(en)A compound of the formula (I):









pharmaceutically acceptable salt or solvate thereof,
wherein
Y is a group of the formula:











wherein Ring A is optionally substituted aryl or optionally substituted heteroaryl, X 3 is COOR 17 or the like
Y is not optionally substituted phenyl which is substituted with the formula: —CR 9 R 10 X 3 at the para position,
R 1 to R 10 are each independently halogen, hydroxy, optionally substituted lower alkyl, optionally substituted aryl or the like,
X 1 is —O—, —S— or the like.

1.ApplicationNumber: US-92099906-A
1.PublishNumber: US-7781469-B2
2.Date Publish: 20100824
3.Inventor: KANDA YASUHIKO

4.Inventor Harmonized: KANDA YASUHIKO(JP)

5.Country: US
6.Claims:
(en)A compound of the formula (I):









pharmaceutically acceptable salt or solvate thereof,
wherein
Y is a group of the formula:











wherein Ring A is optionally substituted aryl or optionally substituted heteroaryl, X 3 is COOR 17 or the like
Y is not optionally substituted phenyl which is substituted with the formula: —CR 9 R 10 X 3 at the para position,
R 1 to R 10 are each independently halogen, hydroxy, optionally substituted lower alkyl, optionally substituted aryl or the like,
X 1 is —O—, —S— or the like.

7.Description:
(en)This application is a U.S. national stage of International Application No. PCT/JP2006/310198 filed May 23, 2006.
FIELD OF THE INVENTION
The present invention relates to new compounds which have an agonistic activity of a peroxisome proliferator-activated receptor (referred to below as PPAR) and which are useful as a medicine.
BACKGROUND ART
Peroxisome proliferators which proliferate an intracellular granule, peroxisome, are thought as important controlling elements of lipid metabolism. A nuclear receptor, PPAR, which is activated by the peroxisome proliferator has turned out to be a multifunctional receptor concerning incretion, metabolism, inflammation or the like. Therefore, the ligand is thought to be able to apply as various medicines and the number of researches is recently increasing.
The subtype genes of PPARs are found from various animal organs and formed a family. In mammals, PPARs are classified into three subtypes of PPARα, PPARδ (also referred to as PPARβ) and PPARγ.
The drugs of the fibrate group used as an antihyperlipemic drug are thought to show the activity by PPARα activation-mediated transcriptional enhancement of the gene group which improves serum lipid. Additionally, it is suggested that PPARα may relate to bone metabolism and expression of the activity of non-steroidal anti-inflammatory drugs.
The thiazolidindion compounds, which are improving drugs for insulin resistance, are ligands of PPARγ. As these compounds show hypoglycemic action, hypolipidemic action, adipocyte differentiation-inducing action or the like, PPARγ agonists are expected to develop as therapeutic agents for diabetes, hyperlipidemia, obesity or the like. Furthermore, PPARγ agonists are expected to be therapeutic agents for chronic pancreatitis, inflammatory colitis, glomerulosclerosis, Alzheimer's disease, psoriasis, parkinsonism, Basedow's disease, chronic rheumatoid arthritis, cancer (breast cancer, colonic cancer, prostatic cancer or the like), sterility or the like.
It was reported that transgenic mice in which PPARδ is overexpressed specifically in adipocyte were difficult to get fat or the like. Therefore, PPARδ agonists can be used as an antiobestic drug or an antidiabetic drug. Additionally, PPARδ agonists are suggested the possibility as therapeutic agents for colonic cancer, osteoporosis, sterility, psoriasis, multiple sclerosis or the like.
Based on these findings, PPAR agonists are expected to be useful for treatment or prevention of hyperlipidemia, diabetes, hyperglycosemia, insulin resistance, obesity, arteriosclerosis, atherosclerosis, hypertension, syndrome X, inflammation, allergic disease (inflammatory colitis, chronic rheumatoid arthritis, chronic pancreatitis, multiple sclerosis, glomerulosclerosis, psoriasis or the like), osteoporosis, sterility, cancer, Alzheimer's disease, parkinsonism, Basedow's disease or the like (Non-Patent Document 1).
Patent Document 1 and Patent Document 2 disclosed various compounds having PPAR agonistic activity, for example, isoxazole compounds. However, compounds of the present invention were not disclosed. Furthermore, isoxazole compounds in Patent Document 2 have substituents on isoxazole in the different position compared to compounds of the present invention. Additionally, although PPARα and (or) PPARγ agonistic activity of the compounds were recognized, no data of PPARδ agonistic activity was disclosed. Furthermore, there was no data of isoxazole compounds even about PPARα or γ agonistic activity. In a word, the PPAR agonistic activity was not recognized.
Although Patent Document 3 disclosed isoxazole compounds, the compounds have substituents on isoxazole in the different position compared to compounds of the present invention. Furthermore, it was disclosed that the compounds are useful for hypercholesterolemia or hyperlipidemia. However, the PPAR agonistic activity was not disclosed.
Although Patent Document 4, 5 and 6 disclosed thiazole, oxazole and pyrazole compounds with PPARδ agonistic activity. However, isoxazole compounds were not suggested.
Patent Document 7, 8 and 9 disclosed isoxazole compounds. However, compounds of this invention were not disclosed.
[Patent Document 1] WO 99/11255 [Patent Document 2] WO 99/58510 [Patent Document 3] EP 0558062 [Patent Document 4] WO 01/00603 [Patent Document 5] WO 99/46232 [Patent Document 6] WO 04/063166 [Patent Document 7] WO 02/053547 [Patent Document 8] WO 03/099793 [Patent Document 9] WO 04/091604 [Non-patent Document 1] Current Medicinal Chemistry, 2003, Vol. 10, p.p. 267-280

DISCLOSURE OF INVENTION
Problems to be solved by the Invention
The objection of the present invention is to provide good PPAR agonists.
Means for Solving the Problem
The present inventors have intensively studied to synthesize new good PPAR agonists as below. Compounds which have hydrogen at the 4 position of isoxazole and phenylacetic acid at the terminal are disclosed in Patent Document 8. However, the present inventors found that PPAR transcription activity of compounds, of which the hydrogen at the 4 position is substituted for the other substituent such as methyl, is greatly improved compared to the compounds before substitution. Furthermore, the inventors found that compounds of the present invention are less toxic and thought to be safe enough for pharmaceutical use.
The present invention is the followings.
(1) A compound of the formula (I):

pharmaceutically acceptable salt or solvate thereof,
wherein Y is a group of the formula:

wherein Ring A is optionally substituted aryl or optionally substituted heteroaryl, R 9 and R 10 are each independently hydrogen, halogen, cyano, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted amino or optionally substituted aryl,
X 3 is COOR 17 , C(═NR 17 )NR 18 OR 19 or a group of the formula:

wherein R 17 to R 19 are each independently hydrogen or optionally substituted lower alkyl, provided that
Y is not optionally substituted phenyl which is substituted with a group of the formula: —CR 9 R 10 X 3 at the para position, R 1 is halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylthio, optionally substituted acyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted hydrazinocarbonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heterocycle, R 2 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylthio, optionally substituted acyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted hydrazinocarbonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heterocycle, R 3 and R 4 are each independently hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl or optionally substituted heterocycle, and X 1 is —O—, —S—, —NR 11 - wherein R 11 is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfony, —CR 12 R 13 CO—, —(CR 12 R 13 )mO—, —(CR 12 R 13 )mS—, —O(CR 12 R 13 )m- wherein R 12 and R13 are each independently hydrogen or optionally substituted lower alkyl, and m is an integer between 1 and 3, —ON═CR 14 - wherein R 14 is hydrogen or optionally substituted lower alkyl, or a group of the formula:

wherein R 15 and R 16 are each independently hydrogen or optionally substituted lower alkyl.

(2) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein Y is a group of the formula:


wherein
R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, cyano, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted acyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heterocycle, and R 9 , R 10 and X 3 have the same meaning as defined in (1).

(3) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein R 1 is optionally substituted aryl or heterocycle.

(4) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein R 2 is optionally substituted lower alkyl.

(5) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein R 3 and R 4 are hydrogen.

(6) The compound, pharmaceutically acceptable salt or solvate thereof according to (2), wherein R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, optionally substituted lower alkyl or optionally substituted lower alkoxy.

(7) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein R 9 and R 10 are each independently hydrogen or halogen.

(8) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein X 1 is O, S or —ON═CR 14 -wherein R 14 is hydrogen.

(9) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein X 3 is COOR 17 wherein R 17 is hydrogen or optionally substituted lower alkyl.

(10) The compound, pharmaceutically acceptable salt or solvate thereof according to (2), wherein R 1 is optionally substituted aryl or heterocycle,
the substituent(s) of said aryl of R 1 is/are selected from a group consisting of halogen, optionally substituted lower alkyl and optionally substituted lower alkoxy, R 2 is optionally substituted lower alkyl, the substituent(s) of said lower alkyl of R 2 is/are selected from a group consisting of optionally substituted lower alkoxy, lower alkylamino, optionally substituted imino, optionally substituted iminooxy, lower alkylsulfonyl, cycloalkyloxy, optionally substituted aryl and optionally substituted heterocycle, R 3 and R 4 are hydrogen, R 5 , R 6 , R 7 and R 8 are each independently, hydrogen, halogen, lower alkyl or lower alkoxy, R 9 and R 10 are each independently hydrogen or halogen, X 1 is O, S or —ON═CR 14 - wherein R 14 is hydrogen, and X 3 is COOR 17 wherein R 17 is hydrogen or lower alkyl.

(11) A pharmaceutical composition comprising the compound, pharmaceutically acceptable salt or solvate thereof according to any one of (1) to (10) as an active ingredient.

(12) A pharmaceutical composition for prevention and/or treatment for a disease concerning peroxisome proliferator-activated receptor(s), which comprises the compound, pharmaceutically acceptable salt or solvate thereof according to any one of (1) to (10) as active ingredient.

Furthermore, the present invention provides a process for PPAR activation characterized by administrating the above compound, a pharmaceutically acceptable salt or a solvate thereof. In details, it is the treatment process and/or prevention process for hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and/or syndrome X.
As the other embodiment, the present invention provides use of the above compound, pharmaceutically acceptable salt or solvate thereof to produce medicines for PPAR activation, for example, medicines for treatment and/or prevention for hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and/or syndrome X.
EFFECT OF THE INVENTION
As the following test results show, compounds of the present invention have PPAR agonistic activity and are very useful as medicine and especially medicine for treatment and/or prevention for hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and/or syndrome X.


BEST MODE FOR CARRYING OUT THE INVENTION
The term “halogen” in the present specification means fluorine, chlorine, bromine or iodine. Especially, fluorine or chlorine is preferable.
The term “lower alkyl” means a C1 to C10, preferably C1 to C6 and more preferably C1 to C3 straight or branched alkyl group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-buthyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like.
The term “lower alkenyl” means C2 to C10, preferably C2 to C6 and more preferably C2 to C4 straight or branched alkenyl having one or more double bond(s) at any position(s). Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
The term “lower alkynyl” means C2 to C10, preferably C2 to C6 and more preferably C2 to C4 straight or branched alkynyl. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decenyl and the like. These have one or more triple bond(s) at any position(s) and can have double bond(s).
A substituent of “optionally substituted lower alkyl”, “optionally substituted lower alkenyl” or “optionally substituted lower alkynyl” is halogen, hydroxy, optionally substituted lower alkoxy, lower alkynyloxy, optionally substituted amino (e.g., lower alkylamino, arylamino, heterocycleamino, acylamino, lower alkoxycarbonylamino, lower alkylsulfonylamino or arylsulfonylamino), mercapto, lower alkylthio, acyl, acyloxy, optionally substituted imino, optionally substituted iminooxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkyl carbamoyl, thiocarbamoyl, lower alkylthiocarbamoyl, carbamoyloxy, lower alkylcarbamoyloxy, thiocarbamoyloxy, lower alkylthiocarbamoyloxy, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfonyl, lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted aryl lower alkoxy, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocycle (wherein a substituent is halogen, hydroxy, lower alkyl, oxo, halogeno lower alkyl, hydroxy lower alkyl, lower alkenyl, lower alkoxy, aryl lower alkoxy, halogeno lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, arylcarbamoyl, acylamino, mercapto, lower alkylthio, amino, lower alkylamino, acyl, acyloxy, cyano, nitro, phenyl, heterocycle or the like) or optionally substituted heterocycleoxy (wherein a substituent is halogen, hydroxy, lower alkyl, oxo, halogeno lower alkyl, hydroxy lower alkyl, lower alkenyl, lower alkoxy, aryl lower alkoxy, halogeno lower alkoxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkyl carbamoyl, aryl carbamoyl, acyl amino, mercapto, lower alkylthio, amino, lower alkylamino, acyl, acyloxy, cyano, nitro, phenyl, heterocycle or the like). They can be substituted at any position(s) with one or more substituent(s) selected from the above.
A substituent of “optionally substituted lower alkyl”, “optionally substituted lower alkenyl”, “optionally substituted lower alkynyl” or the like is preferably morpholino, piperidino, piperazino, furyl, thienyl or pyridyl.
A lower alkyl part of “halogeno lower alkyl”, “hydroxy lower alkyl”, “lower alkoxy”, “halogeno lower alkoxy”, “aryl lower alkoxy”, “hydroxy lower alkoxy”, “lower alkylamino”, “lower alkylthio”, “lower alkylsulfonyl”, “lower alkylsulfonyloxy”, “lower alkylsulfonyl amino”, “lower alkyl carbamoyl”, “lower alkylthio carbamoyl”, “lower alkyl carbamoyloxy”, “lower alkylthio carbamoyloxy”, “lower alkyl sulfamoyl”, “lower alkoxycarbonyl” or “lower alkoxycarbonyl amino” is same as the above “lower alkyl”.
A lower alkynyl part of “lower alkynyloxy” is same as the above “lower alkynyl”.
A substituent of “optionally substituted lower alkoxy”, “optionally substituted lower alkoxycarbonyl”, “optionally substituted lower alkylthio” or “optionally substituted lower alkylsulfonyloxy” is same as a substituent of the above “optionally substituted lower alkyl”.
The term “imino” means a group of —NH— or ═NH in an organic compound. A substituent of “optionally substituted imino” or “optionally substituted iminooxy” is same as a substituent of the above “optionally substituted lower alkyl”. Especially preferable example of the substituent “optionally substituted imino” is optionally substituted alkoxy.
The term “acyl” includes (a) C1-C10, more preferably C1 to C6 and most preferably C1 to C3 straight or branched alkylcarbonyl or alkenyl carbonyl, (b) C4 to C9 and preferably C4 to C7 cycloalkylcarbonyl, (c) C7 to C11 arylcarbonyl or (d) formyl. Examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl, benzoyl and the like.
An acyl part of “acyl amino” or “acyloxy” is same as the above “acyl”.
A substituent of “optionally substituted acyl” is same as a substituent of the above “optionally substituted lower alkyl”. Furthermore, cycloalkyl carbonyl and aryl carbonyl can be substituted with lower alkyl, halogeno lower alkyl, hydroxy lower alkyl, lower alkenyl, halogeno lower alkenyl and/or hydroxy lower alkenyl.
A substituent of “optionally substituted amino” is same as the above “optionally substituted lower alkyl”. Furthermore, “optionally substituted amino” can be substituted with lower alkyl, halogeno lower alkyl, hydroxy lower alkyl, lower alkenyl, halogeno lower alkenyl and/or hydroxy lower alkenyl.
A substituent of “optionally substituted carbamoyl”, “optionally substituted thiocarbamoyl”, “optionally substituted carbamoyloxy”, “optionally substituted thiocarbamoyloxy” or “optionally substituted hydrazinocarbonyl” is same as the above “optionally substituted lower alkyl”.
The term “cycloalkyl” includes C3 to C8 and preferably C5 or C6 cyclic alkyl. For example, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl or the like.
The term “aryl” includes phenyl, naphthyl, anthryl, phenanthryl or the like. Additionally, it includes aryl, which is condensed with the other non-aromatic hydrocarbon ring, for example, indanyl, indenyl, biphenylyl, acenaphthenyl, fluorenyl or the like. In case that aryl is condensed with the other non-aromatic hydrocarbon ring, bonds can be attached to any of the rings. The preferable example of aryl is phenyl.
A substituent of “optionally substituted cycloalkyl” or “optionally substituted aryl” is same as a substituent of the above “optionally substituted lower alkyl” as long as there is not a special provision. Furthermore, it can be substituted with lower alkyl, halogeno lower alkyl, hydroxy lower alkyl, lower alkenyl, halogeno lower alkenyl, hydroxy lower alkenyl, alkylenedioxy and/or oxo.
An aryl part of “aryloxy”, “arylthio”, “aryl lower alkoxy”, “aryl amino” “arylsulfonyl”, “arylsulfonyloxy” or “arylsulfonylamino” is same as the above “aryl”.
A substituent of “optionally substituted aryl lower alkoxy”, “optionally substituted aryloxy”, “optionally substituted arylthio” “optionally substituted arylsulfonyl” or “optionally substituted arylsulfonyloxy” is same as a substituent of the above “optionally substituted aryl” as long as there is not a special provision.
The term “heterocycle” and “optionally substituted heteroaryl” includes heterocycle having 1 or more hetero atom(s) selected from O, S and N in a ring, for example, 5- to 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyradinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl or the like; bicyclic condensed heterocycle such as indolyl, isoindolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, prinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyradino pyridazinyl, quinazolinyl, tetrahydroquinolyl, tetrahydrobenzothienyl or the like; tricyclic condensed heterocycle such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl or the like; non-aromatic heterocycle such as indolinyl, dioxanyl, thiiranyl, oxyranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperidino, morpholinyl, morpholino, oxadiadinyl, dihydropyridyl or the like. In case that heterocycle is a condensed ring, the bonds can be attached to any of the rings.
As “heterocycle” for R 1 and R 2 , pyridyl, benzofuryl, morpholino or piperazino or piperidino is preferred.
A substituent of “optionally substituted heterocycle” or “optionally substituted heteroaryl” is same as the above “optionally substituted aryl”.
A heterocycle part of “heterocycleamino” or “heterocycleoxy” is same as the above “heterocycle”.
Ring A is optionally substituted aryl or optionally substituted heteroaryl (provided that Y is not optionally substituted phenyl which is substituted with a group of the formula: —CR 9 R 10 X 3 at the para position). “Optionally substituted aryl” or “optionally substituted heteroaryl” for Ring A may be substituted with substituent(s) other than the group of the formula: —CR 9 R 10 X 3 . The substituent is the same as the above “optionally substituted aryl”. Especially preferable examples of Ring A are optionally substituted phenyl which is substituted with a group of the formula: —CR 9 R 10 X 3 at the meta or ortho position (the substituent is hydrogen, halogen, optionally substituted lower alkyl or optionally substituted lower alkoxy), optionally substituted pyridine which is substituted with a group of the formula: —CR 9 R 10 X 3 at the meta position, pyrane, furan, thiophene or pyrrole (the substituent is hydrogen, halogen, optionally substituted lower alkyl or optionally substituted lower alkoxy). Furthermore, groups of the following formula are preferable.









R 1 is halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylthio, optionally substituted acyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted hydrazinocarbonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heterocycle. Optionally substituted aryl or heterocycle is especially preferable. Optionally substituted aryl (the substituent is halogen, optionally substituted lower alkoxy or optionally substituted lower alkyl) is more preferable.
R 2 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkylthio, optionally substituted acyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted hydrazinocarbonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heterocycle. Optionally substituted lower alkyl is especially preferable. Optionally substituted lower alkyl (the substituent is halogen, lower alkoxy, lower alkylamino, optionally substituted imino, optionally substituted iminooxy, lower alkylsulfonyl, cycloalkyloxy, optionally substituted aryl or optionally substituted heterocycle) is more preferable.
When R 2 is optionally substituted lower alkyl, the preferable substituent(s) is optionally substituted imino, cycloalkyloxy, optionally substituted lower alkoxy (the substituent is cycloalkyl, optionally substituted heterocycle (the substituent is oxo or lower alkyl) or optionally substituted amino (the substituent is lower alkylsulfonyl or arylsulfonyl)), optionally substituted heterocycleoxy (the substituent is oxo or lower alkyl) or optionally substituted iminooxy (the substituent is lower alkyl or cycloalkyl).
When R 2 is optionally substituted lower alkyl and the substituent is optionally substituted imino, the preferable substituent(s) of imino is hydroxy, optionally substituted lower alkoxy (the substituent is optionally substituted heterocycle (the substituent is oxo or lower alkyl) or optionally substituted amino (the substituent is lower alkylsulfonyl or arylsulfonyl)), cycloalkyloxy, optionally substituted alkyl (the substituent is cycloalkyl) or optionally substituted heterocycleoxy (the substituent is oxo and lower alkyl).
R 3 and R 4 are each independently, hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl or optionally substituted heterocycle. Hydrogen is especially preferable.
R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, cyano, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted acyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heterocycle. Hydrogen, halogen, optionally substituted lower alkyl or optionally substituted lower alkoxy is especially preferable. Hydrogen, halogen, lower alkyl or lower alkoxy is more preferable.
R 9 and R 10 are each independently hydrogen, halogen, cyano, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted amino or optionally substituted aryl. Hydrogen or halogen is especially preferable.
X 1 is —O—, —S—, —NR 11 — wherein R 11 is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl, —CR 12 R 13 CO—, —(CR 12 R 13 )mO—, —(CR 12 R 13 )mS—, —O(CR 12 R 13 )m- wherein R 12 and R 13 are each independently hydrogen or optionally substituted lower alkyl, and m is an integer between 1 and 3, —ON═CR 14 — wherein R 14 is hydrogen or optionally substituted lower alkyl, or a group of the formula:

wherein R 15 and R 16 are each independently hydrogen or optionally substituted lower alkyl. —O—, —S— or —ON═CR 14 — wherein R 14 is hydrogen is especially preferable. —S— is more preferable.

X 3 is COOR 17 , C(═NR 17 )NR 18 OR 19 , or a group of the formula:

wherein R 17 to R 19 are each independently hydrogen or optionally substituted lower alkyl. COOR 17 (R 17 is hydrogen or optionally substituted lower alkyl) is especially preferable. COOR 17 (R 17 is hydrogen) is more preferable.

A compound of the present invention includes pharmaceutically acceptable salts, which can produce each compound. “A pharmaceutically acceptable salt” includes for example, salts of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like; salts of organic acid such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid, citric acid or the like; salts of organic salt group such as ammonium, trimethylammonium or triethylammonium; salts of alkali metal such as sodium or potassium; alkaline-earth metal salts such as calcium, magnesium or the like.
A compound of the present invention includes a solvate thereof and can be coordinate any number of solvent molecules to Compound (I). Preferred is hydrate.
When Compound (I) of the present invention has an asymmetric carbon atom, it contained racemic body and all stereoisomers (a diastereoisomer, an antipode or the like). When Compound (I) of the present invention has a double bond and there is geometrical isomer at a substituent position of double bond, it includes both type of the isomers.
Compound (I) of the present invention can be synthesized, for example, by the following processes.
(Process 1) Synthesis of Compound (Ia) (X 1 ═O, (CR 12 R 13 )mO, O(CR 12 R 13 )m)

wherein the one of A and D is OH and another is (CR 12 R 13 )mOH or both A and D are OH, and the other signs are the same meanings as the above.

Compound (II-1) and Compound (III) are subject to Mitsunobu reaction to obtain Compound (Ia). Mitsunobu reaction can be performed by a well-known process and preferably performed in a solvent of N,N-dimethyl formamide, dimethyl sulfoxide, aromatic hydrocarbon group (e.g., toluene, benzene, xylene or the like), saturated hydrocarbon group (e.g., cyelohexane, hexane or the like), halogenated hydrocarbon group (e.g., dichloromethane, 1,2-dichloroethane or the like), ether group (e.g., tetrahydrofuran, dioxane or the like), ketone group (e.g., acetone, methyl ethylketone or the like), nitryl group (e.g., acetonitrile or the like), water, a mixed solvent thereof or the like under the presence of azodicarboxylate, amide (diethylazodicarboxylate or the like) or phosphine group such as triphenylphosphine or the like at −30° C. to 150° C. and preferably at 0° C. to 100° C. for 0.5 to 90 hours.
As Compound (II-1) and Compound (III), well known compounds and compounds, which are lead from well-known compounds by usual processes, can be used.
(Process 2) Synthesis of Compound (Ib) (X 1 ═O, S or NR 11 )

wherein LG is a leaving group such as halogen, lower alkylsulfonyloxy or the like and the other signs are the same meanings as the above.

Compound (Ib) can be synthesized by reacting Compound (II-2) and Compound (III). The reaction can be performed in an appropriate solvent under the presence of base at −10 to 180° C. and preferably at 0 to 150° C. for 0.5 to 90 hours. As the solvent, the same solvent described in the above process 1 can be used. The base is, for example, metal hydride (e.g., sodium hydride, potassium hydride or the like), metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide or the like), metal carbonate (e.g., sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate or the like), metal alkoxide (e.g., sodium methoxide, sodium ethoxide, Potassium tert-butoxide or the like), sodium hydrogen carbonate, metallic sodium, organic amine (triethylamine, DBU or the like) or the like.
As Compound (II-2) and Compound (III), well known compounds and compounds, which is lead from well-known compounds by usual processes, can be used.
(Process 3) Synthesis of Compound (Ic) (X 1 ═CR 12 ON═CH)
Compound (Ic) can be synthesized by the following route.

wherein LG is a leaving group such as halogen, lower alkylsulfonyl or the like, Hal is halogen and the other signs have the same meanings as the above.

Compound (II-3) and Compound (III) are subject to addition reaction to give Compound (IV). The reaction can be performed preferably in an appropriate solvent under the presence of base at −50° C. to 150° C. and preferably at −20° C. to 100° C. for 0.5 to 60 hours. The solvent described in the above process 1 can be used as the solvent. The base described in the above process 2 can be used as the base.
Compound (IV) is reacted with hydroxylamine of R12NH2 or the hydrochloric acid salt to give Compound (Ic). The reaction can be performed preferably in an appropriate solvent at −10° C. to 180° C. and preferably at −0° C. to 150° C. for 0.5 to 90 hours. The solvent described in the above process 1 can be used as the solvent.
(Process 4) Synthesis of Compound (Id) (X 3 ═C(═NH)NHOH)
Compound (Id) is synthesized by the following process.

wherein each sign has the same meanings as the above.

Compound (V) is reacted with hydroxylamine to give a target Compound (Id). The reaction can be performed in an appropriate solvent at 0° C. to 150° C. and preferably at 20° C. to 100° C. for 0.5 to 90 hours. The solvent described in the above process 1 can be used as the solvent. The base described in the above process 2 can be used as the base.
As Compound (V), well known compounds and compounds, which is lead from well-known compounds by usual methods, can be used.
(Process 5) Synthesis of Compound (Ie) (X 3 =oxadiazolon)

wherein each sign has the same meanings as the above.

Compound (Id) obtained in the above process 4 is reacted with CDI, phosgene, triphosgene or the like to give a target Compound (Ie). The reaction can be performed in an appropriate solvent at −30° C. to 150° C. and preferably at 0° C. to 100° C. for 0.5 to 90 hours. The solvent described in the above process 1 can be used as a solvent. The base described in the above process 2 can be used as the base.
The target oxadiazolon Compound (Ie) substituted with R 17 is obtained by following process. A compound wherein R 17 is H is synthesized by the above process, followed by introducing an appropriate subsistent by the usual process to give target compound.
(Process 6) Synthesis of compound (If) (X 3 =oxadiadinon)

wherein each sign has the same meanings as the above.

Compound (Id) obtained in the above process 4 and a halogen compound are reacted to give target compound (If). The reaction can be performed in an appropriate solvent at −30° C. to 150° C. and preferably at 0° C. to 100° C. for 0.5 to 90 hours reaction. The solvent described in the above process 1 can be used as the solvent. The base described in the above process 2 can be used as the base.
When the compound obtained by the above any process is ester, i.e. X 3 ═COOR 17 , this compound is hydrolyze by the usual process to give carboxylic acid, i.e. X 3 ═COOH.
If necessary, at an appropriate step in the above process for producing, any substituent can be transform to a different substituent by the well-known organic synthesized reaction.
For example, when the compound has halogen, it is reacted with alcohol in a solvent such as DMF, tetrahydrofuran or the like under the presence of base such as sodium hydride, potassium hydride or the like and deacid reagent such as alkali metal hydroxide, alkali metal hydrogencarbonate, alkali metal carbonate, organic base or the like at −20° C. to 100° C. to give compound whose substituent is transformed to lower alkoxy.
When the compound has hydroxy, it is reacted with oxidizing agent such as pyridinium dichromate, Jones reagent, manganese dioxide, potassium permanganate, ruthenium tetroxide or the like in a solvent such as dimethyl formamide, tetrahydrofuran, dichloromethane, benzene, acetone or the like to give a compound whose substituent is transformed to carboxy.
If necessary, after amino or hydroxy of a compound is protected by the usual process at an appropriate step, it is subjected to the reaction and then deprotected by treatment with acid or base at an appropriate step.
As an amino protecting group, phthalimide, lower alkoxycarbonyl, lower alkenyloxy carbonyl, halogeno alkoxycarbonyl, aryl lower alkoxycarbonyl, trialkyl silyl, lower alkylsulfonyl, halogeno lower alkylsulfonyl, arylsulfonyl, lower alkylcarbonyl, arylcarbonyl or the like can be used.
As a hydroxy protecting group, alkyl (t-butyl or the like), aralkyl (triphenylmethyl or benzyl), trialkyl silyl (t-butyldimethylsilyl, triisopropyl silyl or the like), alkyldiarylsilyl (t-butyldiphenylsilyl or the like), triaralkylsilyl (tribenzylsilyl or the like), alkoxyalkyl (methoxymethyl, 1-ethoxyethyl, 1-methyl 1-methoxyethyl or the like), alkoxyalkoxyalkyl (methoxyethoxymethyl or the like), alkylthioalkyl (methylthiomethyl or the like), tetrahydropyranyl (tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl or the like), tetrahydrothiopyranyl (tetrahydrothiopyran-2-yl or the like), tetrahydrofuranyl (tetrahydrofuran-2-yl or the like), tetrahydrothio furanyl (tetrahydrothio furan-2-yl or the like), aralkyloxyalkyl (benzyloxymethyl or the like) alkylsulfonyl, acyl, p-toluenesulfonyl or the like can be used.
Deprotection reaction is accomplished in a solvent such as tetrahydrofuran, dimethylformamide, diethylether, dichloromethane, toluene, benzene, xylene, cyelohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile or a mixed solvent thereof, by using base such as hydrazine, pyridine, sodium hydroxide, potassium hydroxide or the like or acid such as hydrochloric acid, trifluoroacetic acid, hydrofluoric acid or the like.
Preferable compounds in compounds of the present invention are followings.
In the tables, “≡CPh” and “C≡CPh” has the same meaning, —C≡C-Ph.
1) A compound wherein the part (Part A) of the formula:

is the one of the followings.






TABLE 1























Part A No.
R20
n
R2
R3, R4





A1
4-Cl
0
H
H, H


A2
4-Cl
0
H
Me, Me


A3
4-Cl
0
H
Et, Et


A4
4-Cl
0
H
H, Et


A5
4-Cl
0
H
H, Ph


A6
4-Cl
0
H
H, C6H4-4-F


A7
4-Cl
0
Me
H, H


A8
4-Cl
0
Me
Me, Me


A9
4-Cl
0
Me
Et, Et


A10
4-Cl
0
Me
H, Et


A11
4-Cl
0
Me
H, Ph


A12
4-Cl
0
Me
H, C6H4-4-F


A13
4-Cl
0
OMe
H, H


A14
4-Cl
0
OMe
Me, Me


A15
4-Cl
0
OMe
Et, Et


A16
4-Cl
0
OMe
H, Et


A17
4-Cl
0
OMe
H, Ph


A18
4-Cl
0
OMe
H, C6H4-4-F


A19
4-Cl
0
CH2OH
H, H


A20
4-Cl
0
CH2OH
H, C6H4-4-F


A21
4-Cl
0
CH2OMe
H, H


A22
4-Cl
0
CH2OMe
Me, Me


A23
4-Cl
0
CH2OMe
Et, Et


A24
4-Cl
0
CH2OMe
H, Et


A25
4-Cl
0
CH2OMe
H, Ph


A26
4-Cl
0
CH2OMe
H, C6H4-4-F


A27
4-Cl
0
CF3
H, H


A28
4-Cl
0
CF3
Me, Me


A29
4-Cl
0
CF3
Et, Et


A30
4-Cl
0
CF3
H, Et


A31
4-Cl
0
CF3
H, Ph


A32
4-Cl
0
CF3
H, C6H4-4-F


A33
4-Cl
0
CH2OPh
H, H


A34
4-Cl
0
CH2OPh
H, C6H4-4-F


A35
4-Cl
0
CH2OCH2Ph
H, H


A36
4-Cl
0
CH2OCH2Ph
H, C6H4-4-F


A37
4-Cl
0
CH2-morpholino
H, H




































































TABLE 2



Part A No.
R20
n
R2
R3, R4



A38
4-Cl
0
CH2-morpholino
Me, Me

A39
4-Cl
0
CH2-morpholino
Et, Et

A40
4-Cl
0
CH2-morpholino
H, Et

A41
4-Cl
0
CH2-morpholino
H, Ph

A42
4-Cl
0
CH2-morpholino
H, C6H4-4-F

A43
4-Cl
0
CH2NHBu
H, H

A44
4-Cl
0
CH2NHBu
H, C6H4-4-F

A45
4-Cl
0
C≡CPh
H, H

A46
4-Cl
0
C≡CPh
H, C6H4-4-F

A47
4-Cl
0
Ph
H, H

A48
4-Cl
0
Ph
H, C6H4-4-F

A49
4-Cl
0
C6H4-4-CF3
H, H

A50
4-Cl
0
C6H4-4-CF3
H, C6H4-4-F

A51
4-Cl
0
C6H4-3-CF3
H, H

A52
4-Cl
0
C6H4-3-CF3
H, C6H4-4-F

A53
4-Cl
0
C6H4-4-OH
H, H

A54
4-Cl
0
C6H4-4-OH
H, C6H4-4-F

A55
4-Cl
0
CH2Ph
H, H

A56
4-Cl
0
CH2Ph
H, C6H4-4-F

A57
4-Cl
0
CH2C6H4-4-CF3
H, H

A58
4-Cl
0
CH2C6H4-4-CF3
Me, Me

A59
4-Cl
0
CH2C6H4-4-CF3
Et, Et

A60
4-Cl
0
CH2C6H4-4-CF3
H, Et

A61
4-Cl
0
CH2C6H4-4-CF3
H, Ph

A62
4-Cl
0
CH2C6H4-4-CF3
H, C6H4-4-F

A63
4-Cl
0
CH2C6H4-4-OCF3
H, H

A64
4-Cl
0
CH2C6H4-4-OCF3
H, C6H4-4-F

A65
4-Cl
0
CH2C6H4-4-Ph
H, H

A66
4-Cl
0
CH2C6H4-4-Ph
H, C6H4-4-F

A67
4-Cl
0
CH2C6H4-2-Cl
H, H

A68
4-Cl
0
CH2C6H4-2-Cl
H, C6H4-4-F

A69
4-Cl
0
(CH2)2Ph
H, H

A70
4-Cl
0
(CH2)2Ph
H, C6H4-4-F

A71
4-Cl
0
SPh
H, H

A72
4-Cl
0
SPh
H, C6H4-4-F

A73
4-Cl
0
NH2
H, H

A74
4-Cl
0
NH2
H, C6H4-4-F

A75
4-Cl
0
NHMe
H, H

A76
4-Cl
0
NHMe
H, C6H4-4-F

A77
4-Cl
0
CH2-piperazino-Ph
H, H

A78
4-Cl
0
CH2-piperazino-Ph
H, C6H4-4-F

A79
4-Cl
0
CH2-piperidino
H, H

A80
4-Cl
0
CH2-piperidino
H, C6H4-4-F

A81
4-Cl
0
OCH2Ph
H, H

A82
4-Cl
0
OCH2Ph
H, C6H4-4-F

A83
4-Cl
0
Ac
H, H

A84
4-Cl
0
Ac
H, C6H4-4-F

A85
4-Cl
0
CONH2
H, H











































































TABLE 3





Part A No.
R20
n
R2
R3, R4





A86
4-Cl
0
CONH2
H, C6H4-4-F


A87
4-Cl
0
CSNH2
H, H


A88
4-Cl
0
CSNH2
H, C6H4-4-F


A89
4-Cl
0
OCONH2
H, H


A90
4-Cl
0
OCONH2
H, C6H4-4-F


A91
4-Cl
0
OCSNH2
H, H


A92
4-Cl
0
OCSNH2
H, C6H4-4-F


A93
4-Cl
0
OSO2Me
H, H


A94
4-Cl
0
OSO2Me
H, C6H4-4-F


A95
4-Cl
0
OSO2Ph
H, H


A96
4-Cl
0
OSO2Ph
H, C6H4-4-F


A97
4-Cl
0
I
H, H


A98
4-Cl
0
I
H, C6H4-4-F


A99
4-Cl
1
H
H, H


A100
4-Cl
1
H
Me, Me


A101
4-Cl
1
H
Et, Et


A102
4-Cl
1
H
H, Et


A103
4-Cl
1
H
H, Ph


A104
4-Cl
1
H
H, C6H4-4-F


A105
4-Cl
1
Me
H, H


A106
4-Cl
1
Me
Me, Me


A107
4-Cl
1
Me
Et, Et


A108
4-Cl
1
Me
H, Et


A109
4-Cl
1
Me
H, Ph


A110
4-Cl
1
Me
H, C6H4-4-F


A111
4-Cl
1
OMe
H, H


A112
4-Cl
1
OMe
Me, Me


A113
4-Cl
1
OMe
Et, Et


A114
4-Cl
1
OMe
H, Et


A115
4-Cl
1
OMe
H, Ph


A116
4-Cl
1
OMe
H, C6H4-4-F


A117
4-Cl
1
CH2OH
H, H


A118
4-Cl
1
CH2OH
H, C6H4-4-F


A119
4-Cl
1
CH2OMe
H, H


A120
4-Cl
1
CH2OMe
Me, Me


A121
4-Cl
1
CH2OMe
Et, Et


A122
4-Cl
1
CH2OMe
H, Et


A123
4-Cl
1
CH2OMe
H, Ph


A124
4-Cl
1
CH2OMe
H, C6H4-4-F


A125
4-Cl
1
CF3
H, H


A126
4-Cl
1
CF3
Me, Me


A127
4-Cl
1
CF3
Et, Et


A128
4-Cl
1
CF3
H, Et


A129
4-Cl
1
CF3
H, Ph


A130
4-Cl
1
CF3
H, C6H4-4-F


A131
4-Cl
1
CH2OPh
H, H


A132
4-Cl
1
CH2OPh
H, C6H4-4-F


A133
4-Cl
1
CH2OCH2Ph
H, H










































































TABLE 4



Part A No.
R20
n
R2
R3, R4



A134
4-Cl
1
CH2OCH2Ph
H, C6H4-4-F

A135
4-Cl
1
CH2-morpholino
H, H

A136
4-Cl
1
CH2-morpholino
Me, Me

A137
4-Cl
1
CH2-morpholino
Et, Et

A138
4-Cl
1
CH2-morpholino
H, Et

A139
4-Cl
1
CH2-morpholino
H, Ph

A140
4-Cl
1
CH2-morpholino
H, C6H4-4-F

A141
4-Cl
1
CH2NHBu
H, H

A142
4-Cl
1
CH2NHBu
H, C6H4-4-F

A143
4-Cl
1
C≡CPh
H, H

A144
4-Cl
1
C≡CPh
H, C6H4-4-F

A145
4-Cl
1
Ph
H, H

A146
4-Cl
1
Ph
H, C6H4-4-F

A147
4-Cl
1
C6H4-4-CF3
H, H

A148
4-Cl
1
C6H4-4-CF3
H, C6H4-4-F

A149
4-Cl
1
C6H4-3-CF3
H, H

A150
4-Cl
1
C6H4-3-CF3
H, C6H4-4-F

A151
4-Cl
1
C6H4-4-OH
H, H

A152
4-Cl
1
C6H4-4-OH
H, C6H4-4-F

A153
4-Cl
1
CH2Ph
H, H

A154
4-Cl
1
CH2Ph
H, C6H4-4-F

A155
4-Cl
1
CH2C6H4-4-CF3
H, H

A156
4-Cl
1
CH2C6H4-4-CF3
Me, Me

A157
4-Cl
1
CH2C6H4-4-CF3
Et, Et

A158
4-Cl
1
CH2C6H4-4-CF3
H, Et

A159
4-Cl
1
CH2C6H4-4-CF3
H, Ph

A160
4-Cl
1
CH2C6H4-4-CF3
H, C6H4-4-F

A161
4-Cl
1
CH2C6H4-4-OCF3
H, H

A162
4-Cl
1
CH2C6H4-4-OCF3
H, C6H4-4-F

A163
4-Cl
1
CH2C6H4-4-Ph
H, H

A164
4-Cl
1
CH2C6H4-4-Ph
H, C6H4-4-F

A165
4-Cl
1
CH2C6H4-2-Cl
H, H

A166
4-Cl
1
CH2C6H4-2-Cl
H, C6H4-4-F

A167
4-Cl
1
(CH2)2Ph
H, H

A168
4-Cl
1
(CH2)2Ph
H, C6H4-4-F

A169
4-Cl
1
SPh
H, H

A170
4-Cl
1
SPh
H, C6H4-4-F

A171
4-Cl
1
NH2
H, H

A172
4-Cl
1
NH2
H, C6H4-4-F

A173
4-Cl
1
NHMe
H, H

A174
4-Cl
1
NHMe
H, C6H4-4-F

A175
4-Cl
1
CH2-piperazino-Ph
H, H

A176
4-Cl
1
CH2-piperazino-Ph
H, C6H4-4-F

A177
4-Cl
1
CH2-piperidino
H, H

A178
4-Cl
1
CH2-piperidino
H, C6H4-4-F

A179
4-Cl
1
OCH2Ph
H, H

A180
4-Cl
1
OCH2Ph
H, C6H4-4-F

A181
4-Cl
1
Ac
H, H











































































TABLE 5





Part A No.
R20
n
R2
R3, R4





A182
4-Cl
1
Ac
H, C6H4-4-F


A183
4-Cl
1
CONH2
H, H


A184
4-Cl
1
CONH2
H, C6H4-4-F


A185
4-Cl
1
CSNH2
H, H


A186
4-Cl
1
CSNH2
H, C6H4-4-F


A187
4-Cl
1
OCONH2
H, H


A188
4-Cl
1
OCONH2
H, C6H4-4-F


A189
4-Cl
1
OCSNH2
H, H


A190
4-Cl
1
OCSNH2
H, C6H4-4-F


A191
4-Cl
1
OSO2Me
H, H


A192
4-Cl
1
OSO2Me
H, C6H4-4-F


A193
4-Cl
1
OSO2Ph
H, H


A194
4-Cl
1
OSO2Ph
H, C6H4-4-F


A195
4-Cl
1
I
H, H


A196
4-Cl
1
I
H, C6H4-4-F


A197
4-Cl
2
H
H, H


A198
4-Cl
2
H
Me, Me


A199
4-Cl
2
H
Et, Et


A200
4-Cl
2
H
H, Et


A201
4-Cl
2
H
H, Ph


A202
4-Cl
2
H
H, C6H4-4-F


A203
4-Cl
2
Me
H, H


A204
4-Cl
2
Me
Me, Me


A205
4-Cl
2
Me
Et, Et


A206
4-Cl
2
Me
H, Et


A207
4-Cl
2
Me
H, Ph


A208
4-Cl
2
Me
H, C6H4-4-F


A209
4-Cl
2
OMe
H, H


A210
4-Cl
2
OMe
Me, Me


A211
4-Cl
2
OMe
Et, Et


A212
4-Cl
2
OMe
H, Et


A213
4-Cl
2
OMe
H, Ph


A214
4-Cl
2
OMe
H, C6H4-4-F


A215
4-Cl
2
CH2OH
H, H


A216
4-Cl
2
CH2OH
H, C6H4-4-F


A217
4-Cl
2
CH2OMe
H, H


A218
4-Cl
2
CH2OMe
Me, Me


A219
4-Cl
2
CH2OMe
Et, Et


A220
4-Cl
2
CH2OMe
H, Et


A221
4-Cl
2
CH2OMe
H, Ph


A222
4-Cl
2
CH2OMe
H, C6H4-4-F


A223
4-Cl
2
CF3
H, H


A224
4-Cl
2
CF3
Me, Me


A225
4-Cl
2
CF3
Et, Et


A226
4-Cl
2
CF3
H, Et


A227
4-Cl
2
CF3
H, Ph


A228
4-Cl
2
CF3
H, C6H4-4-F


A229
4-Cl
2
CH2OPh
H, H










































































TABLE 6



Part A No.
R20
n
R2
R3, R4



A230
4-Cl
2
CH2OPh
H, C6H4-4-F

A231
4-Cl
2
CH2OCH2Ph
H, H

A232
4-Cl
2
CH2OCH2Ph
H, C6H4-4-F

A233
4-Cl
2
CH2-morpholino
H, H

A234
4-Cl
2
CH2-morpholino
Me, Me

A235
4-Cl
2
CH2-morpholino
Et, Et

A236
4-Cl
2
CH2-morpholino
H, Et

A237
4-Cl
2
CH2-morpholino
H, Ph

A238
4-Cl
2
CH2-morpholino
H, C6H4-4-F

A239
4-Cl
2
CH2NHBu
H, H

A240
4-Cl
2
CH2NHBu
H, C6H4-4-F

A241
4-Cl
2
C≡CPh
H, H

A242
4-Cl
2
C≡CPh
H, C6H4-4-F

A243
4-Cl
2
Ph
H, H

A244
4-Cl
2
Ph
H, C6H4-4-F

A245
4-Cl
2
C6H4-4-CF3
H, H

A246
4-Cl
2
C6H4-4-CF3
H, C6H4-4-F

A247
4-Cl
2
C6H4-3-CF3
H, H

A248
4-Cl
2
C6H4-3-CF3
H, C6H4-4-F

A249
4-Cl
2
C6H4-4-OH
H, H

A250
4-Cl
2
C6H4-4-OH
H, C6H4-4-F

A251
4-Cl
2
CH2Ph
H, H

A252
4-Cl
2
CH2Ph
H, C6H4-4-F

A253
4-Cl
2
CH2C6H4-4-CF3
H, H

A254
4-Cl
2
CH2C6H4-4-CF3
Me, Me

A255
4-Cl
2
CH2C6H4-4-CF3
Et, Et

A256
4-Cl
2
CH2C6H4-4-CF3
H, Et

A257
4-Cl
2
CH2C6H4-4-CF3
H, Ph

A258
4-Cl
2
CH2C6H4-4-CF3
H, C6H4-4-F

A259
4-Cl
2
CH2C6H4-4-OCF3
H, H

A260
4-Cl
2
CH2C6H4-4-OCF3
H, C6H4-4-F

A261
4-Cl
2
CH2C6H4-4-Ph
H, H

A262
4-Cl
2
CH2C6H4-4-Ph
H, C6H4-4-F

A263
4-Cl
2
CH2C6H4-2-Cl
H, H

A264
4-Cl
2
CH2C6H4-2-Cl
H, C6H4-4-F

A265
4-Cl
2
(CH2)2Ph
H, H

A266
4-Cl
2
(CH2)2Ph
H, C6H4-4-F

A267
4-Cl
2
SPh
H, H

A268
4-Cl
2
SPh
H, C6H4-4-F

A269
4-Cl
2
NH2
H, H

A270
4-Cl
2
NH2
H, C6H4-4-F

A271
4-Cl
2
NHMe
H, H

A272
4-Cl
2
NHMe
H, C6H4-4-F

A273
4-Cl
2
CH2-piperazino-Ph
H, H

A274
4-Cl
2
CH2-piperazino-Ph
H, C6H4-4-F

A275
4-Cl
2
CH2-piperidino
H, H

A276
4-Cl
2
CH2-piperidino
H, C6H4-4-F

A277
4-Cl
2
OCH2Ph
H, H











































































TABLE 7





Part A No.
R20
n
R2
R3, R4





A278
4-Cl
2
OCH2Ph
H, C6H4-4-F


A279
4-Cl
2
Ac
H, H


A280
4-Cl
2
Ac
H, C6H4-4-F


A281
4-Cl
2
CONH2
H, H


A282
4-Cl
2
CONH2
H, C6H4-4-F


A283
4-Cl
2
CSNH2
H, H


A284
4-Cl
2
CSNH2
H, C6H4-4-F


A285
4-Cl
2
OCONH2
H, H


A286
4-Cl
2
OCONH2
H, C6H4-4-F


A287
4-Cl
2
OCSNH2
H, H


A288
4-Cl
2
OCSNH2
H, C6H4-4-F


A289
4-Cl
2
OSO2Me
H, H


A290
4-Cl
2
OSO2Me
H, C6H4-4-F


A291
4-Cl
2
OSO2Ph
H, H


A292
4-Cl
2
OSO2Ph
H, C6H4-4-F


A293
4-Cl
2
I
H, H


A294
4-Cl
2
I
H, C6H4-4-F


A295
4-CF3
0
H
H, H


A296
4-CF3
0
H
Me, Me


A297
4-CF3
0
H
Et, Et


A298
4-CF3
0
H
H, Et


A299
4-CF3
0
H
H, Ph


A300
4-CF3
0
H
H, C6H4-4-F


A301
4-CF3
0
Me
H, H


A302
4-CF3
0
Me
Me, Me


A303
4-CF3
0
Me
Et, Et


A304
4-CF3
0
Me
H, Et


A305
4-CF3
0
Me
H, Ph


A306
4-CF3
0
Me
H, C6H4-4-F


A307
4-CF3
0
OMe
H, H


A308
4-CF3
0
OMe
Me, Me


A309
4-CF3
0
OMe
Et, Et


A310
4-CF3
0
OMe
H, Et


A311
4-CF3
0
OMe
H, Ph


A312
4-CF3
0
OMe
H, C6H4-4-F


A313
4-CF3
0
CH2OH
H, H


A314
4-CF3
0
CH2OH
H, C6H4-4-F


A315
4-CF3
0
CH2OMe
H, H


A316
4-CF3
0
CH2OMe
Me, Me


A317
4-CF3
0
CH2OMe
Et, Et


A318
4-CF3
0
CH2OMe
H, Et


A319
4-CF3
0
CH2OMe
H, Ph


A320
4-CF3
0
CH2OMe
H, C6H4-4-F


A321
4-CF3
0
CF3
H, H


A322
4-CF3
0
CF3
Me, Me


A323
4-CF3
0
CF3
Et, Et


A324
4-CF3
0
CF3
H, Et


A325
4-CF3
0
CF3
H, Ph










































































TABLE 8



Part A No.
R20
n
R2
R3, R4



A326
4-CF3
0
CF3
H, C6H4-4-F

A327
4-CF3
0
CH2OPh
H, H

A328
4-CF3
0
CH2OPh
H, C6H4-4-F

A329
4-CF3
0
CH2OCH2Ph
H, H

A330
4-CF3
0
CH2OCH2Ph
H, C6H4-4-F

A331
4-CF3
0
CH2-morpholino
H, H

A332
4-CF3
0
CH2-morpholino
Me, Me

A333
4-CF3
0
CH2-morpholino
Et, Et

A334
4-CF3
0
CH2-morpholino
H, Et

A335
4-CF3
0
CH2-morpholino
H, Ph

A336
4-CF3
0
CH2-morpholino
H, C6H4-4-F

A337
4-CF3
0
CH2NHBu
H, H

A338
4-CF3
0
CH2NHBu
H, C6H4-4-F

A339
4-CF3
0
C≡CPh
H, H

A340
4-CF3
0
C≡CPh
H, C6H4-4-F

A341
4-CF3
0
Ph
H, H

A342
4-CF3
0
Ph
H, C6H4-4-F

A343
4-CF3
0
C6H4-4-CF3
H, H

A344
4-CF3
0
C6H4-4-CF3
H, C6H4-4-F

A345
4-CF3
0
C6H4-3-CF3
H, H

A346
4-CF3
0
C6H4-3-CF3
H, C6H4-4-F

A347
4-CF3
0
C6H4-4-OH
H, H

A348
4-CF3
0
C6H4-4-OH
H, C6H4-4-F

A349
4-CF3
0
CH2Ph
H, H

A350
4-CF3
0
CH2Ph
H, C6H4-4-F

A351
4-CF3
0
CH2C6H4-4-CF3
H, H

A352
4-CF3
0
CH2C6H4-4-CF3
Me, Me

A353
4-CF3
0
CH2C6H4-4-CF3
Et, Et

A354
4-CF3
0
CH2C6H4-4-CF3
H, Et

A355
4-CF3
0
CH2C6H4-4-CF3
H, Ph

A356
4-CF3
0
CH2C6H4-4-CF3
H, C6H4-4-F

A357
4-CF3
0
CH2C6H4-4-OCF3
H, H

A358
4-CF3
0
CH2C6H4-4-OCF3
H, C6H4-4-F

A359
4-CF3
0
CH2C6H4-4-Ph
H, H

A360
4-CF3
0
CH2C6H4-4-Ph
H, C6H4-4-F

A361
4-CF3
0
CH2C6H4-2-Cl
H, H

A362
4-CF3
0
CH2C6H4-2-Cl
H, C6H4-4-F

A363
4-CF3
0
(CH2)2Ph
H, H

A364
4-CF3
0
(CH2)2Ph
H, C6H4-4-F

A365
4-CF3
0
SPh
H, H

A366
4-CF3
0
SPh
H, C6H4-4-F

A367
4-CF3
0
NH2
H, H

A368
4-CF3
0
NH2
H, C6H4-4-F

A369
4-CF3
0
NHMe
H, H

A370
4-CF3
0
NHMe
H, C6H4-4-F

A371
4-CF3
0
CH2-piperazino-Ph
H, H

A372
4-CF3
0
CH2-piperazino-Ph
H, C6H4-4-F

A373
4-CF3
0
CH2-piperidino
H, H











































































TABLE 9





Part A No.
R20
n
R2
R3, R4





A374
4-CF3
0
CH2-piperidino
H, C6H4-4-F


A375
4-CF3
0
OCH2Ph
H, H


A376
4-CF3
0
OCH2Ph
H, C6H4-4-F


A377
4-CF3
0
Ac
H, H


A378
4-CF3
0
Ac
H, C6H4-4-F


A379
4-CF3
0
CONH2
H, H


A380
4-CF3
0
CONH2
H, C6H4-4-F


A381
4-CF3
0
CSNH2
H, H


A382
4-CF3
0
CSNH2
H, C6H4-4-F


A383
4-CF3
0
OCONH2
H, H


A384
4-CF3
0
OCONH2
H, C6H4-4-F


A385
4-CF3
0
OCSNH2
H, H


A386
4-CF3
0
OCSNH2
H, C6H4-4-F


A387
4-CF3
0
OSO2Me
H, H


A388
4-CF3
0
OSO2Me
H, C6H4-4-F


A389
4-CF3
0
OSO2Ph
H, H


A390
4-CF3
0
OSO2Ph
H, C6H4-4-F


A391
4-CF3
0
I
H, H


A392
4-CF3
0
I
H, C6H4-4-F


A393
4-CF3
1
H
H, H


A394
4-CF3
1
H
Me, Me


A395
4-CF3
1
H
Et, Et


A396
4-CF3
1
H
H, Et


A397
4-CF3
1
H
H, Ph


A398
4-CF3
1
H
H, C6H4-4-F


A399
4-CF3
1
Me
H, H


A400
4-CF3
1
Me
Me, Me


A401
4-CF3
1
Me
Et, Et


A402
4-CF3
1
Me
H, Et


A403
4-CF3
1
Me
H, Ph


A404
4-CF3
1
Me
H, C6H4-4-F


A405
4-CF3
1
OMe
H, H


A406
4-CF3
1
OMe
Me, Me


A407
4-CF3
1
OMe
Et, Et


A408
4-CF3
1
OMe
H, Et


A409
4-CF3
1
OMe
H, Ph


A410
4-CF3
1
OMe
H, C6H4-4-F


A411
4-CF3
1
CH2OH
H, H


A412
4-CF3
1
CH2OH
H, C6H4-4-F


A413
4-CF3
1
CH2OMe
H, H


A414
4-CF3
1
CH2OMe
Me, Me


A415
4-CF3
1
CH2OMe
Et, Et


A416
4-CF3
1
CH2OMe
H, Et


A417
4-CF3
1
CH2OMe
H, Ph


A418
4-CF3
1
CH2OMe
H, C6H4-4-F


A419
4-CF3
1
CF3
H, H


A420
4-CF3
1
CF3
Me, Me


A421
4-CF3
1
CF3
Et, Et










































































TABLE 10



Part A No.
R20
n
R2
R3, R4



A422
4-CF3
1
CF3
H, Et

A423
4-CF3
1
CF3
H, Ph

A424
4-CF3
1
CF3
H, C6H4-4-F

A425
4-CF3
1
CH2OPh
H, H

A426
4-CF3
1
CH2OPh
H, C6H4-4-F

A427
4-CF3
1
CH2OCH2Ph
H, H

A428
4-CF3
1
CH2OCH2Ph
H, C6H4-4-F

A429
4-CF3
1
CH2-morpholino
H, H

A430
4-CF3
1
CH2-morpholino
Me, Me

A431
4-CF3
1
CH2-morpholino
Et, Et

A432
4-CF3
1
CH2-morpholino
H, Et

A433
4-CF3
1
CH2-morpholino
H, Ph

A434
4-CF3
1
CH2-morpholino
H, C6H4-4-F

A435
4-CF3
1
CH2NHBu
H, H

A436
4-CF3
1
CH2NHBu
H, C6H4-4-F

A437
4-CF3
1
C≡CPh
H, H

A438
4-CF3
1
C≡CPh
H, C6H4-4-F

A439
4-CF3
1
Ph
H, H

A440
4-CF3
1
Ph
H, C6H4-4-F

A441
4-CF3
1
C6H4-4-CF3
H, H

A442
4-CF3
1
C6H4-4-CF3
H, C6H4-4-F

A443
4-CF3
1
C6H4-3-CF3
H, H

A444
4-CF3
1
C6H4-3-CF3
H, C6H4-4-F

A445
4-CF3
1
C6H4-4-OH
H, H

A446
4-CF3
1
C6H4-4-OH
H, C6H4-4-F

A447
4-CF3
1
CH2Ph
H, H

A448
4-CF3
1
CH2Ph
H, C6H4-4-F

A449
4-CF3
1
CH2C6H4-4-CF3
H, H

A450
4-CF3
1
CH2C6H4-4-CF3
Me, Me

A451
4-CF3
1
CH2C6H4-4-CF3
Et, Et

A452
4-CF3
1
CH2C6H4-4-CF3
H, Et

A453
4-CF3
1
CH2C6H4-4-CF3
H, Ph

A454
4-CF3
1
CH2C6H4-4-CF3
H, C6H4-4-F

A455
4-CF3
1
CH2C6H4-4-OCF3
H, H

A456
4-CF3
1
CH2C6H4-4-OCF3
H, C6H4-4-F

A457
4-CF3
1
CH2C6H4-4-Ph
H, H

A458
4-CF3
1
CH2C6H4-4-Ph
H, C6H4-4-F

A459
4-CF3
1
CH2C6H4-2-Cl
H, H

A460
4-CF3
1
CH2C6H4-2-Cl
H, C6H4-4-F

A461
4-CF3
1
(CH2)2Ph
H, H

A462
4-CF3
1
(CH2)2Ph
H, C6H4-4-F

A463
4-CF3
1
SPh
H, H

A464
4-CF3
1
SPh
H, C6H4-4-F

A465
4-CF3
1
NH2
H, H

A466
4-CF3
1
NH2
H, C6H4-4-F

A467
4-CF3
1
NHMe
H, H

A468
4-CF3
1
NHMe
H, C6H4-4-F

A469
4-CF3
1
CH2-piperazino-Ph
H, H









































































TABLE 11



Part A No.
R20
n
R2
R3, R4



A470
4-CF3
1
CH2-piperazino-Ph
H, C6H4-4-F

A471
4-CF3
1
CH2-piperidino
H, H

A472
4-CF3
1
CH2-piperidino
H, C6H4-4-F

A473
4-CF3
1
OCH2Ph
H, H

A474
4-CF3
1
OCH2Ph
H, C6H4-4-F

A475
4-CF3
1
Ac
H, H

A476
4-CF3
1
Ac
H, C6H4-4-F

A477
4-CF3
1
CONH2
H, H

A478
4-CF3
1
CONH2
H, C6H4-4-F

A479
4-CF3
1
CSNH2
H, H

A480
4-CF3
1
CSNH2
H, C6H4-4-F

A481
4-CF3
1
OCONH2
H, H

A482
4-CF3
1
OCONH2
H, C6H4-4-F

A483
4-CF3
1
OCSNH2
H, H

A484
4-CF3
1
OCSNH2
H, C6H4-4-F

A485
4-CF3
1
OSO2Me
H, H

A486
4-CF3
1
OSO2Me
H, C6H4-4-F

A487
4-CF3
1
OSO2Ph
H, H

A488
4-CF3
1
OSO2Ph
H, C6H4-4-F

A489
4-CF3
1
I
H, H

A490
4-CF3
1
I
H, C6H4-4-F

A491
4-CF3
2
H
H, H

A492
4-CF3
2
H
Me, Me

A493
4-CF3
2
H
Et, Et

A494
4-CF3
2
H
H, Et

A495
4-CF3
2
H
H, Ph

A496
4-CF3
2
H
H, C6H4-4-F

A497
4-CF3
2
Me
H, H

A498
4-CF3
2
Me
Me, Me

A499
4-CF3
2
Me
Et, Et

A500
4-CF3
2
Me
H, Et

A501
4-CF3
2
Me
H, Ph

A502
4-CF3
2
Me
H, C6H4-4-F

A503
4-CF3
2
OMe
H, H

A504
4-CF3
2
OMe
Me, Me

A505
4-CF3
2
OMe
Et, Et

A506
4-CF3
2
OMe
H, Et

A507
4-CF3
2
OMe
H, Ph

A508
4-CF3
2
OMe
H, C6H4-4-F

A509
4-CF3
2
CH2OH
H, H

A510
4-CF3
2
CH2OH
H, C6H4-4-F

A511
4-CF3
2
CH2OMe
H, H

A512
4-CF3
2
CH2OMe
Me, Me

A513
4-CF3
2
CH2OMe
Et, Et

A514
4-CF3
2
CH2OMe
H, Et

A515
4-CF3
2
CH2OMe
H, Ph

A516
4-CF3
2
CH2OMe
H, C6H4-4-F

A517
4-CF3
2
CF3
H, H









































































TABLE 12



Part A No.
R20
n
R2
R3, R4



A518
4-CF3
2
CF3
Me, Me

A519
4-CF3
2
CF3
Et, Et

A520
4-CF3
2
CF3
H, Et

A521
4-CF3
2
CF3
H, Ph

A522
4-CF3
2
CF3
H, C6H4-4-F

A523
4-CF3
2
CH2OPh
H, H

A524
4-CF3
2
CH2OPh
H, C6H4-4-F

A525
4-CF3
2
CH2OCH2Ph
H, H

A526
4-CF3
2
CH2OCH2Ph
H, C6H4-4-F

A527
4-CF3
2
CH2-morpholino
H, H

A528
4-CF3
2
CH2-morpholino
Me, Me

A529
4-CF3
2
CH2-morpholino
Et, Et

A530
4-CF3
2
CH2-morpholino
H, Et

A531
4-CF3
2
CH2-morpholino
H, Ph

A532
4-CF3
2
CH2-morpholino
H, C6H4-4-F

A533
4-CF3
2
CH2NHBu
H, H

A534
4-CF3
2
CH2NHBu
H, C6H4-4-F

A535
4-CF3
2
C≡CPh
H, H

A536
4-CF3
2
C≡CPh
H, C6H4-4-F

A537
4-CF3
2
Ph
H, H

A538
4-CF3
2
Ph
H, C6H4-4-F

A539
4-CF3
2
C6H4-4-CF3
H, H

A540
4-CF3
2
C6H4-4-CF3
H, C6H4-4-F

A541
4-CF3
2
C6H4-3-CF3
H, H

A542
4-CF3
2
C6H4-3-CF3
H, C6H4-4-F

A543
4-CF3
2
C6H4-4-OH
H, H

A544
4-CF3
2
C6H4-4-OH
H, C6H4-4-F

A545
4-CF3
2
CH2Ph
H, H

A546
4-CF3
2
CH2Ph
H, C6H4-4-F

A547
4-CF3
2
CH2C6H4-4-CF3
H, H

A548
4-CF3
2
CH2C6H4-4-CF3
Me, Me

A549
4-CF3
2
CH2C6H4-4-CF3
Et, Et

A550
4-CF3
2
CH2C6H4-4-CF3
H, Et

A551
4-CF3
2
CH2C6H4-4-CF3
H, Ph

A552
4-CF3
2
CH2C6H4-4-CF3
H, C6H4-4-F

A553
4-CF3
2
CH2C6H4-4-OCF3
H, H

A554
4-CF3
2
CH2C6H4-4-OCF3
H, C6H4-4-F

A555
4-CF3
2
CH2C6H4-4-Ph
H, H

A556
4-CF3
2
CH2C6H4-4-Ph
H, C6H4-4-F

A557
4-CF3
2
CH2C6H4-2-Cl
H, H

A558
4-CF3
2
CH2C6H4-2-Cl
H, C6H4-4-F

A559
4-CF3
2
(CH2)2Ph
H, H

A560
4-CF3
2
(CH2)2Ph
H, C6H4-4-F

A561
4-CF3
2
SPh
H, H

A562
4-CF3
2
SPh
H, C6H4-4-F

A563
4-CF3
2
NH2
H, H

A564
4-CF3
2
NH2
H, C6H4-4-F

A565
4-CF3
2
NHMe
H, H









































































TABLE 13



Part A No.
R20
n
R2
R3, R4



A566
4-CF3
2
NHMe
H, C6H4-4-F

A567
4-CF3
2
CH2-piperazino-Ph
H, H

A568
4-CF3
2
CH2-piperazino-Ph
H, C6H4-4-F

A569
4-CF3
2
CH2-piperidino
H, H

A570
4-CF3
2
CH2-piperidino
H, C6H4-4-F

A571
4-CF3
2
OCH2Ph
H, H

A572
4-CF3
2
OCH2Ph
H, C6H4-4-F

A573
4-CF3
2
Ac
H, H

A574
4-CF3
2
Ac
H, C6H4-4-F

A575
4-CF3
2
CONH2
H, H

A576
4-CF3
2
CONH2
H, C6H4-4-F

A577
4-CF3
2
CSNH2
H, H

A578
4-CF3
2
CSNH2
H, C6H4-4-F

A579
4-CF3
2
OCONH2
H, H

A580
4-CF3
2
OCONH2
H, C6H4-4-F

A581
4-CF3
2
OCSNH2
H, H

A582
4-CF3
2
OCSNH2
H, C6H4-4-F

A583
4-CF3
2
OSO2Me
H, H

A584
4-CF3
2
OSO2Me
H, C6H4-4-F

A585
4-CF3
2
OSO2Ph
H, H

A586
4-CF3
2
OSO2Ph
H, C6H4-4-F

A587
4-CF3
2
I
H, H

A588
4-CF3
2
I
H, C6H4-4-F

A589
H
0
H
H, H

A590
3-F
0
H
Me, Me

A591
2-Me
0
H
Et, Et

A592
3-OMe
0
H
H, Et

A593
4-OH
0
H
H, Ph

A594
4-OMe
0
H
H, C6H4-4-F

A595
2-Ac
0
Me
H, H

A596
4-CH═CH2
0
Me
Me, Me

A597
4-CF3, 3-F
0
Me
Et, Et

A598
4-OCF3
0
Me
H, Et

A599
4-SMe
0
Me
H, Ph

A600
3,5-difluoro
0
Me
H, C6H4-4-F

A601
H
0
OMe
H, H

A602
3-F
0
OMe
Me, Me

A603
2-Me
0
OMe
Et, Et

A604
3-OMe
0
OMe
H, Et

A605
4-OH
0
OMe
H, Ph

A606
4-OMe
0
OMe
H, C6H4-4-F

A607
2-Ac
0
CH2OH
H, H

A608
4-CH═CH2
0
CH2OH
H, C6H4-4-F

A609
4-CF3, 3-F
0
CH2OMe
H, H

A610
4-OCF3
0
CH2OMe
Me, Me

A611
4-SMe
0
CH2OMe
Et, Et

A612
3,5-difluoro
0
CH2OMe
H, Et

A613
H
0
CH2OMe
H, Ph

A614
3-F
0
CH2OMe
H, C6H4-4-F

A615
2-Me
0
CF3
H, H

A616
3-OMe
0
CF3
Me, Me












































































TABLE 14



Part A No.
R20
n
R2
R3, R4



A617
4-OH
0
CF3
Et, Et

A618
4-OMe
0
CF3
H, Et

A619
2-Ac
0
CF3
H, Ph

A620
4-CH═CH2
0
CF3
H, C6H4-4-F

A621
4-CF3, 3-F
0
CH2OPh
H, H

A622
4-OCF3
0
CH2OPh
H, C6H4-4-F

A623
4-SMe
0
CH2OCH2Ph
H, H

A624
3,5-difluoro
0
CH2OCH2Ph
H, C6H4-4-F

A625
H
0
CH2-morpholino
H, H

A626
3-F
0
CH2-morpholino
Me, Me

A627
2-Me
0
CH2-morpholino
Et, Et

A628
3-OMe
0
CH2-morpholino
H, Et

A629
4-OH
0
CH2-morpholino
H, Ph

A630
4-OMe
0
CH2-morpholino
H, C6H4-4-F

A631
2-Ac
0
CH2NHBu
H, H

A632
4-CH═CH2
0
CH2NHBu
H, C6H4-4-F

A633
4-CF3, 3-F
0
C≡CPh
H, H

A634
4-OCF3
0
C≡CPh
H, C6H4-4-F

A635
4-SMe
0
Ph
H, H

A636
3,5-difluoro
0
Ph
H, C6H4-4-F

A637
H
0
C6H4-4-CF3
H, H

A638
3-F
0
C6H4-4-CF3
H, C6H4-4-F

A639
2-Me
0
C6H4-3-CF3
H, H

A640
3-OMe
0
C6H4-3-CF3
H, C6H4-4-F

A641
4-OH
0
C6H4-4-OH
H, H

A642
4-OMe
0
C6H4-4-OH
H, C6H4-4-F

A643
2-Ac
0
CH2Ph
H, H

A644
4-CH═CH2
0
CH2Ph
H, C6H4-4-F

A645
4-CF3, 3-F
0
CH2C6H4-4-CF3
H, H

A646
4-OCF3
0
CH2C6H4-4-CF3
Me, Me

A647
4-SMe
0
CH2C6H4-4-CF3
Et, Et

A648
3,5-difluoro
0
CH2C6H4-4-CF3
H, Et

A649
H
0
CH2C6H4-4-CF3
H, Ph

A650
3-F
0
CH2C6H4-4-CF3
H, C6H4-4-F

A651
2-Me
0
CH2C6H4-4-OCF3
H, H

A652
3-OMe
0
CH2C6H4-4-OCF3
H, C6H4-4-F

A653
4-OH
0
CH2C6H4-4-Ph
H, H

A654
4-OMe
0
CH2C6H4-4-Ph
H, C6H4-4-F

A655
2-Ac
0
CH2C6H4-2-Cl
H, H

A656
4-CH═CH2
0
CH2C6H4-2-Cl
H, C6H4-4-F

A657
4-CF3, 3-F
0
(CH2)2Ph
H, H

A658
4-OCF3
0
(CH2)2Ph
H, C6H4-4-F

A659
4-SMe
0
SPh
H, H

A660
3,5-difluoro
0
SPh
H, C6H4-4-F

A661
H
0
NH2
H, H

A662
3-F
0
NH2
H, C6H4-4-F

A663
2-Me
0
NHMe
H, H

A664
3-OMe
0
NHMe
H, C6H4-4-F

A665
4-OH
0
CH2-piperazino-Ph
H, H

A666
4-OMe
0
CH2-piperazino-Ph
H, C6H4-4-F

A667
2-Ac
0
CH2-piperidino
H, H












































































TABLE 15



Part A No.
R20
n
R2
R3, R4



A668
4-CH═CH2
0
CH2-piperidino
H, C6H4-4-F

A669
4-CF3, 3-F
0
OCH2Ph
H, H

A670
4-OCF3
0
OCH2Ph
H, C6H4-4-F

A671
4-SMe
0
Ac
H, H

A672
3,5-difluoro
0
Ac
H, C6H4-4-F

A673
H
0
CONH2
H, H

A674
3-F
0
CONH2
H, C6H4-4-F

A675
2-Me
0
CSNH2
H, H

A676
3-OMe
0
CSNH2
H, C6H4-4-F

A677
4-OH
0
OCONH2
H, H

A678
4-OMe
0
OCONH2
H, C6H4-4-F

A679
2-Ac
0
OCSNH2
H, H

A680
4-CH═CH2
0
OCSNH2
H, C6H4-4-F

A681
4-CF3, 3-F
0
OSO2Me
H, H

A682
4-OCF3
0
OSO2Me
H, C6H4-4-F

A683
4-SMe
0
OSO2Ph
H, H

A684
3,5-difluoro
0
OSO2Ph
H, C6H4-4-F

A685
H
0
I
H, H

A686
3-F
0
I
H, C6H4-4-F

A687
H
1
H
H, H

A688
3-F
1
H
Me, Me

A689
2-Me
1
H
Et, Et

A690
3-OMe
1
H
H, Et

A691
4-OH
1
H
H, Ph

A692
4-OMe
1
H
H, C6H4-4-F

A693
2-Ac
1
Me
H, H

A694
4-CH═CH2
1
Me
Me, Me

A695
4-CF3, 3-F
1
Me
Et, Et

A696
4-OCF3
1
Me
H, Et

A697
4-SMe
1
Me
H, Ph

A698
3,5-difluoro
1
Me
H, C6H4-4-F

A699
H
1
OMe
H, H

A700
3-F
1
OMe
Me, Me

A701
2-Me
1
OMe
Et, Et

A702
3-OMe
1
OMe
H, Et

A703
4-OH
1
OMe
H, Ph

A704
4-OMe
1
OMe
H, C6H4-4-F

A705
2-Ac
1
CH2OH
H, H

A706
4-CH═CH2
1
CH2OH
H, C6H4-4-F

A707
4-CF3, 3-F
1
CH2OMe
H, H

A708
4-OCF3
1
CH2OMe
Me, Me

A709
4-SMe
1
CH2OMe
Et, Et

A710
3,5-difluoro
1
CH2OMe
H, Et

A711
H
1
CH2OMe
H, Ph

A712
3-F
1
CH2OMe
H, C6H4-4-F

A713
2-Me
1
CF3
H, H

A714
3-OMe
1
CF3
Me, Me

A715
4-OH
1
CF3
Et, Et

A716
4-OMe
1
CF3
H, Et

A717
2-Ac
1
CF3
H, Ph

A718
4-CH═CH2
1
CF3
H, C6H4-4-F












































































TABLE 16



Part A No.
R20
n
R2
R3, R4



A719
4-CF3, 3-F
1
CH2OPh
H, H

A720
4-OCF3
1
CH2OPh
H, C6H4-4-F

A721
4-SMe
1
CH2OCH2Ph
H, H

A722
3,5-difluoro
1
CH2OCH2Ph
H, C6H4-4-F

A723
H
1
CH2-morpholino
H, H

A724
3-F
1
CH2-morpholino
Me, Me

A725
2-Me
1
CH2-morpholino
Et, Et

A726
3-OMe
1
CH2-morpholino
H, Et

A727
4-OH
1
CH2-morpholino
H, Ph

A728
4-OMe
1
CH2-morpholino
H, C6H4-4-F

A729
2-Ac
1
CH2NHBu
H, H

A730
4-CH═CH2
1
CH2NHBu
H, C6H4-4-F

A731
4-CF3, 3-F
1
C≡CPh
H, H

A732
4-OCF3
1
C≡CPh
H, C6H4-4-F

A733
4-SMe
1
Ph
H, H

A734
3,5-difluoro
1
Ph
H, C6H4-4-F

A735
H
2
C6H4-4-CF3
H, H

A736
3-F
2
C6H4-4-CF3
H, C6H4-4-F

A737
2-Me
2
C6H4-3-CF3
H, H

A738
3-OMe
2
C6H4-3-CF3
H, C6H4-4-F

A739
4-OH
2
C6H4-4-OH
H, H

A740
4-OMe
2
C6H4-4-OH
H, C6H4-4-F

A741
2-Ac
2
CH2Ph
H, H

A742
4-CH═CH2
2
CH2Ph
H, C6H4-4-F

A743
4-CF3, 3-F
2
CH2C6H4-4-CF3
H, H

A744
4-OCF3
2
CH2C6H4-4-CF3
Me, Me

A745
4-SMe
2
CH2C6H4-4-CF3
Et, Et

A746
3,5-difluoro
2
CH2C6H4-4-CF3
H, Et

A747
H
2
CH2C6H4-4-CF3
H, Ph

A748
3-F
2
CH2C6H4-4-CF3
H, C6H4-4-F

A749
2-Me
2
CH2C6H4-4-OCF3
H, H

A750
3-OMe
2
CH2C6H4-4-OCF3
H, C6H4-4-F

A751
4-OH
2
CH2C6H4-4-Ph
H, H

A752
4-OMe
2
CH2C6H4-4-Ph
H, C6H4-4-F

A753
2-Ac
2
CH2C6H4-2-Cl
H, H

A754
4-CH═CH2
2
CH2C6H4-2-Cl
H, C6H4-4-F

A755
4-CF3, 3-F
2
(CH2)2Ph
H, H

A756
4-OCF3
2
(CH2)2Ph
H, C6H4-4-F

A757
4-SMe
2
SPh
H, H

A758
3,5-difluoro
2
SPh
H, C6H4-4-F

A759
H
2
NH2
H, H

A760
3-F
2
NH2
H, C6H4-4-F

A761
2-Me
2
NHMe
H, H

A762
3-OMe
2
NHMe
H, C6H4-4-F

A763
4-OH
2
CH2-piperazino-Ph
H, H

A764
4-OMe
2
CH2-piperazino-Ph
H, C6H4-4-F

A765
2-Ac
2
CH2-piperidino
H, H

A766
4-CH═CH2
2
CH2-piperidino
H, C6H4-4-F

A767
4-CF3, 3-F
2
OCH2Ph
H, H

A768
4-OCF3
2
OCH2Ph
H, C6H4-4-F

A769
4-SMe
2
Ac
H, H












































































TABLE 17



Part





A

No.
R20
n
R2
R3, R4



A770
3,5-difluoro
2
Ac
H, C6H4-4-F

A771
H
2
CONH2
H, H

A772
3-F
2
CONH2
H, C6H4-4-F

A773
2-Me
2
CSNH2
H, H

A774
3-OMe
2
CSNH2
H, C6H4-4-F

A775
4-OH
2
OCONH2
H, H

A776
4-OMe
2
OCONH2
H, C6H4-4-F

A777
2-Ac
2
OCSNH2
H, H

A778
4-CH═CH2
2
OCSNH2
H, C6H4-4-F

A779
4-CF3, 3-F
2
OSO2Me
H, H

A780
4-OCF3
2
OSO2Me
H, C6H4-4-F

A781
4-SMe
2
OSO2Ph
H, H

A782
3,5-difluoro
2
OSO2Ph
H, C6H4-4-F

A783
H
2
I
H, H

A784
3-F
2
I
H, C6H4-4-F

A785
4-CF3
0
CH═NOH
H, H

A786
4-CF3
0
CH═NOMe
H, H

A787
4-CF3
0
CH═NOEt
H, H

A788
4-CF3
0
CH═NOnPr
H, H

A789
4-CF3
0
CH═NOiPr
H, H

A790
4-CF3
0
CH═NOcPy
H, H

A791
4-CF3
0
CH═NOnBu
H, H

A792
4-CF3
0
CH═NOcBu
H, H

A793
4-CF3
0
CH═NOnPen
H, H

A794
4-CF3
0
CH═NOcPen
H, H

A795
4-CF3
0
CH═NOcHex
H, H

A796
4-CF3
0
CH═NOcHex
H, H

A797
4-CF3
0
CH═NOCH2iPr
H, H

A798
4-CF3
0
CH═NOCH2cPr
H, H

A799
4-CF3
0
CH═NOCH2cBu
H, H

A800
4-CF3
0
CH═NOCH2cPen
H, H

A801
4-CF3
0
CH═NOCH2cHex
H, H

A802
4-CF3
0
CH═NO(CH2)2iPr
H, H

A803
4-CF3
0
CH═NO(CH2)2cPr
H, H

A804
4-CF3
0
CH═NO(CH2)2cBu
H, H

A805
4-CF3
0
CH═NO(CH2)2cPen
H, H

A806
4-CF3
0
CH═NO(CH2)2cHex
H, H

A807
4-CF3
0
CH═NO(CH2)3iPr
H, H

A808
4-CF3
0
CH═NO(CH2)3cPr
H, H

A809
4-CF3
0
CH═NO(CH2)3cBu
H, H

A810
4-CF3
0
CH═NO(CH2)3cPen
H, H

A811
4-CF3
0
CH═NO(CH2)3cHex
H, H



A812
4-CF3
0









H, H



A813
4-CF3
0









H, H



A814
4-CF3
0









H, H











































































TABLE 18



Part A No.
R20
n
R2
R3, R4



A815
4-CF3
0









H, H



A816
4-CF3
0









H, H



A817
4-CF3
0









H, H



A818
4-CF3
0









H, H



A819
4-CF3
0









H, H



A820
4-CF3
0









H, H



A821
4-CF3
0









H, H



A822
4-CF3
0









H, H



A823
4-CF3
0









H, H



A824
4-CF3
0









H, H



A825
4-CF3
0









H, H



A826
4-CF3
0









H, H



A827
4-CF3
0









H, H



A828
4-CF3
0









H, H



A829
4-CF3
0









H, H



A830
4-CF3
0









H, H



A831
4-CF3
0









H, H



A832
4-CF3
0









H, H



A833
4-CF3
0









H, H



A834
4-CF3
0









H, H



A835
4-CF3
0









H, H



A836
4-CF3
0









H, H



A837
4-CF3
0









H, H



A838
4-CF3
0









H, H



A839
4-CF3
0









H, H










































































TABLE 19



Part





A No.
R20
n
R2
R3, R4



A840
4-CF3
0









H, H



A841
4-CF3
0









H, H



A842
4-CF3
0









H, H



A843
4-CF3
0









H, H



A844
4-CF3
0









H, H



A845
4-CF3
0









H, H



A846
4-CF3
0









H, H



A847
4-CF3
0









H, H



A848
4-CF3
0









H, H



A849
4-CF3
0









H, H



A850
4-CF3
0









H, H



A851
4-CF3
0









H, H



A852
4-CF3
0









H, H



A853
4-CF3
0









H, H



A854
4-CF3
0









H, H



A855
4-CF3
0









H, H



A856
4-CF3
0









H, H



A857
4-CF3
0









H, H



A858
4-CF3
0









H, H



A859
4-CF3
0









H, H



A860
4-CF3
0









H, H



A861
4-CF3
0









H, H



A862
4-CF3
0
CH2OcPr
H, H

A863
4-CF3
0
CH2OcBu
H, H

A864
4-CF3
0
CH2OcPen
H, H

A865
4-CF3
0
CH2OcHex
H, H

A866
4-CF3
0
CH2OCH2cPr
H, H

A867
4-CF3
0
CH2OCH2cBu
H, H

A868
4-CF3
0
CH2OCH2cPen
H, H

A869
4-CF3
0
CH2OCH2cHex
H, H

A870
4-CF3
0
CH2O(CH2)2cPr
H, H

A871
4-CF3
0
CH2O(CH2)2cBu
H, H
















































































TABLE 20



Part A No.
R20
n
R2
R3, R4



A872
4-CF3
0
CH2O(CH2)2cPen
H, H

A873
4-CF3
0
CH2O(CH2)2cHex
H, H

A874
4-CF3
0
CH2O(CH2)3cPr
H, H

A875
4-CF3
0
CH2O(CH2)3cBu
H, H

A876
4-CF3
0
CH2O(CH2)3cPen
H, H

A877
4-CF3
0
CH2O(CH2)3cHex
H, H



A878
4-CF3
0









H, H



A879
4-CF3
0









H, H



A880
4-CF3
0









H, H



A881
4-CF3
0









H, H



A882
4-CF3
0









H, H



A883
4-CF3
0









H, H



A884
4-CF3
0









H, H



A885
4-CF3
0









H, H



A886
4-CF3
0









H, H



A887
4-CF3
0









H, H



A888
4-CF3
0









H, H



A889
4-CF3
0









H, H



A890
4-CF3
0









H, H



A891
4-CF3
0









H, H



A892
4-CF3
0









H, H



A893
4-CF3
0









H, H



A894
4-CF3
0









H, H



A895
4-CF3
0









H, H



A896
4-CF3
0









H, H



A897
4-CF3
0









H, H



A898
4-CF3
0









H, H



A899
4-CF3
0









H, H



A900
4-CF3
0









H, H













































































TABLE 21



Part A No.
R20
n
R2
R3, R4



A901
4-CF3
0









H, H



A902
4-CF3
0









H, H



A903
4-CF3
0









H, H



A904
4-CF3
0









H, H



A905
4-CF3
0









H, H



A906
4-CF3
0









H, H



A907
4-CF3
0









H, H



A908
4-CF3
0









H, H



A909
4-CF3
0









H, H



A910
4-CF3
0









H, H



A911
4-CF3
0









H, H



A912
4-CF3
0









H, H



A913
4-CF3
0









H, H



A914
4-CF3
0









H, H



A915
4-CF3
0









H, H



A916
4-CF3
0









H, H



A917
4-CF3
0









H, H



A918
4-CF3
0









H, H



A919
4-CF3
0









H, H



A920
4-CF3
0









H, H



A921
4-CF3
0









H, H



A922
4-CF3
0









H, H



A923
4-CF3
0









H, H



A924
4-CF3
0









H, H



A925
4-CF3
0









H, H



A926
4-CF3
0









H, H



A927
4-CF3
0









H, H



A928
4-CF3
0
CH2ON═CHCH3
H, H
















































































TABLE 22



Part A No.
R20
n
R2
R3, R4



A929
4-CF3
0
CH2ON═CH(CH3)2
H, H



A930
4-CF3
0









H, H



A931
4-CF3
0









H, H



A932
4-Cl
0
CH═NOH
H, H

A933
4-Cl
0
CH═NOMe
H, H

A934
4-Cl
0
CH═NOEt
H, H

A935
4-Cl
0
CH═NOnPr
H, H

A936
4-Cl
0
CH═NOiPr
H, H

A937
4-Cl
0
CH═NocPr
H, H

A938
4-Cl
0
CH═NonBu
H, H

A939
4-Cl
0
CH═NOCH2CH(CH3)2
H, H

A940
4-Cl
0
CH═NocBu
H, H

A941
4-Cl
0
CH═NonPen
H, H

A942
4-Cl
0
CH═NocPen
H, H

A943
4-Cl
0
CH═NonHex
H, H

A944
4-Cl
0
CH═NocHex
H, H

A945
4-Cl
0
CH═NOH
H, H

A946
4-Cl
0
CH═NOCH2iPr
H, H

A947
4-Cl
0
CH═NOCH2cPr
H, H

A948
4-Cl
0
CH═NOCH2cBu
H, H

A949
4-Cl
0
CH═NOCH2cPen
H, H

A950
4-Cl
0
CH═NOCH2cHex
H, H

A951
4-Cl
0
CH═NO(CH2)2iPr
H, H

A952
4-Cl
0
CH═NO(CH2)2cPr
H, H

A953
4-Cl
0
CH═NO(CH2)2cBu
H, H

A954
4-Cl
0
CH═NO(CH2)2cPen
H, H

A955
4-Cl
0
CH═NO(CH2)2cHex
H, H

A956
4-Cl
0
CH═NO(CH2)3iPr
H, H

A957
4-Cl
0
CH═NO(CH2)3cPr
H, H

A958
4-Cl
0
CH═NO(CH2)3cBu
H, H

A959
4-Cl
0
CH═NO(CH2)3cPen
H, H

A960
4-Cl
0
CH═NO(CH2)3cHex
H, H



A961
4-Cl
0









H, H



A962
4-Cl
0









H, H



A963
4-Cl
0









H, H



A964
4-Cl
0









H, H



A965
4-Cl
0









H, H



A966
4-Cl
0









H, H








































































TABLE 23



Part A No.
R20
n
R2
R3, R4



A967
4-Cl
0









H, H



A968
4-Cl
0









H, H



A969
4-Cl
0









H, H



A970
4-Cl
0









H, H



A971
4-Cl
0









H, H



A972
4-Cl
0









H, H



A973
4-Cl
0









H, H



A974
4-Cl
0









H, H



A975
4-Cl
0









H, H



A976
4-Cl
0









H, H



A977
4-Cl
0









H, H



A978
4-Cl
0









H, H



A979
4-Cl
0









H, H



A980
4-Cl
0









H, H



A981
4-Cl
0









H, H



A982
4-Cl
0









H, H



A983
4-Cl
0









H, H



A984
4-Cl
0









H, H



A985
4-Cl
0









H, H



A986
4-Cl
0









H, H



A987
4-Cl
0









H, H



A988
4-Cl
0









H, H



A989
4-Cl
0









H, H



A990
4-Cl
0









H, H








































































TABLE 24



Part A



R3,

No.
R20
n
R2
R4



A991
4-Cl
0









H, H



A992
4-Cl
0









H, H



A993
4-Cl
0









H, H



A994
4-Cl
0









H, H



A995
4-Cl
0









H, H



A996
4-Cl
0









H, H



A997
4-Cl
0









H, H



A998
4-Cl
0









H, H



A999
4-Cl
0









H, H



A1000
4-Cl
0









H, H



A1001
4-Cl
0









H, H



A1002
4-Cl
0









H, H



A1003
4-Cl
0









H, H



A1004
4-Cl
0









H, H



A1005
4-Cl
0









H, H



A1006
4-Cl
0









H, H



A1007
4-Cl
0









H, H



A1008
4-Cl
0









H, H



A1009
4-Cl
0









H, H



A1010
4-Cl
0









H, H



A1011
4-Cl
0
CH2OcPr
H, H

A1012
4-Cl
0
CH2OcBu
H, H

A1013
4-Cl
0
CH2OcPen
H, H

A1014
4-Cl
0
CH2OcHex
H, H

A1015
4-Cl
0
CH2OCH2cPr
H, H

A1016
4-Cl
0
CH2OCH2cBu
H, H

A1017
4-Cl
0
CH2OCH2cPen
H, H

A1018
4-Cl
0
CH2OCH2cHex
H, H

A1019
4-Cl
0
CH2O(CH2)2cPr
H, H

A1020
4-Cl
0
CH2O(CH2)2cBu
H, H

A1021
4-Cl
0
CH2O(CH2)2cPen
H, H

A1022
4-Cl
0
CH2O(CH2)2cHex
H, H














































































TABLE 25



Part A No.
R20
n
R2
R3, R4



A1023
4-Cl
0
CH2O(CH2)3cPr
H, H

A1024
4-Cl
0
CH2O(CH2)3cBu
H, H

A1025
4-Cl
0
CH2O(CH2)3cPen
H, H

A1026
4-Cl
0
CH2O(CH2)3cHex
H, H



A1027
4-Cl
0









H, H



A1028
4-Cl
0









H, H



A1029
4-Cl
0









H, H



A1030
4-Cl
0









H, H



A1031
4-Cl
0









H, H



A1032
4-Cl
0









H, H



A1033
4-Cl
0









H, H



A1034
4-Cl
0









H, H



A1035
4-Cl
0









H, H



A1036
4-Cl
0









H, H



A1037
4-Cl
0









H, H



A1038
4-Cl
0









H, H



A1039
4-Cl
0









H, H



A1040
4-Cl
0









H, H



A1041
4-Cl
0









H, H



A1042
4-Cl
0









H, H



A1043
4-Cl
0









H, H



A1044
4-Cl
0









H, H



A1045
4-Cl
0









H, H



A1046
4-Cl
0









H, H



A1047
4-Cl
0









H, H



A1048
4-Cl
0









H, H



A1049
4-Cl
0









H, H











































































TABLE 26



Part A No.
R20
n
R2
R3, R4



A1050
4-Cl
0









H, H



A1051
4-Cl
0









H, H



A1052
4-Cl
0









H, H



A1053
4-Cl
0









H, H



A1054
4-Cl
0









H, H



A1055
4-Cl
0









H, H



A1056
4-Cl
0









H, H



A1057
4-Cl
0









H, H



A1058
4-Cl
0









H, H



A1059
4-Cl
0









H, H



A1060
4-Cl
0









H, H



A1061
4-Cl
0









H, H



A1062
4-Cl
0









H, H



A1063
4-Cl
0









H, H



A1064
4-Cl
0









H, H



A1065
4-Cl
0









H, H



A1066
4-Cl
0









H, H



A1067
4-Cl
0









H, H



A1068
4-Cl
0









H, H



A1069
4-Cl
0









H, H



A1070
4-Cl
0









H, H



A1071
4-Cl
0









H, H



A1072
4-Cl
0









H, H



A1073
4-Cl
0









H, H



A1074
4-Cl
0









H, H



A1075
4-Cl
0









H, H












































































TABLE 27



Part A No.
R20
n
R2
R3, R4



A1076
4-Cl
0









H, H



A1077
4-Cl
0
CH2ON═CHCH3
H, H

A1078
4-Cl
0
CH2ON═CH(CH3)2
H, H



A1079
4-Cl
0









H, H



A1080
4-Cl
0









H, H



A1081
4-OCF3
0
CH═NOH
H, H

A1082
4-OCF3
0
CH═NOMe
H, H

A1083
4-OCF3
0
CH═NOEt
H, H

A1084
4-OCF3
0
CH═NOnPr
H, H

A1085
4-OCF3
0
CH═NOiPr
H, H

A1086
4-OCF3
0
CH═NOcPr
H, H

A1087
4-OCF3
0
CH═NOnBu
H, H

A1088
4-OCF3
0
CH═NOCH2CH(CH3)2
H, H

A1089
4-OCF3
0
CH═NOcBu
H, H

A1090
4-OCF3
0
CH═NOnPen
H, H

A1091
4-OCF3
0
CH═NOcPen
H, H

A1092
4-OCF3
0
CH═NOnHex
H, H

A1093
4-OCF3
0
CH═NOcHex
H, H

A1094
4-OCF3
0
CH═NOH
H, H

A1095
4-OCF3
0
CH═NOCH2iPr
H, H

A1096
4-OCF3
0
CH═NOCH2cPr
H, H

A1097
4-OCF3
0
CH═NOCH2cBu
H, H

A1098
4-OCF3
0
CH═NOCH2cPen
H, H

A1099
4-OCF3
0
CH═NOCH2cHex
H, H

A1100
4-OCF3
0
CH═NO(CH2)2iPr
H, H

A1101
4-OCF3
0
CH═NO(CH2)2cPr
H, H

A1102
4-OCF3
0
CH═NO(CH2)2cBu
H, H

A1103
4-OCF3
0
CH═NO(CH2)2cPen
H, H

A1104
4-OCF3
0
CH═NO(CH2)2cHex
H, H

A1105
4-OCF3
0
CH═NO(CH2)3iPr
H, H

A1106
4-OCF3
0
CH═NO(CH2)3cPr
H, H

A1107
4-OCF3
0
CH═NO(CH2)3cBu
H, H

A1108
4-OCF3
0
CH═NO(CH2)3cPen
H, H

A1109
4-OCF3
0
CH═NO(CH2)3cHex
H, H



A1110
4-OCF3
0









H, H



A1111
4-OCF3
0









H, H



A1112
4-OCF3
0









H, H



A1113
4-OCF3
0









H, H







































































TABLE 28



Part A No.
R20
n
R2
R3, R4



A1114
4-OCF3
0









H, H



A1115
4-OCF3
0









H, H



A1116
4-OCF3
0









H, H



A1117
4-OCF3
0









H, H



A1118
4-OCF3
0









H, H



A1119
4-OCF3
0









H, H



A1120
4-OCF3
0









H, H



A1121
4-OCF3
0









H, H



A1122
4-OCF3
0









H, H



A1123
4-OCF3
0









H, H



A1124
4-OCF3
0









H, H



A1125
4-OCF3
0









H, H



A1126
4-OCF3
0









H, H



A1127
4-OCF3
0









H, H



A1128
4-OCF3
0









H, H



A1129
4-OCF3
0









H, H



A1130
4-OCF3
0









H, H



A1131
4-OCF3
0









H, H



A1132
4-OCF3
0









H, H



A1133
4-OCF3
0









H, H



A1134
4-OCF3
0









H, H



A1135
4-OCF3
0









H, H



A1136
4-OCF3
0









H, H



A1137
4-OCF3
0









H, H








































































TABLE 29



Part A No.
R20
n
R2
R3, R4



A1138
4-OCF3
0









H, H



A1139
4-OCF3
0









H, H



A1140
4-OCF3
0









H, H



A1141
4-OCF3
0









H, H



A1142
4-OCF3
0









H, H



A1143
4-OCF3
0









H, H



A1144
4-OCF3
0









H, H



A1145
4-OCF3
0









H, H



A1146
4-OCF3
0









H, H



A1147
4-OCF3
0









H, H



A1148
4-OCF3
0









H, H



A1149
4-OCF3
0









H, H



A1150
4-OCF3
0









H, H



A1151
4-OCF3
0









H, H



A1152
4-OCF3
0









H, H



A1153
4-OCF3
0









H, H



A1154
4-OCF3
0









H, H



A1155
4-OCF3
0









H, H



A1156
4-OCF3
0









H, H



A1157
4-OCF3
0









H, H



A1158
4-OCF3
0









H, H



A1159
4-OCF3
0









H, H



A1160
4-OCF3
0
CH2OcPr
H, H

A1161
4-OCF3
0
CH2OcBu
H, H

A1162
4-OCF3
0
CH2OcPen
H, H

A1163
4-OCF3
0
CH2OcHex
H, H

A1164
4-OCF3
0
CH2OCH2cPr
H, H

A1165
4-OCF3
0
CH2OCH2cBu
H, H

A1166
4-OCF3
0
CH2OCH2cPen
H, H

A1167
4-OCF3
0
CH2OCH2cHex
H, H

A1168
4-OCF3
0
CH2O(CH2)2cPr
H, H














































































TABLE 30



Part A No.
R20
n
R2
R3, R4



A1169
4-OCF3
0
CH2O(CH2)2cBu
H, H

A1170
4-OCF3
0
CH2O(CH2)2cPen
H, H

A1171
4-OCF3
0
CH2O(CH2)2cHex
H, H

A1172
4-OCF3
0
CH2O(CH2)3cPr
H, H

A1173
4-OCF3
0
CH2O(CH2)3cBu
H, H

A1174
4-OCF3
0
CH2O(CH2)3cPen
H, H

A1175
4-OCF3
0
CH2O(CH2)3cHex
H, H



A1176
4-OCF3
0









H, H



A1177
4-OCF3
0









H, H



A1178
4-OCF3
0









H, H



A1179
4-OCF3
0









H, H



A1180
4-OCF3
0









H, H



A1181
4-OCF3
0









H, H



A1182
4-OCF3
0









H, H



A1183
4-OCF3
0









H, H



A1184
4-OCF3
0









H, H



A1185
4-OCF3
0









H, H



A1186
4-OCF3
0









H, H



A1187
4-OCF3
0









H, H



A1188
4-OCF3
0









H, H



A1189
4-OCF3
0









H, H



A1190
4-OCF3
0









H, H



A1191
4-OCF3
0









H, H



A1192
4-OCF3
0









H, H



A1193
4-OCF3
0









H, H



A1194
4-OCF3
0









H, H



A1195
4-OCF3
0









H, H



A1196
4-OCF3
0









H, H



A1197
4-OCF3
0









H, H












































































TABLE 31



Part A No.
R20
n
R2
R3, R4



A1198
4-OCF3
0









H, H



A1199
4-OCF3
0









H, H



A1200
4-OCF3
0









H, H



A1201
4-OCF3
0









H, H



A1202
4-OCF3
0









H, H



A1203
4-OCF3
0









H, H



A1204
4-OCF3
0









H, H



A1205
4-OCF3
0









H, H



A1206
4-OCF3
0









H, H



A1207
4-OCF3
0









H, H



A1208
4-OCF3
0









H, H



A1209
4-OCF3
0









H, H



A1210
4-OCF3
0









H, H



A1211
4-OCF3
0









H, H



A1212
4-OCF3
0









H, H



A1213
4-OCF3
0









H, H



A1214
4-OCF3
0









H, H



A1215
4-OCF3
0









H, H



A1216
4-OCF3
0









H, H



A1217
4-OCF3
0









H, H



A1218
4-OCF3
0









H, H



A1219
4-OCF3
0









H, H



A1220
4-OCF3
0









H, H



A1221
4-OCF3
0









H, H



A1222
4-OCF3
0









H, H










































































TABLE 32



Part A No.
R20
n
R2
R3, R4



A1223
4-OCF3
0









H, H



A1224
4-OCF3
0









H, H



A1225
4-OCF3
0









H, H



A1226
4-OCF3
0
CH2ON═CHCH3
H, H

A1227
4-OCF3
0
CH2ON═CH(CH3)2
H, H



A1228
4-OCF3
0









H, H



A1229
4-OCF3
0









H, H



A1230
2-Cl, 4-Cl
0
CH═NOH
H, H

A1231
2-Cl, 4-Cl
0
CH═NOMe
H, H

A1232
2-Cl, 4-Cl
0
CH═NOEt
H, H

A1233
2-Cl, 4-Cl
0
CH═NOnPr
H, H

A1234
2-Cl, 4-Cl
0
CH═NOiPr
H, H

A1235
2-Cl, 4-Cl
0
CH═NocPr
H, H

A1236
2-Cl, 4-Cl
0
CH═NonBu
H, H

A1237
2-Cl, 4-Cl
0
CH═NOCH2CH(CH3)2
H, H

A1238
2-Cl, 4-Cl
0
CH═NocBu
H, H

A1239
2-Cl, 4-Cl
0
CH═NonPen
H, H

A1240
2-Cl, 4-Cl
0
CH═NocPen
H, H

A1241
2-Cl, 4-Cl
0
CH═NonHex
H, H

A1242
2-Cl, 4-Cl
0
CH═NocHex
H, H

A1243
2-Cl, 4-Cl
0
CH═NOH
H, H

A1244
2-Cl, 4-Cl
0
CH═NOCH2iPr
H, H

A1245
2-Cl, 4-Cl
0
CH═NOCH2cPr
H, H

A1246
2-Cl, 4-Cl
0
CH═NOCH2cBu
H, H

A1247
2-Cl, 4-Cl
0
CH═NOCH2cPen
H, H

A1248
2-Cl, 4-Cl
0
CH═NOCH2cHex
H, H

A1249
2-Cl, 4-Cl
0
CH═NO(CH2)2iPr
H, H

A1250
2-Cl, 4-Cl
0
CH═NO(CH2)2cPr
H, H

A1251
2-Cl, 4-Cl
0
CH═NO(CH2)2cBu
H, H

A1252
2-Cl, 4-Cl
0
CH═NO(CH2)2cPen
H, H

A1253
2-Cl, 4-Cl
0
CH═NO(CH2)2cHex
H, H

A1254
2-Cl, 4-Cl
0
CH═NO(CH2)3iPr
H, H

A1255
2-Cl, 4-Cl
0
CH═NO(CH2)3cPr
H, H

A1256
2-Cl, 4-Cl
0
CH═NO(CH2)3cBu
H, H

A1257
2-Cl, 4-Cl
0
CH═NO(CH2)3cPen
H, H

A1258
2-Cl, 4-Cl
0
CH═NO(CH2)3cHex
H, H



A1259
2-Cl, 4-Cl
0









H, H



A1260
2-Cl, 4-Cl
0









H, H



A1261
2-Cl, 4-Cl
0









H, H









































































TABLE 33



Part A





No.
R20
n
R2
R3, R4



A1262
2-Cl, 4-Cl
0









H, H



A1263
2-Cl, 4-Cl
0









H, H



A1264
2-Cl, 4-Cl
0









H, H



A1265
2-Cl, 4-Cl
0









H, H



A1266
2-Cl, 4-Cl
0









H, H



A1267
2-Cl, 4-Cl
0









H, H



A1268
2-Cl, 4-Cl
0









H, H



A1269
2-Cl, 4-Cl
0









H, H



A1270
2-Cl, 4-Cl
0









H, H



A1271
2-Cl, 4-Cl
0









H, H



A1272
2-Cl, 4-Cl
0









H, H



A1273
2-Cl, 4-Cl
0









H, H



A1274
2-Cl, 4-Cl
0









H, H



A1275
2-Cl, 4-Cl
0









H, H



A1276
2-Cl, 4-Cl
0









H, H



A1277
2-Cl, 4-Cl
0









H, H



A1278
2-Cl, 4-Cl
0









H, H



A1279
2-Cl, 4-Cl
0









H, H



A1280
2-Cl, 4-Cl
0









H, H



A1281
2-Cl, 4-Cl
0









H, H



A1282
2-Cl, 4-Cl
0









H, H



A1283
2-Cl, 4-Cl
0









H, H



A1284
2-Cl, 4-Cl
0









H, H



A1285
2-Cl, 4-Cl
0









H, H



A1286
2-Cl, 4-Cl
0









H, H











































































TABLE 34



Part A No.
R20
n
R2
R3, R4



A1287
2-Cl, 4-Cl
0









H, H



A1288
2-Cl, 4-Cl
0









H, H



A1289
2-Cl, 4-Cl
0









H, H



A1290
2-Cl, 4-Cl
0









H, H



A1291
2-Cl, 4-Cl
0









H, H



A1292
2-Cl, 4-Cl
0









H, H



A1293
2-Cl, 4-Cl
0









H, H



A1294
2-Cl, 4-Cl
0









H, H



A1295
2-Cl, 4-Cl
0









H, H



A1296
2-Cl, 4-Cl
0









H, H



A1297
2-Cl, 4-Cl
0









H, H



A1298
2-Cl, 4-Cl
0









H, H



A1299
2-Cl, 4-Cl
0









H, H



A1300
2-Cl, 4-Cl
0









H, H



A1301
2-Cl, 4-Cl
0









H, H



A1302
2-Cl, 4-Cl
0









H, H



A1303
2-Cl, 4-Cl
0









H, H



A1304
2-Cl, 4-Cl
0









H, H



A1305
2-Cl, 4-Cl
0









H, H



A1306
2-Cl, 4-Cl
0









H, H



A1307
2-Cl, 4-Cl
0









H, H



A1308
2-Cl, 4-Cl
0









H, H



A1309
2-Cl, 4-Cl
0
CH2OcPr
H, H

A1310
2-Cl, 4-Cl
0
CH2OcBu
H, H

A1311
2-Cl, 4-Cl
0
CH2OcPen
H, H

A1312
2-Cl, 4-Cl
0
CH2OcHex
H, H

A1313
2-Cl, 4-Cl
0
CH2OCH2cPr
H, H

A1314
2-Cl, 4-Cl
0
CH2OCH2cBu
H, H

A1315
2-Cl, 4-Cl
0
CH2OCH2cPen
H, H

A1316
2-Cl, 4-Cl
0
CH2OCH2cHex
H, H

A1317
2-Cl, 4-Cl
0
CH2O(CH2)2cPr
H, H














































































TABLE 35



Part A No.
R20
n
R2
R3, R4



A1318
2-Cl, 4-Cl
0
CH2O(CH2)2cBu
H, H

A1319
2-Cl, 4-Cl
0
CH2O(CH2)2cPen
H, H

A1320
2-Cl, 4-Cl
0
CH2O(CH2)2cHex
H, H

A1321
2-Cl, 4-Cl
0
CH2O(CH2)3cPr
H, H

A1322
2-Cl, 4-Cl
0
CH2O(CH2)3cBu
H, H

A1323
2-Cl, 4-Cl
0
CH2O(CH2)3cPen
H, H

A1324
2-Cl, 4-Cl
0
CH2O(CH2)3cHex
H, H



A1325
2-Cl, 4-Cl
0









H, H



A1326
2-Cl, 4-Cl
0









H, H



A1327
2-Cl, 4-Cl
0









H, H



A1328
2-Cl, 4-Cl
0









H, H



A1329
2-Cl, 4-Cl
0









H, H



A1330
2-Cl, 4-Cl
0









H, H



A1331
2-Cl, 4-Cl
0









H, H



A1332
2-Cl, 4-Cl
0









H, H



A1333
2-Cl, 4-Cl
0









H, H



A1334
2-Cl, 4-Cl
0









H, H



A1335
2-Cl, 4-Cl
0









H, H



A1336
2-Cl, 4-Cl
0









H, H



A1337
2-Cl, 4-Cl
0









H, H



A1338
2-Cl, 4-Cl
0









H, H



A1339
2-Cl, 4-Cl
0









H, H



A1340
2-Cl, 4-Cl
0









H, H



A1341
2-Cl, 4-Cl
0









H, H



A1342
2-Cl, 4-Cl
0









H, H



A1343
2-Cl, 4-Cl
0









H, H



A1344
2-Cl, 4-Cl
0









H, H



A1345
2-Cl, 4-Cl
0









H, H



A1346
2-Cl, 4-Cl
0









H, H












































































TABLE 36



Part A No.
R20
n
R2
R3, R4



A1347
2-Cl, 4-Cl
0









H, H



A1348
2-Cl, 4-Cl
0









H, H



A1349
2-Cl, 4-Cl
0









H, H



A1350
2-Cl, 4-Cl
0









H, H



A1351
2-Cl, 4-Cl
0









H, H



A1352
2-Cl, 4-Cl
0









H, H



A1353
2-Cl, 4-Cl
0









H, H



A1354
2-Cl, 4-Cl
0









H, H



A1355
2-Cl, 4-Cl
0









H, H



A1356
2-Cl, 4-Cl
0









H, H



A1357
2-Cl, 4-Cl
0









H, H



A1358
2-Cl, 4-Cl
0









H, H



A1359
2-Cl, 4-Cl
0









H, H



A1360
2-Cl, 4-Cl
0









H, H



A1361
2-Cl, 4-Cl
0









H, H



A1362
2-Cl, 4-Cl
0









H, H



A1363
2-Cl, 4-Cl
0









H, H



A1364
2-Cl, 4-Cl
0









H, H



A1365
2-Cl, 4-Cl
0









H, H



A1366
2-Cl, 4-Cl
0









H, H



A1367
2-Cl, 4-Cl
0









H, H



A1368
2-Cl, 4-Cl
0









H, H



A1369
2-Cl, 4-Cl
0









H, H



A1370
2-Cl, 4-Cl
0









H, H



A1371
2-Cl, 4-Cl
0









H, H










































































TABLE 37



Part A No.
R20
n
R2
R3, R4



A1372
2-Cl, 4-Cl
0









H, H



A1373
2-Cl, 4-Cl
0









H, H



A1374
2-Cl, 4-Cl
0









H, H



A1375
2-Cl, 4-Cl
0
CH2ON═CHCH3
H, H

A1376
2-Cl, 4-Cl
0
CH2ON═CH(CH3)2
H, H



A1377
2-Cl, 4-Cl
0









H, H



A1378
2-Cl, 4-Cl
0









H, H



A1379
4-OMe
0
CH═NOH
H, H

A1380
4-OMe
0
CH═NOMe
H, H

A1381
4-OMe
0
CH═NOEt
H, H

A1382
4-OMe
0
CH═NOnPr
H, H

A1383
4-OMe
0
CH═NOiPr
H, H

A1384
4-OMe
0
CH═NOcPr
H, H

A1385
4-OMe
0
CH═NOnBu
H, H

A1386
4-OMe
0
CH═NOCH2CH(CH3)2
H, H

A1387
4-OMe
0
CH═NOcBu
H, H

A1388
4-OMe
0
CH═NOnPen
H, H

A1389
4-OMe
0
CH═NOcPen
H, H

A1390
4-OMe
0
CH═NOnHex
H, H

A1391
4-OMe
0
CH═NOcHex
H, H

A1392
4-OMe
0
CH═NOH
H, H

A1393
4-OMe
0
CH═NOCH2iPr
H, H

A1394
4-OMe
0
CH═NOCH2cPr
H, H

A1395
4-OMe
0
CH═NOCH2cBu
H, H

A1396
4-OMe
0
CH═NOCH2cPen
H, H

A1397
4-OMe
0
CH═NOCH2cHex
H, H

A1398
4-OMe
0
CH═NO(CH2)2iPr
H, H

A1399
4-OMe
0
CH═NO(CH2)2cPr
H, H

A1400
4-OMe
0
CH═NO(CH2)2cBu
H, H

A1401
4-OMe
0
CH═NO(CH2)2cPen
H, H

A1402
4-OMe
0
CH═NO(CH2)2cHex
H, H

A1403
4-OMe
0
CH═NO(CH2)3iPr
H, H

A1404
4-OMe
0
CH═NO(CH2)3cPr
H, H

A1405
4-OMe
0
CH═NO(CH2)3cBu
H, H

A1406
4-OMe
0
CH═NO(CH2)3cPen
H, H

A1407
4-OMe
0
CH═NO(CH2)3cHex
H, H



A1408
4-OMe
0









H, H



A1409
4-OMe
0









H, H



A1410
4-OMe
0









H, H









































































TABLE 38



Part A No.
R20
n
R2
R3, R4



A1411
4-OMe
0









H, H



A1412
4-OMe
0









H, H



A1413
4-OMe
0









H, H



A1414
4-OMe
0









H, H



A1415
4-OMe
0









H, H



A1416
4-OMe
0









H, H



A1417
4-OMe
0









H, H



A1418
4-OMe
0









H, H



A1419
4-OMe
0









H, H



A1420
4-OMe
0









H, H



A1421
4-OMe
0









H, H



A1422
4-OMe
0









H, H



A1423
4-OMe
0









H, H



A1424
4-OMe
0









H, H



A1425
4-OMe
0









H, H



A1426
4-OMe
0









H, H



A1427
4-OMe
0









H, H



A1428
4-OMe
0









H, H



A1429
4-OMe
0









H, H



A1430
4-OMe
0









H, H



A1431
4-OMe
0









H, H



A1432
4-OMe
0









H, H



A1433
4-OMe
0









H, H



A1434
4-OMe
0









H, H



A1435
4-OMe
0









H, H










































































TABLE 39



Part A



R3,

No.
R20
n
R2
R4



A1436
4-OMe
0









H, H



A1437
4-OMe
0









H, H



A1438
4-OMe
0









H, H



A1439
4-OMe
0









H, H



A1440
4-OMe
0









H, H



A1441
4-OMe
0









H, H



A1442
4-OMe
0









H, H



A1443
4-OMe
0









H, H



A1444
4-OMe
0









H, H



A1445
4-OMe
0









H, H



A1446
4-OMe
0









H, H



A1447
4-OMe
0









H, H



A1448
4-OMe
0









H, H



A1449
4-OMe
0









H, H



A1450
4-OMe
0









H, H



A1451
4-OMe
0









H, H



A1452
4-OMe
0









H, H



A1453
4-OMe
0









H, H



A1454
4-OMe
0









H, H



A1455
4-OMe
0









H, H



A1456
4-OMe
0









H, H



A1457
4-OMe
0









H, H



A1458
4-OMe
0
CH2OcPr
H, H

A1459
4-OMe
0
CH2OcBu
H, H

A1460
4-OMe
0
CH2OcPen
H, H

A1461
4-OMe
0
CH2OcHex
H, H

A1462
4-OMe
0
CH2OCH2cPr
H, H

A1463
4-OMe
0
CH2OCH2cBu
H, H

A1464
4-OMe
0
CH2OCH2cPen
H, H

A1465
4-OMe
0
CH2OCH2cHex
H, H

A1466
4-OMe
0
CH2O(CH2)2cPr
H, H















































































TABLE 40



Part A No.
R20
n
R2
R3, R4



A1467
4-OMe
0
CH2O(CH2)2cBu
H, H

A1468
4-OMe
0
CH2O(CH2)2cPen
H, H

A1469
4-OMe
0
CH2O(CH2)2cHex
H, H

A1470
4-OMe
0
CH2O(CH2)3cPr
H, H

A1471
4-OMe
0
CH2O(CH2)3cBu
H, H

A1472
4-OMe
0
CH2O(CH2)3cPen
H, H

A1473
4-OMe
0
CH2O(CH2)3cHex
H, H



A1474
4-OMe
0









H, H



A1475
4-OMe
0









H, H



A1476
4-OMe
0









H, H



A1477
4-OMe
0









H, H



A1478
4-OMe
0









H, H



A1479
4-OMe
0









H, H



A1480
4-OMe
0









H, H



A1481
4-OMe
0









H, H



A1482
4-OMe
0









H, H



A1483
4-OMe
0









H, H



A1484
4-OMe
0









H, H



A1485
4-OMe
0









H, H



A1486
4-OMe
0









H, H



A1487
4-OMe
0









H, H



A1488
4-OMe
0









H, H



A1489
4-OMe
0









H, H



A1490
4-OMe
0









H, H



A1491
4-OMe
0









H, H



A1492
4-OMe
0









H, H



A1493
4-OMe
0









H, H



A1494
4-OMe
0









H, H



A1495
4-OMe
0









H, H












































































TABLE 41



Part A No.
R20
n
R2
R3, R4



A1496
4-OMe
0









H, H



A1497
4-OMe
0









H, H



A1498
4-OMe
0









H, H



A1499
4-OMe
0









H, H



A1500
4-OMe
0









H, H



A1501
4-OMe
0









H, H



A1502
4-OMe
0









H, H



A1503
4-OMe
0









H, H



A1504
4-OMe
0









H, H



A1505
4-OMe
0









H, H



A1506
4-OMe
0









H, H



A1507
4-OMe
0









H, H



A1508
4-OMe
0









H, H



A1509
4-OMe
0









H, H



A1510
4-OMe
0









H, H



A1511
4-OMe
0









H, H



A1512
4-OMe
0









H, H



A1513
4-OMe
0









H, H



A1514
4-OMe
0









H, H



A1515
4-OMe
0









H, H



A1516
4-OMe
0









H, H



A1517
4-OMe
0









H, H



A1518
4-OMe
0









H, H



A1519
4-OMe
0









H, H



A1520
4-OMe
0









H, H










































































TABLE 42



Part A No.
R20
n
R2
R3, R4



A1521
4-OMe
0









H, H



A1522
4-OMe
0









H, H



A1523
4-OMe
0









H, H



A1524
4-OMe
0
CH2ON═CHCH3
H, H

A1525
4-OMe
0
CH2ON═CH(CH3)2
H, H



A1526
4-OMe
0









H, H



A1527
4-OMe
0









H, H



A1528
4-Cl
0
Me
H, 4-pyridyl

A1529
4-Cl
0
CH2OMe
H, CH2CH═CH2

A1530
4-Cl
0
CH2-morpholino
H, C≡CPh

A1531
4-CF3
0
CH2C6H4-4-CF3
H, CH═CH2

A1532
4-CF3
0
OMe
H, C6H4-4-Ph

A1533
4-CF3
0
CF3
H, CH2C≡CH

A1534
4-CF3
0
Me
H, CH═CHPh

A1535
4-CF3
0
CH2OMe
H, 3-furyl










































TABLE 43






















Part A No.
R1
R2
R3, R4





A2353
Me
H
H, H


A2354
Me
H
Me, Me


A2355
Me
H
Et, Et


A2356
Me
H
H, Et


A2357
Me
H
H, Ph


A2358
Me
H
H, C6H4-4-F


A2359
Me
Me
H, H


A2360
Me
Me
Me, Me


A2361
Me
Me
Et, Et


A2362
Me
Me
H, Et


A2363
Me
Me
H, Ph


A2364
Me
Me
H, C6H4-4-F


A2365
Me
CH2OMe
H, H


A2366
Me
CH2OMe
Me, Me


A2367
Me
CH2OMe
Et, Et


A2368
Me
CH2OMe
H, Et


A2369
Me
CH2OMe
H, Ph


A2370
Me
CH2OMe
H, C6H4-4-F


A2371
Me
CF3
H, H


A2372
Me
CF3
Me, Me


A2373
Me
CF3
Et, Et


A2374
Me
CF3
H, Et


A2375
Me
CF3
H, Ph


A2376
Me
CF3
H, C6H4-4-F


A2377
Me
CH2OH
H, H


A2378
Me
CH2OH
H, C6H4-4-F


A2379
Me
CH2NHBu
H, H


A2380
Me
CH2NHBu
H, C6H4-4-F


A2381
Me
CH2C≡CH
H, H


A2382
Me
CH2C≡CH
H, C6H4-4-F


A2383
Me
OMe
H, H


A2384
Me
OMe
H, C6H4-4-F


A2385
Me
NH2
H, H


A2386
Me
NH2
H, C6H4-4-F


































































TABLE 44





Part A No.
R1
R2
R3, R4





A2387
Me
NHMe
H, H


A2388
Me
NHMe
H, C6H4-4-F


A2389
Me
CH2OPh
H, H


A2390
Me
CH2OPh
H, C6H4-4-F


A2391
Me
CH2OCH2Ph
H, H


A2392
Me
CH2OCH2Ph
H, C6H4-4-F


A2393
Me
CH2-morpholino
H, H


A2394
Me
CH2-morpholino
H, C6H4-4-F


A2395
Me
CH═CH-pyridyl
H, H


A2396
Me
CH═CH-pyridyl
H, C6H4-4-F


A2397
Me
C≡CPh
H, H


A2398
Me
C≡CPh
H, C6H4-4-F


A2399
Me
Ph
H, H


A2400
Me
Ph
H, C6H4-4-F


A2401
Me
C6H4-4-CF3
H, H


A2402
Me
C6H4-4-CF3
Me, Me


A2403
Me
C6H4-4-CF3
Et, Et


A2404
Me
C6H4-4-CF3
H, Et


A2405
Me
C6H4-4-CF3
H, Ph


A2406
Me
C6H4-4-CF3
H, C6H4-4-F


A2407
Me
C6H4-3-CF3
H, H


A2408
Me
C6H4-3-CF3
H, C6H4-4-F


A2409
Me
C6H4-4-OH
H, H


A2410
Me
C6H4-4-OH
H, C6H4-4-F


A2411
Me
CH2Ph
H, H


A2412
Me
CH2Ph
H, C6H4-4-F


A2413
Me
CH2C6H4-4-CF3
H, H


A2414
Me
CH2C6H4-4-CF3
Me, Me


A2415
Me
CH2C6H4-4-CF3
Et, Et


A2416
Me
CH2C6H4-4-CF3
H, Et


A2417
Me
CH2C6H4-4-CF3
H, Ph


A2418
Me
CH2C6H4-4-CF3
H, C6H4-4-F


A2419
Me
CH2C6H4-4-OCF3
H, H


A2420
Me
CH2C6H4-4-OCF3
H, C6H4-4-F


A2421
Me
CH2C6H4-4-Ph
H, H


A2422
Me
CH2C6H4-4-Ph
H, C6H4-4-F


A2423
Me
CH2C6H4-2-Cl
H, H


A2424
Me
CH2C6H4-2-Cl
H, C6H4-4-F


A2425
Me
(CH2)2Ph
H, H


A2426
Me
(CH2)2Ph
H, C6H4-4-F


A2427
Me
CH2-piperazino-Ph
H, H


A2428
Me
CH2-piperazino-Ph
Me, Me


A2429
Me
CH2-piperazino-Ph
Et, Et


A2430
Me
CH2-piperazino-Ph
H, Et







































































TABLE 45





Part A No.
R1
R2
R3, R4





A2431
Me
CH2-piperazino-Ph
H, Ph


A2432
Me
CH2-piperazino-Ph
H, C6H4-4-F


A2433
Me
CH2-piperidino
H, H


A2434
Me
CH2-piperidino
H, C6H4-4-F


A2435
Me
SPh
H, H


A2436
Me
SPh
H, C6H4-4-F


A2437
Me
OCH2Ph
H, H


A2438
Me
OCH2Ph
H, C6H4-4-F


A2439
Me
Ac
H, H


A2440
Me
Ac
H, C6H4-4-F


A2441
Me
CONH2
H, H


A2442
Me
CONH2
H, C6H4-4-F


A2443
Me
CSNH2
H, H


A2444
Me
CSNH2
H, C6H4-4-F


A2445
Me
OCONH2
H, H


A2446
Me
OCONH2
H, C6H4-4-F


A2447
Me
OCSNH2
H, H


A2448
Me
OCSNH2
H, C6H4-4-F


A2449
Me
OSO2Me
H, H


A2450
Me
OSO2Me
H, C6H4-4-F


A2451
Me
OSO2Ph
H, H


A2452
Me
OSO2Ph
H, C6H4-4-F


A2453
Me
I
H, H


A2454
Me
I
H, C6H4-4-F


A2455
CF3
H
H, H


A2456
CF3
H
Me, Me


A2457
CF3
H
Et, Et


A2458
CF3
H
H, Et


A2459
CF3
H
H, Ph


A2460
CF3
H
H, C6H4-4-F


A2461
CF3
Me
H, H


A2462
CF3
Me
Me, Me


A2463
CF3
Me
Et, Et


A2464
CF3
Me
H, Et


A2465
CF3
Me
H, Ph


A2466
CF3
Me
H, C6H4-4-F


A2467
CF3
CH2OMe
H, H


A2468
CF3
CH2OMe
Me, Me


A2469
CF3
CH2OMe
Et, Et


A2470
CF3
CH2OMe
H, Et


A2471
CF3
CH2OMe
H, Ph


A2472
CF3
CH2OMe
H, C6H4-4-F


A2473
CF3
CF3
H, H


A2474
CF3
CF3
Me, Me







































































TABLE 46





Part A No.
R1
R2
R3, R4





A2475
CF3
CF3
Et, Et


A2476
CF3
CF3
H, Et


A2477
CF3
CF3
H, Ph


A2478
CF3
CF3
H, C6H4-4-F


A2479
CF3
CH2OH
H, H


A2480
CF3
CH2OH
H, C6H4-4-F


A2481
CF3
CH2NHBu
H, H


A2482
CF3
CH2NHBu
H, C6H4-4-F


A2483
CF3
CH2C≡CH
H, H


A2484
CF3
CH2C≡CH
H, C6H4-4-F


A2485
CF3
OMe
H, H


A2486
CF3
OMe
H, C6H4-4-F


A2487
CF3
NH2
H, H


A2488
CF3
NH2
H, C6H4-4-F


A2489
CF3
NHMe
H, H


A2490
CF3
NHMe
H, C6H4-4-F


A2491
CF3
CH2OPh
H, H


A2492
CF3
CH2OPh
H, C6H4-4-F


A2493
CF3
CH2OCH2Ph
H, H


A2494
CF3
CH2OCH2Ph
H, C6H4-4-F


A2495
CF3
CH2-morpholino
H, H


A2496
CF3
CH2-morpholino
H, C6H4-4-F


A2497
CF3
CH═CH-pyridyl
H, H


A2498
CF3
CH═CH-pyridyl
H, C6H4-4-F


A2499
CF3
C≡CPh
H, H


A2500
CF3
C≡CPh
H, C6H4-4-F


A2501
CF3
Ph
H, H


A2502
CF3
Ph
H, C6H4-4-F


A2503
CF3
C6H4-4-CF3
H, H


A2504
CF3
C6H4-4-CF3
Me, Me


A2505
CF3
C6H4-4-CF3
Et, Et


A2506
CF3
C6H4-4-CF3
H, Et


A2507
CF3
C6H4-4-CF3
H, Ph


A2508
CF3
C6H4-4-CF3
H, C6H4-4-F


A2509
CF3
C6H4-3-CF3
H, H


A2510
CF3
C6H4-3-CF3
H, C6H4-4-F


A2511
CF3
C6H4-4-OH
H, H


A2512
CF3
C6H4-4-OH
H, C6H4-4-F


A2513
CF3
CH2Ph
H, H


A2514
CF3
CH2Ph
H, C6H4-4-F


A2515
CF3
CH2C6H4-4-CF3
H, H


A2516
CF3
CH2C6H4-4-CF3
Me, Me


A2517
CF3
CH2C6H4-4-CF3
Et, Et


A2518
CF3
CH2C6H4-4-CF3
H, Et







































































TABLE 47





Part A No.
R1
R2
R3, R4





A2519
CF3
CH2C6H4-4-CF3
H, Ph


A2520
CF3
CH2C6H4-4-CF3
H, C6H4-4-F


A2521
CF3
CH2C6H4-4-OCF3
H, H


A2522
CF3
CH2C6H4-4-OCF3
H, C6H4-4-F


A2523
CF3
CH2C6H4-4-Ph
H, H


A2524
CF3
CH2C6H4-4-Ph
H, C6H4-4-F


A2525
CF3
CH2C6H4-2-Cl
H, H


A2526
CF3
CH2C6H4-2-Cl
H, C6H4-4-F


A2527
CF3
(CH2)2Ph
H, H


A2528
CF3
(CH2)2Ph
H, C6H4-4-F


A2529
CF3
CH2-piperazino-Ph
H, H


A2530
CF3
CH2-piperazino-Ph
Me, Me


A2531
CF3
CH2-piperazino-Ph
Et, Et


A2532
CF3
CH2-piperazino-Ph
H, Et


A2533
CF3
CH2-piperazino-Ph
H, Ph


A2534
CF3
CH2-piperazino-Ph
H, C6H4-4-F


A2535
CF3
CH2-piperidino
H, H


A2536
CF3
CH2-piperidino
H, C6H4-4-F


A2537
CF3
SPh
H, H


A2538
CF3
SPh
H, C6H4-4-F


A2539
CF3
OCH2Ph
H, H


A2540
CF3
OCH2Ph
H, C6H4-4-F


A2541
CF3
Ac
H, H


A2542
CF3
Ac
H, C6H4-4-F


A2543
CF3
CONH2
H, H


A2544
CF3
CONH2
H, C6H4-4-F


A2545
CF3
CSNH2
H, H


A2546
CF3
CSNH2
H, C6H4-4-F


A2547
CF3
OCONH2
H, H


A2548
CF3
OCONH2
H, C6H4-4-F


A2549
CF3
OCSNH2
H, H


A2550
CF3
OCSNH2
H, C6H4-4-F


A2551
CF3
OSO2Me
H, H


A2552
CF3
OSO2Me
H, C6H4-4-F


A2553
CF3
OSO2Ph
H, H


A2554
CF3
OSO2Ph
H, C6H4-4-F


A2555
CF3
I
H, H


A2556
CF3
I
H, C6H4-4-F


A2557
CH═CHPh
H
H, H


A2558
CH═CHPh
H
Me, Me


A2559
CH═CHPh
H
Et, Et


A2560
CH═CHPh
H
H, Et


A2561
CH═CHPh
H
H, Ph


A2562
CH═CHPh
H
H, C6H4-4-F







































































TABLE 48





Part A No.
R1
R2
R3, R4





A2563
CH═CHPh
Me
H, H


A2564
CH═CHPh
Me
Me, Me


A2565
CH═CHPh
Me
Et, Et


A2566
CH═CHPh
Me
H, Et


A2567
CH═CHPh
Me
H, Ph


A2568
CH═CHPh
Me
H, C6H4-4-F


A2569
CH═CHPh
CH2OMe
H, H


A2570
CH═CHPh
CH2OMe
Me, Me


A2571
CH═CHPh
CH2OMe
Et, Et


A2572
CH═CHPh
CH2OMe
H, Et


A2573
CH═CHPh
CH2OMe
H, Ph


A2574
CH═CHPh
CH2OMe
H, C6H4-4-F


A2575
CH═CHPh
CF3
H, H


A2576
CH═CHPh
CF3
Me, Me


A2577
CH═CHPh
CF3
Et, Et


A2578
CH═CHPh
CF3
H, Et


A2579
CH═CHPh
CF3
H, Ph


A2580
CH═CHPh
CF3
H, C6H4-4-F


A2581
CH═CHPh
CH2OH
H, H


A2582
CH═CHPh
CH2OH
H, C6H4-4-F


A2583
CH═CHPh
CH2NHBu
H, H


A2584
CH═CHPh
CH2NHBu
H, C6H4-4-F


A2585
CH═CHPh
CH2C≡CH
H, H


A2586
CH═CHPh
CH2C≡CH
H, C6H4-4-F


A2587
CH═CHPh
OMe
H, H


A2588
CH═CHPh
OMe
H, C6H4-4-F


A2589
CH═CHPh
NH2
H, H


A2590
CH═CHPh
NH2
H, C6H4-4-F


A2591
CH═CHPh
NHMe
H, H


A2592
CH═CHPh
NHMe
H, C6H4-4-F


A2593
CH═CHPh
CH2OPh
H, H


A2594
CH═CHPh
CH2OPh
H, C6H4-4-F


A2595
CH═CHPh
CH2OCH2Ph
H, H


A2596
CH═CHPh
CH2OCH2Ph
H, C6H4-4-F


A2597
CH═CHPh
CH2-morpholino
H, H


A2598
CH═CHPh
CH2-morpholino
H, C6H4-4-F


A2599
CH═CHPh
CH═CH-pyridyl
H, H


A2600
CH═CHPh
CH═CH-pyridyl
H, C6H4-4-F


A2601
CH═CHPh
C≡CPh
H, H


A2602
CH═CHPh
C≡CPh
H, C6H4-4-F


A2603
CH═CHPh
Ph
H, H


A2604
CH═CHPh
Ph
H, C6H4-4-F


A2605
CH═CHPh
C6H4-4-CF3
H, H


A2606
CH═CHPh
C6H4-4-CF3
Me, Me







































































TABLE 49





Part A No.
R1
R2
R3, R4





A2607
CH═CHPh
C6H4-4-CF3
Et, Et


A2608
CH═CHPh
C6H4-4-CF3
H, Et


A2609
CH═CHPh
C6H4-4-CF3
H, Ph


A2610
CH═CHPh
C6H4-4-CF3
H, C6H4-4-F


A2611
CH═CHPh
C6H4-3-CF3
H, H


A2612
CH═CHPh
C6H4-3-CF3
H, C6H4-4-F


A2613
CH═CHPh
C6H4-4-OH
H, H


A2614
CH═CHPh
C6H4-4-OH
H, C6H4-4-F


A2615
CH═CHPh
CH2Ph
H, H


A2616
CH═CHPh
CH2Ph
H, C6H4-4-F


A2617
CH═CHPh
CH2C6H4-4-CF3
H, H


A2618
CH═CHPh
CH2C6H4-4-CF3
Me, Me


A2619
CH═CHPh
CH2C6H4-4-CF3
Et, Et


A2620
CH═CHPh
CH2C6H4-4-CF3
H, Et


A2621
CH═CHPh
CH2C6H4-4-CF3
H, Ph


A2622
CH═CHPh
CH2C6H4-4-CF3
H, C6H4-4-F


A2623
CH═CHPh
CH2C6H4-4-OCF3
H, H


A2624
CH═CHPh
CH2C6H4-4-OCF3
H, C6H4-4-F


A2625
CH═CHPh
CH2C6H4-4-Ph
H, H


A2626
CH═CHPh
CH2C6H4-4-Ph
H, C6H4-4-F


A2627
CH═CHPh
CH2C6H4-2-Cl
H, H


A2628
CH═CHPh
CH2C6H4-2-Cl
H, C6H4-4-F


A2629
CH═CHPh
(CH2)2Ph
H, H


A2630
CH═CHPh
(CH2)2Ph
H, C6H4-4-F


A2631
CH═CHPh
CH2-piperazino-Ph
H, H


A2632
CH═CHPh
CH2-piperazino-Ph
Me, Me


A2633
CH═CHPh
CH2-piperazino-Ph
Et, Et


A2634
CH═CHPh
CH2-piperazino-Ph
H, Et


A2635
CH═CHPh
CH2-piperazino-Ph
H, Ph


A2636
CH═CHPh
CH2-piperazino-Ph
H, C6H4-4-F


A2637
CH═CHPh
CH2-piperidino
H, H


A2638
CH═CHPh
CH2-piperidino
H, C6H4-4-F


A2639
CH═CHPh
SPh
H, H


A2640
CH═CHPh
SPh
H, C6H4-4-F


A2641
CH═CHPh
OCH2Ph
H, H


A2642
CH═CHPh
OCH2Ph
H, C6H4-4-F


A2643
CH═CHPh
Ac
H, H


A2644
CH═CHPh
Ac
H, C6H4-4-F


A2645
CH═CHPh
CONH2
H, H


A2646
CH═CHPh
CONH2
H, C6H4-4-F


A2647
CH═CHPh
CSNH2
H, H


A2648
CH═CHPh
CSNH2
H, C6H4-4-F


A2649
CH═CHPh
OCONH2
H, H


A2650
CH═CHPh
OCONH2
H, C6H4-4-F







































































TABLE 50





Part A No.
R1
R2
R3, R4





A2651
CH═CHPh
OCSNH2
H, H


A2652
CH═CHPh
OCSNH2
H, C6H4-4-F


A2653
CH═CHPh
OSO2Me
H, H


A2654
CH═CHPh
OSO2Me
H, C6H4-4-F


A2655
CH═CHPh
OSO2Ph
H, H


A2656
CH═CHPh
OSO2Ph
H, C6H4-4-F


A2657
CH═CHPh
I
H, H


A2658
CH═CHPh
I
H, C6H4-4-F


A2659
≡CPh
H
H, H


A2660
≡CPh
H
Me, Me


A2661
≡CPh
H
Et, Et


A2662
≡CPh
H
H, Et


A2663
≡CPh
H
H, Ph


A2664
≡CPh
H
H, C6H4-4-F


A2665
≡CPh
Me
H, H


A2666
≡CPh
Me
Me, Me


A2667
≡CPh
Me
Et, Et


A2668
≡CPh
Me
H, Et


A2669
≡CPh
Me
H, Ph


A2670
≡CPh
Me
H, C6H4-4-F


A2671
≡CPh
CH2OMe
H, H


A2672
≡CPh
CH2OMe
Me, Me


A2673
≡CPh
CH2OMe
Et, Et


A2674
≡CPh
CH2OMe
H, Et


A2675
≡CPh
CH2OMe
H, Ph


A2676
≡CPh
CH2OMe
H, C6H4-4-F


A2677
≡CPh
CF3
H, H


A2678
≡CPh
CF3
Me, Me


A2679
≡CPh
CF3
Et, Et


A2680
≡CPh
CF3
H, Et


A2681
≡CPh
CF3
H, Ph


A2682
≡CPh
CF3
H, C6H4-4-F


A2683
≡CPh
CH2OH
H, H


A2684
≡CPh
CH2OH
H, C6H4-4-F


A2685
≡CPh
CH2NHBu
H, H


A2686
≡CPh
CH2NHBu
H, C6H4-4-F


A2687
≡CPh
CH2C≡CH
H, H


A2688
≡CPh
CH2C≡CH
H, C6H4-4-F


A2689
≡CPh
OMe
H, H


A2690
≡CPh
OMe
H, C6H4-4-F


A2691
≡CPh
NH2
H, H


A2692
≡CPh
NH2
H, C6H4-4-F


A2693
≡CPh
NHMe
H, H


A2694
≡CPh
NHMe
H, C6H4-4-F







































































TABLE 51





Part A No.
R1
R2
R3, R4





A2695
≡CPh
CH2OPh
H, H


A2696
≡CPh
CH2OPh
H, C6H4-4-F


A2697
≡CPh
CH2OCH2Ph
H, H


A2698
≡CPh
CH2OCH2Ph
H, C6H4-4-F


A2699
≡CPh
CH2-morpholino
H, H


A2700
≡CPh
CH2-morpholino
H, C6H4-4-F


A2701
≡CPh
CH═CH-pyridyl
H, H


A2702
≡CPh
CH═CH-pyridyl
H, C6H4-4-F


A2703
≡CPh
C≡CPh
H, H


A2704
≡CPh
C≡CPh
H, C6H4-4-F


A2705
≡CPh
Ph
H, H


A2706
≡CPh
Ph
H, C6H4-4-F


A2707
≡CPh
C6H4-4-CF3
H, H


A2708
≡CPh
C6H4-4-CF3
Me, Me


A2709
≡CPh
C6H4-4-CF3
Et, Et


A2710
≡CPh
C6H4-4-CF3
H, Et


A2711
≡CPh
C6H4-4-CF3
H, Ph


A2712
≡CPh
C6H4-4-CF3
H, C6H4-4-F


A2713
≡CPh
C6H4-3-CF3
H, H


A2714
≡CPh
C6H4-3-CF3
H, C6H4-4-F


A2715
≡CPh
C6H4-4-OH
H, H


A2716
≡CPh
C6H4-4-OH
H, C6H4-4-F


A2717
≡CPh
CH2Ph
H, H


A2718
≡CPh
CH2Ph
H, C6H4-4-F


A2719
≡CPh
CH2C6H4-4-CF3
H, H


A2720
≡CPh
CH2C6H4-4-CF3
Me, Me


A2721
≡CPh
CH2C6H4-4-CF3
Et, Et


A2722
≡CPh
CH2C6H4-4-CF3
H, Et


A2723
≡CPh
CH2C6H4-4-CF3
H, Ph


A2724
≡CPh
CH2C6H4-4-CF3
H, C6H4-4-F


A2725
≡CPh
CH2C6H4-4-OCF3
H, H


A2726
≡CPh
CH2C6H4-4-OCF3
H, C6H4-4-F


A2727
≡CPh
CH2C6H4-4-Ph
H, H


A2728
≡CPh
CH2C6H4-4-Ph
H, C6H4-4-F


A2729
≡CPh
CH2C6H4-2-Cl
H, H


A2730
≡CPh
CH2C6H4-2-Cl
H, C6H4-4-F


A2731
≡CPh
(CH2)2Ph
H, H


A2732
≡CPh
(CH2)2Ph
H, C6H4-4-F


A2733
≡CPh
CH2-piperazino-Ph
H, H


A2734
≡CPh
CH2-piperazino-Ph
Me, Me


A2735
≡CPh
CH2-piperazino-Ph
Et, Et


A2736
≡CPh
CH2-piperazino-Ph
H, Et


A2737
≡CPh
CH2-piperazino-Ph
H, Ph


A2738
≡CPh
CH2-piperazino-Ph
H, C6H4-4-F







































































TABLE 52





Part A No.
R1
R2
R3, R4





A2739
≡CPh
CH2-piperidino
H, H


A2740
≡CPh
CH2-piperidino
H, C6H4-4-F


A2741
≡CPh
SPh
H, H


A2742
≡CPh
SPh
H, C6H4-4-F


A2743
≡CPh
OCH2Ph
H, H


A2744
≡CPh
OCH2Ph
H, C6H4-4-F


A2745
≡CPh
Ac
H, H


A2746
≡CPh
Ac
H, C6H4-4-F


A2747
≡CPh
CONH2
H, H


A2748
≡CPh
CONH2
H, C6H4-4-F


A2749
≡CPh
CSNH2
H, H


A2750
≡CPh
CSNH2
H, C6H4-4-F


A2751
≡CPh
OCONH2
H, H


A2752
≡CPh
OCONH2
H, C6H4-4-F


A2753
≡CPh
OCSNH2
H, H


A2754
≡CPh
OCSNH2
H, C6H4-4-F


A2755
≡CPh
OSO2Me
H, H


A2756
≡CPh
OSO2Me
H, C6H4-4-F


A2757
≡CPh
OSO2Ph
H, H


A2758
≡CPh
OSO2Ph
H, C6H4-4-F


A2759
≡CPh
I
H, H


A2760
≡CPh
I
H, C6H4-4-F


A2762
F
H
Me, Me


A2763
Et
H
Et, Et


A2764
iBu
H
H, Et


A2765
CH═CHMe
H
H, Ph


A2766
OH
H
H, C6H4-4-F


A2767
OEt
Me
H, H


A2768
COPh
Me
Me, Me


A2769
4-pyridyl
Me
Et, Et


A2770
morpholino
Me
H, Et


A2771
NHiPr
Me
H, Ph


A2773
F
CH2OMe
H, H


A2774
Et
CH2OMe
Me, Me


A2775
iBu
CH2OMe
Et, Et


A2776
CH═CHMe
CH2OMe
H, Et


A2777
OH
CH2OMe
H, Ph


A2778
OEt
CH2OMe
H, C6H4-4-F


A2779
COPh
CF3
H, H


A2780
4-pyridyl
CF3
Me, Me


A2781
morpholino
CF3
Et, Et


A2782
NHiPr
CF3
H, Et


A2784
F
CF3
H, C6H4-4-F


A2785
Et
CH2OH
H, H





































































TABLE 53



Part A No.
R1
R2
R3, R4



A2786
iBu
CH2OH
H, C6H4-4-F

A2787
CH═CHMe
CH2NHBu
H, H

A2788
OH
CH2NHBu
H, C6H4-4-F

A2789
OEt
CH2C≡CH
H, H

A2790
COPh
CH2C≡CH
H, C6H4-4-F

A2791
4-pyridyl
OMe
H, H

A2792
morpholino
OMe
H, C6H4-4-F

A2793
NHiPr
NH2
H, H

A2795
F
NHMe
H, H

A2796
Et
NHMe
H, C6H4-4-F

A2797
iBu
CH2OPh
H, H

A2798
CH═CHMe
CH2OPh
H, C6H4-4-F

A2799
OH
CH2OCH2Ph
H, H

A2800
OEt
CH2OCH2Ph
H, C6H4-4-F

A2801
COPh
CH2-morpholino
H, H

A2802
4-pyridyl
CH2-morpholino
H, C6H4-4-F

A2803
morpholino
CH═CH-pyridyl
H, H

A2804
NHiPr
CH═CH-pyridyl
H, C6H4-4-F

A2806
F
C≡CPh
H, C6H4-4-F

A2807
Et
Ph
H, H

A2808
iBu
Ph
H, C6H4-4-F

A2809
CH═CHMe
C6H4-4-CF3
H, H

A2810
OH
C6H4-4-CF3
Me, Me

A2811
OEt
C6H4-4-CF3
Et, Et

A2812
COPh
C6H4-4-CF3
H, Et

A2813
4-pyridyl
C6H4-4-CF3
H, Ph

A2814
morpholino
C6H4-4-CF3
H, C6H4-4-F

A2815
NHiPr
C6H4-3-CF3
H, H

A2817
F
C6H4-4-OH
H, H

A2818
Et
C6H4-4-OH
H, C6H4-4-F

A2819
iBu
CH2Ph
H, H

A2820
CH═CHMe
CH2Ph
H, C6H4-4-F

A2821
OH
CH2C6H4-4-CF3
H, H

A2822
OEt
CH2C6H4-4-CF3
Me, Me

A2823
COPh
CH2C6H4-4-CF3
Et, Et

A2824
4-pyridyl
CH2C6H4-4-CF3
H, Et

A2825
morpholino
CH2C6H4-4-CF3
H, Ph

A2826
NHiPr
CH2C6H4-4-CF3
H, C6H4-4-F

A2828
F
CH2C6H4-4-OCF3
H, C6H4-4-F

A2829
Et
CH2C6H4-4-Ph
H, H

A2830
iBu
CH2C6H4-4-Ph
H, C6H4-4-F

A2831
CH═CHMe
CH2C6H4-2-Cl
H, H

A2832
OH
CH2C6H4-2-Cl
H, C6H4-4-F

A2833
OEt
(CH2)2Ph
H, H




































































TABLE 54



Part A No.
R1
R2
R3, R4



A2834
COPh
(CH2)2Ph
H, C6H4-4-F

A2835
4-pyridyl
CH2-piperazino-Ph
H, H

A2836
morpholino
CH2-piperazino-Ph
Me, Me

A2837
NHiPr
CH2-piperazino-Ph
Et, Et

A2839
F
CH2-piperazino-Ph
H, Ph

A2840
Et
CH2-piperazino-Ph
H, C6H4-4-F

A2841
iBu
CH2-piperidino
H, H

A2842
CH═CHMe
CH2-piperidino
H, C6H4-4-F

A2843
OH
SPh
H, H

A2844
OEt
SPh
H, C6H4-4-F

A2845
COPh
OCH2Ph
H, H

A2846
4-pyridyl
OCH2Ph
H, C6H4-4-F

A2847
morpholino
Ac
H, H

A2848
NHiPr
Ac
H, C6H4-4-F

A2850
F
CONH2
H, C6H4-4-F

A2851
Et
CSNH2
H, H

A2852
iBu
CSNH2
H, C6H4-4-F

A2853
CH═CHMe
OCONH2
H, H

A2854
OH
OCONH2
H, C6H4-4-F

A2855
OEt
OCSNH2
H, H

A2856
COPh
OCSNH2
H, C6H4-4-F

A2857
4-pyridyl
OSO2Me
H, H

A2858
morpholino
OSO2Me
H, C6H4-4-F

A2859
NHiPr
OSO2Ph
H, H

A2861
F
I
H, H

A2862
Et
I
H, C6H4-4-F

A3385
CH2OMe
Me
H, H

A3386
CH2OMe
Me
Me, Me

A3387
CH2OMe
Me
Et, Et

A3388
CH2OMe
Me
H, Et

A3389
CH2OMe
Me
H, Ph

A3390
CH2OMe
Me
H, C6H4-4-F

A3397
CH2OH
Me
H, H

A3552
CH2-piperazino-Ph
CF3
H, Et

A3553
CH2-piperazino-Ph
CF3
H, Ph

A3554
CH2-piperazino-Ph
CF3
H, C6H4-4-F

A3555
CH2-piperidino
CF3
H, H

A3556
CH2-piperidino
CF3
H, C6H4-4-F

A3557
SPh
CF3
H, H

A3558
SPh
CF3
H, C6H4-4-F

A3559
OCH2Ph
CF3
H, H

A3560
OCH2Ph
CF3
H, C6H4-4-F

A3561
Ac
CF3
H, H

A3562
Ac
CF3
H, C6H4-4-F




































































TABLE 55



Part A No.
R1
R2
R3, R4



A3563
CONH2
CF3
H, H

A3564
CONH2
CF3
H, C6H4-4-F

A3565
CSNH2
CF3
H, H

A3566
CSNH2
CF3
H, C6H4-4-F

A3567
OCONH2
CF3
H, H

A3568
OCONH2
CF3
H, C6H4-4-F

A3569
OCSNH2
CF3
H, H

A3570
OCSNH2
CF3
H, C6H4-4-F

A3571
OSO2Me
CF3
H, H

A3572
OSO2Me
CF3
H, C6H4-4-F

A3573
OSO2Ph
CF3
H, H

A3574
OSO2Ph
CF3
H, C6H4-4-F

A3575
I
CF3
H, H

A3576
I
CF3
H, C6H4-4-F

A3627
C6H4-4-CF3
CH═CHPh
Et, Et

A3628
C6H4-4-CF3
CH═CHPh
H, Et

A3629
C6H4-4-CF3
CH═CHPh
H, Ph

A3630
C6H4-4-CF3
CH═CHPh
H, C6H4-4-F

A3631
C6H4-3-CF3
CH═CHPh
H, H

A3632
C6H4-3-CF3
CH═CHPh
H, C6H4-4-F

A3633
C6H4-4-OH
CH═CHPh
H, H

A3634
C6H4-4-OH
CH═CHPh
H, C6H4-4-F

A3635
CH2Ph
CH═CHPh
H, H

A3636
CH2Ph
CH═CHPh
H, C6H4-4-F

A3637
CH2C6H4-4-CF3
CH═CHPh
H, H

A3638
CH2C6H4-4-CF3
CH═CHPh
Me, Me

A3639
CH2C6H4-4-CF3
CH═CHPh
Et, Et

A3640
CH2C6H4-4-CF3
CH═CHPh
H, Et

A3641
CH2C6H4-4-CF3
CH═CHPh
H, Ph

A3642
CH2C6H4-4-CF3
CH═CHPh
H, C6H4-4-F

A3643
CH2C6H4-4-OCF3
CH═CHPh
H, H

A3644
CH2C6H4-4-OCF3
CH═CHPh
H, C6H4-4-F

A3645
CH2C6H4-4-Ph
CH═CHPh
H, H

A3646
CH2C6H4-4-Ph
CH═CHPh
H, C6H4-4-F

A3647
CH2C6H4-2-Cl
CH═CHPh
H, H

A3648
CH2C6H4-2-Cl
CH═CHPh
H, C6H4-4-F

A3649
(CH2)2Ph
CH═CHPh
H, H

A3650
(CH2)2Ph
CH═CHPh
H, C6H4-4-F

A3651
CH2-piperazino-Ph
CH═CHPh
H, H

A3652
CH2-piperazino-Ph
CH═CHPh
Me, Me

A3704
CH2OH
≡CPh
H, C6H4-4-F

A3705
CH2NHBu
≡CPh
H, H

A3706
CH2NHBu
≡CPh
H, C6H4-4-F

A3707
CH2C≡CH
≡CPh
H, H






































































TABLE 56





Part A No.
R1
R2
R3, R4





A3708
CH2C≡CH
≡CPh
H, C6H4-4-F


A3709
OMe
≡CPh
H, H


A3710
OMe
≡CPh
H, C6H4-4-F


A3711
NH2
≡CPh
H, H


A3712
NH2
≡CPh
H, C6H4-4-F


A3713
NHMe
≡CPh
H, H


A3714
NHMe
≡CPh
H, C6H4-4-F


A3715
CH2OPh
≡CPh
H, H


A3716
CH2OPh
≡CPh
H, C6H4-4-F


A3717
CH2OCH2Ph
≡CPh
H, H


A3718
CH2OCH2Ph
≡CPh
H, C6H4-4-F


A3719
CH2-morpholino
≡CPh
H, H


A3720
CH2-morpholino
≡CPh
H, C6H4-4-F


A3721
CH═CH-pyridyl
≡CPh
H, H


A3722
CH═CH-pyridyl
≡CPh
H, C6H4-4-F


A3723
C≡CPh
≡CPh
H, H


A3724
C≡CPh
≡CPh
H, C6H4-4-F


A3725
Ph
≡CPh
H, H


A3726
Ph
≡CPh
H, C6H4-4-F


A3727
C6H4-4-CF3
≡CPh
H, H


A3728
C6H4-4-CF3
≡CPh
Me, Me


A3806
CH2OH
iBu
H, C6H4-4-F


A3807
CH2NHBu
CH═CHMe
H, H


A3808
CH2NHBu
OH
H, C6H4-4-F


A3809
CH2C≡CH
OEt
H, H


A3810
CH2C≡CH
COPh
H, C6H4-4-F


A3811
OMe
4-pyridyl
H, H


A3812
OMe
morpholino
H, C6H4-4-F


A3813
NH2
NHiPr
H, H


A3814
NH2
H
H, C6H4-4-F


A3815
NHMe
F
H, H


A3816
NHMe
Et
H, C6H4-4-F


A3817
CH2OPh
iBu
H, H


A3818
CH2OPh
CH═CHMe
H, C6H4-4-F


A3819
CH2OCH2Ph
OH
H, H


A3820
CH2OCH2Ph
OEt
H, C6H4-4-F


A3821
CH2-morpholino
COPh
H, H


A3822
CH2-morpholino
4-pyridyl
H, C6H4-4-F


A3823
CH═CH-pyridyl
morpholino
H, H


A3824
CH═CH-pyridyl
NHiPr
H, C6H4-4-F


A3825
C≡CPh
H
H, H


A3826
C≡CPh
F
H, C6H4-4-F


A3827
Ph
Et
H, H


A3828
Ph
iBu
H, C6H4-4-F





































































TABLE 57



Part A


R3,

No.
R1
R2
R4



A3829
C6H4-4-CF3
CH═CHMe
H, H

A3830
C6H4-4-CF3
OH
Me,




Me

A3831
C≡CC4H6-4-CF4
CH═NOH
H, H

A3832
C≡CC4H6-4-CF4
CH═NOMe
H, H

A3833
C≡CC4H6-4-CF4
CH═NOEt
H, H

A3834
C≡CC4H6-4-CF4
CH═NOnPr
H, H

A3835
C≡CC4H6-4-CF4
CH═NOiPr
H, H

A3836
C≡CC4H6-4-CF4
CH═NOcPy
H, H

A3837
C≡CC4H6-4-CF4
CH═NOnBu
H, H

A3838
C≡CC4H6-4-CF4
CH═NOcBu
H, H

A3839
C≡CC4H6-4-CF4
CH═NOnPen
H, H

A3840
C≡CC4H6-4-CF4
CH═NOcPen
H, H

A3841
C≡CC4H6-4-CF4
CH═NOnHex
H, H

A3842
C≡CC4H6-4-CF4
CH═NOcHex
H, H

A3843
C≡CC4H6-4-CF4
CH═NOCH2iPr
H, H

A3844
C≡CC4H6-4-CF4
CH═NOCH2cPr
H, H

A3845
C≡CC4H6-4-CF4
CH═NOCH2cBu
H, H

A3846
C≡CC4H6-4-CF4
CH═NOCH2cPen
H, H

A3847
C≡CC4H6-4-CF4
CH═NOCH2cHex
H, H

A3848
C≡CC4H6-4-CF4
CH═NO(CH2)2iPr
H, H

A3849
C≡CC4H6-4-CF4
CH═NO(CH2)2cPr
H, H

A3850
C≡CC4H6-4-CF4
CH═NO(CH2)2cBu
H, H

A3851
C≡CC4H6-4-CF4
CH═NO(CH2)2cPen
H, H

A3852
C≡CC4H6-4-CF4
CH═NO(CH2)2cHex
H, H

A3853
C≡CC4H6-4-CF4
CH═NO(CH2)3iPr
H, H

A3854
C≡CC4H6-4-CF4
CH═NO(CH2)3cPr
H, H

A3855
C≡CC4H6-4-CF4
CH═NO(CH2)3cBu
H, H

A3856
C≡CC4H6-4-CF4
CH═NO(CH2)3cPen
H, H

A3857
C≡CC4H6-4-CF4
CH═NO(CH2)3cHex
H, H



A3858
C≡CC4H6-4-CF4









H, H



A3859
C≡CC4H6-4-CF4









H, H



A3860
C≡CC4H6-4-CF4









H, H



A3861
C≡CC4H6-4-CF4









H, H



A3862
C≡CC4H6-4-CF4









H, H



A3863
C≡CC4H6-4-CF4









H, H



A3864
C≡CC4H6-4-CF4









H, H



A3865
C≡CC4H6-4-CF4









H, H



A3866
C≡CC4H6-4-CF4









H, H



A3867
C≡CC4H6-4-CF4









H, H











































































TABLE 58



Part A No.
R1
R2
R3, R4



A3868
C≡CC4H6-4-CF4









H, H



A3869
C≡CC4H6-4-CF4









H, H



A3870
C≡CC4H6-4-CF4









H, H



A3871
C≡CC4H6-4-CF4









H, H



A3872
C≡CC4H6-4-CF4









H, H



A3873
C≡CC4H6-4-CF4









H, H



A3874
C≡CC4H6-4-CF4









H, H



A3875
C≡CC4H6-4-CF4









H, H



A3876
C≡CC4H6-4-CF4









H, H



A3877
C≡CC4H6-4-CF4









H, H



A3878
C≡CC4H6-4-CF4









H, H



A3879
C≡CC4H6-4-CF4









H, H



A3880
C≡CC4H6-4-CF4









H, H



A3881
C≡CC4H6-4-CF4









H, H



A3882
C≡CC4H6-4-CF4









H, H



A3883
C≡CC4H6-4-CF4









H, H



A3884
C≡CC4H6-4-CF4









H, H



A3885
C≡CC4H6-4-CF4









H, H



A3886
C≡CC4H6-4-CF4









H, H



A3887
C≡CC4H6-4-CF4









H, H



A3888
C≡CC4H6-4-CF4









H, H



A3889
C≡CC4H6-4-CF4









H, H



A3890
C≡CC4H6-4-CF4









H, H



A3891
C≡CC4H6-4-CF4









H, H







































































TABLE 59



Part A No.
R1
R2
R3, R4



A3892
C≡CC4H6-4-CF4









H, H



A3893
C≡CC4H6-4-CF4









H, H



A3894
C≡CC4H6-4-CF4









H, H



A3895
C≡CC4H6-4-CF4









H, H



A3896
C≡CC4H6-4-CF4









H, H



A3897
C≡CC4H6-4-CF4









H, H



A3898
C≡CC4H6-4-CF4









H, H



A3899
C≡CC4H6-4-CF4









H, H



A3900
C≡CC4H6-4-CF4









H, H



A3901
C≡CC4H6-4-CF4









H, H



A3902
C≡CC4H6-4-CF4









H, H



A3903
C≡CC4H6-4-CF4









H, H



A3904
C≡CC4H6-4-CF4









H, H



A3905
C≡CC4H6-4-CF4









H, H



A3906
C≡CC4H6-4-CF4









H, H



A3907
C≡CC4H6-4-CF4









H, H



A3908
C≡CC4H6-4-CF4
CH2OcPr
H, H

A3909
C≡CC4H6-4-CF4
CH2OcBu
H, H

A3910
C≡CC4H6-4-CF4
CH2OcPen
H, H

A3911
C≡CC4H6-4-CF4
CH2OcHex
H, H

A3912
C≡CC4H6-4-CF4
CH2OCH2cPr
H, H

A3913
C≡CC4H6-4-CF4
CH2OCH2cBu
H ,H

A3914
C≡CC4H6-4-CF4
CH2OCH2cPen
H, H

A3915
C≡CC4H6-4-CF4
CH2OCH2cHex
H, H

A3916
C≡CC4H6-4-CF4
CH2O(CH2)2cPr
H, H

A3917
C≡CC4H6-4-CF4
CH2O(CH2)2cBu
H, H

A3918
C≡CC4H6-4-CF4
CH2O(CH2)2cPen
H, H

A3919
C≡CC4H6-4-CF4
CH2O(CH2)2cHex
H, H

A3920
C≡CC4H6-4-CF4
CH2O(CH2)3cPr
H, H

A3921
C≡CC4H6-4-CF4
CH2O(CH2)3cBu
H, H

A3922
C≡CC4H6-4-CF4
CH2O(CH2)3cPen
H, H

A3923
C≡CC4H6-4-CF4
CH2O(CH2)3cHex
H, H



A3924
C≡CC4H6-4-CF4









H, H



A3925
C≡CC4H6-4-CF4









H, H












































































TABLE 60



Part A No.
R1
R2
R3, R4



A3926
C≡CC4H6-4-CF4









H, H



A3927
C≡CC4H6-4-CF4









H, H



A3928
C≡CC4H6-4-CF4









H, H



A3929
C≡CC4H6-4-CF4









H, H



A3930
C≡CC4H6-4-CF4









H, H



A3931
C≡CC4H6-4-CF4









H, H



A3932
C≡CC4H6-4-CF4









H, H



A3933
C≡CC4H6-4-CF4









H, H



A3934
C≡CC4H6-4-CF4









H, H



A3935
C≡CC4H6-4-CF4









H, H



A3936
C≡CC4H6-4-CF4









H, H



A3937
C≡CC4H6-4-CF4









H, H



A3938
C≡CC4H6-4-CF4









H, H



A3939
C≡CC4H6-4-CF4









H, H



A3940
C≡CC4H6-4-CF4









H, H



A3941
C≡CC4H6-4-CF4









H, H



A3942
C≡CC4H6-4-CF4









H, H



A3943
C≡CC4H6-4-CF4









H, H



A3944
C≡CC4H6-4-CF4









H, H



A3945
C≡CC4H6-4-CF4









H, H



A3946
C≡CC4H6-4-CF4









H, H



A3947
C≡CC4H6-4-CF4









H, H



A3948
C≡CC4H6-4-CF4









H, H



A3949
C≡CC4H6-4-CF4









H, H



A3950
C≡CC4H6-4-CF4









H, H









































































TABLE 61



Part A


R3,

No.
R1
R2
R4



A3951
C≡CC4H6-4-CF4









H, H



A3952
C≡CC4H6-4-CF4









H, H



A3953
C≡CC4H6-4-CF4









H, H



A3954
C≡CC4H6-4-CF4









H, H



A3955
C≡CC4H6-4-CF4









H, H



A3956
C≡CC4H6-4-CF4









H, H



A3957
C≡CC4H6-4-CF4









H, H



A3958
C≡CC4H6-4-CF4









H, H



A3959
C≡CC4H6-4-CF4









H, H



A3960
C≡CC4H6-4-CF4









H, H



A3961
C≡CC4H6-4-CF4









H, H



A3962
C≡CC4H6-4-CF4









H, H



A3963
C≡CC4H6-4-CF4









H, H



A3964
C≡CC4H6-4-CF4









H, H



A3965
C≡CC4H6-4-CF4









H, H



A3966
C≡CC4H6-4-CF4









H, H



A3967
C≡CC4H6-4-CF4









H, H



A3968
C≡CC4H6-4-CF4









H, H



A3969
C≡CC4H6-4-CF4









H, H



A3970
C≡CC4H6-4-CF4









H, H



A3971
C≡CC4H6-4-CF4









H, H



A3972
C≡CC4H6-4-CF4









H, H



A3973
C≡CC4H6-4-CF4
CH2ON═CHCH3
H, H

A3974
C≡CC4H6-4-CF4
CH2ON═CH(CH3)2
H, H



A3975
C≡CC4H6-4-CF4









H, H



A3976
C≡CC4H6-4-CF4









H, H



A3977
4-benzofuryl
CH═NOH
H, H

A3978
4-benzofuryl
CH═NOMe
H, H

A3979
4-benzofuryl
CH═NOEt
H, H

A3980
4-benzofuryl
CH═NOnPr
H, H
















































































TABLE 62



Part A No.
R1
R2
R3, R4



A3981
4-benzofuryl
CH═NOiPr
H, H

A3982
4-benzofuryl
CH═NOcPr
H, H

A3983
4-benzofuryl
CH═NOnBu
H, H

A3984
4-benzofuryl
CH═NOcBu
H, H

A3985
4-benzofuryl
CH═NOnPen
H, H

A3986
4-benzofuryl
CH═NOcPen
H, H

A3987
4-benzofuryl
CH═NOnHex
H, H

A3988
4-benzofuryl
CH═NOcHex
H, H

A3989
4-benzofuryl
CH═NOCH2iPr
H, H

A3990
4-benzofuryl
CH═NOCH2cPr
H, H

A3991
4-benzofuryl
CH═NOCH2cBu
H, H

A3992
4-benzofuryl
CH═NOCH2cPen
H, H

A3993
4-benzofuryl
CH═NOCH2cHex
H, H

A3994
4-benzofuryl
CH═NO(CH2)2iPr
H, H

A3995
4-benzofuryl
CH═NO(CH2)2cPr
H, H

A3996
4-benzofuryl
CH═NO(CH2)2cBu
H, H

A3997
4-benzofuryl
CH═N0(CH2)2cPen
H, H

A3998
4-benzofuryl
CH═NO(CH2)2cHex
H, H

A3999
4-benzofuryl
CH═NO(CH2)3iPr
H, H

A4000
4-benzofuryl
CH═NO(CH2)3cPr
H, H

A4001
4-benzofuryl
CH═NO(CH2)3cBu
H, H

A4002
4-benzofuryl
CH═NO(CH2)3cPen
H, H

A4003
4-benzofuryl
CH═NO(CH2)3cHex
H, H



A4004
4-benzofuryl









H, H



A4005
4-benzofuryl









H, H



A4006
4-benzofuryl









H, H



A4007
4-benzofuryl









H, H



A4008
4-benzofuryl









H, H



A4009
4-benzofuryl









H, H



A4010
4-benzofuryl









H, H



A4011
4-benzofuryl









H, H



A4012
4-benzofuryl









H, H



A4013
4-benzofuryl









H, H



A4014
4-benzofuryl









H, H



A4015
4-benzofuryl









H, H



A4016
4-benzofuryl









H, H



A4017
4-benzofuryl









H, H











































































TABLE 63



Part A




No.
R1
R2
R3, R4



A4018
4-benzofuryl









H, H



A4019
4-benzofuryl









H, H



A4020
4-benzofuryl









H, H



A4021
4-benzofuryl









H, H



A4022
4-benzofuryl









H, H



A4023
4-benzofuryl









H, H



A4024
4-benzofuryl









H, H



A4025
4-benzofuryl









H, H



A4026
4-benzofuryl









H, H



A4027
4-benzofuryl









H, H



A4028
4-benzofuryl









H, H



A4029
4-benzofuryl









H, H



A4030
4-benzofuryl









H, H



A4031
4-benzofuryl









H, H



A4032
4-benzofuryl









H, H



A4033
4-benzofuryl









H, H



A4034
4-benzofuryl









H, H



A4035
4-benzofuryl









H, H



A4036
4-benzofuryl









H, H



A4037
4-benzofuryl









H, H



A4038
4-benzofuryl









H, H



A4039
4-benzofuryl









H, H



A4040
4-benzofuryl









H, H



A4041
4-benzofuryl









H, H








































































TABLE 64



Part A




No.
R1
R2
R3, R4



A4042
4-benzofuryl









H, H



A4043
4-benzofuryl









H, H



A4044
4-benzofuryl









H, H



A4045
4-benzofuryl









H, H



A4046
4-benzofuryl









H, H



A4047
4-benzofuryl









H, H



A4048
4-benzofuryl









H, H



A4049
4-benzofuryl









H, H



A4050
4-benzofuryl









H, H



A4051
4-benzofuryl









H, H



A4052
4-benzofuryl









H, H



A4053
4-benzofuryl









H, H



A4054
4-benzofuryl
CH2OcPr
H, H

A4055
4-benzofuryl
CH2OcBu
H, H

A4056
4-benzofuryl
CH2OcPen
H, H

A4057
4-benzofuryl
CH2OcHex
H, H

A4058
4-benzofuryl
CH2OCH2cPr
H, H

A4059
4-benzofuryl
CH2OCH2cBu
H, H

A4060
4-benzofuryl
CH2OCH2cPen
H, H

A4061
4-benzofuryl
CH2OCH2cHex
H, H

A4062
4-benzofuryl
CH2O(CH2)2cPr
H, H

A4063
4-benzofuryl
CH2O(CH2)2cBu
H, H

A4064
4-benzofuryl
CH2O(CH2)2cPen
H, H

A4065
4-benzofuryl
CH2O(CH2)2cHex
H, H

A4066
4-benzofuryl
CH2O(CH2)3cPr
H, H

A4067
4-benzofuryl
CH2O(CH2)3cBu
H, H

A4068
4-benzofuryl
CH2O(CH2)3cPen
H, H

A4069
4-benzofuryl
CH2O(CH2)3cHex
H, H



A4070
4-benzofuryl









H, H



A4071
4-benzofuryl









H, H



A4072
4-benzofuryl









H, H



A4073
4-benzofuryl









H, H



A4074
4-benzofuryl









H, H



A4075
4-benzofuryl









H, H



A4076
4-benzofuryl









H, H



A4077
4-benzofuryl









H, H

















































































TABLE 65



Part A No.
R1
R2
R3, R4



A4078
4-benzofuryl









H, H



A4079
4-benzofuryl









H, H



A4080
4-benzofuryl









H, H



A4081
4-benzofuryl









H, H



A4082
4-benzofuryl









H, H



A4083
4-benzofuryl









H, H



A4084
4-benzofuryl









H, H



A4085
4-benzofuryl









H, H



A4086
4-benzofuryl









H, H



A4087
4-benzofuryl









H, H



A4088
4-benzofuryl









H, H



A4089
4-benzofuryl









H, H



A4090
4-benzofuryl









H, H



A4091
4-benzofuryl









H, H



A4092
4-benzofuryl









H, H



A4093
4-benzofuryl









H, H



A4094
4-benzofuryl









H, H



A4095
4-benzofuryl









H, H



A4096
4-benzofuryl









H, H



A4097
4-benzofuryl









H, H



A4098
4-benzofuryl









H, H



A4099
4-benzofuryl









H, H



A4100
4-benzofuryl









H, H



A4101
4-benzofuryl









H, H































































TABLE 66 Part A No. R1 R2 R3, R4 A4102 4-benzofuryl H, H A4103 4-benzofuryl H, H A4104 4-benzofuryl H, H A4105 4-benzofuryl H, H A4106 4-benzofuryl H, H A4107 4-benzofuryl H, H A4108 4-benzofuryl H, H A4109 4-benzofuryl H, H A4110 4-benzofuryl H, H A4111 4-benzofuryl H, H A4112 4-benzofuryl H, H A4113 4-benzofuryl H, H A4114 4-benzofuryl H, H A4115 4-benzofuryl H, H A4116 4-benzofuryl H, H A4117 4-benzofuryl H, H A4118 4-benzofuryl H, H A4119 4-benzofuryl H, H A4120 4-benzofuryl CH2ON═CHCH3 H, H A4121 4-benzofuryl CH2ON═CH(CH3)2 H, H A4122 4-benzofuryl H, H A4123 4-benzofuryl H, H A4124 C≡CC4H6-4-CF H, H
2) A compound wherein the part (Part B) of the formula:


is the one of the followings.






TABLE 67






















Part B No.
Type
X1
R5, R6, R7, R8





B1
b1
S
H, H, H, H


B2
b1
S
H, Me, H, H


B3
b1
S
H, nPr, H, H


B4
b1
S
H, OCH2CF3, H, H


B5
b1
S
H, OH, H, H


B6
b1
S
H, OMe, H, H


B7
b1
S
H, SMe, H, H


B8
b1
S
Me, H, H, H


B9
b1
S
OMe, H, H, H


B10
b1
S
H, SPh, H, H


B11
b1
S
Me, Me, Me, Me


B12
b1
S
H, Me, H, Me


B13
b1
S
OCH2CF3, H, H, H


B14
b1
S
Cl, Cl, H, H


B15
b1
S
Cl, H, H, H


B16
b1
S
H, Cl, H, H


B17
b1
S
H, F, H, H


B18
b1
S
F, F, H, H


B19
b1
S
F, H, H, H


B20
b1
S
H, CH2CH═CH2, H, H


B21
b1
S
Et, H, H, H


B22
b1
S
nPr, H, H, H


B23
b1
S
CF3, H, H, H


B24
b1
S
CN, H, H, H


B25
b1
S
H, Et, H, H


B26
b1
S
H, CF3, H, H


B27
b1
S
H, CN, H, H



























































TABLE 68





Part B No.
Type
X1
R5, R6, R7, R8





B28
b1
S
H, H, H, Me


B29
b1
S
H, H, H, F


B30
b1
S
H, H, H, Cl


B31
b1
S
H, H, H, OMe


B32
b1
S
H, H, H, OH


B33
b1
S
H, H, Me, H


B34
b1
S
H, H, Et, H


B35
b1
S
H, H, nPr, H


B36
b1
S
H, H, F, H


B37
b1
S
H, H, Cl, H


B38
b1
S
H, H, Br, H


B39
b1
S
H, H, OMe, H


B40
b1
S
H, H, CF3, H


B41
b1
S
H, H, CN, H


B42
b1
S
H, H, C≡CH, H


B43
b1
S
H, H, CH═CH2, H


B44
b1
O
H, H, H, H


B45
b1
O
H, Me, H, H


B46
b1
O
H, nPr, H, H


B47
b1
O
H, OCH2CF3, H, H


B48
b1
O
H, OH, H, H


B49
b1
O
H, OMe, H, H


B50
b1
O
H, SMe, H, H


B51
b1
O
Me, H, H, H


B52
b1
O
OMe, H, H, H


B53
b1
O
Me, Me, H, H


B54
b1
O
Me, Me, Me, Me


B55
b1
O
H, OPh, H, H


B56
b1
O
OCH2CF3, H, H, H


B57
b1
O
Cl, Cl, H, H


B58
b1
O
Cl, H, H, H


B59
b1
O
H, Cl, H, H


B60
b1
O
H, F, H, H


B61
b1
O
F, F, H, H


B62
b1
O
F, H, H, H


B63
b1
O
H, CH2CH═CH2, H, H


B64
b1
O
Et, H, H, H


B65
b1
O
nPr, H, H, H


B66
b1
O
CF3, H, H, H


B67
b1
O
CN, H, H, H


B68
b1
O
H, Et, H, H


B69
b1
O
H, CF3, H, H


B70
b1
O
H, CN, H, H


B71
b1
O
H, H, H, Me







































































TABLE 69





Part B No.
Type
X1
R5, R6, R7, R8





B72
b1
O
H, H, H, F


B73
b1
O
H, H, H, Cl


B74
b1
O
H, H, H, OMe


B75
b1
O
H, H, H, OH


B76
b1
O
H, H, Me, H


B77
b1
O
H, H, Et, H


B78
b1
O
H, H, nPr, H


B79
b1
O
H, H, F, H


B80
b1
O
H, H, Cl, H


B81
b1
O
H, H, Br, H


B82
b1
O
H, H, OMe, H


B83
b1
O
H, H, CF3, H


B84
b1
O
H, H, CN, H


B85
b1
O
H, H, C≡CH, H


B86
b1
O
H, H, CH═CH2, H


B87
b1
CH2CO
H, H, H, H


B88
b1
CH2CO
H, Me, H, H


B89
b1
CH2CO
H, nPr, H, H


B90
b1
CH2CO
H, OCH2CF3, H, H


B91
b1
CH2CO
H, OH, H, H


B92
b1
CH2CO
H, OMe, H, H


B93
b1
CH2CO
H, SMe, H, H


B94
b1
CH2CO
Cl, H, H, H


B95
b1
CH2CO
OMe, H, H, H


B96
b1
CH2CO
Me, Me, H, H


B97
b1
CH2CO
Me, CH═CH2, Me, Me


B98
b1
CH2CO
H, Me, H, NHMe


B99
b1
CH2CO
OCH2CF3, H, H, H


B100
b1
CH2CO
Cl, Cl, H, H


B101
b1
CH2CO
Cl, H, H, H


B102
b1
CH2CO
H, F, H, H


B103
b1
CH2CO
H, CH2CH═CH2, H, H


B104
b1
NH
H, H, H, H


B105
b1
NH
H, Me, H, H


B106
b1
NH
H, nPr, H, H


B107
b1
NH
H, OCH2CF3, H, H


B108
b1
NH
H, OH, H, H


B109
b1
NH
H, OMe, H, H


B110
b1
NH
H, SMe, H, H


B111
b1
NH
Me, H, H, H


B112
b1
NH
OMe, H, H, H


B113
b1
NH
Me, C≡CH, H, H


B114
b1
NH
Me, Me, Me, Me


B115
b1
NH
H, Ac, H, H





































































TABLE 70



Part B No.
Type
X1
R5, R6, R7, R8



B116
b1
NH
OCH2CF3, H, H, H

B117
b1
NH
Cl, Cl, H, H

B118
b1
NH
Cl, H, H, H

B119
b1
NH
H, F, H, H

B120
b1
NH
H, CH2CH═CH2, H, H

B121
b1
NMe
H, H, H, H

B122
b1
NMe
H, Me, H, H

B123
b1
NMe
H, nPr, H, H

B124
b1
NMe
H, OCH2CF3, H, H

B125
b1
NMe
H, OH, H, H

B126
b1
NMe
H, OMe, H, H

B127
b1
NMe
H, SMe, H, H

B128
b1
NMe
Me, H, H, H

B129
b1
NMe
H, Ph, H, H

B130
b1
NMe
Me, Me, H, H

B131
b1
NMe
Me, Me, Me, Me

B132
b1
NMe
H, Me, H, Me

B133
b1
NMe
OCH2CF3, H, H, H

B134
b1
NMe
Cl, Cl, H, H

B135
b1
NMe
Cl, H, H, H

B136
b1
NMe
H, F, H, H

B137
b1
NMe
H, CH2CH═CH2, H, H

B138
b1
NEt
H, H, H, H

B139
b1
NEt
H, Me, H, H

B140
b1
NCH2Ph
H, nPr, H, H

B141
b1
NCH2Ph
H, H, H, H

B142
b1
NAc
H, OCH2CF3, H, H

B143
b1
NAc
H, H, H, H

B144
b1
NCOEt
H, OMe, H, H

B145
b1
NCOEt
H, H, H, H

B146
b1
NCOPh
Me, H, H, H

B147
b1
NCOPh
H, H, H, H

B148
b1
NSO2Me
H, Ph, H, H

B149
b1
NSO2Me
H, H, H, H

B150
b1
NSO2Et
Me, Me, H, H

B151
b1
NSO2Et
H, H, H, H

B152
b1
NSO2Ph
Me, Me, Me, Me

B153
b1
NSO2Ph
H, H, H, H

B154
b1
NSO2C6H4-p-Me
OCH2CF3, H, H, H

B155
b1
NSO2C6H4-p-Me
H, H, H, H

B156
b1
4-piperadin-1-yl
H, H, H, H

B157
b1
4-methylpiperadin-1-yl
H, H, H, H

B158
b1
ON═CH
H, H, H, H

B159
b1
CH2O
H, H, H, H






































































TABLE 71





Part B No.
Type
X1
R5, R6, R7, R8





B160
b1
CH2O
H, Me, H, H


B161
b1
CH2O
H, nPr, H, H


B162
b1
CH2O
H, OCH2CF3, H, H


B163
b1
CH2O
H, OH, H, H


B164
b1
CH2O
H, OMe, H, H


B165
b1
CH2O
H, Cl, H, H


B166
b1
CH2O
Me, H, H, H


B167
b1
CH2O
H, Ph, H, H


B168
b1
CH2O
Me, Me, H, H


B169
b1
CH2O
Me, Me, Me, Me


B170
b1
CH2O
H, Me, H, Me


B171
b1
CHEtO
OCH2CF3, H, H, H


B172
b1
CHEtO
H, H, H, H


B173
b1
OCH2
H, H, H, H


B174
b1
OCH2
H, Me, H, H


B175
b1
OCH2
H, nPr, H, H


B176
b1
OCH2
H, OCH2CF3, H, H


B177
b1
OCH2
H, OH, H, H


B178
b1
OCH2
H, OMe, H, H


B179
b1
OCH2
H, SMe, H, H


B180
b1
OCH2
Me, H, H, H


B181
b1
OCH2
H, Ph, H, H


B182
b1
OCH2
H, F, H, H


B183
b1
OCH2
Me, Me, Me, Me


B184
b1
OCH2
H, Me, H, Me


B185
b1
OCHMe
OCH2CF3, H, H, H


B186
b1
OCHMe
H, H, H, H


B187
b2
O
H, H, H


B188
b2
O
Me, H, H


B189
b2
O
H, Me, H


B190
b2
S
H, H, H


B191
b2
S
Me, H, H


B192
b3
O
H, H, H,


B193
b3
O
Me, H, H


B194
b3
O
H, Me, H


B195
b3
S
H, H, H,


B196
b3
S
Me, H, H


B197
b3
S
H, Me, H


B198
b4
O
H, H, H,


B199
b4
O
Me, H, H


B200
b4
O
H, Me, H


B201
b4
S
H, H, H,


B202
b4
S
Me, H, H


B203
b4
S
H, Me, H







































































TABLE 72





Part B No.
Type
X1
R5, R6, R7, R8





B204
b5
S
H, H, H, H


B205
b5
S
F, H, H, H


B206
b5
S
Cl, H, H, H


B207
b5
S
Me, H, H, H


B208
b5
S
Et, H, H, H


B209
b5
S
OMe, H, H, H


B210
b5
S
H, F, H, H


B211
b5
S
H, Cl, H, H


B212
b5
S
H, Me, H, H


B213
b5
S
H, Et, H, H


B214
b5
S
H, OMe, H, H


B215
b5
S
H, H, F, H


B216
b5
S
H, H, Cl, H


B217
b5
S
H, H, Me, H


B218
b5
S
H, H, Et, H


B219
b5
S
H, H, OMe, H


B220
b5
S
H, H, H, F


B221
b5
O
H, H, H, Cl


B222
b5
O
H, H, H, Me


B223
b5
O
H, H, H, Et


B224
b5
O
H, H, H, OMe


B225
b5
O
H, H, H, H


B226
b5
O
F, H, H, H


B227
b5
O
Cl, H, H, H


B228
b5
O
Me, H, H, H


B229
b5
O
Et, H, H, H


B230
b5
O
OMe, H, H, H


B231
b5
O
H, F, H, H


B232
b5
O
H, Cl, H, H


B233
b5
O
H, Me, H, H


B234
b5
O
H, Et, H, H


B235
b5
O
H, OMe, H, H


B236
b5
O
H, H, F, H


B237
b5
O
H, H, Cl, H


B238
b5
O
H, H, Me, H


B239
b5
O
H, H, Et, H


B240
b5
O
H, H, OMe, H


B241
b5
O
H, H, H, F


B242
b5
O
H, H, H, Cl


B243
b5
O
H, H, H, Me


B244
b5
O
H, H, H, Et


B245
b5
O
H, H, H, OMe


B246
b5
OCH2CO
H, H, H, H


B247
b5
OCH2
H, H, H, H





























































TABLE 73 Part B No. Type X1 R5, R6, R7, R8 B248 b5 CH2O H, H, H, H B249 b5 NH H, H, H, H B250 b5 NMe H, H, H, H B251 b5 NEt H, H, H, H B252 b5 NCH2Ph H, H, H, H B253 b5 NAc H, H, H, H B254 b5 NCH2Ph H, H, H, H B255 b5 NCH2Et H, H, H, H B256 b5 NSO2Me H, H, H, H B257 b5 NSO2Et H, H, H, H B258 b5 NSO2Ph H, H, H, H B259 b5 NSO2C6H4-p-Me H, H, H, H B260 b5 4-piperadin-1-yl H, H, H, H B261 b5 4-methylpiperadin-1-yl H, H, H, H B262 b5 ON═CH H, H, H, H B263 b6 O H, H B264 b6 O Me, H B265 b6 O H, Me B266 b6 S H, H B267 b6 S Me, H B268 b6 S H, Me
3) A compound wherein the part (Part C) of the formula:


is one of the followings.






TABLE 74






















Part C No.
Type
R9, R10
R17





C1
c1
H, H
H


C2
c1
H, H
Me


C3
c1
Me, H
H


C4
c1
Me, H
Me


C5
c1
Et, H
H


C6
c1
CH2OMe, H
Me


C7
c1
nPr, H
H


C8
c1
nPr, H
Me


C9
c1
Me, Me
H


C10
c1
Ph, Me
Me


C11
c1
CH2Ph, H
H


C12
c1
Et, H
Et


C13
c1
nPr, H
iPr


C14
c1
Me, Me
Me


C15
c1
Me, Me
tBu


C16
c1
Et, H
Me


C17
c2
H, H
H


C18
c2
H, H
Me


C19
c2
Me, H
H


C20
c2
Me, H
Me


C21
c2
Et, H
H


C22
c2
CH2OMe, H
Me


C23
c2
nPr, H
H


C24
c2
nPr, H
Me


C25
c2
Me, Me
H


C26
c2
Ph, Me
Me


C27
c2
CH2Ph, H
H


C28
c2
Et, H
Et


C29
c2
nPr, H
iPr


C30
c2
Me, Me
Me


C31
c2
Me, Me
tBu


C32
c2
Et, H
Me


C33
c3
H, H
H

































































TABLE 75





Part C No.
Type
R9, R10
R17





C34
c3
H, H
Me


C35
c3
Me, H
H


C36
c3
Me, H
Me


C37
c3
Et, H
H


C38
c3
CH2OMe, H
Me


C39
c3
nPr, H
H


C40
c3
nPr, H
Me


C41
c3
Me, Me
H


C42
c3
Ph, Me
Me


C43
c3
CH2Ph, H
H


C44
c3
Et, H
Et


C45
c3
nPr, H
iPr


C46
c3
Me, Me
Me


C47
c3
Me, Me
tBu


C48
c3
Et, H
Me


C49
c4
H, H
H


C50
c4
H, H
Me


C51
c4
Me, H
H


C52
c4
Me, H
Me


C53
c4
Et, H
H


C54
c4
CH2OMe, H
Me


C55
c4
nPr, H
H


C56
c4
nPr, H
Me


C57
c4
Me, Me
H


C58
c4
Ph, Me
Me


C59
c4
CH2Ph, H
H


C60
c4
Et, H
Et


C61
c4
nPr, H
iPr


C62
c4
Me, Me
Me


C63
c4
Me, Me
tBu


C64
c4
Et, H
Me


C65
c5
H, H
H


C66
c5
H, H
Me


C67
c5
Me, H
H


C68
c5
Me, H
Me


C69
c5
Et, H
H


C70
c5
CH2OMe, H
Me


C71
c5
nPr, H
H


C72
c5
nPr, H
Me


C73
c5
Me, Me
H


C74
c5
Ph, Me
Me


C75
c5
CH2Ph, H
H


C76
C5
Et, H
Et


C77
c5
nPr, H
iPr


C78
c5
Me, Me
Me








































































TABLE 76





Part C No.
Type
R9, R10
R17





C79
c5
Me, Me
tBu


C80
c5
Et, H
Me


C81
c6
H, H
H


C82
c6
H, H
Me


C83
c6
Me, H
H


C84
c6
Me, H
Me


C85
c6
Et, H
H


C86
c6
CH2OMe, H
Me


C87
c6
nPr, H
H


C88
c6
nPr, H
Me


C89
c6
Me, Me
H


C90
c6
Ph, Me
Me


C91
c6
CH2Ph, H
H


C92
c6
Et, H
Et


C93
c6
nPr, H
iPr


C94
c6
Me, Me
Me


C95
c6
Me, Me
tBu


C96
c6
Et, H
Me



































Concretely, a compound by the combination of Part A, B and C of Compound (I) is preferable.
A pharmaceutical composition for PPAR agonist of this invention can be effectively acted on all diseases concerning PPAR and especially for prevention and/or treatment of hyperlipidemia, dyslipidosis, disorder of lipid metabolism, Low HDL, High LDL, High VLDL, High TG, diabetes, hyperglycosemia, insulin resistance, obesity, bulimia, arteriosclerosis, atherosclerosis, hypertension, syndrome X, ischemic disease, inflammation, allergic disease (inflammatory bowel disease, rheumatoid arthritis, chronic pancreatitis, multiple sclerosis, glomerulosclerosis, psoriasis, eczema or the like), osteoporosis, sterility, cancer (breast cancer, colonic cancer, colon cancer, ovarian cancer, lung cancer or the like), Alzheimer's disease, parkinsonism or Basedow's disease. Especially, a compound having PPARδ selective agonistic activity in a compound of the present invention having PPAR agonistic activity can be good medicine. The reason is, for example, that it can be expected to have a high HDL increasing activity or that the side effect can be lightened.
When administering a compound of the present invention as a pharmaceutical composition for PPAR agonist, it can be administered orally or parenterally. For oral administration, the compound of the present invention can be used in any form of usual formulations, for example, tablets, granules, powders, capsules, pills, solutions, syrup, buccals, sublingual tablets or the like which are made by the usual process. For parenteral administration, the compound of the present invention can be used in any form of usual formulations, for example, injections such as intramuscular administration and intravenous administration, suppository, transdermal therapeutic agent, insufflation or the like. A compound of the present invention can be preferably used as an oral agent because it has high oral bioavailability.
The formulation according to the present invention may be manufactured by combining a curatively effective amount of a compound of the present invention with various pharmaceutically acceptable excipients such as binder, moistening agent, disintegrating agents, lubricant, diluent or the like, if necessary. When the formulation is injection, the compound of the present invention may be manufactured by sterilization treatment with an appropriate carrier.
For example, the excipient is lactose, saccharose, glucose, starch, calcium carbonate, crystalline cellulose or the like. The binder is methylcellulose, carboxy methylcellulose, hydroxy propylcellulose, gelatin, polyvinylpyrrolidone or the like. The disintegrating agent is carboxy methyl cellulose, carboxymethylcellulose sodium, starch, sodium alginate, powdered agar, sodium lauryl sulfate or the like. The lubricant is talc, magnesium stearate, macrogol or the like. As a basis for suppository, cocoa butter, macrogol, methylcellulose or the like can be used. When the present invention is manufactured as liquid medicine, emulsion injection or suspension injection, solubilizing agent, suspending agent, emulsifying agent, stabilizing agent, preservatives, isotonic agent or the like which is usually used can be appropriately added. In case of oral administration, sweetening agent, flavoring agent or the like can be added.
The dose as a pharmaceutical composition for PPAR agonist of a compound of the present invention is preferably established depending on age, body weight, kind of disease, conditions of the patient, the administration route or the like. In case of the oral administration for an adult, it is usually 0.05 to 100 mg/kg/day and preferably 0.1 to 10 mg/kg/day. In case of the parenteral administration, although it is very different depending on route of administration, it is usually 0.005 to 10 mg/kg/day and preferably 0.01 to 1 mg/kg/day. This can be separated and administrated at 1 to few times a day.
The following examples are provided to explain in more detail and do not restrict the present invention.
EXAMPLE
In the examples, the meaning of each abbreviation is as below.
Me methyl Et ethyl nBu n-butyl tBu tert-butyl nPr n-propyl Ph phenyl Bn benzyl Ac acetyl Ms methanesulfonyl TMS trimethylsilyl PCC pyridinium chlorochromate CDI 1,1′-carbonyldiimidazole DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DME 1,2-dimethoxyethane DPM diphenylmethyl TBS 3-tert-butyldimethylsilyl TFMP 4-trifluoromethylphenyl
Reference 1

(4-Chloro-3-hydroxyphenyl)acetic acid methyl ester

The First Step

1-Chloro-4-chloromethyl-2-methoxybenzene
To a suspension of lithium aluminum hydride (1.52 g) in tetrahydrofuran (100 ml) was added 4-chloro3-methoxybenzoic acid (5.16 g) under ice-cooling. The mixture was stirred at room temperature for 22 hours. The reaction solution was cooled with ice, and water (1.5 ml), 2N sodium hydroxide solution (1.5 ml) and water (4.6 ml) were added thereto. The mixture was stirred at room temperature for 1 hour. 2N sodium hydroxide solution (1.5 ml), anhydrous magnesium sulfate and the mixture of hexane and diethyl ether were added and stirred under ice-cooling for 30 min. The mixture was filtrated and the filtrate was condensed to give oil (4.61 g). This oil was dissolved in methylene chloride (40 ml), and thionyl chloride (5.0 ml) and pyridine (2.4 ml) were added thereto under ice-cooling. The mixture was stirred for 25 minutes. The reaction solution was condensed under reduced pressure. Then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (4.53 g). The yield was 86%.
1 H-NMR (CDCl 3 ) δ: 3.92 (3H, s), 4.55 (2H, s), 6.91 (1H, dd, J=1.8, 7.8 Hz), 6.96 (1H, d, J=1.8 Hz), 7.33 (1H, d, J=7.8 Hz).
The Second Process
4-Chloro-3-methoxyphenylacetonitrile
To a solution of 1-chloro-4-chloromethyl-2-methoxybenzene (4.52 g) in dimethylsulfoxide (70 ml) was added sodium cyanide (1.16 g). The mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (3.81 g). The yield was 89%.
1 H-NMR (CDCl 3 ) δ: 3.74 (2H, s), 3.93 (3H, s), 6.82-6.90 (2H, m), 7.36 (1H, d, J=7.8 Hz).
The Third Process
(4-Chloro-3-methoxyphenyl)acetic acid methyl ester
Potassium hydroxide (5.86 g) was dissolved in water (25 ml) and the mixture was added to a solution of 4-chloro-3-methoxyphenylacetonitrile (3.80 g) in ethanol (80 ml) at room temperature. The reaction solution was refluxed for 1.5 hours. After cooling, concentrated hydrochloric acid (8.8 ml) and water (50 ml) were added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (100 ml) and concentrated sulphuric acid was added thereto. The mixture was refluxed for 1.45 hours. After cooling, the reaction solvent was evaporated under reduced pressure and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give a title compound (4.43 g). The yield was 99%.
1 H-NMR (CDCl 3 ) δ: 3.61 (2H, s), 3.71 (3H, s), 3.91 (3H, s), 6.81 (1H, dd, J=1.8, 8.1 Hz), 6.87 (1H, d, J=1.8 Hz), 7.30 (1H, d, J=8.1 Hz).
The Fourth Step
(4-Chloro-3-hydroxyphenyl)acetic acid methyl ester
To a solution of (4-chloro-3-methoxyphenyl)acetic acid methyl ester (4.43 g) in methylene chloride (62 ml) was added 1.0 M boron tribromide methylene chloride solution (62 ml) under ice-cooling for 30 minutes. After the mixture was stirred for 30 minutes, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (3.73 g). The yield was 90%.
1 H-NMR (CDCl 3 ) δ: 3.57 (2H, s), 3.70 (3H, s), 5.53 (1H, s), 6.79 (1H, dd, J=1.8, 8.1 Hz), 6.96 (1H, d, J=1.8 Hz), 726 (1H, d, J=8.1 Hz).
The following compounds were synthesized in a similar way as above.
(4-fluoro-3-hydroxyphenyl)acetic acid methyl ester

1 H-NMR (CDCl 3 ) δ: 3.53 (3H, s), 3.60 (2H, s), 5.21 (1H, s), 6.83-7.15 (3H, m).
(3-hydroxy-4-methylphenyl)acetic acid methyl ester
1 H-NMR (CDCl 3 ) δ: 2.21 (3H, s), 3.55 (2H, s), 3.69 (3H, s), 5.22 (1H, s), 6.60-7.10 (3H, m).
(3-hydroxy-4-methoxyphenyl)acetic acid methyl ester
1 H-NMR (CDCl 3 ) δ: 3.68 (2H, s), 3.72 (3H, s), 5.39 (1H, s), 6.74-7.00 (3H, m).
(2-fluoro-3-hydroxy phenyl)acetic acid methyl ester
1 H-NMR (CDCl 3 ) δ: 2.19 (3H, s), 3.65 (2H, s), 3.70 (3H, s), 4.85 (1H, s), 6.67-7.06 (3H, m).
(3-hydroxy-2-methylphenyl)acetic acid methyl ester
1 H-NMR (CDCl 3 ) δ: 2.19 (3H, s), 3.65 (2H, s), 3.70 (3H, s), 4.85 (1H, s), 6.67-7.06 (3H, m).
(2-fluoro-5-hydroxy phenyl)acetic acid methyl ester
1 H-NMR (CDCl 3 ) δ: 3.62 (2H, s), 3.72 (3H, s), 6.66-6.95 (3H, m).
Reference 2
(5-Methyl-3-hydroxyphenyl)acetic acid methyl ester

The First Step

3,5-Dimethyl-1-methoxymethoxybenzene
To a solution of 3,5-dimethylphenol (6.14 g) in tetrahydrofuran (60 ml) were added diisopropylethylamine (13.1 ml) and chloromethylmethylether (4.1 ml). The mixture was refluxed for 6 hours. After cooling, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (6.96 g). The yield was 83%.
1 H-NMR (CDCl 3 ) δ: 2.29 (6H, s), 3.48 (3H, s), 5.15 (2H, s), 6.66 (3H, s).
The Second Step
1-Bromomethyl-3-methoxymethoxy-5-methylbenzene
To a solution of 3,5-dimethyl-1-methoxymethoxybenzene (6.44 g) in carbon tetrachloride (60 ml) were added N-bromosuccinimide (7.24 g) and 2,2′-azobisisobutyronitrile (191 mg). The mixture was refluxed for 30 minutes. After cooling, the reaction solution was filtrated and the filtrate was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (6.94 g). The yield was 58%.
1 H-NMR (CDCl 3 ) δ: 2.32 (3H, s), 3.48 (3H, s), 4.42 (2H, s), 5.16 (2H, s), 6.63 (1H, s), 6.79 (2H, s).
The Third Step
3-Methoxymethoxy-5-methylphenylacetonitrile
To a solution of 1-bromomethyl-3-methoxymethoxy-5-methylbenzene (6.94 g) in dimethylsulfoxide (100 ml) was added sodium cyanide (1.18 g). The mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (4.00 g). The yield was 87%.
1 H-NMR (CDCl 3 ) δ: 2.34 (3H, s), 3.48 (3H, s), 3.68 (2H, s), 5.17 (2H, s), 6.77-6.85 (1H, m).
The Fourth Step
(3-Hydroxy-5-methylphenyl)acetic acid methyl ester
Potassium hydroxide (5.87 g) was dissolved in water (20 ml) and the solution was added to a solution of 3-methoxymethoxy-5-methylphenylacetonitrile (4.00 g) in ethanol (40 ml) at room temperature. The reaction solution was refluxed for 2 hours. After cooling, 2N hydrochloric acid (55 ml) and water were added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The obtained residue was dissolved in methanol (100 ml) and concentrated sulphuric acid was added thereto. The mixture was refluxed for 1 hour. After cooling, the reaction solvent was evaporated under reduced pressure and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give a title compound (3.18 g). The yield was 84%.
1 H-NMR (CDCl 3 ) δ: 2.29 (3H, s), 3.53 (2H, s), 3.70 (3H, s), 4.80 (1H, s), 6.57 (1H, s), 6.66 (2H, s).
The following compound was synthesized in a similar way as above.
(2-Chloro-5-hydroxyphenyl)acetic acid methyl ester

1 H-NMR (CDCl 3 ) δ: 3.72 (2H, s), 3.73 (3H, s), 5.19 (1H, s), 6.69 (1H, dd, J=3.0, 8.7 Hz), 6.77 (1H, d, J=3.0 Hz), 7.22 (1H, d, J=8.7 Hz).
Reference 3
(3-Hydroxy-5-methoxyphenyl)acetic acid methyl ester









To a solution of (3,5-dihydroxyphenyl)acetic acid methyl ester (2.73 g) in dimethylformamide (20 ml) was added sodium hydride (659 mg) under ice-cooling. The mixture was stirred at room temperature for 30 minutes. Iodomethane (1.03 ml) was added thereto and the mixture was stirred at room temperature for 15 hours. 2N hydrochloric acid and water were added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (1.18 g). The yield was 40%.
1 H-NMR (CDCl 3 ) δ: 3.53 (2H, s), 3.70 (3H, s), 3.77 (3H, s), 4.96 (1H, s), 6.30-6.43 (3H, m).
Reference 4
(3-Fluoro-5-hydroxyphenyl)acetic acid methyl ester









To a solution of (3-benzyloxy-5-fluorophenyl)acetic acid methyl ester (522 mg) described in J. Med. Chem., 2004, 47, 720-725 in methylene chloride (5 ml) was added aluminum chloride (761 mg) at room temperature. The mixture was stirred for 1 hour. 2N hydrochloric acid was added to the reaction solution and the mixture was extracted with methylene chloride. The organic layer was washed successively with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatograph on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (135 mg). The yield was 39%.
1 H-NMR (CDCl 3 ) δ: 3.55 (2H, s), 3.71 (3H, s), 6.48 (1H, dt, J=2.4, 10.0 Hz), 6.57 (2H, dt, J=5.0, 9.9 Hz).
Reference 5
(4-Fluoro-3-mercaptophenyl)acetic acid methyl ester

The First Step

(3-Dimethylthiocarbamoyloxy-4-fluorophenyl)acetic acid methyl ester
A mixture of (3-hydroxy-4-fluorophenyl)acetic acid methyl ester (1.36 g), N,N-dimethylthiocarbamoylchloride (1.10 g), triethylamine (1.54 ml), N,N-dimethylaminopyridine (90 mg) and dioxane (20 ml) was refluxed for 15 hours. After cooling, water and 2N hydrochloric acid were added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatograph on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (1.95 g). The yield was 97%.
1 H-NMR (CDCl 3 ) δ: 3.36 (3H, s), 3.60 (3H, s), 3.62 (2H, s), 3.70 (3H, s), 7.05-7.16 (3H, m).
The Second Step
(3-Dimethylcarbamoyl sulfanyl-4-fluorophenyl)acetic acid methyl ester
A mixture of (3-dimethylthiocarbamoyloxy-4-fluorophenyl)acetic acid methyl ester (1.95 g) and SAS-296 (10 ml) was stirred at 270° C. for 1 hour. The reaction solution was cooled to room temperature, and then purified by column chromatography on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (1.74 g). The yield was 89%.
1 H-NMR (CDCl 3 ) δ: 2.95-3.20 (6H, m), 3.60 (2H, s), 3.70 (3H, s), 7.11 (1H, d, J=8.4 Hz), 7.30-7.39 (1H, m), 7.40 (1H, dd, J=2.4, 6.6 Hz).
The Third Step
(4-Fluoro-3-mercaptophenyl)acetic acid methyl ester
To a solution of (3-dimethylcarbamoyl sulfanyl-4-fluorophenyl)acetic acid methyl ester (1.74 g) in methanol (20 ml) was added 1 N sodium methoxide (methanol solution) (7.7 ml). The mixture was stirred under heating for 2.5 hours. After cooling, the reaction solution was added to 2N hydrochloric acid-ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatograph on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (951 mg). The yield was 74%.
1 H-NMR (CDCl 3 ) δ: 3.54 (2H, s), 3.59 (1H, s), 3.70 (3H, s), 6.99-7.26 (3H, m).
The following compound was synthesized in a similar way as above.
3-Mercaptophenylacetic acid methyl ester

1 H-NMR (CDCl 3 ) δ: 3.45 (1H, s), 3.57 (2H, s), 3.70 (3H, s), 7.04-7.24 (3H, m).
Reference 6

The First Step

5-(4-Trifluoromethylphenyl) isoxazole-3-carboxylic acid ethyl ester
To dry ether (60 ml) was added lithium bis(trimethylsilyl) amide solution (15 ml). The mixture was cooled to −70° C. or less and a solution of 4-trifluoromethylacetophenone (2.82 g) in ether (15 ml) was added dropwise under −65° C. for 6 minutes. The mixture was stirred at room temperature for 17 hours. Ether (100 ml) was added to the reaction solution and the mixture was cooled with ice. The deposited crystal was filtrated to give a lithium salt of pyruvate (2.9 g) as the first crystal. The filtrate was condensed, diluted with ether and cooled with ice to give the second crystal (610 mg). To this lithium salt (3.5 g) were added ethanol (35 ml) and hydroxylamine hydrochloride (1.22 g). The mixture was refluxed for 20 hours. The solvent was evaporated and water was added thereto. The mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The obtained residue was purified by column chromatograph on silica gel (eluting with ethyl acetate:hexane=1:1) to give a title compound (2.55 g) as a colorless crystal.
NMR (CDCl 3 ): 1.46 (3H, t, J=6.9 Hz), 4.49 (2H, q, J=6.9 Hz), 7.04 (1H, s), 7.77 (2H, d, J=8.7 Hz), 7.95 (2H, d, J=8.7 Hz).
The Second Step
5-(4-Trifluoromethylphenyl) isoxazole-3-yl]methanol
5-(4-Trifluoromethylphenyl)-isoxazole-3-carboxylic acid ethyl ester (1.0 g) was dissolved in methanol (15 ml). Sodium borohydride (358 mg) was added thereto under ice-cooling. After 5 minutes, the mixture was heated to room temperature and stirred for 2 hours. Hydrochloric acid (1M solution) was added to the reaction solution under 10° C. The solvent was evaporated under reduced pressure. Water was added to the residual solution and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatograph on silica gel (eluting with ethyl acetate:hexane=1:8) to give a title compound (820 mg) as a crystal.
mp; 111-113° C.
The Third Step
3-Methoxymethoxymethyl-5-(4-trifluoromethylphenyl) isoxazole
To a mixture of [5-(4-trifluoromethylphenyl) isoxazole-3-yl]methanol (21.9 g) and tetrahydrofuran (300 ml) was added sodium hydride (60%) (4.14 g) under ice-cooling. The mixture was stirred at room temperature for 1 hour. Chloromethylmethyl ether (9.42 g) was added to the reaction solution and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (eluting with ethyl acetate: n-hexane=1:4) to give a title compound (20.8 g).
NMR (CDCl 3 ): δ 3.44 (3H, s), 4.73 (2H, s), 4.76 (2H, s), 6.70 (1H, s), 7.72 (2H, d, J=8.7 Hz), 7.92 (2H, d, J=8.7 Hz)
The Fourth Step
3-Methoxymethoxymethyl-5-(4-trifluoromethylphenyl) isoxazole-4-carboxaldehyde
To a mixture of 3-methoxymethoxymethyl-5-(4-trifluoromethylphenyl) isoxazole (286 mg) and tetrahydrofuran (6 ml) was added n-butyllithium (1.6 M hexane solution) (1.56 ml) at −78° C. After stirring at −78° C. for 0.5 hour, N,N-dimethylformamide (257 mg) was added at once. After heating the reaction solution to room temperature, ice water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (eluting with ethyl acetate: n-hexane=1:5) to give a title compound (179 mg).
1 H-NMR (CDCl 3 ): δ 3.45 (3H, s), 4.81 (2H, s), 4.96 (2H, s), 7.84 (2H, d, J=8.4 Hz), 8.08 (2H, d, J=8.4 Hz), 10.14 (1H, s)
The Fifth Step
3-Methoxymethoxymethyl-5-(4-trifluoromethylphenyl) isoxazole-4-carbaldehyde ethyl oxime
A mixture of 3-methoxymethoxymethyl-5-(4-trifluoromethylphenyl) isoxazole-4-carbaldehyde (12.4 g), ethoxyamine hydrochloride (4.79 g) and tetrahydrofuran (300 ml) was stirred at 60° C. for 3 hours. The solvent was evaporated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel eluting with ethyl acetate: n-hexane (5:95) to give a title compound (10.6 g).
NMR (CDCl 3 ): δ 1.33 (3H, t, J=7.2 Hz), 3.46 (3H, s), 4.23 (2H, q, J=7.2 Hz), 4.18 (2H, s), 4.89 (2H, s), 7.77 (2H, d, J=8.4 Hz), 7.88 (2H, d, J=8.4 Hz), 8.17 (1H, s).
The Sixth Step
3-Hydroxymethyl-5-(4-trifluoromethylphenyl) isoxazole-4-carbaldehyde ethyl oxime
A mixture of 3-methoxymethoxymethyl-5-(4-trifluoromethylphenyl) isoxazole-4-carbaldehyde ethyl oxime (10.6 g), 6N hydrochloric acid (20 ml) and methanol (172 ml) was refluxed for 4.5 hours. The solvent was evaporated and water was added thereto. The mixture was extracted with ethyl acetate. The obtained residue was recrystallized from ethyl acetate/n-hexane to give a title compound (7.97 g).
TLC Rf 0.27(ethyl acetate/n-hexane, 1/4)

The Seventh Step


Methanesulfonic acid 4-(ethoxyiminomethyl)-5-(4-trifluoromethylphenyl) isoxazole-3-yl methyl ester
A mixture of 3-hydroxymethyl-5-(4-trifluoromethylphenyl) isoxazole-4-carbaldehyde ethyl oxime (7.90 g), methanesulfonic chloride (2.37 ml), triethylamine (4.23 g) and methylene chloride (200 ml) was stirred at 0° C. for 1 hour. The reaction solution was poured into ice water and the mixture was extracted with chloroform to give a title compound (9.72 g).
NMR (CDCl 3 ) δ 1.34 (3H, t, J=7.2 Hz), 3.18 (3H, s), 4.26 (2H, q, J=7.2 Hz), 5.58 (2H, s), 7.80-7.81 (4H, m), 8.17 (1H, s).
Reference 7

The First Step

3-Hydroxy methyl-5-(4-trifluoromethylphenyl) isoxazole-4-carbaldehyde
A mixture of 3-methoxymethoxymethyl-5-(4-trifluoromethylphenyl) isoxazole-4-carbaldehyde (41.8 g), 6N hydrochloric acid (60 ml) and methanol (300 ml) was refluxed for 3 hours. The solvent was evaporated and water was added thereto. The mixture was extracted with ethyl acetate. The obtained crude product was purified by column chromatograph on silica gel to give a title compound (21.1 g).
TLC Rf 0.25(ethyl acetate/n-hexane, 1/2)

The Second Step


Methanesulfonic acid 4-formyl-5-(4-trifluoromethylphenyl) isoxazole-3-yl methyl ester
3-Hydroxymethyl-5-(4-trifluoromethylphenyl) isoxazole-4-carboxaldehyde (21.0 g), methanesulfonyl chloride (6.6 ml) and triethylamine (13 ml) were dissolved in methylene chloride (300 ml) and the mixture was stirred at 0° C. for 5 hours. Water and 2N hydrochloric acid were added thereto and the mixture was extracted with chloroform. The obtained crude product was recrystallized from ethyl acetate/diisopropylether to give a title compound (25.8 g).
TLC Rf 0.37 (toluene/ethyl acetate, 6/1)
Example 1
{3-[4-(Ethoxyiminomethyl-5-(4-trifluoromethylphenyl) isoxazole-3-yl methoxy]phenyl}acetic acid

The First Step

{3-[4-(Ethoxyiminomethyl-5-(4-trifluoromethylphenyl) isoxazole-3-yl methoxy]phenyl}acetic acid methyl ester
To a solution of (5-methyl-3-hydroxyphenyl)acetic acid methyl ester (100 mg) in acetonitrile (2 ml) were added methanesulfonic acid 4-(ethoxyiminomethyl)-5-(4-trifluoromethylphenyl) isoxazole-3-yl methyl ester (218 mg) and cesium carbonate (217 mg). The mixture was stirred at 60° C. for 30 minutes. The reaction solution was filtrated and the filtrate was evaporated under reduced pressure. The obtained residue was purified by column chromatograph on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (264 mg). The yield was 100%.
1 H-NMR (CDCl 3 ) δ: 1.24 (3H, t, J=6.6 Hz), 2.32 (3H, s), 3.57 (2H, s), 3.69 (3H, s), 4.10 (2H, q, J=6.6 Hz), 5.33 (2H, s), 6.74 (1H, s), 6.76 (2H, s), 7.77 (2H, d, J=8.4 Hz), 7.90 (2H, d, J=8.4 Hz), 8.19 (1H, s).
The Second Step
{3-[4-(Ethoxyiminomethyl-5-(4-trifluoromethylphenyl) isoxazole-3-yl methoxy]phenyl}acetic acid
To a solution of {3-[4-(ethoxyiminomethyl-5-(4-trifluoromethylphenyl) isoxazole-3-yl methoxy]phenyl}acetic acid methyl ester (263 mg) in tetrahydrofuran (2.5 ml)-methanol (2.5 ml) was added 2N sodium hydroxide solution (0.55 ml). The mixture was stirred at room temperature for 1 hour. Hydrochloric acid (2N solution, 0.6 ml) and water (2 ml) were added to the reaction solution and the mixture was stirred under ice-cooling. Water (8 ml) was added thereto. The precipitate was collected, washed with water and dried to give a title compound (217 mg). The yield was 85%.
1 H-NMR (CDCl 3 ) δ: 1.23 (3H, t, J=7.0 Hz), 2.33 (3H, s), 3.60 (2H, s), 4.09 (2H, q, J=7.0 Hz), 5.33 (2H, s), 6.75 (1H, s), 6.77 (2H, s), 7.77 (2H, d, J=8.4 Hz), 7.90 (2H, d, J=8.4 Hz), 8.19 (1H, s).
Example 2
{3-[4-(2-Fluoroethoxyiminomethyl)-5-(4-trifluoromethylphenyl) isoxazole-3-yl methoxy]phenyl}acetic acid

The First Step

{3-[4-Formyl-5-(4-trifluoromethylphenyl) isoxazole-3-yl methyl sulfanyl]phenyl}acetic acid methyl ester
To a solution of (3-mercaptophenyl)acetic acid methyl ester (8.00 g) in acetonitrile (200 ml) were added methanesulfonic acid 4-formyl-5-(4-trifluoromethylphenyl) isoxazole-3-yl methyl ester (5.42 g) and cesium carbonate (9.70 g). The mixture was stirred at room temperature for 17 hours. The reaction solution was evaporated under reduced pressure and 2N hydrochloric acid (140 ml) was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatograph on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (1.86 g). The yield was 19%.
1 H-NMR (CDCl 3 ) δ: 3.59 (2H, s), 3.68 (3H, s), 4.40 (2H, s), 7.14-7.38 (4H, m), 7.84 (2H, d, J=8.4 Hz), 8.01 (2H, d, J=8.4 Hz), 10.12 (1H, s).
The Second Step
{3-[4-(2-Fluoroethoxyiminomethyl)-5-(4-trifluoromethylphenyl) isoxazole-3-yl methyl sulfanyl]phenyl}acetic acid methyl ester
A solution of {3-[4-formyl-5-(4-trifluoromethylphenyl) isoxazole-3-yl methyl sulfanyl]phenyl}acetic acid methyl ester (269 mg) and O-(2-fluoroethyl)-hydroxylamine hydrochloride (143 mg) in tetrahydrofuran (10 ml) was stirred at room temperature for 24 hours. The saturated sodium hydrogencarbonate solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatograph on silica gel (eluting with the mixed solvent of ethyl acetate-hexane) to give a title compound (249 mg). The yield was 81%.
1 H-NMR (CDCl 3 ) δ: 3.59 (2H, s), 3.69 (3H, s), 4.32-4.80 (4H, m), 4.37 (2H, s), 7.12-7.37 (4H, m), 7.77 (2H, d, J=8.4 Hz), 7.82 (2H, d, J=8.4 Hz), 8.26 (1H, s).
The Third Step
{3-[4-(2-Fluoroethoxyiminomethyl)-5-(4-trifluoromethylphenyl) isoxazole-3-yl methyl sulfanyl]phenyl}acetic acid
To a solution of {3-[4-(2-fluoroethoxyiminomethyl)-5-(4-trifluoromethylphenyl) isoxazole-3-yl methylsulfanyl]phenyl}acetic acid methyl ester (247 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) was added 4N lithium hydroxide solution (0.37 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. Citric acid solution (0.5 M) was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from hexane to give a title compound (220 mg). The yield was 92%.
1 H-NMR (CDCl 3 ) δ: 3.62 (2H, s), 4.32-4.79 (4H, m), 4.37 (2H, s), 7.12-7.38 (4H, m), 7.76 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.1 Hz), 8.25 (1H, s).
The present invention includes the following compounds synthesized in a similar way as above.





TABLE 77























No
R1
R2
R3, R4
X1
Y
1H-NMR(CDCl3 or DMSO-d6) δ



X-1









Me
H, H
O









2.32(3H, s), 3.65(2H, s), 5.19(2H, s), 6.92-7.32(4H, m), 7.75(2H, d, J = 8.4 Hz), 7.84(2H, d, J = 8.4 Hz)



X-2









CH2OEt
H, H
O









1.22(3H, t, J = 6.9 Hz), 3.58(2H, q, J = 6.9 Hz), 3.65(2H, s), 4.55(2H, s), 5.25(2H, s), 6.90-7.32(4H, m), 7.76(2H, d, J = 8.7 Hz), 7.94(2H, d, J = 8.7 Hz)



X-3









CH2OCH2cPr
H, H
O









0.10-0.15(2H, m), 0.39-0.45(2H, m), 0.94-1.05(1H, m), 3.31(2H, d, J = 6.9 Hz), 3.55(2H, s), 4.57(2H, s), 5.28(2H, s), 6.90(1H, d, J = 7.8 Hz), 6.97-6.99(2H, m), 7.24-7.30(1H, m), 7.97(2H, d, J = 8.4 Hz), 8.06(2H, d, J = 8.24 Hz), 12.33(1H, s)



X-4









CH═NOEt
H, H
O









1.21(3H, t, J = 7.1 Hz), 3.64(2H, s), 4.07(2H, q, J = 7.1 Hz), 5.35(2H, s), 6.90-7.31(4H, m), 7.77(2H, d, J = 8.4 Hz), 7.90(2H, d, J = 8.4 Hz), 8.19(1H, s)



X-5









Me
H, H
S









2.51(3H, s), 3.62(2H, s), 4.15(2H, s), 7.12-7.36(4H, m), 7.73(2H, d, J = 8.1 Hz), 7.80(2H, d, J = 8.1 Hz)



X-6









CH═NOCH2CH2F
H,H
S









3.62(2H, s), 4.32-4.79(4H, m), 4.37(2H, s), 7.12-7.38(4H, m), 7.76(2H, d, J = 8.1 Hz), 7.81(2H, d, J = 8.1 Hz), 8.25(1H, s)



X-7









CH═NOEt
H, H
O









1.22(3H, t, J = 7.1 Hz), 3.62(2H, s), 4.07 (2H, q, J = 7.1 Hz), 5.42(2H, s), 6.86-7.10 (3H, m), 7.77(2H, d, J = 8.4 Hz), 7.88(2H, d, J = 8.4 Hz), 8.19(1H, s)



X-8









CH═NOEt
H, H
S









1.34(3H, t, J = 6.9 Hz), 3.59(2H, s), 4.27 (2H, q, J = 6.9 Hz), 4.35(2H, s), 7.03(1H, t, J = 8.7 Hz), 7.14-7.22(3H, m), 7.38(1H, dd, J = 2.4, 6.9 Hz), 7.75(2H, d, J = 8.4 Hz), 7.81(2H, d, J = 8.4 Hz), 8.17(1H, s)



X-9









CH═NOEt
H, H
O









8.22(s, 1H), 7.90(d, 2H, J = 8.4 Hz), 7.77(d, 2H, J = 8.4 Hz), 7.34(d, 1H, J = 8.1 Hz), 7.04(d, 1H, J = 1.8 Hz), 6.88(dd, 1H, J = 8.1, 1.8 Hz), 5.42(s, H), 4.07(q, 2H, J = 6.9 Hz), 3.64(s, 2H), 1.22(t, 3H, J = 6.9 Hz)



X-10









CH═NOEt
H, H
O









1.24(3H, t, J = 7.0 Hz), 3.59(2H, s), 4.10 (2H, q, J = 7.0 Hz), 5.39(2H, s), 6.85-7.00(3H, m), 7.76(2H, d, J = 8.4 Hz), 7.92(2H, d, J = 8.4 Hz), 8.24(1H, s)



X-11









CH═NOEt
H, H
O









1.23(3H, t, J = 7.0 Hz), 2.33(3H, s), 3.60 (2H, s), 4.09(2H, q, J = 7.0 Hz), 5.33 (2H, s), 6.75(1H, s), 6.77(2H, s), 7.77(2H, d, J = 8.4 Hz), 7.90(2H, d, J = 8.4 Hz), 8.19(1H, s)



X-12









CH═NOEt
H, H
O









2.32(3H, s), 3.61(2H, s), 3.79(3H, s), 5.16(2H, s), 6.48-6.60(4H, m), 7.75(2H, d, J = 8.4 Hz), 7.84(2H, d, J = 8.4 Hz)



X-13









CH═NOEt
H, H
O









8.18(s, 1H), 7.87(d, 2H, J = 8.7 Hz), 7.78(d, 2H, J = 8.7 Hz), 7.32(d, 1H, J = 9.0 Hz), 6.99(d, 1H, 2.7 Hz), 6.92(dd, 1H, J = 9.0, 2.7 Hz), 5.34(s, 2H), 4.09(q, 2H, J = 6.9 Hz), 3.79(s, 2H), 1.23(t, 3H, 6.9 Hz)



















































TABLE 78





























1H-NMR(CDCl3 or DMSO-d6)

No
R1
R2
R3, R4
X1
Y
δ



X-14









CH═NOEt
H, H
O









1.21(3H, t, J = 7.2 Hz), 2.21 (3H, s), 3.70(2H, s), 4.06(2H, q, J =7.2 Hz), 5.35(2H, s), 6.35-7.20(3H, m), 7.77(2H, d, J = 8.4 Hz), 7.91(2H, d, J = 8.4 Hz), 8.19(1H, s)



Y-1









Me
H, H
—ON═CH—









2.33(3H, s), 3.67(2H, s), 5.31 (2H, s), 7.29-7.37(2H, m), 7.48-7.52(2H, m), 7.74(2H, d, J = 8.4 Hz), 7.84(2H, d, J = 8.4 Hz), 8.11(1H, s)



X-82









CH═NOnPr
H, H
S









0.91(3H, t, J = 7.2 Hz), 1.68 (2H, m), 3.59(2H, s), 4.06(2H, t, J = 6.8 Hz), 4.53(2H, s), 7.21 (1H, s), 7.25(1H, s), 7.43(1H, s), 7.93(2H, d, J = 8.4 Hz), 8.03(2H, d, J = 8.3 Hz), 8.36(1 Hz, s), 12.55(1H, brs)



X-97









CH═NOCH2CH2F
H, H
S









3.55(2H, s), 4.28(1H, t, J = 3.0 Hz), 4.36(1H, t, J = 3.0 Hz), 4.57(2H, s), 4.61(1H, t, J = 3.0 Hz), 4.73(1H, t, J = 3.0 Hz), 7.12-7.13(2H, m), 7.27-7.30 (2H, m), 7.64(2H, d, J = 6.3 Hz), 7.83(2H, d, J = 6.3 Hz), 8.38(1H, s), 12.30(1H, br)



X-104









CH═NOCH2CH2F
H, H
O









2.10(3H, s), 3.52(2H, s), 4.27 (1H, t, J = 3.0 Hz), 4.08(1H, t, J = 3.0 Hz), 4.15(1H, t, J = 3.0 Hz), 4.54(1H, t, J = 3.0 Hz), 5.33(2H, s), 6.78(1H, d, J = 6.0 Hz), 7.00(1H, s), 7.08(1H, d, J = 6.0 Hz), 7.66(2H, d, J = 6.3 Hz), 7.89(2H, d, J = 6.3 Hz), 8.37(1H, s), 12.30(1H, br)



X-111









CH═NOCH2CH2F
H, H
S









2.24(3H, s), 3.51(2H, s), 4.27 (1H, t, J = 3.0 Hz), 4.35(1H, t, J = 3.0 Hz), 4.39(2H, s), 4.59 (1H, t, J = 3.0 Hz), 4.71(1H, t, J = 3.0 Hz), 7.04(1H, d, J = 6.0 Hz), 7.16(1H, d, J = 6.0 Hz), 7.34(1H, s), 7.64(2H, d, J = 6.3 Hz), 7.83(2H, d, J = 6.3 Hz), 8.37(1H, s), 12.30(1H, br)



X-184









CH2OCH2cPr
H, H
O









0.098(2H, m), 0.40(2H, m), 0.97(1H, m), 3.30(2H, d, J = 4.4 Hz), 3.61(2H, s), 4.61(2H, s), 5.36(2H, s), 6.94(1H, d, J = 8.2 Hz), 7.30(1H, s), 7.40(1H, d, J = 8.2 Hz), 7.60(2H, d, J = 8.2 Hz), 7.98(2H, d, J = 8.2 Hz), 12.44(1H, brs)



X-186









CH═NOEt
H, H
O









1.21(3H, t, J = 7.2 Hz), 3.64 (2H, S), 4.05(2H, q, J = 7.2 Hz), 5.41(2H, s), 6.87(1H, dd, J = 1.5 Hz, 7.8 Hz), 7.03(1H, d, J = 1.5 Hz), 7.34(1H, d, J = 7.8 Hz), 7.35(2H, d, J = 8.7 Hz), 7.81(2H, d, J = 8.7 Hz), 8.20 (1H, s)



X-208









CH═NOnPr
H, H
S









0.91(3H, t, J = 7.2 Hz), 1.68 (2H, m), 3.59(2H, s), 4.05(2H, t, J = 6.8 Hz), 4.51(2H, s), 7.20 (1H, s), 7.24(1H, s), 7.42(1H, s), 7.56(2H, d, J = 8.4 Hz), 7.95(2H, d, J = 8.8 Hz), 8.32 (1 Hz, s), 12.50(1H, brs)



X-216









CH═NOCH2CH2F
H, H
O









3.61(2H, s), 4.16(1H, t, J = 4.1 Hz), 4.26(1H, t, J = 4.1 Hz), 4.46(1H, t, J = 4.1 Hz), 4.61 (1H, t, J = 4.1 Hz), 5.31(2H, s), 6.97-6.84(3H, m), 7.37(2H, d, J = 8.7 Hz), 7.77(2H, d, J = 8.7 Hz), 8.24(1H, s)














































TABLE 79























No
R1
R2
R3, R4
X1
Y




X-224









CH═NOEt
H, H
S









(1H-NMR, acetone-d6) 8.10(s, 1H), 7.87 (d, 2H, J = 9.0 Hz), 7.75(d, 2H, J = 8.1 Hz), 6.16 (s, 1H), 4.08(s, 2H), 4.02(q, 2H, J = 7.2 Hz), 3.54(s, 3H), 3.35(s, 2H), 1.12(t, 3H, 7.2 Hz)



X-225









CH2OcBu
H, H
S









(1H-NMR, DMSO-d6) 1.43-1.52(1H, m), 1.60-1.70(1H, m), 1.82-1.92(2H, m), 2.10-2.15(2H, m), 3.55(2H, s), 3.99-4.10(1H, m), 4.36(2H, s), 4.44(2H, s), 7.14(1H, d, J = 5.4 Hz), 7.27-7.35(3H, m), 7.94-8.01(4H, m), 12.35(1H, br)



X-226









CH2OcBu
H, H
O









(1H-NMR, DMSO-d6) 1.37-1.46(1H, m), 1.53-1.60(1H, m), 1.75-1.85(2H, m), 1.93-2.08(2H, m), 3.61(2H, s), 3.98-4.05(1H, m), 4.52(2H, s), 5.36 (2H, s), 6.93(1H, d, J = 6.3 Hz), 7.30(1H, s), 7.39- 7.41(1H, d, J = 6.3 Hz), 7.97(2H, d, J = 6.3 Hz), 8.05(2H, d, J = 6.3 Hz), 12.41(1H, br)



X-227









CH2OcBu
H, H
S









(1H-NMR, DMSO-d6) 1.40-1.52(1H, m), 1.60-1.70(1H, m), 1.82-1.92(2H, m), 2.10-2.15(2H, m), 2.26(3H, s), 2.50(2H, s), 3.55(2H, s), 3.99-4.06(1H, m), 4.34(2H, s), 4.43(2H, s), 6.95(1H, s), 7.11(1H, s), 7.16(1H, s), 7.95(2H, d, J = 6.3 Hz), 7.99(2H, d, J = 6.3 Hz), 12.35(1H, br)



X-228









CH2OcBu
H, H
S









(1H-NMR, DMSO-d6) 1.40-2.20(6H, m), 3.58(2H, s), 3.97-4.12(1H, m), 4.42(2H, s), 4.42(2H, s), 7.18-7.47(3H, m), 7.58(2H, d, J = 8.7 Hz), 7.90(2H, d, J = 8.7 Hz)



X-229









CH2OcBu
H, H
S









(1H-NMR, CDCl3) 1.50-2.30(6H, m), 3.60(2H, s), 3.98-4.10(1H, m), 4.25(2H, s), 4.44(2H, s), 7.12-7.35(3H, m), 7.75(2H, d, J = 8.4 Hz), 7.86(2H, d, J = 8.4 Hz)



X-230









CH2OCH2cPr
H,H
O









(1H-NMR, CDCl3) 0.15-0.20(2H, m), 0.50-0.56(2H, m), 1.06(1H, m), 3.38(2H, d, J = 7.2 Hz), 4.59(2H, s), 5.28(2H, s), 7.14(1H, d, J = 8.1 Hz), 7.26-7.27(2H, m), 7.39(1H, t, J = 8.1 Hz), 7.76(2H, d, J = 8.1 Hz), 7.93(2H, d, J = 8.1 Hz)



X-231









CH═NOEt
H, H
S









(1H-NMR, CDCl3) 1.35(3H, t, J = 7.2 Hz), 4.24(2H, q, J = 7.2H), 4.41(2H, s), 7.39(1H, t, J = 7.8 Hz), 7.48(1H, d, J = 7.8 Hz), 7.59(1H, d, J = 7.8 Hz), 7.63(1H, s), 7.75(2H, d, J = 8.4 Hz), 7.80(2H, d, J = 8.4 Hz), 8.19(1H, s)



X-232









CH2OcBu
H, H
O









(1H-NMR, DMSO-d6) 1.35-1.61(2H, m), 1.76-1.85(2H, m), 2.00-2.09(2H, m), 3.59(2H, s), 3.96-4.05(1H, m), 4.49(2H, s), 5.34(2H, s), 6.93(1H, dd, J = 8.1 Hz, 1.5 Hz), 7.29(1H, d, J = 1.5 Hz), 7.40(1H, d, J = 8.1 Hz), 7.61(2H, d, J = 8.4 Hz), 7.96(2H, d, J = 8.4 Hz), 12.45(1H, s)



X-233









CH2OcBu
H, H
S









(1H-NMR, DMSO-d6) 1.41-1.68(2H, m), 1.80-1.93(2H, m), 2.08-2.16(2H, m), 3.55(2H, s), 3.97-4.07(1H, m), 4.34(2H, s), 4.41(2H, s), 7.13(1H, d, J = 7.2 Hz), 7.26-7.34(3H, m), 7.58(2H, d, J = 8.4 Hz), 7.90(2H, d, J = 8.4 Hz), 12.35(1H, s)













































TABLE 80























No
R1
R2
R3, R4
X1
Y




X-234









CH2OcBu
H, H
S









(1H-NMR, DMSO-d6) 1.41-1.68(2H, m), 1.81 -1.94(2H, m), 2.08-2.16(2H, m), 3.58(2H, s), 3.99-4.09(1H, m), 4.40(2H, s), 4.43(2H, s), 7.15(1H, d, J = 8.1 Hz), 7.43(1H, d, J = 8.1 hZ), 7.49(1H, s), 7.59(2H, d, J = 9.0 Hz), 7.91(2H, d, J = 9.0 Hz), 12.43(1H, s)



X-235









CH2OcBu
H, H
O









(1H-NMR, DMSO-d6) 1.37-1.64(2H, m), 1.75-1.84(2H, m), 2.04-2.11(2H, m), 3.55(2H, s), 3.96-4.05(1H, m), 4.44(2H, s), 5.26(2H, s), 6.89-6.97(3H, m), 7.27(1H, t, J = 7.8 Hz), 7.61(2H, d, J = 9.0 Hz), 7.95(2H, d, J = 9.0 Hz), 12.33(1H, s)



X-236









CH2OcBu
H, H
S









(1H-NMR, DMSO-d6) 1.41-1.68(2H, m), 1.80-1.93(2H, m), 2.07-2.16(2H, m), 2.27(3H, s), 3.51(2H, s), 3.97-4.06(1H, m), 4.28(2H, s), 4.38(2H, s), 7.06(1H, d, J = 7.8 Hz), 7.17(1H, d, J = 7.8 Hz), 7.37(1H, s), 7.59(2H, d, J = 8.7 Hz), 7.90(2H, d, J = 8.7 Hz), 12.33(1H, s)



X-237









CH2OcBu
H, H
O









(1H-NMR, DMSO-d6) 1.36-1.63(2H, m), 1.77-1.83(2H, m), 2.06-2.14(2H, m), 3.53(2H, s), 3.97-4.02(1H, m), 4.45(2H, s), 5.24(2H, s), 6.80(1H, d, J = 7.8 Hz), 7.06(1H, s), 7.10(1H, d, J = 7.8 Hz), 7.62(2H, d, J = 8.4 Hz), 7.96(2H, d, J = 8.4 Hz), 12.28(1H, s)



Z-1









CH2OCH2cPr
H, H
S









(1H NMR, CDCl3) 7.65(1H, dt, J = 7.8, 0.6), 7.54(1H, dd, J = 8.1, 0.6), 7.38(1H, dt, 7.2, 1.2), 7.29(1H, dt, J = 7.8, 1.2), 7.14(2H, d, J = 9.6), 6.94(1H, s), 5.86(2H, s), 4.27 (2H, s), 3.55(2H, s), 3.37(2H, d, J = 6.9), 2.30(3H, s), 1.3-1.8(1H, m), 0.55(2H, dt, J = 6.0, 4.5), 0.22(2H, dt, J = 6, 4.8)



































TABLE 81























No
R1
R2
X1
R3, R4
Y
m/z



X-15









CH═NOCH2CH2Cl
S
H, H









497[M − H]−



X-16


















S
H, H









597[M + H]−



X-17









CH═NOEt
O
H, H









463[M + H]+



X-18









CH═NOEt
O
H, H









467(M + 1)



X-19









CH═NOEt
O
H, H









467(M + 1)



X-20









CH═NOEt
O
H, H









467[M + H]+



X-21









CH═NOEt
O
H, H









479(M + 1)







































TABLE 82























No
R1
R2
R3, R4
X1
Y
TLC Rf



X-22









CH2OCH2cPr
H, H
S









0.58 (AcOEt)



X-23









CH2ON═C(CH3)2
H, H
S









0.54 (AcOEt)





























TABLE 83























No
R1
R2
R3, R4
X1
Y
mp



X-24









CH2OEt
H, H
S









94-95



X-25









CH═NOEt
H, H
S









131-133



X-81









CH═NOEt
H, H
S









132-134



X-173









CH═NOnPr
H, H
O









128-130



X-221









CH═NOEt
H, H
S









113-115



X-223









CH═NOCH2CH2F
H, H
S









120-122



Z-2









CH═NOEt
H, H
S









158-160



Z-3









CH═NOEt
H, H
S









143-146









































TABLE 84






















No
R1
R2
R3, R4
X1
Y



X-26









CH═NOMe
H, H
O












X-27









CH═NOnPr
H, H
O












X-28









CH═NOCH2CH2F
H, H
O












X-29









CH═NOMe
H, H
S












X-30









CH═NOnPr
H, H
S












X-31









Me
H, H
O












X-32









CH2OEt
H, H
O












X-33









CH2OCH2cPr
H, H
O












X-34









CH═NOMe
H, H
O












X-35









CH═NOnPr
H, H
O












X-36









CH═NOCH2CH2F
H, H
O












X-37









Me
H, H
S












X-38









CH2OEt
H, H
S












X-39









CH2OCH2cPr
H, H
S












X-40









CH═NOMe
H, H
S












X-41









CH═NOEt
H, H
S












X-42









CH═NOnPr
H, H
S












X-43









CH═NOCH2CH2F
H, H
S












X-44









Me
H, H
O












X-45









CH2OEt
H, H
O












X-46









CH2OCH2cPr
H, H
O












X-47









CH═NOMe
H, H
O














































































TABLE 85






















No
R1
R2
R3, R4
X1
Y



X-48









CH═NOnPr
H, H
O












X-49









CH═NOCH2CH2F
H, H
O












X-50









Me
H, H
S












X-51









CH2OEt
H, H
S












X-52









CH2OCH2cPr
H, H
S












X-53









CH═NOMe
H, H
S












X-54









CH═NOEt
H, H
S












X-55









CH═NOnPr
H, H
S












X-56









CH═NOCH2CH2F
H, H
S












X-57









Me
H, H
O












X-58









CH2OEt
H, H
O












X-59









CH2OCH2cPr
H, H
O












X-60









CH═NOMe
H, H
O












X-61









CH═NOnPr
H, H
O












X-62









CH═NOCH2CH2F
H, H
O












X-63









Me
H, H
S












X-64









CH2OEt
H, H
S












X-65









CH2OCH2cPr
H, H
S












X-66









CH═NOMe
H, H
S








































































TABLE 86






















No
R1
R2
R3, R4
X1
Y



X-67









CH═NOEt
H, H
S












X-68









CH═NOnPr
H, H
S












X-69









CH═NOCH2CH2F
H, H
S












X-70









Me
H, H
O












X-71









CH2OEt
H, H
O












X-72









CH2OCH2cPr
H, H
O












X-73









CH═NOMe
H, H
O












X-74









CH═NOEt
H, H
O












X-75









CH═NOnPr
H, H
O












X-76









CH═NOCH2CH2F
H, H
O












X-77









Me
H, H
S












X-78









CH2OEt
H, H
S












X-79









CH2OCH2cPr
H, H
S












X-80









CH═NOMe
H, H
S












X-83









CH═NOCH2CH2F
H, H
S












X-84









Me
H, H
O


































































TABLE 87






















No
R1
R2
R3, R4
X1
Y



X-85









CH2OEt
H, H
O












X-86









CH2OCH2cPr
H, H
O












X-87









CH═NOMe
H, H
O












X-88









CH═NOEt
H, H
O












X-89









CH═NOnPr
H, H
O












X-90









CH═NOCH2CH2F
H, H
O












X-91









Me
H, H
S












X-92









CH2OEt
H, H
S












X-93









CH2OCH2cPr
H, H
S












X-94









CH═NOMe
H, H
S












X-95









CH═NOEt
H, H
S












X-96









CH═NOnPr
H, H
S












X-98









Me
H, H
O












X-99









CH2OEt
H, H
O












X-100









CH2OCH2cPr
H, H
O












X-101









CH═NOMe
H, H
O












X-102









CH═NOEt
H, H
O












X-103









CH═NOnPr
H, H
O












X-105









Me
H, H
S












X-106









CH2OEt
H, H
S












X-107









CH2OCH2cPr
H, H
S












X-108









CH═NOMe
H, H
S














































































TABLE 88






















No
R1
R2
R3, R4
X1
Y



X-109









CH═NOEt
H, H
S












X-110









CH═NOnPr
H, H
S












X-112









Me
H, H
O












X-113









CH2OEt
H, H
O












X-114









CH2OCH2cPr
H, H
O












X-115









CH═NOMe
H, H
O












X-116









CH═NOEt
H, H
O












X-117









CH═NOnPr
H, H
O












X-118









CH═NOCH2CH2F
H, H
O












X-119









Me
H, H
S












X-120









CH2OEt
H, H
S












X-121









CH2OCH2cPr
H, H
S












X-122









CH═NOMe
H, H
S












X-123









CH═NOEt
H, H
S












X-124









CH═NOnPr
H, H
S












X-125









CH═NOCH2CH2F
H, H
S












X-126









Me
H, H
O












X-127









CH2OEt
H, H
O












X-128









CH2OCH2cPr
H, H
O












X-129









CH═NOMe
H, H
O












X-130









CH═NOEt
H, H
O












































































TABLE 89






















No
R1
R2
R3, R4
X1
Y



X-131









CH═NOnPr
H, H
O












X-132









CH═NOCH2CH2F
H, H
O












X-133









Me
H, H
S












X-134









CH2OEt
H, H
S












X-135









CH2OCH2cPr
H, H
S












X-136









CH═NOMe
H, H
S












X-137









CH═NOEt
H, H
S












X-138









CH═NOnPr
H, H
S












X-139









CH═NOCH2CH2F
H, H
S












X-140









Me
H, H
O












X-141









CH2OEt
H, H
O












X-142









CH2OCH2cPr
H, H
O












X-143









CH═NOMe
H, H
O












X-144









CH═NOEt
H, H
O












X-145









CH═NOnPr
H, H
O












X-146









CH═NOCH2CH2F
H, H
O












X-147









Me
H, H
S












X-148









CH2OEt
H, H
S






































































TABLE 90






















No
R1
R2
R3, R4
X1
Y



X-149









CH2OCH2cPr
H, H
S












X-150









CH═NOMe
H, H
S












X-151









CH═NOEt
H, H
S












X-152









CH═NOnPr
H, H
S












X-153









CH═NOCH2CH2F
H, H
S












X-154









Me
H, H
O












X-155









CH2OEt
H, H
O












X-156









CH2OCH2cPr
H, H
O












X-157









CH═NOMe
H, H
O












X-158









CH═NOEt
H, H
O












X-159









CH═NOnPr
H, H
O












X-160









CH═NOCH2CH2F
H, H
O












X-161









Me
H, H
S












X-162









CH2OEt
H, H
S












X-163









CH2OCH2cPr
H, H
S












X-164









CH═NOMe
H, H
S












X-165









CH═NOEt
H, H
S












X-166









CH═NOnPr
H, H
S












X-167









CH═NOCH2CH2F
H, H
S












X-168









Me
H, H
O












X-169









CH2OEt
H, H
O












X-170









CH2OCH2cPr
H, H
O














































































TABLE 91






















No
R1
R2
R3, R4
X1
Y



X-171









CH═NOMe
H, H
O












X-172









CH═NOEt
H, H
O












X-174









CH═NOCH2CH2F
H, H
O












X-175









Me
H, H
S












X-176









CH2OEt
H, H
S












X-177









CH2OCH2cPr
H, H
S












X-178









CH═NOMe
H, H
S












X-179









CH═NOEt
H, H
S












X-180









CH═NOnPr
H, H
S












X-181









CH═NOCH2CH2F
H, H
S












X-182









Me
H, H
O












X-183









CH2OEt
H, H
O












X-185









CH═NOMe
H, H
O












X-187









CH═NOnPr
H, H
O












X-188









CH═NOCH2CH2F
H, H
O












X-189









Me
H, H
S












X-190









CH2OEt
H, H
S












X-191









CH2OCH2cPr
H, H
S












X-192









CH═NOMe
H, H
S












X-193









CH═NOEt
H, H
S












X-194









CH═NOnPr
H, H
S












X-195









CH═NOCH2CH2F
H, H
S














































































TABLE 92






















No
R1
R2
R3, R4
X1
Y



X-196









Me
H, H
O












X-197









CH2OEt
H, H
O












X-198









CH2OCH2cPr
H, H
O












X-199









CH═NOMe
H, H
O












X-200









CH═NOEt
H, H
O












X-201









CH═NOnPr
H, H
O












X-202









CH═NOCH2CH2F
H, H
O












X-203









Me
H, H
S












X-204









CH2OEt
H, H
S












X-205









CH2OCH2cPr
H, H
S












X-206









CH═NOMe
H, H
S












X-207









CH═NOEt
H, H
S












X-209









CH═NOCH2CH2F
H, H
S












X-210









Me
H, H
O












X-211









CH2OEt
H, H
O












X-212









CH2OCH2cPr
H, H
O












X-213









CH═NOMe
H, H
O












X-214









CH═NOEt
H, H
O






































































TABLE 93






















No
R1
R2
R3, R4
X1
Y



X-215









CH═NOnPr
H, H
O












X-217









Me
H, H
S












X-218









CH2OEt
H, H
S












X-219









CH2OCH2cPr
H, H
S












X-220









CH═NOMe
H, H
S












X-222









CH═NOnPr
H, H
S














































TABLE 94






















No
R1
R2
R3, R4
X1
Y



Y-2









CH2OEt
H, H
—ON═CH—












Y-3









CH2OCH2cPr
H, H
—ON═CH—












Y-4









CH═NOMe
H, H
—ON═CH—












Y-5









CH═NOEt
H, H
—ON═CH—












Y-6









CH═NOnPr
H, H
—ON═CH—












Y-7









CH═NOCH2CH2F
H, H
—ON═CH—












Y-8









Me
H, H
—ON═CH—












Y-9









CH2OEt
H, H
—ON═CH—












Y-10









CH2OCH2cPr
H, H
—ON═CH—












Y-11









CH═NOMe
H, H
—ON═CH—












Y-12









CH═NOEt
H, H
—ON═CH—












Y-13









CH═NOnPr
H, H
—ON═CH—












Y-14









CH═NOCH2CH2F
H, H
—ON═CH—












Y-15









CH═NOEt
H, H
—ON═CH—












Y-16









Me
H, H
—ON═CH—












Y-17









CH2OEt
H, H
—ON═CH—












Y-18









CH2OCH2cPr
H, H
—ON═CH—












Y-19









CH═NOMe
H, H
—ON═CH—












Y-20









CH═NOEt
H, H
—ON═CH—












Y-21









CH═NOnPr
H, H
—ON═CH—












Y-22









CH═NOCH2CH2F
H, H
—ON═CH—












Y-23









CH═NOEt
H, H
—ON═CH—














































































TABLE 95






















No
R1
R2
X1
R3, R4
Y



Y-24









Me
—ON═CH—
H, H












Y-25









CH2OEt
—ON═CH—
H, H












Y-26









CH2OCH2cPr
—ON═CH—
H, H












Y-27









CH═NOMe
—ON═CH—
H, H












Y-28









CH═NOEt
—ON═CH—
H, H












Y-29









CH═NOnPr
—ON═CH—
H, H












Y-30









CH═NOCH2CH2F
—ON═CH—
H, H












Y-31









CH═NOEt
—ON═CH—
H, H












Y-32









Me
—ON═CH—
H, H












Y-33









CH2OEt
—ON═CH—
H, H












Y-34









CH2OCH2cPr
—ON═CH—
H, H












Y-35









CH═NOMe
—ON═CH—
H, H












Y-36









CH═NOEt
—ON═CH—
H, H












Y-37









CH═NOnPr
—ON═CH—
H, H












Y-38









CH═NOCH2CH2F
—ON═CH—
H, H












Y-39









CH═NOEt
—ON═CH—
H, H












Y-40









CH═NOEt
—ON═CH—
H, H




































































TABLE 96






















No
R1
R2
R3, R4
X1
Y



Y-41









CH═NOEt
H, H
—ON═CH—












Y-42









CH═NOEt
H, H
—ON═CH—












Y-43









CH═NOEt
H, H
—ON═CH—












Y-44









CH═NOEt
H, H
—ON═CH—












Y-45









Me
H, H
—ON═CH—












Y-46









CH2OEt
H, H
—ON═CH—












Y-47









CH2OCH2cPr
H, H
—ON═CH—












Y-48









CH═NOMe
H, H
—ON═CH—












Y-49









CH═NOEt
H, H
—ON═CH—












Y-50









CH═NOnPr
H, H
—ON═CH—












Y-51









CH═NOCH2CH2F
H, H
—ON═CH—












Y-52









Me
H, H
—ON═CH—












Y-53









CH2OEt
H, H
—ON═CH—












Y-54









CH2OCH2cPr
H, H
—ON═CH—












Y-55









CH═NOMe
H, H
—ON═CH—












Y-56









CH═NOEt
H, H
—ON═CH—












Y-57









CH═NOnPr
H, H
—ON═CH—












Y-58









CH═NOCH2CH2F
H, H
—ON═CH—












Y-59









Me
H, H
—ON═CH—












Y-60









CH2OEt
H, H
—ON═CH—












Y-61









CH2OCH2cPr
H, H
—ON═CH—












































































TABLE 97






















No
R1
R2
R3, R4
X1
Y



Y-62









CH═NOMe
H, H
—ON═CH—












Y-63









CH═NOEt
H, H
—ON═CH—












Y-64









CH═NOnPr
H, H
—ON═CH—












Y-65









CH═NOCH2CH2F
H, H
—ON═CH—












Y-66









Me
H, H
—ON═CH—












Y-67









CH2OEt
H, H
—ON═CH—












Y-68









CH2OCH2cPr
H, H
—ON═CH—












Y-69









CH═NOMe
H, H
—ON═CH—












Y-70









CH═NOEt
H, H
—ON═CH—












Y-71









CH═NOnPr
H, H
—ON═CH—












Y-72









CH═NOCH2CH2F
H, H
—ON═CH—












Y-73









Me
H, H
—ON═CH—












Y-74









CH2OEt
H, H
—ON═CH—












Y-75









CH2OCH2cPr
H, H
—ON═CH—












Y-76









CH═NOMe
H, H
—ON═CH—












Y-77









CH═NOEt
H, H
—ON═CH—












Y-78









CH═NOnPr
H, H
—ON═CH—




































































TABLE 98






















No
R1
R2
R3, R4
X1
Y



Y-79









CH═NOCH2CH2F
H, H
—ON═CH—












Y-80









Me
H, H
—ON═CH—












Y-81









CH2OEt
H, H
—ON═CH—












Y-82









CH2OCH2cPr
H, H
—ON═CH—












Y-83









CH═NOMe
H, H
—ON═CH—












Y-84









CH═NOEt
H, H
—ON═CH—












Y-85









CH═NOnPr
H, H
—ON═CH—












Y-86









CH═NOCH2CH2F
H, H
—ON═CH—












Y-87









Me
H, H
—ON═CH—












Y-88









CH2OEt
H, H
—ON═CH—












Y-89









CH2OCH2cPr
H, H
—ON═CH—












Y-90









CH═NOMe
H, H
—ON═CH—












Y-91









CH═NOEt
H, H
—ON═CH—












Y-92









CH═NOnPr
H, H
—ON═CH—












Y-93









CH═NOCH2CH2F
H, H
—ON═CH—












Y-94









Me
H, H
—ON═CH—












Y-95









CH2OEt
H, H
—ON═CH—












Y-96









CH2OCH2cPr
H, H
—ON═CH—












Y-97









CH═NOMe
H, H
—ON═CH—












Y-98









CH═NOEt
H, H
—ON═CH—












Y-99









CH═NOnPr
H, H
—ON═CH—












































































TABLE 99






















No
R1
R2
R3, R4
X1
Y



Y-100









CH═NOCH2CH2F
H, H
—ON═CH—












Y-101









Me
H, H
—ON═CH—












Y-102









CH2OEt
H, H
—ON═CH—












Y-103









CH2OCH2cPr
H, H
—ON═CH—












Y-104









CH═NOMe
H, H
—ON═CH—












Y-105









CH═NOEt
H, H
—ON═CH—












Y-106









CH═NOnPr
H, H
—ON═CH—












Y-107









CH═NOCH2CH2F
H, H
—ON═CH—












Y-108









Me
H, H
—ON═CH—












Y-109









CH2OEt
H, H
—ON═CH—












Y-110









CH2OCH2cPr
H, H
—ON═CH—












Y-111









CH═NOMe
H, H
—ON═CH—












Y-112









CH═NOEt
H, H
—ON═CH—












Y-113









CH═NOnPr
H, H
—ON═CH—












Y-114









CH═NOCH2CH2F
H, H
—ON═CH—



























































Test Example 1 Test for Transcriptional Activity of PPARδ and α
A chimeric transcription factor assay, which is commonly used to detect nuclear receptor activity, was employed to measure PPAR transcriptional activity. Specifically, two plasmids, one that expresses the fusion protein of DNA binding domain of yeast transcription factor GAL4 and a ligand binding domain of a receptor, and a reporter plasmid were transiently transfected to CHO cells. The activity of the promoter containing a recognition sequence of GAL4 coded on the reporter plasmid was used as a parameter to estimate the activity of the receptor.
Plasmid: The ligand binding domain of human PPARδ (hPPARδ) or α (hPPARα) (δ: aa 139-C-end; α: aa 167-C-end) is obtained by PCR amplification using Human Universal Quick-Clone cDNA (CLONTECH). Each amplified cDNA was subcloned into pCR2.1-TOPO vector (Invitrogen) and the identity of the cDNA clones was confirmed by the DNA sequence. Then, each obtained cDNA fragment was subcloned into pBIND vector (Promega) to construct a plasmid expressing the fusion protein with DNA binding domain of yeast transcription factor GAL4. pG51uc vector (Promega) was used as a reporter plasmid. Cell culturing and transfection: CHO cells were cultured in 10% FBS-αMEM. With a 96-well plate (Costar), CHO cells, that were dispersed with trypsin treatment, 20000 cells per well and the two plasmids obtained by the above procedure, 25 ng per well, were transfected with FuGene Reagent (Roche) by following the instruction of the manufacture. Measurement of the transcriptional activity: CHO cells 100 μl per well, which were transfected as above, were dispensed into the wells in which a test compound dissolved in DMSO 0.5 μl was spotted in advance. After the cells and a test compound were cultured together for 24 hours in a CO 2 incubator, the luciferase activity was measured by adding luciferase substrates, PicaGene LT2.0 (Toyo ink) 100 μl per well. LUMINOUS CT-9000D (DIA-IATRON) is used to measure the activity.

As to PPARδ, the concentration of a test compound which shows ½ of maximum luciferase activity was calculated using an Excel program to obtain the EC50 value for PPARδ activity of a test compound. The result is shown in Table 100.






TABLE 100




EC 50 (nM)

No.
hPPARδ








A reference compound
37













X-6
9.8

X-8
9.8

X-25
12



























Test Example 2 Test for Inhibition of Cyp2C9 Enzyme
The test for inhibition of CYP2C9 enzyme was carried out with human liver microsomes and hydration activity of 4-position of tolbutamide that is a typical reaction of CYP2C9 as a parameter.
The reaction condition was as below: A substrate, 5 μM Tolbutamide ( 14 C labeled compound); the reaction time, 30 minutes; the reaction temperature, 37° C.; the protein concentration, 0.25 mg/ml (human liver microsomes, 15 pol, Lot. 210296, XenoTech).
To the HEPES Buffer (pH 7.4), was added the protein (human liver microsomes), a drug solution and a substrate with the composition as the above. NADPH, which is a coenzyme of the reaction, was added thereto to start the reaction. After reacting for the fixed hours, 2N hydrochloric acid solution was added thereto and the reaction was stopped by removing protein. The remaining substrate drug and the generating metabolite were extracted with chloroform. The solvent was removed and the residue was redissolved in methanol. This solution was spotted on TLC, developed with chloroform:methanol:acetic acid=90:10:1, contacted on the imaging plate for about 14-20 hours and analyzed by BAS2000. As to the generation activity of the metabolite, Tolbutamide 4-potition hydration body, the activity in case that the solvent dissolving a drug was added to the reaction assay was used as a control (100%). The residual activity (%) in case that the test drug solution was added to the reaction was calculated to confirm the compounds of the present invention had little effect on inhibition of CYP2C9 enzyme.
Test Example 3 Test for Metabolic Stability
Test for Metabolic Stability in Hepatic Microsomes: To trishydrochloric acid buffer (pH 7.4), were added NADPH (the final concentration was 1 mM in case of oxidative metabolism), Hepatic Microsomes (the final concentration was 0.5 mg protein/ml) and each compound (the final concentration was 2 μM). The mixture was reacted at 37° C. for 0 and 30 minutes. In case of conjugated glucuronic acid, UDPGA (the final concentration is 5 mM) was added instead of NADPH. The reaction was stopped by adding acetonitrile/methanol=1/1 (v/v) which is 2 parts by volume based on 1 part by volume of the reaction solution and then compounds in the centrifugal supernatant were measured by HPLC. By comparing the values between 0 and 30 minutes the disappearance volume of the compounds by the metabolic reaction was calculated to confirm metabolic stability of the compounds of the present invention.
Test Example 4 Test for Solubility
The compounds of the present invention and test solvents (JP-2 solution, and JP-2 solution containing 20 mM sodium taurocholate) were stirred at 37° C. for 3 hours. The mixture was filtrated with a 0.45 μm filter and the concentration of the filtrate was measured with HPLC method to confirm solubility of compounds of the present invention.
Test Example 5 Test for Toxicity
The compounds of the present invention (30 to 300 mg/kg/day) were administered to rats. After administration, number of deaths, conditions, food intake and body weight of rats were checked and histopathological examination and the like were performed.
Additionally, as a hematological examination, after few days from administration, the blood was collected and PT, APTT and Fbg were measured after blood treatment. The activities of extrinsic blood coagulation factors (F-III, F-V, F-VII, F-X) and intrinsic blood coagulation factors (F-VIII, F-IX, F-XI, F-XII) were measured. The coagulation times of extrinsic or intrinsic blood coagulation factors were measured by a method for measurement of PT (extrinsic) or APTT (intrinsic) after adding plasma which is deficient a factor of each measuring object (Dade Boehringer Marburg) to plasma of rat and preincubating. Plasma of control rats was mixed and calibration curve was made with diluent which the plasma was sequentially double-diluted with Owren's Veronal Buffer as a reference material. Activity percentage was calculated with coagulation time measured by a method for coagulation time with factor deficient plasma and calibration curve and activities of each coagulation factor were evaluated by activity percentage compared to plasma of intact rat.
As the above, toxicities of compounds of the present invention were confirmed.