more preferably a 9- to 10-membered ring. Examples of aromatic heterocyclyl, which is bicyclic, include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl.
[0550] The aromatic heterocyclyl, which is polycyclic having three or more rings, is preferably a 13- to 15-membered ring. Examples of aromatic heterocyclyl, which is polycyclic having three or more rings, include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.
[0551] The term “aromatic heterocycle” means a ring derived from the above “aromatic heterocyclyl”.
[0552] The term “aromatic nitrogen-containing heterocyclyl” means an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more N and optionally containing one or more, same or different heteroatom(s) selected independently from O, S and N. The aromatic nitrogen-containing heterocyclyl, which is polycyclic having two or more rings, includes a fused ring group wherein an aromatic nitrogen-containing heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”, the bond may be held in any ring.
[0553] The aromatic nitrogen-containing heterocyclyl, which is monocyclic, is preferably a 5- to 8-membered ring and more preferably a 5- to 6-membered ring. Examples of the 5-membered aromatic nitrogen-containing heterocyclyl include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of the 6-membered aromatic nitrogen-containing heterocyclyl include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.
[0554] The aromatic nitrogen-containing heterocyclyl, which is bicyclic, is preferably a 8- to 10-membered ring and more preferably a 9- to 10-membered ring. Examples of aromatic nitrogen-containing heterocyclyl, which is bicyclic, include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl.
[0555] The aromatic nitrogen-containing heterocyclyl, which is polycyclic having three or more rings, is preferably a 13- to 15-membered ring. Examples of aromatic nitrogen-containing heterocyclyl, which is polycyclic having three or more rings, include carbazolyl, acridinyl, and phenothiazinyl.
[0556] The term “non-aromatic heterocyclyl” means a non-aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N. The “non-aromatic heterocyclyl”, which is polycyclic having two or more rings, includes a non-aromatic heterocyclyl fused with a ring of the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”, and further includes a non-aromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, fused with a ring of the above “aromatic heterocyclyl”, the bond may be held in any ring.
[0557] In addition, examples of the “non-aromatic heterocyclyl” also include a group having a bridge or a group to form a spiro ring as follows:
##STR00066##
[0558] The non-aromatic heterocyclyl, which is monocyclic, is preferably a 3- to 8-membered and more preferably a 5- to 6-membered ring.
[0559] Examples of the 3-membered non-aromatic heterocyclyl include thiiranyl, oxiranyl and aziridinyl. Examples of the 4-membered non-aromatic heterocyclyl include oxetanyl and azetidinyl. Examples of the 5-membered non-aromatic heterocyclyl include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of the 6-membered non-aromatic heterocyclyl include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, and thiazinyl. Examples of the 7-membered non-aromatic heterocyclyl include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. Examples of the 8-membered non-aromatic heterocyclyl include azocane, thiocane and oxocane.
[0560] The non-aromatic heterocyclyl, which is polycyclic having two or more rings, is preferably a 8- to 20-membered and more preferably a 8- to 10-membered ring. Examples of non-aromatic heterocyclyl, which is polycyclic having two or more rings, include indolinyl, isoindolinyl, chromanyl, and isochromanyl.
[0561] The term “non-aromatic nitrogen-containing heterocyclyl” means an non-aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more N. The non-aromatic nitrogen-containing heterocyclyl, which is polycyclic having two or more rings, includes a fused ring group wherein an non-aromatic nitrogen-containing heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”, the bond may be held in any ring.
[0562] Examples include rings as follows.
##STR00067##
[0563] Furthermore. “non-aromatic nitrogen-containing heterocyclyl” also include a group having a bridge or a group to form a spiro ring as follows:
##STR00068##
[0564] The term “non-aromatic heterocycle” means a ring derived from the above “non-aromatic heterocyclyl”.
[0565] The term “non-aromatic heterocycle that R.sup.9 and R.sup.10 are taken together to form” means rings as follows as examples.
##STR00069##
[0566] The term “non-aromatic carbocycle that R.sup.22 and R.sup.23 are taken together with the carbon atom to which they are bonded to form” means rings as follows as examples.
##STR00070##
[0567] The term “trialkylsilyl” means a group in which the above three “alkyls” are bound to a silicon atom. The three alkyls may be the same or different. Examples include trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl.
[0568] In the present description, the phrase “may be substituted with substituent group α” means that “may be substituted with one or more group(s) selected from substituent group α”. The same also applies to substituent groups β, γ, and γ′.
[0569] Substituents for “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylcarbonyloxy”, “substituted alkenylcarbonyloxy”, “substituted alkynylcarbonyloxy”, “substituted alkylcarbonyl”, “substituted alkenylcarbonyl”, “substituted alkynylcarbonyl”, “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonyl”, “substituted alkynyloxycarbonyl”, “substituted alkylsulfanyl”, “substituted alkenylsulfanyl”, “substituted alkynylsulfanyl”, “substituted alkylsulfinyl”, “substituted alkenylsulfinyl”, “substituted alkynylsulfinyl”, “substituted alkylsulfonyl”, “substituted alkenylsulfonyl”, “substituted alkynylsulfonyl”, “substituted dialkylsulfoxyimino”, and the like include the following substituent group A. A carbon atom at any position may be bonded to one or more group(s) selected from the following substituent group A.
[0570] Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, [0571] alkyloxy which may be substituted with substituent group α, alkenyloxy which may be substituted with substituent group α, alkynyloxy which may be substituted with substituent group α, alkylcarbonyloxy which may be substituted with substituent group α, alkenylcarbonyloxy which may be substituted with substituent group α, alkynylcarbonyloxy which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkyloxycarbonyl which may be substituted with substituent group α, alkenyloxycarbonyl which may be substituted with substituent group α, alkynyloxycarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α, [0572] amino which may be substituted with substituent group α, imino which may be substituted with substituent group α, carbamoyl which may be substituted with substituent group β, sulfamoyl which may be substituted with substituent group β, aromatic carbocyclyl which may be substituted with substituent group γ, non-aromatic carbocyclyl which may be substituted with substituent group γ′, aromatic heterocyclyl which may be substituted with substituent group γ, non-aromatic heterocyclyl which may be substituted with substituent group γ′, aromatic carbocyclyloxy which may be substituted with substituent group γ, non-aromatic carbocyclyloxy which may be substituted with substituent group γ′, aromatic heterocyclyloxy which may be substituted with substituent group γ, non-aromatic heterocyclyloxy which may be substituted with substituent group γ′, aromatic carbocyclylcarbonyloxy which may be substituted with substituent group γ, non-aromatic carbocyclylcarbonyloxy which may be substituted with substituent group γ′, aromatic heterocyclylcarbonyloxy which may be substituted with substituent group γ, non-aromatic heterocyclylcarbonyloxy which may be substituted with substituent group γ′, aromatic carbocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclylcarbonyl which may be substituted with substituent group γ′, aromatic heterocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclylcarbonyl which may be substituted with substituent group γ′, aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic carbocyclylalkyloxy which may be substituted with substituent group γ, non-aromatic carbocyclylalkyloxy which may be substituted with substituent group γ′, aromatic heterocyclylalkyloxy which may be substituted with substituent group γ, non-aromatic heterocyclylalkyloxy which may be substituted with substituent group γ′, aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group γ′, aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfanyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfanyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfinyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfonyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfonyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfonyl which may be substituted with substituent group γ, and non-aromatic heterocyclylsulfonyl which may be substituted with substituent group γ′.
[0573] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
[0574] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted with substituent group α, alkenyl which may be substituted with substituent group α, alkynyl which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α, [0575] aromatic carbocyclyl which may be substituted with substituent group γ, non-aromatic carbocyclyl which may be substituted with substituent group γ′, aromatic heterocyclyl which may be substituted with substituent group γ, non-aromatic heterocyclyl which may be substituted with substituent group γ′, aromatic carbocyclylalkyl which may be substituted with substituent group γ, non-aromatic carbocyclylalkyl which may be substituted with substituent group γ′, aromatic heterocyclylalkyl which may be substituted with substituent group γ, non-aromatic heterocyclylalkyl which may be substituted with substituent group γ′, aromatic carbocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclylcarbonyl which may be substituted with substituent group γ′, aromatic heterocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclylcarbonyl which may be substituted with substituent group γ′, aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfanyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfanyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfinyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfonyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfonyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfonyl which may be substituted with substituent group γ, and non-aromatic heterocyclylsulfonyl which may be substituted with substituent group γ′.
[0576] Substituent group γ: substituent group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.
[0577] Substituent group γ′: substituent group γ and oxo.
[0578] The substituents on the rings of “aromatic carbocycle” and “aromatic heterocycle”, such as “substituted aromatic carbocyclyl”, “substituted aromatic heterocyclyl”, “substituted aromatic nitrogen-containing heterocyclyl”, “substituted aromatic carbocyclyloxy”. “substituted aromatic heterocyclyloxy”, “substituted aromatic carbocyclylcarbonyloxy”, “substituted aromatic heterocyclylcarbonyloxy”, “substituted aromatic carbocyclylcarbonyl”, “substituted aromatic heterocyclylcarbonyl”, “substituted aromatic carbocyclyloxycarbonyl”, “substituted aromatic heterocyclyloxycarbonyl”. “substituted aromatic carbocyclylsulfanyl”, “substituted aromatic heterocyclylsulfanyl”, “substituted aromatic carbocyclylsulfinyl”, “substituted aromatic heterocyclylsulfinyl”, “substituted aromatic carbocyclylsulfonyl”, and “substituted aromatic heterocyclylsulfonyl” include the following substituent group B. An atom at any position on the ring may be bonded to one or more group(s) selected from the following substituent group B.
[0579] Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, [0580] alkyl which may be substituted with substituent group α, alkenyl which may be substituted with substituent group α, alkynyl which may be substituted with substituent group α, alkyloxy which may be substituted with substituent group α, alkenyloxy which may be substituted with substituent group α, alkynyloxy which may be substituted with substituent group α, alkylcarbonyloxy which may be substituted with substituent group α, alkenylcarbonyloxy which may be substituted with substituent group α, alkynylcarbonyloxy which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkyloxycarbonyl which may be substituted with substituent group α, alkenyloxycarbonyl which may be substituted with substituent group α, alkynyloxycarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α, [0581] amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, sulfamoyl which may be substituted with substituent group β, [0582] aromatic carbocyclyl which may be substituted with substituent group γ, non-aromatic carbocyclyl which may be substituted with substituent group γ′, aromatic heterocyclyl which may be substituted with substituent group γ, non-aromatic heterocyclyl which may be substituted with substituent group γ′, aromatic carbocyclyloxy which may be substituted with substituent group γ, non-aromatic carbocyclyloxy which may be substituted with substituent group γ′, aromatic heterocyclyloxy which may be substituted with substituent group γ, non-aromatic heterocyclyloxy which may be substituted with substituent group γ′, aromatic carbocyclylcarbonyloxy which may be substituted with substituent group γ, non-aromatic carbocyclylcarbonyloxy which may be substituted with substituent group γ′, aromatic heterocyclylcarbonyloxy which may be substituted with substituent group γ, and non-aromatic heterocyclylcarbonyloxy which may be substituted with substituent group γ′, aromatic carbocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclylcarbonyl which may be substituted with substituent group γ′, aromatic heterocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclylcarbonyl which may be substituted with substituent group γ′, aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic carbocyclylalkyl which may be substituted with substituent group γ, non-aromatic carbocyclylalkyl which may be substituted with substituent group γ′, aromatic heterocyclylalkyl which may be substituted with substituent group γ, non-aromatic heterocyclylalkyl which may be substituted with substituent group γ′, aromatic carbocyclylalkyloxy which may be substituted with substituent group γ, non-aromatic carbocyclylalkyloxy which may be substituted with substituent group γ′, aromatic heterocyclylalkyloxy which may be substituted with substituent group γ, non-aromatic heterocyclylalkyloxy which may be substituted with substituent group γ′, aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclylalkyloxycarbonyl which may be substituted with substituent group γ′, aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclylalkyloxycarbonyl which may be substituted with substituent group γ′, aromatic carbocyclylalkyloxyalkyl which may be substituted with substituent group γ, non-aromatic carbocyclylalkyloxyalkyl which may be substituted with substituent group γ′, aromatic heterocyclylalkyloxyalkyl which may be substituted with substituent group γ, non-aromatic heterocyclylalkyloxyalkyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfanyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfanyl which may be substituted with substituent group γ, aromatic carbocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfinyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfonyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfonyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfonyl which may be substituted with substituent group γ, and non-aromatic heterocyclylsulfonyl which may be substituted with substituent group γ′.
[0583] The substituents on the ring of “non-aromatic carbocycle” and “non-aromatic heterocycle” of “substituted non-aromatic carbocyclyl”. “substituted non-aromatic heterocyclyl”, “substituted non-aromatic nitrogen-containing heterocyclyl”, “substituted heterocyclyl which R.sup.9 and R.sup.10 are taken together to form”. “substituted heterocyclyl which R.sup.22 and R.sup.23 are taken together with the carbon atom to which they are bonded to form”, “substituted non-aromatic carbocyclyloxy”. “substituted non-aromatic heterocyclyloxy”. “substituted non-aromatic carbocyclylcarbonyloxy”, “substituted non-aromatic heterocyclylcarbonyloxy”. “substituted non-aromatic carbocyclylcarbonyl”, “substituted non-aromatic heterocyclylcarbonyl”, “substituted non-aromatic carbocyclyloxycarbonyl”. “substituted non-aromatic heterocyclyloxycarbonyl”, “substituted non-aromatic carbocyclylsulfanyl”, “substituted non-aromatic heterocyclylsulfanyl”. “substituted non-aromatic carbocyclylsulfinyl”, “substituted non-aromatic heterocyclylsulfinyl”, “substituted non-aromatic carbocyclylsulfonyl”, and “substituted non-aromatic heterocyclylsulfonyl”, include the following substituent group C. An atom at any position on the ring may be bonded to one or more group(s) selected from the following substituent group C.
[0584] Substituent group C: substituent group B and oxo.
[0585] When the “non-aromatic carbocycle”, the “non-aromatic heterocycle” and the “non-aromatic nitrogen-containing heterocycle” are substituted with “oxo”, this means a ring in which two hydrogen atoms on a carbon atom are substituted as follows.
##STR00071##
[0586] The substituents for “substituted amino”, “substituted imino”, “substituted carbamoyl”, and “substituted sulfamoyl” include the following substituent group D. These moieties may be substituted with one or two group(s) selected from substituent group D.
[0587] Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl which may be substituted with substituent group α, alkenyl which may be substituted with substituent group α, alkynyl which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α, [0588] amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, sulfamoyl which may be substituted with substituent group β, [0589] aromatic carbocyclyl which may be substituted with substituent group γ, non-aromatic carbocyclyl which may be substituted with substituent group γ′, aromatic heterocyclyl which may be substituted with substituent group γ, non-aromatic heterocyclyl which may be substituted with substituent group γ′, aromatic carbocyclylalkyl which may be substituted with substituent group γ, non-aromatic carbocyclylalkyl which may be substituted with substituent group γ′, aromatic heterocyclylalkyl which may be substituted with substituent group γ, non-aromatic heterocyclylalkyl which may be substituted with substituent group γ′, aromatic carbocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclylcarbonyl which may be substituted with substituent group γ′, aromatic heterocyclylcarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclylcarbonyl which may be substituted with substituent group γ′, aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclyloxycarbonyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfanyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfanyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic carbocyclylsulfinyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfinyl which may be substituted with substituent group γ, non-aromatic heterocyclylsulfinyl which may be substituted with substituent group γ′, aromatic carbocyclylsulfonyl which may be substituted with substituent group γ, non-aromatic carbocyclyl sulfonyl which may be substituted with substituent group γ′, aromatic heterocyclylsulfonyl which may be substituted with substituent group γ, and non-aromatic heterocyclylsulfonyl which may be substituted with substituent group γ′.
[0590] With regard to a compound represented by Formula (I) or Formula (II), preferred embodiments of R.sup.1, R.sup.2, R.sup.3, n, R.sup.4, L, R.sup.8, R.sup.5, R.sup.6, p, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.21, R.sup.22, R.sup.23 and m will be shown below. Regarding the compound represented by Formula (I) and Formula (II), embodiments of all the combinations of specific examples shown below are mentioned as examples.
[0591] R.sup.1 may be substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl (hereinafter, referred to as A-1).
[0592] R.sup.1 may be substituted or unsubstituted aromatic heterocyclyl (hereinafter, referred to as A-2).
[0593] R.sup.1 may be substituted or unsubstituted aromatic nitrogen-containing heterocyclyl, (hereinafter, referred to as A-3).
[0594] R.sup.1 may be substituted or unsubstituted 5-membered aromatic heterocyclyl, substituted or unsubstituted 6-membered aromatic heterocyclyl, or substituted or unsubstituted 10-membered aromatic heterocyclyl (hereinafter, referred to as A-4).
[0595] R.sup.1 may be substituted or unsubstituted 6-membered aromatic heterocyclyl, or substituted or unsubstituted 5-membered aromatic heterocyclyl (hereinafter, referred to as A-5).
[0596] R.sup.1 may be 5-membered aromatic heterocyclyl substituted with alkyl; unsubstituted 5-membered aromatic heterocyclyl; 6-membered aromatic heterocyclyl substituted with one or more substituent(s) selected from the group consisting of halogen, alkyloxy, cyano, haloalkyl and alkyl; or unsubstituted 6-membered aromatic heterocyclyl halogen (hereinafter, referred to as A-6).
[0597] R.sup.1 may be substituted or unsubstituted 5-membered aromatic heterocyclyl (hereinafter, referred to as A-7).
[0598] R.sup.1 may be 5-membered aromatic heterocyclyl substituted with alkyl, or unsubstituted 5-membered aromatic heterocyclyl (hereinafter, referred to as A-8).
[0599] R.sup.1 may be substituted or unsubstituted 6-membered aromatic heterocyclyl (hereinafter, referred to as A-9).
[0600] R.sup.1 may be 6-membered aromatic heterocyclyl substituted with one or more substituent(s) selected from the group consisting of halogen, alkyloxy, cyano, haloalkyl and alkyl, or unsubstituted 6-membered aromatic heterocyclyl (hereinafter, referred to as A-10).
[0601] R.sup.1 may be substituted or unsubstituted 10-membered aromatic heterocyclyl (hereinafter, referred to as A-11).
[0602] R.sup.1 may be unsubstituted 10-membered aromatic heterocyclyl (hereinafter, referred to as A-12).
[0603] R.sup.1 may be substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted indolyl (hereinafter referred to as A-13).
[0604] R.sup.1 may be substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrrolyl, or substituted or unsubstituted pyrazolyl (hereinafter referred to as A-14).
[0605] R.sup.1 may be substituted or unsubstituted pyridyl, substituted or unsubstituted pyrrolyl, or substituted or unsubstituted pyrazolyl (hereinafter referred to as A-15).
[0606] R.sup.1 may be substituted or unsubstituted pyrrolyl, or substituted or unsubstituted pyrazolyl (hereinafter referred to as A-16).
[0607] R.sup.1 may be substituted or unsubstituted pyridyl (hereinafter referred to as A-17).
[0608] R.sup.1 may be pyridyl substituted with one or more substituent(s) selected from the group consisting of halogen, alkyloxy, cyano, haloalkyl and alkyl, or unsubstituted pyridyl (hereinafter, referred to as A-18).
[0609] R.sup.1 may be pyridyl substituted with halogen and/or haloalkyl, or unsubstituted pyridyl (hereinafter, referred to as A-19).
[0610] R.sup.1 may be pyridyl substituted with halogen, or unsubstituted pyridyl (hereinafter, referred to as A-20).
[0611] R.sup.1 may be pyridyl substituted with halogen (hereinafter, referred to as A-21).
[0612] R.sup.1 may be pyridyl substituted with haloalkyl, or unsubstituted pyridyl (hereinafter, referred to as A-22).
[0613] R.sup.1 may be pyridyl substituted with haloalkyl (hereinafter, referred to as A-23).
[0614] R.sup.1 may be substituted or unsubstituted pyrazolyl (hereinafter, referred to as A-24).
[0615] R.sup.1 may be pyrazolyl substituted with haloalkyl and/or alkyl, or unsubstituted pyrazolyl (hereinafter, referred to as A-25).
[0616] R.sup.1 may be pyrazolyl substituted with alkyl, or unsubstituted pyrazolyl (hereinafter, referred to as A-26).
[0617] R.sup.1 may be pyrazolyl substituted with alkyl (hereinafter, referred to as A-27).
[0618] R.sup.1 may be substituted or unsubstituted pyrrolyl (hereinafter, referred to as A-28).
[0619] R.sup.1 may be pyrrolyl substituted with haloalkyl and/or alkyl, or unsubstituted pyrrolyl (hereinafter, referred to as A-29).
[0620] R.sup.1 may be pyrrolyl substituted with alkyl, or unsubstituted pyrrolyl (hereinafter, referred to as A-30).
[0621] R.sup.1 may be pyrrolyl substituted with alkyl (hereinafter, referred to as A-31).
[0622] R.sup.2 may be each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter, referred to as B-1).
[0623] R.sup.2 may be each independently a hydrogen atom (hereinafter, referred to as B-2).
[0624] R.sup.3 may be each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter, referred to as C-1).
[0625] R.sup.3 may be each independently a hydrogen atom (hereinafter, referred to as C-2).
[0626] n may be 1 or 2 (hereinafter, referred to as D-1).
[0627] n may be 1 (hereinafter, referred to as D-2).
[0628] R.sup.4 may be substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl (hereinafter, referred to as E-1).
[0629] R.sup.4 may be substituted or unsubstituted 4 to 7-membered non-aromatic nitrogen-containing heterocyclyl (hereinafter, referred to as E-2).
[0630] R.sup.4 may be substituted or unsubstituted 6-membered non-aromatic nitrogen-containing heterocyclyl (hereinafter, referred to as E-3).
[0631] R.sup.4 may be substituted or unsubstituted piperidinyl (hereinafter, referred to as E-4).
[0632] R.sup.4 may be a group represented by Formula:
##STR00072## [0633] wherein R.sup.21 is a hydrogen atom or substituted or unsubstituted alkyl; [0634] R.sup.22 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; [0635] R.sup.23 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; or R.sup.22 and R.sup.23 are taken together with the carbon atom to which they are bonded to form a substituted or unsubstituted non-aromatic carbocycle (hereinafter, referred to as E-5).
[0636] R.sup.4 may be a group represented by Formula:
##STR00073## [0637] wherein R.sup.21 is a hydrogen atom or substituted or unsubstituted alkyl; [0638] R.sup.22 is halogen or substituted or unsubstituted alkyl; [0639] R.sup.23 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; or [0640] R.sup.22 and R.sup.23 are taken together with the carbon atom to which they are bonded to form a substituted or unsubstituted non-aromatic carbocycle, (hereinafter, referred to as E-6).
[0641] R.sup.4 may be a group represented by Formula:
##STR00074## [0642] wherein R.sup.21 is a hydrogen atom or substituted or unsubstituted alkyl (hereinafter, referred to as E-7).
[0643] R.sup.4 may be a group represented by Formula:
##STR00075## [0644] wherein R.sup.21, R.sup.22 and R.sup.23 have the same meaning as E-5 (hereinafter, referred to as E-8).
[0645] R.sup.4 may be a group represented by Formula:
##STR00076## [0646] wherein R.sup.21, R.sup.22 and R.sup.23 have the same meaning as E-6 (hereinafter, referred to as E-9).
[0647] R.sup.4 may be a group represented by Formula:
##STR00077## [0648] wherein R.sup.21 is a hydrogen atom or substituted or unsubstituted alkyl (hereinafter, referred to as E-10).
[0649] R.sup.4 may be a group represented by Formula:
##STR00078## [0650] wherein R.sup.21 is a hydrogen atom or substituted or unsubstituted alkyl; [0651] R.sup.22 is halogen (hereinafter, referred to as E-11).
[0652] L may be —NR.sup.8—, —O—, or a single bond (hereinafter, referred to as F-1).
[0653] L may be —NR.sup.8— (hereinafter, referred to as F-2).
[0654] L may be —O— (hereinafter, referred to as F-3).
[0655] L may be a single bond (hereinafter, referred to as F-4).
[0656] R.sup.8 may be a hydrogen atom or substituted or unsubstituted alkyl (hereinafter, referred to as G-1).
[0657] R.sup.8 may be a hydrogen atom (hereinafter, referred to as G-2).
[0658] R.sup.5 may be each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter, referred to as 11-1).
[0659] R.sup.5 may be each independently a hydrogen atom (hereinafter, referred to as H-2).
[0660] R.sup.6 may be each independently a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (hereinafter, referred to as J-1).
[0661] R.sup.6 may be each independently a hydrogen atom (hereinafter, referred to as J-2).
[0662] p may be 1 or 2 (hereinafter, referred to as K-1).
[0663] p may be 1 (hereinafter, referred to as K-2).
[0664] R.sup.7 may be a group represented by Formula:
##STR00079## [0665] wherein R.sup.9 is a hydrogen atom, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkyl; [0666] R.sup.10 is a hydrogen atom, hydroxy, halogen or substituted or unsubstituted alkyl; or [0667] R.sup.9 and R.sup.10 are taken together to form a substituted or unsubstituted non-aromatic heterocycle; [0668] R.sup.11 is halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; [0669] m is 0 or 1 (hereinafter, referred to as L-1). [0670] R.sup.7 may be a group represented by Formula:
##STR00080## [0671] wherein R.sup.9 is substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkyl; [0672] R.sup.10 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; or [0673] R.sup.9 and R.sup.10 are taken together to form a substituted or unsubstituted non-aromatic heterocycle; [0674] R.sup.11 is halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; [0675] m is 0 or 1 (hereinafter, referred to as L-2).
[0676] R.sup.7 may be a group represented by Formula:
##STR00081## [0677] wherein R.sup.9 is substituted or unsubstituted alkyloxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl; [0678] R.sup.10 is a hydrogen atom, halogen or substituted or unsubstituted alkyl; or [0679] R.sup.9 and R.sup.10 are taken together to form a substituted or unsubstituted non-aromatic heterocycle; [0680] R.sup.11 is halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; [0681] m is 0 or 1 (hereinafter, referred to as L-3).
[0682] R.sup.7 may be a group represented by Formula:
##STR00082## [0683] wherein R.sup.9 is substituted or unsubstituted alkyloxy, R.sup.10 is a hydrogen atom, m is 0, [0684] or a group represented by Formula:
##STR00083## [0685] wherein R.sup.9 and R.sup.10 are taken together to form a substituted or unsubstituted non-aromatic heterocycle, m is 0 (hereinafter, referred to as L-4).
[0686] R.sup.7 may be a group represented by Formula:
##STR00084## [0687] wherein R.sup.9 is substituted or unsubstituted alkyloxy, R.sup.10 is a hydrogen atom, m is 0 (hereinafter, referred to as L-5).
[0688] R.sup.7 may be a group represented by Formula:
##STR00085## [0689] wherein R.sup.5 is alkyloxy substituted with halogen, or unsubstituted alkyloxy, R.sup.10 is a hydrogen atom, m is 0 (hereinafter, referred to as L-6).
[0690] R.sup.7 may be a group represented by Formula:
##STR00086## [0691] wherein R.sup.5 and R.sup.10 are taken together to form a substituted or unsubstituted non-aromatic heterocycle, m is 0 (hereinafter, referred to as L-7).
[0692] R.sup.7 may be a group represented by Formula:
##STR00087## [0693] wherein R.sup.9 is substituted or unsubstituted alkyloxy (hereinafter, referred to as L-8).
[0694] R.sup.7 may be a group represented by Formula:
##STR00088## [0695] wherein R.sup.9 is substituted or unsubstituted C2-C4 alkyloxy (hereinafter, referred to as L-9).
[0696] R.sup.7 may be a group represented by Formula:
##STR00089## [0697] wherein R.sup.9 is amino substituted with substituted or unsubstituted alkyl (hereinafter, referred to as L-10).
[0698] R.sup.7 may be a group represented by Formula:
##STR00090## [0699] wherein R.sup.9 is substituted or unsubstituted C2-C4 alkyloxy, or substituted or unsubstituted amino (hereinafter, referred to as L-11).
[0700] In particular, the following embodiments are preferable. [0701] (i) A serotonin 5-HT2A receptor inverse agonist comprising a compound represented by Formula (I):
##STR00091## [0702] wherein R.sup.1 is A-17; [0703] R.sup.2 is a hydrogen atom; [0704] R.sup.3 is a hydrogen atom; [0705] n is 1; [0706] R.sup.4 is E-4; [0707] L is —NR.sup.8—, [0708] R.sup.8 is a hydrogen atom; [0709] R.sup.5 is a hydrogen atom; [0710] R.sup.6 is a hydrogen atom; [0711] p is 1; [0712] R.sup.7 is a group represented by Formula:
##STR00092## [0713] wherein R.sup.9 is substituted or unsubstituted alkyloxy, [0714] or a pharmaceutically acceptable salt thereof. [0715] (ii) A serotonin 5-HT2A receptor inverse agonist comprising a compound represented by Formula (I):
##STR00093## [0716] wherein R.sup.1 is A-24; [0717] R.sup.2 is a hydrogen atom; [0718] R.sup.a is a hydrogen atom; [0719] n is 1; [0720] R.sup.4 is E-4; [0721] L is —NR—; [0722] R.sup.8 is a hydrogen atom; [0723] R.sup.5 is a hydrogen atom; [0724] R.sup.6 is a hydrogen atom; [0725] p is 1; [0726] R.sup.7 is a group represented by Formula:
##STR00094## [0727] wherein R.sup.9 is substituted or unsubstituted alkyloxy, [0728] or a pharmaceutically acceptable salt thereof. [0729] (iii) A serotonin 5-HT2A receptor inverse agonist comprising a compound represented by Formula (I):
##STR00095## [0730] wherein R.sup.1 is A-28; [0731] R.sup.2 is a hydrogen atom; [0732] R.sup.3 is a hydrogen atom; [0733] n is 1; [0734] R.sup.4 is E-4; [0735] L is —NR.sup.8—; [0736] R.sup.8 is a hydrogen atom; [0737] R.sup.5 is a hydrogen atom; [0738] R.sup.6 is a hydrogen atom; [0739] p is 1; [0740] R.sup.7 is a group represented by Formula:
##STR00096## [0741] wherein R.sup.9 is substituted or unsubstituted alkyloxy, [0742] or a pharmaceutically acceptable salt thereof. [0743] (iv) A composition for serotonin 5-HT2A receptor inverse agonism comprising a compound represented by Formula (I):
##STR00097## [0744] wherein R.sup.1 is A-17; [0745] R.sup.2 is a hydrogen atom; [0746] R.sup.3 is a hydrogen atom; [0747] n is 1; [0748] R.sup.4 is E-4; [0749] L is —NR.sup.8—; [0750] R.sup.8 is a hydrogen atom; [0751] R.sup.5 is a hydrogen atom; [0752] R.sup.6 is a hydrogen atom; [0753] p is 1; [0754] R.sup.7 is a group represented by Formula:
##STR00098## [0755] wherein R.sup.9 is substituted or unsubstituted alkyloxy, [0756] or a pharmaceutically acceptable salt thereof. [0757] (v) A composition for serotonin 5-HT2A receptor inverse agonism comprising a compound represented by Formula (I):
##STR00099## [0758] wherein R.sup.1 is A-24; [0759] R.sup.2 is a hydrogen atom; [0760] R.sup.3 is a hydrogen atom; [0761] n is 1; [0762] R.sup.4 is E-4; [0763] L is —NR.sup.8—; [0764] R.sup.8 is a hydrogen atom; [0765] R.sup.5 is a hydrogen atom; [0766] R.sup.6 is a hydrogen atom; [0767] p is 1; [0768] R.sup.7 is a group represented by Formula:
##STR00100## [0769] wherein R.sup.9 is substituted or unsubstituted alkyloxy, [0770] or a pharmaceutically acceptable salt thereof. [0771] (vi) A composition for serotonin 5-HT2A receptor inverse agonism comprising a compound represented by Formula (I):
##STR00101## [0772] wherein R.sup.1 is A-28; [0773] R.sup.2 is a hydrogen atom; [0774] R.sup.3 is a hydrogen atom; [0775] n is 1; [0776] R.sup.4 is E-4; [0777] L is —NR.sup.8—; [0778] R.sup.8 is a hydrogen atom; [0779] R.sup.5 is a hydrogen atom; [0780] R.sup.6 is a hydrogen atom; [0781] p is 1; [0782] R.sup.7 is a group represented by Formula:
##STR00102## [0783] wherein R.sup.5 is substituted or unsubstituted alkyloxy, [0784] or a pharmaceutically acceptable salt thereof. [0785] (vii) A compound represented by Formula (II):
##STR00103## [0786] wherein R.sup.1 is substituted or unsubstituted aromatic nitrogen-containing heterocyclyl; [0787] R.sup.2 is a hydrogen atom; [0788] R.sup.3 is a hydrogen atom; [0789] n is 1; [0790] R.sup.4 is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl; [0791] R.sup.8 is a hydrogen atom; [0792] R.sup.5 is a hydrogen atom; [0793] R.sup.6 is a hydrogen atom; [0794] R.sup.7 is a group represented by Formula:
##STR00104## [0795] wherein R.sup.9 is substituted or unsubstituted C2-C4 alkyloxy, or substituted or unsubstituted amino, [0796] or a pharmaceutically acceptable salt thereof. [0797] (viii) A compound represented by Formula (II):
##STR00105## [0798] wherein R.sup.1 is A-17; [0799] R.sup.2 is a hydrogen atom; [0800] R.sup.3 is a hydrogen atom; [0801] n is 1; [0802] R.sup.4 is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl; [0803] R.sup.8 is a hydrogen atom; [0804] R.sup.5 is a hydrogen atom; [0805] R.sup.6 is a hydrogen atom; [0806] R.sup.7 is a group represented by Formula:
##STR00106## [0807] wherein R.sup.9 is substituted or unsubstituted alkyloxy, [0808] or a pharmaceutically acceptable salt thereof. [0809] (ix) A compound represented by Formula (II):
##STR00107## [0810] wherein R.sup.1 is A-24; [0811] R.sup.2 is a hydrogen atom; [0812] R.sup.3 is a hydrogen atom; [0813] n is 1; [0814] R.sup.4 is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl; [0815] R.sup.8 is a hydrogen atom; [0816] R.sup.5 is a hydrogen atom; [0817] R.sup.6 is a hydrogen atom; [0818] R.sup.7 is a group represented by Formula:
##STR00108## [0819] wherein R.sup.9 is substituted or unsubstituted alkyloxy, [0820] or a pharmaceutically acceptable salt thereof. [0821] (x) A compound represented by Formula (II):
##STR00109## [0822] wherein R.sup.1 is A-28; [0823] R.sup.2 is a hydrogen atom; [0824] R.sup.3 is a hydrogen atom; [0825] n is 1; [0826] R.sup.4 is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl; [0827] R.sup.8 is a hydrogen atom; [0828] R.sup.5 is a hydrogen atom; [0829] R.sup.6 is a hydrogen atom; [0830] R.sup.7 is a group represented by Formula:
##STR00110## [0831] wherein R.sup.9 is substituted or unsubstituted alkyloxy, [0832] or a pharmaceutically acceptable salt thereof. [0833] (xi) A compound represented b Formula (III):
##STR00111## [0834] wherein R.sup.1 is substituted or unsubstituted 6-membered aromatic nitrogen-containing heterocyclyl, or substituted or unsubstituted 5-membered aromatic nitrogen-containing heterocyclyl; [0835] R.sup.4 is a group represented by Formula:
##STR00112## [0836] wherein R.sup.21 is a hydrogen atom or substituted or unsubstituted alkyl; [0837] R.sup.22 and R.sup.23 are taken together with the carbon atom to which they are bonded to form a substituted or unsubstituted non-aromatic carbocycle; [0838] R.sup.7 is a group represented by Formula:
##STR00113## [0839] wherein R.sup.9 is substituted or unsubstituted C2-C4 alkyloxy or substituted or unsubstituted amino, [0840] or a pharmaceutically acceptable salt thereof.
[0841] The compounds represented by Formulas (I) or Formula (II) are not limited to specific isomers, but include all possible isomers (eg, keto-enol isomers, imine-enamin isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.
[0842] One or more hydrogen, carbon, and/or other atom(s) of the compounds represented by Formula (I) or Formula (II) may be substituted by isotope(s) of hydrogen, carbon, and/or other atom(s), respectively. Examples of such isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, as in the cases of .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.123I, and .sup.36Cl, respectively. The compounds represented by Formula (I) or Formula (II) also include compounds substituted with such isotopes. The compounds substituted with the isotopes are also useful as pharmaceutical products and include all radiolabeled forms of the compounds represented by Formula (I) or Formula (II). Furthermore, a “radiolabeling method” for producing the “radiolabeled forms” is also included in the present invention, and the “radiolabeled forms” are useful as tools for metabolic pharmacokinetics studies, studies on binding assay, and/or diagnostics.
[0843] Radiolabeled forms of the compounds represented by Formula (I) or Formula (II) can be prepared by methods well known in the pertinent art. For example, a tritium-labeled compound represented by Formula (I) or Formula (II) can be prepared by introducing tritium into a specific compound represented by Formula (I) or Formula (II), by a catalytic dehalogenation reaction using tritium. This method comprises reacting an appropriately-halogenated precursor of the compound of Formula (I) or Formula (II) with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absence of a base. The other appropriate method of preparing a tritium-labeled compound can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. A .sup.14C-labeled compound can be prepared by using a raw material having .sup.14C carbon.
[0844] The pharmaceutically acceptable salts of the compounds represented by Formula (I) or Formula (II) include, for example, salts of compounds represented by Formula (I) or Formula (II) with alkaline metal (e.g., lithium, sodium, or potassium), alkaline earth metal (e.g., calcium or barium), magnesium, transition metal (e.g., zinc or iron), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, or quinoline), or amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, or hydroiodic acid) or organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid). These salts can be formed by the usual methods.
[0845] The compounds represented by Formula (I) or Formula (II) of the present invention or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates), co-crystal and/or crystal polymorphs. The present invention encompasses those various solvates, co-crystal and crystal polymorphs. The “solvates” may have the compounds represented by Formula (I) or Formula (II) coordinated with any number of solvent molecules (e.g., water molecules). When the compounds represented by Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof are allowed to stand in the atmosphere, the compounds may absorb water, resulting in attachment of adsorbed water or formation of hydrates. Recrystallization of the compounds represented by Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof may produce crystal polymorphs. The “Co-crystal” means that a compound represented by Formula (I) or Formula (II), or a salt thereof and a counter molecule exist in the same crystal lattice, and it can include any number of counter molecules.
[0846] The compounds represented by Formula (I) or Formula (II) of the present invention or pharmaceutically acceptable salts thereof may form prodrugs. The present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds according to the present invention that have chemically or metabolically degradable groups, and compounds that are converted to the pharmaceutically active compounds according to the present invention through solvolysis or under physiological conditions in vivo. Prodrugs include compounds that are converted to the compounds represented by Formula (I) or Formula (II) through enzymatic oxidation, reduction, hydrolysis or the like under physiological conditions in vivo, compounds that are converted to the compounds represented by Formula (I) or Formula (II) through hydrolysis by gastric acid etc., and the like. Methods for selecting and preparing suitable prodrug derivatives are described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs themselves may have some activity.
[0847] When the compounds represented by Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof have hydroxyl group(s), prodrugs include acyloxy derivatives and sulfonyloxy derivatives that are prepared by, for example, reacting compounds having hydroxyl group(s) with suitable acyl halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonyl anhydride and mixed anhydride, or with a condensing agent. For example, they include CH.sub.3COO—, C.sub.2H.sub.5COO—, tert-BuCOO—, C.sub.15H.sub.31COO—, PhCOO—, (m-NaOOCPh)COO—, NaOOCCH.sub.2CH.sub.2COO—, CH.sub.3CH(NH.sub.2)COO—, CH.sub.2N(CH.sub.3).sub.2COO—, CH.sub.3SO.sub.3—, CH.sub.3CH.sub.2SO.sub.3—, CF.sub.3SO.sub.3—, CH.sub.2FSO.sub.3—, CF.sub.3CH.sub.2SO.sub.3—, p-CH.sub.3O-PhSO.sub.3—, PhSO.sub.3— and p-CH.sub.3PhSO.sub.3—.
[0848] Since the compound according to the present invention has serotonin 5-HT2A receptor inverse agonism, the compound is useful as a therapeutic and/or prophylactic agent for a disease or condition associated with serotonin 5-HT2A receptor. Diseases associated with serotonin 5-HT2A receptor include serotonin-mediated diseases such as Parkinson's disease-related hallucinations and delusions, dementia-related hallucinations and delusions, schizophrenia-related hallucinations and delusions, depression-related hallucinations and delusions, neurodegenerative diseases-related hallucinations and delusions, depression, schizophrenia, autism, dependence, dyskinesia, sleep disorder, Parkinson's disease-related irritability, dementia-related irritability, schizophrenia-related irritability, sexual dysfunction and the like. Preferable examples include Parkinson's disease-related hallucinations and delusions, dementia-related hallucinations and delusions, schizophrenia-related hallucinations and delusions, depression-related hallucinations and delusions, Parkinson's disease-related irritability, dementia-related irritability, and schizophrenia-related irritability. More preferable examples include Parkinson's disease-related hallucinations and delusions, and dementia-related hallucinations and delusions.
[0849] The “serotonin 5-HT2A receptor inverse agonist” means a drug having a serotonin 5-HT2A receptor inverse agonism.
[0850] The “composition for serotonin 5-HT2A receptor inverse agonism” means a composition having a serotonin 5-IT2A receptor inverse agonism, and it is not limited to pharmaceutical use.
(Method for Producing Compounds of the Present Invention)
[0851] The compounds represented by Formula (I) or Formula (II) according to the present invention can be produced by, for example, the general synthesis method described below. Regarding extraction, purification, and the like, the treatments carried out in ordinary experiments of organic chemistry may be carried out.
[0852] The compounds of the present invention can be synthesized with reference to methods known in the art.
(When R.SUP.3 .is a Hydrogen Atom and L is —NH—)
[0853] ##STR00114## [0854] wherein each symbol has the same meaning as the above (1), and R.sup.1A— is R.sup.1— or R.sup.1R.sup.2CH—.
Step 1
[0855] Compound (a-2) can be obtained by reacting compound (a-1) and CDI in an appropriate solvent.
[0856] CDI can be used in an amount of 1.0 mol equivalent or more, preferably 1.2 mol equivalents relative to compound (a-1).
[0857] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0858] The reaction temperature is 0 to 80° C., preferably 0 to 20° C.
[0859] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
[0860] The obtained desired compound (a-2) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
Step 2
[0861] Compound (a-5) can be obtained by reacting compound (a-3) and compound (a-4) with an appropriate reducing agent and acetic acid in an appropriate solvent.
[0862] Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride and the like, and the reducing agent can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents relative to compound (a-3).
[0863] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0864] The reaction temperature is 0 to 80° C., preferably 0 to 20° C.
[0865] The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours.
[0866] The obtained desired compound (a-5) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
Step 3
[0867] Compound (I-a) can be obtained by reacting compound (a-5) and compound (a-2) in an appropriate solvent.
[0868] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0869] The reaction temperature is 0 to 100° C., preferably 0 to 80° C.
[0870] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
[0871] The obtained desired compound (I-a) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
##STR00115## [0872] wherein PG is an appropriate protecting group for the amino group, ring A is substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group, and R.sup.a is substituted or unsubstituted alkyl.)
Step 1
[0873] Compound (b-3) can be obtained by reacting compound (b-1) and compound (b-2) with an appropriate reducing agent and, if necessary, acetic acid in an appropriate solvent.
[0874] Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride and the like, and the reducing agent can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents, relative to compound (b-3).
[0875] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0876] The reaction temperature is 0 to 80° C., preferably 0 to 20° C.
[0877] The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours.
[0878] The obtained desired compound (b-3) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
Step 2
[0879] Compound (b-4) can be obtained by reacting compound (b-3) and compound (a-2) in an appropriate solvent.
[0880] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0881] The reaction temperature is 0 to 100° C., preferably 0 to 80° C.
[0882] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
[0883] The obtained desired compound (b-4) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
Step 3
[0884] Compound (b-5) can be obtained by reacting compound (b-4) in the presence of an acid in the absence of a solvent or in an appropriate solvent.
[0885] Examples of the acid include hydrochloric acid, sulfuric acid, TFA, formic acid and the like, the acid can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 30 molar equivalents relative to the compound (b-4).
[0886] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0887] The reaction temperature is 0 to 80° C., preferably 0 to 20° C.
[0888] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
[0889] The obtained desired compound (b-5) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
Step 4
[0890] Compound (I-b) can be obtained by reacting compound (b-5) and compound (b-6) with an appropriate reducing agent and, if necessary, acetic acid in an appropriate solvent.
[0891] Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride and the like, and the reducing agent can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents relative to compound (b-5).
[0892] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0893] The reaction temperature is 0 to 80° C., preferably 0 to 20° C.
[0894] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
[0895] The obtained desired compound (I-b) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
##STR00116##
Step 1
[0896] Compound (I-c) can be obtained by reacting compound (a-5) and compound (c-1) with an appropriate condensing agent and, if necessary, a base in an appropriate solvent.
[0897] Examples of the condensing agent include HOBt, HOAt, DCC, DIC, EDC HCl, HATU. PyBOP and the like, and the condensing agent can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents relative to compound (b-5).
[0898] Examples of the base include triethylamine, DIEA and the like, the base can be used in an amount of 1.0 molar equivalent or more, preferably 1.0 to 2.0 molar equivalents relative to compound (a-5).
[0899] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0900] The reaction temperature is 0 to 80° C., preferably 0 to 20° C.
[0901] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.
[0902] The obtained desired compound (I-c) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
##STR00117##
Step 1
[0903] Compound (I-c) can be obtained by reacting compound (a-5) and compound (d-1) with a base in an appropriate solvent.
[0904] Examples of the base include triethylamine, DIEA, pyridine and the like, the base can be used in an amount of 1.0 mol equivalent or more, preferably 1.0 to 5.0 molar equivalents relative to compound (a-5).
[0905] Reaction solvents include alcohols (e.g., methanol, ethanol, tert-butanol, isopropanol, etc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), DMF, DMSO, NMP, acetonitrile, pyridine, etc., each solvent can be used alone or mixed with the others.
[0906] The reaction temperature is 0 to 120° C., preferably 0 to 80° C.
[0907] The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
[0908] The obtained desired compound (I-d) can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.) if necessary.
[0909] Since the compound according to the present invention has serotonin 5-HT2A receptor inverse agonism, the compound is useful as a therapeutic and/or prophylactic agent for a disease or condition associated with serotonin 5-IT2A receptor.
[0910] Furthermore, the compound according to the present invention has utility as a medicine, and preferably, the compound has any one or a plurality of the following excellent features.
[0911] a) Inhibitory activity against CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) is weak.
[0912] b) Satisfactory pharmacokinetics such as high bioavailability and adequate clearance are exhibited.
[0913] c) Metabolic stability is high.
[0914] d) Irreversible inhibitory activity is not exhibited against CYP enzymes (for example, CYP3A4) within the concentration range of the measurement conditions described in the present description.
[0915] e) Mutagenicity is not exhibited.
[0916] f) The cardiovascular risk is low.
[0917] g) High solubility is exhibited.
[0918] h) High binding ability for serotonin 5-HT2A is exhibited.
[0919] i) High binding ability for serotonin 5-HT2C is exhibited.
[0920] j) Brain distribution ability is high.
[0921] k) P-gp substrate property is low.
[0922] A pharmaceutical composition of the present invention can be administered orally or parenterally. Methods for parenteral administration include dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, inner ear or vaginal administration.
[0923] In the case of oral administration of pharmaceutical composition of the present invention, any forms, which are usually used, such as oral solid formulations (e.g., tablets, powders, granules, capsules, pills, or films), and oral liquid formulations (e.g., suspension, emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract, decoction, or tincture) may be prepared according to the usual method and administered. The tablets can be sugar-coated tablets, film-coated tablets, enteric-coating tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets. Powders and granules can be dry syrups. Capsules can be soft capsules, micro capsules or sustained-release capsules.
[0924] In the case of parenteral administration of pharmaceutical composition of the present invention, any forms, which are usually used, such as injections, drips, and external preparations (e.g., ophthalmic drops, nasal drops, ear drops, aerosols, inhalations, lotion, infusion, liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch, cataplasm, external powder, or suppository) can be preferably administered. Injections can be emulsions whose type is O/W, W/O, O/W/O. W/O/W or the like.
[0925] A pharmaceutical composition can be obtained by mixing an effective amount of the compound according to the present invention with various pharmaceutical additives appropriate for the dosage form, such as an excipient, a binder, a disintegrating agent, and a lubricating agent, as necessary. Furthermore, the pharmaceutical composition can be prepared into a pharmaceutical composition for use for a child, an elderly, a patient with a serious case, or a surgical operation, by appropriately changing the effective amount of the compound according to the present invention, the dosage form, and/or various pharmaceutical additives. For example, a pharmaceutical composition for use for a child may be administered to a neonate (less than 4 weeks after birth), an infant (from 4 weeks after birth to less than 1 year), a preschool child (from 1 year to less than 7 years), a child (from 7 years to less than 15 years), or a patient 15 year to 18 years of age. For example, a pharmaceutical composition for an elderly may be administered to a patient 65 years of age or older.
[0926] It is desirable to set the amount of administration of the pharmaceutical composition of the present invention, after considering the age and body weight of the patient, the type and degree of the disease, the route of administration, and the like; however, in the case of oral administration, the amount of administration is usually 0.05 to 100 mg/kg/day and is preferably in the range of 0.1 to 10 mg/kg/day. In the case of parenteral administration, the amount of administration may vary greatly depending on the route of administration; however, the amount of administration is usually 0.005 to 10 mg/kg/day and is preferably in the range of 0.01 to 1 mg/kg/day. This may be administered once a day or several times a day.
[0927] The compound according to the present invention can be used in combination with another therapeutic agent for Parkinson's disease, Alzheimer's disease, psychosis or depression (hereinafter, referred to as concomitant drug), for the purpose of enhancing the action of the compound, reducing the amount of administration of the compound, or the like. At this time, the timing of administration for the compound according to the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the target of administration or may be administered with a time difference. Furthermore, the compound according to the present invention and the concomitant drug may be administered as two or more kinds of preparations each including active ingredients, or may be administered as a single preparation including those active ingredients.
[0928] The amount of administration of the concomitant drug can be appropriately selected based on the clinically used dosage. Furthermore, the blending ratio of the compound according to the present invention and the concomitant drug can be appropriately selected according to the target of administration, the route of administration, the target disease, symptoms, combination, and the like. For example, when the target of administration is a human being, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound according to the present invention.
[0929] Examples of the therapeutic agent for Parkinson's disease include levodopa preparations.
[0930] Examples of the therapeutic agent for Alzheimer's disease include donepezil.
[0931] Examples of the therapeutic agent for psychosis include quetiapine.
[0932] Examples of the therapeutic agent for depression include escitalopram.
EXAMPLES
[0933] Hereinafter, the present invention will be described in more detail by way of Examples. Reference Examples, and Test Examples: however, the present invention is not intended to be limited by these.
[0934] Furthermore, abbreviations used in the present description denote the following meanings.
[0935] AcOH: Acetic acid
[0936] CDCl.sub.3: Deuterated chloroform
[0937] CDI: Carbonyldiimidazole
[0938] DCC: N,N′-Dicyclohexylcarbodiimide
[0939] DIC: N,N′-Diisopropylcarbodiimide
[0940] DIEA: N,N-Diisopropylethylamine
[0941] DMF: N,N-Dimethylformamide
[0942] DMSO: Dimethyl sulfoxide
[0943] EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
[0944] HATU: O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
[0945] HOAt: 1-Hydroxy-7-azabenzotriazole
[0946] HOBt: 1-Hydroxybenzotriazole
[0947] NaBH(OAc).sub.3: Sodium triacetoxyborohydride
[0948] NMP: N-Methylpyrrolidone
[0949] TFA: Trifluoroacetic acid
[0950] PyBOP (registered trademark): (Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate
(Method for Identifying Compound)
[0951] The NMR analysis obtained in each Example was performed at 400 MHz, and measurement was made using DMSO-d.sub.6, CDCl.sub.3. Furthermore, when NMR data are shown, there are occasions in which all the measured peaks are not described.
[0952] The term RT in the description indicates retention time in an LC/MS: liquid chromatography/mass analysis, and the retention time was measured under the following conditions.
[0953] (Measurement Condition 1)
[0954] Column: Shim-pack XR-ODS (2.2 μm, i.d. 3.0×50 mm) (Shimadzu)
[0955] Flow rate: 1.6 mL/min
[0956] UV detection wavelength: 254 nm
[0957] Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, and [B] was 0.1% formic acid-containing acetonitrile solution.
[0958] Gradient: A linear gradient of 10% to 100% solvent [B] was carried out for 3 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.
[0959] (Measurement Condition 2)
[0960] Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters)
[0961] Flow rate: 0.8 mL/min
[0962] UV detection wavelength: 254 nm
[0963] Mobile phase: [A] was 0.1% formic acid-containing aqueous solution, and [B] was 0.1% formic acid-containing acetonitrile solution.
[0964] Gradient: A linear gradient of 5% to 100% solvent [B] was carried out for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.
[0965] Incidentally, in the description, the description of MS(m/z) indicates a value observed by mass analysis.
Example 1
Synthesis of Compound (I-008)
[0966] ##STR00118##
Step 1 Synthesis of Compound 1
[0967] 4-Isobutoxyphenylmethaneamine (6.00 g, 33.5 mmol) and CDI (651 mg, 40.2 mmol) were dissolved in acetonitrile (60 mL) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 1 (7.92 g, yield 87%).
[0968] .sup.1H-NMR (CDCl.sub.3) δ: 1.02 (d, J=6.5 Hz, 6H), 2.00-2.14 (m, 1H), 3.68-3.77 (m, 2H), 4.49-4.59 (m, 21H), 6.03 (brs, 1H), 6.90 (d, J=7.3 Hz, 21), 7.07 (s, 1H), 7.22-7.35 (m, 3H), 8.10 (s, 1H).
Step 2 Synthesis of Compound 2
[0969] 5-Fluoropicoline aldehyde (1.00 g, 7.99 mmol) and 1-methylpiperidine 4-amine (913 mg, 7.99 mmol) were dissolved in dichloromethane (20 mL) and sodium triacetoxyborohydride (3.39 g, 16.0 mmol) and acetic acid (0.914 mL, 16.0 mmol) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford Compound 2 (970 mg, yield 55%).
[0970] .sup.1H-NMR (CDCl.sub.3) δ: 1.42-1.53 (m, 2H), 1.81-2.03 (m, 4H), 2.27 (s, 3H), 2.45-2.54 (m, 1H), 2.83 (d, J=11.8 Hz, 2H), 3.92 (s, 2H), 7.31-7.40 (m, 2H), 8.40 (d, J=2.5 Hz, 1H).
Step 3 Synthesis of Compound (I-008)
[0971] Compound 1 (673 mg, 2.46 mmol) and Compound 2 (500 mg, 2.24 mmol) were dissolved in toluene (5 mL) and stirred at 80° C., for 1 hour. After allowing to cool, the solvent was distilled off under reduced pressure, and the obtained residue was purified by amino column chromatography (hexane-ethyl acetate) to afford compound (I-008) (525 mg, yield 55%).
Example 21
Synthesis of Compound (I-042)
[0972] ##STR00119##
Step 1 Synthesis of Compound (I-042)
[0973] Compound 2 (74.4 mg, 0.333 mmol) was dissolved in N, N-dimethylformamide (1.15 ml), 4-isobutoxybenzyl (4-nitrophenyl) carbonate (74.4 mg, 0.333 mmol) and triethylamine (0.14 mL, 1.00 mmol) were added, and the mixture was stirred at 70° C., for 8 hours. Water was added and the mixture was extracted with ethyl acetate. After washing the organic layer with water, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford compound (1-042) (40 mg, yield 28%).
Example 31
Synthesis of Compound (I-050)
[0974] ##STR00120##
Step 1 Synthesis of Compound 5
[0975] To Compound 4 (300 mg, 1.33 mmol) were added dichloromethane (5 mL), (5-fluoropyridin-2-yl) methaneamine (202 mg, 1.60 mmol), AcOH (0.07 mL, 1.33 mmol), and sodium triacetoxyborohydride (423 mg, 2.00 mmol), and the mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added, and the mixture was stirred at room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to afford Compound 5 (402 mg, yield 90%).
[0976] .sup.1H-NMR (CDCl.sub.3) δ: 0.28-0.33 (m, 1H), 0.40-0.48 (m, 3H), 1.44 (s, 9H), 1.62-1.68 (m, 1H), 1.75-1.82 (m, 1H), 2.15 (t. J=3.6 Hz, 1H), 2.94-3.10 (m, 1H), 3.33-3.42 (m, 1H), 3.46-3.53 (m, 1H), 3.65-3.82 (m, 1H), 3.84 (d, J=14.4 Hz, 1H), 3.90 (d, J=14.4 Hz, 1H), 7.31-7.39 (m, 2H), 8.40 (d, J=2.6 Hz, 1H).
Step 2 Synthesis of Compound 6
[0977] To Compound 5 (150 mg, 0.45 mmol) were added acetonitrile (2 mL) and N-(4-isobutoxybenzyl)-1H-imidazole-1-carboxamide (147 mg, 0.54 mmol), and the mixture was stirred at 80° C., for 8 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 6 (195 mg, yield 81%).
[0978] .sup.1H-NMR (CDCl.sub.3) δ: 0.32-0.50 (m, 3H), 0.52-0.58 (m, 1H), 1.02 (d, J=6.8 Hz, 6H), 1.44 (9H, s), 1.56-1.62 (m, 1H), 1.69-1.76 (m, 1H), 1.80-1.91 (m, 1H), 2.04-2.11 (m, 1H), 2.80-3.01 (m, 1H), 3.06-3.48 (m, 2H), 3.70 (d, J=6.7 Hz, 2H), 5.80-6.18 (m, 1H), 6.82 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H), 7.21-7.25 (m, 1H), 7.35 (td, J=8.3, 2.8 Hz, 1H), 8.28 (s, 1H).
Step 3 Synthesis of Compound (I-051)
[0979] To Compound 6 (195 mg, 0.36 mmol) were added dichloromethane (2 mL) and TFA (0.5 mL, 6.49 mmol), and the mixture was stirred at room temperature for 3 hours. A 20% aqueous solution of potassium carbonate (4 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford compound (I-051) (152 mg, yield 96%).
[0980] 1H-NMR (CDCl3) δ: 0.28-0.32 (m, 1H), 0.39-0.42 (m, 1H), 0.42-0.48 (m, 1H), 0.57-0.62 (m, 1H), 1.01 (d, J=6.7 Hz, 6H), 1.95-2.10 (m, 3H), 2.35 (d, J=13.6 Hz, 1H), 2.87 (t, J=10.8 Hz, 1H), 3.17 (d, J=12.2 Hz, 1H), 3.28 (d, J=12.9 Hz, 1H), 3.70 (d, J=6.5 Hz, 2H), 4.24-4.57 (m, 6H), 6.05 (s, 1H), 6.82 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 7.22-7.26 (m, 1H), 7.35 (td, J=8.3, 2.9 Hz, 1H), 8.27 (d, J=2.8 Hz, 1H).
Step 4 Synthesis of Compound (I-050)
[0981] To compound (1-051) (85 mg, 0.19 mmol) were added ethanol (2 mL), 37% formaldehyde solution (0.03 mL, 0.39 mmol), and sodium triacetoxyborohydride (61 mg, 0.29 mmol), the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added, and the mixture was stirred at room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to afford compound (1-050) (80 mg, yield 91%).
Example 41
Synthesis of Compound (I-068)
[0982] ##STR00121##
Step 1 Synthesis of Compound (I-068)
[0983] Compound 2 (75.0 mg, 0.336 mmol) was dissolved in N, N-dimethylformamide (0.75 mL), and 2-(4-isobutoxyphenyl) acetic acid (84.0 mg, 0.403 mmol) (synthesis method of the compound has been described in WO2019/40104), HOBt (54.5 mg, 0.403 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (77.0 mg, 0.403 mmol) were added and the mixture was stirred at room temperature for 1.5 hours. An aqueous solution of potassium carbonate was added, and the mixture was extracted with ethyl acetate. After washing the organic layer with water, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford compound (I-068) (104 mg, yield 75%).
Reference Example 1
Synthesis of Compound 8
[0984] ##STR00122##
Step 1 Synthesis of Compound 8
[0985] To a solution of p-tolylmethaneamine (0.6 g, 5.00 mmol) in tetrahydrofuran (14 ml) was added CDI (0.97 g, 6.00 mmol), and the mixture was stirred at 45° C., for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford Compound 8 (0.66 g, yield 61%).
[0986] 1H-NMR (400 MHz, CDCl3) δ: 1.60 (s, 3H), 2.34 (s, 3H), 4.56 (d, J=5.5 Hz, 2H), 6.06 (s, 1H), 7.07 (s, 1H), 7.19 (d, J=7.9 Hz, 2H), 7.22-7.26 (m, 2H), 7.31 (s, 1H), 8.09 (s, 1H).
Example 5
Synthesis of Compound (I-120)
[0987] ##STR00123##
Step 1 Synthesis of Compound 9
[0988] Under ice-cooling, to (S)-1-phenethyl-1-amine (1.29 g, 10.7 mmol) were added dichloromethane (30 mL), triethylamine (5.39 g, 53.3 mmol), titanium tetrachloride (4.44 ml, 4.44 mmol) and compound 4 (2 g, 8.88 mmol), and the mixture was stirred at room temperature for 18 hours. Diethyl ether (60 ml) was added and the mixture was stirred at room temperature for 30 minutes. After removing the resulting solid by filtration, the solvent was removed under reduced pressure to afford Compound 9 (2.8 g, yield 96%).
Step 2 Synthesis of Compound 10
[0989] To a solution of Compound 9 (2.8 g, 8.52 mmol) in ethanol (28 ml) was added sodium borohydride (0.16 g, 4.26 mmol) at −78° C., and the mixture was stirred at −78° C., for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to afford Compound 10 (2.1 g, yield 75%).
[0990] .sup.1H-NMR (CDCl.sub.3) δ: 0.29-0.50 (m, 4H), 1.30 (d, J=6.4 Hz, 2H), 1.42 (s, 9H), 1.45-1.70 (m, 2H), 2.18 (s, 1H), 2.92-3.06 (s, 1H), 3.28-3.49 (m, 3H), 3.83 (q. J=6.6 Hz, 1H), 7.22 (dd, J=8.7, 4.5 Hz, 1H), 7.30 (d, J=4.3 Hz, 4H).
Step 3 Synthesis of Compound 11
[0991] To Compound 10 (157 mg, 0.48 mmol) were added methanol (1.6 mL), ammonium formate (150 mg, 2.38 mmol), and palladium hydroxide on carbon (40 mg, 0.14 mmol), and the mixture was stirred at 60° C., for 1 hour. After the reaction solution was filtered to remove palladium hydroxide on carbon, the solvent was removed under reduced pressure to afford Compound 11 (102 mg, yield 95%).
[0992] 1H-NMR (CDCl.sub.3) δ: 0.32-0.50 (m, 4H), 1.45 (s, 9H), 1.50-1.62 (m, 1H), 1.80-1.88 (m, 1H), 2.62 (dd, J=10.0, 6.4 Hz, 1H), 3.05 (d, J=12.2 Hz, 1H), 3.41 (d, J=13.6 Hz, 1H), 3.45-3.62 (m, 2H).
Step 4 Synthesis of Compound 12
[0993] Compound 12 was obtained by using Compound 11 (49 mg, 0.22 mmol) instead of 1-methylpiperidine 4-amine in Step 2 of Example 1.
Step 5 Synthesis of Compound 13
[0994] Compound 13 was obtained by using Compound 12 instead of Compound 5 and Compound 8 instead of N-(4-isobutoxybenzyl)-1H-imidazole-1-carboxamide in Step 2 of Example 3.
Step 6 Synthesis of Compound 14
[0995] Compound 14 was obtained by using Compound 13 instead of compound 6 in Step 3 of Example 3.
Step 7 Synthesis of 1-120
[0996] Compound (I-120) (38 mg, total yield of 4 steps 53%) was obtained by using Compound 14 instead of Compound (I-051) in step 4 of Example 3.
Example 61
Synthesis of Compound (I-136)
[0997] ##STR00124##
Step 1 Synthesis of Compound 16
[0998] To Compound 15 (500 mg, 3.02 mmol) were added ethanol (5 mL), methyl acrylate (0.03 mL, 3.02 mmol) and triethylamine (0.42 mL, 3.02 mmol), and the mixture was stirred at room temperature for 48 hours. The solvent was evaporated under reduced pressure to afford Compound 16 (654 mg, 101% yield) as a crude product.
Step 2 Synthesis of Compound 17
[0999] To Compound 16 (654 mg, 3.02 mmol) were added methanol (5 mL), 37% formaldehyde solution (0.67 mL, 9.06 mmol) and NaBH(OAc).sub.3 (61 mg, 0.29 mmol), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added, and the mixture was stirred at room temperature. Water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford compound 17 (687 mg, 99% yield) as a crude product.
Step 3 Synthesis of Compound 18
[1000] To Compound 17 (195 mg, 0.36 mmol) were added toluene (7 mL) and 28% sodium methoxide solution (2.2 mL, 8.87 mmol), and the mixture was stirred at reflux for 4 hours. After distilling off the solvent under reduced pressure, methanol (3 mL) and water (3 mL) were added, and the mixture was stirred at reflux for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford Compound 18 (432 mg, yield 105%) as a crude product.
Step 4 Synthesis of Compound 19
[1001] To Compound 18 (132 mg, 0.95 mmol) were added dichloromethane (5 mL), (5-fluoropyridin-2-yl)methaneamine (120 mg, 0.95 mmol), AcOH (0.07 mL, 1.14 mmol) and NaBH(OAc).sub.3 (241 mg, 1.14 mmol), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added, and the mixture was stirred at room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford compound 19 (157 mg, 67% yield) as a crude product.
Step 5 Synthesis of Compound (I-136)
[1002] To Compound 19 (18 mg, 0.07 mmol) were added acetonitrile (0.2 mL) and N-(4-isobutoxybenzyl)-1H-imidazole-1-carboxamide (22 mg, 0.08 mmol), the mixture was stirred at 80° C., for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound (1-136) (22 mg, yield 67%).
[1003] 1H-NMR (CDCl3) δ: 0.30-0.36 (m, 1H), 0.43-0.48 (m, 1), 0.58-0.71 (m, 2H), 1.02 (d, 6H, J=6.5 Hz), 1.37-1.47 (m, 1H), 1.86-1.97 (m, 1H), 2.03-2.10 (m, 1H), 2.21-2.37 (m, 4H), 2.85-2.99 (m, 2H), 3.70 (d, 2H, J=5.0 Hz), 4.33 (t, 2H, J=4.5 Hz), 4.42 (s, 3H), 6.20 (br s, 1H), 6.82 (d, 2H, J=8.0 Hz), 7.15 (d, 2H, J=8.0 Hz), 7.28-7.40 (m, 2H), 8.29 (s, 1H).
Example 71
Synthesis of Compound (I-139)
[1004] ##STR00125##
Step 1 Synthesis of Compound 21
[1005] To Compound 20 (300 mg, 1.37 mmol) were added dichloromethane (5 mL), 1,5-dimethyl-1H-pyrazolecarbaldehyde (171 mg, 1.37 mmol), AcOH (0.39 mL, 6.87 mmol), and NaBH(OAc).sub.3 (583 mg, 2.75 mmol), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was stirred at room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to afford Compound 21 (359 mg, yield 80%).
[1006] .sup.1H-NMR (CDCl.sub.3) δ: 1.45 (s, 9H), 1.59-1.81 (m, 2H), 2.24 (s, 311), 2.69-3.02 (m, 2H), 3.72 (s, 3H), 3.72 (s, 3H), 3.80 (s, 2H), 3.69-4.20 (m, 1H), 4.23-4.42 (m, 1H), 4.69-4.81 (m, 1H), 5.96 (s, 1H).
Step 2 Synthesis of Compound 22
[1007] To Compound 21 (142 mg, 0.44 mmol) were added acetonitrile (3 mL) and N-(4-normalpropoxybenzyl)-1H-imidazole-1-carboxamide (113 mg, 0.44 mmol), and the mixture was stirred at 80° C., for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to afford compound 22 (195 mg, yield 81%).
[1008] .sup.1H-NMR (CDCl.sub.3) δ: 1.03 (t, 3H, J=7.4 Hz), 1.47 (s, 9H), 1.56-1.65 (m, 1H), 1.75-1.84 (m, 1H), 2.15-2.24 (m, 4H), 2.75-3.10 (m, 2H), 3.56 (s, 3H), 3.90 (t, 2H, J=6.6 Hz), 4.25-4.42 (m, 5H), 4.74-4.63 (m, 1H), 4.76-4.89 (m, 1H), 5.92 (s, 1H), 5.92 (s, 1H), 6.82 (d, J=8.5 Hz, 21), 7.15 (d, J=8.5 Hz, 2H).
Step 3 Synthesis of Compound 23
[1009] To Compound 22 (80 mg, 0.36 mmol) were added dichloromethane (1 mL), 2,6-lutidine (0.08 mL, 0.695 mmol), trimethylsilyl triflate (0.08 mL, 0.695 mmol), and the mixture was stirred at room temperature for 10 minutes. A 20% aqueous solution of potassium carbonate (4 mL) was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to afford Compound 23 (52 mg, yield 80%).
[1010] 1H-NMR (CDCl3) δ: 1.01 (6H, d, J=6.8 Hz), 1.62 (1H, br s), 2.02-2.12 (2H, m), 2.21 (3H, s), 2.74-2.92 (2H, m), 3.24 (2H, dd, J=29.7, 14.9 Hz), 3.57 (3H, s), 3.69 (2H, d, J=6.5 Hz), 4.30-4.34 (4H, m), 4.57 (1H, dt, J=35.4, 6.4 Hz), 4.78 (1H, d, J=50.8 Hz), 5.92 (1H, s), 6.82 (1H, br s), 6.81 (2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.5 Hz).
Step 4 Synthesis of Compound (I-139)
[1011] To Compound 23 (30 mg, 0.19 mmol) were added methanol (1 ml), 37% formaldehyde solution (0.03 mL, 0.36 mmol) and NaBH(OAc).sub.3 (45 mg, 0.22 mmol), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was stirred at room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (hexane-ethyl acetate) to afford compound (I-139) (20 mg, yield 66%).
[1012] 1H-NMR (CDCl3) δ: 1.03 (t, 3H, J=7.5 Hz), 1.61-1.68 (m, 1H), 1.75-1.84 (m, 2H), 2.15-2.37 (m, 9H), 3.00 (d, 1H, J=10.8 Hz), 3.14 (t, 1H, J=11.9 Hz), 3.56 (s, 3H), 3.90 (t, 2H, J=6.7 Hz), 4.26-4.51 (m, 5H), 4.79-4.91 (m, 1H), 5.93 (br s, 1H), 6.70 (br s, 1H), 6.81 (d, 2H, J=8.5 Hz), 7.15 (d, 2H, J=8.5 Hz).
[1013] The following compounds were synthesized according to the above general synthetic method and the method described in Examples. The structure and physical properties (LC/MS data) are shown in the table below.
[1014] Incidentally, in the structural formula, “wedge shape” and “dashed line” indicate the configuration. Particularly, with regard to compounds whose configurations are described, a compound described as “racemate” in the item of “Configuration” is a racemic compound whose relative configuration has been specified.
[1015] In addition, with regard to compounds in which the bonds forming an asymmetric carbon are described by solid lines, a compound described as “racemate” in the item of “Configuration” is a racemic compound.
[1016] A compound described as “diastereo mixture” in the item of “Configuration” is diastereomer mixture.
TABLE-US-00001 TABLE 1 LC/MS Retention Compound Measurement time Configu- No. Structure condition (min) m/z ration I-001
TABLE-US-00002 TABLE 2 I-007
TABLE-US-00003 TABLE 3 I-014
TABLE-US-00004 TABLE 4 I-021
TABLE-US-00005 TABLE 5 I-028
TABLE-US-00006 TABLE 6 I-035
TABLE-US-00007 TABLE 7 I-042
TABLE-US-00008 TABLE 8 I-049
TABLE-US-00009 TABLE 9 I-056
TABLE-US-00010 TABLE 10 I-063
TABLE-US-00011 TABLE 11 I-069
TABLE-US-00012 TABLE 12 I-077
TABLE-US-00013 TABLE 13 I-085
TABLE-US-00014 TABLE 14 I-092
TABLE-US-00015 TABLE 15 I-099
TABLE-US-00016 TABLE 16 I-107
TABLE-US-00017 TABLE 17 I-114
TABLE-US-00018 TABLE 18 I-122
TABLE-US-00019 TABLE 19 I-128
TABLE-US-00020 TABLE 20 I-136
TABLE-US-00021 TABLE 21 I-144
TABLE-US-00022 TABLE 22 Compound No. NMR I - 001 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.55-1.82 (m, 4H), 2.03-2.13 (m, 3H), 2.28 (s, 3H), 2.89 (d, J = 10.3 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.26-4.38 (m, 5H), 6.82 (d, J = 8.5 Hz, 2H), 7.07 (s, 1H), 7.15-7.22 (m, 3H), 7.26-7.29 (m, 1H), 7.65 (t, J = 7.2 Hz, 1 H), 8.42 (d, J = 4.1 Hz, 1H). I - 002 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.8 Hz, 6H), 1.56-1.75 (m, 4H), 2.01-2.10 (m, 3H), 2.25 (s, 3H), 2.86 (d, J = 11.4 Hz 2H), 3.68 (d, J = 6.5 Hz, 2H), 4.12-4.22 (m, 1H), 4.32 (d, J = 5.1 Hz, 2H), 4.43 (s, 2H), 4.47-4.51 (m, 1H), 6.80 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 7.23 (dd, J = 7.7, 5.2 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 8.50 (s, 2H). I - 003 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.56-1.74 (m, 4H), 2.02-2.09 (m, 3H), 2.25 (s, 3H), 2.85 (d, J = 11.5 Hz, 2H), 3.68 (d, J = 6.5 Hz, 2H), 4.15-4.24 (m, 1H), 4.32 (d, J = 5.1 Hz, 2H), 4.38-4.45 (m, 3H), 6.80 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 7.15 (m, J = 5.3 Hz, 2H), 8.53 (d, J = 5.8 Hz, 2H). I - 004 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.57-1.66 (m, 2H), 1.74-1.86 (m, 2H), 2.00-2.10 (m, 3H), 2.26 (s, 3H), 2.87 (d, J = 10.9 Hz, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.18-4.28 (m, 1H), 4.36 (d, J = 5.3 Hz, 2H), 4.53 (s, 2H), 6.67 (s, 1H), 6.83 (d, J = 8.5 Hz, 2H), 7.18 (t, J = 4.9 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 8.63 (d, J = 4.9 Hz, 2H). I - 005 1H-NMR (CDCl3) δ: 1.01 (d, J = 8.8 Hz, 6H), 1.59-2.14 (m, 7H), 2.27 (s, 3H), 2.89 (d, J = 11.5 Hz, 2H), 3.68 (d, J = 6.5 Hz, 2H), 4.12-4.26 (m, 1H), 4.33 (d, J = 5.3 Hz, 2H), 4.64 (s, 2H), 6.11 (s, 1H), 6.82 (d, J = 9.3 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.39-7.55 (m, 2H), 9.10 (dd, J = 4.8, 1.5 Hz, 2H). I - 006 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.67-1.80 (m, 4H), 2.00-2.12 (m, 3H), 2.27 (s, 3H), 2.89 (d, J = 11.7 Hz, 2H), 3.70 (d, J = 6.7 Hz, 2H), 4.16-4.24 (m, 1H), 4.36 (d, J = 5.3 Hz, 2H), 4.46 (s, 2H), 6.36 (s, 1H), 6.84 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 8.40-8.43 (m, 1H). 8.49 (d, J = 2.5 Hz, 1H), 8.61 (d, J = 1.4 Hz, 1H) I - 007 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.8 Hz, 6H), 1.65-1.74 (m, 4H), 1.96-2.12 (m, 3H), 2.25 (s, 3H), 2.87 (d, J = 11.8 Hz, 2H), 3.70 (d, J = 6.5 Hz, 2H), 3.76-3.84 (m, 1H), 4.37 (d, J = 5.1 Hz, 2H), 4.48 (s, 2H), 4.56-4.64 (m, 1H), 6.85 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 8.66 (s, 2H), 9.11 (s, 1H). I - 008 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.8 Hz, 6H), 1.59-1.78 (m, 4H), 2.01-2.10 (m, 3H), 2.27 (s, 3H), 2.88 (d, J = 11.8 Hz, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.23- 4.35 (m, 3H), 4.37 (s, 2H), 6.61 (brs, 1H), 6.33 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.24-7.30 (m, 1H), 7.36 (td, J = 8.3, 2.8 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H). I - 009 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.7 Hz, 6H), 1.64-1.75 (m, 4H), 2.02-2.12 (m, 3H), 2.27 (s, 3H), 2.88 (d, J = 11.7 Hz, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.23-4.31 (m, 1H), 4.33 (d, J = 5.3 Hz, 2H), 4.37 (s, 2H), 6.46 (s, 1H), 6.83 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3, 2.5 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H). I - 010 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.5 Hz, 6H), 1.59-1.82 (m, 4H), 2.01-2.13 (m, 3H), 2.28 (s, 3H), 2.89 (d, J = 11.3 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 3.83 (s, 3H), 4.31 (s, 3H), 4.34 (d, J = 5.3 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 7.07 (brs, 1H), 7.12-7.22 (m, 4H), 8.07 (d, J = 2.5 Hz, 1H).
TABLE-US-00023 TABLE 23 I - 011 1H-NMR (400 MHz, d6-DMSO) δ 0.97 (d, J = 6.7 Hz, 6H), 1.51 (m, 4H), 1.92 (m, 2H), 2.00 (td, J = 13.3 Hz, 6.7 Hz, 1H), 2.10 (s, 3H), 2.71 (d, J = 11.4 Hz, 2H), 3.70 (d, J = 6.7 Hz, 2H), 3.93 (m, 1H), 4.17 (d, J = 5.6 Hz, 2H), 4.54 (s, 2H), 6.84 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 5.6 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.2 Hz, 1H), 8.23 (dd, J = 11.3 Hz, 4.0 Hz, 1H), 8.94 (d, J = 1.5 Hz, 1H) I - 012 1H-NMR (400 MHz, CDCl3) δ 1 01 (d, J = 6.7 Hz 6H), 1.57-1.77 (m, 4H), 2.02- 2.12 (m, 3H), 2.27 (s, 3H), 2.89 (d, J = 11.5 Hz, 2H), 3.69 (d, J = 6.3 Hz, 2H), 4.19-4.29 (m, 1H), 4.34 (d, J = 5.3 Hz, 2H), 4.47 (s, 2H), 6.25 (br, s, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.88 (dd, J = 8.5 Hz, 1.7 Hz, 1H), 8.69 (s, 1H) I - 013 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.8 Hz, 6H), 1.64-1.79 (m, 4H), 2.03-2.10 (m, 3H), 2.27 (s, 3H), 2.30 (s, 3H), 2.88 (d, J = 11.5 Hz, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.27-4.34 (m, 5H), 6.81 (d, J = 8.8 Hz, 2H), 7.13-7.19 (m, 4H), 7.44 (dd, J = 7.9, 1.8 Hz, 1H), 8.22 (d, J = 1.9 Hz, 1H). I - 014 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.7 Hz, 6H), 1.60-1.78 (m, 4H), 2.02-2.10 (m, 3H), 2.26 (s, 3H), 2.87 (d, J = 11.5 Hz, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.19 (tt, J = 12.0, 4.0 Hz, 1H), 4.36 (d, J = 5.3 Hz, 2H), 4.46 (s, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.95 (s, 1H), 7.17-7.20 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 8.15 (d, J = 2.3 Hz, 1H). I - 015 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.58-1.67 (m, 4H), 2.00-2.12 (m, 3H), 2.24 (s, 3H), 2.84 (d, J = 11.8 Hz, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.12-4.19 (m, 1H), 4.35 (d, J = 5.4 Hz, 2H), 4.57 (s, 2H), 5.95 (s, 1H), 6.84 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.45 (dd, J = 7.7, 2.6 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H). I - 016 1H-NMR (400 MHz, d6-DMSO) δ 0.96 (d, J = 6.8 Hz, 6H), 1.51 (m, 4H), 1.87 (m, 2H), 1.99 (m, 1H), 2.10 (s, 3H), 2.71 (d, J = 11.4 Hz, 2H), 3.70 (d, J = 6.6 Hz, 2H), 3.94 (m, 1H), 4.17 (d, J = 5.5 Hz, 2H), 4.55 (s, 2H), 6.84 (d, J = 8.7 Hz, 2H), 7.03 (t, J = 5.6 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 7.37 (m, 1H), 7.67 (t, J = 9.3 Hz, 1H), 8.36 (d, J = 4.6 Hz, 1H) I - 017 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.8 Hz, 6H), 1.65-1.75 (m, 4H), 2.01-2.13 (m, 3H), 2.28 (s, 3H), 2.89 (d, J = 11.7 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.22- 4.32 (m, 1H), 4.34 (d, J = 5.3 Hz, 2H), 4.39 (s, 2H), 6.62 (brs, 1H), 6.89-6.95 (m, 1H), 7.02 (d, J = 9.2 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.24-7.30 (m, 1H), 7.36 (td, J = 8.3, 2.8 Hz, 1H), 8.39 (dd, J = 8.3, 5.6 Hz, 1H). I - 018 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.64-1.73 (m, 4H), 2.02-2.11 (m, 3H), 2.26 (s, 3H), 2.87 (d, J = 11.5 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.29- 4.30 (m, 1H), 4.30-4.39 (m, 3H), 6.06 (brs, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.12- 7.17 (m, 3H), 7.69-7.79 (m, 1H). I - 019 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.83-1.91 (m, 2H), 2.45-2.51 (m, 2H), 2.76 (s, 3H), 2.93-3.05 (m, 2H), 3.47 (d, J = 12.9 Hz, 2H), 3.68 (d, J = 6.5 Hz, 2H), 4.30 (d, J = 5.4 Hz, 2H), 4.49 (d, J = 9.0 Hz, 2H), 4.67 (s, 1H), 5.14 (s, 1H), 6.80 (d, J = 8.7 Hz, 2H), 6.88 (dd, J = 8.5, 2.8 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 7.71 (1, J = 6.8 Hz, 1H), 8.12 (s, 1H). I - 020 1H-NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.5 Hz, 6H), 1.64-1.77 (m, 4H), 1.92- 2.06 (m, 3H), 2.19 (s, 3H), 2.80 (d, J = 12.0 Hz, 2H), 3.63 (d, J = 6.8 Hz, 2H), 4.08-4.29 (m, 1H), 4.28 (d, J = 5.5 Hz, 2H), 4.46 (s, 2H), 6.26 (br, 1H), 6.76 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 8.41 (s, 2H)
TABLE-US-00024 TABLE 24 I - 021 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.3 Hz, 6H), 1.68-1.85 (m, 4H), 2.02-2.14 (m, 3H), 2.28 (s, 3H), 2.91 (d, J = 11.7 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 3.73 (s, 3H), 4.21 (s, 2H), 4.30-4.40 (m, 3H), 6.10 (d, J = 2.3 Hz, 1H), 6.22 (brs, 1H), 6.81 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 2.3 Hz, 1H). I - 022 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.64-1.77 (m, 4H), 1.92- 2.06 (m, 3H), 2.26 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.63 (d, J = 6.5 Hz, 2H), 3.81 (s, 3H), , 4.20 (s, 2H) 4.25 (m, 1H), 4.28 (d, J = 5.3 Hz, 2H), 4.64. (br t, J = 4.8 Hz 1H), 6.81 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.15 (s, 1H), 7.33 (s, 1H) I - 023 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.56-1.77 (m, 4H), 1.97- 2.11 (m, 3H), 2.26 (s, 3H), 2.86 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 3.77 (s, 3H), 4.02-4.18(m, 1H), 4.32 (d, J = 5.3 Hz, 2H), 4.36 (s, 2H), 4.60. (t, J = 5.7 Hz 1H), 6.08 (s, 1H) 6.81 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 1.77 Hz, 1H) I - 024 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.66-1.78 (m, 4H), 1.98- 2.14 (m, 3H), 2.26 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.64 (s, 3H) 3.69 (d, J = 6.5 Hz, 2H), 4.03-4.17(m, 1H), 4.33 (d, J = 5.3 Hz, 2H), 4.39 (s, 2H), 4.89 (t, J = 5.7 Hz, 1H), 6.77 (d, J = 1.0 Hz, 1H), 6.91 (d, t = 1.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H) I - 025 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.60-1.86 (m, 4H), 1.98-2.14 (m, 3H), 2.27 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.62 (s, 3H) 3.69 (d, J = 6.5 Hz, 2H), 4.18 (s, 2H), 4.24-4.34(m, 1H), 4.35 (d, J = 5.3 Hz, 2H), 6.67 (s, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 9.50 (br, 1H) I - 026 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.61-1.89 (m, 4H), 1.98- 2.11 (m, 3H), 2.27 (s, 3H), 2.90 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 3.97-4.49(m, 5H), 6.18 (s, 1H), 6.81 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 2.0 Hz, 2H) I - 027 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.61-1.76 (m, 4H), 1.98- 2.11 (m, 3H), 2.27 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.54 (s, 3H), 3.69 (d, J = 6.5 Hz, 2H), 4.16 (s, 2H), 4.26 (d, J = 5.3 Hz, 2H), 4.33-4.42(m, 1H), 4.94 (t, J = 5.3 Hz, 1H), 5.95 (t, J = 2.0 Hz, 1H), 6.37 (br, s, 1H), 6.54 (t, J = 2.0 Hz, 1H), 6.78 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H) I - 028 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.61-1.76 (m, 4H), 1.98- 2.11 (m, 3H), 2.27 (s, 3H), 2.86 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.22-4.34(m, 5H), 4.89 (t, J = 5.7 Hz, 1H), 5.96 (br, s, 1H), 6.01 (1, J = 2.5 Hz, 1H), 6.55 (t, J = 2.5 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H) I - 029 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.61-1.82 (m, 4H), 1.98- 2.11 (m, 3H), 2.27 (s, 3H), 2.89 (d, J = 12.0 Hz, 2H), 3.50 (s, 3H), 3.69 (d, J = 6.5 Hz, 2H), 4.21-4.34(m, 1H), , 4.30 (d, J = 5.3 Hz, 2H), 4.50 (s, 2H), 4.73 (t, J = 5.5 Hz, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.87-6.94 (m, 2H), 7.03 (d, J = 8.5 Hz, 2H), 7.21(d, J = 5.0 Hz, 1H) I - 030 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.65-1.81 (m, 4H), 1.98- 2.13 (m, 3H), 2.27 (s, 3H), 2.42 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.24-4.34(m, 1H), 4.29 (d, J = 5.3 Hz, 2H), 4.40 (s, 2H), 4.78 (t, J = 5.7 Hz, 1H), 6.53 (d, J = 3.3 Hz, 1H), 6.66 (d, J = 3.3 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H)
TABLE-US-00025 TABLE 25 I - 031 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.65-1.81 (m, 4H), 1.98- 2.13 (m, 3H), 2.16 (s, 3H), 2.27 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.24-4.34(m, 1H), 4.29 (d, J = 5.3 Hz, 2H), 4.42 (s, 2H), 4.74 (t, J = 6.5 Hz, 1H), 6.68 (s, 1H), 6.77 (s, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H) I - 032 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.71-1.82 (m, 4H), 2.00- 2.14 (m, 3H), 2.29 (s, 3H), 2.91 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.20-4.31(m, 1H), 4.35 (d, J = 5.3 Hz, 2H), 4.59 (s, 2H), 6.18 (t, J = 4.8 Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 3.5 Hz, 1H), 7.66 (d, J = 3.5 Hz, 1H) I - 033 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.64-1.85 (m, 4H), 1.92- 2.13 (m, 3H), 2.54 (s, 3H), 2.90 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 3.81 (s, 3H), 4.11-4.27(m, 1H), 4.35 (d, J = 5.3 Hz, 2H), 4.38 (s, 2H), 5.96 (t, J = 4.8 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 7.03 (s, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.58 (s, 1H), I - 034 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.7 Hz, 6H), 1.70-1.74 (m, 4H), 1.99- 2.12 (m, 3H), 2.28 (s, 3H), 2.88 (d, J = 11.8 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 3.84-3.96 (m, 1H), 4.36 (d, J = 5.3 Hz, 2H), 4.55-4.63 (m, 1H), 4.66 (s, 2H), 6.83 (d, J = 6.7 Hz, 2H), 7.01 (s, 1H), 7.14 (d, J = 8.5 Hz, 2H), 8.35 (d, J = 1.5 Hz, 1H). I - 035 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.68-1.80 (m, 4H), 1.98- 2.13 (m, 3H), 2.28 (s, 3H), 2.39 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.15-4.26(m, 1H), 4.29 (s, 2H), 4.31 (d, J = 5.3 Hz, 2H), 5.30 (br, 1H), 5.91 (s, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H) I - 036 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.5 Hz, 6H), 1.64-1.85 (m, 4H), 1.98- 2.13 (m, 3H), 2.26 (s, 3H), 2.54 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.71 (d, J = 6.5 Hz, 2H), 3.81 (s, 3H), 4.38 (s, 2H), 4.06-4.19(m, 1H), 4.35 (d, J = 5.3 Hz, 2H), 4.38 (s, 2H), 5.81 (t, J = 4.7 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H) I - 037 1H-NMR (400 MHz, CDCl3) δ 1.02 (d, J = 6.7 Hz, 6H), 1.68-1.87 (m, 4H), 1.99- 2.14 (m, 3H), 2.29 (s, 3H), 2.91 (d, J = 12.0 Hz, 2H), 3.66 (d, J = 6.5 Hz, 2H), 4.30-4.42 (m, 1H), 4.36 (d, J = 5.2 Hz, 2H), 4.53 (s, 2H), 6.75 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 5.5 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.49-7.56 (m, 1H), 7.60-7.69 (m, 2H), 7.79 (d, J = 8.3, 1H), 8.13 (d, J = 8.3, 1H) I - 038 1H-NMR (400 MHz, CDCl3) δ 1.03 (d, J = 6.7 Hz, 6H), 1.50-1.87 (m, 4H), 1.99- 2.14 (m, 3H), 2.23 (s, 3H), 2.81 (d, J = 12.0 Hz, 2H), 3.66 (d, J = 6.5 Hz, 2H), 4.20-4.31 (m, 1H), 4.39 (d, J = 5.2 Hz, 2H), 4.98 (s, 2H), 6.75 (br, 1H)), 6.82 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 5.5 Hz, 1H), 7.64 (t, J = 8.3 Hz, 1H), 7.71 (t, J = 8.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 8.21 (d, J = 8.3, 1H), 8.38 (d, J = 5.5, 1H) I - 039 1H-NMR (400 MHz, CDCl3) δ 0.99 (d, J = 6.7 Hz, 6H), 1.62-1.86 (m, 4H), 1.99- 2.12 (m, 3H), 2.23 (s, 3H), 2.84 (d, J = 10.7 Hz, 2H), 3.76 (d, J = 6.5 Hz, 2H), 4.31 (d, J = 5.2 Hz, 2H), 4.40-4.51 (m, 1H), 4.53 (t, J = 5.2 Hz, 1H), ), 4.99 (s, 2H), 6.76 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.61 (t, J = 8.3 Hz, 1H), 7.68 (d, J = 5.8 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 8.59 (d, J = 5.8 Hz, 1H), 9.39 (s, 1H)
TABLE-US-00026 TABLE 26 I - 040 1H-NMR (400 MHz, CDCl3) δ 1.03 (d, J = 6.7 Hz, 6H), 1.50-1.87 (m, 4H), 1.99- 2.14 (m, 3H), 2.23 (s, 3H), 2.86 (d, J = 12.0 Hz, 2H), 3.66 (d, J = 6.5 Hz, 2H), 4.27 (d, J = 5.2 Hz, 2H), 4.40-4.55 (m, 1H), 5.03 (s, 2H), 5.63 (t, J = 5.5 Hz, 1H)), 6.72 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 7.38 (dd, J = 8.3, 4.3 Hz, 1H), 7.49 (t, J = 8.3 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 8.28 (dd, J = 8.3, 2.0 Hz, 1H), 8.68 (dd, J = 4.3, 2.0, 1H) I - 041 1H-NMR (400 MHz, CDCl3) δ 1.02 (d, J = 6.7 Hz 6H), 1.50-1.61 (m, 4H), 1.84- 2.14 (m, 3H), 2.23 (s, 3H), 2.86 (d, J = 12.0 Hz, 2H), 3.31-3.43 (m, 1H), 3.71 (d, J = 6.5 Hz, 2H), 4.45 (d, J = 5.2 Hz, 2H), 4.80 (s, 2H), 4.87 (t, J = 5.5 Hz, 1H), , 6.51 (t, J = 2.3 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 6.92-7.09 (m, 2H), 7.14- 7.20 (m, 3H), 7.56 (d, J = 8.3 Hz, 1H), 10.5 (s, 1H) I - 042 1H-NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.7 Hz, 6H), 1.51-2.2 (m, 7H), 2.23 (s, 3H), 2.82 (d, J = 11.4 Hz, 2H), 3.64-76 (m, 2H), 4.06-4.22 (m, 1H), 4.39- 4.63 (m, 2H), 4.95-5.22 (m, 2H), 6.65-7.37 (m, 6H), 8.33 (s, 1H) I - 043 1H-NMR (CDCl3) δ: 1.57-1.80 (m, 4H), 2.07 (td, J = 11.5, 2.7 Hz, 2H), 2.28 (s, 3H), 2.88 (d, J = 11.7 Hz, 2H), 3.79 (s, 3H), 4.24-4.36 (m, 3H), 4.37 (s, 2H), 6.65 (brs, 1H), 6.84 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.26-7.31 (m, 1H), 7.36 (td, J = 8.3, 2.8 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H). I - 044 1H-NMR (400 MHz, d6-DMSO) δ 1.43 (d, J = 9.5 Hz, 2H), 1.53 (q, J = 10.2 Hz, 2H), 1.88 (t, J = 10.7 Hz, 2H), 2.71 (d, J = 11.8 Hz, 2H), 3.12 (t, J = 8.7 Hz, 3H), 3.92 (m, 1H), 4.11 (d, J = 5.9 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H), 4.46 (s, 3H), 4.48 (t, J = 8.7 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 7.9, 1H), 7.00 (t, J = 5.7, 1H), 7.05 (s, 1H), 7.31 (dd, J = 8.5 Hz, 4.5 Hz, 1H), 7.66 (td, J = 8.8 Hz, 2.8 Hz, 1H), 8.46 (d, J = 2.9 Hz, 1H) I - 045 1H-NMR (400 MHz, d6-DMSO) δ 1.43 (d, J = 10.4 Hz, 2H), 1.53 (q, J = 12.0 Hz, 2H), 1.87 (m, 4H), 2.10 (s, 3H), 2.69 (m, 4H), 3.92 (m, 1H), 4.07 (dd, J = 13.6 Hz, 8.7 Hz, 2H), 4.13 (d, J = 5.4 Hz, 2H), 4.45 (s, 2H), 6.63 (d, J = 8.3 Hz, 1H), 6.85 (s, 1H), 6.90 (d, J = 8.4, 1H), 6.98 (d, J = 5.0, 1H), 7.32 (dd, J = 8.7 Hz, 4.6 Hz, 1H), 7.67 (td, J = 8.8 Hz, 2.8 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H) I - 046 1H-NMR (CDCl3) δ: 0.34 (d, J = 3.8 Hz, 2H), 0.64 (d, J = 7.4 Hz, 2H), 1.25 (1H, m), 1.63-1.79 (m, 4H), 2.07 (t, J = 11.0 Hz, 3H), 2.27 (s, 3H), 2.89 (d, J = 10.9 Hz, 2H), 3.78 (d, J = 6.9 Hz, 2H), 4.23-4.39 (m, 5H), 6.65 (s, 1H), 6.83 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 8.0 Hz, 1H), 8.26 (s, 1H). I - 047 1H-NMR (CDCl3) δ: 1.03 (t, J = 7.4 Hz, 3H), 1.64-1.84 (m, 6H), 2.07 (t, J = 10.2 Hz, 3H), 2.28 (s, 3H), 2.88 (d, J = 11.2 Hz, 2H), 3.90 (t, J = 6.6 Hz, 2H), 4.26- 4.38 (m, 5H), 6.61 (s, 1H), 6.83 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 8.4 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H). I - 048 1H-NMR (400 MHz, d6-DMSO) δ 1.50 (m, 4H), 1.87 (t, J = 10.7 Hz, 2H), 2.10 (s, 3H), 2.71 (d, J = 10.2 Hz, 2H), 3.91 (m, 1H), 4.24 (d, J = 4.9 Hz, 2H), 4.47 (s, 2H), 6.63 (d, J = 8.3 Hz, 1H), 7.14 (m, 3H), 7.31 (m, 4H), 7.67 (t, J = 7.3 Hz, 1H), 8.48 (s, 1H) I - 049 1H-NMR (CDCl3) δ: 1.01 (t, J = 6.8 Hz, 6H), 1.74-1.81(m 1H), 2.04-2.40 (m, 5H), 2.37(s, 3H), 2.97 (d, J = 11.7 Hz, 1H), 3.06-3.12 (m, 1H), 3.70 (d, J = 6.5 Hz, 2H), 4.32 (d, J = 5.1 Hz, 2H), 4.54 (s, 2H), 4.81-4.93 (m, 1H), 6.81 (dd, J = 8.5 Hz, 2H), 6.89 (s, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.34-7.40 (m, 2H), 8.22 (d, J = 2.1 Hz, 1H).
TABLE-US-00027 TABLE 27 I - 050 1H-NMR (CDCl3) δ: 0.21-0.26 (m, 1H), 0.44-0.47 (m, 2H), 0.51-0.55 (m, 1H), 1.01 (t, J = 6.7 Hz, 6H), 1.72 (dd, J = 11.8, 3.0 Hz, 2H), 1.98-2.12 (m, 3H), 2.16- 2.21 (m, 1H), 2.26 (s, 3H), 2.54 (d, J = 11.7 Hz, 1H), 2.96 (d, J = 11.8 Hz, 1H), 3.70 (d, J = 6.7 Hz, 2H), 4.26 (dd, J = 14.4, 5.1 Hz, 1H), 4.35 (dd, J = 14.4, 5.1 Hz, 1H), 4.42-4.49 (m, 3H), 5.96 (s, 1H), 6.82 (t, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.22 (dd, J = 8.7, 4.3 Hz, 1H), 7.34 (td, J = 8.4, 2.8 Hz, 1H), 8.27 (d, J = 2.9 Hz, 1H). I - 051 1H-NMR (CDCl3) δ: 0.28-0 32 (m, 1H), 0.39-0.42 (m, 1H), 0.42-0.48 (m, 1H), 0.57-0.62 (m, 1H), 1.01 (d, J = 6.7 Hz, 6H), 1.95-2.10 (m, 3H), 2.35 (d, J = 13.6 Hz, 1H), 2.87 (t, J = 10.8 Hz, 1H), 3.17 (d, J = 12.2 Hz, 1H), 3.28 (d, J = 12.9 Hz, 1H), 3.70 (d, J = 6.5 Hz, 2H), 4.24-4.57 (m, 6H), 6.05 (s, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.22-7.26 (m, 1H), 7.35 (td, J = 8.3, 2.9 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H). I - 052 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.8 Hz, 6H), 1.62-1.97 (m, 9H), 2.02-2.10 (m, 2H), 2.58-2.72 (m, 2H), 2.79-2.85 (m, 2H), 3.10 (brs, 1H), 3.70 (d, J = 6.5 Hz, 2H), 4.29-4.39 (m, 2H), 4.42 (s, 2H), 4.50-4.58 (m, 1H), 6.61 (s, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.29 (dd, J = 8.7, 4.4 Hz, 1H), 7.37 (td, J = 8.3, 2.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H). I - 053 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.8 Hz, 6H), 1.43-1.60 (m, 2H), 1.68-2.28 (m, 10H), 3.05-3.25 (m, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.34 (d, J = 5.1 Hz, 2H), 4.37- 4.50 (m, 3H), 6.68-6.88 (m, 3H), 7.17 (d, J = 8.5 Hz, 2H), 7.32-7.40 (m, 2H), 8.26 (s, 1H). I - 054 1H-NMR (CDCl3) δ: 1.47-1.66 (m, 2H), 2.11-2.38 (m, 1H), 2.68-2.94 (m, 2H), 3.13-3.32 (m, 2H), 4.40 (d, J = 5.5 Hz, 1H), 4.46-4.64 (m, 3H), 4.84 (d, J = 51 Hz, 1H), 6.49 (t, J = 74 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.33-7.43 (m, 3H), 8.25 (d, J = 2.2 Hz, 1H). I - 055 1H-NMR (CDCl3) δ: 1.47-1.66 (m, 1H), 2.11-2.38 (m, 3H), 2.32 (s, 3H), 2.98 (d, J = 12 Hz, 1H), 3.13 (t, J = 12 Hz, 1H), 4.31-4.65 (m, 5H), 4.84 (d, J = 51 Hz, 1H), 6.49 (t, J = 73 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 7.32-7.43 (m, 2H), 7.59 (t, J = 5.1 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H). I - 056 1H-NMR (CDCl3) δ: 1.03 (t, J = 7.3 Hz 3H), 1.47-1.66 (m, 1H), 1.73-2.11 (m, 3H), 2.69-2.97 (m, 1H), 3.12-3.33 (m, 1H), 3.91 (t, J = 7.0 Hz, 2H), 4.34 (d, J = 5.3 Hz, 2H) 4.49-4.61 (m, 3H), 4.77 (d, J = 51 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 4.84 (d, J = 51 Hz, 1H) 7.09 (t, J = 4.5 Hz, 1H), 7.28-7.41 (m, 2H), 8.23 (d, J = 2.0 Hz, 1H). I - 057 1H-NMR (CDCl3) δ: 1.03 (t, J = 7.3 Hz, 3H), 1.47-1.66 (m, 1H), 1.73-1.87(d, J = 12 Hz, 2H), 2.11-2.36 (m, 3H), 2.32 (s, 3H), 2.98 (d, J = 12 Hz, 1H), 3.13 (t, J = 12 Hz, 1H), 3.91 (t, J = 6.7 Hz, 2H), 4.31-4.61 (m, 5H), 4.84 (d, J = 51 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.28-7.41 (m, 3H), 8.23 (d, J = 2.2 Hz, 1H). I - 058 1H-NMR (CDCl3) δ: 1.02 (d, J = 7.0 Hz, 6H), 1.47-1.66 (m, 1H), 1.94-2.14 (m, 3H), 2.69-2.95 (m, 2H), 3.13-3.33 (m, 2H), 3.68 (d, J = 7.0 Hz, 2H), 4.33 (d, J = 5.2 Hz, 2H), 4.49-4.66 (m, 3H), 4.84 (d, J = 51 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 7.08 (t, J = 4.5 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.32-7.44 (m, 2H), 8.23 (d, J = 2.0 Hz, 1H).
TABLE-US-00028 TABLE 28 I - 059 1H-NMR (CDCl3) δ: 1.02 (d, J = 7.0 Hz, 6H), 1.47-1.66 (m, 1H), 2.11-2.36 (m, 4H), 2.32 (s, 3H), 2.98 (d, J = 12 Hz, 1H), 3.13 (t, J = 12 Hz, 1H), 3.68 (d, J = 7.0 Hz, 2H), 4.31-4.61 (m, 5H), 4.84 (d, J = 51 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.28-7.41 (m, 3H), 8.23 (d, J = 2.0 Hz, 1H). I - 060 1H-NMR (CDCl3) δ: 0.27-0.32 (m, 1H), 0.36-0.41 (m, 1H), 0.42-0.50 (m, 1H), 0.55-0.63 (m, 1H), 1.77 (dd, J = 12.4, 3.1 Hz, 1H), 1.93-2.04 (m, 1H), 2.34 (d, J = 13.1 Hz, 1H), 2.84-2.90 (m, 1H), 3.17 (d, J = 13.1 Hz, 1H), 3.28 (d, J = 12.8 Hz, 1H), 3.80 (s, 3H), 4.25-4.50 (m, 4H), 4.57 (d, J = 8.8 Hz, 1H), 6.13 (s, 1H), 6.83 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.25 (dd, J = 8.7, 4.4 Hz, 1H), 7.35 (td, J = 8.3, 2.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H). I - 061 1H-NMR (CDCl3) δ: 0.21-0.25 (m, 1H), 0.43-0.47 (m, 2H), 0.49-0.53 (m, 1H), 1.69-1.73 (m, 1H), 1.98-2.05 (m, 2H), 2.15-2.18 (m, 1H), 2.24 (s, 3H), 2.52 (d, J = 11.3 Hz, 1H), 2.93 (d, J = 11.2 Hz, 1H), 3.79 (s, 3H), 4.27 (dd, J = 14.4, 5.1 Hz, 1H), 4.36 (dd, J = 14.3, 5.4 Hz, 1H), 4.44-4.49 (m, 3H), 5.97 (s, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 7.22 (td, J = 8.4, 4.3 Hz, 1H), 7.34 (td, J = 8.4, 2.9 Hz, 1H), 8.27 (d, J = 2.9 Hz, 1H). I - 062 1H-NMR (CDCl3) δ: 0.27-0.32 (m, 1H), 0.35-0.43 (m, 1H), 0.45-0.51 (m, 1H), 0.55-0.65 (m, 1H), 1.03 (t, J = 7.3 Hz, 3H), 1.74-1.85 (m, 3H), 1.94-2.05 (m, 1H), 2.33-2.40 (m, 1H), 2.84-2.92 (m, 1H), 3.15-3.20 (m, 1H), 3.25-3.34 (m, 1H), 3.90 (t, J = 6.5 Hz, 2H), 4.20-4.50 (m, 4H), 4.58 (d, J = 10.7 Hz, 1H), 6.12 (s, 1H), 6.82 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H), 8.27 (s, 1H). I - 063 1H-NMR (CDCl3) δ: 0.20-0.25 (m, 1H), 0.40-0.55 (m, 3H), 1.03 (t, J = 7.4 Hz, 3H), 1.68-1.74 (m, 1H), 1.75-1.83 (m, 2H), 2.00 (d, J = 11.8 Hz, 2H), 2.16 (t, J = 10.7 Hz, 1H), 2.24 (s, 3H), 2.52 (d, J = 12.0 Hz, 1H), 2.93 (d, J = 10.9 Hz, 1H), 3.90 (t, J = 6.5 Hz, 2H), 4.23-4.50 (m, 5H), 5.93 (s, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.22 (dd, J = 8.5, 4.3 Hz, 1H), 7.34 (td, J = 8.3, 2.7 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H). I - 064 1H-NMR (CDCl3) δ: 0.18-0.24 (m, 1H), 0.40-0.45 (m, 1H), 0.47-0.55 (m, 2H), 1.01 (d, J = 6.7 Hz, 6H), 1.83 (d, J = 11.5 Hz, 1H), 2.00-2.23 (m, 4H), 2.26 (s, 3H), 2.55 (d, J = 11.7 Hz, 1H), 2.99 (d, J = 10.8 Hz, 1H), 3.66-3.75 (m, 5H), 4.17-4.38 (m, 4H). 4.61 (d, J = 11.7 Hz, 1H),6.02 (s, 1H), 6.08 (s, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H). I - 065 1H-NMR (CDCl3) δ: 0.19-0.22 (m, 1H), 0.40-0.45 (m, 1H) 0.49-0.55 (2H, m), 1.02 (t, J = 7.4 Hz, 3H), 1.74-1.87 (m, 3H), 1.97-2.24 (m, 3H), 2.26 (s, 3H), 2.54 (d, J = 11.7 Hz, 1H), 2.99 (d, J = 10.9 Hz, 1H), 3.70 (s, 3H), 3.89 (t, J = 6.6 Hz, 2H), 4.17-4.38 (m, 4H), 4.61 (d, J = 11.2 Hz, 1H), 6.02 (s, 1H), 6.08 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H). I - 066 1H-NMR (CDCl3) δ: 0.20-0.27 (m, 1H), 0.29-0.37 (m, 3H), 0.39-0.40 (m, 1H), 0.50-0.58 (m, 1H), 0.61-0.67 (m, 2H), 1.24-1.31 (m, 1H), 1.67-1.84 (m, 2H), 2.19 (d, J = 13.6 Hz, 1H), 2.75-2.83 (m, 1H), 3.08-3.21 (m, 2H), 3.78 (d, J = 7.1 Hz, 2H), 4.27 (dd, J = 14.6, 5.3 Hz, 1H), 4.33-4.42 (m, 2H), 4.47-4.54 (m, 2H), 5.74 (s, 1H), 6.83 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.23 (dd, J = 8.5, 4.3 Hz, 1H), 7.34 (td, J = 8.3, 2.5 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H).
TABLE-US-00029 TABLE 29 I - 067 1H-NMR (CDCl3) δ: 0.20-0.26 (m, 1H), 0.32-0.37 (m, 2H), 0.41-0.55 (m, 3H), 0.61-0.67 (m, 2H), 1.68-1.75 (m, 1H), 1.96-2.06 (m, 2H), 2.12-2.20 (m, 1H), 2.24 (s, 3H), 2.51 (d, J = 11.8 Hz, 1H), 2.89-2.96 (m, 1H), 3.78 (d, J = 7.0 Hz, 2H), 4.26 (dd, J = 14.3, 5.0 Hz, 1H), 4.32-4.50 (m, 4H), 5.94 (s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 7.22 (dd, J = 8.5, 4.3 Hz, 1H), 7.34 (td, J = 8.3, 2.8 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H). I - 068 1H-NMR (400 MHz, CDCl3) δ 1.00 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H), 1.28-1.92 (m, 5 Hz), 1.99-2.13 (m, 2H), 2.21 (s, 1.5 Hz), 2.23 (s, 1.5 Hz), 2.76- 2.85 (m, 2H), 3.58 (s, 1H), 3.68 (d, J = 6.5 Hz, 1H), 3.71 (d, J = 6.5 Hz, 1H), 3.78 (s, 1H), 4.55 (s, 1H), 4.62 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 7.13-7.39 (m, 4H), 8.32 (d, J = 3.0 Hz, 0.5 H), 8.43 (d, J = 3.0 Hz, 0.5H).
TABLE-US-00030 TABLE 30 I - 069 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.48 (d, J = 12.6 Hz, 1H), 2.00-2.51 (m, 4H), 2.30 (s, 3H), 2.96 (d, J = 11.8 Hz, 1H), 3.31 (t, J = 12.3 Hz, 1H), 3.70 (d, J = 6.5 Hz, 2H), 4.21-4.47 (m, 3H), 4.57 (d, J = 16.6 Hz, 1H), 4.84 (d, J = 16.6 Hz, 1H), 4.88 (d, J = 49.7 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.19-7.28 (3H, m), 7.39 (t, J = 8.5 Hz, 1H), 7.71 (br, t, J = 5.3 Hz, 1H), 8.21 (d, J = 4.5 Hz 1H). I - 070 1H-NMR (CDCl3) δ: 1.03 (d, J = 6.7 Hz, 6H), 1.50-1.87 (m, 4H), 1.99-2.14 (m, 3H), 2.25 (s, 3H), 2.86 (d, J = 12.0 Hz, 2H), 3.66 (d, J = 6.5 Hz, 2H), 4.27 (d, J = 5.2 Hz, 2H), 4.40-4.55 (m, 1H), 4.97 (s, 2H), 5.56 (t, J = 5.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 7.15 (t, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.5, 4.2 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 8.41 (dd, J = 8.5, 1.5 Hz, 1H), 8.70 (dd, J = 4.3, 1.8, 1H). I - 071 1H-NMR (CDCl3) δ: 1.03 (d, J = 6.7 Hz, 6H), 1.61-1.87 (m, 4H), 2.00-2.14 (m, 3H), 2.25 (s, 3H), 2.84 (d, J = 12.0 Hz, 2H), 3.66 (d, J = 6.5 Hz, 2H), 4.29 (d, J = 5.2 Hz, 2H), 4.27-4.45 (m, 1H), 4.61 (t, J = 5.1 Hz, 1H), 4.63 (s, 2H), 6.77 (d, J = 8.5 Hz, 2H), 6.82-6.89 (m, 2H), 7.03 (d, J = 8.5 Hz, 2H), 7.06-7.13 (m, 1H), 7.54 (d, J = 2.0 Hz, 2H). I - 072 1H-NMR (CDCl3) δ: 1.00 (d, J = 10.2 Hz, 6H), 1.66-1.76 (m, 4H), 2.03- 2.11 (m, 3H), 2.28 (s, 3H), 2.90 (d, J = 11.5 Hz, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.22 (s, 2H), 4.25-4.36 (m, 7H), 6.77 (s, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.10 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.94 (s, 1H). I - 073 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.42 (d, J = 12.6 Hz, 1H), 2.00-2.18 (m, 2H), 2.65-2.93 (m, 2H), 3.11-3.30 (m, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.30-4.64 (m, 4H), 4.70-4.89 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.19-7.28 (3H, m), 7.39 (t, J = 8.5 Hz, 1H), 7.69 (bt, J = 5.3 Hz, 1H), 8.23 (d, J = 4.7 Hz, 1H). I - 074 1H-NMR (CDCl3) δ: 1.03 (d, J = 6.7 Hz, 6H), 1.70-1.98 (m, 4H), 2.00-2.14 (m, 3H), 2.29 (s, 3H), 2.92 (d, J = 12.0 Hz, 2H), 3.68 (d, J = 6.5 Hz, 2H), 3.76 (s, 3H), 4.29-4.42 (m, 1H), 4.33 (d, J = 5.2 Hz, 2H), 4.63 (s, 2H), 6.77 (d, J = 8.5 Hz, 2H), 7.04-7.10 (m, 1H), 7.12-7.22 (m, 3H), 7.56 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 6.3 Hz, 1H), 8.11 (d, J = 4.5 Hz, 2H)
TABLE-US-00031 TABLE 31 I - 075 1H-NMR (CDCl3) δ: 1.60-1.67 (m, 2H), 1.69-1.80 (m, 2H), 2.07 (t, J = 10.8 Hz, 2H), 2.28 (s, 3H), 2.89 (d, J = 11.5 Hz, 2H), 4.23-4.29 (m, 1H) 4.33 (s, 2H), 4.37 (d, J = 5.4 Hz, 2H), 6.70 (d, J = 8.0 Hz, 1H), 6.75-6.81 (m, 2H), 7.01 (s, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.22 (dd, J = 8.5, 4.1 Hz, 1H), 7.33 (td, J = 8.3, 2.8 Hz, 1H), 8.26 (d, J = 2.6 Hz, 1H). I - 076 1H-NMR (CDCl3) δ: 1.59-1.64 (m, 2H), 1.67-1.80 (m, 2H), 2.06 (t, J = 10.9 Hz, 2H), 2.28 (s, 3H), 2.88 (d, J = 11.5 Hz, 2H), 4.21 (t, J = 11.9 Hz, 1H), 4.30-4.34 (m, 4H), 6.81 (t, J = 7.3 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.16-7.21 (m, 1H), 7.25 7.24-7.27 (m, 1H), 7.37 (dt, J = 12.0, 4.2 Hz, 1H), 7.67 (s, 1H), 8.29 (d, J = 2.5 Hz, 1H), 10.34 (s, 1H). I - 077 1H-NMR (CDCl3)δ: 1.00 (d, J = 6.7 Hz, 6H), 1.60 (d, J = 11.9 Hz, 2H), 1.70-1.81 (m, 2H), 2.00-2.10 (m, 1H), 2.16 (t, J = 11.4 Hz, 2H), 2.30 (s, 3H), 2.94 (d, J = 11.8 Hz, 2H), 3.66 (d, J = 6.5 Hz, 2H), 4.28-4.39 (m, 5H), 6.55 (d, J = 11.3 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.73 (s, 1H). I - 078 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.57-1 90 (m, 4H), 2.00-2.14 (m, 3H), 2.27 (s, 3H), 2.54 (s, 3H), 2.88 (d, J = 12.0 Hz, 2H), 3.70 (d, J = 7.0 Hz, 2H), 4.16-4.29 (m, 1H), 4.35 (d, J = 5.2 Hz, 2H), 4.40 (s, 2H), 6.57 (br, t, 1H), 6.84 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 1H), 8.25 (s, 1H), 8.47 (s, 1H) I - 079 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.3 Hz, 6H), 1.68-1.85 (m, 4H), 1.99- 2.14 (m, 3H), 2.25 (s, 3H), 2.86 (d, J = 11.7 Hz, 2H), 3.62-3.70 (m, 5H), 4.26 (d, J = 5.3 Hz, 1H), 4.36-4.55 (m, 3H), 4.89 (t, J = 5.5. Hz, 1H), 6.74 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 7.10 (t, J = 6.8 Hz, 1H), 7.21-7.33 (m, 2H), 7.49 (d, J = 8.5 Hz, 1H) I - 080 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.5 Hz, 6H), 1.60 (d, J = 10.8 Hz, 2H), 1-95-2.12 (m, 5H), 2.26 (s, 3H), 2.92 (d, J = 9.0 Hz, 2H), 3.52 (s, 1H), 3.71 (d, J = 6.4 Hz, 2H), 4.40 (d, J = 4.4 Hz, 2H), 4.57 (s, 2H), 6.79-6.88 (m, 3H), 7.22 (d, J = 8.2 Hz, 2H), 7.86 (s, 1H). I - 081 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.7 Hz, 6H), 1.52-1.58(m, 2H), 1.84-1.95 (m, 4H), 2.05-2.11 (m, 1H), 2.22 (s, 3H), 2.85 (d, J = 9.2 Hz, 2H), 3.23-3.33 (m, 1H), 3.71 (d, J = 6.5 Hz, 2H), 4.46 (d, J = 5.3 Hz, 2H), 4.77 (s, 2H), 4.86 (s, 1H), 6.58 (s, 1H), 6.65 (dd, J = 10.0, 8.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 6.94 (dd, J = 7.5, 4.9 Hz, 1H), 7.14 (s, 1H), 7.19 (d, J = 8.5 Hz, 2H), 10.87 (s, 1H). I - 082 1H-NMR (CDCl3) δ: 1.65-1.77 (4H, m), 2.06 (2H, ddd, J = 15.0, 6.0, 4.3 Hz), 2.28 (3H, s), 2.90 (2H, bd), 4.24-4.30 (1H, m), 4.37 (4H, d, J = 8.0 Hz), 6.98 (1H, br s), 7.15 (2H, d, J = 8.4 Hz), 7.29 (1H, dd, J = 8.7, 4.3 Hz), 7.38-7.41 (3H, m), 8.28 (1H, d, J = 2.6 Hz).
TABLE-US-00032 TABLE 32 I - 083 1H-NMR (CDCl3) δ: 1.70-1.76 (4H, m), 2.07 (2H, ddd, J = 16.5, 5.2, 5.1 Hz), 2.27 (3H, s), 2.88 (2H, d, J = 11.3 Hz), 4.27-4.31 (1H, m), 4.39-4.40 (4H, m), 5.22 (1H, d, J = 10.9 Hz), 5.72 (1H, d, J = 17.6 Hz), 6.70 (1H, dd, J = 17.6, 10.9 Hz), 6.79 (1H, br s), 7.22 (2H, d, J = 7.9 Hz), 7.30 (1H, t, J = 4.3 Hz), 7.34-7.40 (3H, m), 8.27 (1H, d, J = 2.6 Hz). I - 084 1H-NMR (CDCl3) δ: 1.70-1.79 (m, 4H), 2.07 (t, J = 10.6 Hz, 2H), 2.28 (s, 3H), 2.89 (d, J = 11.5 Hz, 2H), 4.28 (dd, J = 14.0, 9.7 Hz, 1H), 4.38 (s, 4H), 6.98 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.26-7.32 (m, 3H), 7.39 (td, J = 8.3, 2.8 Hz, 1H), 8.28 (d, J = 2.6 Hz, 1H). I - 085 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.54 (d, J = 12.6 Hz, 1H), 1.92-2.44 (m, 4H), 2.31 (s, 3H), 2.97 (d, J = 10.3 Hz, 1H), 3.13 (t, J = 11.5 Hz, 1H), 3.70 (d, J = 6.3 Hz, 2H), 4.34 (d, J = 5.3 Hz, 2H), 4.45 (br, dd, J = 36, 14 Hz, 1H), 4.54 (br. s, 2H), 4.85 (d, J = 51 Hz, 1H), 6.83 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.28-7.41 (m, 1H), 8.23 (d, J = 2.0 Hz, 1H). I - 086 1H-NMR (CDCl3) δ: 0.21 (d, J = 9.4 Hz, 1H), 0.43 (d, J = 9.7 Hz, 1H), 0.49- 0.53 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H), 1.74-1.86 (m, 3H), 1.98-2.13 (m, 2H), 2.19 (t, J = 10.7 Hz, 1H), 2.26 (s, 3H), 2.54 (d, J = 11.8 Hz, 1H), 2.99 (d, J = 10.8 Hz, 1H), 3.70 (s, 3H), 3.89 (t, J = 6.6 Hz, 2H), 4.18-4.28 (m, 3H), 4.31-4.38 (m, 1H), 4.61 (d, J = 9.0 Hz, 1H), 6.02 (s, 1H), 6.08 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 1.9 Hz, 1H). I - 087 1H-NMR (CDCl3) δ: 0.21 (d, J = 9.4 Hz, 1H), 0.43 (d, J = 10.0 Hz, 1H), 0.47-0.55 (m, 2H), 1.01 (d, J = 6.7 Hz, 6H), 1.83 (d, J = 11.5 Hz, 1H), 2.00- 2.13 (m, 3H), 2.20 (t, J = 11.4 Hz, 1H), 2.26 (s, 3H), 2.55 (d, J = 11.7 Hz, 1H), 2.99 (d, J = 10.8 Hz, 1H), 3.66-3.73 (m, 5H), 4.18-4.31 (m, 3H), 4.35 (dd, J = 14.5, 5.5 Hz, 1H), 4.61 (d, J = 11.7 Hz, 1H), 6.01(s, 1H), 6.08 (s, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H). I - 088 1H-NMR (CDCl3) δ: 1.01 (6H, d, J = 6.8 Hz), 2.02-2.10 (4H, m), 2.34 (3H, s), 2.87 (1H, d, J = 12.5 Hz), 3.16 (1H, d, J = 8.5 Hz), 3.64-3.74 (4H, m), 4.23-4.35 (3H, m), 5.74 (1H, br, s), 6.82 (1H, d, J = 8.5 Hz), 7.13 (2H, J = 8.5 Hz), 7.32 (1H, t, J = 4.3 Hz), 7.41 (1H, td, J = 8.3 Hz, 2.7 Hz), 7.69 (1H, s), 8.31 (1H, d, J = 2.8 Hz). I - 089 diastereomeric ratio 3:2 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.7 Hz), 2.00-2.15 (4H, m), 2.38- 2.66 (5H, m), 2.89 (2H, s), 2.96 (2H, s), 3.03-3.23 (2H, m), 3.70 (2H, d, J = 7.8 Hz), 3.87-3.98 (1H, m), 4.30-4.57 (4H, m), 6.83 (2H, d, J = 8.5 Hz), 6.97 (1H, br, s), 7.17 (2H, d, J = 8.5 Hz), 7.32-7.41 (2H, m), 8.02 (0.4H, s), 8.26 (0.6H, s).
TABLE-US-00033 TABLE 33 I - 090 1H-NMR (CDCl3) δ: 0.28-0.33 (m, 1H), 0.40-0.48 (m, 1H), 0.52-0.66 (m, 2H), 1.01 (d, J = 6.8 Hz, 6H), 1.93 (d, J = 11 Hz, 1H), 2.02-2.16 (m, 2H), 2.46 (d, J = 13.1 Hz, 1H), 2.94 (t, J = 11.0 Hz, 1H), 3.20 (d, J = 12.9 Hz, 1H), 3.37 (d, J = 12.3 Hz, 1H), 3.69 (d, J = 6.5 Hz, 2H), 3.72 (s, 3H), 4.18- 4.23 (m, 3H), 4.30-4.37 (m, 1H), 4.64-4.70 (m, 1H), 6.08 (d, J = 2.0 Hz, H), 6.14 (s, 1H), 6.80 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 1.8 Hz, 1H). I - 091 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.83 (d, J = 12.3 Hz, 1H), 1.97 (ddd, J = 25.3, 12.9, 4.9 Hz, 1H), 2.04-2.12 (m, 1H), 2.76-2.94 (m, 2H), 3.14-3.28 (m, 2H), 3.70 (d, J = 6.5 Hz, 2H), 4.32 (d, J = 5.1 Hz, 2H), 4.55 (dd, J = 19.4, 16.9 Hz, 2H), 5.00 (tt, J = 16.7, 5.4 Hz, 1H), 6.64 (s, 1H), 6.79-6.83 (m, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.34-7.42 (m, 2H), 8.23 (d, J = 2.5 Hz, 1H). I - 092 1H-NMR (CDCl3) δ: 1.62-1.79 (m, 4H), 1.77 (t, J = 19.0 Hz, 3H), 2.02-2.11 (m, 2H), 2.28 (s, 3H), 2.85-2.92 (m, 2H), 4.09 (t, J = 11.3 Hz, 2H), 4.23- 4.33 (m, 1H), 4.35 (d, J = 5.5 Hz, 2H), 4.37 (s, 2H), 6.71-6.78 (br, 1H), 6.86 d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 8.7, 4.3 Hz, 1H), 7.37 (td, J = 8.2, 3.0 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H). I - 093 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.5 Hz, 6H), 1.64(d, J = 12.6 Hz, 1H), 1.94-2.14 (m, 2H), 2.72-2.95 (m, 2H), 3.14-3.32 (m, 2H), 3.55 (s, 3H) 3.68 (d, J = 6.5 Hz, 2H), 4.20-4.45 (m, 4H), 4.64 (ddd, J = 34.9, 13.3, 1.51 Hz, 1H), 4.80 (d, J = 51.4 Hz, 1H), 5.11 (br, t, J = 5.3 Hz, 1H), 5.97 (t, J = 2.2 Hz, 1H), 6.39 (br, s, 1H), 6.52 (t, J = 2.5 Hz, 1H), 6.79 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H) I - 094 1H-NMR (CDCl3) δ: 0.18-0.22 (m, 1H), 0.41-0.44 (m, 1H), 0.48-0.54 (m, 2H), 1.00 (d, J = 6.8 Hz, 6H), 1.80-1.85 (m, 1H), 1.97-2.23 (m, 4H), 2.18 (s, 3H), 2.26 (s, 3H), 2.54 (d, J = 11.6 Hz, 1H), 2.97-3.01 (m, 1H), 3.55 (s, 3H), 3.68 (d, J = 6.8 Hz, 2H), 4.09-4.25 (m, 3H), 4.34 (dd, J = 14.4, 6.4 Hz, 1H), 4.59-4.64 (m, 1H), 5.83 (s, 1H), 6.05 (br s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H). I - 095 1H-NMR (CDCl3) δ: 1.63-1.79 (m, 4H), 2.02-2.12 (m, 2H), 2.27 (s, 3H), 2.85-2.93 (m, 2H), 4.23-4.40 (m, 7H), 6.77-6.84 (br, 1H), 6.88 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 8.8, 4.5 Hz, 1H), 7.38 (td, J = 8.0, 2.5 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H). I - 096 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.57-1.84 (m, 4H), 2.00-2.14 (m, 3H), 2.20 (s, 3H), 2.90 (d, J = 12.0 Hz, 2H), 3.57 (s, 3H), 3.68 (d, J = 6.8 Hz, 2H), 4.13 (s, 2H), 4.29-4.41 (m, 1H), 4.31 (d, J = 5.2 Hz, 2H), 5.86 (s, 1H), 6.28 (t, J = 5.0, 1H), 6.80 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 1H). I - 097 1H-NMR (CDCl3) δ: 1.46 (dd, J = 23.6, 6.5 Hz, 3H), 1.62-1.79 (m, 4H), 2.02-2.12 (m, 2H), 2.27 (s, 3H), 2.84-2.92 (m, 2H), 3.94-4.16 (m, 2H), 4.23-4.33 (m, 1H), 4.35 (d, J = 5.5 Hz, 2H), 4.37 (s, 2H), 4.90-5.11 (m, 1H), 6.65-6.71 (br, 1H), 6.85 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.28 (dd, J = 8.5, 4.3 Hz, 1H), 7.37 (td, J = 8.3, 2.8 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H).
TABLE-US-00034 TABLE 34 I - 098 1H-NMR (CDCl3) δ: 1.46 (dd, J = 23.6, 6.5 Hz, 3H), 1.63-1.79 (m, 4H), 2.02-2.11 (m, 2H), 2.27 (s, 3H), 2.84-2.95 (m, 2H), 3.94-4.16 (m, 2H), 4.23-4.33 (m, 1H), 4.35 (d, J = 5.3 Hz, 2H), 4.37 (s, 2H), 4.89-5.11 (m, 1H), 6.64-6.73 (br, 1H), 6.85 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.29 (dd, J = 8.8, 4.3 Hz, 1H), 7.37 (td, J = 8.0, 2.5 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H). I - 099 1H-NMR (DMSO-D6) δ: 0.28-0.66 (m, 4H), 1.81-1.88 (m, 1H), 1.95-2.08 (m, 1H), 2.68 (s, 3H), 2.77 (d, J = 12.4 Hz, 1H), 2.95-3.14 (m, 1H), 3.20- 3.48 (m, 2H), 3.71 (s, 3H), 4.04-4.28 (m, 3H), 4.60-4.70 (m, 2H), 6.82 (d, J = 8.5 Hz, 2H), 6.99 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.22-7.31 (m, 1H), 7.66-7.70 (m, 1H), 8.49 (d, J = 2.5 Hz, 1H), 9.80-10.02 (m, 1H). I - 100 1H-NMR (CDCl3) δ: 0.21-0.25 (m, 1H), 0.43-0.56 (m, 3H), 1.71-1.73(m, 1H), 1.97-2.05(m, 2H), 2.16 (t, J = 10.4 Hz, 1H), 2.24 (s, 3H), 2.33 (s, 3H), 2.51 (d, J = 11.8 Hz, 1H), 2.93 (d, J = 10.0 Hz, 1H), 4.28-4.50 (m, 5H), 5.99 (s, 1H), 7.10 (s, 4H), 7.21-7.26 (m, 1H), 7.34 (td, J = 8.3, 2.7 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H). I - 101 1H-NMR (CDCl3) δ: 0.31-0.35 (m, 1H), 0.40-0.44 (m, 1H), 0.45-0.52 (m, 1H), 0.58-0.65 (m, 1H), 1.75-1.81 (m, 1H), 2.00-2.05 (m, 1H), 2.33 (s, 3H), 2.40 (d, J = 13.4 Hz, 1H), 2.90 (t, J = 11.9 Hz, 1H), 3.19 (d, J = 13.2 Hz, 1H), 3.31 (d, J = 12.2 Hz, 1H), 4.28-4.50 (m, 5H), 4.59 (d, J = 12.5 Hz, 1H), 6.25 (s, 1H), 7.11 (s, 4H), 7.24-7.26 (m, 1H), 7.36 (dd, J = 11.0, 5.2 Hz, 1H), 8.28 (s, 1H). I - 102 1H-NMR (CDCl3) δ: 0.21 (d, J = 9.4 Hz, 1H), 0.43 (d, J = 9.7 Hz, 1H), 0.49- 0.53 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H), 1.74-1.86 (m, 3H), 1.98-2.13 (m, 2H), 2.19 (t, J = 10.7 Hz, 1H), 2.26 (s, 3H), 2.54 (d, J = 11.8 Hz, 1H), 2.99 (d, J = 10.8 Hz, 1H), 3.70 (s, 3H), 3.89 (t, J = 6.6 Hz, 2H), 4.18-4.28 (m, 3H), 4.31-4.38 (m, 1H), 4.61 (d, J = 9.0 Hz, 1H), 6.02 (s, 1H), 6.08 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 1.9 Hz, 1H). I - 103 1H-NMR (CDCl3) δ: 0.30-0.35 (m, 1H), 0.40-0.47 (m, 1H), 0.50-0.66 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H), 1.79 (td, J = 13.9, 6.9 Hz, 2H), 1.93 (d, J = 10.7 Hz, 1H), 2.08-2.18 (m, 2H), 2.48-2.50 (m, 1H), 2.92-2.98 (m, 1H), 3.21 (d, J = 12.9 Hz, 1H), 3.38 (d, J = 12.2 Hz, 1H), 3.69 (t, J = 11.1 Hz, 3H), 3.89 (t, J = 6.6 Hz, 2H), 4.19-4.18 (m, 3H), 4.33 (dt, J = 18.4, 6.3 Hz, 1H), 4.67 (d, J = 10.5 Hz, 1H), 6.07 (s, 1H), 6.17 (s, 1H), 6.81 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.23 (s, 1H). I - 104 1H-NMR (CDCl3) δ: 0.18-0.22 (m, 1H), 0.41-0.44 (m, 1H), 0.48-0.54 (m, 2H), 1.82-1.85 (m, 1H), 1.99-2.22 (m, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 2.54 (d, J = 11.2 Hz, 1H), 2.97-3.01 (m, 1H), 3.55 (s, 3H), 3.78 (s, 3H), 4.09- 4.25 (m, 3H), 4.35 (dd, J = 14.4, 6.0 Hz, 1H), 4.59-4.63 (m, 1H), 5.83 (s, 1H), 6.08 (br s, 1H), 6.79 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H).
TABLE-US-00035 TABLE 35 I - 105 1H-NMR (CDCl3) δ: 0.18-0.22 (m, 1H), 0.41-0.44 (m, 1H), 0.49-0.54 (m, 2H), 1.82-1.85 (m, 1H), 1.99-2.22 (m, 3H), 2.19 (s, 3H), 2.25 (s, 3H), 2.31 (s, 3H), 2.54 (d, J = 11.6 Hz, 1H), 2.97-3.01 (m, 1H), 3.55 (s, 3H), 4.12 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 4.25 (dd, J = 12.4, 4.8 Hz, 1H), 4.37 (dd, J = 14.4, 6.0 Hz, 1H), 4.59-4.63 (m, 1H), 5.84 (s, 1H), 6.09 (br s, 1H), 7.06 (br s, 4H). I - 106 1H-NMR (CDCl3) δ: 1.58-1.70 (m, 2H), 1.70-2.06 (m, 4H), 2.25 (s, 3H), 2.86 (d, J = 11.3 Hz, 2H), 3.53 (s, 3H), 3.81 (s, 3H), 4.23 (br, s, 2H), 5.11 (s, 2H), 5.85-6.12 (m, 1H), 5.85-6.12 (m, 1H), 6.21-6.44 (m, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H). I - 107 1H-NMR (CDCl3) δ: 0.30-0.35 (m, 1H), 0.40-0.47 (m, 1H), 0.50-0.66 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H), 1.79 (td, J = 13.9, 6.9 Hz, 2H), 1.93 (d, J = 10.7 Hz, 1H), 2.08-2.18 (m, 2H), 2.48-2.50 (m, 1H), 2.92-2.98 (m, 1H), 3.21 (d, J = 12.9 Hz, 1H), 3.38 (d, J = 12.2 Hz, 1H), 3.69 (t, J = 11.1 Hz, 3H), 3.89 (t, J = 6.6 Hz, 2H), 4.19-4.18 (m, 3H), 4.33 (dt, J = 18.4, 6.3 Hz, 1H), 4.67 (d, J = 10.5 Hz, 1H), 6.07 (s, 1H), 6.17 (s, 1H), 6.81 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.23 (s, 1H). I - 108 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.8 Hz, 6H), 1.67 (d, J = 14.3 Hz, 1H), 1.96-2.40 (m, 4H), 2.31 (s, 3H), 2.97 (d, J = 12.6 Hz, 1H), 3.14 (t, J = 11.8 Hz, 1H), 3.55 (s, 3H), 3.68 (d, J = 6.5 Hz, 2H), 4.19-4.62 (m, 6H), 4.70-4.97 (m, 2H), 5.14 (br, t, J = 5.0, 1H), 5.97 (br, s, 1H), 6.38 (br, s, 1H), 6.51 (br, s, 1H), 6.79 (d, J = 8.8, 2H), 7.00 (d, J = 8.8, 2H). I - 109 1H-NMR (CDCl3) δ: 0.18-0.22 (m, 1H), 0.41-0.44 (m, 1H), 0.48-0.54 (m, 2H), 1.02 (t, J = 6.8 Hz, 3H), 1.75-1.86 (m, 3H), 1.98-2.23 (m, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 2.54 (d, J = 10.4 Hz, 1H), 2.97-3.02 (m, 1H), 3.55 (s, 3H), 3.88 (t, J = 6.8 Hz, 2H), 4.09-4.24 (m, 3H), 4.34 (dd, J = 14.4, 5.2 Hz, 1H), 4.59-4.64 (m, 1H), 5.83 (s, 1H), 6.06 (br s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H). I - 110 1H-NMR (CDCl3) δ: 0.19-0.22 (m, 1H), 0.31-0.35 (m, 2H), 0.41-0.44 (m, 1H), 0.47-0.49 (m, 2H), 0.61-0.65 (m, 2H), 0.86-0.90 (m, 1H), 1.81-1.85 (m, 1H), 1.99-2.22 (m, 3H), 2.25 (s, 3H), 2.54 (d, J = 11.6 Hz, 1H), 2.96- 3.01 (m, 1H), 3.70 (s, 3H), 3.76 (d, J = 6.8 Hz, 2H), 4.17-4.37 (m, 4H), 4.59-4.62 (m, 1H), 6.02 (br s, 1H), 6.07 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 2.0 Hz, 1H). I - 111 1H-NMR (CDCl3) δ: 0.19-0.22 (m, 1H), 0.43-0.53 (m, 3H), 0.61-0.65 (m, 2H), 1.81-1.85 (m, 1H), 1.99-2.22 (m, 3H), 2.26 (s, 3H), 2.53 (d, J = 11.2 Hz, 1H), 2.97-3.01 (m, 1H), 3.69 (s, 3H), 4.18-4.32 (m, 3H), 4.42 (dd, J = 14.8, 6.0 Hz, 1H), 4.59-4.63 (m, 1H), 6.08 (d, J = 1.6 Hz, 1H), 6.22 (br s, 1H), 6.47 (t, J = 74.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 1.6 Hz, 1H). I - 112 1H-NMR (CDCl3) δ: 0.98 (d, J = 6.5 Hz, 6H), 1.63-1.78 (m, 4H), 1.81-1.94 (m, 1H), 2.02-2.11 (m, 2H), 2.27 (s, 3H), 2.83-2.95 (m, 4H), 3.59-3.74 (br, 1H), 4.22-4.33 (m, 1H), 4.28 (d, J = 5.1 Hz, 2H), 4.37 (s, 2H), 6.31-6.39 (br, 1H), 6.53 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.24-7.29 (m, 1H), 7.35 (td, J = 8.2, 2.6 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H).
TABLE-US-00036 TABLE 36 I - 113 1H-NMR (CDCl3) δ: 0.73-0.79 (m, 4H), 1.63-1.83 (m, 4H), 2.02-2.12 (m, 2H), 2.27 (s, 3H), 2.84-2.92 (m, 2H), 3.68-3.75 (m, 1H), 4.23-4.33 (m, 1H), 4.35 (d, J = 5.3 Hz, 2H), 4.37 (s, 2H), 6.58-6.68 (br, 1H), 6.98 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.28 (dd, J = 8.5, 4.3 Hz, 1H), 7.36 (td, J = 8.4, 3.0 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H). I - 114 1H-NMR (CDCl3) δ: 0.21 (d, J = 9.4 Hz, 1H), 0.43 (d, J = 10.0 Hz, 1H), 0.47-0.55 (m, 2H), 1.01 (d, J = 6.7 Hz, 6H), 1.83 (d, J = 11.5 Hz, 1H), 2.00- 2.13 (m, 3H), 2.20 (t, J = 11.4 Hz, 1H), 2.26 (s, 3H), 2.55 (d, J = 11.7 Hz, 1H), 2.99 (d, J = 10.8 Hz, 1H), 3.66-3.73 (m, 5H), 4.18-4.31 (m, 3H), 4.35 (dd, J = 14.5, 5.5 Hz, 1H), 4.61 (d, J = 11.7 Hz, 1H), 6.01(s, 1H), 6.08 (s, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H). I - 115 1H-NMR (CDCl3) δ: 1.01 (t, J = 6.5 Hz, 6H), 1.51-1.55 (m, 1H), 1.98-2.07 (m, 2H), 2.73-2.92 (m, 2H), 3.14-3.29 (m, 2H), 3.70 (d, J = 6.7 Hz, 2H), 4.33 (d, J = 5.0 Hz, 2H), 4.51-4.65 (m, 1H), 4.54 (s, 2H), 4.78 (d, J = 50.7 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 7.08 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.35-7.40 (m, 2H), 8.24 (d, J = 1.9 Hz, 1H). I - 116 1H-NMR (CDCl3) δ: 1.22 (3H, t, J = 7.7 Hz), 1.69-1.77 (4H, m), 2.07 (2H, ddd, J = 15.2, 5.6, 5.2 Hz), 2.27 (3H, s), 2.63 (2H, q, J = 7.7 Hz), 2.87-2.90 (2H, br m), 4.28-4.31 (1H, m), 4.38 (4H, br s), 6.64 (1H, br s), 7.15 (4H, q, J = 8.3 Hz), 7.29-7.30 (1H, m), 7.36 (1H, td, J = 8.3, 2.7 Hz), 8.26 (1H, d, J = 2.7 Hz). I - 117 1H-NMR (CDCl3) δ: 1.61-1.79 (m, 4H), 2.01-2.11 (m, 2H), 2.27 (s, 3H), 2.84-2.92 (m, 2H), 4.22-4.40 (m, 7H), 6.06 (tt, J = 53.2, 5.1 Hz, 1H), 6.77- 6.84 (br, 1H), 6.86 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 8.5, 4.3 Hz, 1H), 7.38 (td, J = 8.3, 2.9 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H). I - 118 1H-NMR (CDCl3) δ: 1.02 (d, J = 6.8 Hz, 6H), 1.69-1.82 (m, 4H), 1.99-2.13 (m, 3H), 2.28 (s, 3H), 2.86-2.95 (m, 2H), 3.69 (d, J = 6.5 Hz, 2H), 4.25-4.37 (m, 1H), 4.28 (s, 2H), 4.31 (d, J = 5.0 Hz, 2H), 5.61-5.68 (br, 1H), 6.35 (d, J = 2.5 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 6.91 (t, J = 60.7 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 2.5 Hz, 1H). I - 119 1H-NMR (CDCl3) δ: 1.03 (t, J = 7.4 Hz, 3H), 1.54 (d, J = 11.5 Hz, 1H), 1.74-1.85 (m, 2H), 2.00-2.10 (m, 1H), 2.62-2.94 (m, 2H), 3.16-3.32 (m, 2H), 3.90 (t, J = 6.6 Hz, 2H), 4.33 (d, J = 5.1 Hz, 2H), 4.54 (s, 2H), 4.504.68 (m, 1H), 4.79 (d, J = 50.9 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 7.12 (s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 7.35-7.38 (m, 2H), 8.24 (d, J = 1.9 Hz, 1H). I - 120 1H-NMR (CDCl3) δ: 0.19-0.27 (m, 1H), 0.40-0.56 (m, 3H), 1.68-1.75 (m, 1H), 1.94-2.06 (m, 2H), 2.11-2.20 (m, 1H), 2.24 (s, 3H), 2.33 (s, 3H), 2.48- 2.54 (m, 1H), 2.89-2.97 (m, 1H), 4.27-4.52 (m, 5H), 5.93-6.04 (m, 1H), 7.08-7.13 (m, 4H), 7.23 (dd, J = 8.5, 4.3 Hz, 1H), 7.34 (td, J = 8.4, 2.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H).
TABLE-US-00037 TABLE 37 I - 121 1H-NMR (CDCl3) δ: 1.69 (4H, br s), 2.05-2.07 (2H, m), 2.27 (3H, s), 2.86- 2.89 (2H, br m), 2.93 (6H, s), 4.29-4.30 (3H, m), 4.37 (2H, s), 6.39 (1H, s), 6.68 (2H, d, J = 8.5 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.29 (1H, d, J = 4.5 Hz), 7.33-7.37 (1H, m), 8.27 (1H, d, J = 2.8 Hz). I - 122 1H-NMR (CDCl3) δ: 1.02 (t, J = 7.4 Hz, 3H), 1.60-1.65 (m, 1H), 1.79 (qt, J = 7.4 Hz, 6.6 Hz, 2H), 2.02-2.13 (m, 1H), 2.73-2.92 (m, 2H), 3.18-3.30 (m, 2H), 3.71 (s, 3H), 3.89 (t, J = 6.6 Hz, 2H), 4.27-4.37 (m, 2H), 4.40 (s, 2H), 4.50-4.66 (m, 1H), 4.78 (d, J = 51.2 Hz, 1H), 6.15 (d, J = 1.6 Hz, 1H), 6.50 (br s, 1H), 6.81 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 1.6 Hz, 1H). I - 123 1H-NMR (CDCl3) δ: 1.03 (t, J = 7.4 Hz, 3H), 1.60-1.65 (m, 1H), 1.79 (qt, J = 7.4 Hz, 6.5 Hz, 2H), 2.08 (ddd, J = 25.1, 12.6, 4.1 Hz, 1H), 2.21 (s, 3H), 2.73-2.92 (m, 2H), 3.18-3.31 (m, 2H), 3.57 (s, 3H), 3.90 (t, J = 6.5 Hz, 2H), 4.49-4.64 (m, 1H), 4.79 (d, J = 51.3 Hz, 1H), 5.92 (s, 3H), 6.58 (br s, 1H), 6.81 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H) I - 124 1H-NMR (CDCl3) δ: 1.01 (d, J = 6.7 Hz, 6H), 1.60-1.67 (m, 1H), 1.93-2.11 (m, 2H), 2.72-2.94 (m, 2H), 3.16-3.29 (m, 2H), 3.55 (s, 3H), 3.70 (d, J = 6.4 Hz, 2H), 4.20-4.42 (m, 4H), 4.55-4.69 (m, 1H), 4.80 (d, J = 51.3 Hz, 1H), 5.11 (br s, 1H), 5.97 (br s, 1H), 6.39 (br s, 1H), 6.52 (br s, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H). I - 125 1H-NMR (CDCl3) δ: 0.64-0.68 (2H, m), 0.91-0.96 (2H, m), 1.73-1.76 (4H, m), 1.84-1.90 (1H, m), 2.06-2.09 (2H, m), 2.28 (3H, s), 2.89 (2H, d, J = 11.4 Hz), 4.25-4.31 (1H, m), 4.37 (4H, d, J = 7.3 Hz), 6.66 (1H, s), 7.00 (2H, d, J = 7.9 Hz), 7.14 (2H, d, J = 7.9 Hz), 7.29 (1H, t, J = 4.3 Hz), 7.36 (1H, td, J = 8.3, 2.4 Hz), 8.26 (1H, d, J = 2.4 Hz). I - 126 1H-NMR (CDCl3) δ: 0.18-0.22 (m, 1H), 0.41-0.44 (m, 1H), 0.48-0.54 (m, 2H), 1.02 (t, J = 6.8 Hz, 3H), 1.75-1.86 (m, 3H), 1.98-2.23 (m, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 2.54 (d, J = 10.4 Hz, 1H), 2.97-3.02 (m, 1H), 3.55 (s, 3H), 3.88 (t, J = 6.8 Hz, 2H), 4.09-4.24 (m, 3H), 4.34 (dd, J = 14.4, 5.2 Hz, 1H), 4.59-4.64 (m, 1H), 5.83 (s, 1H), 6.06 (br s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H). I - 127 1H-NMR (CDCl3) δ: 0.18-0.22 (m, 1H), 0.41-0.44 (m, 1H), 0.48-0.54 (m, 2H), 1.02 (t, J = 6.8 Hz, 3H), 1.75-1.86 (m, 3H), 1.98-2.23 (m, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 2.54 (d, J = 10.4 Hz, 1H), 2.97-3.02 (m, 1H), 3.55 (s, 3H), 3.88 (t, J = 6.8 Hz, 2H), 4.09-4.24 (m, 3H), 4.34 (dd, J = 14.4, 5.2 Hz, 1H), 4.59-4.64 (m, 1H), 5.83 (s, 1H), 6.06 (br s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H).
TABLE-US-00038 TABLE 38 I - 128 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.7 Hz), 1.69-1.76 (m, 4H), 2.00-2.12 (m, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 2.90 (d, 2H, J = 10.9 Hz), 3.69 (d, 2H, J = 6.5 Hz), 3.95-4.07 (m, 1H), 4.33 (d, 2H, J = 5.4 Hz), 4.47 (s, 2H), 4.61- 4.67 (m, 1H), 5.98 (d, 2H, J = 53.7 Hz), 5.99 (s, 1H), 6.83 (d, 2H, J = 8.5 Hz), 7.14 (d, 2H, J = 8.4 Hz). I - 129 1H-NMR (CDCl3) δ: 0.98 (d, 6H, J = 6.5 Hz), 1.48-1.68 (m, 3H), 1.82-1.94 (m, 1H), 1.95-2.08 (m, 1H), 2.71-2.96 (m, 4H), 3.16-3.29 (m, 2H), 4.27 (d, 2H, J = 4.8 Hz), 4.50-4.90 (m, 2H), 4.53 (s, 2H), 6.54 (d, 2H, J = 8.0 Hz), 6.87 (br s, 1H), 7.05 (d, 2H, J = 8.0 Hz), 7.35-7.36 (m, 2H), 8.24 (s, 1H). I - 130 1H-NMR (400 MHz, CDCl3) δ1.66-1.82 (m, 4H), 2.05-2.10 (m, 2H), 2.28 (s, 3H), 2.30 (s, 3H), 2.89 (d, J = 11.2 Hz, 2H), 3.73 (s, 3H), 4.28-4.32 (m, 1H), 4.34 (s, 2H), 4.42 (d, J = 6.0 Hz, 2H), 4.43 (s, 2H), 7.17 (d, J = 8.0 Hz), 7.24-7.28 (m, 4H), 7.32-7.34 (m, 1H), 7.46 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H). I - 131 1H-NMR (400 MHz, CDCl3) δ1.60-1.80 (m, 4H), 2.15-2.12 (m, 2H) 2.28 (s, 3H), 2.90 (d, J = 11.2 Hz, 2H), 3.73 (s, 3H), 4.26-4.32 (m, 1H), 4.39 (s, 2H), 4.41 (d, J = 6.0 Hz, 2H), 4.45(s, 2H), 6.76-6.82 (m, 1H), 7.23-7.31 (m, 4H), 7.37 (dd, J = 2.8, 8.4 Hz, 1H), 8.26 (d, J = 2.4, 1H). I - 132 1H-NMR (CDCl3) δ: 1.01 (6H, d, J = 6.7 Hz), 1.63 (1H, br s), 2.03-2.10 (2H, m), 2.74-2.94 (2H, m), 3.19-3.31 (2H, m), 3.69-3.72 (5H, m), 4.27- 4.37 (2H, m), 4.41 (2H, s), 4.58 (1H, dd, J = 35.7, 10.4 Hz), 4.79 (1H, d, J = 50.8 Hz), 6.16 (1H, d, J = 1.8 Hz), 6.51 (1H, br s), 6.81 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz), 7.24 (1H, d, J = 1.9 Hz). I - 133 1H-NMR (CDCl3) δ: 1.01 (6H, d, J = 6.8 Hz), 1.62 (1H, br s), 2.02-2.12 (2H, m), 2.21 (3H, s), 2.74-2.92 (2H, m), 3.24 (2H, dd, J = 29.7, 14.9 Hz), 3.57 (3H, s), 3.69 (2H, d, J = 6.5 Hz), 4.30-4.34 (4H, m), 4.57 (1H, dt, J = 35.4, 6.4 Hz), 4.78 (1H, d, J = 50.8 Hz), 5.92 (1H, s), 6.82 (1H, br s), 6.81 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz). I - 134 1H-NMR (CDCl3) δ: 1.03 (3H, t, J = 7.4 Hz), 1.64 (1H, d, J = 12.7 Hz), 1.75-1.84 (2H, m), 1.95-2.05 (1H, m), 2.74-2.94 (2H, m), 3.16-3.30 (2H, m), 3.55 (3H, s), 3.89 (2H, t, J = 6.6 Hz), 4.21-4.42 (4H, m), 4.55-4.69 (1H, m), 4.80 (1H, d, J = 51.1 Hz), 5.12 (1H, br s), 5.97 (1H, s), 6.39 (1H, s), 6.52 (1H, s), 6.79 (2H, d, J = 8.5 Hz), 7.00 (2H, d, J = 8.5 Hz). I - 135 1H-NMR (CDCl3) δ: 1.01 (6H, d, J = 6.5 Hz), 1.72-1.73 (4H, m), 2.08 (3H, s), 2.29 (3H, s), 2.91 (2H, d, J = 11.5 Hz), 3.53 (3H, s), 3.69 (2H, d, J = 6.8 Hz), 4.11 (2H, s), 4.31-4.33 (3H, m), 5.62 (1H, d, J = 5.8 Hz), 5.98 (1H, s), 6.81 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz).
TABLE-US-00039 TABLE 39 I - 136 1H-NMR (CDCl3) δ: 0.30-0.36 (m, 1H), 0.43-0.48 (m, 1H), 0.58-0.71 (m, 2H), 1.02 (d, 6H, J = 6.5 Hz), 1.37-1.47 (m, 1H), 1.86-1.97 (m, 1H), 2.03- 2.10 (m, 1H), 2.21-2.37 (m, 4H), 2.85-2.99 (m, 2H), 3.70 (d, 2H, J = 5.0 Hz), 4.33 (t, 2H, J = 4.5 Hz), 4.42 (s, 3H), 6.20 (br s, 1H), 6.82 (d, 2H, J = 8.0 Hz), 7.15 (d, 2H, J = 8.0 Hz), 7.28-7.40 (m, 2H), 8.29 (s, 1H). I - 137 1H-NMR (CDCl3) δ: 1.25 (d, 6H, J = 6.9 Hz), 1.65-1.80 (m, 4H), 2.03-2.13 (m, 2H), 2.28 (s, 3H), 2.47-2.53 (m, 1H), 2.86-2.93 (m, 2H), 4.22-4.33 (m, 1H), 4.35-4.40 (m, 4H), 6.80 (br s, 1H), 7.16 (br s, 1H), 7.22 (d, 2H, J = 8.3 Hz), 7.29 (dd, 1H, J = 8.6, 4.3 Hz), 7.37 (td, 1H, J = 8.3, 2.7 Hz), 7.46 (d, 2H, J = 8.3 Hz), 8.27 (d, 1H, J = 2.6 Hz). I - 138 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.5 Hz), 1.58-1.67 (m, 1H), 2.02-2.10 (m, 1H), 2.15-2.38 (m, 9H), 3.00 (d, 1H, J = 11.5 Hz), 3.14 (t, 1H, J = 11.9 Hz), 3.56 (s, 3H), 3.69 (d, 2H, J = 6.5 Hz), 4.27-4.50 (m, 5H), 4.79-4.91 (m, 1H), 5.93 (br s, 1H), 6.69 (br s, 1H), 6.81(d, 2H, J = 8.5 Hz), 7.14 (d, 2H, J = 8.5 Hz). I - 139 1H-NMR (CDCl3) δ: 1.03 (t, 3H, J = 7.5 Hz), 1.61-1.68 (m, 1H), 1.75-1.84 (m, 2H), 2.15-2.37 (m, 9H), 3.00 (d, 1H, J = 10.8 Hz), 3.14 (t, 1H, J = 11.9 Hz), 3.56 (s, 3H), 3.90 (t, 2H, J = 6.7 Hz), 4.26-4.51 (m, 5H), 4.79-4.91 (m, 1H), 5.93 (br s, 1H), 6.70 (br s, 1H), 6.81(d, 2H, J = 8.5 Hz), 7.15 (d, 2H, J = 8.5 Hz). I - 140 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.8 Hz), 1.60-1.70 (m, 1H), 1.75-1.84 (m, 2H), 2.01-2.11 (m, 1H), 2.15-2.33 (m, 6H), 2.97 (d, 1H, J = 11.0 Hz), 3.14 (t, 1H, J = 11.5 Hz), 3.55 (s, 3H), 3.70 (t, 2H, J = 7.9 Hz), 4.21-4.54 (m, 5H), 4.81-4.93 (m, 1H), 5.14 (t, 1H, J = 5.3 Hz), 5.96 (br s, 1H), 6.38 (br s, 1H), 6.51 (br s, 1H), 6.79(d, 2H, J = 8.5 Hz), 7.00 (d, 2H, J = 8.5 Hz). I - 141 1H-NMR (CDCl3) δ: 1.02 (t, 3H, J = 7.4 Hz), 1.66-1.84 (m, 2H), 2.16-2.34 (m, 6H), 2.98 (d, 1H, J = 9.0 Hz), 3.13 (t, 1H, J = 11.4 Hz), 3.55 (s, 3H), 3.89 (t, 2H, J = 6.7 Hz), 4.21-4.55 (m, 5H), 4.81-4.94 (m, 1H), 5.14 (t, 1H, J = 5.3 Hz), 5.96 (br s, 1H), 6.38 (br s, 1H), 6.51 (br s, 1H), 6.79(d, 2H, J = 8.5 Hz), 7.00 (d, 2H, J = 8.5 Hz). I - 142 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.7 Hz), 1.70-1.79 (m, 4H), 2.01-2.12 (m, 1H), 2.27 (s, 3H), 2.89 (d, 2H, J = 11.4 Hz), 3.68 (d, 2H, J = 6.5 Hz), 4.22 (s, 2H), 4.36-4.44 (m, 1H), 4.93 (t, 1H, J = 5.0 Hz), 6.08 (br s, 1H), 6.59 (br s, 1H), 6.73 (br s, 1H), 6.78 (d, 2H, J = 8.5 Hz), 7.02 (d, 2H, J = 8.5 Hz), 8.15 (br s, 1H). I - 143 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.7 Hz), 1.67-1.87 (m, 4H), 2.03-2.08 (m, 3H), 2.28 (s, 3H), 2.90 (d, 2H, J = 11.3 Hz), 3.69 (d, 2H, J = 6.5 Hz), 4.12 (br s, 1H), 4.31-4.35 (m, 4H), 6.19 (br s, 1H), 6.81 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.47 (br s, 1H). I - 144 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.8 Hz), 1.69-1.77 (m, 3H), 2.01-2.15 (m, 6H), 2.27 (s, 3H), 2.87 (d, 2H, J = 11.8 Hz), 3.39 (s, 3H), 3.68 (d, 2H, J = 6.7 Hz), 4.10 (s, 2H), 4.21 (d, 2H, J = 5.3 Hz), 4.34-4.42 (m, 1H), 5.00 (br s, 1H), 5.69 (br s, 1H), 6.29 (br s, 1H), 6.78 (d, 2H, J = 8.5 Hz), 7.02 (d, 2H, J = 8.5 Hz).
TABLE-US-00040 TABLE 40 I - 145 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.7 Hz), 1.57-1.65 (m, 2H), 2.02-2.12 (m, 2H), 2.74-2.93 (m, 2H), 3.19-3.31 (m, 2H), 3.69 (d, 2H, J = 6.8 Hz), 3.72 (s, 3H), 4.32 (d, 2H, J = 6.5 Hz), 4.38 (s, 3H), 4.53-4.84 (m, 2H), 5.23- 5.35 (m, 3H), 6.26 (br s, 1H), 6.26 (br s, 1H), 6.82(d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 8.5 Hz). I - 146 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.7 Hz), 1.60-1.67 (m, 2H), 2.02-2.10 (m, 1H), 2.15-2.36 (m, 6H), 3.00 (d, 1H, J = 11.5 Hz), 3.14 (t, 1H, J = 11.9 Hz), 3.69 (d, 2H, J = 6.8 Hz), 3.72 (s, 3H), 4.27-4.53 (m, 5H), 4.78-4.91 (m, 1H), 5.23-5.35 (m, 2H), 6.26 (br s, 1H), 6.26 (br s, 1H), 6.82(d, 2H, J = 8.5 Hz), 7.13 (d, 2H, J = 8.5 Hz). I - 147 1H-NMR (CDCl3) δ: 0.92 (d, 6H, J = 6.5 Hz), 1.49-1.66 (m, 3H), 2.01-2.08 (m, 1H), 2.13-2.34 (m, 4H), 2.92-3.00 (m, 4H), 3.05-3.18 (m, 3H), 4.29 (d, 2H, J = 5.0 Hz), 4.50-4.58 (m, 3H), 4.79-5.00 (m, 1H), 6.58 (d, 2H, J = 8.0 Hz), 7.08 (br s, 1H), 7.10 (d, 2H, J = 8.0 Hz), 7.31-7.38 (m, 2H), 8.23 (s, 1H). I - 148 1H-NMR (CDCl3) δ: 1.01 (d, 6H, J = 6.7 Hz), 1.64-1.77 (m, 4H), 2.01-2.12 (m, 1H), 2.27 (s, 3H), 2.88 (d, 2H, J = 11.4 Hz), 3.70 (d, 2H, J = 6.7 Hz), 4.19-4.28 (m, 3H), 4.36 (d, 2H, J = 5.3 Hz), 6.27 (br s, 1H), 6.84 (d, 2H, J = 8.5 Hz), 7.22 (d, 2H, J = 8.5 Hz), 7.52 (br s, 1H), 7.80 (br s, 1H).
[1017] The following is a description of a biological test example of the compound according to the present invention.
[1018] The compound represented by the Formula (I) or Formula (II) according to the present invention may have serotonin 5-HT2A receptor inverse agonism, and may antagonize the human serotonin 5-HT2A receptor.
[1019] Specifically, in the evaluation method described below, the Ki value is preferably 5000 nM or less, more preferably 1000 nM or less, even more preferably 100 nM or less.
Test Example 1: 5-HT2A Receptor Binding Inhibition Test
(Each Experimental Condition)
[1020] Cell membrane: 15 μg of Jump-In HEK cell membrane (expressing human recombinant 5-HT2A receptor) per well
[1021] Assay buffer: Tris-HCl 50 mmol/L (pH 7.4) containing NaCl 120 mmol/L, MgCl.sub.2.6H.sub.2O 1 mmol/L, KCl 5 mmol/L, 0.1% BSA and CaCl.sub.2 2 mmol/L
[1022] Radioactive ligand: [.sup.3H]-Ketanserin with a final concentration of 3 nmol/L
[1023] Non-specific ligand: Serotonin HCl with a final concentration of 500 μmol/L
[1024] The Kd value was calculated when the lot of cell membrane was changed. In advance, 0.5 μL of a 1 mmol/L compound for non-specific binding calculation dissolved in DMSO or DMSO was dispensed into a microplate, and the cell membrane was diluted with an Assay buffer. The radioactive ligand solution was serially diluted from 16 nM at a 2-fold ratio and the count was confirmed with a liquid scintillator. Assay buffer containing diluted cell membrane was dispensed into a microplate at 50 μL/well. Then, the radioactive ligand solution was dispensed into a microplate at 50 μL/well, and the plate was sealed. It was allowed to stand at room temperature (25° C.) for 1.5 hours. During this period, 50 mmol/L Tris-HCl (pH 7.4) was dispensed into a GF/B UniFilter plate at 50 μL/well and allowed to stand at 4° C. for 1 hour or longer. After that, filtration was performed with Cell harvester (PerkinElmer). The radioactive ligand solution was dispensed into an empty well of the GF/B UniFilter plate at 10 μL/well. After the GF/B UniFilter plate was dried at room temperature, MicroScinti 20 was dispensed into the GF/B UniFilter plate at 50 μL/well to seal the plate. The GF/B UniFilter plate was allowed to stand overnight at room temperature. The radioactivity of [.sup.3H]-Ketanserin bound to the 5-HT2A receptor was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min/well. The Saturation curve was drawn from the measured value, and the Kd value was calculated from the slope of the Scatchard Plot.
(Binding Test of the Compound According to the Present Invention)
[1025] In advance, 0.5 μL of the compound solution dissolved in DMSO was dispensed into a microplate, and the cell membrane and the hot ligand were diluted with Assay buffer, respectively. Then, the Assay buffer containing the diluted cell membrane was dispensed into a microplate at 50 μL/well. Then, the radioactive ligand solution was dispensed into a microplate at 50 μL/well, and the plate was sealed. Then, it was allowed to stand at room temperature (25° C.) for 1.5 hours. During this period, 50 mmol/L Tris-HCl (pH 7.4) was dispensed into a GF/B UniFilter plate at 50 μL/well and allowed to stand at 4° C., for 1 hour or longer. After that, filtration was performed with Cell harvester (PerkinElmer). After the GF/B UniFilter plate was dried at room temperature. MicroScinti 20 was dispensed into the GF/B UniFilter plate at 50 μL/well, and the plate was sealed. The GF/B UniFilter plate was allowed to stand at room temperature overnight. The radioactivity of [.sup.3H]-Ketanserin bound to the 5-HT2A receptor was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min/well. The non-specific binding was calculated from the radioactivity of [.sup.3H]-Ketanserin in the presence of 500 μmol/L Serotonin HCl with the unlabeled ligand, and the total binding was calculated from the radioactivity of [.sup.3H]-Ketanserin in the absence of the compound according to the present invention (Vehicle). Finally, the Ki value was calculated from the dose-response curve.
[1026] (The binding activity of the compound according to the present invention was calculated from the following binding inhibition rate (%).)
Inhibition rate (%)=[1.Math.(c.Math.a)/(b.Math.a)]×100
[1027] a: mean cpm of non-specific binding
[1028] b; average cpm of total binding
[1029] c; cpm in the presence of the test compound
(Result)
[1030] The evaluation results regarding the human serotonin 5-HT2A receptor binding activity of the compound according to the present invention are shown below. In the table shown below, “A” means that the Ki value is less than 10 nM, “B” means that the Ki value is 10 nM or more, and less than 100 nM, and “C” means that the Ki value is 100 nM or more. [1031] Compound I-009: 0.291 nM [1032] Compound I-021: 0.858 nM [1033] Compound I-037: 0.654 nM [1034] Compound I-042: 1.15 nM [1035] Compound I-043: 2.52 nM [1036] Compound I-068: 6.52 nM [1037] Compound I-071: 13.3 nM [1038] Compound I-072: 219 nM [1039] Compound I-075: 130 nM [1040] Compound I-076: 62 nM [1041] Compound I-082: 3.74 nM [1042] Compound I-084: 5.61 nM [1043] Compound I-085: 23.8 nM [1044] Compound I-088: 25.7 nM [1045] Compound I-102: 0.919 nM [1046] Compound I-116: 1.45 nM [1047] Compound I-124: 0.690 nM [1048] Compound I-126: 1.92 nM [1049] Compound I-129: 0.85 nM [1050] Compound I-130: 15.3 nM [1051] Compound I-134: 0.475 nM [1052] Compound I-136: 8.02 nM [1053] Compound I-139: 2.93 nM [1054] Compound I-146: 1.94 nM [1055] Compound I-147: 0.758 nM
TABLE-US-00041 TABLE 41 Compound No. h-5-HT2A Ki I - 001 A I - 002 C I - 003 C I - 004 C I - 005 C I - 006 C I - 007 C I - 008 A I - 010 A I - 011 B I - 012 A I - 013 A I - 014 A I - 015 C I - 016 B I - 017 B I - 018 B I - 019 C I - 020 B I - 022 C I - 023 C I - 024 C I - 025 A I - 026 B I - 027 A I - 028 A I - 029 A I - 030 A I - 031 A I - 032 B I - 033 C I - 034 C I - 035 B I - 036 C I - 038 B I - 039 C I - 040 A I - 041 A I - 044 A I - 045 A I - 046 A I - 047 A I - 048 A I - 049 A I - 050 A I - 051 A I - 052 A I - 053 A I - 054 A I - 055 A I - 056 A I - 057 A I - 058 A I - 059 A I - 060 A I - 061 A I - 062 A I - 063 A I - 064 A I - 065 A I - 066 A I - 067 A
TABLE-US-00042 TABLE 42 Compound No. h-5-HT2A Ki I-069 B I-070 A I-073 B I-074 B I-077 B I-078 B I-079 C I-080 B I-081 C I-083 A I-086 C I-087 C I-089 A I-090 A I-091 A I-092 A I-093 A I-094 A I-095 A I-096 A I-097 A I-098 A I-099 A I-100 A I-101 A I-103 A I-104 A I-105 A I-106 A I-107 A I-108 A I-109 A I-110 A I-111 A I-112 A I-113 A I-114 A I-115 A I-117 A I-118 A I-119 A I-120 A I-121 B I-122 A I-123 A I-125 A I-127 C
TABLE-US-00043 TABLE 43 Compound No. h-5-HT2A Ki I - 128 B I - 131 B I - 132 A I - 133 A I - 135 A I - 137 C I - 138 A I - 140 A I - 141 A I - 142 B I - 143 B I - 144 A I - 145 A I - 148 B
Test Example 2: 5-HT2C Receptor Binding Inhibition Test
(Each Experimental Condition)
[1056] Cell membrane: 0.5 μg of Jump-In HIEK cell membrane (expressing human recombinant 5-HT2C receptor) per well
[1057] Assay buffer: Tris-HCl 50 mmol/L (pH 7.4) containing NaCl 120 mmol/L, MgCl.sub.2.6H.sub.2O 1 mmol/L, KCl 5 mmol/L, 0.1% BSA and CHCl.sub.2 2 mmol/L
[1058] Radioactive ligand: [.sup.3H]-Mesulergine with a final concentration of 1 nmol/L
[1059] Non-specific ligand: Serotonin HCl with a final concentration of 500 μmol
[1060] The Kd value was calculated when the lot, of cell membrane was changed. In advance, 0.5 μL of a 1 mmol/L compound for non-specific binding calculation dissolved in DMSO or DMSO was dispensed into a microplate, and the cell membrane was diluted with an Assay buffer. The radioactive ligand solution was serially diluted from 16 nM at a 2-fold ratio and the count was confirmed with a liquid scintillator. Assay buffer containing diluted cell membrane was dispensed into a microplate at 50 μL/well. Then, the radioactive ligand solution was dispensed into a microplate at 50 μL/well, and the plate was sealed. It was allowed to stand at room temperature (25° C.) for 1.5 hours. During this period, 50 mmol/L Tris-HCl (pH 7.4) was dispensed into a GF/B UniFilter plate at 50 μL/well and allowed to stand at 4° C. for 1 hour or longer. After that, filtration was performed with Cell harvester (PerkinElmer). The radioactive ligand solution was dispensed into an empty well of the GF/B UniFilter plate at 10 μL/well. After the GF/B UniFilter plate was dried at room temperature, MicroScinti 20 was dispensed into the GF/B UniFilter plate at 50 μL/well to seal the plate. The GF/B UniFilter plate was allowed to stand overnight at room temperature. The radioactivity of [.sup.3H]-Ketanserin bound to the 5-HT2A receptor was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min/well. The Saturation curve was drawn from the measured value, and the Kd value was calculated from the slope of the Scatchard Plot.
(Binding Test of the Compound According to the Present Invention)
[1061] In advance, 0.5 μL of the compound solution dissolved in DMSO was dispensed into a microplate, and the cell membrane and the hot ligand were diluted with Assay buffer, respectively. Then, the Assay buffer containing the diluted cell membrane was dispensed into a microplate at 50 μL/well. Then, the radioactive ligand solution was dispensed into a microplate at 50 μL/well, and the plate was sealed. Then, it was allowed to stand at room temperature (25° C.) for 1.5 hours. During this period, 50 mmol/L Tris-HCl (pH 7.4) was dispensed into a GF/B UniFilter plate at 50 μL/well and allowed to stand at 4° C., for 1 hour or longer. After that, filtration was performed with Cell harvester (PerkinElmer). After the GF/B UniFilter plate was dried at room temperature, MicroScinti 20 was dispensed into the GF/B UniFilter plate at 50 μL/well, and the plate was sealed. The GF/B UniFilter plate was allowed to stand at room temperature overnight. The radioactivity of [.sup.3H]-Mesulergine bound to the 5-HT2A receptor was measured using Microbeta2 (PerkinElmer) at a measurement time of 1 min/well. The non-specific binding was calculated from the radioactivity of [.sup.3H]-Mesulergine in the presence of 500 μmol/L Serotonin HCl with the unlabeled ligand, and the total binding was calculated from the radioactivity of [.sup.3H]-Mesulergine in the absence of the compound according to the present invention (Vehicle). Finally, the Ki value was calculated from the dose-response curve.
[1062] (The binding activity of the compound according to the present invention was calculated from the following binding inhibition rate (%).)
Inhibition rate (%)=[1.Math.(c.Math.a)/(b.Math.a)]×100
[1063] a: mean cpm of non-specific binding
[1064] b: average cpm of total binding
[1065] c: cpm in the presence of the test compound
(Result)
[1066] The evaluation results regarding the human serotonin 5-HT2C receptor binding activity of the compound according to the present invention are shown below. In the table shown below, “A” means that the Ki value is less than 10 nM, “B” means that the Ki value is 10 nM or more, and less than 100 nM, and “C” means that the Ki value is 100 nM or more. [1067] Compound I-009: 7.92 nM [1068] Compound I-021: 50.7 nM [1069] Compound I-037: 28.2 nM [1070] Compound I-042: 2.31 nM [1071] Compound I-043: 55.7 nM [1072] Compound I-068: 49.9 nM [1073] Compound I-071: 60.7 nM [1074] Compound I-072: 617 nM [1075] Compound I-075: 1310 nM [1076] Compound I-076: 263 nM [1077] Compound I-082: 28.8 nM [1078] Compound I-084: 65.2 nM [1079] Compound I-085: 96.2 nM [1080] Compound I-088: 134 nM [1081] Compound I-102: 4.01 nM [1082] Compound I-116: 12.2 nM [1083] Compound I-124: 2.22 nM [1084] Compound I-126: 1.09 nM [1085] Compound I-129: 1.51 nM [1086] Compound I-130: 348 nM [1087] Compound I-134: 3.2 nM [1088] Compound I-136: 148 nM [1089] Compound I-139: 11.1 nM [1090] Compound I-146: 4.96 nM [1091] Compound I-147: 2.12 nM
TABLE-US-00044 TABLE 44 Compound No. h5-HT2C Ki I - 001 B I - 002 C I - 003 C I - 004 C I - 005 C I - 006 C I - 007 C I - 008 A I - 010 B I - 011 C I - 012 B I - 013 A I - 014 B I - 015 C I - 016 C I - 017 C I - 018 C I - 019 C I - 020 B I - 022 C I - 023 C I - 024 C I - 025 B I - 026 C I - 027 A I - 028 C I - 029 B I - 030 B I - 031 B I - 032 C I - 033 C I - 034 C I - 035 C I - 036 C I - 038 C I - 039 C I - 040 B I - 041 B I - 044 C I - 045 C I - 046 B I - 047 A I - 048 B I - 049 B I - 050 A I - 051 A I - 052 B I - 053 A I - 054 A I - 055 A I - 056 A I - 057 A I - 058 A I - 059 A I - 060 B I - 061 A I - 062 A I - 063 A I - 064 A I - 065 A I - 066 A I - 067 A
TABLE-US-00045 TABLE 45 Compound No. h-5-HT2C Ki I-069 C I-070 B I-073 C I-074 B I-077 C I-078 C I-079 C I-080 B I-081 C I-083 B I-086 C I-087 B I-089 B I-090 A I-091 A I-092 A I-093 A I-094 A I-095 A I-096 B I-097 B I-098 B I-099 A I-100 B I-101 B I-103 A I-104 A I-105 A I-106 A I-107 B I-108 A I-109 A I-110 A I-111 A I-112 A I-113 B I-114 A I-115 A I-117 A I-118 B I-119 A I-120 A I-121 C I-122 B I-123 B I-125 B I-127 C
TABLE-US-00046 TABLE 46 Compound No. h-5-HT2C Ki I - 128 B I - 131 C I - 132 B I - 133 A I - 135 B I - 137 C I - 138 A I - 140 A I - 141 A I - 142 C I - 143 C I - 144 A I - 145 A I - 148 C
Test Example 3: hERG Test
[1092] For the purpose of assessing risk of an electrocardiogram QT interval prolongation of the compound according to the present invention, effects of the compound according to the present invention on delayed rectifier K.sup.+ current (I.sub.Kr), which plays an important role in the ventricular repolarization process, was studied using CHO cells expressing human ether-a-go-go related gene (hERG) channel.
[1093] After a cell was retained at a membrane potential of −80 mV by whole cell patch clamp method using an automated patch clamp system (QPatch; Sophion Bioscience A/S) and gave a leak potential of −50 mV, IKr induced by depolarization pulse stimulation at +20 mV for 2 seconds, and further, repolarization pulse stimulation at −50 mV for 2 seconds, was recorded. A vehicle, which was the 0.1% dimethyl sulfoxide solution in extracellular solution (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCI.sub.2: 2 mmol/L, MgCl.sub.2: 1 mmol/L, glucose:10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH7.4), or the compound according to the present invention had been dissolved at an objective concentration in the extracellular solution, each of the extracellular solution was applied to the cell at room temperature for 15 minutes or more. From the recording I.sub.Kr, an absolute value of the tail peak current was measured based on the current value at the resting membrane potential using analysis software (QPatch Assay software; Sophion Bioscience A/S). The % inhibition of the tail peak current after application of the compound according to the present invention relative to the tail peak current after application of the vehicle was calculated, and further correction was performed using the inhibition rate result of the negative control to assess influence of the compound according to the present invention on I.sub.Kr.
(Results) The inhibition rate at a compound concentration of 3 μmol/L is shown below. [1094] Compound I-129: 31.4% [1095] Compound I-133: 6.60% [1096] Compound I-134: 31.2% [1097] Compound I-139: 14.2% [1098] Compound I-141: 49.3%
Test Example 4: BA Test
[1099] Materials and methods for experiments to evaluate oral absorption [1100] (1) Experimental animals: Mise or rats are used. [1101] (2) Rearing condition: Mice or rats are allowed free access to solid feed and sterilized tap water. [1102] (3) Setting of dosage and grouping: Oral administration and intravenous administration are performed with the predetermined dosage. Grouping is set as below. (Dosage can be changed per compound) [1103] Oral administration 2 to 60 μmol/kg or 1 to 30 mg/kg (n=2 to 3) [1104] Intravenous administration 1 to 20 pimol/kg or 0.5 to 10 mg/kg (n=2 to 3) [1105] (4) Preparation of administration solutions: Oral administration is performed as solution or suspension. Intravenous administration is performed after solubilization. [1106] (5) Routes of administration: Oral administration is performed mandatory into the stomach by oral sonde. Intravenous administration is performed from caudal vein by syringes with needle. [1107] (6) Evaluation items: Blood is collected serially and concentration of a compound according to the present invention in plasma is measured by LC/MS/MS. [1108] (7) Statistical analysis: About transition of concentration of a compound according to the present invention in plasma, the area under the plasma concentration versus time curve (AUC) is calculated by moment analysis method, and bioavailability (BA) of a compound according to the present invention is calculated from dosages and AUCs of the oral administration group and the intravenous administration group. The dilution concentration or the dilution solvent are changed as necessary.
Test Example 5: Clearance Test
Materials and Methods for Experiments
[1109] (1) Experimental animals: SD rats are used. [1110] (2) Rearing condition: SD rats are allowed free access to solid feed and sterilized tap water. [1111] (3) Setting of dosage and grouping: Intravenous administration was performed with the predetermined dosage. Grouping is set as below. [1112] Intravenous administration 1 μmol/kg (n=2) [1113] (4) Preparation of administration solutions: Administration is performed after solubilization by using dimethyl sulfoxide/propylene glycol=1/1 as the solvent. [1114] (5) Routes of administration: Intravenous administration is performed from caudal vein by syringes with needle. [1115] (6) Evaluation items: Blood is collected serially and concentration of a compound according to the present invention in plasma is measured by LC/MS/MS. [1116] (7) Statistical analysis: About transition of concentration of a compound according to the present invention in plasma, total clearance (CLtot) of a compound according to the present invention is calculated by the moment analysis method. The dilution concentration or the dilution solvent are changed as necessary.
Test Example 6: Metabolism Stability Test
[1117] Using commercially available pooled human hepatic microsomes, a compound according to the present invention is reacted for a constant time, and a remaining rate is calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver is assessed.
[1118] A reaction is performed (oxidative reaction) at 37° C., for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL, of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes. After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound according to the present invention in the supernatant is quantified by LC/MS/MS or Solid Phase Extraction (SPE)/MS, and a remaining amount of the compound according to the present invention after the reaction is calculated, letting a compound amount at 0 minute reaction time be 100%.
Test Example 7: P-gp Substrate Test
[1119] The compound according to the present invention is added to one side of a Transwell (registered trademark, CORNING) in which human MDR1-expressing cells or parent cells are cultured in a single layer, and reacted for a certain period of time. For MDR1-expressing cells and parent cells, the membrane permeability coefficients from the Apical side to the Basolaternal side (A.fwdarw.B) and from the Basolaternal side to the Apical side (B.fwdarw.A) are calculated, and Efflux Ratio (ER: Ratio of membrane permeability coefficients of B.fwdarw.A and A.fwdarw.B) value of the MDR1-expressing cells and the parent cells are calculated. The Efflux Ratio (ER value) of the MDR1-expressing cell and the parent cell are compared to determine whether the compound according to the present, invention is a P-gp substrate or not.
[1120] The following formulation examples are merely examples, and are not intended to limit the scope of the invention.
[1121] The compound according to the present invention can be administered as a pharmaceutical composition by any conventional route, in particular enterally, for example, orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injectable solutions or suspensions, topically, for example, in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants and the like and active ingredients. Compositions for injection can be solutions or suspension, may be sterilized, and may contain preservatives, stabilizers, buffering agents, and the like.
INDUSTRIAL APPLICABILITY
[1122] The compound according to the present invention has serotonin 5-HT2A receptor inverse agonism, and the compound is considered to be useful as a therapeutic and/or prophylactic agent for a disease or condition associated with serotonin 5-HT2A receptor.