Patent Application
20090286974
The present invention relates to compounds which have an agonistic activity of a peroxisome proliferator-activated receptor (referred to below as PPAR) and which are useful as a medicine.
Peroxisome which is an intracellular granule is a small granule in the cytoplasm containing catalase and a group of oxidases. Peroxisome proliferators which proliferate peroxisome are thought as important controlling elements of lipid metabolism in the body. 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 PPARγ 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 antiobesity or 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 disclosed benzothiazole derivatives containing piperazine which can be used as antiobesity drugs or the like. However, it did not disclose the PPAR agonistic activity at all.
Patent Document 2 disclosed benzothiazole or benzoxazole derivatives containing piperazine or piperidine as antiviral drugs. However, it did not disclose the PPAR agonistic activity at all.
Patent Document 3 disclosed benzoxazole derivatives containing pyrrolidine as PPARγ agonists. However, it did not disclose a compound containing piperazine or piperidine.
Patent Document 4 and 5 disclosed that compounds containing piperazine have antiallergic action or the like. Non-patent Document 2 disclosed compounds containing piperazine as glycoprotein IIb/IIIa antagonists. Patent Document 6 disclosed compounds containing piperazine as CB1 antagonists. However, they did not disclose the PPAR agonistic activity at all.
Patent Document 7 and 8 disclosed compounds containing piperazine or piperidine as PPAR modulators. However, these compounds are characterized by having a sulfonyl group between piperazine and a phenyl group as a linker.
The objection of the present invention is to provide good PPAR agonists.
The present inventors have intensively studied to synthesize excellent PPAR agonists and carried out search for compounds having desired pharmacological activities by using computerized molecular design technology as a means to discover candidate compounds. The inventors carried out an automatic search program of a compound from a three-dimensional compound database based on the three-dimensional structure of peroxisome proliferator-activated receptors whose structures are registered in PDB (Protein Data Bank), and by virtual screenings, they selected compounds having potentials as PPAR agonists from compounds registered in databases of commercial compounds. The inventors synthesized a lot of derivatives on the basis of the skeletons of the selected compounds and carried out tests of the synthesized derivatives such as assays for transcriptional activation of PPAR δ, α and ≡, assays for cell toxicity and the like. The inventors selected compounds having strong and desired pharmacological activities, and further prepared their derivatives to achieve the present invention. Additionally, the inventors found that compounds of the present invention have PPAR transcriptional activity, less inhibition of drug-metabolizing enzymes and good metabolic stability and solubility. Furthermore, compounds of the present invention are less toxic and thought to be safe enough for pharmaceutical use.
The present invention includes the followings.
(1) A compound of the formula (I):
a pharmaceutically acceptable salt or solvate thereof,
wherein
Ring Q is optionally substituted monocyclic aryl, optionally substituted monocyclic heteroaryl, optionally substituted fused aryl or optionally substituted fused heteroaryl provided that Ring Q is not unsubstituted 11H-dibenz[b,e]-azepine-6-yl,
Y1 is a bond, —NR6— or —NR6—CO— wherein R6 is hydrogen or optionally substituted lower alkyl,
provided that Y1 is —NR6—CO— when Ring Q is unsubstituted monocyclic aryl, and Ring Q is phenyl substituted with alkyl halide when Ring Q is monocyclic aryl and Y1 is a bond,
Ring A is optionally substituted nonaromatic heterocyclediyl, provided that Ring Q binds with a nitrogen atom of Ring A when Y1 is a bond,
a group of the formula: -Y2 Z1- is a group of the formula:
provided that a group of the formula: -Y2 Z1- is not —SO2— and, a group of the formula: -Y2 Z1- is not —CH2—CH2—O— or —O— when Ring Q is unsubstituted benzothiazole-2-yl or unsubstituted benzoxazole-2-yl,
R7 are each independently hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl,
R8 and R9 are each independently hydrogen or optionally substituted lower alkyl,
n is an integer between 0 and 3,
Z1 is a bond, —O—, —S— or —NR9— wherein R9 is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl,
Ring B is optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl,
Y3 is a bond, optionally substituted lower alkylene optionally intervened by —O—, cycloalkylene optionally intervened by —O— or optionally substituted lower alkenylene,
Z2 is COOR3, C(═NR1)NR14OR15, CONHCN or a group of the formula:
R3, R14 and R15 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted aryl or optionally substituted heteroaryl, and
provided that a compound wherein a group of the formula: -Y2 Z1- is a group of the formula:
n is 0 and Z1 is a bond is excluded.
(2) The compound, pharmaceutically acceptable salt or solvate thereof according to (1),
wherein
Ring A is a group of the formula:
wherein
X4 is N or CR5 wherein R5 is hydrogen or optionally substituted lower alkyl, X5 is O, S, NR16 or CR17R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl, provided that a compound wherein X4 is CR5 and X5 is CR17R18 is excluded,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
m is an integer between 0 and 2,
the bond from X4 binds with Y1 and the other bond binds with Y2, and the other bond can bind with X5 when X5 is NR16 or CR17R18.
(3) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein
Ring A is a group of the formula:
X4 is N or CR5 wherein R5 is hydrogen or optionally substituted lower alkyl,
X5 is NR16 or CR17R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
m is an integer between 0 and 2,
the bond from X4 binds with Y1 and the other bond binds with Y2, and the other bond can bind with X5.
(4) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein
Ring A is a group of the formula:
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy, and
m is an integer of 1 or 2.
(5) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein
Ring A is a group of the formula:
R17 is optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl, the bond from N binds with Y1 and the bond from C binds with Y2.
(6) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein
Ring A is a group of the formula:
X4 is N or CR5 wherein R5 is hydrogen or optionally substituted lower alkyl,
X5 is NR16 or CR17R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl, provided that a compound wherein X4 is CR5 and X5 is CR17R18 is excluded,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
m is an integer between 0 and 2,
the bond from X4 binds with Y1 and the other bond binds with Y2, and the other bond can bind with X5.
(7) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein Ring Q is substituted fused heteroaryl.
(8) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein Ring Q is substituted benzofuryl, substituted benzothienyl, substituted benzopyrolyl, substituted benzoxazolyl, substituted benzoisoxazolyl, substituted benzothiazolyl, substituted benzoisothiazolyl, substituted benzoimidazolyl or substituted benzopyrazolyl.
(9) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein
a group of the formula:
is a group of the formula:
R1 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
R2 is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl, or
R1 and R2 can be taken together with the neighboring carbon atom and 5-membered ring including X1 and X3 as the constructive atoms to form a substituted fused heteroaryl,
X1 is N or CR10, and
X3 is NR11, O or S wherein R10 and R11 are each independently hydrogen or optionally substituted lower alkyl.
(11) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein
a group of the formula:
is a group of the formula:
R1 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy,
R2 is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl, or
R1 and R2 can be taken together with the neighboring carbon atom and 5-membered ring including X1 and X3 as the constructive atoms to form a substituted fused heteroaryl, X1 is N or CR12, and
X3 is NR13, O or S wherein R12 and R13 are each independently hydrogen or optionally substituted lower alkyl.
(12) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein
a group of the formula:
is a group of the formula:
R1 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy,
R2 is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl,
X1 is N or CR19, and
X3 is N or CR20 wherein R19 and R20 are each independently hydrogen or optionally substituted lower alkyl, provided that either X1 or X3 is N.
(13) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein
a group of the formula: -Y2Z1- is a group of the formula:
R8 and R9 are each independently hydrogen or lower alkyl,
n is an integer between 0 and 2, and
Z1 is a bond, —O— or —S—.
(14) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein Ring B is optionally substituted phenylene, optionally substituted indolediyl, optionally substituted benzofurandiyl, optionally substituted benzothiophenediyl, optionally substituted furandiyl or optionally substituted thiophenediyl.
(15) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein Y3 is a bond, optionally substituted lower alkylene, —O-optionally substituted lower alkylene or optionally substituted lower alkenylene.
(16) The compound, pharmaceutically acceptable salt or solvate thereof according to (1) or (2), wherein Z2 is COOR3 wherein R3 is hydrogen or optionally substituted lower alkyl.
(17) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein
a group of the formula:
is a group of the formula:
R1 is hydrogen,
R2 is optionally substituted aryl or
R1 and R2 can be taken together with the neighboring carbon atom and 5-membered ring including X1 and X3 as the constructive atoms to form a substituted fused heteroaryl,
X1 is N or CR10 wherein R10 is hydrogen,
X3 is O or S,
Y1 is a bond,
Ring A is a group of the formula:
X4 is N,
X5 is NR16 or CR17R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
m is an integer between 0 and 2,
the bond from X4 binds with Y1 and the other bond binds with Y2, and the other bond can bind with X5,
a group of the formula: -Y2Z1- is a group of the formula:
R8 and R9 are each independently hydrogen or lower alkyl,
n is an integer between 0 and 2, Z1 is a bond, —O— or —S—,
Ring B is optionally substituted phenylene, optionally substituted furandiyl or optionally substituted thiophendiyl,
the substituent(s) of said phenylene, furandiyl or thiophendiyl of Ring B is/are selected from a group consisting of halogen, lower alkyl and lower alkoxy,
Y3 is a bond, optionally substituted lower alkylene, —O— optionally substituted lower alkylene or optionally substituted lower alkenylene,
the substituent(s) of said lower alkylene or lower alkenylene of Y3 is/are selected from a group consisting of halogen and lower alkylene, and
Z2 is COOR3 wherein R3 is hydrogen or lower alkyl.
(18) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein
a group of the formula:
is a group of the formula:
R1 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy,
R2 is optionally substituted alkyl or optionally substituted aryl,
X1 is N or CR19,
X3 is N or CR20 wherein R19 and R20 are each independently hydrogen or optionally substituted lower alkyl, provided that either X1 or X3 is N,
Y1 is a bond,
Ring A is a group of the formula:
X4 is N,
X5 is NR16 or CR17R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
m is an integer between 0 and 2, the bond from X4 binds with Y1 and the other bond binds with Y2, and the other bond can bind with X5,
a group of the formula: -Y2 Z1- is a group of the formula:
R8 and R9 are each independently hydrogen or lower alkyl,
n is an integer between 0 and 2,
Z1 is a bond, —O— or —S—,
Ring B is optionally substituted phenylene, optionally substituted furandiyl or optionally substituted thiophendiyl,
the substituent(s) of said phenylene, furandiyl or thiophendiyl of Ring B is/are selected from a group consisting of halogen, lower alkyl and lower alkoxy,
Y3 is a bond, optionally substituted lower alkylene, —O— optionally substituted lower alkylene or optionally substituted lower alkenylene,
the substituent(s) of said lower alkylene or lower alkenylene of Y3 is/are selected from a group consisting of halogen and lower alkylene, and
Z2 is COOR3 wherein R3 is hydrogen or lower alkyl.
(19) The compound, pharmaceutically acceptable salt or solvate thereof according to (1), wherein
Y1 is a bond,
Ring A is a group of the formula:
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy,
m is an integer of 1 or 2,
a group of the formula: -Y2 Z1- is a group of the formula:
R8 and R9 are each independently hydrogen or lower alkyl,
n is an integer of 1 or 2,
Z1 is a bond or —O—,
Ring B is optionally substituted phenylene,
Y3 is optionally substituted lower alkylene or —O— optionally substituted lower alkylene,
the substituent(s) of said lower alkylene of Y3 is/are selected from a group consisting of halogen and lower alkylene, and
Z2 is COOR3 wherein R3 is hydrogen or lower alkyl.
(20) The compound, pharmaceutically acceptable salt or solvate thereof according to (1),
wherein
Y1 is a bond,
Ring A is a group of the formula:
R17 is optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
the bond from N binds with Y1 and the bond from C binds with Y2,
a group of the formula: Y2 Z1- is a group of the formula:
R8 and R9 are each independently hydrogen or lower alkyl,
n is 2,
Z1 is —O—,
Ring B is optionally substituted phenylene,
Y3 is optionally substituted lower alkylene or —O— optionally substituted lower alkylene, and the substituent(s) of said lower alkylene of Y3 is/are selected from a group consisting of halogen and lower alkylene, and
Z2 is COOR3 wherein R3 is hydrogen or lower alkyl.
(21) A pharmaceutical composition comprising the compound, pharmaceutically acceptable salt or solvate thereof according to any one of (1) to (20) as an active ingredient.
(22) 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 (20) as active ingredient.
(23) A compound of the formula:
a salt or solvate thereof,
wherein
Ring Q has the same meaning as defined in (1), and
R4 is halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy.
(24) A compound of the formula:
salt or solvate thereof,
wherein
Y2, Z1, Ring B, Y3 and Z2 have the same meanings as defined in (1),
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl, and
RX is hydrogen or amino protecting group.
(25) A compound of the formula:
a salt or solvate thereof,
wherein
Ring Q has the same meaning as defined in (1),
R17 is optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
R8 and R9 are each independently hydrogen or lower alkyl,
n is an integer between 1 and 3, and
X10 is halogen or hydroxy.
(26) A compound of the formula:
a salt or solvate thereof,
wherein
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy,
m is 1 or 2, and
Rx is hydrogen or amino protecting group.
(27) A compound of the formula:
a salt or solvate thereof,
wherein
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy,
R8 and R9 are each independently hydrogen or lower alkyl,
n is an integer between 1 and 3,
RX is hydrogen or amino protecting group, and
X10 is hydroxy or halogen.
(28) A compound of the formula:
a salt or solvate thereof,
wherein
R17 is optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
R8 and R9 are each independently hydrogen or lower alkyl,
n is an integer between 1 and 3,
X10 is halogen or hydroxy, and
RX is hydrogen or amino protecting group.
Furthermore, the present invention provides a process for PPAR activation characterized by administrating the above compound, pharmaceutically acceptable salt or 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.
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.
Each term used in this description is explained below. The each term has the same meaning in this description both when it is used alone each term and when it is used with the other term.
The term “monocyclic aryl” means C6 to C12 monocyclic aromatic carbon ring. Examples include phenyl and the like.
The term “fused aryl” means aromatic carbon ring which 1 to 4 monocyclic aromatic carbon ring(s) (C6 to C12 monocyclic aromatic carbon ring(s)) is condensed with C6 to C12 monocyclic aromatic carbon ring. Examples include naphthyl, anthryl, phenanthryl and the like. The bonds can be attached to any of the rings. Naphthyl is preferable.
The term “aryl” means the above “monocyclic aryl” and “fused aryl”.
The term “aralkyl” means the above “alkyl” substituted with 1 to 3 of the above “aryl”. Examples include benzyl, phenethyl, phenylpropyl, trityl and the like.
The term “monocyclic heteroaryl” means 4- to 8-membered monocyclic aromatic heterocycle having 1 or more hetero atom(s) selected from O, S and N in the ring. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like. 5- or 6-membered monocyclic aromatic heterocycle is especially preferable.
The term “fused heteroaryl” means a group derived from condensed aromatic heterocycle which aromatic carbon ring (aromatic carbon ring derived from the above “aryl”) or aromatic heterocycle (4- to 8-membered aromatic heterocycle having 1 or more hetero atom(s) selected from O, S and N in the ring) is condensed with monocyclic aromatic heterocycle derived from the above “monocyclic heteroaryl”. Examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, prinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyradinopyridazinyl, quinazolinyl, tetrahydroquinolyl, tetrahydrobenzothienyl, carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like. In case of “fused heteroaryl”, the bonds can be attached to any of the rings. A condensed fused heteroaryl which benzene ring is condensed with 5- or 6-membered monocyclic aromatic heterocycle is especially preferable.
The term “heteroaryl” means the above “monocyclic heteroaryl” and “fused heteroaryl”.
The term “heteroaralkyl” means the above “alkyl” substituted with 1 to 3 of the above “heteroaryl”.
The term “nonaromatic heterocycle” means a condensed nonaromatic heterocycle which aromatic carbon ring (aromatic carbon ring derived from the above “aryl”), aromatic heterocycle (4- to 8-membered aromatic heterocycle having 1 or more hetero atom(s) selected from O, S and N in the ring), monocyclic nonaromatic heterocycle (monocyclic nonaromatic heterocycle derived from the above “monocyclic nonaromatic heterocycle”) or cycloalkane (a ring derived from the below “cycloalkyl”) is condensed with 4- to 8-membered monocyclic nonaromatic heterocycle having 1 or more hetero atom(s) selected from O, S and N in the ring or the above “monocyclic nonaromatic heterocycle”. Examples include indolinyl, dioxanyl, thiiranyl, oxyranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperadino, morpholinyl, morpholino, oxadiadinyl, dihydropyridyl and the like.
The term “heterocycle” include the above “heteroaryl” and “nonaromatic heterocycle”. Examples include morpholino, piperidino, piperadino, furyl, thienyl, pyridyl and the like.
The term “nonaromatic heterocyclediyl” includes a bivalent group derived by removing 2 hydrogen atoms from 4- to 10-membered nonaromatic heterocycle having 1 or more hetero atom(s) selected from O, S and N in the ring. The nonaromatic heterocycle can be bridged by alkylene. The preferable examples include piperidinediyl, piperadinediyl, morpholinediyl, dioxanediyl, pyrrolidinediyl, pyrrolinediyl, imidazolinediyl, imidazolidinediyl and the like. Examples of “nonaromatic heterocyclediyl” of Ring A include the following groups.
A group of the formula:
wherein
X4 is N or CR5 wherein R5 is hydrogen or optionally substituted lower alkyl,
X5 is O, S, NR16 or CR17R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl, provided that a compound wherein X4 is CR5 and X5 is CR17R18 is excluded,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl, and
m is an integer between 0 and 2,
the bond from X4 binds with Y1 and the other bond binds with Y2, and the other bond can bind with X5 when X5 is NR16 or CR17R18. The other bond preferably binds with X5.
“The other bond can bind with X5 when X5 is NR16” means the below.
wherein each symbol has the same meaning as defined above.
“The other bond can bind with X5 when X5 is CR17R18” means the below.
wherein each symbol has the same meaning as defined above.
The term “aromatic carbocyclediyl” includes a bivalent group derived by removing a hydrogen atom from the above “aryl”. Examples include phenylene, naphthylene and the like. Phenylene is preferable.
The term “aromatic heterocyclediyl” includes a bivalent group derived by removing a hydrogen atom from the above “heteroaryl”. Examples includes pyrroldiyl, imidazolediyl, pyrazolediyl, pyridinediyl, pyridazinediyl, pyrimidinediyl, pyrazinediyl, triazolediyl, triazinediyl, isoxazolediyl, oxazolediyl, oxadiazolediyl, isothiazolediyl, thiazolediyl, thiadiazolediyl, furandiyl, thiophenediyl, indolediyl, benzofurandiyl, benzothiophenediyl and the like. Indolediyl, benzofurandiyl, benzothiophenediyl, furandiyl or thiophenediyl is preferable. Monocyclic aromatic heterocyclediyl is especially preferable. Furandiyl (especially furan-2,5-diyl) or thiophenediyl (especially thiophene-2,5-diyl) is more preferable.
The term “lower alkyl” means C1 to C10, preferably C1 to C6 and more preferably C1 to C4 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 arbitrary 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 arbitrary position(s) and can have double bond(s).
The term “cycloalkyl” includes C3 to C9 and preferably C3 to C6 cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl and the like.
The term “cycloalkylene” includes C3 to C9 and preferably C3 to C6 cycloalkylene. Examples include cyclopropylene, cyclobutylene, cyclopenthylene, cyclohexylene, cycloheptylene, cycloethylene and the like. Cyclopropylene is especially preferable.
“Cycloalkylene optionally intervened by —O—” means cycloalkylene which is the above “cycloalkylene” optionally intervened by 1 or 2-O—. Examples include a group of the formula:
The term “acyl” includes (a) carbonyl substituted with the above “alkyl” or “alkenyl”, (b) carbonyl substituted with the above “cycloalkyl”, (c) carbonyl substituted with the above “aryl” or (d) formyl. Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl, benzoyl and the like.
The term “lower alkylene” includes C1 to 10, preferably C1 to 6 and more preferably C1 to 3 straight or branched alkylene. Examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, propylene, dimethylmethylene, 1,1-dimethylethylene, 1,2-dimethylethylene and the like. Methylene, ethylene or dimethylmethylene is especially preferable.
“Lower alkylene optionally intervened by —O—” means alkylene which is the above “alkylene” optionally intervened by 1 to 3-O—. Alkylene which —O— is intervened at the end is also included. Examples include —O—CH2—, —CH2—O—, —CH2—O—CH2—, —O—CH2—CH2—, —CH2—CH2—O—, —O—CH(CH3)—, —O—C(CH3)2—, —O—CH2—CH2—O—, —O—CH(CH3)—O—, —O—C(CH3)2—O— and the like.
“—O-optionally substituted lower alkylene” means alkylene which —O— is intervened at the end.
The term “lower alkenylene” includes C2 to 10, preferably C2 to C6 and more preferably C2 to C4 straight or branched alkenylene having one or more double bond(s) at arbitrary position(s). Examples include vinylene, propenylene and the like.
The term “halogen” means fluorine, chlorine, bromine or iodine. Especially, fluorine, chlorine or bromine is preferable.
An alkyl part of “lower alkoxy” is the same as the above “lower alkyl”.
Examples of the substituent of “optionally substituted lower alkyl”, “optionally substituted lower alkylsulfonyl”, “optionally substituted lower alkenyl”, “optionally substituted lower alkynyl”, “optionally substituted lower alkylene”, “optionally substituted lower alkenylene”, “optionally substituted lower alkoxy” or “optionally substituted acyl” include halogen, hydroxy, optionally substituted lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocycle, optionally substituted heterocycleoxy, optionally substituted lower alkylene, optionally substituted lower alkylenedioxy and oxo. They can be substituted at arbitrary position(s) with one or more group(s) selected from the above. In case that optionally substituted lower alkylene or optionally substituted lower alkylenedioxy is the substituent, the two bonds bind with one carbon atom to form a spiro ring, or bind with different atoms and are taken together with the neighboring carbon atom to form a ring.
A heterocycle part of “heterocycleoxy” is the same as the above “heterocycle”.
Examples of the substituent of “optionally substituted monocyclic aryl”, “optionally substituted monocyclic heteroaryl”, “optionally substituted aryl”, “optionally substituted aralkyl”, “optionally substituted aryloxy”, “optionally substituted arylthio”, “optionally substituted heteroaryl”, “optionally substituted hetroaralkyl”, “optionally substituted heteroaryloxy”, “optionally substituted heteroarylthio”, “substituted fused aryl”, “substituted fused heteroaryl”, “optionally substituted arylsulfonyl”, “optionally substituted aromatic carbocyclediyl”, “optionally substituted aromatic heterocyclediyl” or “optionally substituted nonaromatic heterocyclediyl” include optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, halogen, hydroxy, optionally substituted lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocycle, optionally substituted heterocycleoxy, optionally substituted lower alkylene and optionally substituted lower alkylenedioxy. They can be substituted at arbitrary position(s) with one or more group(s) selected from the above. In case that optionally substituted lower alkylene or optionally substituted lower alkylenedioxy is the substituent, the bonds can bind with different atoms and be taken together with the neighboring carbon atom to form a ring.
Preferable examples in the above substituents include halogen, hydroxy, optionally substituted lower alkyl (the substituent is halogen or hydroxy), optionally substituted lower alkenyl (the substituent is halogen or hydroxy), optionally substituted lower alkoxy (the substituent is halogen or aryl), carboxy, lower alkoxycarbonyl, optionally substituted carbamoyl (the substituent is lower alkyl or aryl), optionally substituted amino (the substituent is acyl or lower alkyl), mercapto, lower alkylthio, acyl, acyloxy, cyano, nitro, aryl, heterocycle, lower alkylene and lower alkylenedioxy. Halogen or optionally substituted lower alkyl (the substituent is halogen) is especially preferable.
A substituent of “substituted benzofuryl”, “substituted benzothienyl”, “substituted benzopyronyl”, “substituted benzoxazolyl”, “substituted benzisoxazolyl”, “substituted benzothiazolyl”, “substituted benzisothiazolyl”, “substituted benzimidazolyl” or “substituted benzopyrazolyl” is the same as the substituent of the above “substituted fused heteroaryl”.
A substituent of “optionally substituted phenylene” is the same as the substituent of “optionally substituted aromatic carbocyclediyl”.
A substituent of “optionally substituted indolediyl”, “optionally substituted benzofurandiyl”, “optionally substituted benzothiophenediyl”, “optionally substituted furandiyl” or “optionally substituted thiophenediyl” is the same as the substituent of the above “optionally substituted aromatic heterocyclediyl”.
Examples of a substituent of “optionally substituted nonaromatic heterocyclediyl” include halogen, hydroxy, optionally substituted lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocycle, optionally substituted heterocycleoxy, optionally substituted lower alkylene, optionally substituted lower alkylenedioxy and oxo. It can be optionally substituted at arbitrary position(s) with one or more group(s) selected from the above. In case that optionally substituted lower alkylene or optionally substituted lower alkylenedioxy is a substituent, the two bonds bind with one carbon atom to form a spiro ring, or bind with different atoms and are taken together to with the neighboring carbon atom to form a ring.
A substituent of “optionally substituted lower alkynyloxy”, “optionally substituted lower alkylthio”, “optionally substituted lower alkoxycarbonyl”, “optionally substituted lower alkylsulfonyloxy”, “optionally substituted cycloalkyl”, “optionally substituted cycloalkyloxy”, “optionally substituted arylsulfonyl”, “optionally substituted arylsulfonyloxy”, “optionally substituted heterocycle”, “optionally substituted heterocycleoxy” or “optionally substituted lower alkylenedioxy” is the same as the substituent of the above “optionally substituted lower alkyl”.
A substituent of “optionally substituted amino”, “optionally substituted imino”, “optionally substituted carbamoyl”, “optionally substituted thiocarbamoyl”, “optionally substituted carbamoyloxy”, “optionally substituted thiocarbamoyloxy” or “optionally substituted sulfamoyl” is the same as the substituent of the above “optionally substituted lower alkyl”. These substituents can be mono- or di-substituted on a nitrogen atom. Lower alkyl, aryl, heterocycle, acyl, lower alkoxycarbonyl, lower alkylsulfonyl or arylsulfonyl is especially preferable.
Preferable embodiments of each substituent for a compound of the formula (I) are explained below.
Ring Q is optionally substituted monocyclic aryl, optionally substituted monocyclic heteroaryl, optionally substituted fused aryl or optionally substituted fused heteroaryl. Preferable examples include monocyclic aryl substituted with one or more of R2 and optionally substituted with other group(s), monocyclic heteroaryl substituted with one or more of R2 and optionally substituted with other group(s) wherein each R2 is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaryloxy or optionally substituted heteroarylthio, substituted fused aryl or substituted fused heteroaryl. Monocyclic heteroaryl substituted with one of R2 and optionally substituted with other group(s) wherein R2 is halogen, optionally substituted alkyl or optionally substituted aryl, substituted fused aryl or substituted fused heteroaryl is especially preferable.
“and optionally substituted with other group(s)” means to be optionally substituted except for the substituent, R2. The substituent(s) can be the same substituent as R2.
Examples of substituted fused heteroaryl include substituted benzofuryl, substituted benzothienyl, substituted benzopyronyl, substituted benzoxazolyl, substituted benzisoxazolyl, substituted benzothiazolyl, substituted benzisothiazolyl, substituted benzimidazolyl, substituted benzopyrazolyl and the like. Substituted benzothiazolyl wherein the substituent is halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, aryl, lower alkylsulfonyl or optionally substituted carbamoyl is especially preferable.
Especially preferable examples of Ring Q include below.
A group of the formula:
R1 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
R2 is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl, or
R1 and R2 can be taken together with the neighboring carbon atom to form optionally substituted ring,
X1 is N or CR10, and
X3 is NR11, O or S wherein R10 and R11 are each independently hydrogen or optionally substituted lower alkyl,
a group of the formula:
R1 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy,
R2 is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl, or
R1 and R2 can be taken together with the neighboring carbon atom to form optionally substituted ring,
X1 is N or CR12, and
X3 is NR13, O or S wherein R12 and R13 are each independently hydrogen or optionally substituted lower alkyl, or
a group of the formula:
R1 are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy,
R2 is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio or optionally substituted heteroaryl,
X1 is N or CR19, and
X3 is N or CR20 wherein R19 and R20 are each independently hydrogen or optionally substituted lower alkyl, provided that either X1 or X3 is N.
The following embodiments are preferable as “substituted fused heteroaryl” of Ring Q.
R is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, halogen, hydroxy, optionally substituted lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocycle, optionally substituted heterocycleoxy,
The following embodiments are also preferable as “monocyclic heteroaryl substituted with one or more of R2 and optionally substituted with other group(s)” for ring Q.
R1 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl, and
R and R′ are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkoxy, optionally substituted lower alkynyl oxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocycle, optionally substituted heterocyclyloxy or the like.
Y1 is a bond, —NR6— or —NR6—CO— wherein R6 is hydrogen or optionally substituted lower alkyl. A bond is especially preferable.
Ring A is optionally substituted nonaromatic heterocyclediyl, provided that Ring Q binds with a nitrogen atom of Ring A when Y1 is a bond. Especially preferable examples include a group of the formula:
wherein
X4 is N or CR5 wherein R5 is hydrogen or optionally substituted lower alkyl,
X5 is O, S, NR16 or CR18R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl, provided that a compound wherein X4 is CR5 and X5 is CR17R18 is excluded,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl, and
m is an integer between 0 and 2,
the bond from X4 binds with Y1 and the other bond binds with Y2, and the other bond can bind with X5 when X5 is NR16 or CR17R18.
More preferable examples include a group of the formula:
wherein
X4 is N or CR5 wherein R5 is hydrogen or optionally substituted lower alkyl,
X5 is NR16 or CR17R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl, provided that a compound wherein X4 is CR5 and X5 is CR17R18 is excluded,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
m is an integer between 0 and 2,
the bond from X4 binds with Y1 and the other bond binds with Y2, and the other bond can bind with X5 when X5 is NR16 or CR17R18.
Much more preferable examples include a group of the formula:
wherein
X4 is N,
X5 is NR16 or CR17R18 wherein R16 to R18 are each independently hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
m is an integer between 0 and 2,
the bond from X4 binds with Y1 and the other bond binds with Y2.
Especially preferable examples of m include 1 and 2. R4 are especially each independently optionally substituted lower alkyl and the preferable examples include C1 to C4 straight or branched alkyl. Much more preferable examples include a group of the formula:
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl or optionally substituted lower alkoxy, and
m is an integer of 1 or 2, or
a group of the formula:
R17 is optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
the bond from N binds with Y1 and the bond from C binds with Y2.
A group of the formula: -Y2 Z1- is a group of the formula:
R7 are each independently hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl,
R8 and R9 are each independently hydrogen or optionally substituted lower alkyl,
n is an integer between 0 and 3,
Z1 is a bond, —O—, —S— or —NR9— wherein R9 is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl. Especially preferable examples include a group of the formula:
R8 and R9 are each independently hydrogen or lower alkyl,
n is an integer between 0 and 2, and
Z1 is a bond, —O— or —S—.
The following embodiments are also preferable as a group of the formula: -Y1-Ring A-Y2-Z1
R17 is hydrogen, optionally substituted lower alkyl, cyano, optionally substituted nonaromatic heterocycle, optionally substituted heteroaryl, optionally substituted amino, optionally substituted lower alkoxy, aryl lower alkyl or optionally substituted cycloalkyl,
R6 is hydrogen or optionally substituted lower alkyl,
R7 is hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl,
R4 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy or optionally substituted aryl,
Z1 is a bond, O, S or NR9 wherein R9 is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl,
n is an integer between 0 and 3.
R17 is especially nonaromatic heterocycle. Preferable examples include pyrrolidinyl, piperidyl, azepanyl, morpholinyl and the like.
Ring B is optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl. Especially preferable examples include optionally substituted phenylene, optionally substituted furandiyl and optionally substituted thiophenediyl, and the substituent(s) of said phenylene, furandiyl or thiophendiyl is/are selected from a group consisting of halogen, lower alkyl and lower alkoxy.
Y3 is a bond, optionally substituted lower alkylene optionally intervened by —O—, cycloalkylene optionally intervened by —O— or optionally substituted lower alkenylene. Especially preferable examples include a bond, optionally substituted lower alkylene, —O-optionally substituted lower alkylene and optionally substituted lower alkenylene, and the substituent(s) of said lower alkylene or lower alkenylene is/are selected from a group consisting of lower alkylene and halogen.
Z1 is COOR3, C(═NR3)NR14OR15, CONHCN or a group of the formula:
R3, R14 and R15 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted aryl or optionally substituted heteroaryl. Especially preferable examples include COOR3 wherein R3 is hydrogen or optionally substituted lower alkyl.
The following embodiments are also preferable as a group of the formula: -Z1-Ring B—Y3-Z2.
Z1 is a bond, —O—, —S— or —NR9— wherein R9 is hydrogen, optionally substituted lower alkyl, optionally substituted acyl, optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl, and
R, R′ and R″ are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkoxy, optionally substituted lower alkynyloxy, optionally substituted amino, mercapto, optionally substituted lower alkylthio, acyl, acyloxy, optionally substituted imino, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted carbamoyloxy, optionally substituted thiocarbamoyloxy, optionally substituted sulfamoyl, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, cyano, nitro, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heterocycle, optionally substituted heterocyclyloxy, optionally substituted lower alkylene, optionally substituted lower alkylenedioxy or oxo.
A compound of the present invention includes producible and pharmaceutically acceptable salts of each compound. Examples of “a pharmaceutically acceptable salt” include 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; and 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). Hydrate is preferable.
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 the double bond, it includes both type of the isomers.
The popular methods for production of compounds of the present invention are described below.
wherein X is halogen or the like, and the other symbols have the same meaning as defined in the above (1).
This step is a method for production of Compound (C) by reacting Compound (A) and (B).
This step is especially preferably carried out especially under the presence of base. Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium hydride, triethylamine, N,N-diisopropylethylamine and the like. Examples of the reaction solvent include N,N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, acetonitrile, dimethylsulfoxide and the like. The reaction can be performed at room temperature to 100° C.
The acid addition salt can be used as Compound (B). In that case, the value of the base used in the reaction is increased.
wherein X is halogen or the like, and the other symbols have the same meaning as defined in the above (1).
This step is a method for production of Compound (C) by reacting Compound (D) and (E).
This step can be carried out under the same conditions as Step B.
wherein X is halogen or the like, and the other symbols have the same meaning as defined in the above (1).
This step is a method for production of Compound (H) by reacting Compound (F) and (G).
This step can be carried out under the same conditions as Step A and B.
wherein X is halogen or the like, and the other symbols have the same meaning as defined in the above (1).
This step is a method for production of Compound (L) by reacting Compound (J) and (K).
This step can be carried out under the same conditions as Step A, B and C.
wherein each symbol has the same meaning as defined in the above (1).
This step is a method for production of Compound (O) by reacting Compound (M) and (N).
This step can be carried out by Mitsunobu reaction under the presence of azodicarboxylate and triphenylphosphine. Instead of azodicarboxylate, 1,1-azodicarbonyldipiperidine, N,N,N′N′-tetramethylazodicarboxamide or the like can be used. Instead of triphenylphosphine, tributyl phosphine or the like can be used. Examples of the reaction solvent include tetrahydrofuran, toluene, benzene and the like. The reaction can be carried out at room temperature.
wherein X is halogen or the like, and the other symbols have the same meaning as defined in the above (1).
This step is a method for production of Compound (R) by reacting Compound (P) and (Q).
This step can be carried out under the same conditions as Step A, B, C and D.
wherein X is halogen or the like, and the other symbols have the same meaning as defined in the above (1).
This step is a method for production of Compound (O) by reacting Compound (P) and (S).
This step can be carried out under the same conditions as Step A, B, C, D and F.
When the compound obtained by the above any step is ester of COOR3, this compound is hydrolyze by the usual method to give carboxylic acid of COOH.
If necessary, at an appropriate step in the above method for production, any substituent can be transform to a different substituent by the well-known organic synthesized reaction.
For example, when any 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 a compound whose substituent is transformed to lower alkoxy.
When any compound has alkyl 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 (e.g., butoxycarbonyl (Boc)), lower alkenyloxycarbonyl, halogenoalkoxycarbonyl, aryl lower alkoxycarbonyl, trialkylsilyl, lower alkylsulfonyl, halogeno lower alkylsulfonyl, arylsulfonyl, lower alkylcarbonyl, arylcarbonyl, aryl lower alkyl (e.g., benzyl) or the like can be used.
As a hydroxy protecting group, alkyl (e.g., t-butyl), aralkyl (triphenylmethyl or benzyl), trialkylsilyl (e.g., t-butyldimethylsilyl or triisopropylsilyl), alkyldiarylsilyl (e.g., t-butyldiphenylsilyl), triaralkylsilyl (e.g., tribenzylsilyl), alkoxyalkyl (e.g., methoxymethyl, 1-ethoxyethyl or 1-methyl-1-methoxyethyl), alkoxyalkoxyalkyl (e.g., methoxyethoxymethyl), alkylthioalkyl (e.g., methylthiomethyl), tetrahydropyranyl (e.g., tetrahydropyran-2-yl or 4-methoxytetrahydropyran-4-yl), tetrahydrothiopyranyl (e.g., tetrahydrothiopyran-2-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl), tetrahydrothiofuranyl (e.g., tetrahydrothiofuran-2-yl), aralkyloxyalkyl (e.g., benzyloxymethyl)alkylsulfonyl, acyl, p-toluenesulfonyl or the like can be used.
Deprotection reaction is carried out 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.
wherein RX is an amino protecting group (e.g., benzyl or tert-butoxycarbonyl) or the like, X10 is halogen, and the other symbols have the same meanings as above.
Compound (O1) is reacted with a derivative having Ring Q under the presence of a base to give Compound (O2). The protecting group of the obtained Compound (O2) is removed and the compound is reacted with Compound (O4) to give Compound (O5).
wherein RX is an amino protecting group (e.g., benzyl or tert-butoxycarbonyl) or the like, RY is lower alkyl or the like, X10 is hydroxy, Z1 is O, S or NR9, and the other symbols have the same meanings as above.
A compound of the formula: X—C(R8R9)n-1—COORY is reacted to Compound (P1) under the presence of the base (e.g., potassium carbonate) to give Compound (P2). As the solvent, dimethylformamide or the like can be used.
The obtained Compound (P2) is reduced to give Compound (P3). The reduction can be used with lithium aluminium hydride or the like.
The obtained Compound (P3) is reacted with mesyl chloride or the like to transform X10 to a leaving group and coupled with a compound having Ring B.
After that, Compound (P5) is obtained by deprotection of RX and reacted with phenylisocyanate derivatives or the like to give Compound (P6).
Compound (P7) can be also obtained by reacting with a compound having Ring Q.
A compound wherein Z1 is —S— or —NR9— can be obtained by transforming X10 of Compound (P3) to halogen and reacting with a compound having Ring B.
wherein RX is an amino protecting group (e.g., benzyl or tert-butoxycarbonyl) or the like, RY is lower alkyl or the like, X10 is hydroxy or halogen, Z1 is —O—, —S— or —NR9—, and the other symbols have the same meanings as above.
COORY is reduced by introducing from Compound (Q1) to Compound (Q2). The reduction can be carried out with lithium aluminium hydride or the like. Next, the deprotection of RX is carried out. When the protecting group is benzyl, the deprotection is carried out by a catalytic reduction or the like. After the deprotection, a compound having Ring Q is reacted under the presence of base (e.g., potassium carbonate) to give Compound (Q4). Next, a compound having Ring B is reacted to the obtained Compound (Q4) to give Compound (Q5). A compound wherein Z1 is —S— or —NR9— can be also obtained by transforming X10 of Compound (Q4) to halogen and reacting with a compound having Ring B.
A pharmaceutical composition for PPAR agonist of the present 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 (e.g., inflammatory bowel disease, rheumatoid arthritis, chronic pancreatitis, multiple sclerosis, glomerulosclerosis, psoriasis or eczema), osteoporosis, sterility, cancer (e.g., breast cancer, colonic cancer, colon cancer, ovarian cancer or lung cancer), Alzheimer's disease, parkinsonism or Basedow's disease. Especially, a compound having PPARδ selective agonistic activity in compounds of the present invention having PPAR agonistic activity can be a 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.
Furthermore, a compound of the present invention has the good characters, for example,
a) weak CYP enzyme inhibition
b) high water solubility
c) good drug disposition such as high bioavailability
d) low toxicity of anemia-inducing activity or the like, or
e) high metabolic stability.
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, diluents 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 time to few times a day.
The following examples are provided to explain in more detail and do not restrict the present invention.
Compounds in Reference Examples 1 to 6 were obtained by the methods described in US patent application publication no. US2004-0224997 or WO 95/22531.
Yield: 88%, 1H-NMR (CDCl3): δ7.41 (1H, dd, J=8.5, 2.0 Hz), 7.45 (1H, d, J=8.5 Hz), 7.95 (1H, d, J=2.0 Hz).
Yield: 90%, 1H-NMR (CDCl3): δ7.60 (1H, dd, J=8.5, 2.0 Hz), 7.82 (1H, d, J=8.5 Hz), 7.93 (1H, d, J=2.0 Hz).
Yield: 76%, 1H-NMR (CDCl3): δ7.23 (1H, td, J=8.0, 2.5 Hz), 7.48 (1H, dd, J=8.0, 2.5 Hz), 7.91 (1H, dd, J=8.0, 4.0 Hz).
Yield: 65%, 1H-NMR (CDCl3): δ7.73 (1H, d, J=7.0 Hz), 7.82 (1H, d, J=9.0 Hz).
Yield: 89%, 1H-NMR (CDCl3): δ7.78 (1H, d, J=6.5 Hz), 8.06 (1H, d, J=10.5 Hz).
Yield: 66%, 1H-NMR (CDCl3): δ8.00 (1H, d, J=8.5 Hz), 8.17 (1H, d, J=8.5 Hz), 8.45 (1H, s), 8.89 (1H, s).
To a mixture of 2-amino-5-phenylthiazole described in Journal of Medicinal Chemistry, 1983, Vol. 26 (8), 1158-1163, (1.00 g; 5.67 mmol), copper (II) chloride dihydrate (1.94 g; 11.3 mmol), concentrated hydrochloric acid (8 ml) and acetic acid (8 ml) was added sodium nitrite (0.47 g; 6.80 mmol) under ice-cooling. The mixture was stirred at 40° C. for 1 hour. After returning the reaction solution to room temperature, water and chloroform were added and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (methylene chloride) to give 2-chloro-5-phenylthiazole as pale yellow crystal (0.68 g; 62%).
1H-NMR (CDCl3): δ7.32-7.53 (5H, m), 7.71 (1H, s).
To a mixture of 3-(methoxymethoxy)-4-methylbenzyl alcohol described in WO2004/022551 (9.80 g; 53.78 mmol), triethylamine (7.90 ml; 56.47 mmol) and anhydrous THF (50 ml) was added dropwise methanesulfonyl chloride (4.40 ml; 56.47 mmol) under ice-cooling. The mixture was stirred at the same temperature for 1.5 hours. The precipitate was collected and condensed under reduced pressure. Then, to the residue were added sodium cyanide (7.91 g; 0.161 mol) and anhydrous N,N-dimethylformamide (50 ml). The mixture was stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=3:1) to give [3-(methoxymethoxy)-4-methylphenyl]acetonitrile as blackish brown oil (7.87 g; 77%).
1H-NMR (CDCl3): δ2.23 (3H, s), 3.49 (3H, s), 3.70 (2H, s), 5.21 (2H, s), 6.89 (1H, dd, J=7.5, 1.5 Hz), 6.98 (1H, d, J=1.5 Hz), 7.14 (1H, d, J=7.5 Hz).
A mixture of [3-(methoxymethoxy)-4-methylphenyl]acetonitrile (7.87 g; 41.2 mmol), sodium hydroxide (8.30 g; 210 mmol), water (30 ml) and ethanol (70 ml) was refluxed for 5 hours. The reaction solution was condensed under reduced pressure. Water and ethyl acetate were added thereto and back-extracted. The water layer became pH=7 by adding 2N-aqueous hydrochloric acid. Ethyl acetate was added thereto and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to give 3-(methoxymethoxy)-4-methylphenylacetate as pale blackish brown oil (5.52 g; 64%).
1H-NMR (CDCl3): δ2.22 (3H, s), 3.48 (3H, s), 3.59 (2H, s), 5.19 (2H, s), 6.83 (1H, dd, J=7.5, 1.5 Hz), 6.95 (1H, d, J=1.5 Hz), 7.13 (1H, d, J=7.5 Hz), 9.83 (1H, brs).
A mixture of [3-(methoxymethoxy)-4-methyl]phenylacetate (5.52 g; 26.3 mmol), concentrated hydrochloric acid (2 ml) and ethanol (20 ml) was refluxed for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogencarbonate to become pH=7. Ethyl acetate was added thereto and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=3:1) to give 3-hydroxy-4-methylphenylethyl acetate as pale yellow oil (2.40 g; 47%).
1H-NMR (CDCl3): δ1.26 (3H, t, J=7 Hz), 2.21 (3H, s), 3.53 (2H, s), 4.14 (2H, q, J=7 Hz), 5.13 (1H, s), 6.72 (1H, s), 6.74 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=7.5 Hz).
To a mixture of 4-chloro-3-methylcresol (15.0 g; 0.105 mol), N,N-diisopropylethylamine (23.3 ml; 0.137 mol) and THF (150 ml), was added dropwise chloromethylmethyl ether (9.50 ml; 0.126 mol) at room temperature. The mixture was stirred at 60° C. for 27.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=5:1) to give 2-chloro-5-(methoxyethoxy)toluene as dark reddish-brown oil (17.7 g; 90%).
1H-NMR (CDCl3): δ2.34 (3H, s), 3.47 (3H, s), 5.13 (2H, s), 6.81 (1H, dd, J=8.5, 3.0 Hz), 6.92 (1H, d, J=3.0 Hz), 7.22 (1H, d, J=8.5 Hz).
A mixture of 2-chloro-5-(methoxyethoxy)toluene (5.00 g; 26.8 mmol), N-bromosuccinimide (4.77 g; 26.8 mmol) and 2,2-azobis(isobutyronitrile) (0.09 g; 0.53 mmol) in carbon tetrachloride (25 ml) was refluxed for 2 hours. After air cooling and filtration the precipitate, the filtrate was condensed under reduced pressure. To the residue were added sodium cyanide (2.77 g; 80.4 mol) and anhydrous N,N-dimethylformamide (30 ml). The mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=6:1→4:1) to give [2-chloro-5-(methoxymethoxy)phenyl]acetonitrile as colorless oil (2.64 g; 47%).
1H-NMR (CDCl3): δ3.48 (3H, s), 3.80 (2H, s), 5.17 (2H, s), 6.99 (1H, dd, J=9.0, 3.0 Hz), 7.19 (1H, d, J=3.0 Hz), 7.32 (1H, d, J=9.0 Hz).
To a mixture of [2-chloro-5-(methoxymethoxy)phenyl]acetonitrile (2.60 g; 12.3 mmol), sodium hydroxide (2.46 g; 61.5 mmol), water (10.4 ml) and ethanol (33.8 ml) was stirred at 80° C. for 3 hours. After cooling, the solvent was evaporated under reduced pressure. To the residue was added water and 2N-aqueous hydrochloric acid to become acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. To the residue, were added concentrated hydrochloric acid (0.65 ml) and ethanol (15 ml). The mixture was stirred at 80° C. for 8 hours. After cooling, the reaction solution was condensed under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give [2-chloro-5-hydroxyphenyl]ethyl acetate as colorless oil (0.69 g; 26%).
1H-NMR (CDCl3): δ1.28 (3H, t, J=7.0 Hz), 3.70 (2H, s), 4.20 (2H, q, J=7.0 Hz), 5.66 (1H, s), 6.64 (1H, dd, J=8.5, 3.0 Hz), 6.73 (1H, d, J=3.0 Hz), 7.18 (1H, d, J=8.5 Hz).
It was synthesized by the method described in Reference Example 77 of WO2004/022551.
1H-NMR (CDCl3); δ2.29 (3H, s), 2.35 (3H, s), 4.44 (2H, s), 6.85 (1H, s), 6.94 (1H, s), 7.08 (1H, s).
A mixture of 3,5-dimethylmethyl benzoate (5.00 g; 30.5 mmol), N-bromosuccinimide (5.69 g; 32.0 mmol) and 2,2-azobis(isobutyronitrile) (0.10 g; 0.61 mmol) in carbon tetrachloride (25 ml) was refluxed for 1 hour. After cooling and filtration of the precipitate, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=10:1) to give 3-bromomethyl-5-methylmethyl benzoate as colorless oil (3.78 g; 51%).
1H-NMR (CDCl3): δ2.40 (3H, s), 3.92 (3H, s), 4.49 (2H, s), 7.40 (1H, s), 7.79 (1H, s), 7.89 (1H, s).
Compounds in Reference Examples 16 and 17 were obtained by similar methods as Reference Example 15.
Yield: 56%, 1H-NMR (CDCl3): δ3.93 (3H, s), 4.61 (2H, s), 7.47 (1H, d, J=8.5 Hz), 7.91 (1H, dd, J=8.5, 2 Hz), 8.11 (1H, d, J=2 Hz).
Yield: 75%, 1H-NMR (CDCl3): δ2.33 (3H, s), 4.40 (2H, s), 7.08 (1H, s), 7.10 (1H, s), 7.18 (1H, s).
A mixture of (3-bromomethyl-5-chloro) toluene (1.67 g; 7.62 mmol), sodium cyanide (0.42 g; 8.51 mmol) and anhydrous N,N-dimethylformamide (15 ml) were stirred at 40° C. for 2 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (methylene chloride) to give [(3-chloro-5-methyl)phenyl]acetonitrile as pale yellow oil (0.75 g; 59%).
1H-NMR (CDCl3): δ2.35 (3H, s), 3.69 (2H, s), 7.04 (1H, s), 7.12 (1H, s), 7.14 (1H, s).
To [(3-chloro-5-methylphenyl)]acetonitrile (0.38 g; 2.29 mmol) were added 2N aqueous sodium hydroxide solution (2.1 ml) and ethanol (5 ml). The mixture was stirred at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure. To the residue were added water and 2N-aqueous HCl to become neutral. Ethyl acetate was added thereto and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to give colorless crystal. Concentrated sulfuric acid (0.02 ml) and ethanol (2 ml) were added thereto, and the mixture was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure. To the residue were added water and 2N-aqueous sodium hydroxide solution to become neutral. Ethyl acetate was added thereto and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=6:1) to give 3-chloro-5-methylphenylethyl acetate as colorless oil (0.31 g; 63%).
1H-NMR (CDCl3): δ1.26 (3H, t, J=7.2 Hz), 2.32 (3H, s), 3.53 (2H, s), 4.16 (2H, q, J=7.2 Hz), 6.97 (1H, s), 7.08 (2H, s).
A mixture of 3-chloro-5-methylphenylethyl acetate (0.20 g; 0.958 mol), N-bromosuccinimide (0.21 g; 1.21 mmol) and 2,2-azobis(isobutyronitrile) (0.01 g; 0.037 mmol) in carbon tetrachloride (2 ml) were refluxed for 2 hours. After cooling and filtration of the precipitate, the filtrate was condensed under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=20:1) to give 3-bromomethyl-5-chlorophenylethyl acetate as colorless oil (0.16 g; 57%).
1H-NMR (CDCl3): δ1.27 (3H, t, J=7.2 Hz), 3.58 (2H, s), 4.17 (2H, t, J=7.2 Hz), 4.42 (2H, s), 7.20 (1H, s), 7.22 (1H, s), 7.30 (1H, s).
Compounds in Reference Examples 21 and 22 were synthesized as above.
Yield: 56%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 3.61 (2H, s), 4.16 (2H, q, J=7.0 Hz), 4.48 (2H, s), 7.18-7.38 (4H, m).
Yield: 70%, 1H-NMR (CDCl3): δ1.28 (3H, t, J=7 Hz), 3.51 (3H, s), 3.59 (2H, s), 4.17 (2H, q, J=7 Hz), 4.45 (2H, s), 7.04 (1H, s), 7.12 (2H, s).
A mixture of 4-hydroxy-3-methyl benzoic acid (3.01 g; 19.78 mmol), concentrated sulfuric acid (0.20 ml) and ethanol (40 ml) was refluxed for 6 hours. The reaction solution was concentrated under reduced pressure. To the residue were added water and 2N-aqueous sodium hydroxide solution to become neutral. Ethyl acetate was added and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to give 4-hydroxy-3-methylethyl benzoate as yellow crystal (3.40 g; 95
1H-NMR (CDCl3): δ1.38 (3H, t, J=7.2 Hz), 2.28 (3H, s), 4.35 (2H, q, J=7.2 Hz), 5.75 (1H, s), 6.81 (1H, d, J=8.1 Hz), 8.40 (1H, d, J=8.1 Hz), 7.84 (1H, s).
A mixture of 4-hydroxy-3-methylethyl benzoate (2.15 g; 11.93 mmol), methoxymethoxychloride (1.60 ml; 21.2 mmol), diisopropylethylamine (4.10 ml; 23.9 mmol) and THF (40 ml) was refluxed at 60° C. for 9 hours. After cooling, water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=20:1) to give 4-(methoxymethoxy)-3-methylethyl benzoate as colorless oil (1.94 g; 73%).
1H-NMR (CDCl3): δ1.38 (3H, t, J=7.2 Hz), 2.27 (3H, s), 3.49 (3H, s), 4.34 (2H, q, J=7.2 Hz), 5.26 (2H, s), 7.05 (1H, d, J=9.3 Hz), 7.84-7.86 (2H, m).
To a suspension of lithium aluminium hydride (0.26 g; 6.76 mmol) in anhydrous THF (5 ml) were added dropwise a mixture of 4-(methoxymethoxy)-3-methylethyl benzoate (1.02 g; 4.55 mmol) and anhydrous THF (10 ml) at 0° C. After stirring at the same temperature for 1 hour, 2N-aqueous sodium hydroxide solution was added dropwise to the reaction solution. The residue was filtrated. To the filtrate were added ethyl acetate and brine. The organic layer was separated and dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=3:1) to give [4-(methoxymethoxy)-3-methyl]benzyl alcohol as colorless oil (0.80 g; 97%).
1H-NMR (CDCl3): δ1.63 (1H, brs), 2.25 (3H, s), 3.48 (3H, s), 4.59 (2H, d, J=3.9 Hz), 5.20 (2H, s), 7.01-7.17 (3H, m)
To a mixture of [4-(methoxymethoxy)-3-methyl]benzyl alcohol (0.49 g; 2.69 mmol), triethylamine (0.42 ml; 3.01 mmol) and methylene chloride (14 ml) was added dropwise methanesulfonyl chloride (0.23 ml; 2.97 mmol) under ice-cooling. The mixture was stirred for 4.5 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=6:1) to give 5-chloromethyl-2-(methoxymethoxy)toluene as pale blackish brown oil (0.53 g; 99%).
1H-NMR (CDCl3): δ2.25 (3H, s), 3.48 (3H, s), 4.54 (2H, s), 5.20 (2H, s), 7.02 (1H, d, J=8.4 Hz), 7.14-7.18 (2H, m).
The following compound was synthesized by referring to Synthetic Communications, 2004, Vol. 34, 4111 to 4118.
To a solution of 2-aminobutanoic acid (10.0 g; 96.97 mmol) in methanol (65 ml) was added dropwise thionyl chloride (30 ml; 411.28 mmol) under ice-cooling. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. Diisopropyl ether (20 ml) was added to the residue. The mixture was azeotroped under reduced pressure to give colorless crystal.
To the above crystal (5.00 g) were added water (15 ml) and sodium hydrogencarbonate (6.66 g; 79.28 mmol) and added dropwise a solution of chloroacetylchloride (2.6 ml; 32.64 mmol) in toluene (10 ml) under ice-cooling. The mixture was stirred at room temperature for 18 hours. The reaction solution was separated and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give 2-(N-chloroacetamide)methyl butanoate as colorless oil (4.75 g; 75%).
1H-NMR (CDCl3): δ0.94 (3H, t, J=7.2 Hz), 1.74-1.86 (1H, m), 1.8-2.02 (1H, m), 3.78 (3H, s), 4.08 (2H, s), 4.59 (1H, q, J=6.6 Hz), 7.07 (1H, s).
Compounds in Reference Examples 28 to 37 were obtained as above.
Yield: 74%, 1H-NMR (CDCl3): δ0.94 (3H, t, J=7.5 Hz), 1.70-2.00 (2H, m), 3.78 (3H, s), 4.09 (2H, s), 4.54-4.63 (1H, m), 7.10 (1H, brs).
Yield: 70%, 1H-NMR (CDCl3): δ0.94 (3H, t, J=7.5 Hz), 1.65-2.00 (2H, m), 3.78 (3H, s), 4.11 (2H, s) 4.50-4.65 (1H, m), 7.09 (1H, brs).
Yield: 97%, 1H-NMR (CDCl3): δ0.95 (3H, t, J=7.2 Hz), 1.26-1.41 (2H, m), 1.66-1.78 (1H, m), 1.81-1.89 (1H, m), 3.77 (3H, s), 4.08 (2H, s), 4.62 (1H, dt, J=7.8 Hz), 7.03 (1H, s)
Yield: 91%, 1H-NMR (CDCl3): δ0.95 (3H, t, J=7.5 Hz), 1.24-1.43 (2H, m), 1.66-1.78 (1H, m), 1.81-1.93 (1H, m), 3.77 (3H, s), 4.08 (2H, s), 4.62 (1H, q, J=7.5 Hz), 7.02 (1H, s)
Yield: 99%, 1H-NMR (CDCl3): δ0.91 (3H, t, J=7 Hz), 1.23-1.40 (4H, m), 1.67-1.80 (1H, m), 1.81-1.96 (1H, m), 3.77 (3H, s), 4.08 (2H, s), 4.57-4.65 (1H, m), 7.03 (1H, brs).
Yield: 86%, 1H-NMR (CDCl3): δ0.91 (3H, t, J=7 Hz), 1.23-1.40 (4H, m), 1.65-1.80 (1H, m), 1.82-1.95 (1H, m), 3.77 (3H, s), 4.08 (2H, s), 4.55-4.65 (1H, m), 7.02 (1H, brs).
Yield: 93%, 1H-NMR (CDCl3): δ0.96 (6H, d, J=6.0 Hz), 1.58-1.74 (3H, m), 3.76 (3H, s), 4.08 (2H, s), 4.66 (1H, t, J=8.4 Hz), 6.90 (1H, br)
Yield: quant. %, 1H-NMR (CDCl3): δ0.96 (6H, d, J=6.0 Hz), 1.54-1.78 (3H, m), 3.76 (3H, s), 4.08 (2H, s), 4.60-4.70 (1H, m), 6.83-6.95 (1H, m).
Yield: 93%, 1H-NMR (CDCl3): δ0.95 (6H, d, J=6 Hz), 1.56-1.75 (3H, m), 3.76 (3H, s), 4.08 (2H, s), 4.60-4.70 (1H, m), 6.93 (1H, brs).
Yield: 90%, 1H-NMR (CDCl3): δ0.96 (6H, t, J=6.5 Hz), 2.16-2.30 (1H, m), 3.77 (3H, s), 4.10 (2H, s), 4.51-4.60 (1H, m), 7.04 (1H, brs).
A mixture of 2-(N-chloroacetamide)methyl butanoate (4.00 g; 20.71 mmol), triethylamine (8.8 ml; 63.14 mmol), benzylamine (2.8 ml; 25.64 mmol) and methanol (45 ml) was refluxed for 16 hours. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the residue and extracted. To the organic layer was added 1N aqueous hydrochloric acid to separate. To the organic layer was added aqueous sodium hydrogencarbonate water solution to become neutral. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was washed with diisopropyl ether to give 1-benzyl-3-ethylpiperazine-2,5-dion as colorless crystal (1.58 g; 33%).
1H-NMR (CDCl3): δ0.98 (3H, t, J=7.2 Hz), 1.71-2.02 (2H, m), 3.84 (2H, dd, J=0.9, 5.1 Hz), 4.03-4.08 (1H, m), 4.51 (1H, d, J=14.4 Hz), 4.71 (1H, d, J=14.4 Hz), 7.25-7.36 (5H, m)
Compounds in Reference Examples 39 to 48 were obtained as above.
Yield: 44%, 1H-NMR (CDCl3): δ0.98 (3H, t, J=7.5 Hz), 1.83-2.03 (2H, m), 3.83 (2H, d, J=5.5 Hz), 4.00-4.10 (1H, m), 4.50 (1H, d, J=14.5 Hz), 4.71 (1H, d, J=14.5 Hz), 7.05 (1H, brs), 7.23-7.40 (5H, m).
Yield: 32%, 1H-NMR (CDCl3): δ0.98 (3H, t, J=7.5 Hz), 1.85-2.05 (2H, m), 3.83 (2H, dd, J=6, 1 Hz), 4.02-4.10 (1H, m), 4.50 (1H, d, J=14.5 Hz), 4.71 (1H, d, J=14.5 Hz), 6.95 (1H, brs), 7.20-7.40 (5H, m).
Yield: 41%, 1H-NMR (CDCl3): δ0.97 (3H, t, J=7.2 Hz), 1.36-1.48 (2H, m), 1.82-1.90 (2H, m), 3.83 (2H, dd, J=0.9, 5.4 Hz), 4.07 (1H, td, J=2.6, 5.7 Hz), 4.60 (2H, dd, J=14.1, 39.9 Hz), 7.24-7.38 (5H, m)
Yield: 45%, 1H-NMR (CDCl3): δ0.97 (3H, t, J=7.2 Hz), 1.36-1.48 (2H, m), 1.82-1.90 (2H, m), 3.83 (2H, dd, J=0.9, 5.4 Hz), 4.04-4.09 (1H, m), 4.53 (1H, d, J=14.4 Hz), 4.67 (1H, d, J=14.4 Hz), 7.24-7.39 (5H, m)
Yield: 49%, 1H-NMR (CDCl3): δ0.85-1.00 (3H, m), 1.24-1.45 (4H, m), 1.80-1.96 (2H, m), 3.83 (2H, d, J=6 Hz), 4.02-4.12 (1H, m), 4.53 (1H, d, J=14.5 Hz), 4.67 (1H, d, J=14.5 Hz), 6.68 (1H, brs), 7.21-7.40 (5H, m).
Yield: 43%, 1H-NMR (CDCl3): δ0.85-0.95 (3H, m), 1.30-1.50 (4H, m), 1.80-1.98 (2H, m), 3.72-3.91 (2H, m), 4.04-4.10 (1H, m), 4.53 (1H, d, J=14.5 Hz), 4.67 (1H, d, J=14.5 Hz), 6.45 (1H, brs), 7.23-7.40 (5H, m).
Yield: 34%, 1H-NMR (CDCl3): δ0.97 (6H, dd, J=6.0, 8.1 Hz), 1.61-1.73 (2H, m), 1.76-1.88 (1H, m), 3.83 (2H, d, J=6.3 Hz), 4.02-4.07 (1H, m), 4.59 (2H, q, J=14.7 Hz), 6.65 (1H, s), 7.23-7.35 (5H, m)
Yield: 55%, 1H-NMR (CDCl3): δ0.96 (3H, d, J=6.5 Hz), 0.98 (3H, d, J=6.5 Hz), 1.58-1.89 (3H, m), 3.80 (1H, d, J=17.5 Hz), 3.83 (1H, d, J=17.5 Hz), 4.01-4.10 (1H, m), 4.55 (1H, d, J=14.5 Hz), 4.65 (1H, d, J=14.5 Hz), 6.66 (1H, s), 7.21-7.40 (5H, m).
Yield: 50%, 1H-NMR (CDCl3): δ0.90-1.05 (6H, m), 1.58-1.90 (3H, m), 3.83 (2H, d, J=6.5 Hz), 4.02-4.10 (1H, m), 4.54 (1H, d, J=14.5 Hz), 4.65 (1H, d, J=14.5 Hz), 6.75 (1H, brs), 7.20-7.40 (5H, m).
Yield: 12%, 1H-NMR (CDCl3): δ0.88 (3H, d, J=6.5 Hz), 1.02 (3H, d, J=6.5 Hz), 2.42-2.55 (1H, m), 3.83 (2H, d, J=11 Hz), 3.90-3.96 (1H, m), 4.45 (1H, d, J=14 Hz), 4.77 (1H, d, J=14 Hz), 6.43 (1H, brs), 7.21-7.45 (5H, m).
To a suspension of lithium aluminium hydride (0.87 g; 22.9 mmol) in anhydrous THF (20 ml) was added dropwise a solution of 1-benzyl-3-ethylpiperazine-2,5-dion (1.50 g; 6.46 mmol) in anhydrous THF (10 ml) under ice-cooling. After stirring at room temperature for 18 hours, a mixture of water (0.25 ml) and THF (5 ml) and 2N-aqueous sodium hydroxide solution (0.5 ml) were added dropwise sequentially under ice-cooling. The mixture was stirred at room temperature for 1 hour. After filtration of aluminium hydroxide, the filtrate was condensed under reduced pressure. To the residue were added ethyl acetate and brine to separate. The organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to give 1-benzyl-3-ethylpiperazine as pale yellow oil (1.29 g; 98%).
1H-NMR (CDCl3): δ0.90 (3H, t, J=7.5 Hz), 1.30-1.40 (2H, m), 1.70 (1H, t, J=10.8 Hz), 2.01 (1H, dt, J=3.6, 10.8 Hz), 2.61-2.70 (1H, m), 2.73-2.89 (2H, m), 2.92-3.00 (1H, m), 3.49 (2H, dt, J=6.9 Hz), 3.68 (1H, t, J=5.7 Hz), 7.23-7.31 (5H, m)
Compounds in Reference Examples 50 to 60 were obtained as above.
Yield: 96%, 1H-NMR (CDCl3): δ0.90 (3H, t, J=7.5 Hz), 1.29-1.36 (2H, m), 1.70 (1H, t, J=10.5 Hz), 2.01 (1H, td, J=11, 3.5 Hz), 2.60-3.00 (5H, m), 3.46 (1H, d, J=13 Hz), 3.53 (1H, d, J=13 Hz), 7.20-7.40 (5H, m).
Yield: 89%, 1H-NMR (CDCl3): δ0.90 (3H, t, J=7.5 Hz), 1.35 (2H, quant, J=7.5 Hz), 1.70 (1H, t, J=10.5 Hz), 2.01 (1H, td, J=11, 3.5 Hz), 2.60-3.00 (5H, m), 3.46 (1H, d, J=13 Hz), 3.53 (1H, d, J=13 Hz), 7.20-7.40 (5H, m).
Yield: 73%, 1H-NMR (CDCl3): δ0.89 (3H, t, J=6.9 Hz), 1.29-1.40 (4H, m), 1.69 (1H, t, J=9.9 Hz), 2.00 (1H, td, J=3.6, 10.5 Hz), 2.73-2.99 (5H, m), 3.49 (2H, d, J=5.4 Hz), 7.21-7.35 (5H, m)
Yield: 68%, 1H-NMR (CDCl3): δ0.89 (3H, t, J=6.8 Hz), 1.26-1.40 (4H, m), 1.69 (1H, t, J=9.9 Hz), 2.00 (1H, td, J=3.6, 10.8 Hz), 2.72-2.95 (5H, m), 3.49 (2H, d, J=5.1 Hz), 7.23-7.32 (5H, m)
Yield: quant. %, 1H-NMR (CDCl3): δ0.88 (3H, t, J=6.5 Hz), 1.20-1.40 (6H, m), 1.50 (1H, brs), 1.70 (1H, t, J=10 Hz), 2.00 (1H, td, J=11, 4 Hz), 2.65-3.00 (5H, m), 3.46 (1H, d, J=13 Hz), 3.52 (1H, d, J=13 Hz), 7.20-7.40 (5H, m).
Yield: quant. %, 1H-NMR (CDCl3): δ0.88 (3H, d, J=6.5 Hz), 1.20-1.39 (6H, m), 1.70 (1H, t, J=10 Hz), 2.00 (1H, td, J=11, 4 Hz), 2.65-3.00 (5H, m), 3.46 (1H, d, J=13 Hz), 3.52 (1H, d, J=13 Hz), 7.20-7.40 (5H, m).
Yield: 88%, 1H-NMR (CDCl3): δ0.88 (6H, dd, J=5.1, 6.6 Hz), 1.09-1.26 (2H, m), 1.59-1.72 (3H, m), 2.00 (1H, dt, J=3.9, 10.8 Hz), 2.74-2.84 (3H, m), 2.88-2.94 (2H, m), 3.49 (2H, d, J=7.5 Hz), 7.31 (3H, s), 7.32 (2H, s)
Yield: quant. %, 1H-NMR (CDCl3): δ0.87 (3H, d, J=6.5 Hz), 0.89 (3H, d, J=6.5 Hz), 1.05-1.29 (2H, m), 1.57-1.74 (2H, m), 2.00 (1H, td, J=10.5, 4.0 Hz), 2.70-2.99 (5H, m), 3.43 (1H, d, J=13.0 Hz), 3.50 (1H, d, J=13.0 Hz), 7.20-7.38 (5H, m).
Yield: 90%, 1H-NMR (CDCl3): δ0.87 (3H, d, J=5 Hz), 0.89 (3H, d, J=5 Hz), 1.16-1.30 (2H, m), 1.58-1.74 (2H, m), 2.00 (1H, td, J=11, 4 Hz), 2.70-3.00 (5H, m), 3.45 (1H, d, J=13 Hz), 3.52 (1H, d, J=13 Hz), 7.20-7.40 (5H, m).
Yield: 92%, 1H-NMR (CDCl3): δ0.88 (3H, d, J=6.5 Hz), 0.93 (3H, d, J=6.5 Hz), 1.55 (1H, sextet, J=6.5 Hz), 1.78 (1H, t, J=10.5 Hz), 1.97 (1H, td, J=11, 3.5 Hz), 2.67-3.03 (5H, m), 3.44 (1H, d, J=13 Hz), 3.56 (1H, d, J=13 Hz), 7.20-7.40 (5H, m).
Yield: 80%, 1H-NMR (CDCl3): δ0.91 (3H, d, J=7.0 Hz), 0.94 (3H, d, J=7.0 Hz), 1.43-1.60 (1H, m), 2.27-2.37 (1H, m), 2.38-2.48 (1H, m), 2.65-2.85 (2H, m), 2.86-2.94 (1H, m), 2.96-3.06 (2H, m).
A mixture of 1-benzyl-3-ethylpiperazine (1.16 g; 5.68 mmol), 5% palladium carbon (0.11 g), trifluoroacetic acid (1.1 ml; 14.8 mmol) and methanol (30 ml) was stirred at room temperature under the presence of hydrogen gas for 17 hours. The reaction solution was filtrated and the filtrate was condensed under reduced pressure. The residue was washed with diisopropyl ether to give 3-ethylpiperazine ditrifluoroacetate as colorless crystal (1.65 g; 85%).
1H-NMR (D2O): δ0.74 (3H, t, J=7.5 Hz), 1.44-1.54 (2H, m), 2.90 (1H, dd, J=12.0 Hz), 3.07-3.15 (2H, m), 3.20-3.34 (1H, m), 3.43-3.51 (3H, m)
Compounds in Reference Examples 62 to 71 were obtained as above.
Yield: 88%, 1H-NMR (DMSO-d6): δ0.94 (3H, t, J=7.5 Hz), 1.60 (2H, quant, J=7.5 Hz), 2.93 (1H, t, J=12.5 Hz), 3.00-3.65 (6H, m), 9.24 (2H, brs).
Yield: 80%, 1H-NMR (DMSO-d6): δ0.94 (3H, t, J=7.5 Hz), 1.61 (2H, quant, J=7.5 Hz), 2.93 (1H, t, J=12.5 Hz), 3.00-3.60 (6H, m), 9.27 (2H, brs).
Yield: 59%, 1H-NMR (D2O): δ0.76 (3H, t, J=7.5 Hz), 1.25 (2H, m), 1.53 (2H, q, J=7.5 Hz), 3.00 (1H, t, J=12.9 Hz), 3.13-3.29 (2H, m), 3.39-3.48 (1H, m), 3.52-3.59 (3H, m)
Yield: 61%, 1H-NMR (D2O): δ0.79 (3H, t, J=7.2 Hz), 1.22-1.35 (2H, m), 1.52-1.60 (2H, m), 3.03 (1H, dd, J=12.2 Hz), 3.16-3.32 (2H, m), 3.40-3.51 (1H, m), 3.55-3.63 (3H, m)
Yield: 76%, 1H-NMR (DMSO-d6): δ0.88 (3H, t, J=7 Hz), 1.20-1.40 (4H, m), 1.48-1.70 (2H, m), 2.96 (1H, t, J=12.5 Hz), 3.05-3.28 (2H, m), 3.30-3.44 (1H, m), 3.45-3.60 (3H, m), 9.39 (2H, brs).
Yield: 74%, 1H-NMR (DMSO-d6): δ0.87 (3H, t, J=7.5 Hz), 1.20-1.40 (4H, m), 1.45-1.67 (2H, m), 2.94 (1H, t, J=7 Hz), 3.16 (2H, quant, J=12.5 Hz), 3.29-2.65 (4H, m), 9.35 (2H, brs).
Yield: 78%, 1H-NMR (D2O): δ0.82 (6H, dd, J=1.8, 6.0 Hz), 1.49 (2H, t, J=6.9 Hz), 1.54-1.65 (1H, m), 3.06 (1H, dd, J=11.7 Hz), 3.20-3.37 (2H, m), 3.48-3.55 (1H, m), 3.57-3.66 (3H, m)
1H-NMR (CDCl3): δ0.87 (3H, d, J=6.5 Hz), 0.89 (3H, d, J=6.5 Hz), 1.44 (2H, t, J=7.0 Hz), 1.61-1.78 (1H, m), 2.85-3.00 (1H, m), 3.03-3.32 (2H, m), 3.35-3.59 (4H, m), 9.34 (2H, brs).
Yield: 82%, 1H-NMR (DMSO-d6): 0.88 (6H, t, J=6.5 Hz), 1.43 (2H, t, J=6.5 Hz), 1.70 (1H, quant, J=6.5 Hz), 2.90 (1H, t, J=13 Hz), 3.00-3.28 (2H, m), 3.35-3.55 (4H, m), 9.17 (2H, brs).
Yield: 49%, 1H-NMR (DMSO-d6): 0.94 (3H, d, J=7 Hz), 0.98 (3H, d, J=7 Hz), 1.84-1.98 (1H, m), 2.94 (1H, t, J=12.5 Hz), 3.05-3.25 (3H, m), 3.47 (2H, d, J=10.5 Hz), 3.52 (1H, d, J=15 Hz), 9.12 (2H, brs).
To a mixture of 3-ethylpiperazine ditrifluoroacetate (0.51 g; 1.47 mmol) and acetonitrile (10 ml) were added triethylamine (0.62 ml; 4.45 mmol) and di-t-butyldicarbonate (0.35 g; 1.59 mmol) under ice-cooling. The mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure. To the residue were added ethyl acetate and water and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (chloroform:methanol=20:1) to give 1-tert-butoxycarbonyl-3-ethylpiperazine as colorless crystal (0.27 g; 85%).
1H-NMR (CDCl3): δ 1.03 (3H, t, J=7.5 Hz), 1.47 (9H, s), 1.60-1.81 (2H, m), 2.96 (3H, br), 3.26 (2H, d, J=12.6 Hz), 4.08 (2H, d, J=14.1 Hz)
Compounds in Reference Examples 73 to 83 were obtained as above.
Yield: 99%, 1H-NMR (CDCl3): 0.95 (3H, t, J=7.5 Hz), 1.30-1.45 (2H, m), 1.46 (9H, s), 1.67 (1H, brs), 2.30-2.55 (2H, m), 2.68-2.90 (2H, m), 2.91-3.01 (1H, m), 3.80-4.05 (2H, m).
Yield: 80%, 1H-NMR (CDCl3): 0.95 (3H, t, J=7.5 Hz), 1.30-1.45 (2H, m), 1.46 (9H, s), 1.69 (1H, brs), 2.30-2.55 (2H, m), 2.68-2.88 (2H, m), 2.90-3.00 (1H, m), 3.85-4.02 (2H, m).
Yield: quant. %, 1H-NMR (CDCl3, 328K): 0.94 (3H, t, J=6.9 Hz), 1.29-1.46 (4H, m), 1.46 (9H, s), 2.64-2.86 (3H, m), 2.96-3.14 (2H, m), 3.64-4.04 (2H, m)
Yield: quant. %, 1H-NMR (CDCl3, 328K): 0.94 (3H, t, J=6.9 Hz), 1.36-1.60 (4H, m), 1.47 (9H, s), 2.82-2.93 (3H, m), 3.12-3.21 (2H, m), 3.99-4.10 (2H, m)
Yield: 96%, 1H-NMR (CDCl3): 0.90 (3H, t, J=6 Hz), 1.25-1.40 (6H, m), 1.46 (9H, s), 1.54 (1H, brs), 2.30-2.60 (2H, m), 2.67-2.86 (2H, m), 2.90-2.99 (1H, m), 3.80-4.05 (2H, m).
Yield: 94%, 1H-NMR (CDCl3): 0.85-0.95 (3H, m), 1.25-1.40 (6H, m), 1.46 (9H, s), 1.56 (1H, brs), 2.30-3.00 (5H, m), 3.80-4.05 (2H, m).
Yield: 90%, 1H-NMR (CDCl3): 0.94 (6H, dd, J=3.3, 6.3 Hz), 1.47 (9H, s), 1.43-1.54 (2H, m), 1.68-1.79 (1H, m), 2.97 (2H, dt, J=3.3, 12.3 Hz), 3.08 (1H, br), 3.22-3.28 (2H, m), 4.08 (2H, d, J=13.8 Hz)
Yield: 74%, 1H-NMR (CDCl3): 0.90 (3H, d, J=6.5 Hz), 0.93 (3H, d, J=6.5 Hz), 1.11-1.30 (2H, m), 1.47 (9H, s), 1.60-1.78 (1H, m), 2.41 (1H, brs), 2.56-2.87 (3H, m), 2.90-3.00 (1H, m), 3.82-4.03 (2H, m).
Yield: 99%, 1H-NMR (CDCl3): 0.92 (6H, t, J=7 Hz), 1.15-1.30 (2H, m), 1.46 (9H, s), 1.47 (1H, brs), 1.62-1.76 (1H, m), 2.30-2.52 (1H, m), 2.58-3.00 (4H, m), 3.82-4.04 (2H, m).
Yield: 59%, 1H-NMR (CDCl3): 0.95 (3H, d, J=13.5 Hz), 0.96 (3H, d, J=13.5 Hz), 1.46 (9H, s), 1.47-1.69 (1H, m), 2.22-2.35 (1H, m), 2.38-2.63 (1H, brs), 2.65-2.86 (2H, m), 2.93-3.04 (1H, m), 3.80-4.17 (2H, m).
Yield: 75%, 1H-NMR (CDCl3): 0.94 (3H, d, J=2.5 Hz), 0.96 (3H, d, J=2.5 Hz), 1.46 (9H, s), 1.53-1.70 (2H, m), 2.24-2.35 (1H, m), 2.36-2.65 (1H, m), 2.66-2.86 (2H, m), 2.93-3.04 (1H, m), 3.80-4.16 (2H, m).
A mixture of 2,6-dichlorobenzothiazole (1.00 g; 4.90 mmol), 1-piperazine-tert-butyl ester (0.96 g; 5.15 mmol), potassium carbonate (0.71 g; 5.15 mmol) and anhydrous N,N-dimethylformamide (10 ml) was stirred at room temperature for 14 hours and at 50° C. for 3 hours. Water was added to the reaction solution. The precipitate was collected and washed with diisopropyl ether to give 4-(6-chlorobenzothiazole-2-yl)piperazine-1-carboxylic acid tert-butyl ester as pale blackish brown crystal (1.50 g; 87%).
1H-NMR (DMSO-d6): δ1.43 (9H, s), 3.44-3.53 (4H, m), 3.55-3.60 (4H, m), 7.30 (1H, dd, J=8, 2 Hz), 7.44 (1H, d, J=8 Hz), 7.93 (1H, d, J=2 Hz).
Compounds in Reference Examples 85 to 154 were obtained by similar methods as Reference Example 84.
Yield: 97%, 1H-NMR (CDCl3); δ1.42 (9H, d, J=8.4 Hz), 2.01-2.07 (2H, m), 3.36 (1H, t, J=6.0 Hz), 3.44 (1H, t, J=5.7 Hz) 3.63-3.76 (6H, m) 7.24 (1H, dd, J=8.7, 2.1 Hz), 7.43 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.4 Hz).
Yield: 51%, 1H-NMR (DMSO-d6): δ1.43 (9H, s), 3.44-3.53 (4H, m), 3.55-3.65 (4H, m), 7.58 (2H, s), 8.27 (1H, s)
Yield: 47%, 1H-NMR (CDCl3): δ1.44 (9H, s), 2.06 (2H, quant, J=6 Hz), 3.35-3.50 (2H, m), 3.60-3.85 (6H, m), 7.50-7.60 (2H, m), 7.85 (1H, s).
Yield: 43%, 1H-NMR (CDCl3): δ1.29 (3H, d, J=7 Hz), 1.49 (9H, s), 2.85-3.10 (1H, m), 3.10-3.30 (1H, m), 3.40 (1H, td, J=13, 3.5 Hz), 3.75-4.25 (4H, m), 7.24 (1H, dd, J=8.5, 2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2 Hz).
Yield: 69%, 1H-NMR (CDCl3): δ1.16 (3H, d, J=6 Hz), 1.76 (1H, brs), 2.80 (1H, dd, J=12, 12 Hz), 2.90-2.95 (1H, m), 3.00 (1H, dd, J=12, 3 Hz), 3.15 (1H, td, J=12, 3 Hz), 3.21 (1H, dd, J=12, 3 Hz), 3.84-4.00 (2H, m), 7.24 (1H, dd, J=8.5, 2.5 Hz), 7.44 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.5 Hz).
Yield: 90%, 1H-NMR (CDCl3): δ1.15 (6H, d, J=6 Hz), 1.61 (1H, brs), 2.73 (2H, dd, J=12.5, 10 Hz), 2.95-3.10 (2H, m), 3.94 (2H, dd, J=12.5, 2.5 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=2 Hz), 7.55 (1H, d, J=8.5 Hz).
Yield: 40%, 1H-NMR (CDCl3): δ1.27 (3H, d, J=7 Hz), 1.37 (3H, d, J=7 Hz), 2.64 (1H, dd, J=12, 2.5 Hz), 3.20-3.35 (1H, m), 3.42 (1H, dd, J=12, 4.5 Hz), 3.50-3.65 (2H, m), 4.10-4.25 (1H, m), 7.23 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: 87%, 1H-NMR (CDCl3): δ1.16 (3H, d, J=6 Hz), 1.62 (1H, brs), 2.84 (1H, t, J=10.5 Hz), 2.90-3.00 (1H, m), 3.01 (1H, dd, J=12, 3 Hz), 3.14 (1H, dt, J=12, 2.5 Hz), 3.25 (1H, td, J=12, 3.5 Hz), 4.01 (2H, t, J=12 Hz), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield: 8%, 1H-NMR (CDCl3): δ1.27 (3H, d, J=6.5 Hz), 1.40 (3H, d, J=6.5 Hz), 1.65 (1H, brs), 2.66 (1H, dd, J=13, 2 Hz), 3.25-3.40 (1H, m), 3.43 (1H, dd, J=13, 4.5 Hz), 3.61 (2H, d, J=3 Hz), 4.20-4.28 (1H, m), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 38%, 1H-NMR (CDCl3): δ1.16 (6H, d, J=6.5 Hz), 1.54 (1H, brs), 2.76 (1H, d, J=12.5 Hz), 2.80 (1H, d, J=12.5 Hz), 2.95-3.08 (2H, m), 3.95-4.03 (2H, m), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield: 71%, 1H-NMR (CDCl3): δ1.15 (3H, d, J=6.3 Hz), 2.80 (1H, dd, J=12.3 Hz), 2.88-3.02 (2H, m), 3.08-3.23 (2H, m), 3.94 (2H, dd, J=12.3 Hz), 7.24 (1H, dd, J=2.1, 8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.1 Hz)
Yield: 77%, 1H-NMR (CDCl3): δ1.15 (3H, d, J=6.0 Hz), 2.80 (1H, dd, J=12.3 Hz), 2.89-3.02 (2H, m), 3.10-3.23 (2H, m), 3.95 (2H, t, J=12.3 Hz), 7.24 (1H, dd, J=2.4, 8.4 Hz), 7.44 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=2.4 Hz)
Yield: 48%, 1H-NMR (CDCl3): δ1.16 (3H, d, J=6.0 Hz), 2.86 (1H, d, J=12.0 Hz), 2.88-3.03 (2H, m), 3.11-3.16 (1H, m), 3.23 (1H, dt, J=3.3, 12.0 Hz), 4.01 (2H, t, J=12.6 Hz), 7.51-7.59 (2H, m), 7.85 (1H, s)
Yield: 63%, 1H-NMR (CDCl3): δ1.01 (3H, t, J=7.2 Hz), 1.44-1.53 (2H, m), 2.67-2.76 (1H, m), 2.80-2.88 (1H, m), 2.91-3.00 (1H, m), 3.10-3.20 (2H, m), 3.91-4.01 (2H, m), 7.24 (1H, dd, J=2.1, 8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.1 Hz), 8.02 (1H, s)
Yield: quant. %, 1H-NMR (CDCl3): δ1.16 (3H, d, J=6 Hz), 1.75 (1H, brs), 2.80-3.05 (3H, m), 3.08-3.18 (1H, m), 3.25 (1H, dd, J=12, 3.5 Hz), 4.00 (2H, t, J=12 Hz), 7.53 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield: quant. %, 1H-NMR (CDCl3): δ1.98 (1H, brs), 3.06-3.30 (3H, m), 3.38 (1H, dd, J=12, 3.5 Hz), 3.93 (1H, dd, J=10.5, 3 Hz), 4.05-4.18 (2H, m), 7.30-7.60 (7H, m), 7.86 (1H, s).
Yield: quant. %, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.38-1.60 (2H, m), 1.75 (1H, brs), 2.65-2.80 (1H, m), 2.85-3.00 (2H, m), 3.10-3.20 (1H, m), 3.25 (1H, td, J=12, 3.5 Hz), 3.95-4.10 (2H, m), 7.52 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=1.5 Hz).
Yield: 93%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.38-1.60 (2H, m), 1.78 (1H, brs), 2.67-2.78 (1H, m), 2.82-3.03 (2H, m), 3.09-3.32 (2H, m), 3.95-4.10 (2H, m), 7.52 (1H, d, J=8.5 Hz), 7.70 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield: quant. %, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.38-1.60 (2H, m), 1.83 (1H, brs), 2.65-2.78 (1H, m), 2.85-3.03 (2H, m), 3.10-3.18 (1H, m), 3.24 (1H, td, J=12, 3.5 Hz), 3.93-4.10 (2H, m), 7.52 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=1.5 Hz).
Yield: 84%, 1H-NMR (CDCl3): δ0.90-1.05 (3H, m), 1.35-1.54 (4H, m), 1.55-1.66 (2H, m), 2.75-3.02 (3H, m), 3.14 (1H, dt, J=12, 2 Hz), 3.25 (1H, td, J=12.5, 3.5 Hz), 4.01 (1H, t, J=11.5 Hz), 7.52 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=1.5 Hz).
Yield: 87%, 1H-NMR (CDCl3): δ0.96-0.99 (3H, m), 1.42-1.50 (4H, m), 2.83-3.01 (3H, m), 3.12-3.29 (2H, m), 4.01 (2H, t, J=9.9 Hz), 7.51-7.59 (2H, m), 7.85 (1H, s), 8.02 (1H, s)
Yield: quant. %, 1H-NMR (CDCl3): δ0.94 (3H, t, J=7.5 Hz), 1.29-1.54 (6H, m), 1.56-1.70 (2H, m), 2.73-3.05 (3H, m), 3.13 (1H, dt, J=12, 2 Hz), 3.25 (1H, td, J=12, 3.5 Hz), 4.01 (1H, t, J=10 Hz), 7.52 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=1.5 Hz).
Yield: 56%, 1H-NMR (CDCl3): δ0.95 (6H, dd, J=6.6, 8.4 Hz), 1.25-1.33 (2H, m), 1.71-1.80 (1H, m), 2.77-2.92 (2H, m), 2.96-3.00 (1H, m), 3.10-3.24 (2H, m), 3.95 (2H, d, J=10.5 Hz), 7.24 (1H, dd, J=2.1, 8.4 Hz), 7.44 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=2.1 Hz)
Yield: quant. %, 1H-NMR (CDCl3): δ0.93 (3H, d, J=6.5 Hz), 0.96 (3H, d, J=6.5 Hz), 1.26-1.35 (2H, m), 1.68 (1H, brs), 1.69-1.83 (1H, m), 2.73-3.03 (3H, m), 3.07-3.25 (2H, m), 3.90-4.00 (2H, m), 7.23 (1H, dd, J=8.5, 2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: quant. %, 1H-NMR (CDCl3): δ0.93 (3H, d, J=6.5 Hz), 0.96 (3H, d, J=6.5 Hz), 1.20-1.38 (2H, m), 1.60-1.84 (2H, m), 2.72-3.03 (2H, m), 3.05-3.26 (2H, m), 3.87-4.02 (2H, m), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.0 Hz).
Yield: quant. %, 1H-NMR (CDCl3): δ0.94 (3H, d, J=6.5 Hz), 0.97 (3H, d J=6.5 Hz), 1.27-1.37 (2H, m), 1.66 (1H, brs), 1.70-1.83 (1H, m), 2.80-3.03 (3H, m), 3.09-3.30 (2H, m), 3.95-4.05 (2H, m), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield 91%, 1H-NMR (CDCl3): δ0.94 (3H, d, J=6.5 Hz), 0.97 (3H, d, J=6.5 Hz), 1.27-1.36 (2H, m), 1.62-1.84 (2H, m), 2.81-3.03 (2H, m), 3.09-3.30 (2H, m), 3.94-4.07 (2H, m), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield: 91%, 1H-NMR (CDCl3): δ1.16 (3H, d, J=6 Hz), 1.58 (1H, brs), 2.80-3.03 (3H, m), 3.07-3.17 (1H, m), 3.24 (1H, td, J=12, 3.5 Hz), 3.99 (2H, t, J=11 Hz), 7.26 (1H, d, J=12 Hz), 7.75 (1H, d, J=6.5 Hz).
Yield: 91%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.37-1.62 (2H, m), 1.90 (1H, brs), 2.64-2.78 (1H, m), 2.84-3.03 (2H, m), 3.10-3.20 (1H, m), 3.21-3.32 (1H, m), 3.92-4.09 (2H, m), 7.27 (1H, d, J=12.5 Hz), 7.76 (1H, d, J=6.5 Hz).
Yield: 75%, 1H-NMR (CDCl3): δ1.32 (3H, d, J=6.5 Hz), 1.50 (9H, s), 2.90-3.30 (2H, m), 3.44 (1H, td, J=12.5, 3.5 Hz), 3.80-4.40 (4H, m), 7.53 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.86 (1H, d, J=1.5 Hz).
Yield: 61%, 1H-NMR (CDCl3): δ1.29 (3H, d, J=6 Hz), 1.49 (9H, s), 2.90-3.30 (2H, m), 3.34-3.48 (1H, m), 3.80-4.30 (4H, m), 7.25 (1H, dd, J=8.5, 2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=2 Hz).
Yield: 31%, 1H-NMR (CDCl3): δ1.30 (3H, d, J=6.5 Hz), 1.49 (9H, s), 2.91-3.29 (2H, m), 3.33-3.47 (1H, m), 3.76-4.34 (4H, m), 7.25 (1H, dd, J=8.5, 2.0 Hz), 7.44 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=2.0 Hz).
Yield: 65%, 1H-NMR (CDCl3): δ1.31 (3H, d, J=6.5 Hz), 1.50 (9H, s), 2.90-3.30 (2H, m), 3.44 (1H, td, J=12.5, 3.5 Hz), 3.85-4.35 (4H, m), 7.53 (1H, dd, J=8.5, 1.5 Hz), 7.58 (1H, d, J=8.5 Hz), 7.86 (1H, d, J=1.5 Hz).
Yield: 50%, 1H-NMR (CDCl3): δ1.32 (3H, d, J=6.5 Hz), 1.50 (9H, s), 2.85-3.27 (2H, m), 3.32-3.52 (1H, m), 3.82-4.38 (4H, m), 7.54 (1H, d, J=8.5 Hz), 7.58 (1H, d, J=8.5 Hz), 7.86 (1H, s).
Yield: 22%, 1H-NMR (CDCl3): δ1.00 (3H, t, J=7.5 Hz), 1.49 (9H, s), 1.63-1.78 (2H, m), 2.83-3.17 (2H, m), 3.26-3.41 (1H, m), 3.82-4.31 (4H, m), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.41 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2.0 Hz).
Yield: 41%, 1H-NMR (CDCl3): δ1.00 (3H, t, J=7.5 Hz), 1.49 (9H, s), 1.72 (2H, quant, J=7.5 Hz), 2.90-3.20 (3H, m), 3.26-3.42 (1H, m), 3.85-4.00 (2H, m), 4.10-4.30 (1H, m), 7.24 (1H, dd, J=8.5, 2 Hz), 7.41 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 25%, 1H-NMR (CDCl3): δ1.00 (3H, t, J=7.5 Hz), 1.49 (9H, s), 1.63-1.78 (2H, m), 2.82-3.19 (2H, m), 3.26-3.43 (1H, m), 3.80-4.30 (4H, m), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.41 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield: 67%, 1H-NMR (CDCl3): δ1.01 (3H, t, J=7.5 Hz), 1.49 (9H, s), 1.68-1.80 (2H, m), 2.90-3.20 (2H, m), 3.32-3.46 (1H, m), 3.90-4.32 (4H, m), 7.54 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield: 60%, 1H-NMR (CDCl3): δ1.01 (3H, t, J=7.5 Hz), 1.49 (9H, s), 1.74 (2H, quant, J=7.5 Hz), 2.90-3.20 (2H, m), 3.33-3.46 (1H, m), 3.92-4.31 (4H, m), 7.50-7.58 (2H, m), 7.85 (1H, s).
Yield: 43%, 1H-NMR (CDCl3): δ0.96 (3H, t, J=7.0 Hz), 1.25-1.75 (4H, m), 1.49 (9H, s), 2.84-3.18 (2H, m), 3.36 (1H, td, J=12.5, 3.0 Hz), 3.85-4.32 (4H, m), 7.24 (1H, dd, J=8.5, 2.0 Hz), 7.41 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.0 Hz).
Yield: 33%, 1H-NMR (CDCl3, 328K): δ0.96 (3H, t, J=7.2 Hz), 1.36-1.49 (2H, m), 1.49 (9H, s), 1.59-1.71 (2H, m), 2.98 (1H, t, J=11.1 Hz), 3.10 (1H, d, J=11.1 Hz), 3.36 (1H, dt, J=3.3, 13.2 Hz), 3.93-4.12 (4H, m), 7.22 (1H, s), 7.41 (1H, d, J=8.4 Hz), 7.54 (1H, s)
Yield: 40%, 1H-NMR (CDCl3): δ0.97 (3H, t, J=7.0 Hz), 1.20-1.55 (2H, m), 1.50 (9H, s), 1.56-1.77 (2H, m), 2.83-3.21 (2H, m), 3.40 (1H, td, J=13.0, 3.0 Hz), 3.88-4.35 (4H, m), 7.52 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 64%, 1H-NMR (CDCl3, 328K): δ0.97 (3H, t, J=7.2 Hz), 1.27-1.49 (2H, m), 1.49 (9H, s), 1.69 (2H, br), 2.99 (1H, t, J=11.7 Hz), 3.11 (1H, d, J=12.6 Hz), 3.39 (1H, td, J=12.6 Hz), 3.97-4.14 (4H, m), 7.53 (2H, s, J=Hz), 7.83 (1H, s)
Yield: 18%, 1H-NMR (CDCl3): δ0.85-0.97 (3H, m), 1.30-1.45 (4H, m), 1.49 (9H, s), 1.59-1.75 (2H, m), 2.86-3.19 (2H, m), 3.30-3.43 (1H, m), 3.90-4.30 (4H, m), 7.24 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 50%, 1H-NMR (CDCl3): δ0.84-0.98 (3H, m), 1.25-1.75 (15H, m), 2.85-3.20 (2H, m), 3.30-3.45 (1H, m), 3.90-4.30 (4H, m), 7.24 (1H, dd, J=9, 2 Hz), 7.42 (1H, d, J=9 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 58%, 1H-NMR (CDCl3): δ0.85-0.97 (3H, m), 1.30-1.45 (4H, m), 1.50 (9H, s), 1.63-1.78 (2H, m), 2.85-3.20 (2H, m), 3.33-3.43 (1H, m), 3.95-4.35 (4H, m), 7.50-7.58 (2H, m), 7.85 (1H, s).
Yield: 11%, 1H-NMR (CDCl3): δ0.92 (3H, d, J=6.5 Hz), 1.13 (3H, d, J=6.5 Hz), 1.49 (9H, s), 2.07-2.27 (1H, m), 2.70-3.15 (2H, m), 3.25-3.44 (1H, m), 3.59-3.75 (1H, m), 3.95-4.46 (3H, m), 7.52 (1H, s), 7.53 (1H, s), 7.83 (1H, s).
Yield: 31%, 1H-NMR (CDCl3): δ0.91 (3H, d, J=6.5 Hz), 1.13 (3H, d, J=6.5 Hz), 1.49 (9H, s), 2.12-2.24 (1H, m), 2.84-3.13 (2H, m), 3.27-3.43 (1H, m), 3.60-3.75 (1H, m), 4.02-4.40 (3H, m), 7.53 (2H, s), 7.83 (1H, s).
Yield: 26%, 1H-NMR (CDCl3): δ0.98 (3H, d, J=6.5 Hz), 1.00 (3H, d, J=6.5 Hz), 1.33-1.75 (3H, m), 1.49 (9H, s), 2.84-3.22 (2H, m), 3.37 (1H, td, J=13.0, 3.5 Hz), 3.88-4.32 (4H, m), 7.24 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.0 Hz).
Yield: 54%, 1H-NMR (CDCl3): δ0.90-1.05 (6H, m), 1.35-1.48 (2H, m), 1.49 (9H, s), 1.58-1.73 (1H, m), 2.85-3.20 (2H, m), 3.30-3.43 (1H, m), 3.90-4.30 (4H, m), 7.35 (1H, dd, J=8.5, 2 Hz), 7.41 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=2 Hz).
Yield: 43%, 1H-NMR (CDCl3): δ0.99 (3H, d, J=6.5 Hz), 1.00 (3H, d, J=6.5 Hz), 1.37-1.52 (1H, m), 1.49 (9H, s), 1.57-1.75 (2H, m), 2.84-3.23 (2H, m), 3.40 (1H, td, J=13.0, 3.5 Hz), 3.94-4.35 (4H, m), 7.48-7.58 (2H, m), 7.85 (1H, s).
Yield: 57%, 1H-NMR (CDCl3, 328K): δ1.00 (6H, t, J=6.0 Hz), 1.40-1.52 (1H, m), 1.49 (9H, s), 1.60-1.69 (2H, m), 2.99 (1H, t, J=10.8 Hz), 3.12 (1H, d, J=10.8 Hz), 3.40 (1H, dt, J=3.6, 12.9 Hz), 3.98-4.13 (4H, m), 7.49-7.56 (2H, m), 7.84 (1H, s)
Yield: 46%, 1H-NMR (CDCl3): δ1.10 (3H, d, J=7.0 Hz), 1.26 (3H, d, J=7.0 Hz), 2.98 (1H, td, J=12.5, 3.5 Hz), 3.06-3.17 (2H, m), 3.35 (1H, td, J=12.5, 3.5 Hz), 3.75-3.93 (1H, m), 4.00-4.18 (1H, m), 7.46-7.62 (2H, m), 7.85 (1H, s).
Yield: 96%, 1H-NMR (CDCl3): δ1.49 (9H, s), 3.54-3.70 (8H, m), 7.29 (1H, d, J=7.0 Hz), 7.78 (1H, d, J=11.5 Hz).
Yield: 90%, 1H-NMR (CDCl3): δ1.43 (9H, s), 2.00-2.13 (2H, m), 3.32-3.54 (2H, m), 3.62-3.89 (6H, m), 7.28 (1H, d, J=7.0 Hz), 7.75 (1H, d, J=11.5 Hz).
Yield: 64%, 1H-NMR (CDCl3): δ1.32 (3H, d, J=7.0 Hz), 1.50 (9H, s), 2.94-3.15 (2H, m), 3.44 (1H, td, J=12.5, 3.5 Hz), 3.77-4.42 (4H, m), 7.28 (1H, d, J=12.0 Hz), 7.77 (1H, d, J=7.0 Hz).
Yield: 57%, 1H-NMR (CDCl3): δ1.32 (3H, d, J=7.0 Hz), 1.50 (9H, s), 2.88-3.32 (2H, m), 3.45 (1H, td, J=12.5, 3.5 Hz), 3.75-4.36 (4H, m), 7.29 (1H, d, J=12.0 Hz), 7.77 (1H, d, J=7.0 Hz).
Yield: 93%, 1H-NMR (CDCl3): δ1.17 (6H, d, J=6.0 Hz), 2.76 (1H, d, J=12.5 Hz), 2.81 (1H, d, J=12.5 Hz), 2.94-3.08 (2H, m), 3.97 (2H, d, J=12.5 Hz), 7.27 (1H, d, J=11.5 Hz), 7.75 (1H, d, J=7.0 Hz).
Yield: 55%, 1H-NMR (CDCl3): δ1.49 (9H, s), 3.43-3.66 (8H, m), 7.22 (1H, t, J=7.5 Hz), 7.33 (2H, t, J=7.5 Hz), 7.41 (1H, s), 7.43 (2H, d, J=7.5 Hz).
Yield: 78%, 1H-NMR (CDCl3): δ1.49 (9H, s), 3.55-3.67 (8H, m), 7.10 (1H, td, J=8.0, 1.0 Hz), 7.31 (1H, td, J=8.0, 1.0 Hz), 7.57 (1H, dd, J=8.0, 1.0 Hz), 7.61 (1H, dd, J=8.0, 1.0 Hz).
Yield: 42%, H-NMR (CDCl3): δ1.00 (3H, t, J=7.5 Hz), 1.49 (9H, s), 1.64-1.79 (2H, m), 2.85-3.19 (2H, m), 3.28-3.44 (1H, m), 3.83-4.33 (4H, m), 7.27 (1H, d, J=10.0 Hz), 7.55 (1H, d, J=7.0 Hz).
Yield: 60%, 1H-NMR (CDCl3): δ1.50 (9H, s), 3.55-3.68 (4H, m), 3.73-3.85 (4H, m), 7.37-7.47 (1H, m), 7.59 (1H, td, J=8.0, 1.0 Hz), 7.69 (1H, dd, J=8.0, 1.0 Hz), 7.89 (1H, dd, J=8.0, 1.0 Hz), 8.58 (1H, s).
Yield: 60%, 1H-NMR (CDCl3): δ1.50 (9H, s), 3.56-3.67 (4H, m), 3.73-3.84 (4H, m), 7.53 (1H, dd, J=9.0, 2.0 Hz), 7.62 (1H, d, J=9.0 Hz), 7.88 (1H, d, J=2.0 Hz), 8.57 (1H, s).
Yield: 70%, 1H-NMR (CDCl3): δ1.20 (3H, d, J=6.5 Hz), 2.68 (1H, dd, J=13.0, 10.5 Hz), 2.86-3.22 (4H, m), 4.37-4.48 (2H, m), 7.35-7.44 (1H, m), 7.53-7.62 (1H, m), 7.68 (1H, dd, J=8.5, 1.5 Hz), 7.88 (1H, dd, J=8.5, 1.5 Hz), 8.58 (1H, s).
Yield: 27%, 1H-NMR (CDCl3): δ1.50 (9H, s), 3.53-3.64 (4H, m), 3.68-3.78 (4H, m), 6.98 (1H, d, J=9.0 Hz), 7.25 (1H, td, J=8.0, 1.5 Hz), 7.55 (1H, td, J=8.0, 1.5 Hz), 7.61 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=8.0 Hz), 7.92 (1H, d, J=9.0 Hz)
Yield: 51%, 1H-NMR (CDCl3): δ1.20 (6H, d, J=6.0 Hz), 2.58 (1H, d, J=12.5 Hz), 2.62 (1H, d, J=12.5 Hz), 2.93-3.07 (2H, m), 4.43 (2H, dd, J=12.5, 2.0 Hz), 7.38 (1H, td, J=8.5, 1.5 Hz), 7.57 (1H, td, J=8.5, 1.5 Hz), 7.68 (1H, dd, J=8.5, 1.5 Hz), 7.87 (1H, dd, J=8.5, 1.5 Hz), 8.58 (1H, s).
Yield: 88%, 1H-NMR (CDCl3): δ1.20 (6H, d, J=6.5 Hz), 2.58 (1H, d, J=13.0 Hz), 2.62 (1H, d, J=13.0 Hz), 2.92-3.07 (2H, m), 4.42 (2H, dd, J=13.0, 2.0 Hz), 7.50 (1H, dd, J=9.0, 2.0 Hz), 7.60 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=2.0 Hz), 8.57 (1H, s).
Yield: quant. %, 1H-NMR (CDCl3): δ1.21 (6H, d, J=6.0 Hz), 2.62 (1H, d, J=12.5 Hz), 2.66 (1H, d, J=12.5 Hz), 2.92-3.06 (2H, m), 4.49 (2H, dd, J=12.5, 2.0 Hz), 7.71-7.75 (2H, m), 8.14 (1H, s), 8.63 (1H, s).
Yield: 52%, 1H-NMR (CDCl3): δ1.31 (3H, d, J=6.5 Hz), 1.51 (9H, s), 2.95-3.19 (1H, m), 3.21-3.31 (1H, m), 3.32-3.45 (1H, m), 3.92-4.41 (3H, m), 4.68-4.82 (1H, m), 7.72 (1H, s), 7.73 (1H, s), 8.17 (1H, s), 8.60 (1H, s).
Yield: 72%, 1H-NMR (CDCl3): δ1.50 (9H, s), 2.73 (3H, s), 3.37-3.46 (4H, m), 3.62-3.70 (4H, m), 7.76 (1H, d, J=9.0 Hz), 7.89 (1H, d, J=9.0 Hz), 8.19 (1H, s).
To 4N solution of hydrochloric acid-dioxane was added 4-(6-chlorobenzothiazole-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.50 g; 4.239 mmol). The mixture was stirred at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was washed with ethyl acetate to give 4-(6-chlorobenzothiazole-2-yl)piperazine dihydrochloride as colorless crystal (1.40 g; 100%).
1H-NMR (DMSO-d6): δ3.15-3.25 (4H, m), 3.84 (4H, t, J=5 Hz), 6.88 (1H, brs), 7.34 (1H, dd, J=8.5, 2 Hz), 7.50 (1H, d, J=8.5 Hz), 7.99 (1H, d, J=2 Hz), 9.71 (2H, brs).
Compounds in Reference Examples 156 to 194 were obtained by similar methods as Reference Example 155.
Yield: 100%, 1H-NMR (DMSO-d6): δ2.13-2.20 (2H, m), 3.20-3.22, (2H, m), 3.33-3.35 (2H, m), 3.68-3.72 (2H, m), 3.98-4.00 (2H, m), 7.33 (1H, dd, J=8.7 Hz, 2.4 Hz), 7.47 (1H, d, J=9.0 Hz), 7.97 (1H, d, J=2.1 Hz), 9.35 (2H, br-s).
Yield: 99%, 1H-NMR (DMSO-d6): δ3.26 (4H, t, J=5 Hz), 3.90 (4H, t, J=5 Hz), 7.64 (2H, s), 8.34 (1H, s), 8.65 (1H, brs), 9.77 (2H, s).
Yield: 99%, 1H-NMR (DMSO-d6): δ2.10-2.25 (2H, m), 3.20-3.30 (2H, m), 3.30-3.40 (2H, m), 3.70-3.80 (2H, m), 4.00-4.10 (2H, m), 6.64 (1H, brs), 7.60 (2H, s), 8.30 (1H, s), 9.47 (2H, s).
Yield: 91%, 1H-NMR (DMSO-d6): δ1.39 (3H, d, J=7 Hz), 3.03-3.18 (1H, m), 3.25-3.40 (4H, m), 3.95-4.05 (1H, m), 4.44-4.55 (1H, m), 7.34 (1H, dd, J=8.5, 2 Hz), 7.49 (1H, d, J=8.5 Hz), 7.96 (1H, d, J=2 Hz), 9.09 (1H, brs), 9.55 (2H, brs).
Yield: 82%, 1H-NMR (CDCl3): δ1.40 (3H, d, J=6.5 Hz), 1.67 (1H, brs), 2.77-2.95 (2H, m), 3.05-3.15 (2H, m), 3.40 (1H, td, J=12.5, 3.5 Hz), 3.87 (1H, dd, J=12.5, 3.5 Hz), 4.15-4.30 (1H, m), 7.51 (1H, dd, J=8.5, 1 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1 Hz).
Yield: quant. %, 1H-NMR (DMSO-d6): δ1.42 (3H, d, J=7 Hz), 2.95-3.15 (1H, m), 3.15-3.40 (3H, m), 3.48-3.65 (1H, m), 3.95 (1H, m), 4.40-4.55 (1H, m), 7.33 (1H, dd, J=8.5, 2 Hz), 7.48 (1H, d, J=8.5 Hz), 7.98 (1H, d, J=2 Hz), 8.16 (1H, brs), 9.51 (1H, brs), 9.94 (1H, brs).
Yield: 94%, 1H-NMR (DMSO-d6): δ1.42 (3H, d, J=7.0 Hz), 2.98-3.15 (1H, m), 3.16-3.38 (3H, m), 3.47-3.63 (1H, m), 3.96-4.08 (1H, m), 4.40-4.53 (1H, m), 5.10 (1H, s), 7.33 (1H, dd, J=8.5, 2.0 Hz), 7.49 (1H, d, J=8.5 Hz), 7.97 (1H, d, J=2.0 Hz), 9.35-9.53 (1H, br), 9.82-9.98 (1H, br).
Yield: 100%, 1H-NMR (CDCl3): δ1.40 (3H, d, J=7 Hz), 2.84-2.96 (2H, m), 3.05-3.15 (2H, m), 3.39 (1H, dt, J=12.5, 3.5 Hz), 3.88 (1H, dd, J=12.5, 2.5 Hz), 4.15-4.25 (1H, m), 7.52 (1H, dd, J=8.5, 1.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=1.5 Hz).
Yield: 80%, 1H-NMR (DMSO-d6): δ1.41 (3H, d, J=7.0 Hz), 3.00-3.17 (1H, m), 3.18-3.38 (3H, m), 3.49-3.64 (1H, m), 4.05-4.14 (1H, m), 4.45-4.58 (1H, m), 6.03 (1H, brs) 7.61 (2H, m), 8.31 (1H, s), 9.25-9.50 (1H, m), 9.73-9.92 (1H, m).
Yield: 71%, 1H-NMR (DMSO-d6): δ0.91 (3H, t, J=7.5 Hz), 1.80-1.96 (2H, m), 3.01-3.16 (1H, m), 3.17-3.42 (3H, m), 3.43-3.59 (1H, m), 4.08-4.27 (2H, m), 4.43 (1H, s), 7.33 (1H, dd, J=8.5, 2.0 Hz), 7.46 (1H, d, J=8.5 Hz), 7.94 (1H, d, J=2.0 Hz), 9.22-9.44 (1H, m), 9.60-9.75 (1H, m).
Yield: 99%, 1H-NMR (CDCl3): δ0.98 (3H, t, J=7.5 Hz), 1.63 (1H, brs), 1.88 (2H, quant, J=7.5 Hz), 2.88 (1H, td, J=12, 3.5 Hz), 2.95-3.10 (3H, m), 3.34 (1H, td, J=12.5, 3.5 Hz), 3.77-3.86 (1H, m), 3.90-4.00 (1H, m), 7.22 (1H, dd, J=8.5, 2 Hz), 7.40 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2 Hz).
Yield: quant. % 1H-NMR (DMSO-d6): δ0.90 (3H, t, J=7.5 Hz), 1.84-2.05 (2H, m), 2.94-3.62 (5H, m), 4.07-4.26 (2H, m), 6.71 (1H, brs), 7.32 (1H, dd, J=8.5, 2.0 Hz), 7.46 (1H, d, J=8.5 Hz), 7.96 (1H, d, J=2.0 Hz), 9.35-9.58 (1H, m), 9.73-9.95 (1H, m).
Yield: quant. %, 1H-NMR (CDCl3): δ0.98 (3H, t, J=7.5 Hz), 1.61 (1H, brs), 1.90 (2H, quant, J=7.5 Hz), 2.89 (1H, td, J=12, 3.5 Hz), 2.95-3.13 (3H, m), 3.37 (1H, td, J=12.5, 3.5 Hz), 3.83-3.94 (1H, m), 3.95-4.06 (1H, m), 7.45-7.56 (2H, m), 7.83 (1H, s).
Yield: quant. %, 1H-NMR (CDCl3): δ0.98 (3H, t, J=7.5 Hz), 1.72 (1H, brs), 1.91 (2H, quant, J=7.5 Hz), 2.89 (1H, td, J=12.5, 3.5 Hz), 2.95-3.13 (3H, m), 3.38 (1H, td, J=12.5, 3.5 Hz), 3.84-3.95 (1H, m), 3.95-4.08 (1H, m), 7.50 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield: quant. %, 1H-NMR (DMSO-d6): δ0.92 (3H, t, J=7.0 Hz), 1.20-1.45 (2H, m), 1.78-1.92 (2H, q, J=7.5 Hz), 2.97-3.38 (4H, m), 3.42-3.59 (1H, m), 4.04-4.17 (1H, m), 4.22-4.34 (1H, m), 5.64 (1H, br), 7.31 (1H, dd, J=8.5, 2.5 Hz), 7.45 (1H, d, J=8.5 Hz), 7.96 (1H, d, J=2.5 Hz), 9.04-9.20 (1H, m), 9.50-9.64 (1H, m).
Yield: quant. %, 1H-NMR (CDCl3): δ0.99 (3H, t, J=6.6 Hz), 1.26-1.49 (4H, m), 2.11 (2H, br), 3.63-3.83 (3H, m), 4.10 (1H, br), 4.51 (1H, br), 4.64 (1H, br), 7.22 (1H, s), 7.56-7.63 (2H, m)
Yield: quant. %, 1H-NMR (DMSO-d6): δ0.93 (3H, t, J=7.5 Hz), 1.18-1.46 (2H, m), 1.80-1.95 (2H, m), 3.00-3.40 (4H, m), 3.45-3.62 (1H, m), 4.12-4.24 (1H, m), 4.29-4.42 (1H, m), 7.54-7.65 (2H, m), 8.31 (1H, s), 9.14-9.32 (1H, m), 9.60-9.72 (1H, m).
Yield: quant. %, 1H-NMR (CDCl3): δ1.00 (3H, t, J=6.0 Hz), 1.26-1.54 (4H, m), 2.17 (2H, br), 3.63-3.86 (3H, m), 4.11 (1H, br), 4.54 (1H, br), 4.70 (1H, br), 7.50 (1H, d, J=7.5 Hz), 7.72 (1H, d, J=7.5 Hz), 7.91 (1H, s)
Yield: quant. %, 1H-NMR (DMSO-d6): δ0.87 (3H, t, J=7 Hz), 1.20-1.39 (4H, m), 1.78-1.95 (2H, m), 3.00-3.15 (1H, m), 3.15-3.40 (3H, m), 3.42-3.55 (1H, m), 4.07-4.20 (1H, m), 4.20-4.30 (1H, m), 4.55 (1H, brs), 7.31 (1H, dd, J=8.5, 2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.95 (1H, d, J=2 Hz), 9.00 (1H, brs), 9.48 (1H, brs).
Yield: quant. %, 1H-NMR (DMSO-d6): δ0.87 (3H, t, J=7 Hz), 1.18-1.40 (4H, m), 1.77-1.98 (2H, m), 2.95-3.14 (1H, m), 3.14-3.37 (3H, m), 3.40-3.51 (1H, m), 4.08-4.20 (1H, m), 4.20-4.31 (1H, m), 6.89 (1H, brs), 7.31 (1H, dd, J=8.5, 2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.95 (1H, d, J=2 Hz), 9.25 (1H, brs), 9.62 (1H, brs).
Yield: quant. %, 1H-NMR (DMSO-d6): δ0.85-0.90 (3H, m), 1.20-1.40 (4H, m), 1.85-2.00 (2H, m), 3.00-3.59 (5H, m), 4.15-4.23 (1H, m), 4.24-4.35 (1H, m), 7.60 (2H, s), 8.29 (1H, s), 9.36 (2H, brs), 9.75 (1H, s).
Yield: quant. %, 1H-NMR (DMSO-d6): δ0.86 (3H, d, J=6.5 Hz), 1.04 (3H, d, J=6.5 Hz), 3.00-3.35 (4H, m), 3.38-3.60 (2H, m), 3.87-4.02 (1H, m), 4.16-4.31 (1H, m), 5.20 (1H, br), 7.57 (1H, d, J=8.5 Hz), 7.61 (1H, d, J=8.5 Hz), 8.29 (1H, s), 9.05-9.22 (1H, m), 9.37-9.50 (1H, m).
Yield: 93%, H-NMR (DMSO-d6): δ0.86 (3H, d, J=6.5 Hz), 1.00 (3H, d, J=6.5 Hz), 2.50-2.60 (1H, m), 3.03-3.31 (3H, m), 3.44-3.60 (2H, m), 3.90-4.00 (1H, m), 4.20-4.30 (1H, m), 7.54-7.63 (2H, m), 8.29 (1H, s), 9.23 (1H, brs), 9.48 (2H, brs).
Yield: 96%, 1H-NMR (DMSO-d6): δ0.95 (6H, d, J=6.5 Hz), 1.50-1.90 (3H, m), 2.96-3.37 (4H, m), 3.40-3.60 (1H, m), 4.03-4.16 (1H, m), 4.27-4.40 (1H, m), 6.30 (1H, br), 7.32 (1H, dd, J=8.5, 2.0 Hz), 7.45 (1H, d, J=8.5 Hz), 7.97 (1H, d, J=2.0 Hz), 9.10-9.32 (1H, m), 9.52-9.75 (1H, m).
Yield: quant. %, 1H-NMR (DMSO-d6): δ0.94 (6H, d, J=6.5 Hz), 1.52-1.94 (3H, m), 2.95-3.35 (4H, m), 3.45-3.57 (1H, m), 4.04-4.16 (1H, m), 4.29-4.40 (1H, m), 7.32 (1H, dd, J=8.5, 2 Hz), 7.45 (1H, d, J=8.5 Hz), 7.97 (1H, d, J=2 Hz), 9.45 (1H, brs), 9.81 (1H, brs), 9.84 (1H, brs).
Yield: quant. %, 1H-NMR (DMSO-d6): δ0.96 (6H, d, J=6.5 Hz), 1.50-1.90 (3H, m), 2.99-3.39 (4H, m), 3.46-3.63 (1H, m), 4.08-4.22 (1H, m), 4.35-4.48 (1H, m), 6.11 (1H, brs), 7.60 (2H, s), 8.31 (1H, s), 9.10-9.29 (1H, m), 9.54-9.67 (1H, m).
Yield: 97%, 1H-NMR (CDCl3): δ1.04 (6H, s), 1.68 (1H, br), 1.98 (1H, br), 2.07 (1H, br), 3.54 (3H, br), 3.71 (1H, br), 3.98 (1H, s), 4.46 (2H, br), 7.52 (1H, d, J=7.5 Hz), 7.65 (1H, d, J=7.5 Hz), 7.90 (1H, s)
Yield: 94%, 1H-NMR (DMSO-d6): δ3.24 (4H, t, J=5.0 Hz), 3.74 (4H, t, J=5.0 Hz), 5.12 (1H, s), 7.26 (1H, t, J=7.5 Hz), 7.39 (2H, t, J=7.5 Hz), 7.51 (2H, d, J=7.5 Hz), 7.71 (1H, s), 9.58 (2H, s).
Yield: 96%, 1H-NMR (DMSO-d6): δ3.17-3.34 (4H, m), 3.83-3.96 (4H, m), 5.12 (1H, brs), 7.55 (1H, d, J=12.5 Hz), 8.36 (1H, d, J=7.5 Hz), 9.69 (2H, brs).
Yield: 92%, 1H-NMR (DMSO-d6): δ2.14-2.27 (2H, m), 3.16-3.30 (2H, m), 3.31-3.43 (2H, m), 3.66-3.84 (2H, m), 3.97-4.13 (2H, m), 4.78 (1H, brs), 7.53 (1H, d, J=12.5 Hz), 8.32 (1H, d, J=7.5 Hz), 9.53 (2H, brs).
Yield: 89%, 1H-NMR (CDCl3): δ1.44 (3H, d, J=7.0 Hz), 3.00-3.13 (1H, m), 3.14-3.40 (3H, m), 3.53-3.69 (1H, m), 4.02-4.15 (1H, m), 4.46-4.60 (1H, m), 6.90 (1H, brs), 7.55 (1H, d, J=12.5 Hz), 8.35 (1H, d, J=7.0 Hz), 9.50 (1H, br), 9.94 (1H, br).
Yield: 83%, 1H-NMR (DMSO-d6): δ1.44 (3H, d, J=7.0 Hz), 3.01-3.19 (1H, m), 3.20-3.45 (3H, m), 3.51-3.70 (1H, m), 4.01-4.16 (1H, m), 4.45-4.62 (1H, m), 5.95 (1H, brs), 7.55 (1H, d, J=12.5 Hz), 8.35 (1H, d, J=7.5 Hz), 9.49 (1H, br), 9.89 (1H, br).
Yield: 83%, 1H-NMR (DMSO-d6): δ0.90 (3H, t, J=7.5 Hz), 1.80-2.00 (2H, m), 2.97-3.40 (4H, m), 3.41-3.56 (1H, m), 4.06-4.26 (2H, m), 7.49 (1H, d, J=10.5 Hz), 8.10 (1H, d, J=7.5 Hz), 9.02-9.25 (1H, m), 9.43-9.65 (1H, m).
Yield: quant. %, 1H-NMR (DMSO-d6): δ3.16-3.32 (4H, m), 3.98-4.12 (4H, m), 7.42-7.51 (1H, m), 7.60-7.72 (2H, m), 7.88 (1H, d, J=8.0 Hz), 8.90 (1H, s), 9.54 (2H, s).
Yield: 92%, 1H-NMR (DMSO-d6): δ2.19-3.32 (4H, m), 3.80-3.90 (4H, m), 7.15 (1H, td, J=8.0, 1.0 Hz), 7.34 (1H, td; J=8.0, 1.0 Hz), 7.54 (1H, dd, J=8.0, 1.0 Hz), 7.85 (1H, dd, J=8.0, 1.0 Hz), 9.65 (2H, s).
Yield: 91%, 1H-NMR (DMSO-d6): δ3.30 (4H, s), 3.80 (1H, br), 4.16 (4H, s), 7.38-7.60 (2H, m), 7.68-7.81 (1H, m), 7.84-7.97 (1H, m), 8.16 (1H, br), 8.32-8.52 (1H, m), 9.57 (2H, brs).
Yield: 63%, 1H-NMR (DMSO-d6): δ3.24 (4H, s), 3.87 (1H, brs), 4.03 (4H, s), 7.66 (2H, s), 7.93 (1H, s), 8.92 (1H, s), 9.38 (2H, brs).
Yield: 82%, 1H-NMR (DMSO-d6): δ2.71 (3H, s), 3.24-3.35 (4H, m), 3.62-3.73 (4H, m), 7.91 (1H, d, J=9.0 Hz), 7.97 (1H, d, J=9.0 Hz), 8.23 (1H, s), 9.32 (2H, brs).
Yield: 80%, 1H-NMR (DMSO-d6): δ1.39 (3H, d, J=7.0 Hz), 3.00-3.16 (1H, m), 3.18-3.54 (5H, m), 4.68 (1H, d, J=14.0 Hz), 5.05-5.17 (1H, m), 7.79 (1H, d, J=8.5 Hz), 7.89 (1H, d, J=8.5 Hz), 8.20 (1H, s), 8.97 (1H, s), 9.19 (1H, brs), 9.53 (1H, brs).
A mixture of 4-(6-chlorobenzothiazole-2-yl)piperazine dihydrochloride (3.00 g; 9.18 mmol), 3-(bromomethyl)methyl butanoate (2.31 g; 10.1 mmol), potassium carbonate (3.81 g; 27.6 mmol) and anhydrous N,N-dimethylformamide (30 ml) was stirred at room temperature for 14 hours. Water was added to the reaction solution. The precipitate was collected and washed with diisopropyl ether to give 3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]benzoic acid methyl ester as colorless crystal (3.06 g; 83%).
1H-NMR (CDCl3): δ2.58 (4H, t, J=5 Hz), 3.61 (2H, s), 3.64 (4H, t, J=5 Hz), 3.93 (3H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.35-7.45 (1H, m), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz), 7.55-7.60 (1H, m), 7.96 (1H, d, J=7.5 Hz), 8.01 (1H, s).
Compounds in Example 2 to 127 were obtained by similar methods as Example 1.
Yield: 88%, 1H-NMR (CDCl3): δ2.01-2.05 (2H, m), 2.69 (2H, t, J=5.4 Hz), 2.80-2.83 (2H, m), 3.67 (2H, s) 3.72-3.78 (4H, m), 3.92 (3H, s), 7.23 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.37-7.44 (2H, m), 7.53 (1H, s), 7.55 (1H, d, J=2.1 Hz), 7.94 (1H, d, J=7.5 Hz), 7.99 (1H, s).
Yield: 73%, 1H-NMR (CDCl3): δ2.60 (4H, t, J=5 Hz), 3.62 (2H, s), 3.67 (4H, t, J=5 Hz), 3.97 (3H, s), 7.43 (1H, t, J=7.5 Hz), 7.50-7.60 (3H, m), 7.85 (1H, s), 7.97 (1H, d, J=7.5 Hz), 8.02 (1H, s).
Yield: q.y, 1H-NMR (CDCl3): δ2.00-2.20 (2H, m), 2.70 (2H, t, J=5.5 Hz), 2.83 (2H, t, J=5.5 Hz), 3.69 (2H, s), 3.70-3.85 (4H, m), 3.92 (3H, s), 7.40 (1H, t, J=7.5 Hz), 7.50-7.60 (3H, m), 7.84 (1H, s), 7.94 (1H, d, J=7.5 Hz), 7.99 (1H, s).
Yield: 97%, 1H-NMR (CDCl3): δ1.41 (3H, d, J=6 Hz), 2.28 (1H, td, J=11.5, 3.5 Hz), 2.36 (1H, dd, J=11.5, 3.5 Hz), 2.69 (1H, d, J=11.5 Hz), 2.90 (1H, d, J=11.5 Hz), 3.40-3.55 (2H, m), 3.63 (1H, d, J=12.5 Hz), 3.80-3.90 (1H, m), 3.93 (3H, s), 4.10-4.25 (1H, m), 7.22 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.43 (1H, t, J=7.5 Hz), 7.54 (1H, d, J=2 Hz), 7.58 (1H, d, J=7.5 Hz), 7.95 (1H, d, J=7.5 Hz), 8.02 (1H, s).
Yield: q.y, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6 Hz), 2.25-2.35 (1H, m), 2.60-2.73 (1H, m), 2.73-2.82 (1H, m), 3.17 (1H, dd, J=12.5, 9 Hz), 3.33 (1H, d, J=13.5 Hz), 3.35-3.45 (1H, m), 3.65-3.75 (1H, m), 3.85-3.90 (1H, m), 3.93 (3H, s), 4.08 (1H, d, J=13.5 Hz), 7.22 (1H, dd, J=8.5, 2 Hz), 7.41 (1H, t, J=7.5 Hz), 7.43 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz), 7.56 (1H, d, J=7.5 Hz), 7.94 (1H, d, J=7.5 Hz), 8.01 (1H, s).
Yield: 83%, 1H-NMR (CDCl3): δ1.15 (6H, d, J=6 Hz), 2.75-2.85 (2H, m), 3.06 (2H, dd, J=13, 12.5 Hz), 3.80-3.92 (4H, m), 3.92 (3H, s), 7.24 (1H, dd, J=8.5, 2 Hz), 7.37 (1H, d, J=7.5 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz), 7.62 (1H, d, J=7.5 Hz), 7.89 (1H, d, J=7.5 Hz), 8.04 (1H, s).
Yield: 79%, 1H-NMR (CDCl3): δ1.10 (3H, d, J=6.5 Hz), 1.38 (3H, d, J=6.5 Hz), 2.31 (1H, d, J=12 Hz), 2.91 (1H, dd, J=12.4 Hz), 3.10-3.20 (1H, m), 3.59 (2H, t, J=14 Hz), 3.71 (2H, t, J=14 Hz), 3.93 (3H, s), 4.16-4.28 (1H, m), 7.22 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.43 (1H, d, J=7.5 Hz), 7.53 (1H, d, J=2 Hz), 7.61 (1H, d, J=7.5 Hz), 7.95 (1H, d, J=7.5 Hz), 8.06 (1H, s).
Yield 92%, 1H-NMR (CDCl3): δ2.45 (3H, s), 2.58 (4H, t, J=5 Hz), 3.55 (2H, s), 3.61 (4H, t, J=5 Hz), 3.91 (3H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.24 (1H, d, J=8 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz), 7.87 (1H, dd, J=8, 1.5 Hz), 7.92 (1H, d, J=1.5 Hz).
Yield 93%, 1H-NMR (CDCl3): δ2.66 (4H, t, J=5 Hz), 3.66 (4H, t, J=5 Hz), 3.71 (2H, s), 3.96 (3H, s), 7.24 (1H, dd, J=8.5, 2 Hz), 7.44 (1H, d, J=8.5 Hz), 7.45 (1H, d, J=8 Hz), 7.55 (1H, d, J=2 Hz), 7.88 (1H, dd, J=8.2 Hz), 8.15 (1H, d, J=2 Hz).
Yield 79%, 1H-NMR (CDCl3): δ1.99-2.05 (2H, m), 2.40 (3H, s), 2.69 (2H, t, J=5.1 Hz), 2.79-2.82 (2H, m), 3.61 (2H, s), 3.71-3.75 (4H, m), 3.90 (3H, s), 7.21-7.25 (2H, m), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.4 Hz), 7.38-7.87 (1H, m), 7.92 (1H, s).
Yield 79%, 1H-NMR (CDCl3): δ2.03-2.10 (2H, m), 2.75 (2H, t, J=5.4 Hz), 2.87-2.90 (2H, m), 3.73-3.80 (6H, m), 3.92 (3H, s), 7.22-7.26 (1H, m), 7.41 (1H, s), 7.44 (1H, s), 7.55 (1H, d, J=2.1 Hz), 7.87 (1H, dd, J=8.4 Hz, 2.1 Hz), 8.15 (1H, d, J=2.1 Hz).
Yield 90%, 1H-NMR (CDCl3): δ2.38 (3H, s), 2.57 (4H, t, J=5 Hz), 3.51 (2H, s), 3.64 (4H, t, J=5 Hz), 3.92 (3H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.37 (1H, s), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz), 7.78 (1H, s), 7.80 (1H, s).
Yield 90%, 1H-NMR (CDCl3): δ1.59 (3H, s), 2.00-2.06 (2H, m), 2.39 (3H, s), 2.69 (2H, t, J=5.4 Hz), 2.79-2.82 (2H, m), 3.64 (2H, s) 3.74-3.77 (4H, m), 7.23 (1H, dd, J=8.4 Hz, 1.8 Hz), 7.35 (1H, s), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=1.8 Hz), 7.75 (1H, s), 7.78 (1H, s).
1H-NMR (CDCl3): δ2.65 (4H, t, J=5.1 Hz), 3.64-3.67 (4H, m), 3.78 (2H, s), 3.88 (3H, s), 6.93 (1H, d, J=3.3 Hz), 7.24 (1H, dd, J=8.7, 2.1 Hz), 7.44 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.1 Hz), 7.67 (1H, d, J=3.3 Hz).
Yield 65%, 1H-NMR (CDCl3): δ2.01-2.08 (2H, m), 2.71-2.75 (2H, m), 2.85-2.89 (2H, m), 3.72-3.76 (2H, m), 3.79-3.82 (2H, m), 3.86 (2H, s), 3.87 (3H, s), 6.89 (1H, d, J=3.9 Hz), 7.23 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.42 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.4 Hz), 7.65 (1H, d, J=3.9 Hz).
1H-NMR (CDCl3): δ1.37 (3H, t, J=7 Hz), 2.65 (4H, t, J=5 Hz), 3.65 (4H, t, J=5 Hz), 3.69 (2H, s), 4.36 (2H, q, J=7 Hz), 6.37 (1H, d, J=3.5 Hz), 7.13 (1H, d, J=3.5 Hz), 7.24 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
1H-NMR (CDCl3): δ2.56-2.60 (4H, m), 3.62-3.66 (6H, m), 3.92 (3H, s), 7.24 (1H, dd, J=8.7, 2.1 Hz), 7.42-7.44 (3H, m), 7.55 (1H, d, J=2.1 Hz), 8.01 (2H, d, J=8.4 Hz).
Yield 76%, 1H-NMR (CDCl3): δ2.41 (3H, s), 2.59 (4H, t, J=5 Hz), 3.58 (2H, s), 3.69 (4H, t, J=5 Hz), 3.96 (3H, s), 7.37 (1H, s), 7.50-7.60 (2H, m), 7.79 (1H, s), 7.80 (1H, s), 7.85 (1H, s).
Yield 74%, 1H-NMR (CDCl3): δ2.00-2.10 (2H, m), 2.38 (3H, s), 2.70 (2H, t, J=5 Hz), 2.82 (2H, t, J=5 Hz), 3.65 (2H, s), 3.70-3.90 (4H, m), 3.91 (3H, s), 7.34 (1H, s), 7.50-7.60 (2H, m), 7.75 (1H, s), 7.79 (1H, s), 7.85 (1H, s).
Yield 98%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.5 Hz), 2.25-2.37 (1H, m), 2.64-2.75 (1H, m), 2.75-2.83 (1H, m), 3.23 (1H, dd, J=13, 9 Hz), 3.29 (1H, d, J=13.5 Hz), 3.40-3.50 (1H, m), 3.70-3.80 (1H, m), 3.87-3.95 (1H, m), 3.93 (3H, s), 4.08 (1H, d, J=13.5 Hz), 7.42 (1H, t, J=7.5 Hz), 7.50-7.60 (3H, m), 7.84 (1H, s), 7.95 (1H, d, J=8 Hz), 8.01 (1H, s).
Yield 85%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.5 Hz), 2.23-2.35 (1H, m), 2.41 (3H, s), 2.60-2.73 (1H, m), 2.80 (1H, dt, J=12, 3.5 Hz), 3.21 (1H, d, J=13 Hz), 3.24 (1H, d, J=13.5 Hz), 3.39-3.50 (1H, m), 3.70-3.80 (1H, m), 3.91 (3H, s), 3.91-3.95 (1H, m), 4.05 (1H, d, J=13.5 Hz), 7.36 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.77 (1H, s), 7.80 (1H, s), 7.84 (1H, s).
Yield 96%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.3 Hz), 2.24-2.32 (1H, m), 2.40 (3H, s), 2.63-2.68 (1H, m), 2.78 (1H, dt, J=3.6, 12.0 Hz), 3.17 (1H, dd, J=9.0 Hz), 3.22 (1H, d, J=13.2 Hz), 3.35-3.43 (1H, m), 3.71 (1H, dt, J=3.3, 12.6 Hz), 3.88 (1H, dd, J=3.0, 15.0 Hz), 3.91 (3H, s), 4.05 (1H, d, J=13.2 Hz), 7.23 (1H, dd, J=2.4, 8.4 Hz), 7.36 (1H, s), 7.43 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=2.4 Hz, 7.76 (1H, s), 7.79 (1H, s)
Yield 98%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.3 Hz), 2.28 (1H, ddd, J=3.3, 8.7, 9.6 Hz), 2.40 (3H, s), 2.62-2.68 (1H, m), 2.78 (1H, dt, J=3.6, 12.0 Hz), 3.17 (1H, dd, J=8.7, 12.6 Hz), 3.22 (1H, d, J=12.9 Hz), 3.39 (1H, m), 3.71 (1H, d, 12.3 Hz), 3.88 (1H, dd, 3.3, 13.2 Hz), 3.92 (3H, s), 4.05 (1H, d, J=13.2 Hz), 7.23 (1H, dd, J=2.1, 8.4 Hz), 7.36 (1H, s), 7.43 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=2.1 Hz), 7.76 (1H, s), 7.79 (1H, s)
Yield 86%, 1H-NMR (CDCl3): δ1.11 (6H, d, J=6 Hz), 2.40 (3H, s), 2.70-2.85 (2H, m), 3.00-3.15 (2H, m), 3.83 (2H, s), 3.83-3.90 (2H, m), 3.91 (3H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.40 (1H, s), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz), 7.72 (1H, s), 7.84 (1H, s).
Yield 67%, 1H-NMR (CDCl3): δ1.13 (6H, d, J=6.5 Hz), 2.40 (3H, s), 2.75-2.88 (2H, m), 3.05-3.18 (2H, m), 3.84 (2H, s), 3.91 (3H, s), 3.91-3.95 (2H, m), 7.40 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.72 (1H, s), 7.84 (2H, s).
Yield 75%, 1H-NMR (CDCl3): δ1.42 (3H, d, J=6.5 Hz), 2.26 (1H, td, J=11.5, 3.5 Hz), 2.36 (1H, dd, J=11.5, 3.5 Hz), 2.41 (3H, s), 2.65-2.75 (1H, m), 2.85-2.95 (1H, m), 3.47 (1H, d, J=13.5 Hz), 3.48-3.55 (1H, m), 3.60 (1H, d, J=13.5 Hz), 3.80-3.90 (1H, m), 3.91 (3H, s), 4.20-4.30 (1H, m), 7.38 (1H, s), 7.51 (1H, dd, J=8.5, 2 Hz), 7.56 (1H, d, J=8.5 Hz), 7.77 (1H, s), 7.83 (1H, d, J=2 Hz), 7.84 (1H, s).
Yield 78%, 1H-NMR (CDCl3): δ1.24 (3H, t, J=6.0 Hz), 2.24-2.36 (1H, m), 2.41 (3H, s), 2.61-2.73 (1H, m), 2.75-2.84 (1H, m), 3.21 (1H, d, J=13.0 Hz), 3.24 (1H, d, J=13.5 Hz), 3.38-3.51 (1H, m), 3.71-3.82 (1H, m), 3.88-3.98 (1H, m), 3.92 (3H, s), 4.05 (1H, d, J=13.0 Hz), 7.36 (1H, s), 7.51 (1H, d, J=8.5), 7.56 (1H, d, J=8.5 Hz), 7.77 (1H, s), 7.80 (1H, s), 7.84 (1H, s).
Yield 58%, 1H-NMR (DMSO-d6): δ2.25 (3H, s), 2.31 (3H, s), 2.51 (4H, t, J=5 Hz), 3.51 (2H, s), 3.57 (4H, t, J=5 Hz), 6.85 (1H, s), 6.89 (1H, s), 7.04 (1H, s), 7.28 (1H, dd, J=8.5, 2.5 Hz), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2.5 Hz).
Yield 89%, 1H-NMR (CDCl3): δ1.99-2.06 (2H, m), 2.29 (3H, s), 2.34 (3H, s), 2.68 (2H, t, J=5.7 Hz), 2.78-2.82 (2H, m), 3.61 (2H, s), 3.72-3.78 (4H, m), 6.79 (1H, s), 6.88 (1H, s), 6.98 (1H, s), 7.22 (1H, dd, J=7.5 Hz, 3.3 Hz), 7.42 (1H, d, J=6.3 Hz), 7.54 (1H, d, J=2.1 Hz).
Yield 71%, 1H-NMR (CDCl3): δ2.30 (3H, s), 2.36 (3H, s), 2.59 (4H, t, J=5 Hz), 3.53 (2H, s), 3.68 (4H, t, J=5 Hz), 6.83 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.50-7.60 (2H, m), 7.85 (1H, s).
Yield 65%, 1H-NMR (CDCl3): δ1.95-2.10 (2H, m), 2.28 (3H, s), 2.34 (3H, s), 2.69 (2H, t, J=5 Hz), 2.83 (2H, t, J=5 Hz), 3.61 (2H, s), 3.70-3.85 (4H, m), 6.80 (1H, s), 6.89 (1H, s), 6.99 (1H, s), 7.48-7.60 (2H, m), 7.85 (1H, s).
Yield 69%, 1H-NMR (CDCl3): δ2.31 (3H, s), 2.57 (4H, t, J=5.1 Hz), 3.55 (2H, s), 3.63 (4H, t, J=5.1 Hz), 7.06 (2H, d, J=8.1 Hz), 7.24 (1H, dd, J=8.4, 2.1 Hz), 7.35 (2H, d, J=8.1 Hz), 7.43 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield 56%, 1H-NMR (CDCl3): δ1.22 (3H, d, J=6 Hz), 2.24-2.35 (1H, m), 2.29 (3H, s), 2.35 (3H, s), 2.62-2.72 (1H, m), 2.83 (1H, dt, J=12, 4 Hz), 3.15-3.25 (2H, m), 3.40-3.50 (1H, m), 3.70-3.80 (1H, m), 3.87-3.95 (1H, m), 4.03 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 41%, 1H-NMR (CDCl3): δ1.10 (6H, d, J=6 Hz), 2.29 (3H, s), 2.34 (3H, s), 2.70-2.85 (2H, m), 3.00-3.10 (2H, m), 3.79 (2H, s), 3.80-3.90 (2H, m), 6.76 (1H, s), 6.95 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield 63%, 1H-NMR (CDCl3): δ1.11 (6H, d, J=6 Hz), 2.30 (3H, s), 2.35 (3H, s), 2.70-2.86 (2H, m), 3.00-3.15 (2H, m), 3.80 (2H, s), 3.85-3.95 (2H, m), 6.77 (1H, s), 6.95 (1H, s), 7.02 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield 53%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.55-1.78 (2H, m), 2.30 (3H, s), 2.30-2.35 (1H, m), 2.36 (3H, s), 2.49-2.60 (1H, m), 2.78-2.90 (1H, m), 3.26 (1H, d, J=13.5 Hz), 3.38-3.46 (1H, m), 3.46-3.58 (1H, m), 3.63-3.72 (1H, m), 3.85 (1H, dd, J=13, 3.5 Hz), 3.98 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J=8.5, 1.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 3 (1H, d, J=1.5 Hz)
Yield 69%, 1H-NMR (CDCl3): δ2.25-2.35 (1H, m), 2.30 (3H, s), 2.34 (3H, s), 2.86 (1H, d, J=13.5 Hz), 3.02 (1H, d, J=11.5 Hz), 3.25-3.50 (3H, m), 3.82 (1H, d, J=13.5 Hz), 4.00-4.10 (2H, m), 6.79 (1H, s), 6.82 (1H, s), 6.93 (1H, s), 7.30-7.45 (3H, m), 7.48-7.55 (4H, m), 7.84 (1H, d, J=0.5 Hz).
Yield 48%, 1H-NMR (CDCl3): δ1.40 (3H, d, J=6.5 Hz), 2.15-2.30 (2H, m), 2.31 (3H, s), 2.36 (3H, s), 2.68-2.75 (1H, m), 2.85-2.95 (1H, m), 3.38-3.60 (3H, m), 3.80-3.90 (1H, m), 4.15-4.25 (1H, m), 6.81 (1H, s), 6.92 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield 81%, 1H-NMR (CDCl3): δ1.42 (3H, d, J=6.5 Hz), 2.18-2.29 (1H, m), 2.30 (3H, s), 2.30-2.35 (1H, m), 2.36 (3H, s), 2.75 (1H, d, J=11.5 Hz), 2.92 (1H, d, J=11.5 Hz), 3.43 (1H, d, J=13.5 Hz), 3.52 (1H, td, J=12.5, 3.5 Hz), 3.57 (1H, d, J=13.5 Hz), 3.91 (1H, d, J=12.5 Hz), 4.17-4.30 (1H, m), 6.81 (1H, s), 6.92 (1H, s), 7.02 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 57%, 1H-NMR (CDCl3): δ1.42 (3H, d, J=6.5 Hz), 2.18-2.38 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 2.70-2.80 (1H, m), 2.86-2.97 (1H, m), 3.38-3.61 (3H, m), 3.85-3.97 (1H, m), 4.17-4.30 (1H, m), 6.82 (1H, s), 6.92 (1H, s), 7.03 (1H, s), 7.48-7.59 (2H, m), 7.84 (1H, s).
Yield 63%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.60-1.75 (2H, m), 2.30 (3H, s), 2.30-2.35 (1H, m), 2.36 (3H, s), 2.48-2.58 (1H, m), 2.79-2.90 (1H, m), 3.26 (1H, d, J=13.5 Hz), 3.38-3.58 (2H, m), 3.63-3.73 (1H, m), 3.80-3.90 (1H, m), 3.98 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 79%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.57-1.80 (2H, m), 2.21 (3H, s), 2.21-2.35 (1H, m), 2.36 (3H, s), 2.50-2.60 (1H, m), 2.80-2.90 (1H, m), 3.26 (1H, d, J=13.5 Hz), 3.38-3.60 (2H, m), 3.63-3.74 (1H, m), 3.85 (1H, dd, J=12.5, 3.5 Hz), 3.98 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.53 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 63%, 1H-NMR (CDCl3): δ1.20 (3H, t, J=7.5 Hz), 1.30-1.70 (4H, m), 2.29 (3H, s), 2.29-2.35 (1H, m), 2.36 (3H, s), 2.55-2.65 (1H, m), 2.79-2.89 (1H, m), 3.28 (1H, d, J=13.5 Hz), 3.41 (1H, dd, J=13, 7.5 Hz), 3.50-3.60 (1H, m), 3.60-3.70 (1H, m), 3.84 (1H, dd, J=13, 3 Hz), 3.97 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J=8.5, 1.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.83 (1H, d, J=1.5 Hz).
Yield 62%, 1H-NMR (CDCl3): δ0.95 (3H, t, J=7.2 Hz), 1.36-1.43 (2H, m), 1.50-1.66 (2H, m), 2.30 (3H, s), 2.35 (3H, s), 2.32-2.39 (1H, m), 2.58-2.63 (1H, m), 2.80-2.87 (1H, m), 3.28 (1H, d, J=13.5 Hz), 3.41 (1H, dd, J=7.5, 12.6 Hz), 3.50-3.59 (1H, m), 3.62-3.68 (1H, m), 3.84 (1H, dd, J=3.0, 12.6 Hz), 3.97 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.53-7.55 (2H, m), 7.83 (1H, s)
Yield 70%, 1H-NMR (CDCl3): δ0.93 (3H, t, J=7.5 Hz), 1.23-1.75 (6H, m), 2.30 (3H, s), 2.30-2.34 (1H, m), 2.35 (3H, s), 2.54-2.64 (1H, m), 2.79-2.89 (1H, m), 3.27 (1H, d, J=13.5 Hz), 3.41 (1H, dd, J=12.5, 7.5 Hz), 3.49-3.60 (1H, m), 3.61-3.71 (1H, m), 3.84 (1H, dd, J=12.5, 2.5 Hz), 3.97 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J=8.5, 1.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1.5 Hz).
Yield 69%, 1H-NMR (CDCl3): δ0.91 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=6.5 Hz), 1.33-1.45 (1H, m), 1.45-1.58 (1H, m), 1.62-1.77 (1H, m), 2.29 (3H, s), 2.35 (3H, s), 2.36-2.45 (1H, m), 2.62-2.73 (1H, m), 2.77-2.88 (1H, m), 3.33 (1H, d, J=13.5 Hz), 3.35 (1H, dd, J=13, 7 Hz), 3.58 (2H, t, J=5.5 Hz), 3.75 (1H, dd, J=13, 3.5 Hz), 3.90 (1H, d, J=13.5 Hz), 6.80 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield 49%, 1H-NMR (CDCl3): δ0.92 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=6.5 Hz), 1.32-1.60 (2H, m), 1.62-1.78 (1H, m), 2.29 (3H, s), 2.31-2.46 (1H, m), 2.35 (3H, s), 2.62-2.72 (1H, m), 2.75-2.88 (1H, m), 3.29-3.42 (2H, m), 3.58 (2H, t, J=5.0 Hz), 3.75 (1H, dd, J=13.0, 3.5 Hz), 3.90 (1H, d, J=13.5 Hz), 6.80 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.43 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield 72%, 1H-NMR (CDCl3): δ0.92 (3H, d, J=7.5 Hz), 0.95 (3H, d, J=7.5 Hz), 1.33-1.45 (1H, m), 1.46-1.60 (1H, m), 1.64-1.78 (1H, m), 2.30 (3H, s), 2.35 (3H, s), 2.36-2.46 (1H, m), 2.63-2.75 (1H, m), 2.77-2.88 (1H, m), 3.35 (1H, d, J=13.5 Hz), 3.40 (1H, dd, J=13, 6.5 Hz), 3.55-3.70 (2H, m), 3.79 (1H, dd, J=12, 3 Hz), 3.90 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.91 (1H, s), 7.02 (1H, s), 7.51 (1H, dd, J=8.5, 1.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.83 (1H, d, J=1.5 Hz).
Yield 65%, 1H-NMR (CDCl3): δ1.98-2.08 (2H, m), 2.28 (3H, s), 2.34 (3H, s), 2.65-2.74 (2H, m), 2.78-2.85 (2H, m), 3.61 (2H, s), 3.65-3.88 (4H, m), 6.80 (1H, s), 6.88 (1H, s), 6.99 (1H, s), 7.27 (1H, d, J=12.0 Hz), 7.75 (1H, d, J=7.0 Hz).
Yield 57%, 1H-NMR (CDCl3): δ1.11 (6H, d, J=6.0 Hz), 2.29 (3H, s), 2.34 (3H, s), 2.71-2.86 (2H, m), 3.07 (1H, d, J=13.0 Hz), 3.10 (1H, d, J=13.0 Hz), 3.79 (2H, s), 3.88 (2H, d, J=13.0 Hz), 6.77 (1H, s), 6.96 (1H, s), 7.01 (1H, s), 7.26 (1H, d, J=11.5 Hz), 7.73 (1H, d, J=7.0 Hz).
Yield 57%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6 Hz), 2.24-2.29 (1H, m), 2.30 (3H, s), 2.36 (3H, s), 2.60-2.72 (1H, m), 2.83 (1H, dt, J=12, 3.5 Hz), 3.18 (1H, d, J=13.5 Hz), 3.18-3.25 (1H, m), 3.48-3.51 (1H, m), 3.67-3.80 (1H, m), 3.85-3.95 (1H, m), 4.02 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.26 (1H, d, J=12 Hz), 7.73 (1H, d, J=7 Hz).
Yield 65%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.50-1.78 (2H, m), 2.26-2.42 (1H, m), 2.30 (3H, s), 2.36 (3H, s), 2.48-2.59 (1H, m), 2.78-2.89 (1H, m), 3.27 (1H, d, J=13.5 Hz), 3.38-3.58 (2H, m), 3.61-3.72 (1H, m), 3.78-3.89 (1H, m), 3.98 (1H, d, J=13.5 Hz), 6.81 (1H, s), 6.90 (1H, s), 7.01 (1H, s), 7.26 (1H, d, J=12.0 Hz), 7.74 (1H, d, J=7.0 Hz).
Yield 61%, 1H-NMR (CDCl3): δ2.29 (3H, s), 2.36 (3H, s), 2.58 (4H, t, J=5.0 Hz), 3.52 (2H, s), 3.53 (4H, t, J=5.0 Hz), 6.82 (1H, s), 6.90 (1H, s), 7.02 (1H, s), 7.17-7.24 (1H, m), 7.27-7.37 (2H, m), 7.38-7.47 (3H, m).
Yield 49%, 1H-NMR (CDCl3): δ1.15 (6H, d, J=6.0 Hz), 2.30 (3H, s), 2.35 (3H, s), 2.68-2.83 (2H, m), 2.94 (1H, d, J=13.0 Hz), 2.97 (1H, d, J=13.0 Hz), 3.80 (2H, s), 4.33 (2H, d, J=14.0 Hz), 6.76 (1H, s), 6.97 (1H, s), 7.04 (1H, s), 7.34-7.43 (1H, m), 7.52-7.61 (1H, m), 7.67 (1H, d, J=8.0, 1.5 Hz), 7.87 (1H, dd, J=8.0, 1.5 Hz), 8.56 (1H, s)
Yield 56%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6.0 Hz), 1.18-2.30 (1H, m), 2.28 (3H, s), 2.35 (3H, s), 2.52-2.65 (1H, m), 2.78-2.89 (1H, m), 3.05-3.20 (2H, m), 3.27-3.41 (1H, m), 3.97-4.12 (2H, m), 4.15-4.25 (1H, m), 6.80 (1H, s), 6.92 (1H, s), 7.01 (1H, s), 7.32-7.40 (1H, m), 7.50-7.59 (1H, m), 7.67 (1H, dd, J=8.0, 1.5 Hz), 7.87 (1H, dd, J=8.0, 1.5 Hz), 8.53 (1H, s).
Yield 55%, 1H-NMR (CDCl3): δ1.14 (6H, d, J=6.0 Hz), 2.29 (3H, s), 2.35 (3H, s), 2.68-2.82 (2H, m), 2.94 (1H, d, J=13.0 Hz), 2.98 (1H, d, J=13.0 Hz), 3.80 (2H, s), 4.30 (2H, d, J=13.0 Hz), 6.76 (1H, s), 6.97 (1H, s), 7.03 (1H, s), 7.50 (1H, dd, J=9.0, 2.5 Hz), 7.59 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=2.5 Hz), 8.54 (1H, s).
Yield 34%, 1H-NMR (CDCl3): δ1.13 (6H, d, J=6.0 Hz), 2.28 (3H, s), 2.34 (3H, s), 2.65-2.79 (2H, m), 2.95 (1H, d, J=13.0 Hz), 2.98 (1H, d, J=13.0 Hz), 3.78 (2H, s), 4.34 (2H, d, J=13.0 Hz), 6.77 (1H, s), 6.98 (1H, s), 7.02 (1H, s), 7.67-7.73 (2H, m), 8.13 (1H, s), 8.58 (1H, s).
Yield 92%, 1H-NMR (CDCl3): δ2.25 (3H, s), 2.56 (4H, t, J=5.1 Hz), 3.48 (2H, s), 3.50 (3H, s), 3.63 (4H, t, J=5.1 Hz), 5.20 (2H, s), 7.00 (1H, d), 7.08 (1H, d, 8.1 Hz), 7.12 (1H, s), 7.23 (1H, dd, J=8.7, 2.1 Hz), 7.43 (1H, d, J=8.7 Hz), 7.53 (1H, d, 2.1 Hz).
Yield 90%, 1H-NMR (CDCl3): δ1.98-2.05 (2H, m), 2.24 (3H, s), 2.68 (2H, t, J=5.4 Hz), 2.79 (2H, t, J=4.8 Hz), 3.49 (3H, s), 3.55 (2H, s), 3.71-3.78 (4H, m), 5.19 (2H, s), 6.98 (1H, s), 7.07 (2H, m), 7.22 (1H, dd, 8.7, 2.1 Hz), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz).
Yield 60%, 1H-NMR (CDCl3): δ2.57 (4H, t, J=5.1 Hz), 3.48 (3H, s), 3.50 (2H, s), 3.64 (4H, t, J=5.1 Hz), 5.17 (2H, s), 6.91 (1H, s), 6.97-7.01 (2H, m), 7.24 (1H, dd, 8.7, 2.1 Hz), 7.44 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.1 Hz).
Yield 70%, 1H-NMR (CDCl3): δ1.22 (3H, d, J=6.5 Hz), 2.24 (3H, s), 2.24-2.35 (1H, m), 2.60-2.70 (1H, m), 2.78-2.88 (1H, m), 3.19 (1H, dt, J=13, 4.5 Hz), 3.24 (1H, d, J=13 Hz), 3.38-3.50 (1H, m), 3.50 (3H, s), 3.70-3.80 (1H, m), 3.85-3.93 (1H, m), 4.01 (1H, d, J=13 Hz), 5.21 (2H, s), 6.89 (1H, d, J=7.5 Hz), 7.02 (1H, s), 7.10 (1H, d, J=7.5 Hz), 7.50 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield 92%, 1H-NMR (CDCl3): δ1.22 (3H, d, J=6.0 Hz), 2.23-2.33 (1H, m), 2.33 (3H, s), 2.60-2.67 (1H, m), 2.83 (1H, dt, J=3.3, 12.0 Hz), 3.16 (2H, dd, J=4.2, 13.2 Hz), 3.44-3.35 (1H, m), 3.49 (3H, s), 3.71 (1H, d, J=12.0 Hz), 3.86 (1H, dd, J=2.1, 12.6 Hz), 3.99 (1H, d, J=13.2 Hz), 5.17 (2H, s), 6.77 (1H, s), 6.80 (1H, s), 6.83 (1H, s), 7.23 (1H, dd, J=2.1, 8.7 Hz), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield 95%, 1H-NMR (CDCl3): δ1.22 (3H, d, J=6.0 Hz), 2.25-2.31 (1H, m), 2.33 (3H, s), 2.60-2.67 (1H, m), 2.83 (1H, dt, J=3.6, 12.0 Hz), 3.16 (2H, dt, J=3.6, 13.5 Hz), 3.44-3.35 (1H, m), 3.49 (3H, s), 3.71 (1H, dt, J=3.0, 12.3 Hz), 3.86 (1H, ddd, J=1.5, 3.6, 12.6 Hz), 3.99 (1H, d, J=13.5 Hz), 5.16 (2H, s), 6.77 (1H, s), 6.80 (1H, s), 6.83 (1H, s), 7.23 (1H, dd, J=2.1, 8.7 Hz), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz),
Yield 38%, 1H-NMR (CDCl3): δ1.27 (3H, t, J=7.2 Hz), 2.57 (4H, t, J=4.8 Hz), 3.52 (2H, s), 3.59 (2H, s), 3.64 (4H, t, J=4.8 Hz), 4.17 (2H, q, J=7.2 Hz), 7.14 (1H, s), 7.20 (1H, s), 7.23 (1H, dd, J=7.8, 2.4 Hz), 7.26 (1H, s), 7.43 (1H, d, J=7.8 Hz), 7.56 (1H, d, J=2.4 Hz).
Yield 60%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.2 Hz), 1.98-2.06 (2H, m), 2.68 (2H, t, J=5.4 Hz), 2.80 (2H, t, J=5.4 Hz), 3.56 (2H, s), 3.60 (2H, s), 3.71-3.78 (4H, m), 4.16 (2H, q, J=7.2 Hz), 7.12 (1H, s), 7.18 (1H, s), 7.23 (1H, dd, J=8.4, 2.1 Hz), 7.25 (1H, s), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz)
Yield 89%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7 Hz), 2.57 (4H, t, J=5 Hz), 3.55 (2H, s), 3.61 2H, s), 3.62 (4H, t, J=5 Hz), 4.15 (2H, q, J=7 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.25-7.35 (4H, m), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield 79%, 1H-NMR (CDCl3): δ1.13 (6H, d, J=6 Hz), 1.25 (3H, t, J=7 Hz), 2.73-2.90 (2H, m), 3.05-3.15 (2H, m), 3.61 (2H, s), 3.85 (2H, s), 3.85-3.95 (2H, m), 4.14 (2H, q, J=7 Hz), 7.10-7.35 (4H, m), 7.52 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 54%, 1H-NMR (CDCl3): δ1.09 (6H, d, J=6.5 Hz), 1.26 (3H, t, J=7 Hz), 2.70-2.95 (2H, m), 3.10 (2H, dd, J=13, 13 Hz), 3.58 (2H, s), 3.78 (2H, s), 3.86-3.96 (2H, m), 4.15 (2H, q, J=7 Hz), 7.14 (1H, s), 7.17 (1H, s), 7.33 (1H, s), 7.53 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield 71%, 1H-NMR (CDCl3): δ1.08 (3H, d, J=6.5 Hz), 1.25 (3H, t, J=7 Hz), 1.40 (3H, d, J=6.5 Hz), 2.25-2.35 (1H, m), 2.90 (1H, dd, J=12, 4 Hz), 3.10-3.20 (1H, m), 3.52 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.63-3.78 (3H, m), 4.16 (2H, q, J=7 Hz), 4.20-4.35 (1H, m), 7.20-7.35 (4H, m), 7.45-7.56 (2H, m), 7.82 (1H, s).
Yield 92%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6 Hz), 1.25 (3H, t, J=7 Hz), 2.23-2.35 (1H, m), 2.60-2.75 (1H, m), 2.83 (1H, dt, J=12, 4 Hz), 3.20 (1H, d, J=12.5 Hz), 3.22 (1H, d, J=13 Hz), 3.38-3.50 (1H, m), 3.62 (2H, s), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 4.05 (1H, d, J=13 Hz), 4.16 (2H, q, J=7 Hz), 7.15-7.35 (4H, m), 7.45-7.60 (2H, m), 7.84 (1H, s).
Yield 88%, 1H-NMR (CDCl3): δ1.23 (3H, t, J=7.2 Hz), 1.26 (3H, t, J=6.9 Hz), 2.27 (1H, ddd, J=3.3, 8.7, 9.9 Hz), 2.61-2.67 (1H, m), 2.80 (1H, dt, J=3.3, 11.7 Hz), 3.21 (2H, d, J=13.5 Hz), 3.34-3.43 (1H, m), 3.62 (2H, s), 3.71 (1H, d, J=12.6 Hz), 3.87 (1H, dd, J=2.1, 12.6 Hz), 4.05 (1H, d, J=13.5 Hz), 4.16 (2H, q, J=7.2 Hz), 7.18-7.32 (5H, m), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.4 Hz)
Yield 93%, 1H-NMR (CDCl3): δ1.24 (3H, t, J=6.0 Hz), 1.26 (3H, t, J=7.2 Hz), 2.27 (1H, ddd, J=3.3, 8.7, 9.9 Hz), 2.62-2.67 (1H, m), 2.80 (1H, dt, J=3.6, 12.0 Hz), 3.21 (2H, d, J=13.5 Hz), 3.39-3.42 (1H, m), 3.62 (2H, s), 3.71 (1H, dt, J=12.0 Hz), 3.87 (1H, dd, J=2.1, 12.6 Hz), 4.06 (1H, d, J=13.5 Hz), 4.16 (2H, q, J=7.2 Hz), 7.18-7.32 (5H, m), 7.42 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield 82%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6 Hz), 1.26 (3H, t, J=7 Hz), 2.20-2.35 (1H, m), 2.34 (3H, s), 2.58-2.71 (1H, m), 2.82 (1H, dt, J=12, 4 Hz), 3.16 (1H, d, J=13.5 Hz), 3.16-3.25 (1H, m), 3.38-3.50 (1H, m), 3.58 (2H, s), 3.70-3.80 (1H, m), 3.86-3.96 (1H, m), 4.03 (1H, d, J=13.5 Hz), 4.15 (2H, q, J=7 Hz), 7.01 (1H, s), 7.05 (2H, s), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 92%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.2 Hz), 1.26 (3H, t, J=7.2 Hz), 1.61-1.74 (2H, m), 2.29-2.37 (1H, m), 2.50-2.55 (1H, m), 2.79-2.84 (1H, m), 3.29 (1H, d, J=13.5 Hz), 3.37 (1H, dd, J=8.1, 12.9 Hz), 3.40-3.50 (1H, m), 3.62 (3H, s), 3.80 (1H, dd, J=3.3, 12.9 Hz), 4.01 (1H, d, J=13.5 Hz), 4.16 (2H, t, J=7.2 Hz), 7.18 (5H, m), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield 90%, 1H-NMR (CDCl3): δ0.93 (6H, dd, J=6.3, 11.7 Hz), 1.26 (3H, t, J=7.2 Hz), 1.35-1.44 (1H, m), 1.50-1.56 (1H, m), 1.65-1.76 (1H, m), 2.37-2.44 (1H, m), 2.67-2.72 (1H, m), 2.78-2.85 (1H, m), 3.36 (1H, d, J=12.9 Hz), 3.39 (1H, d, J=13.2 Hz), 3.58 (2H, t, J=4.8 Hz), 3.61 (2H, s), 3.75 (1H, dd, J=3.3, 12.9 Hz), 3.93 (1H, d, J=13.2 Hz), 4.16 (2H, q, J=7.2 Hz), 7.17-7.31 (5H, m), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=1.8 Hz)
Yield 68%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7 Hz), 1.42 (3H, d, J=6.5 Hz), 2.25 (1H, td, J=11.5, 3.5 Hz), 2.32 (1H, dd, J=11.5, 4 Hz), 2.74 (1H, d, J=11.5 Hz), 2.91 (1H, dt, J=11.5, 2 Hz), 3.46 (1H, d, J=13.5 Hz), 3.52 (1H, td, J=11.5, 4 Hz), 3.59 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.85-4.00 (1H, m), 4.15 (2H, q, J=7 Hz), 4.20-4.30 (1H, m), 7.15-7.33 (4H, m), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 86%, 1H-NMR (CDCl3): δ1.25 (3H, t, J=7 Hz), 1.40 (3H, d, J=6.5 Hz), 2.24 (1H, td, J=11.5, 3.5 Hz), 2.33 (1H, dd, J=11.5, 3.5 Hz), 2.72 (1H, d, J=11 Hz), 2.91 (1H, d, J=11 Hz), 3.43 (1H, d, J=13.5 Hz), 3.49 (1H, td, J=11.5, 3.5 Hz), 3.59 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.80-3.90 (1H, m), 4.10-4.18 (1H, m), 4.19 (2H, q, J=7 Hz), 7.15-7.35 (5H, m), 7.42 (1H, d, J=7.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield 71%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 1.40 (3H, d, J=7.0 Hz), 2.17-2.38 (2H, m), 2.68-2.77 (1H, m), 2.88-2.96 (1H, m), 3.41-3.67 (5H, m), 3.82-3.92 (1H, m), 4.07-4.23 (1H, m), 4.16 (2H, q, J=7.0 Hz), 7.16-7.34 (5H, m), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield 85%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7 Hz), 1.40 (3H, d, J=6.5 Hz), 2.23 (1H, td, J=11.5, 3.5 Hz), 2.27-2.33 (1H, m), 2.34 (3H, s), 2.72 (1H, d, J=11.5 Hz), 2.90 (1H, d, J=11.5 Hz), 3.41 (1H, d, J=13.5 Hz), 3.45-3.54 (1H, m), 3.55 (1H, d, J=13.5 Hz), 3.58 (2H, s), 3.85 (1H, d, J=12 Hz), 4.10-4.15 (1H, m), 4.16 (2H, q, J=7 Hz), 7.01 (1H, s), 7.07 (1H, s), 7.08 (1H, s), 7.22 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield 74%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 1.40 (3H, d, J=7.0 Hz), 2.16-2.37 (5H, m), 2.68-2.77 (1H, m), 2.86-2.96 (1H, m), 3.36-3.62 (5H, m), 3.80-3.90 (1H, m), 4.15 (3H, m), 7.01 (1H, s), 7.04-7.10 (2H, m), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield 83%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7 Hz), 1.42 (3H, d, J=6.5 Hz), 2.25 (1H, dt, J=12.5, 3.5 Hz), 2.33 (1H, dd, J=11, 3.5 Hz), 2.73 (1H, d, J=11 Hz), 2.93 (1H, d, J=11 Hz), 3.42-3.60 (3H, m), 3.62 (2H, s), 3.85-3.97 (1H, m), 4.16 (2H, q, J=7 Hz), 4.18-4.28 (1H, m), 7.18-7.35 (4H, m), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 72%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 1.42 (3H, d, J=6.5 Hz), 2.25 (1H, td, J=11.5, 3.5 Hz), 2.34 (1H, dd, J=11.5, 3.5 Hz), 2.74 (1H, d, J=11.5 Hz), 2.93 (1H, d, J=11.5 Hz), 3.42-3.66 (5H, m), 3.91 (1H, d, J=11.5 Hz), 4.08-4.29 (3H, m), 7.16-7.35 (4H, m), 7.47-7.60 (2H, m), 7.84 (1H, s).
Yield 74%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7 Hz), 1.42 (3H, d, J=6.5 Hz), 2.18-2.34 (2H, m), 2.35 (3H, s), 2.74 (1H, d, J=11 Hz), 2.92 (1H, d, J=11.5 Hz), 3.42 (1H, d, J=13.5 Hz), 3.53 (1H, td, J=11.5, 3.5 Hz), 3.56 (1H, d, J=13.5 Hz), 3.58 (2H, s), 3.91 (1H, d, J=12 Hz), 4.15 (2H, q, J=7 Hz), 4.15-4.30 (1H, m), 7.02 (1H, s), 7.07 (1H, s), 7.09 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 69%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 1.43 (3H, d, J=6.5 Hz), 2.17-2.39 (5H, m), 2.70-2.79 (1H, m), 2.87-2.97 (1H, m), 3.43 (1H, d, J=13.0 Hz), 3.46-3.62 (4H, m), 3.85-3.97 (1H, m), 4.16 (2H, q, J=7.0 Hz), 4.17-4.29 (1H, m), 7.02 (1H, s), 7.05-7.11 (2H, m), 7.47-7.59 (2H, m), 7.84 (1H, s).
Yield 86%, 1H-NMR (CDCl3): δ1.27 (3H, t, J=7 Hz), 1.43 (3H, d, J=6.5 Hz), 2.26 (1H, td, J=12, 3.5 Hz), 2.36 (1H, dd, J=11, 3.5 Hz), 2.72 (1H, d, J=11 Hz), 2.91 (1H, d, J=11 Hz), 3.44 (1H, d, J=13.5 Hz), 3.52 (1H, td, J=12.5, 3.5 Hz), 3.55 (1H, d, J=13.5 Hz), 3.59 (2H, s), 3.86-3.96 (1H, m), 4.16 (2H, q, J=7 Hz), 4.20-4.30 (1H, m), 7.17 (1H, s), 7.20 (1H, s), 7.29 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 41%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7.5 Hz), 1.26 (3H, t, J=7.0 Hz), 1.80-2.02 (2H, m), 2.16-2.30 (2H, m), 2.79-2.94 (2H, m), 3.38-3.52 (2H, m), 3.54-3.65 (3H, m), 3.76-3.88 (1H, m), 3.94-4.06 (1H, m), 4.15 (2H, q, J=7.0 Hz), 7.15-7.34 (5H, m), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.0 Hz).
Yield 79%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7.5 Hz), 1.26 (3H, t, J=7 Hz), 1.85-2.00 (2H, m), 2.18-2.29 (2H, m), 2.80-2.84 (2H, m), 3.42 (1H, d, J=13.5 Hz), 3.44 (1H, td, J=12.5, 3.5 Hz), 3.59 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.70-3.86 (1H, m), 3.95-4.05 (1H, m), 4.15 (2H, q, J=7 Hz), 7.15-7.33 (5H, m), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2 Hz).
Yield 25%, 1H-NMR (CDCl3): δ0.88 (3H, t, J=7.5 Hz), 1.26 (3H, t, J=7 Hz), 1.83-2.03 (2H, m), 2.22 (2H, td, J=12.5, 3.5 Hz), 2.34 (3H, s), 2.80-2.92 (2H, m), 3.38 (1H, d, J=13.5 Hz), 3.45 (1H, td, J=12.5, 3.5 Hz), 3.55 (1H, d, J=13.5 Hz), 3.57 (2H, s), 3.75-3.88 (1H, m), 3.95-4.03 (1H, m), 4.15 (2H, q, J=7 Hz), 7.01 (1H, s), 7.05 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J=8.5, 2 Hz), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2 Hz).
Yield 67%, 1H-NMR (CDCl3): δ0.88 (3H, t, J=7.5 Hz), 1.26 (3H, t, J=7.0 Hz), 1.80-2.03 (2H, m), 2.22 (2H, td, J=11.5, 3.5 Hz), 2.34 (3H, s), 2.80-2.93 (2H, m), 3.38 (1H, d, J=13.0 Hz), 3.46 (1H, td, J=12.5, 3.0 Hz), 3.56 (1H, d, J=13.0 Hz), 3.57 (2H, s), 3.76-3.87 (1H, m), 3.94-4.05 (1H, m), 4.15 (2H, q, J=7.0 Hz), 7.01 (1H, s), 7.06 (2H, s), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.0 Hz).
Yield 80%, 1H-NMR (CDCl3): δ0.88 (3H, t, J=7.5 Hz), 1.26 (3H, t, J=7 Hz), 1.96 (2H, quant, J=7.5 Hz), 2.19-2.30 (2H, m), 2.82-2.95 (2H, m), 3.44 (1H, d, J=13.5 Hz), 3.49 (1H, td, J=12.5, 3.5 Hz), 3.59 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.73-3.83 (1H, m), 4.00-4.10 (1H, m), 4.17 (2H, q, J=7 Hz), 7.15-7.33 (4H, m), 7.48-7.55 (2H, m), 7.82 (1H, s).
Yield 53%, 1H-NMR (CDCl3): δ0.89 (3H, t, J=7.5 Hz), 1.20 (3H, t, J=7 Hz), 1.87-2.03 (2H, m), 2.24 (2H, td, J=11, 3.5 Hz), 2.34 (3H, s), 2.82-2.95 (2H, m), 3.38 (1H, d, J=13 Hz), 3.49 (1H, td, J=13, 3.5 Hz), 3.56 (1H, d, J=13 Hz), 3.57 (2H, s), 3.80-3.95 (1H, m), 4.00-4.10 (1H, m), 4.16 (2H, q, J=7 Hz), 7.01 (1H, s), 7.05 (1H, s), 7.06 (1H, s), 7.48-7.55 (2H, m), 7.82 (1H, s).
Yield 74%, 1H-NMR (CDCl3): δ0.90 (3H, t, J=7.5 Hz), 1.27 (3H, t, J=7 Hz), 1.94 (2H, quant, J=7.5 Hz), 2.20-2.32 (2H, m), 2.80-2.93 (2H, m), 3.41 (1H, d, J=13.5 Hz), 3.49 (1H, td, J=12.5, 3.5 Hz), 3.55 (1H, d, J=13.5 Hz), 3.59 (2H, s), 3.85-3.95 (1H, m), 4.00-4.10 (1H, m), 4.17 (2H, q, J=7 Hz), 7.14 (1H, s), 7.20 (1H, s), 7.28 (1H, s), 7.45-7.56 (2H, m), 7.82 (1H, s).
Yield 85%, 1H-NMR (CDCl3): δ0.88 (3H, t, J=7.5 Hz), 1.20 (3H, t, J=7 Hz), 1.94 (2H, quant, J=7.5 Hz), 2.19-2.30 (2H, m), 2.80-2.95 (2H, m), 3.43 (1H, d, J=13.5 Hz), 3.51 (1H, td, J=12.5, 3.5 Hz), 3.59 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 4.00-4.10 (1H, m), 4.15 (2H, q, J=7 Hz), 7.15-7.33 (4H, m), 7.50 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=8.5 Hz), 7.82 (1H, s).
Yield 73%, 1H-NMR (CDCl3): δ0.88 (3H, t, J=7.5 Hz), 1.26 (3H, t, J=7 Hz), 1.95 (2H, quant, J=7.5 Hz), 2.15-2.28 (2H, m), 2.34 (3H, s), 2.82-2.93 (2H, m), 3.39 (1H, d, J=13.5 Hz), 3.48 (1H, td, J=12.5, 3.5 Hz), 3.55 (1H, d, J=13.5 Hz), 3.57 (2H, s), 3.80-3.95 (1H, m), 3.98-4.10 (1H, m), 4.15 (2H, q, J=7 Hz), 7.01 (1H, s), 7.06 (2H, s), 7.52 (2H, s), 7.82 (1H, s).
Yield 67%, 1H-NMR (CDCl3): δ0.93 (3H, t, J=7.5 Hz), 1.19-1.35 (2H, m), 1.26 (3H, t, J=7.0 Hz), 1.73-2.00 (2H, m), 2.15-2.30 (2H, m), 2.81 (1H, d, J=11.5 Hz), 2.88 (1H, d, J=11.0 Hz), 3.42 (1H, d, J=13.5 Hz), 3.46 (1H, td, J=12.5, 3.5 Hz), 3.58 (1H, d, J=13.5 Hz), 3.61 (2H, s), 3.84-4.05 (2H, m), 4.16 (2H, q, J=7.0 Hz), 7.14-7.34 (5H, m), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.0 Hz).
Yield 64%, 1H-NMR (CDCl3): δ0.93 (3H, t, J=7.2 Hz), 1.21-1.31 (5H, m), 1.78-1.96 (2H, m), 2.19-2.28 (2H, m), 2.81 (1H, d, J=11.4 Hz), 2.88 (1H, d, J=11.4 Hz), 3.42 (1H, d, J=13.2 Hz), 3.47 (1H, td, J=3.3, 12.6 Hz), 3.59 (1H, d, J=13.2 Hz), 3.62 (2H, s), 3.90 (1H, s), 4.00 (1H, d, J=12.6 Hz), 4.16 (2H, q, J=7.2 Hz), 7.19-7.33 (5H, m), 7.39 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=2.1 Hz)
Yield 58%, 1H-NMR (CDCl3): δ0.34 (3H, t, J=7.0 Hz), 1.19-1.35 (2H, m), 1.26 (3H, t, J=7.0 Hz), 1.72-2.02 (2H, m), 2.15-2.29 (2H, m), 2.34 (3H, s), 2.81 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.37 (1H, d, J=13.5 Hz), 3.47 (1H, td, J=13.5, 3.0 Hz), 3.57 (1H, d, J=13.5 Hz), 3.57 (2H, s), 3.83-3.93 (1H, m), 3.94-4.04 (1H, m), 4.16 (2H, q, J=7.0 Hz), 7.01 (1H, s), 7.05 (2H, s), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.0 Hz).
Yield 68%, 1H-NMR (CDCl3): δ0.94 (3H, t, J=7.5 Hz), 1.24-1.31 (5H, m), 1.73-1.85 (1H, m), 1.89-2.01 (1H, m), 2.17-2.27 (2H, m), 2.34 (3H, s), 2.81 (1H, d, J=11.4 Hz), 2.88 (1H, d, J=11.1 Hz), 3.37 (1H, d, J=13.5 Hz), 3.47 (1H, dt, J=3.3, 12.6 Hz), 3.57 (1H, d, J=13.5 Hz), 3.57 (2H, s), 3.89 (1H, s), 3.99 (1H, d, J=12.0 Hz), 4.16 (2H, q, J=7.2 Hz), 7.01 (1H, s), 7.06 (2H, s), 7.22 (1H, dd, J=2.1, 8.4 Hz), 7.39 (1H, d, J=8.4 Hz), 7.52 (1H, d, J=2.1 Hz)
Yield 69%, 1H-NMR (CDCl3): δ0.93 (3H, t, J=7.0 Hz), 1.18-1.35 (2H, m), 1.26 (3H, t, J=7.0 Hz), 1.76-1.99 (2H, m), 2.16-2.29 (2H, m), 2.82 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.42 (1H, d, J=13.5 Hz), 3.49 (1H, td, J=13.0, 3.5 Hz), 3.59 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.90-4.09 (2H, m), 4.16 (2H, q, J=7.0 Hz), 7.15-7.34 (4H, m), 7.49 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=8.5 Hz), 7.81 (1H, s).
Yield 80%, 1H-NMR (CDCl3): δ0.94 (3H, t, J=7.2 Hz), 1.24-1.31 (5H, m), 1.83-1.91 (2H, m), 2.20-2.29 (2H, m), 2.83 (1H, d, J=11.4 Hz), 2.90 (1H, d, J=11.4 Hz), 3.34 (1H, d, J=13.5 Hz), 3.50 (1H, td, J=3.6, 12.6 Hz), 3.60 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.97 (1H, s), 4.05 (1H, d, J=12.6 Hz), 4.16 (2H, q, J=7.2 Hz), 7.19-7.33 (4H, m), 7.51 (2H, s), 7.82 (1H, s)
Yield 79%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7 Hz), 1.15-1.40 (7H, m), 1.74-2.00 (2H, m), 2.17-2.29 (2H, m), 2.77-2.94 (2H, m), 3.41 (1H, d, J=13.5 Hz), 3.46 (1H, td, J=13, 3.5 Hz), 3.59 (1H, d, J=13.5 Hz), 3.61 (2H, s), 3.80-3.93 (1H, m), 3.95-4.08 (1H, m), 4.16 (2H, q, J=7 Hz), 7.15-7.32 (5H, m), 7.39 (1H, d, J=9 Hz), 7.52 (1H, d, J=2 Hz).
Yield 75%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7 Hz), 1.15-1.40 (7H, m), 1.76-2.01 (2H, m), 2.20-2.30 (2H, m), 2.77-2.93 (2H, m), 3.42 (1H, d, J=13.5 Hz), 3.46 (1H, td, J=13, 3.5 Hz), 3.59 (1H, d, J=13.5 Hz), 3.61 (2H, s), 3.80-3.92 (1H, m), 3.95-4.06 (1H, m), 4.16 (2H, q, J=7 Hz), 7.16-7.33 (5H, m), 7.39 (1H, d, J=9 Hz), 7.52 (1H, d, J=2 Hz).
Yield 75%, 1H-NMR (CDCl3): δ0.88 (3H, t, J=7 Hz), 1.15-1.40 (7H, m), 1.75-2.03 (2H, m), 2.17-2.30 (2H, m), 2.34 (3H, s), 2.80-2.96 (2H, m), 3.37 (1H, d, J=13.5 Hz), 3.50 (1H, td, J=13, 3.5 Hz), 3.57 (2H, s), 3.58 (1H, d, J=13.5 Hz), 3.85-4.00 (1H, m), 4.00-4.10 (1H, m), 4.15 (2H, q, J=7 Hz), 7.01 (1H, s), 7.05 (1H, s), 7.07 (1H, s), 7.45-7.55 (2H, m), 7.82 (1H, s).
Yield 44%, 1H-NMR (CDCl3): δ0.90 (3H, d, J=6.5 Hz), 0.91 (3H, d, J=6.5 Hz), 1.26 (3H, t, J=7.0 Hz), 2.12 (1H, dd, J=11.5, 3.5 Hz), 2.23 (1H, td, J=11.5, 3.5 Hz), 2.34 (3H, s), 2.56-2.72 (1H, m), 2.88 (1H, d, J=11.5 Hz), 2.98 (1H, d, J=11.5 Hz), 3.34 (1H, d, J=13.0 Hz), 3.40-3.65 (2H, m), 3.56 (1H, d, J=13.0 Hz), 3.57 (2H, s), 4.08-4.22 (1H, m), 4.15 (2H, q, J=7.0 Hz), 7.01 (1H, s), 7.05 (2H, s), 7.49 (2H, s), 7.79 (1H, s).
Yield 70%, 1H-NMR (CDCl3): δ0.90 (3H, d, J=2.5 Hz), 0.91 (3H, d, J=2.5 Hz), 1.26 (3H, t, J=7 Hz), 2.12 (1H, dd, J=11.5, 3.5 Hz), 2.23 (1H, td, J=11.5, 3.5 Hz), 2.34 (3H, s), 2.55-2.73 (1H, m), 2.88 (1H, d, J=9.5 Hz), 2.98 (1H, d, =9.5 Hz), 3.34 (1H, d, J=13 Hz), 3.40-3.54 (1H, m), 3.56 (1H, d, J=13 Hz), 3.57 (2H, s), 3.57-3.60 (1H, m), 4.11-4.15 (1H, m), 4.16 (2H, q, J=7 Hz), 7.01 (1H, s), 7.04 (1H, s), 7.05 (1H, s), 7.49-7.50 (2H, m), 7.79 (1H, s).
Yield 73%, 1H-NMR (CDCl3): δ0.93 (6H, d, J=6.5 Hz), 1.26 (3H, t, J=7.0 Hz), 1.32-1.53 (1H, m), 1.54-1.67 (1H, m), 1.85-1.98 (1H, m), 2.24 (2H, td, J=11.5, 3.5 Hz), 2.79 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.40 (1H, d, J=13.5 Hz), 3.47 (1H, td, J=13.0, 3.5 Hz), 3.61 (1H, d, J=13.5 Hz), 3.61 (2H, s), 3.88-4.08 (2H, m), 4.16 (2H, q, J=7.0 Hz), 7.15-7.33 (5H, m), 7.39 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2.0 Hz).
Yield 81%, 1H-NMR (CDCl3): δ0.93 (6H, d, J=6.5 Hz), 1.26 (3H, t, J=7 Hz), 1.38-1.47 (1H, m), 1.55-1.67 (1H, m), 1.85-1.96 (1H, m), 2.19-2.30 (2H, m), 2.78 (1H, d, J=11.5 Hz), 2.88 (1H, d, J=11.5 Hz), 3.40 (1H, d, J=13.5 Hz), 3.47 (1H, td, J=13, 3.5 Hz), 3.60 (1H, d, J=13.5 Hz), 3.61 (2H, s), 3.90-4.08 (2H, m), 4.15 (2H, q, J=7 Hz), 7.15-7.35 (5H, m), 7.39 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2 Hz).
Yield 63%, 1H-NMR (CDCl3): δ0.93 (3H, d, J=6.5 Hz), 0.94 (3H, d, J=6.5 Hz), 1.26 (3H, t, J=7.0 Hz), 1.36-1.64 (2H, m), 1.88-2.02 (1H, m), 2.13-2.44 (2H, m), 2.34 (3H, s), 2.79 (1H, d, J=11.0 Hz), 2.89 (1H, d, J=11.0 Hz), 3.35 (1H, d, J=13.5 Hz), 3.41-3.68 (2H, m), 3.57 (2H, s), 3.86-4.09 (2H, m), 4.16 (2H, q, J=7.0 Hz), 7.01 (1H, s), 7.04 (1H, s), 7.06 (1H, s), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.39 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2.0 Hz).
Yield 81%, 1H-NMR (CDCl3): δ0.92 (3H, d, J=3 Hz), 0.95 (3H, d, J=3 Hz), 1.26 (3H, t, J=7 Hz), 1.39-1.65 (2H, m), 1.90-2.02 (1H, m), 2.15-2.32 (2H, m), 2.34 (3H, s), 2.78 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.35 (1H, d, J=13.5 Hz), 3.48 (1H, td, J=13, 3.5 Hz), 3.57 (2H, s), 3.59 (1H, d, J=13.5 Hz), 3.86-4.08 (2H, m), 4.15 (2H, q, J=7 Hz), 7.01 (1H, s), 7.04 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J=8.5, 2 Hz), 7.39 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2 Hz).
Yield 47%, 1H-NMR (CDCl3): δ0.94 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=6.5 Hz), 1.27 (3H, t, J=7.0 Hz), 1.38-1.67 (2H, m), 1.89-2.04 (1H, m), 2.14-2.38 (2H, m), 2.34 (3H, s), 2.80 (1H, d, J=11.5 Hz), 2.90 (1H, d, J=11.5 Hz), 3.35 (1H, d, J=13.5 Hz), 3.44-3.64 (2H, m), 3.57 (2H, s), 3.94-4.21 (2H, m), 4.16 (2H, q, J=7.0 Hz), 7.01 (1H, s), 7.06 (2H, s), 7.49 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=8.5 Hz), 7.82 (1H, s).
Yield 80%, 1H-NMR (CDCl3): δ0.94 (6H, dd, J=3.0, 6.3 Hz), 1.26 (3H, t, J=7.2 Hz), 1.44-1.48 (1H, m), 1.56-1.62 (1H, m), 1.91-2.00 (1H, m), 2.18-2.26 (2H, m), 2.34 (3H, s), 2.80 (1H, d, J=11.4 Hz), 2.91 (1H, d, J=11.4 Hz), 3.36 (1H, d, J=13.2 Hz), 3.52 (1H, dt, J=3.6, 12.6 Hz), 3.57 (2H, s), 3.60 (1H, d, J=13.2 Hz), 4.04 (2H, br), 4.16 (2H, q, J=7.2 Hz), 7.01 (1H, s), 7.04 (1H, s), 7.06 (1H, s), 7.2 (2H, s), 7.83 (1H, s)
Yield 69%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 2.59 (4H, t, J=5.0 Hz), 3.57 (2H, s), 3.62 (2H, s), 3.68 (4H, t, J=5.0 Hz), 4.16 (2H, q, J=7.0 Hz), 7.18-7.34 (5H, m), 7.75 (1H, d, J=7.0 Hz).
Yield 72%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 2.34 (3H, s), 2.58 (4H, t, J=5.0 Hz), 3.52 (2H, s), 3.58 (2H, s), 3.68 (4H, t, J=5.0 Hz), 4.16 (2H, q, J=7.0 Hz), 7.00-7.12 (3H, m), 7.26 (1H, d, J=11.5 Hz), 7.75 (1H, d, J=7.0 Hz).
Yield 41%, 1H-NMR (CDCl3): δ1.25 (3H, t, J=7.0 Hz), 1.96-2.08 (2H, m), 2.32 (3H, s), 2.69 (2H, t, J=5.0 Hz), 2.75-2.85 (2H, m), 3.56 (2H, s), 3.60 (2H, s), 3.61-3.89 (4H, m), 4.15 (2H, q, J=7.0 Hz), 6.50-7.07 (3H, m), 7.26 (1H, d, J=12.0 Hz), 7.73 (1H, d, J=7.0 Hz).
Yield 80%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6 Hz), 1.26 (3H, t, J=7 Hz), 2.23-2.33 (1H, m), 2.34 (3H, s), 2.69-2.70 (1H, m), 2.82 (1H, dt, J=12, 4 Hz), 3.17 (1H, d, J=13 Hz), 3.18-3.26 (1H, m), 3.36-3.48 (1H, m), 3.58 (2H, s), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 4.02 (1H, d, J=13 Hz), 4.13 (2H, q, J=7 Hz), 7.01 (1H, s), 7.04 (1H, s), 7.05 (1H, s), 7.26 (1H, d, J=12 Hz), 7.73 (1H, d, J=7 Hz).
Yield 63%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 1.43 (3H, d, J=7.0 Hz), 2.17-2.37 (2H, m), 2.34 (3H, s), 2.71-2.79 (1H, m), 2.87-2.98 (1H, m), 3.43 (1H, d, J=13.0 Hz), 3.46-3.60 (2H, m), 3.58 (2H, s), 3.83-3.94 (1H, m), 4.15-4.28 (1H, m), 4.16 (2H, q, J=7.0 Hz), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.26 (1H, d, J=11.5 Hz), 7.74 (1H, d, J=7.0 Hz).
Yield 60%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 1.43 (3H, d, J=7.0 Hz), 2.16-2.36 (2H, m), 2.34 (3H, s), 2.70-2.79 (1H, m), 2.87-2.98 (1H, m), 3.43 (1H, d, J=13.0 Hz), 3.45-3.61 (4H, m), 3.84-3.94 (1H, m), 4.14-4.28 (1H, m), 4.16 (2H, q, J=7.0 Hz), 7.01 (1H, s), 7.04-7.12 (2H, m), 7.26 (1H, d, J=11.5 Hz), 7.74 (1H, d, J=7.0 Hz).
Yield 90%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7.5 Hz), 1.25 (3H, t, J=7.0 Hz), 1.82-2.03 (2H, m), 2.14-2.53 (2H, m), 2.33 (3H, s), 2.78-2.93 (2H, m), 3.37 (1H, d, J=13.5 Hz), 3.45 (1H, td, J=12.5, 3.5 Hz), 3.55 (1H, d, J=13.5 Hz), 3.57 (2H, s), 3.76-3.88 (1H, m), 3.90-4.03 (1H, m), 4.15 (2H, q, J=7.0 Hz), 7.00 (1H, s), 7.03-7.09 (2H, m), 7.24 (1H, d, J=10.5 Hz), 7.49 (1H, d, J=7.0 Hz).
Yield 18%, 1H-NMR (CDCl3): δ1.20 (3H, d, J=6.5 Hz), 1.25 (3H, t, J=7.0 Hz), 1.36 (3H, d, J=6.5 Hz), 2.15 (1H, td, J=12.0, 3.5 Hz), 2.60-2.72 (1H, m), 2.74-2.84 (1H, m), 2.98 (1H, d, J=13.5 Hz), 3.40 (1H, td, J=12.5, 3.5 Hz), 3.62 (2H, s), 3.67-3.81 (1H, m), 4.03-4.22 (4H, m), 7.13-7.34 (4H, m), 7.50 (1H, dd, J=8.5, 1.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=1.5 Hz).
Yield 73%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 2.58 (4H, t, J=5.0 Hz), 3.54 (4H, t, J=5.0 Hz), 3.56 (2H, s), 3.62 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.17-7.24 (2H, m), 7.25-7.37 (5H, m), 7.39-7.45 (2H, m), 7.40 (1H, s).
Yield 56%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 2.61 (4H, t, J=5.0 Hz), 3.57 (2H, s), 3.63 (2H, s), 3.81 (4H, t, J=5.0), 4.16 (2H, q, J=7.0 Hz), 7.14-7.34 (4H, m), 7.35-7.43 (1H, m), 7.53-7.62 (1H, m), 7.68 (1H, dd, J=8.0, 1.5 Hz), 7.87 (1H, dd, J=8.0, 1.5 Hz), 8.57 (1H, s).
Yield 70%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 2.58 (4H, t, J=5.0 Hz), 3.56 (2H, s), 3.62 (2H, s), 3.65 (4H, t, J=5.0 Hz), 4.16 (2H, q, J=7.0 Hz), 7.07 (1H, t, J=7.5 Hz), 7.16-7.34 (5H, m), 7.55 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=8.0 Hz).
Yield 66%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 2.59 (4H, t, J=5.0 Hz), 3.57 (2H, s), 3.63 (2H, s), 3.76 (4H, t, J=5.0 Hz), 4.16 (2H, q, J=7.0 Hz), 6.97 (1H, d, J=9.0 Hz), 7.17-7.38 (5H, m), 7.48-7.64 (2H, m), 7.69 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=9.0 Hz).
Yield 88%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 2.60 (4H, t, J=5.0 Hz), 3.57 (2H, s), 3.63 (2H, s), 3.80 (4H, t, J=5.0 Hz), 4.16 (2H, q, J=7.0 Hz), 7.16-7.35 (4H, m), 7.50 (1H, dd, J=90, 2.5 Hz), 7.59 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=2.5 Hz), 8.55 (1H, s).
Yield 80%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 1.39 (3H, d, J=7.0 Hz), 2.20 (1H, t, J=11.5, 3.5 Hz), 2.25-2.37 (4H, m), 2.82 (1H, d, J=11.5 Hz), 3.00 (1H, d, J=11.5 Hz), 3.31-3.46 (2H, m), 3.53-3.63 (3H, m), 4.16 (2H, q, J=7.0 Hz), 4.33-4.43 (1H, m), 4.64-4.77 (1H, m), 7.02 (1H, s), 7.09 (1H, s), 7.11 (1H, s), 7.70 (2H, s), 8.14 (1H, s), 8.58 (1H, s).
Yield 90%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.0 Hz), 2.66 (4H, t, J=5.0 Hz), 2.70 (3H, s), 3.47 (4H, t, J=5.0 Hz), 3.60 (2H, s), 3.63 (2H, s), 4.16 (2H, q, J=7.0 Hz), 7.16-7.34 (4H, m), 7.74 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=8.5 Hz), 8.16 (1H, s).
To a mixture of [3-(methoxymethoxy)-4-methyl]benzyl alcohol described in Reference Example 68 of WO2004/022551 (1.23 g; 6.75 mmol), triethylamine (0.55 ml; 7.09 mmol) and THF (12 ml) was added dropwise methanesulfonyl chloride (0.55 ml; 7.09 mmol) under ice-cooling. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. To the residue were added 4-(6-chlorobenzothiazole-2-yl)piperazine dihydrochloride (2.10 g; 6.43 mmol), potassium carbonate (2.67 g; 19.3 mmol) and anhydrous N,N-dimethylformamide (20 ml). The mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, and the precipitate was collected and washed with diisopropyl ether to give 6-chloro-2-[4-(3-methoxymethoxy-4-methylbenzyl)piperazine-1-yl]benzothiazole as colorless crystal (1.70 g; 63%).
1H-NMR (CDCl3): δ2.24 (3H, s), 2.57 (4H, t, J=5 Hz), 3.50 (3H, s), 3.52 (2H, s), 3.63 (4H, t, J=5 Hz), 5.22 (2H, s), 6.89 (1H, d, J=7.5 Hz), 7.03 (1H, s), 7.10 (1H, d, J=7.5 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.45 (1H, d, J=8.5 Hz), 7.59 (1H, d, J=2 Hz).
To a suspension of lithium aluminium hydride (0.52 g; 13.7 mmol) in anhydrous THF (27 ml) was added dropwise a solution of 3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]methyl butanoate (2.76 g; 6.87 mmol) in anhydrous THF (27 ml) under ice-cooling. After stirring at room temperature for 1 hour, a mixture of water/THF (0.25 ml/5 mL) and 2N-aqueous sodium hydroxide solution (0.5 ml) was sequentially added dropwise thereto under ice-cooling. The mixture was stirred at room temperature for 1 hour. After filtration of aluminium hydroxide, the filtrate was concentrated under reduced pressure. To the residue were added ethyl acetate and brine to separate. The organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to give yellow crystal. The crystal was washed with diisopropyl ether to give 3-[4-[(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]benzyl alcohol as pale yellow crystal (2.35 g; 92%).
1H-NMR (CDCl3): 1.83 (1H, t, J=5.5 Hz), 2.57 (4H, t, J=5 Hz), 3.51 (2H, s), 3.63 (4H, t, J=5 Hz), 4.71 (2H, d, J=5.5 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.25-7.38 (4H, m), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d. J=2 Hz).
Compounds in Example 130 to 153 were obtained by similar methods as Example 129.
Yield: 100%, 1H-NMR (CDCl3); δ1.65 (1H, brs), 1.98-2.05 (2H, m), 2.70 (2H, t, J=5.1 Hz), 2.79-2.82 (2H, m), 3.65 (2H, s), 3.71-3.77 (4H, m), 4.69 (2H, s), 7.23 (1H, dd, J=8.7 Hz, 2.4 Hz), 7.26-7.34 (4H, m), 7.43 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 100%, 1H-NMR (CDCl3); δ1.26 (1H, brs), 2.59 (4H, t, J=5 Hz), 3.58 (2H, s), 3.68 (4H, t, J=5 Hz), 4.72 (2H, s), 7.20-7.40 (4H, m), 7.50-7.60 (2H, m), 7.84 (1H, s).
Yield: 60%, 1H-NMR (DMSO-d6): δ1.88-1.99 (2H, m), 2.58-2.67 (2H, m), 2.74-2.84 (2H, m), 3.62 (2H, s), 3.63-3.85 (4H, m), 4.47 (2H, d, J=5.5 Hz), 5.16 (1H, t, J=5.5 Hz), 7.13-7.20 (2H, m), 7.22-7.30 (2H, m), 7.52-7.57 (2H, m), 8.22 (1H, s).
Yield: 96% 1H-NMR (CDCl3); δ1.41 (3H, d, J=6.5 Hz), 1.63 (1H, brs), 2.25 (1H, td, J=11.5, 3.5 Hz), 2.33 (1H, dd, J=11.5, 3.5 Hz), 2.72 (1H, d, J=11.5 Hz), 2.86-2.95 (1H, m), 3.47 (1H, td, J=12.5, 3.5 Hz), 3.48 (1H, d, J=13.5 Hz), 3.60 (1H, d, J=13.5 Hz), 3.85 (1H, d, J=12.5 Hz), 4.10-4.25 (1H, m), 4.72 (2H, s), 7.22 (1H, dd, J=8.5, 2 Hz), 7.25-7.40 (4H, m), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: 98%, 1H-NMR (CDCl3); δ1.23 (3H, d, J=6.5 Hz), 1.55-1.70 (1H, m), 2.22-2.32 (1H, m), 2.60-2.70 (1H, m), 2.75-2.85 (1H, m), 3.10-3.20 (1H, m), 3.22 (1H, d, J=13.5 Hz), 3.35-3.45 (1H, m), 3.65-3.75 (1H, m), 3.83-3.90 (1H, m), 4.06 (1H, d, J=13.5 Hz), 4.71 (2H, s), 7.20-7.35 (5H, m), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: q.y., 1H-NMR (CDCl3); δ1.12 (6H, d, J=6 Hz), 1.64 (1H, brs), 2.75-2.85 (2H, m), 3.05 (2H, dd, J=13, 12.5 Hz), 3.85 (2H, s), 3.80-3.90 (2H, m), 4.70 (2H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.25-7.28 (1H, m), 7.30-7.35 (2H, m), 7.38 (1H, s), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: q.y., 1H-NMR (CDCl3); δ1.08 (3H, d, J=6.5 Hz), 1.38 (3H, d, J=6.5 Hz), 1.74 (1H, brs), 2.33 (1H, d, J=11.5 Hz), 2.89 (1H, dd, J=11.5, 4 Hz), 3.06-3.19 (1H, m), 3.53 (1H, d, J=14.5 Hz), 3.60-3.75 (3H, m), 4.15-4.28 (1H, m), 4.70 (2H, s), 7.21 (1H, dd, J=8.5, 2 Hz), 7.25-7.35 (4H, m), 7.40 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2 Hz).
Yield: 60%, 1H-NMR (CDCl3); δ1.71 (1H, brs), 2.38 (3H, s), 2.58 (4H, t, J=5 Hz), 3.52 (2H, s), 3.61 (4H, t, J=5 Hz), 4.67 (2H, s), 7.15-7.20 (2H, m), 7.23 (1H, dd, J=8.5, 2 Hz), 7.25-7.28 (1H, m), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 39%, 1H-NMR (CDCl3); δ1.80 (1H, brs), 2.65 (4H, t, J=5 Hz), 3.65 (4H, t, J=5 Hz), 3.68 (2H, s), 4.70 (2H, s), 7.23 (1H, dd, J=8.2 Hz), 7.24 (1H, dd, 8.5, 2 Hz), 7.36 (1H, d, J=8 Hz), 7.42 (1H, d, J=8.5 Hz), 7.48 (1H, d, J=2 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 92%, 1H-NMR (CDCl3); δ1.66-1.73, (1H, br-s), 1.97-2.04 (2H, m), 2.33 (3H, s), 2.69 (2H, t, J=5.4 Hz), 2.78-2.81 (2H, m), 3.59 (2H, s), 3.70-3.75 (4H, m), 4.65 (2H, s), 7.16-7.17 (2H, m), 7.23 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.28 (1H, s), 7.43 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.4 Hz).
Yield: 100%, 1H-NMR (CDCl3); δ1.70-1.88 (1H, br-s), 1.98-2.07 (2H, m), 2.75 (2H, t, J=5.4 Hz), 2.84-2.89 (2H, m), 3.72-3.84 (6H, m), 4.68 (2H, s), 7.17-7.25 (2H, m), 7.33 (1H, d, J=8.1 Hz), 7.44 (1H, d, J=8.1 Hz), 7.50 (1H, d, J=2.1 Hz), 7.55 (1H, d, J=2.4 Hz).
Yield: 30%, 1H-NMR (CDCl3); δ1.90 (1H, brs), 2.62 (4H, t, J=5 Hz), 3.64 (4H, t, J=5 Hz), 3.74 (2H, s), 4.79 (2H, s), 6.79 (1H, d, J=3.5 Hz), 6.85 (1H, d, J=3.5 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 80%, 1H-NMR (CDCl3); δ1.86 (1H, s), 2.00-2.07 (2H, m), 2.71-2.74 (2H, m), 2.84-2.87 (2H, m), 3.73 (2H, t, J=6.0 Hz), 3.77-3.80 (2H, m), 3.82 (2H, s), 4.78 (2H, s), 6.76 (1H, d, J=3.3 Hz), 6.84 (1H, d, J=3.3 Hz), 7.23 (1H, dd, J=8.7, 2.4 Hz), 7.42 (1H, d, J=9.0 Hz), 7.55 (1H, d, J=2.4 Hz).
Yield: 90%, 1H-NMR (CDCl3); δ1.81 (1H, brs), 2.36 (3H, s), 2.57 (4H, t, J=5 Hz), 3.53 (2H, s), 3.63 (4H, t, J=5 Hz), 4.67 (2H, s), 7.08 (1H, s), 7.11 (1H, s), 7.13 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: q. y, 1H-NMR (CDCl3); δ1.79 (1H, t, J=4.5 Hz), 2.36 (3H, s), 2.59 (4H, t, J=5 Hz), 3.54 (2H, s), 3.68 (4H, t, J=5 Hz), 4.67 (2H, d, J=4.5 Hz), 7.09 (1H, s), 7.11 (1H, s), 7.14 (1H, s), 7.45-7.60 (2H, m), 7.84 (1H, s).
Yield: 93%, 1H-NMR (CDCl3); δ1.70 (1H, s), 1.99-2.06 (2H, m), 2.35 (3H, s), 2.70 (2H, t, J=5.4 Hz), 2.79-2.82 (2H, m), 3.61 (2H, s), 3.71-3.77 (4H, m), 4.65 (2H, s), 7.07 (1H, s), 7.09 (1H, s), 7.13 (1H, s), 7.23 (1H, dd, J=8.7 Hz, J=2.1 Hz), 7.43 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: q. y, 1H-NMR (CDCl3); δ1.77 (1H, brs), 1.95-2.10 (2H, m), 2.34 (3H, s), 2.68 (2H, t, J=5.5 Hz), 2.82 (2H, t, J=5.5 Hz), 3.61 (2H, s), 3.70-3.85 (4H, m), 4.65 (2H, s), 7.06 (1H, s), 7.08 (1H, s), 7.13 (1H, s), 7.45-7.60 (2H, m), 7.84 (1H, s).
Yield: 80%, 1H-NMR (DMSO-d6): δ1.59 (1H, brs), 2.57 (4H, t, J=5 Hz), 2.88 (2H, t, J=6.5 Hz), 3.55 (2H, s), 3.63 (4H, t, J=5 Hz), 3.88 (2H, t, J=6.5 Hz), 7.20 (2H, d, J=7.5 Hz), 7.26 (1H, dd, J=8.5, 2 Hz), 7.29 (2H, d, J=7.5 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 46%, 1H-NMR (CDCl3): δ1.14 (6H, d, J=6 Hz), 1.68 (1H, brs), 2.30 (3H, s), 2.70-2.87 (2H, m), 3.03-3.15 (2H, m), 3.82 (2H, s), 3.85-3.95 (2H, m), 4.66 (2H, s), 7.05 (1H, s), 7.11 (1H, s), 7.17 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 95%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6 Hz), 1.69 (1H, brs), 2.20-2.35 (1H, m), 2.36 (3H, s), 2.60-2.72 (1H, m), 2.82 (1H, dt, J=12, 3.5 Hz), 3.15-3.25 (2H, m), 3.35-3.48 (1H, m), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 4.04 (1H, d, J=13.5 Hz), 4.67 (2H, s), 7.00-7.15 (3H, m), 7.52 (1H, dd, J=8.5, 1 Hz), 7.56 (1H, d, J=8.5 Hz), 7.83 (1H, d, J=1 Hz).
Yield: quant. %, 1H-NMR (DMSO-d6): δ1.30 (3H, d, J=7 Hz), 2.05-2.25 (2H, m), 2.27 (3H, s), 2.65-2.75 (1H, m), 2.80-2.95 (1H, m), 3.30-3.85 (3H, m), 4.15-4.30 (1H, m), 4.43 (2H, d, J=5.5 Hz), 4.48 (1H, t, J=5 Hz), 5.21 (1H, t, J=5.5 Hz), 7.00 (2H, s), 7.06 (1H, s), 7.54 (2H, s), 8.19 (1H, s).
Yield: 45%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6.3 Hz), 2.26 (1H, ddd, J=3.3, 9.5, 12.3 Hz), 2.36 (3H, s), 2.60-2.66 (1H, m), 2.80 (1H, dt, J=3.3, 12.0 Hz), 3.17 (2H, d, J=13.2 Hz), 3.20-3.33 (1H, m), 3.71 (1H, dt, J=2.1, 12.0 Hz), 3.87 (1H, dd, J=2.1, 12.6 Hz), 4.03 (1H, d, J=13.2 Hz), 4.67 (2H, s), 7.09 (2H, s), 7.14 (1H, s), 7.23 (1H, dd, J=2.1, 8.4 Hz), 7.42 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield: 54%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.3 Hz), 2.23-2.31 (1H, m), 2.36 (3H, s), 2.60-2.66 (1H, m), 2.81 (1H, dt, J=3.3, 11.7 Hz), 3.18 (2H, d, J=12.9 Hz), 3.34-3.42 (1H, m), 3.71 (1H, d, J=12.9 Hz), 3.87 (1H, d, J=10.2 Hz), 4.04 (1H, d, J=13.5 Hz), 4.67 (2H, s), 7.09 (2H, s), 7.14 (1H, s), 7.23 (1H, dd, J=2.4, 8.4 Hz), 7.43 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.4 Hz)
Yield: 84%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.0 Hz), 1.63-1.73 (1H, m), 2.23-2.34 (1H, m), 2.37 (3H, s), 2.59-2.72 (1H, m), 2.78-2.88 (1H, m), 3.15-3.26 (1H, m), 3.19 (1H, d, J=13.0 Hz), 3.37-3.48 (1H, m), 3.72-3.83 (1H, m), 3.86-3.97 (1H, m), 4.04 (1H, d, J=13.0 Hz), 4.67 (2H, d, J=4.5 Hz), 7.07-7.17 (3H, m), 7.48-7.59 (2H, m), 7.84 (1H, s).
To 3-[4-[(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]benzyl alcohol (2.35 g; 6.29 mmol) was added thionyl chloride (12 ml) at room temperature. The mixture was stirred at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure. To the obtained residue were added ice water and 10% aqueous sodium hydroxide solution to become neutral. The precipitate was collected to give 6-chloro[4-(3-chloromethylbenzyl)piperazine-1-yl]benzothiazole monohydrochloride as colorless crystal (2.50 g; 93%).
1H-NMR (DMSO-d6): δ3.20-3.30 (2H, m), 3.35-3.45 (2H, m), 3.55-3.75 (2H, m), 4.10-4.25 (2H, m), 4.35-4.40 (2H, m), 4.80 (2H, s), 7.34 (1H, dd, J=8.5, 2 Hz), 7.45-7.60 (3H, m), 7.60-7.70 (2H, m), 8.00 (1H, d, J=2 Hz), 11.45 (1H, brs).
Compounds in Examples 155 to 178 were obtained by similar methods as Example 154.
Yield: 77%, 1H-NMR (CDCl3); δ1.99-2.06 (2H, m), 2.69 (2H, t, J=5.4 Hz), 2.80-2.83 (2H, m), 3.65 (2H, s), 3.72-3.79 (4H, m), 4.58 (2H, s), 7.21-7.31 (4H, m), 7.36 (1H, s), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.4 Hz).
Yield: 77%, 1H-NMR (CDCl3); δ2.60 (4H, t, J=5 Hz), 3.59 (2H, s), 3.70 (4H, t, J=5 Hz), 4.60 (2H, s), 7.25-7.40 (4H, m), 7.50-7.60 (2H, m), 7.85 (1H, s).
Yield: 95%, 1H-NMR (CDCl3); δ1.95-2.12 (2H, m), 2.61-2.71 (2H, m), 2.77-2.88 (2H, m), 3.66 (2H, s), 3.68-3.90 (4H, m), 4.58 (2H, s), 7.22-7.40 (4H, m), 7.48-7.60 (2H, m), 7.85 (1H, s).
Yield: 95%, 1H-NMR (CDCl3); δ1.41 (3H, d, J=6.5 Hz), 2.25 (1H, td, J=11, 3 Hz), 2.34 (1H, dd, J=11, 3 Hz), 2.71 (1H, d, J=11 Hz), 2.92 (1H, d, J=11 Hz), 3.47 (1H, d, J=13.5 Hz), 3.49 (1H, td, J=12, 3 Hz), 3.62 (1H, d, J=13.5 Hz), 3.87 (1H, d, J=12 Hz), 4.15-4.25 (1H, m), 4.60 (2H, s), 7.22 (1H, dd, J=8.5, 2 Hz), 7.30-7.38 (3H, m), 7.38-7.42 (1H, m), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz)
Yield: 63%, 1H-NMR (CDCl3); δ1.23 (3H, d, J=6 Hz), 2.24-2.34 (1H, m), 2.60-2.73 (1H, m), 2.75-2.85 (1H, m), 3.13-3.23 (1H, m), 3.22 (1H, d, J=13.5 Hz), 3.34-3.44 (1H, m), 3.66-3.76 (1H, m), 3.84-3.92 (1H, m), 4.06 (1H, d, J=13.5 Hz), 4.60 (2H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.25-7.40 (4H, m), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 71%, 1H-NMR (CDCl3); δ1.11 (6H, d, J=6 Hz), 2.70-2.85 (2H, m), 3.06 (2H, dd, J=13, 13 Hz), 3.84 (2H, s), 3.85-3.90 (2H, m), 4.60 (2H, s), 7.20-7.45 (6H, m), 7.55 (1H, d, J=2 Hz).
Yield: 90%, 1H-NMR (CDCl3); δ1.09 (3H, d, J=6.5 Hz), 1.39 (3H, d, J=6.5 Hz), 2.32 (1H, d, J=10.5 Hz), 2.89 (1H, dd, J=12, 4 Hz), 3.08-3.20 (1H, m), 3.52 (1H, d, J=13.5 Hz), 3.64 (1H, d, J=12 Hz), 3.70 (1H, d, J=13.5 Hz), 3.73 (1H, dd, J=12, 4 Hz), 4.15-4.30 (1H, m), 4.60 (2H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.25-7.35 (3H, m), 7.41 (1H, d, J=8.5 Hz), 7.44 (1H, s), 7.53 (1H, d, J=2 Hz).
Yield: 85%, 1H-NMR (CDCl3); δ2.38 (3H, s), 2.58 (4H, t, J=5 Hz), 3.52 (2H, s), 3.63 (4H, t, J=5 Hz), 4.60 (2H, s), 7.15-7.30 (4H, m), 7.44 (1H, d, J=8 Hz), 7.56 (1H, d, J=2 Hz).
Yield: 68%, 1H-NMR (CDCl3); δ2.66 (4H, t, J=5 Hz), 3.66 (4H, t, J=5 Hz), 3.68 (2H, s), 4.58 (2H, s), 720-7.25 (2H, m), 7.37 (1H, d, J=8 Hz), 7.44 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz), 7.56 (1H, d, J=2 Hz).
Yield: 99%, 1H-NMR (CDCl3); δ1.97-2.05 (2H, m), 2.33 (3H, s), 2.67 (2H, t, J=5.4 Hz), 2.79-2.82 (2H, m), 3.58 (2H, s), 3.72-3.77 (4H, m), 4.56 (2H, s), 7.12-7.25 (3H, m), 7.30 (1H, d, J=1.8 Hz), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.4 Hz).
Yield: 81%, 1H-NMR (CDCl3); δ2.01-2.09 (2H, m), 2.75 (2H, t, J=5.1 Hz), 2.87-2.90 (2H, m), 3.74-3.83 (6H, m), 4.54 (2H, s), 7.20-7.25 (2H, m), 7.33 (1H, d, J=8.4 Hz), 7.43 (1H, d, J=9.0 Hz), 7.52 (1H, d, J=2.1 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 85%, 1H-NMR (CDCl3); δ2.36 (3H, s), 2.58 (4H, t, J=5 Hz), 3.53 (2H, s), 3.64 (4H, t, J=5 Hz), 4.56 (2H, s), 7.12 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 91%, 1H-NMR (CDCl3); δ1.98-2.06 (2H, m), 2.34 (3H, s), 2.69 (2H, t, J=5.4 Hz), 2.78-2.83 (2H, m), 3.61 (2H, s), 3.72-3.78 (4H, m), 4.55 (2H, s), 7.09-7.11 (2H, m), 7.14 (1H, s), 7.23 (1H, dd, J=8.4, 2.1 Hz), 7.43 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 45%, 1H-NMR (DMSO-d6): δ2.55 (4H, t, J=5 Hz), 3.57 (4H, t, J=5 Hz), 3.74 (2H, s), 4.99 (2H, s), 6.86 (1H, d, J=3.5 Hz), 7.04 (1H, d, J=3.5 Hz), 7.28 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2 Hz).
Yield: 45%, 1H-NMR (CDCl3); δ2.00-2.07 (2H, m), 2.71-2.74 (2H, m), 2.84-2.87 (2H, m), 3.73 (2H, t, J=6.0 Hz), 3.75-3.81 (2H, m), 3.81 (2H, s), 4.76 (2H, s), 6.73 (1H, d, J=3.3 Hz), 6.91 (1H, d, J=3.3 Hz), 7.23 (1H, dd, J=8.7, 2.4 Hz), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 59%, 1H-NMR (CDCl3); δ2.37 (3H, s), 2.59 (4H, t, J=5 Hz), 3.54 (2H, s), 3.69 (4H, t, J=5 Hz), 4.57 (2H, s), 7.12 (1H, s), 7.13 (1H, s), 7.17 (1H, s), 7.50-7.60 (2H, m), 7.85 (1H, s).
Yield: 71%, 1H-NMR (CDCl3); δ1.95-2.10 (2H, m), 2.34 (3H, s), 2.70 (2H, t, J=5.5 Hz), 2.82 (2H, t, J=5.5 Hz), 3.61 (2H, s), 3.70-3.90 (4H, m), 4.54 (2H, s), 7.05-7.14 (2H, m), 7.15 (1H, s), 7.48-7.60 (2H, m), 7.85 (1H, s).
Yield: 77%, 1H-NMR (CDCl3); δ2.57 (4H, t, J=5 Hz), 3.07 (2H, t, J=7.5 Hz), 3.55 (2H, s), 3.63 (4H, t, J=5 Hz), 3.72 (2H, t, J=7.5 Hz), 7.19 (2H, d, J=8 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.29 (2H, d, J=8 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 91%, 1H-NMR (CDCl3): δ1.12 (6H, d, J=6 Hz), 2.35 (3H, s), 2.68-2.86 (2H, m), 3.05-3.15 (2H, m), 3.81 (2H, s), 3.85-3.98 (2H, m), 4.56 (2H, s), 7.07 (1H, s), 7.14 (1H, s), 7.21 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 74%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6 Hz), 2.23-2.35 (1H, m), 2.36 (3H, s), 2.60-2.70 (1H, m), 2.80 (1H, dt, J=13, 3.5 Hz), 3.17 (1H, d, J=13.5 Hz), 3.18-3.26 (1H, m), 3.38-3.50 (1H, m), 3.72-3.80 (1H, m), 3.87-3.95 (1H, m), 4.03 (1H, d, J=13.5 Hz), 4.56 (2H, s), 7.11 (2H, s), 7.17 (1H, s), 7.53 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 81%, 1H-NMR (CDCl3): δ1.43 (3H, d, J=6.5 Hz), 2.26 (1H, td, J=11.5, 3.5 Hz), 2.30-2.36 (1H, m), 2.37 (3H, s), 2.73 (1H, d, J=11.5 Hz), 2.93 (1H, d, J=11.5 Hz), 3.43 (1H, d, J=13.5 Hz), 3.54 (1H, td, J=12.5, 3.5 Hz), 3.58 (1H, d, J=13.5 Hz), 3.85-3.98 (1H, m), 4.20-4.30 (1H, m), 4.57 (2H, s), 7.12 (2H, s), 7.21 (1H, s), 7.51 (1H, dd, J=8.5, 1.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1.5 Hz).
Yield: 83%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6.0 Hz), 2.23-2.31 (1H, m), 2.36 (3H, s), 2.61-2.83 (1H, m), 2.80 (1H, dt, J=3.6, 11.7 Hz), 3.13-3.20 (2H, m), 3.35-3.43 (1H, m), 3.72 (1H, dt, J=2.7 Hz), 3.87 (1H, dd, J=1.8, 12.3 Hz), 4.03 (1H, d, J=13.2 Hz), 4.56 (2H, s), 7.11 (2H, s), 7.16 (1H, s), 7.23 (1H, dd, J=2.1, 8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield: 77%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6.0 Hz), 2.27 (1H, ddd, J=3.3, 8.7, 9.9 Hz), 2.35 (3H, s), 2.61-2.67 (1H, m), 2.80 (1H, dt, J=3.6, 12.0 Hz), 3.13-3.20 (2H, m), 3.35-3.43 (1H, m), 3.72 (1H, d, J=12.6 Hz), 3.87 (1H, dd, J=1.8, 12.6 Hz), 4.03 (1H, d, J=13.2 Hz), 4.56 (2H, s), 7.11 (2H, s), 7.16 (1H, s), 7.23 (1H, dd, J=1.8, 8.7 Hz), 7.53 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=1.8 Hz)
Yield: 60%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.0 Hz), 2.23-2.34 (1H, m), 2.36 (3H, s), 2.60-2.72 (1H, m), 2.77-2.87 (1H, m), 3.14-3.27 (2H, m), 3.38-3.51 (1H, m), 3.72-3.82 (1H, m), 3.87-3.98 (1H, m), 4.04 (1H, d, J=13.0 Hz), 4.56 (2H, s), 7.12 (2H, s), 7.17 (1H, s), 7.48-7.59 (2H, m), 7.84 (1H, s).
The mixture of 6-chloro[4-(3-chloromethylbenzyl)piperazine-1-yl]benzothiazole monohydrochloride (0.50 g; 1.27 mmol) and sodium cyanide (0.19 g; 3.82 mmol) in anhydrous N,N-dimethylformamide (5 ml) were stirred at 40° C. for 1.5 hours. After cooling, water and ethyl acetate were added to the reaction solution. The organic layer was separated and washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure and the percipitate was washed with diisopropyl ether to give {3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]phenyl}acetonitrile as pale blackish brown crystal (0.35 g; 72%).
1H-NMR (CDCl3): δ2.58 (4H, t, J=5 Hz), 3.57 (2H, s), 3.67 (4H, t, J=5 Hz), 3.77 (2H, s), 7.24 (1H, dd, J=8.5, 2 Hz), 7.25-7.40 (4H, m), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Compounds in Examples 180 to 203 were obtained by similar methods as Example 179.
Yield: 95%, 1H-NMR (CDCl3); δ1.98-2.06 (2H, m), 2.69 (2H, t, J=5.4 Hz), 2.79-2.83 (2H, m), 3.65 (2H, s) 3.72-3.80 (6H, m), 7.21-7.25 (2H, m), 7.29-7.33 (3H, m), 7.43 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.4 Hz).
Yield: 99%, 1H-NMR (CDCl3); δ2.59 (4H, t, J=5 Hz), 3.58 (2H, s), 3.69 (4H, t, J=5 Hz), 3.77 (2H, s), 7.20-7.40 (4H, m), 7.50-7.60 (2H, m), 7.85 (1H, d, J=0.5 Hz).
Yield: 74%, 1H-NMR (CDCl3); δ1.98-2.10 (2H, m), 2.64-2.74 (2H, m), 2.77-2.88 (2H, m), 3.65 (2H, s), 3.68-3.90 (4H, m), 3.74 (2H, s), 7.18-7.38 (4H, m), 7.48-7.59 (2H, m), 7.84 (1H, s).
Yield: 68%, 1H-NMR (CDCl3); δ1.41 (3H, d, J=6.5 Hz), 2.26 (1H, td, J=11, 2.5 Hz), 2.35 (1H, dd, J=11, 4 Hz), 2.71 (1H, d, J=11 Hz), 2.89 (1H, d, J=11 Hz), 3.47 (1H, d, J=13 Hz), 3.50 (1H, td, J=13, 3 Hz), 3.61 (1H, d, J=13 Hz), 3.77 (2H, s), 3.87 (1H, d, J=13 Hz), 4.15-4.25 (1H, m), 7.23 (1H, dd, J=8.5, 2 Hz), 7.25-7.30 (1H, m), 7.30-7.40 (3H, m), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 86%, 1H-NMR (CDCl3); δ1.23 (3H, d, J=6.5 Hz), 2.23-2.35 (1H, m), 2.58-2.72 (1H, m), 2.72-2.85 (1H, m), 3.10-3.20 (1H, m), 3.22 (1H, d, J=13.5 Hz), 3.33-3.45 (1H, m), 3.60-3.75 (1H, m), 3.76 (2H, s), 3.83-3.93 (1H, m), 4.06 (1H, d, J=13.5 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.25-7.35 (4H, m), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 59%, 1H-NMR (CDCl3); δ1.10 (6H, d, J=6 Hz), 2.70-2.85 (2H, m), 3.05 (2H, dd, J=13, 13 Hz), 3.76 (2H, s), 3.83 (2H, s), 3.88 (2H, dd, J=13, 2 Hz), 7.18 (1H, d, J=7 Hz), 7.25 (1H, dd, J=8.5, 2 Hz), 7.30-7.40 (3H, m), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 97%, 1H-NMR (CDCl3); δ1.09 (3H, d, J=6.5 Hz), 1.39 (3H, d, J=6.5 Hz), 2.31 (1H, d, J=11.5 Hz), 2.90 (1H, dd, J=11.5, 4 Hz), 3.08-3.20 (1H, m), 3.53 (1H, t, J=14 Hz), 3.64 (1H, d, J=12.5 Hz), 3.70 (1H, d, J=14 Hz), 3.72 (1H, dd, J=12.5, 4 Hz), 3.76 (2H, s), 4.18-4.30 (1H, m), 7.21 (1H, dd, J=8.5, 2 Hz), 7.21-7.25 (1H, m), 7.30-7.40 (3H, m), 7.41 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2 Hz).
Yield: 35%, 1H-NMR (CDCl3); δ2.37 (3H, s), 2.58 (4H, t, J=5 Hz), 3.52 (2H, s), 3.63 (4H, t, J=5 Hz), 3.73 (2H, s), 7.10-7.30 (4H, m), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 69%, 1H-NMR (CDCl3); δ2.65 (4H, t, J=5 Hz), 3.66 (4H, t, J=5 Hz), 3.68 (2H, s), 3.76 (2H, s), 7.19 (1H, dd, J=8, 2 Hz), 7.24 (1H, dd, 8.5, 2 Hz), 7.38 (1H, d, J=8 Hz), 7.44 (1H, d, J=8.5 Hz), 7.51 (1H, d, J=2 Hz), 7.56 (1H, d, J=2 Hz).
Yield: 78%, 1H-NMR (CDCl3); δ1.99-2.05 (2H, m), 2.32 (3H, s), 2.67 (2H, t, J=5.4 Hz), 2.79-2.83 (2H, m), 3.58 (2H, s), 3.70 (2H, s), 3.72-3.78 (4H, m), 7.13-7.14 (2H, m), 7.21-7.26 (2H, m), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 99%, 1H-NMR (CDCl3); δ2.03-2.07 (2H, m), 2.75 (2H, t, J=5.4 Hz), 2.87-2.90 (2H, m), 3.70 (2H, s), 3.75 (2H, s), 3.75 (2H, t, J=6.0 Hz), 3.82 (2H, t, J=5.1 Hz), 7.16 (1H, dd, J=8.1, 2.1 Hz), 7.23 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.35 (1H, d, J=8.4 Hz), 7.42 (1H, d, J=8.4 Hz), 7.49 (1H, d, J=2.4 Hz), 7.56 (1H, d, J=2.1 Hz).
Yield: 78%, 1H-NMR (CDCl3); δ2.36 (3H, s), 2.57 (4H, t, J=5 Hz), 3.51 (2H, s), 3.64 (4H, t, J=5 Hz), 3.72 (2H, s), 7.06 (1H, s), 7.10 (1H, s), 7.11 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: q. y, 1H-NMR (CDCl3); δ1.99-2.06 (2H, m), 2.35 (3H, s), 2.67 (2H, t, J=5.4 Hz), 2.78-2.82 (2H, m), 3.60 (2H, s), 3.70-3.78 (6H, m), 7.04 (1H, s), 7.09 (2H, s), 7.23 (1H, dd, J=8.7, 2.1 Hz), 7.43 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 68%, 1H-NMR (CDCl3); δ2.50-2.60 (4H, m), 3.50-3.60 (4H, m), 3.72 (2H, s), 4.24 (2H, s), 6.88 (1H, d, J=3 Hz), 6.91 (1H, d, J=3 Hz), 7.28 (1H, dd, J=8.5, 1.5 Hz), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=1.5 Hz).
Yield: 32%, 1H-NMR (CDCl3); δ1.99-2.07 (2H, m), 2.70-2.74 (2H, m), 2.83-2.87 (2H, m), 3.73 (2H, t, J=6.0 Hz), 3.77-3.80 (2H, m), 3.80 (2H, s), 3.86 (2H, s), 6.76 (1H, d, J=3.3 Hz), 6.88 (1H, td, J=3.3, 0.9 Hz), 7.23 (1H, dd, J=8.7, 2.1 Hz), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.4 Hz).
Yield: 93%, 1H-NMR (CDCl3); δ2.27 (3H, s), 2.58 (4H, t, J=5 Hz), 3.53 (2H, s), 3.69 (4H, t, J=5 Hz), 3.72 (2H, s), 7.07 (1H, s), 7.11 (1H, s), 7.12 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield: 86%, 1H-NMR (CDCl3); δ1.95-2.10 (2H, m), 2.34 (3H, s), 2.69 (2H, t, J=5.5 Hz), 2.82 (2H, t, J=5.5 Hz), 3.61 (2H, s), 3.69 (2H, s), 3.70-3.90 (4H, m), 7.04 (1H, s), 7.08 (1H, s), 7.09 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.85 (1H, s).
Yield: 85%, 1H-NMR (DMSO-d6): δ2.45-2.55 (4H, m), 2.81 (2H, t, J=5 Hz), 2.87 (2H, t, J=5 Hz), 3.52 (2H, s), 3.56 (4H, t, J=5.5 Hz), 7.20-7.35 (5H, m), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2 Hz).
Yield: 84%, 1H-NMR (CDCl3): δ1.12 (6H, d, J=6 Hz), 2.36 (3H, s), 2.75-2.87 (2H, m), 3.10 (1H, d, J=13 Hz), 3.13 (1H, d, J=13 Hz), 3.71 (2H, s), 3.79 (2H, s), 3.92 (2H, dd, J=13, 2 Hz), 7.00 (1H, s), 7.14 (1H, s), 7.16 (1H, s), 7.52 (1H, dd, J=8.5, 1 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1 Hz).
Yield: 86%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6 Hz), 2.20-2.35 (1H, m), 2.36 (3H, s), 2.61-2.73 (1H, m), 2.80 (1H, dt, J=12, 3.5 Hz), 3.15-3.28 (2H, m), 3.40-3.50 (1H, m), 3.71 (2H, s), 3.71-3.81 (1H, m), 3.87-3.97 (1H, m), 4.02 (1H, d, J=13.5 Hz), 7.05 (1H, s), 7.11 (2H, s), 7.50 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s)
Yield: 79%, 1H-NMR (CDCl3): δ1.43 (3H, d, J=6.5 Hz), 2.26 (1H, td, J=11.5, 3.5 Hz), 2.30-2.33 (1H, m), 2.34 (3H, s), 2.72 (1H, d, J=11 Hz), 2.91 (1H, d, J=11.5 Hz), 3.45 (1H, d, J=13.5 Hz), 3.54 (1H, td, J=13, 3.5 Hz), 3.58 (1H, d, J=13.5 Hz), 3.72 (2H, s), 3.92 (1H, d, J=13 Hz), 4.20-4.30 (1H, m), 7.06 (1H, s), 7.13 (1H, s), 7.15 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 90%, 1H-NMR (CDCl3): δ1.22 (3H, d, J=6.3 Hz), 2.23-2.32 (1H, m), 2.36 (3H, s), 2.59-2.69 (1H, m), 2.78 (1H, dt, J=3.6, 8.1 Hz), 3.17 (2H, dt, J=3.6, 13.5 Hz), 3.35-3.44 (1H, m), 3.70-3.75 (1H, m), 3.71 (2H, s), 3.85-3.90 (1H, m), 4.02 (1H, s), 7.05 (1H, s), 7.11 (2H, s), 7.23 (1H, dd, J=2.1, 8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.1 Hz)
Yield: 98%, 1H-NMR (CDCl3): δ1.22 (3H, d, J=6.3 Hz), 2.23-2.32 (1H, m), 2.36 (3H, s), 2.62-2.66 (1H, m), 2.78 (1H, dt, J=3.9, 11.7 Hz), 3.17 (2H, dt, J=3.9, 13.5 Hz), 3.35-3.44 (1H, m), 3.71 (2H, s), 3.70-3.74 (1H, m), 3.87 (1H, dd, J=2.1, 12.6 Hz), 4.02 (1H, d, J=13.5 Hz), 7.05 (1H, s), 7.11 (2H, s), 7.23 (1H, dd, J=2.1, 8.4 Hz), 7.43 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz)
Yield: 85%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.5 Hz), 2.23-2.34 (1H, m), 2.37 (3H, s), 2.60-2.73 (1H, m), 2.80 (1H, dt, J=12.0, 3.5 Hz), 3.13-3.27 (2H, m), 3.39-3.51 (1H, m), 3.70-3.83 (3H, m), 3.87-3.97 (1H, m), 4.03 (1H, d, J=13.5 Hz), 7.06 (1H, s), 7.11 (2H, s), 7.48-7.59 (2H, m), 7.84 (1H, s).
To a suspension of sodium hydride (0.15 g; 60%, 3.81 mmol) in anhydrous THF suspension was added dropwise diethyl malonate (0.58 ml; 3.81 mmol) under ice-cooling. The mixture was stirred at room temperature for 30 minutes. To the reaction solution was added 6-chloro[4-(3-chloromethylbenzyl)piperazine-1-yl]benzothiazole monohydrochloride (0.50 g; 1.27 mmol). The mixture was stirred at the same temperature for 14.5 hours and at 50° C. for 38 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=3:1) to give 2-{3-[4-(6-chlorobenzothiazole-2-yl)piperazine-1-ylmethyl]benzyl}diethyl malonate as colorless oil (0.38 g; 58%).
1H-NMR (DMSO-d6): δ1.10 (6H, t, J=7 Hz), 2.49 (4H, t, J=5 Hz), 3.08 (2H, d, J=8 Hz), 3.50 (2H, s), 3.56 (4H, t, J=5 Hz), 3.81 (1H, t, J=8 Hz), 4.06 (4H, q, J=7 Hz), 7.10-7.20 (3H, m), 7.24 (1H, d, J=7.5 Hz), 7.28 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2 Hz).
Compounds in Examples 205 and 206 were obtained by similar methods as Example 204.
Yield: 46%, 1H-NMR (CDCl3); δ1.26 (6H, t, J=7 Hz), 2.59 (4H, t, J=5 Hz), 3.38 (2H, d, J=7.5 Hz), 3.60-3.68 (5H, m), 3.69 (2H, s), 4.24 (4H, q, J=7 Hz), 6.68 (1H, d, J=3 Hz), 6.71 (1H, d, J=3 Hz), 7.25 (1H, dd, J=9, 2 Hz), 7.43 (1H, d, J=9 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 5%, 1H-NMR (CDCl3); δ1.21-1.32 (6H, m), 2.00-2.05 (2H, m), 2.70 (2H, t, J=5.4 Hz), 2.81-2.84 (2H, m), 3.36-3.38 (2H, m), 3.62-3.82 (7H, m), 4.14-4.24 (4H, m), 6.65-6.68 (2H, m), 7.22 (1H, dd, J=9.0, 1.8 Hz), 7.42 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=1.8 Hz).
A mixture of 2,6-dichlorobenzothiazole (3.00 g; 14.7 mmol), 4-piperidine ethanol (2.09 g; 16.2 mmol), potassium carbonate (2.33 g; 16.2 mmol) and anhydrous N,N-dimethylformamide (15 ml) was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The precipitate was washed with diisopropyl ether to give 6-chloro-2-[4-(2-hydroxyethyl)piperidine-1-yl]benzothiazole as green crystal (2.92 g; 67%).
1H-NMR (CDCl3): δ1.26-1.44 (3H, m), 1.57 (2H, q, J=6.5 Hz), 1.68-1.91 (3H, m), 3.06-3.19 (2H, m), 3.74 (2H, q, J=6.5 Hz), 4.07-4.17 (2H, m), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Compounds in Reference Examples 196 to 211 were obtained by similar methods as Reference Example 195.
Yield: 64%, 1H-NMR (CDCl3); δ1.60-1.75 (3H, m), 1.95-2.18 (2H, m), 3.34-3.48 (2H, m), 3.87-4.10 (3H, m), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2 Hz).
Yield: 100%, 1H-NMR (DMSO-d6): δ1.15-1.25 (2H, m), 1.60-1.75 (1H, m), 1.75-1.85 (2H, m), 3.05-3.20 (2H, m), 3.25-3.30 (2H, m), 3.95-4.10 (2H, m), 4.56 (1H, brs), 7.27 (1H, dd, J=8.5, 2 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2 Hz).
Yield: 95%, 1H-NMR (CDCl3); δ1.65 (1H, s), 2.60-2.67 (6H, m), 3.63-3.69 (6H, m), 7.23 (1H, d, J=8.5, 2.0 Hz), 7.44 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=2.0 Hz).
Yield: 99%, 1H-NMR (CDCl3); δ2.00-2.07 (2H, m), 2.69 (2H, t, J=5.1 Hz), 2.76 (2H, t, J=5.4 Hz), 2.89-2.93 (2H, m), 2.96 (1H, s), 3.60 (2H, t, J=5.4 Hz), 3.73 (2H, t, J=6.0 Hz), 3.80-3.83 (2H, m), 7.24 (1H, dd, J=7.8, 2.1 Hz), 7.42 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 48%, 1H-NMR (CDCl3); δ1.28-1.46 (2H, m), 1.58 (2H, q, J=6.5 Hz), 1.72-1.94 (3H, m), 3.11-3.24 (2H, m), 3.76 (2H, t, J=6.5 Hz), 4.11-4.22 (2H, m), 7.48-7.57 (2H, m), 7.83 (1H, s).
Yield: 70%, 1H-NMR (DMSO-d6): δ2.49 (2H, t, J=6 Hz), 2.57 (4H, t, J=5 Hz), 3.55 (2H, t, J=6 Hz), 3.62 (4H, t, J=5 Hz), 4.51 (1H, brs), 7.57 (2H, s), 8.25 (1H, s).
Yield: 85%, 1H-NMR (DMSO-d6): δ1.83-1.90 (2H, m), 2.55 (2H, t, J=5.5 Hz), 2.67 (2H, t, J=5 Hz), 2.87 (2H, t, J=5 Hz), 3.47 (2H, q, J=5.5 Hz), 3.60-3.80 (4H, m), 4.39 (1H, t, J=5.5 Hz), 7.55 (1H, s), 7.95 (1H, s), 8.21 (1H, s).
Yield: 63%, 1H-NMR (CDCl3); δ1.23-1.44 (3H, m), 1.53-1.63 (2H, m), 1.68-1.90 (3H, m), 3.08-3.20 (2H, m), 3.75 (2H, q, J=6.0 Hz), 4.08-4.18 (2H, m), 7.02 (1H, dd, J=8.5, 2.0 Hz), 7.46 (1H, d, J=8.5 Hz), 7.49 (1H, d, J=2.0 Hz).
Yield: 36%, 1H-NMR (CDCl3); δ1.25-1.45 (3H, m), 1.57 (2H, q, J=6.5 Hz), 1.70-1.91 (3H, m), 3.08-3.23 (2H, m), 3.75 (2H, t, J=6.5 Hz), 4.08-4.21 (2H, m), 7.04 (1H, dd, J=8.0, 1.0 Hz), 7.21 (1H, t, J=8.0 Hz), 7.39 (1H, dd, J=8.0, 1.0 Hz).
Yield: 52%, 1H-NMR (CDCl3); δ1.26 (1H, t, J=6.5 Hz), 1.27-1.44 (2H, m), 1.57 (2H, q, J=6.5 Hz), 1.68-1.91 (3H, m), 3.06-3.19 (2H, m), 3.75 (2H, q, J=6.5 Hz), 4.05-4.19 (2H, m), 7.35-7.40 (2H, m), 7.68 (1H, s).
Yield: 31%, 1H-NMR (CDCl3); δ1.22 (1H, t, J=5.0 Hz), 1.27-1.45 (2H, m), 1.57 (2H, q, J=5.0 Hz), 1.65-1.90 (3H, m), 2.38 (3H, s), 3.03-3.19 (2H, m), 3.75 (2H, q, J=5.0 Hz), 4.06-4.17 (2H, m), 7.08 (1H, d, J=8.0 Hz), 7.39 (1H, s), 7.42 (1H, d, J=8.0 Hz).
Yield: 9%, 1H-NMR (CDCl3); δ1.23-1.45 (3H, m), 1.52-1.64 (2H, m), 1.67-1.94 (3H, m), 3.40-3.22 (2H, m), 3.68-3.83 (2H, m), 4.03-4.17 (2H, m), 7.00 (1H, td, J=8.5, 2.5 Hz), 7.29 (1H, dd, J=8.5, 2.5 Hz), 7.40 (1H, dd, J=8.5, 4.0 Hz).
Yield: 48%, 1H-NMR (DMSO-d6): δ1.12-1.29 (2H, m), 1.40 (2H, q, J=6.5 Hz), 1.57-1.81 (3H, m), 2.95-3.10 (2H, m), 3.47 (2H, q, J=6.5 Hz), 3.84-3.97 (2H, m), 4.40 (1H, t, J=6.5 Hz), 7.20 (1H, t, J=7.5 Hz), 7.35 (2H, t, J=7.5 Hz), 7.44 (2H, d, J=7.5 Hz), 7.57 (1H, s).
Yield: 88%, 1H-NMR (CDCl3): δ1.14-1.32 (2H, m), 1.40 (2H, q, J=6.5 Hz), 1.54-1.83 (3H, m), 2.95-3.08 (2H, m), 3.47 (2H, q, J=6.5 Hz), 3.88-4.00 (2H, m), 4.40 (1H, t, J=6.5 Hz), 7.22 (1H, s), 7.27 (1H, t, J=7.5 Hz), 7.38 (2H, t, J=7.5 Hz), 7.87 (2H, d, J=7.5 Hz).
Yield: 71%, 1H-NMR (DMSO-d6): δ1.82-1.93 (2H, m), 2.55 (2H, t, J=6.0 Hz), 2.62-2.70 (2H, m), 2.78-2.86 (2H, m), 3.47 (2H, q, J=6.0 Hz), 3.59 (2H, t, J=6.0 Hz), 3.61-3.68 (2H, m), 4.38 (1H, t, J=6.0 Hz), 7.18 (1H, t, J=7.5 Hz), 7.34 (2H, t, J=7.5 Hz), 7.45 (2H, d, J=7.5 Hz), 7.57 (1H, s).
Yield: 93%, 1H-NMR (DMSO-d6): δ1.80-2.01 (2H, m), 2.57 (2H, t, J=6.0 Hz), 2.64-2.77 (2H, m), 2.82-2.96 (2H, m), 3.42-3.53 (2H, m), 3.45-3.94 (4H, br), 4.34-4.46 (1H, m), 7.45 (1H, d, J=7.0 Hz), 8.23 (1H, d, J=12.5 Hz).
To 6-chloro-2-[4-(2-hydroxyethyl)piperidine-1-yl]benzothiazole (1.20 g; 4.03 mmol) was added thionyl chloride (10 ml). The mixture was stirred at 60° C. for 1 hour. The reaction solution was poured into ice water. 5N aqueous sodium hydroxide was added thereto to neutralize and the precipitate was collected. The precipitate was washed with diisopropyl ether to give 6-chloro-2-[4-(2-chloroethyl)piperidine-1-yl]benzothiazole as colorless crystal (0.98 g; 77%).
1H-NMR (CDCl3): δ 1.25-1.44 (2H, m), 1.70-1.94 (5H, m), 3.08-3.22 (2H, m), 3.62 (2H, t, J=6.5 Hz), 4.07-4.20 (2H, m), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.0).
Compounds in Reference Examples 213 to 225 were obtained by similar methods as Reference Example 212.
Yield: q. y, 1H-NMR (DMSO-d6): δ1.20-1.42 (2H, m), 1.80-2.00 (3H, m), 3.10-3.25 (2H, m), 3.60 (2H, d, J=6.5 Hz), 4.00-4.10 (2H, m), 7.28 (1H, dd, J=8.5, 2 Hz), 7.41 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=2 Hz).
Yield: 95%, 1H-NMR (CDCl3); δ2.63-2.72 (4H, m), 2.80 (2H, t, J=7.0 Hz), 3.58-3.73 (6H, m), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.44 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.0 Hz).
Yield: 58%, 1H-NMR (CDCl3); δ1.98-2.06 (2H, m), 2.78 (2H, t, J=5.4 Hz), 2.90-2.96 (4H, m), 3.56 (2H, t, J=7.2 Hz), 3.72 (2H, t, J=6.0 Hz), 3.78-3.81 (2H, m), 7.23 (1H, dd, J=8.4, 2.1 Hz), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 68%, 1H-NMR (CDCl3); δ1.25-1.43 (2H, m), 1.70-1.94 (5H, m), 3.08-3.22 (2H, m), 3.62 (2H, t, J=6.5 Hz), 4.08-4.22 (2H, m), 7.03 (1H, dd, J=8.5, 2.0 Hz), 7.46 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.0 Hz).
Yield: 90%, 1H-NMR (CDCl3); δ1.26-1.44 (2H, m), 1.71-1.93 (5H, m), 3.08-3.23 (2H, m), 3.62 (2H, t, J=6.5 Hz), 4.10-4.22 (2H, m), 7.04 (1H, d, J=8.0 Hz), 7.22 (1H, t, J=8.0 Hz), 7.40 (1H, d, J=8.0 Hz).
Yield: 95%, 1H-NMR (CDCl3); δ1.25-1.43 (2H, m), 1.71-1.92 (5H, m), 3.07-3.23 (2H, m), 3.61 (2H, t, J=6.5 Hz), 4.06-4.21 (2H, m), 7.35-7.43 (2H, m), 7.69 (1H, s).
Yield: 65%, 1H-NMR (CDCl3); δ1.22-1.41 (2H, m), 1.68-1.90 (5H, m), 2.38 (3H, s), 3.02-3.18 (2H, m), 3.59 (2H, t, J=6.5 Hz), 4.05-4.18 (2H, m), 7.06-7.12 (1H, m), 7.36-7.39 (1H, m), 7.43 (1H, d, J=8.0 Hz).
Yield: 91%, 1H-NMR (CDCl3); δ1.27-1.45 (2H, m), 1.72-1.95 (5H, m), 3.12-3.27 (2H, m), 3.62 (2H, t, J=6.5 Hz), 4.12-4.26 (2H, m), 7.49-7.59 (2H, m), 7.84 (1H, s).
Yield: 42%, 1H-NMR (CDCl3); δ2.68 (4H, t, J=5 Hz), 2.81 (2H, t, J=7 Hz), 3.63 (2H, t, J=7 Hz), 3.71 (4H, t, J=5 Hz), 7.53 (1H, d, J=8.5 Hz), 7.58 (1H, d, J=8.5 Hz), 7.86 (1H, s).
Yield: 23%, 1H-NMR (CDCl3); δ1.94-2.07 (2H, m), 2.70-2.80 (2H, m), 2.83-2.99 (4H, m), 3.50-3.58 (2H, m), 3.64-3.88 (4H, m), 7.48-7.60 (2H, m), 7.84 (1H, s).
Yield: 89%, 1H-NMR (CDCl3); δ1.27-1.44 (2H, m), 1.72-1.88 (5H, m), 2.99-3.13 (2H, m), 3.62 (2H, t, J=6.5 Hz), 3.99-4.10 (2H, m), 7.17-7.24 (1H, m), 7.30-7.37 (2H, m), 7.38-7.45 (3H, m).
Yield: 35%, 1H-NMR (DMSO-d6): δ1.81-1.94 (2H, m), 2.66-2.76 (2H, m), 2.77-2.93 (4H, m), 3.55-3.72 (6H, m), 7.18 (1H, t, J=7.5 Hz), 7.34 (2H, t, J=7.5 Hz), 7.44 (2H, d, J=7.5 Hz), 7.57 (1H, s).
Yield: quant. %, 1H-NMR (CDCl3): δ1.95-2.10 (2H, m), 2.73-2.84 (2H, m), 2.85-3.01 (4H, m), 3.56 (2H, t, J=7.0 Hz), 3.66-3.89 (4H, m), 7.27 (1H, d, J=11.5 Hz), 7.75 (1H, d, J=7.0 Hz).
To a mixture of 4-(6-chlorobenzothiazole-2-yl)piperazine dihydrochloride (0.50 g; 1.53 mmol), triethylamine (0.32 ml; 2.25 mmol) and anhydrous THF (10 ml) was added dropwise chloroacetylchloride (0.18 ml; 2.25 mmol) under ice-cooling. The mixture was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The precipitate was washed with hexane to give 2-chloro-1-[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]ethane-1-on as blackish brown crystal (0.15 g; 30%).
1H-NMR (CDCl3): δ3.61-3.81 (8H, m), 4.12 (2H, s), 7.28 (1H, dd, J=8.5, 2.0 Hz), 7.47 (1H, d, J=8.5 Hz), 7.60 (1H, d, J=2.0 Hz).
To a mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ol (1.43 g; 5.32 mmol), triethylamine (0.78 ml; 5.59 mmol) and anhydrous THF (30 ml) was added dropwise methanesulfonyl chloride (0.43 ml; 5.59 mmol) under ice-cooling. The mixture was stirred at room temperature for 30 minutes. The reaction solution was condensed under reduced pressure. Water was added to the residue, and the precipitate was collected to give [(6-chlorobenzothiazole-1-yl)piperidine-4-yl]methanesulfonate as pale blackish brown crystal (1.66 g; 90%).
1H-NMR (CDCl3): δ1.97-2.20 (4H, m), 3.08 (3H, s), 3.57-3.68 (2H, m), 3.80-3.91 (2H, m), 4.97-5.08 (1H, m), 7.25 (1H, dd, J=8.5, 2.0 Hz), 7.44 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=2.0 Hz).
A mixture of 6-chloro-2-[4-(2-chloroethyl)piperidine-1-yl]benzothiazole (0.50 g; 1.59 mmol), cesium carbonate (0.78 g; 2.39 mmol), 3-hydroxy ethyl benzoate (0.40 g; 2.39 mmol) and anhydrous N,N-dimethylformamide (5 ml) was stirred at 60° C. for 9 hours. The reaction solution was returned to room temperature. Water and ethyl acetate was added thereto and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (methylene chloride) to give 3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}ethyl benzoate as colorless crystal (0.43 g; 62%).
1H-NMR (CDCl3): δ1.30-1.51 (5H, m), 1.74-1.97 (5H, m), 3.09-3.22 (2H, m), 4.04-4.18 (4H, m), 4.38 (2H, q, J=7.0 Hz), 7.09 (1H, dd, J=8.0, 1.5 Hz), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.35 (1H, t, J=8.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.52-7.58 (2H, m), 7.65 (1H, dd, J=8.0, 1.5 Hz).
Compounds in Examples 208 to 253 were obtained by similar methods as Example 207.
Yield: 39%, 1H-NMR (CDCl3); δ1.40 (3H, t, J=7.0 Hz), 1.92-2.16 (4H, m), 3.60-3.72 (2H, m), 3.80-3.92 (2H, m), 4.38 (2H, q, J=7.0 Hz), 4.65-4.74 (1H, m), 7.13 (1H, m), 7.24 (1H, dd, J=8.5, 2.0 Hz), 7.37 (1H, t, J=8.0 Hz), 7.44 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.0 Hz), 7.58-7.63 (1H, m), 7.67 (1H, m).
Yield: 16%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.90-2.12 (4H, m), 3.56-3.70 (4H, m), 3.78-3.90 (2H, m), 4.16 (2H, q, J=7.0 Hz), 4.61 (1H, m), 6.80-6.93 (3H, m), 7.20-7.28 (2H, m), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.0 Hz).
Yield: 39%, 1H-NMR (CDCl3); δ1.34 (3H, t, J=7 Hz), 1.45-1.65 (2H, m), 1.95-2.10 (2H, m), 2.10-2.25 (1H, m), 3.10-3.30 (2H, m), 3.92 (2H, d, J=6 Hz), 4.15-4.25 (2H, m), 4.32 (2H, q, J=7 Hz), 6.93 (1H, d, J=7.5 Hz), 6.98 (1H, td, J=7.5, 1 Hz), 7.24 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.46 (1H, td, J=7.5, 1 Hz), 7.55 (1H, d, J=2 Hz), 7.80 (1H, dd, J=7.5, 1 Hz).
Yield: 39%, 1H-NMR (CDCl3); δ1.40 (3H, t, J=7 Hz), 1.45-1.60 (2H, m), 1.95-2.05 (2H, m), 2.05-2.20 (1H, m), 3.10-3.25 (2H, m), 3.90 (2H, d, J=6 Hz), 4.15-4.25 (2H, m), 4.37 (2H, q, J=7 Hz), 7.09 (1H, dd, J=8, 1.5 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.34 (1H, t, J=8 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=1.5 Hz), 7.56 (1H, d, J=2 Hz), 7.64 (1H, dd, J=8, 1.5 Hz)
Yield: 52%, 1H-NMR (CDCl3); δ1.38 (3H, t, J=7 Hz), 1.45-1.60 (2H, m), 1.90-2.05 (2H, m), 2.05-2.20 (1H, m), 3.10-3.25 (2H, m), 3.90 (2H, d, J=6 Hz), 4.10-4.25 (2H, m), 4.35 (2H, q, J=7 Hz), 6.89 (2H, d, J=9 Hz), 7.24 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz), 7.99 (2H, d, J=9 Hz).
Yield: 63%, 1H-NMR (DMSO-d6): δ1.25-1.45 (2H, m), 1.70-1.85 (1H, m), 1.85-2.00 (2H, m), 3.03 (2H, d, J=7 Hz), 3.08-3.24 (2H, m), 3.86 (3H, s), 3.95-4.10 (2H, m), 7.27 (1H, dd, J=8.5, 2 Hz), 7.40 (1H, d, J=8.5 Hz), 7.48 (1H, t, J=8 Hz), 7.64 (1H, d, J=8 Hz), 7.75 (1H, d, J=8 Hz), 7.84 (1H, s), 7.88 (1H, d, J=2 Hz).
Yield: 79%, 1H-NMR (CDCl3); δ1.30-1.50 (2H, m), 1.75-2.00 (1H, m), 1.95-2.05 (2H, m), 2.89 (2H, d, J=7 Hz), 3.05-3.18 (2H, m), 3.60 (2H, s), 3.70 (3H, s), 4.05-4.20 (2H, m), 7.20-7.30 (5H, m), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: 86%, 1H-NMR (CDCl3); δ1.25-1.50 (5H, m), 1.77-2.00 (5H, m), 3.06-3.23 (2H, m), 4.05-4.20 (4H, m), 4.35 (2H, q, J=7.0 Hz), 6.93-7.04 (2H, m), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.37-7.49 (2H, m), 7.54 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=8.0, 1.5 Hz).
Yield: 65%, 1H-NMR (CDCl3); δ1.34-1.53 (5H, m), 1.76-1.98 (5H, m), 3.09-3.24 (2H, m), 4.06-4.23 (4H, m), 4.35 (2H, q, J=7.0 Hz), 6.91 (2H, d, J=8.5 Hz), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.0 Hz), 8.00 (2H, d, J=8.5 Hz).
Yield: 72%, 1H-NMR (CDCl3); δ1.40 (3H, t, J=7.0 Hz), 1.33-1.52 (2H, m), 1.79-1.98 (5H, m), 2.27 (3H, s), 3.08-3.21 (2H, m), 4.07-4.18 (4H, m), 4.37 (2H, q, J=7.0 Hz), 7.19 (1H, dd, J=7.5, 1.5 Hz), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.47 (1H, d, J=1.5 Hz), 7.55 (1H, d, J=2.0 Hz), 7.57 (1H, dd, J=7.5, 1.5 Hz).
Yield: 46%, 1H-NMR (CDCl3); δ1.24 (3H, t, J=7.0 Hz), 1.23-1.44 (2H, m), 1.67-1.92 (5H, m), 3.02-3.16 (2H, m), 3.57 (2H, s), 3.98 (2H, t, J=6.0 Hz), 4.02-4.15 (2H, m), 4.14 (2H, q, J=7.0 Hz), 6.75-6.90 (3H, m), 7.16-7.26 (2H, m), 7.41 (1H, d, J=8.5 Hz), 7.51 (1H, d, J=2.0 Hz).
Yield: 17%, 1H-NMR (CDCl3); δ1.23-1.44 (2H, m), 1.67-1.90 (5H, m), 3.02-3.16 (2H, m), 3.55 (2H, s), 3.67 (3H, s), 3.98 (2H, t, J=6.0 Hz), 4.02-4.14 (2H, m), 6.84 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 7.20 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.51 (1H, d, J=2.0).
Yield: 58%, 1H-NMR (CDCl3); δ1.23 (3H, t, J=7.0 Hz), 1.33-1.50 (2H, m), 1.74-1.96 (5H, m), 2.60 (2H, t, J=8.0 Hz), 2.95 (2H, t, J=8.0 Hz), 3.08-3.22 (2H, m), 4.02-4.19 (6H, m), 6.83 (1H, d, J=7.5 Hz), 6.88 (1H, td, J=7.5, 1.0 Hz), 7.14-7.20 (2H, m), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.0 Hz).
Yield: 71%, 1H-NMR (CDCl3); δ1.24 (3H, t, J=7.0 Hz), 1.31-1.49 (2H, m), 1.73-1.95 (5H, m), 2.62 (2H, t, J=8.0 Hz), 2.93 (2H, t, J=8.0 Hz), 3.08-3.21 (2H, m), 4.02 (2H, t, J=6.0 Hz), 4.07-4.20 (2H, m), 4.13 (2H, q, J=7.0 Hz), 6.71-6.84 (3H, m), 7.16-7.25 (2H, m), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield: 58%, 1H-NMR (CDCl3); δ1.30-1.47 (2H, m), 1.72-1.95 (5H, m), 2.60 (2H, t, J=8.0 Hz), 2.90 (2H, t, J=8.0 Hz), 3.08-3.20 (2H, m), 3.67 (3H, s), 4.01 (2H, t, J=6.0 Hz), 4.06-4.18 (2H, m), 6.82 (2H, d, J=8.5 Hz), 7.12 (2H, d, J=8.5 Hz), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield: 58%, 1H-NMR (CDCl3); δ1.24-1.43 (2H, m), 1.61-1.92 (5H, m), 2.97-3.20 (4H, m), 3.93 (3H, s), 4.06-4.18 (2H, m), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.36 (1H, t, J=7.5 Hz), 7.41 (1H, d, J=8.5 Hz), 7.49 (1H, dt, J=7.5, 1.5 Hz), 7.54 (1H, d, J=2.0 Hz), 7.84 (1H, dt, J=7.5, 1.5 Hz), 7.98 (1H, t, J=1.5 Hz).
Yield: 45%, 1H-NMR (DMSO-d6): δ1.12-1.30 (2H, m), 1.50-1.61 (2H, m), 1.65-1.86 (3H, m), 2.96-3.21 (4H, m), 3.61 (3H, s), 3.67 (2H, s), 3.94-4.07 (2H, m), 7.06 (1H, d, J=7.0 Hz), 7.18-7.32 (4H, m), 7.39 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz).
Yield: 50%, 1H-NMR (CDCl3): δ1.26 (3H, t, J=7.2 Hz), 1.39-1.46 (2H, m), 1.73-1.80 (1H, m), 1.89 (3H, d, J=12.3 Hz), 2.31 (3H, s), 3.54 (3H, s), 4.01 (2H, t, J=6.0 Hz), 4.05-4.15 (2H, m), 4.15 (2H, q, J=7.2 Hz), 4.10-4.12 (2H, m), 6.58-6.67 (2H, m), 6.69 (1H, m), 7.22 (1H, dd, J=8.7, 2.1 Hz), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz).
Yield: 53%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.31-1.51 (2H, m), 1.76-1.98 (5H, m), 3.07-3.23 (2H, m), 3.57 (2H, s), 4.04-4.20 (6H, m), 6.81 (1H, dd, J=7.5, 1.5 Hz), 6.87 (1H, d, J=1.5 Hz), 7.19-7.34 (2H, m), 7.42 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2.0 Hz).
Yield: 93%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7 Hz), 1.30-1.50 (1H, m), 1.75-2.00 (4H, m), 3.05-3.23 (2H, m), 3.55 (2H, s), 4.05-4.15 (6H, m), 4.18 (2H, q, J=7 Hz), 6.75-6.85 (1H, m), 6.91 (1H, dd, J=8, 2 Hz), 6.92 (1H, dd, J=11, 2 Hz), 7.22 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: 67%, 1H-NMR (CDCl3); δ1.39 (3H, t, J=7.0 Hz), 2.77 (4H, t, J=5.0 Hz), 2.93 (2H, t, J=5.5 Hz), 3.65 (4H, t, J=5.0 Hz), 4.21 (2H, t, J=5.5 Hz), 4.35 (2H, q, J=7.0 Hz), 6.98 (1H, d, J=7.5 Hz), 7.00 (1H, t, J=7.5 Hz), 7.24 (1H, dd, J=8.5, 2.0 Hz), 7.44 (1H, d, J=8.5 Hz), 7.46 (1H, t, J=7.5 Hz), 7.56 (1H, d, J=2.0 Hz), 7.79 (1H, dd, J=7.5, 2.0 Hz).
Yield: 76%, 1H-NMR (CDCl3); δ1.40 (3H, t, J=7.0 Hz), 2.73 (4H, t, J=5.0 Hz), 2.90 (2H, t, J=5.5 Hz), 3.67 (4H, t, J=5.0 Hz), 4.19 (2H, t, J=5.5 Hz), 4.38 (2H, q, J=7.0 Hz), 7.11 (1H, dd, J=8.0, 2.5 Hz), 7.24 (1H, dd, J=8.5, 2.0 Hz), 7.35 (1H, t, J=8.0 Hz), 7.44 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.0 Hz), 7.58 (1H, s), 7.66 (1H, dd, J=8.0, 2.5 Hz).
Yield: 82%, 1H-NMR (CDCl3); δ1.38 (3H, t, J=7.0 Hz), 2.73 (4H, t, J=5.0 Hz), 2.90 (2H, t, J=5.5 Hz), 3.66 (4H, t, J=5.0 Hz), 4.19 (2H, t, J=5.5 Hz), 4.35 (2H, q, J=7.0 Hz), 6.93 (2H, d, J=9.0 Hz), 7.24 (1H, dd, J=8.5, 2.0 Hz), 7.43 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.0 Hz), 8.00 (2H, d, J=9.0 Hz).
Yield: 18%, 1H-NMR (CDCl3); δ1.27-1.48 (2H, m), 1.64-1.95 (5H, m), 3.05-3.19 (2H, m), 3.84 (3H, s), 4.06-4.19 (4H, m), 6.22 (1H, d, J=4.0 Hz), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.51-7.27 (2H, m).
Yield: 46%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 2.72 (4H, t, J=5.0 Hz), 2.87 (2H, t, J=5.5 Hz), 3.58 (2H, s), 3.66 (4H, t, J=5.0 Hz), 4.14 (2H, t, J=5.5 Hz), 4.15 (2H, q, J=7.0 Hz), 6.79-6.91 (3H, m), 7.23 (1H, d, J=8.0 Hz), 7.24 (1H, dd, J=8.5, 2.0 Hz), 7.44 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2.0 Hz).
Yield: 81%, 1H-NMR (CDCl3); δ1.32-1.51 (5H, m), 1.74-1.99 (5H, m), 3.11-3.27 (2H, m), 4.04-4.24 (4H, m), 4.38 (2H, q, J=7.0 Hz), 7.06-7.13 (1H, m), 7.35 (1H, t, J=8.0 Hz), 7.48-7.57 (3H, m), 7.65 (1H, d, J=8.0 Hz), 7.84 (1H, s).
Yield: 58%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.31-1.50 (2H, m), 1.72-1.98 (5H, m), 3.12-3.25 (2H, m), 3.59 (2H, s), 4.04 (2H, t, J=6.0 Hz), 4.10-4.24 (4H, m), 6.77-6.91 (3H, m), 7.23 (1H, t, J=7.5 Hz), 7.48-7.59 (2H, m), 7.84 (1H, s).
Yield: 51%, 1H-NMR (DMSO-d6): δ1.26 (3H, t, J=7 Hz), 2.20 (3H, s), 2.77 (4H, t, J=5 Hz), 2.92 (2H, t, J=5.5 Hz), 3.56 (2H, s), 3.70 (4H, t, J=5 Hz), 4.13 (2H, t, J=5.5 Hz), 4.16 (2H, q, J=7 Hz), 6.75-6.80 (2H, m), 7.08 (1H, d, J=7 Hz), 7.52 (1H, dd, J=8.5, 1.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=0.5 Hz).
Yield: 49%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.32-1.51 (2H, m), 1.78-2.00 (5H, m), 3.12-3.27 (2H, m), 3.57 (2H, s), 4.05-4.24 (6H, m), 6.81 (1H, dd, J=8.0, 2.0 Hz), 6.87 (1H, d, J=2.0 Hz), 7.30 (1H, d, J=8.0 Hz), 7.47-7.59 (2H, m), 7.83 (1H, s).
Yield: 39%, 1H-NMR (CDCl3); δ1.27 (3H, t, J=7.0 Hz), 1.30-1.48 (2H, m), 1.72-1.94 (5H, m), 3.08-3.21 (2H, m), 3.72 (2H, s), 3.97-4.04 (2H, m), 4.07-4.19 (2H, m), 4.19 (2H, q, J=7.0 Hz), 6.76 (1H, dd, J=8.5, 3.0 Hz), 6.84 (1H, d, J=3.0 Hz), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.27 (1H, d, J=8.5 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield: 69%, 1H-NMR (CDCl3); δ2.00-2.08 (2H, m), 2.84 (2H, t, J=8.4 Hz), 2.96-3.02 (4H, m), 3.59 (2H, s), 3.69 (3H, s), 3.73 (2H, t, J=6.0 Hz), 3.79-3.84 (2H, m), 4.07 (2H, t, J=5.4 Hz), 6.79-6.88 (3H, m), 7.20-7.27 (2H, m), 7.43 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 49%, 1H-NMR (CDCl3); δ1.25 (3H, t, J=0.7 Hz), 1.98-2.08 (2H, m), 2.18 (3H, s), 2.82-2.90 (2H, m), 2.98-3.05 (4H, m), 3.55 (2H, s), 3.73 (2H, t, J=5.5 Hz), 3.75-3.85 (2H, m), 4.05-4.10 (2H, m), 4.15 (2H, q, J=7 Hz), 6.74 (1H, s), 6.76 (1H, d, J=7.5 Hz), 7.07 (1H, d, 7.5 Hz), 7.22 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: 45%, 1H-NMR (CDCl3); δ1.25 (3H, t, J=7 Hz), 1.95-2.10 (2H, m), 2.88 (2H, t, J=5.5 Hz), 3.00-3.10 (4H, m), 3.55 (2H, s), 3.73 (2H, t, J=5.5 Hz), 3.75-3.85 (2H, m), 4.10-4.15 (2H, m), 4.15 (2H, q, J=7 Hz), 6.80 (1H, dd, J=8, 2 Hz), 6.85 (1H, d, J=2 Hz), 7.22 (1H, dd, J=8.5, 2.5 Hz), 7.29 (1H, d, J=8 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.5 Hz).
Yield: 74%, 1H-NMR (CDCl3); δ1.25 (3H, t, J=7.0 Hz), 1.20-2.11 (2H, m), 2.79-2.90 (2H, m), 2.93-3.06 (4H, m), 3.57 (2H, s), 3.69-3.90 (4H, m), 4.04-4.12 (2H, m), 4.15 (2H, q, J=7.0 Hz), 6.76-6.90 (3H, m), 7.22 (1H, t, J=8.0 Hz), 7.48-7.59 (2H, m), 7.84 (1H, s).
Yield: 42%, 1H-NMR (CDCl3); δ1.25 (3H, t, J=7.0 Hz), 1.99-2.09 (2H, m), 2.86-2.94 (2H, m), 3.02-3.12 (4H, m), 3.55 (2H, s), 3.69-3.90 (4H, m), 4.10-4.20 (4H, m), 6.81 (1H, dd, J=8.0, 2.0 Hz), 6.87 (1H, d, J=2.0 Hz), 7.29 (1H, d, J=8.0 Hz), 7.48-7.59 (2H, m), 7.84 (1H, s).
Yield: 51%, 1H-NMR (CDCl3); δ1.31-1.49 (5H, m), 1.75-1.96 (5H, m), 3.09-3.22 (2H, m), 4.05-4.19 (4H, m), 4.38 (2H, q, J=7.0 Hz), 7.02 (1H, dd, J=8.0, 2.0 Hz), 7.09 (1H, ddd, J=8.0, 2.5, 1.0 Hz), 7.35 (1H, t, J=8.0 Hz), 7.47 (1H, d, J=8.0 Hz), 7.50 (1H, d, J=2.0 Hz), 7.56 (1H, dd, J=2.5, 1.5 Hz), 7.65 (1H, dt, J=8.0, 1.5, 1.0 Hz).
Yield: 44%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=6.5 Hz), 130-1.48 (2H, m), 1.72-1.95 (5H, m), 3.08-3.21 (2H, m), 3.58 (2H, s), 4.03 (2H, t, J=6.0 Hz), 4.08-4.21 (2H, m), 4.15 (2H, q, J=6.5 Hz), 6.76-6.90 (3H, m), 7.02 (1H, dd, J=8.5, 2.0 Hz), 7.22 (1H, d, J=7.5 Hz), 7.47 (1H, d, J=8.5 Hz), 7.50 (1H, d, J=2.0 Hz).
Yield: 57%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.31-1.48 (2H, m), 1.71-1.96 (5H, m), 3.09-3.22 (2H, m), 3.58 (2H, s), 4.03 (2H, t, J=6.0 Hz), 4.09-4.21 (4H, m), 6.77-6.91 (3H, m), 7.03 (1H, dd, J=8.0, 1.0 Hz), 7.17-7.28 (2H, m), 7.40 (1H, dd, J=8.0, 1.0 Hz).
Yield: 81%, 1H-NMR (CDCl3); δ1.32-1.50 (5H, m), 1.75-1.95 (5H, m), 3.09-3.21 (2H, m), 4.05-4.18 (4H, m), 4.38 (2H, q, J=7.0 Hz), 7.06-7.12 (1H, m), 7.32-7.39 (3H, m), 7.54-7.58 (1H, m), 7.62-7.67 (1H, m), 7.67-7.69 (1H, m).
Yield: 44%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.31-1.48 (2H, m), 1.73-1.96 (5H, m), 3.08-3.20 (2H, m), 3.58 (2H, s), 4.00-4.18 (4H, m), 4.16 (2H, q, J=7.0 Hz), 6.78-6.90 (3H, m), 7.20-7.28 (1H, m), 7.36 (2H, m), 7.69 (1H, m).
Yield: 48%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.30-1.49 (2H, m), 1.72-1.95 (5H, m), 2.39 (3H, s), 3.06-3.19 (2H, m), 3.58 (2H, s), 3.98-4.21 (6H, m), 6.77-6.91 (3H, m), 7.06-7.12 (1H, m), 7.23 (1H, t, J=7.5 Hz), 7.37-7.47 (2H, m).
Yield: 54%, 1H-NMR (CDCl3); δ1.25 (3H, t, J=7.0 Hz), 3.56-3.82 (10H, m), 4.14 (2H, q, J=7.0 Hz), 4.74 (2H, s), 6.83-6.96 (3H, m), 7.22-7.29 (2H, m), 7.45 (1H, d, J=8.5 Hz), 7.58 (1H, d, J=2.0 Hz).
Yield: 49%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.31-1.50 (2H, m), 1.73-1.93 (5H, m), 2.99-3.12 (2H, m), 3.58 (2H, s), 3.98-4.09 (4H, m), 4.15 (2H, q, J=7.0 Hz), 6.78-6.90 (3H, m), 7.16-7.47 (7H, m).
Yield: 54%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.35-1.52 (2H, m), 1.78-1.97 (5H, m), 3.01-3.14 (2H, m), 3.58 (2H, s), 3.99-4.21 (6H, m), 6.81 (1H, dd, J=8.0, 2.0 Hz), 6.87 (1H, d, J=2.0 Hz), 7.16-7.24 (1H, m), 7.27-7.37 (3H, m), 7.38-7.47 (3H, m).
Yield: 58%, 1H-NMR (DMSO-d6): δ1.18 (3H, t, J=7.0 Hz), 1.83-1.95 (2H, m), 2.74-2.84 (2H, m), 2.89-3.01 (4H, m), 3.56-3.72 (6H, m), 4.08 (2H, q, J=7.0 Hz), 4.09-4.17 (2H, m), 6.84 (1H, dd, J=8.0, 1.5 Hz), 7.09 (1H, d, J=1.5 Hz), 7.18 (1H, t, J=7.5 Hz), 7.29-7.38 (3H, m), 7.44 (2H, d, J=7.5 Hz), 7.57 (1H, s).
Yield: 31%, 1H-NMR (CDCl3): δ1.24 (3H, t, J=7.0 Hz), 1.95-2.08 (2H, m), 2.88 (2H, t, J=5.5 Hz), 2.98-3.12 (4H, m), 3.55 (2H, s), 3.60-3.90 (4H, m), 4.06-4.19 (4H, m), 6.79 (1H, dd, J=8.0, 1.5 Hz), 6.86 (1H, d, J=1.5 Hz), 7.25 (1H, d, J=12.0 Hz), 7.27 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=7.0 Hz).
To a mixture of 6-chloro-2-[4-(2-hydroxyethyl)piperidine-1-yl]benzothiazole (0.17 g; 0.562 mmol), [3-hydroxy-2-methyl]phenyl ethyl acetate described in Reference Example 67 of WO2004/0225 (510.11 g; 0.552 mmol), 1,1-azodicarbonyldipiperidine (0.21 g; 0.844 mmol) and anhydrous THF (6 ml) was added dropwise tributyl phosphine (0.21 ml; 0.841 mmol) under argon and ice-cooling. After stirring the reaction solution at the same temperature for 2.5 hours, water and ethyl acetate were added thereto. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=10:1→5:1) to give 3-{2-[(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}-2-methylphenyl ethyl acetate as colorless oil (0.16 g; 59%).
1H-NMR (CDCl3): δ1.26 (3H, t, J=7.2 Hz), 1.38-1.47 (2H, m), 1.78-1.93 (5H, m), 2.18 (3H, s), 3.14 (2H, td, J=12.6, 2.4 Hz), 3.64 (2H, s), 4.02 (2H, t, J=5.7 Hz), 4.10-4.16 (2H, m), 4.15 (2H, t, J=7.2 Hz), 6.80 (2H, q, J=7.8 Hz), 7.11 (1H, t, J=7.8 Hz), 7.23 (1H, dd, J=8.4, 1.8 Hz), 7.42 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=1.8 Hz).
Compounds in Examples 255 and 256 were obtained by similar methods as Example 254.
Yield: 39%, 1H-NMR (CDCl3); δ1.26 (3H, t, J=7.0 Hz), 1.28-1.50 (2H, m), 1.70-1.98 (5H, m), 3.04-3.21 (2H, m), 3.58 (2H, s), 3.97-4.22 (4H, m), 4.15 (2H, q, J=7.0 Hz), 6.75-6.92 (3H, m), 7.00 (1H, td, J=9.0, 3.0 Hz), 7.23 (1H, t, J=8.0 Hz), 7.29 (1H, dd, J=9.0, 3.0 Hz), 7.44 (1H, dd, J=9.0, 5.0 Hz).
Yield: 22%, 1H-NMR (CDCl3): δ1.24 (3H, t, J=7.0 Hz), 1.26-1.50 (2H, m), 1.68-1.92 (5H, m), 2.94-3.09 (2H, m), 3.58 (2H, m), 3.94-4.13 (4H, m), 4.14 (2H, q, J=7.0 Hz), 6.72 (1H, s), 6.75-6.93 (3H, m), 7.24 (2H, m), 7.35 (2H, t, J=7.0 Hz), 7.83 (2H, d, J=7.0 Hz).
A mixture of 3-{2-[(6-bromobenzothiazole-2-yl)piperidine-4-yl]ethoxy}phenyl ethyl acetate (0.30 g; 0.596 mmol), phenylboronic acid (0.09 g; 0.775 mmol), tetrakis (triphenylphosphine) palladium (0) (0.03 g; 0.03 mmol), cesium carbonate (0.25 g; 0.775 mmol) and dioxane (3 ml) was refluxed under argon for 3 hours. The reaction solution was cooled to room temperature and condensed under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=3:1) to give 3-{2-[(6-phenylbenzothiazole-2-yl)piperidine-4-yl]ethoxy}phenyl ethyl acetate as colorless crystal (0.08 g; 26%).
1H-NMR (CDCl3): δ 1.25 (3H, t, J=7.0 Hz), 1.28-1.48 (2H, m), 1.66-1.96 (5H, m), 3.04-3.21 (2H, m), 3.57 (2H, s), 3.94-4.07 (2H, m), 4.08-4.25 (4H, m), 6.73-6.92 (3H, m), 7.17-7.34 (2H, m), 7.36-7.47 (2H, m), 7.48-7.64 (4H, m), 7.79 (1H, d, J=2.0 Hz).
A mixture of acetic acid 3-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-5-methylphenyl ester (1.97 g; 4.88 mmol), 2N-aqueous sodium hydroxide (10 ml) and methanol (20 ml) was stirred at 40° C. for 1 hour. The solvent was evaporated under reduced pressure. To the residue were added water and 2N-aqueous hydrochloric acid to be neutral. Ethyl acetate was added thereto and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (ethyl acetate) to give 3-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-5-methylphenol as colorless amorphous solid (1.83 g; 100%).
1H-NMR (CDCl3): δ2.29 (3H, s), 2.57 (4H, t, J=5 Hz), 3.47 (2H, s), 3.67 (4H, t, J=5 Hz), 6.59 (1H, s), 6.67 (2H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.45 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Compounds in Examples 259 to 286 were obtained by similar methods as Example 258.
Yield: 85%, 1H-NMR (CDCl3); δ1.74 (1H, brs), 1.96-2.05 (2H, m), 2.26 (3H, s), 2.67 (2H, t, J=5.1 Hz), 2.75-2.79 (2H, m), 3.52 (2H, s), 3.68-3.74 (4H, m), 6.55 (1H, s), 6.61 (1H, s), 6.65 (1H, s), 7.22 (1H, dd, J=8.7, 2.1 Hz), 7.43 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=2.1 Hz).
Yield: 100%, 1H-NMR (CDCl3); δ2.29 (3H, s), 2.61 (4H, t, J=5 Hz), 3.50 (2H, s), 3.71 (4H, t, J=5 Hz), 6.60 (1H, s), 6.69 (2H, s), 7.52 (1H, d, J=7.5 Hz), 7.58 (1H, d, J=7.5 Hz), 7.85 (1H, s).
Yield: 71%, 1H-NMR (CDCl3); δ2.00-2.10 (2H, m), 2.28 (3H, s), 2.65-2.75 (2H, m), 2.80-2.90 (2H, m), 3.57 (2H, s), 3.70-3.90 (4H, m), 6.56 (1H, s), 6.65-6.70 (2H, m), 7.45-7.60 (2H, m), 7.85 (1H, s).
Yield: 99%, 1H-NMR (CDCl3): δ1.22 (3H, d, J=6 Hz), 1.64 (1H, brs), 2.25-2.29 (1H, m), 2.30 (3H, s), 2.60-2.70 (1H, m), 2.80-2.83 (1H, m), 3.13 (1H, d, J=13.5 Hz), 3.17-3.25 (1H, m), 3.40-3.50 (1H, m), 3.73-3.83 (1H, m), 3.85-3.95 (1H, m), 3.98 (1H, d, J=13.5 Hz), 6.57 (1H, s), 6.66 (1H, s), 6.69 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: quant. %, 1H-NMR (CDCl3): δ1.11 (6H, d, J=6 Hz), 2.28 (3H, s), 2.70-2.85 (2H, m), 2.95-3.10 (2H, m), 3.70-3.90 (4H, m), 6.53 (1H, s), 6.68 (1H, s), 6.72 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: quant. %, 1H-NMR (CDCl3): δ1.10 (6H, d, J=6 Hz), 2.28 (3H, s), 2.70-2.85 (2H, m), 3.00-3.15 (2H, m), 3.75 (2H, s), 3.82-3.94 (2H, m), 5.53 (1H, brs), 6.52 (1H, s), 6.69 (1H, s), 6.72 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: quant. %, 1H-NMR (CDCl3): δ1.42 (3H, d, J=7 Hz), 2.20-2.28 (1H, m), 2.28 (3H, s), 2.30-2.45 (1H, m), 2.70-2.85 (1H, m), 2.90-3.00 (1H, m), 3.43 (1H, d, J=13.5 Hz), 3.45-3.55 (1H, m), 3.58 (1H, d, J=13.5 Hz), 3.80-3.90 (1H, m), 4.15-4.25 (1H, m), 6.60 (1H, s), 6.66 (1H, s), 6.77 (1H, s), 7.22 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: quant. %, 1H-NMR (CDCl3): δ1.01 (3H, t, J=7.5 Hz), 1.55-1.78 (2H, m), 2.29 (3H, s), 2.30-2.40 (1H, m), 2.48-2.56 (1H, m), 2.79-2.83 (1H, m), 3.18 (1H, d, J=13.5 Hz), 3.37-3.56 (2H, m), 3.65-3.77 (1H, m), 3.82 (1H, dd, J=13, 3 Hz), 3.93 (1H, d, J=13.5 Hz), 6.57 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.52 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1.5 Hz).
Yield 99%, 1H-NMR (CDCl3): δ2.27 (3H, s), 2.27-2.35 (1H, m), 2.77 (1H, d, J=13.5 Hz), 3.02 (1H, d, J=11.5 Hz), 3.28-3.50 (3H, m), 3.75 (1H, d, J=13.5 Hz), 3.98 (1H, d, J=11 Hz), 4.10-4.18 (1H, m), 5.61 (1H, brs), 6.54 (1H, s), 6.61 (1H, s), 6.64 (1H, s), 7.30-7.43 (3H, m), 7.45-7.60 (4H, m), 7.86 (1H, s).
Yield: 96%, 1H-NMR (CDCl3): δ1.42 (3H, d, J=6.5 Hz), 2.18 (1H, td, J=12, 3.5 Hz), 2.29 (3H, s), 2.29-2.40 (1H, m), 2.74 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.39 (1H, d, J=13 Hz), 3.47 (1H, d, J=13 Hz), 3.55 (1H, td, J=12.5, 3.5 Hz), 3.90 (1H, d, J=13 Hz), 4.16-4.29 (1H, m), 6.58 (1H, s), 6.69 (1H, s), 6.70 (1H, s), 7.51 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1.5 Hz).
Yield: quant. %, 1H-NMR (CDCl3): δ1.43 (3H, d, J=6.5 Hz), 2.14-2.41 (5H, m), 2.71-2.80 (1H, m), 2.86-2.92 (1H, m), 3.35-3.59 (3H, m), 3.85-3.97 (1H, m), 4.17-4.29 (1H, m), 6.58 (1H, s), 6.69 (1H, s), 6.72 (1H, s), 7.48-7.60 (2H, m), 7.84 (1H, s).
Yield: 96%, 1H-NMR (CDCl3): δ1.00 (3H, t, J=7.5 Hz), 1.55-1.75 (2H, m), 2.29 (3H, s), 2.29-2.38 (1H, m), 2.47-2.57 (1H, m), 2.78-2.88 (1H, m), 3.17 (1H, d, J=13.5 Hz), 3.37-3.55 (2H, m), 3.65-3.85 (2H, m), 3.93 (1H, d, J=13.5 Hz), 6.57 (1H, s), 6.67 (1H, s), 6.69 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 92%, 1H-NMR (CDCl3): δ1.01 (3H, t, J=7.5 Hz), 1.57-1.79 (2H, m), 2.29 (3H, s), 2.29-2.40 (1H, m), 2.46-2.58 (1H, m), 2.77-2.89 (1H, m), 3.18 (1H, d, J=13 Hz), 3.32-3.58 (2H, m), 3.65-3.87 (2H, m), 3.93 (1H, d, J=13 Hz), 6.57 (1H, s), 6.67 (1H, s), 6.69 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 95%, 1H-NMR (CDCl3): δ0.93 (3H, t, J=7.5 Hz), 1.30-1.70 (4H, m), 2.29 (3H, s), 2.29-2.39 (1H, m), 2.55-2.65 (1H, m), 2.79-2.88 (1H, m), 3.19 (1H, d, J=13.5 Hz), 3.41 (1H, dd, J=12.5, 8 Hz), 3.48-3.58 (1H, m), 3.65-3.75 (1H, m), 3.82 (1H, dd, J=12.5, 2.5 Hz), 3.92 (1H, d, J=13.5 Hz), 6.57 (1H, s), 6.68 (1H, s), 6.70 (1H, s), 7.51 (1H, dd, J=8.5, 1.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1.5 Hz).
Yield: 98%, 1H-NMR (CDCl3): δ0.93 (3H, t, J=7.5 Hz), 1.30-1.41 (1H, m), 1.48-1.63 (3H, m), 2.29 (3H, s), 2.29-2.36 (1H, m), 2.56-2.62 (1H, m), 2.79-2.86 (1H, m), 3.19 (1H, d, J=13.5 Hz), 3.41 (1H, dd, J=7.8, 12.9 Hz), 3.50-3.57 (1H, m), 3.69-3.81 (2H, m), 3.92 (1H, d, J=13.5 Hz), 6.67 (1H, s), 6.68 (2H, s), 7.50-7.59 (2H, m), 7.84 (1H, s)
Yield: 98%, 1H-NMR (CDCl3): δ0.91 (3H, t, J=7 Hz), 1.26-1.75 (6H, m), 2.30 (3H, s), 2.30-2.40 (1H, m), 2.52-2.63 (1H, m), 2.77-2.87 (1H, m), 3.19 (1H, d, J=13.5 Hz), 3.35-3.45 (1H, m), 3.47-3.57 (1H, m), 3.65-3.75 (1H, m), 3.81 (1H, dd, J=12.5, 2.5 Hz), 3.92 (1H, d, J=13.5 Hz), 5.49 (1H, brs), 6.57 (1H, s), 6.67 (1H, s), 6.69 (1H, s), 7.52 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1.5 Hz)
Yield: 96%, 1H-NMR (CDCl3): δ0.91 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=6.5 Hz), 1.32-1.46 (1H, m), 1.47-1.59 (1H, m), 1.62-1.78 (1H, m), 2.29 (3H, s), 2.33-2.45 (1H, m), 2.62-2.74 (1H, m), 2.75-2.87 (1H, m), 3.27 (1H, d, J=13.5 Hz), 3.36 (1H, dd, J=12.5, 7.5 Hz), 3.55-3.65 (2H, m), 3.70-3.79 (1H, m), 3.86 (1H, d, J=13.5 Hz), 6.56 (1H, s), 6.69 (2H, s), 7.22 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: quant. %, 1H-NMR (CDCl3): δ0.91 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=6.5 Hz), 1.30-1.59 (2H, m), 1.62-1.79 (1H, m), 2.18 (1H, s), 2.29 (3H, s), 2.30-2.45 (1H, m), 2.60-2.72 (1H, m), 2.75-2.88 (1H, m), 3.27 (1H, d, J=13.5 Hz), 3.29-3.42 (1H, m), 3.53-3.65 (2H, m), 3.74 (1H, dd, J=12.5, 3.5 Hz), 3.86 (1H, d, J=13.5 Hz), 6.56 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.43 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield: 98%, 1H-NMR (CDCl3): δ0.91 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=6.5 Hz), 1.37-1.45 (1H, m), 1.46-1.60 (1H, m), 1.64-1.77 (1H, m), 2.29 (3H, s), 2.36-2.47 (1H, m), 2.64-2.75 (1H, m), 2.78-2.90 (1H, m), 3.29 (1H, d, J=13.5 Hz), 3.42 (1H, dd, J=12.5, 7.5 Hz), 3.65 (2H, t, J=5 Hz), 3.78 (1H, dd, J=13, 3 Hz), 3.86 (1H, d, J=13.5 Hz), 6.57 (1H, s), 6.70 (2H, s), 7.51 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, d, J=1.5 Hz).
Yield: 99%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6 Hz), 2.22-2.28 (1H, m), 2.29 (3H, s), 2.59-2.70 (1H, m), 2.83 (1H, dt, J=12, 3.5 Hz), 3.13 (1H, d, J=13.5 Hz), 3.21 (1H, dd, J=11, 8.5 Hz), 3.39-3.50 (1H, m), 3.72-3.83 (1H, m), 3.84-3.93 (1H, m), 3.97 (1H, d, J=13.5 Hz), 6.56 (1H, s), 6.65 (1H, s), 6.70 (1H, s), 7.26 (1H, d, J=11.5 Hz), 7.73 (1H, d, J=7 Hz).
Yield: quant. %, 1H-NMR (CDCl3): δ2.00-2.14 (2H, m), 2.22 (3H, s), 2.68-2.93 (4H, m), 3.53-3.95 (6H, m), 6.60 (2H, s), 6.72 (1H, s), 7.24 (1H, d, J=11.5 Hz), 7.72 (1H, d, J=7.0 Hz), 7.85 (1H, s).
Yield: 89%, 1H-NMR (CDCl3): δ1.13 (6H, d, J=6.0 Hz), 2.29 (3H, s), 2.72-2.88 (2H, m), 3.01-3.19 (2H, m), 3.77 (2H, s), 3.89 (2H, d, J=12.0 Hz), 6.52 (1H, s), 6.70 (1H, s), 6.72 (1H, s), 7.27 (1H, d, J=11.5 Hz), 7.75 (1H, d, J=6.5 Hz).
Yield: 95%, 1H-NMR (CDCl3): δ1.01 (3H, t, J=7.5 Hz), 1.48-1.80 (2H, m), 2.25-2.40 (1H, m), 2.30 (3H, s), 2.46-2.58 (1H, m), 2.78-2.89 (1H, m), 3.19 (1H, d, J=13.5 Hz), 3.32-3.57 (2H, m), 3.64-3.75 (1H, m), 3.76-3.87 (1H, m), 3.93 (1H, d, J=13.5 Hz), 6.57 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.27 (1H, d, J=11.5 Hz), 7.74 (1H, d, J=7.0 Hz).
Yield: quant %, 1H-NMR (CDCl3): δ2.23 (3H, s), 2.62-2.80 (4H, m), 3.52-3.73 (6H, m), 6.63 (1H, s), 6.65 (1H, s), 6.78 (1H, s), 7.20 (1H, t, J=7.5 Hz), 7.31 (2H, t, J=7.5 Hz), 7.35-7.44 (3H, m), 8.70 (1H, brs).
Yield: 93%, 1H-NMR (CDCl3): δ1.13 (6H, d, J=6.0 Hz), 2.29 (3H, s), 2.65-2.80 (2H, m), 2.90 (2H, t, J=11.5 Hz), 3.76 (2H, s), 4.29 (2H, d, J=13.0 Hz), 6.54 (1H, s), 6.70 (1H, s), 6.75 (1H, s), 7.34-7.43 (1H, m), 7.53-7.62 (1H, m), 7.69 (1H, d, J=8.0 Hz), 7.88 (1H, d, J=8.0 Hz), 8.55 (1H, s).
Yield: 93%, 1H-NMR (CDCl3): δ1.25 (3H, d, J=5.5 Hz), 2.21-2.34 (1H, m), 2.29 (3H, s), 2.54-2.70 (1H, m), 2.83-2.94 (1H, m), 3.07-3.22 (1H, m), 3.14 (1H, d, J=13.5 Hz), 3.30-3.45 (1H, m), 4.02 (1H, d, J=13.5 Hz), 4.06-4.17 (1H, m), 4.18-4.28 (1H, m), 6.58 (1H, s), 6.66-6.74 (2H, m), 7.34-7.43 (1H, m), 7.53-7.61 (1H, m), 7.68 (1H, dd, J=8.5, 1.0 Hz), 7.88 (1H, dd, J=8.5, 1.0 Hz), 8.55 (1H, s).
Yield: 88%, 1H-NMR (CDCl3): δ1.16 (6H, d, J=6.0 Hz), 2.29 (3H, s), 2.65-2.83 (2H, m) 2.94 (2H, t, J=11.5 Hz), 3.77 (2H, s), 4.30 (2H, d, J=14.0 Hz), 6.52 (1H, s), 6.72 (1H, s), 6.75 (1H, s), 7.50 (1H, dd, J=9.0, 2.5 Hz), 7.60 (1H, d, J=9.0 Hz), 7.85 (1H, d, J=2.5 Hz), 8.54 (1H, s).
Yield: 97%, 1H-NMR (CDCl3): δ1.17 (6H, d, J=6.0 Hz), 2.28 (3H, s), 2.66-2.83 (2H, m), 2.90-3.06 (2H, m), 3.79 (2H, s), 4.34 (2H, d, J=13.0 Hz), 6.55 (1H, s), 6.69 (1H, s), 6.75 (1H, s), 7.72 (2H, s), 8.14 (1H, s), 8.59 (1H, s).
A mixture of 6-chloro-2-[4-(2-methoxymethoxy-3-methylbenzyl)piperazine-1-yl]benzothiazole (1.70 g; 4.067 mmol) and 4N hydrochloric acid/dioxane solution (8.5 ml) was stirred at 60° C. for 2 hours. After cooling, the reaction solution was condensed under reduced pressure. To the residue was added saturated aqueous sodium hydrogencarbonate to be alkaline and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The precipitate was washed with diisopropyl ether to give 5-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-2-methylphenol as colorless crystal (1.33 g; 87%).
1H-NMR (CDCl3): δ2.24 (3H, s), 2.55 (4H, t, J=5 Hz), 3.46 (2H, s), 3.63 (4H, t, J=5 Hz), 5.95 (1H, brs), 6.76 (1H, d, J=7.5 Hz), 6.81 (1H, s), 7.07 (1H, d, J=7.5 Hz), 7.23 (1H, dd, J=8, 2 Hz), 7.45 (1H, d, J=8 Hz), 7.55 (1H, d, J=2 Hz).
Compounds in Examples 288 to 292 were obtained by similar methods as Example 287.
Yield: 100%, 1H-NMR (DMSO-d6): δ2.12 (3H, s), 3.08-3.18 (2H, m), 3.39 (2H, d, J=12.0 Hz), 3.65 (2H, t, J=12.0 Hz), 4.13-4.21 (4H, m), 6.85 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=8.4 Hz), 7.28 (1H, s), 7.28 (1H, m), 7.49 (1H, d, J=8.7 Hz), 7.99 (1H, d, J=2.1 Hz).
Yield: 80%, 1H-NMR (DMSO-d6): δ2.12 (3H, s), 2.16-2.26 (2H, m), 3.03-3.15 (2H, m), 3.49-3.76 (4H, m), 4.02 (4H, s) 6.83 (1H, d, J=8.1 Hz), 7.19 (1H, d, J=8.1 Hz), 7.25 (1H, s), 7.31 (1H, dd, J=2.4, 8.7 Hz), 7.45 (1H, d, J=9.7 Hz), 7.95 (1H, d, J=2.4 Hz).
Yield: 77%, 1H-NMR (DMSO-d6): δ1.59 (3H, d, J=6.3 Hz), 2.24 (3H, s), 3.12 (2H, br), 3.54 (1H, br), 3.65 (2H, br), 3.89-3.96 (1H, m), 4.09 (1H, d, J=14.1 Hz), 4.21 (1H, d, J=12.9 Hz), 4.63 (1H, d, J=11.2 Hz), 6.68 (1H, s), 6.81 (1H, s), 6.88 (1H, s), 7.34 (1H, dd, J=2.1, 8.7 Hz), 7.50 (1H, d, J=8.7 Hz), 8.00 (1H, d, J=2.1 Hz), 11.6 (1H, s)
Yield: 84%, 1H-NMR (DMSO-d6): δ1.58 (3H, d, J=6.0 Hz), 2.24 (3H, s), 3.16 (2H, br), 3.53 (1H, br), 3.64 (1H, br), 3.89-3.96 (2H, m), 4.08 (1H, d, J=12.9 Hz), 4.21 (1H, d, J=12.9 Hz), 4.63 (1H, d, J=12.0 Hz), 6.68 (1H, s), 6.81 (1H, s), 6.87 (1H, s), 7.34 (1H, dd, J=2.1, 8.7 Hz), 7.50 (1H, d, J=8.7 Hz), 8.00 (1H, d, J=2.1 Hz), 11.6 (1H, br)
Yield: 84%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6 Hz), 2.24 (3H, s), 2.25-2.33 (1H, m), 2.59-2.70 (1H, m), 2.81 (1H, dt, J=12, 3 Hz), 3.14 (1H, d, J=13.5 Hz), 3.15-3.25 (1H, m), 3.39-3.50 (1H, m), 3.73-3.83 (1H, m), 3.84-3.94 (1H, m), 3.98 (1H, d, J=13.5 Hz), 5.18 (1H, brs), 6.79 (1H, d, J=7.5 Hz), 6.80 (1H, s), 7.07 (1H, d, J=7.5 Hz), 7.51 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, s).
A mixture of 3-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-5-methylphenol (0.50 g; 1.34 mmol), bromoethyl acetate (0.22 ml; 2.01 mmol) and cesium carbonate (0.65 g; 2.01 mmol) in anhydrous N,N-dimethylformamide (5 ml) was stirred at 50° C. for 17 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give {3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]-5-methyl}+phenoxyethyl acetate as pale yellow oil (0.48 g; 78%).
1H-NMR (CDCl3): δ1.28 (3H, t, J=7 Hz), 2.32 (3H, s), 2.56 (4H, t, J=5 Hz), 3.49 (2H, s), 3.63 (4H, t, J=5 Hz), 4.27 (2H, q, J=7 Hz), 4.61 (2H, s), 6.64 (1H, s), 6.74 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Compounds in Examples 294 to 329 were obtained by similar methods as Example 293.
Yield: 84%, 1H-NMR (CDCl3); δ1.27 (3H, t, J=7 Hz), 1.59 (6H, s), 2.29 (3H, s), 2.55 (4H, t, J=5 Hz), 3.46 (2H, s), 3.62 (4H, t, J=5 Hz), 4.26 (2H, q, J=7 Hz), 6.55 (1H, s), 6.60 (1H, s), 6.77 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 78%, 1H-NMR (CDCl3); δ1.31 (3H, t, J=7 Hz), 2.32 (3H, s), 2.58 (4H, t, J=5 Hz), 3.50 (2H, s), 3.68 (4H, t, J=5 Hz), 4.28 (2H, q, J=7 Hz), 4.62 (2H, s), 6.65 (1H, s), 6.74 (1H, s), 6.78 (1H, s), 7.50-7.60 (2H, m), 7.85 (1H, s).
Yield: 93%, 1H-NMR (CDCl3); δ1.30 (3H, t, J=6.9 Hz), 1.98-2.05 (2H, m), 2.30 (3H, s), 2.67 (2H, t, J=5.1 Hz), 2.77-2.81 (2H, m), 3.57 (2H, s), 3.71-3.75 (4H, m), 4.27 (2H, q, J=7.2 Hz), 4.60 (2H, s), 6.63 (1H, s), 6.73 (1H, s), 6.76 (1H, s), 7.23 (1H, dd, J=8.7, 2.4 Hz), 7.42 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 66%, 1H-NMR (CDCl3); δ1.29 (3H, t, J=7 Hz), 1.98-2.06 (2H, m), 2.30 (3H, s), 2.68 (2H, t, J=5.5 Hz), 2.81 (2H, t, J=5.5 Hz), 3.57 (2H, s), 3.70-3.85 (4H, m), 4.27 (2H, q, J=7 Hz), 4.60 (2H, s), 6.63 (1H, s), 6.73 (1H, s), 6.76 (1H, s), 7.48-7.58 (2H, m), 7.84 (1H, s).
Yield: 68%, 1H-NMR (CDCl3); δ1.29 (3H, t, J=7 Hz), 2.28 (3H, s), 2.55 (4H, t, J=5 Hz), 3.50 (2H, s), 3.62 (4H, t, J=5 Hz), 4.26 (2H, q, J=7 Hz), 4.65 (2H, s), 6.74 (1H, s), 6.84 (1H, d, J=7.5 Hz), 7.10 (1H, d, J=7.5 Hz), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 84%, 1H-NMR (CDCl3); δ1.30 (3H, t, J=7.2 Hz), 2.30 (3H, s), 2.55 (4H, t, J=5.1 Hz), 3.46 (2H, s), 3.62 (4H, t, J=5.1 Hz), 4.27 (2H, q, J=7.2 Hz), 4.64 (2H, s), 6.66 (1H, dd, J=8.1 Hz), 7.07 (1H, d, J=8.1 Hz), 7.13 (1H, s), 7.23 (1H, dd, J=8.4, 2.1 Hz), 7.43 (1H, dd, J=8.1 Hz), 7.55 (1H, d, J=2.1 Hz)
Yield: 90%, 1H-NMR (CDCl3); δ1.30 (3H, t, J=7.2 Hz), 1.98-2.05 (2H, m), 2.28 (3H, s), 2.67 (2H, t, J=5.1 Hz), 2.78 (2H, t, J=5.1 Hz), 3.54 (2H, s), 3.71-3.78 (4H, m), 4.27 (2H, q, J=7.2 Hz), 4.63 (2H, s), 6.64 (1H, d, J=8.1 Hz), 7.05 (1H, d, J=8.1 Hz), 7.11 (1H, s), 7.22 (1H, dd, J=8.7, 2.1 Hz), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz).
Yield: 92%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6 Hz), 1.31 (3H, t, J=7 Hz), 2.20-2.32 (1H, m), 2.33 (3H, s), 2.60-2.70 (1H, m), 2.77-2.85 (1H, m), 3.05-3.25 (2H, m), 3.35-3.50 (1H, m), 3.70-3.80 (1H, m), 3.85-3.95 (1H, m), 3.98 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.75 (1H, s), 6.78 (1H, s), 7.53 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 74%, 1H-NMR (CDCl3): δ1.10 (6H, d, J=6 Hz), 1.30 (3H, t, J=7 Hz), 2.31 (3H, s), 2.70-2.85 (2H, m), 3.01 (1H, d, J=10.5 Hz), 3.05 (1H d, J=10.5 Hz), 3.76 (2H, s), 3.80-3.90 (2H, m), 4.27 (2H, q, J=7 Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.83 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 93%, 1H-NMR (CDCl3): δ1.12 (6H, d, J=6 Hz), 1.30 (3H, t, J=7 Hz), 2.31 (3H, s), 2.70-2.90 (2H, m), 3.00-3.15 (2H, m), 3.77 (2H, s), 3.85-3.95 (2H, m), 4.27 (2H, q, J=7 Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.84 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 95%, 1H-NMR (CDCl3): δ1.30 (3H, t, J=7 Hz), 1.41 (3H, d, J=7 Hz), 2.21 (1H, td, J=12, 3.5 Hz), 2.25-2.35 (1H, m), 2.32 (3H, s), 2.73 (1H, d, J=11 Hz), 2.90 (1H, d, J=11 Hz), 3.38 (1H, d, J=13.5 Hz), 3.48 (1H, td, J=12, 3.5 Hz), 3.52 (1H, d, J=13.5 Hz), 3.85 (1H, d, J=12 Hz), 4.15-4.25 (1H, m), 4.27 (2H, q, J=7 Hz), 4.61 (2H, s), 6.64 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.22 (1H, dd, J=8, 2 Hz), 7.42 (1H, d, J=8 Hz), 7.54 (1H, d, J=2 Hz).
Yield: 43%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6 Hz), 1.30 (3H, t, J=7 Hz), 2.20-2.27 (1H, m), 2.28 (3H, s), 2.60-2.70 (1H, m), 2.75-2.85 (1H, m), 3.10-3.25 (2H, m), 3.35-3.50 (1H, m), 3.68-3.78 (1H, m), 3.85-3.95 (1H, m), 4.01 (1H, d, J=13 Hz), 4.27 (2H, q, J=7 Hz), 4.65 (2H, s), 6.74 (1H, s), 6.85 (1H, d, J=7.5 Hz), 7.11 (1H, d, J=7.5 Hz), 7.53 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 79%, 1H-NMR (CDCl3): δ1.22 (3H, d, J=6.5 Hz), 1.31 (3H, t, J=7 Hz), 2.23-2.35 (1H, m), 2.60-2.73 (1H, m), 2.75-2.90 (1H, m), 3.15-3.25 (2H, m), 3.40-3.50 (1H, m), 3.70-3.82 (1H, m), 3.85-3.95 (1H, m), 4.03 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7 Hz), 4.63 (2H, s), 6.80 (1H, dd, J=8, 1.5 Hz), 6.93-7.02 (2H, m), 7.25 (1H, t, J=8 Hz), 7.53 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 81%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.31 (3H, t, J=7 Hz), 1.58-1.79 (2H, m), 2.31 (3H, s), 2.31-2.38 (1H, m), 2.47-2.58 (1H, m), 2.78-2.88 (1H, m), 3.23 (1H, d, J=13.5 Hz), 3.36-3.58 (2H, m), 3.64-3.75 (1H, m), 3.84 (1H, d, J=11 Hz), 3.95 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7 Hz), 4.62 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s)
Yield: 91%, 1H-NMR (CDCl3): δ1.31 (3H, t, J=7 Hz), 2.25-2.35 (4H, m), 2.82 (1H, d, J=13.5 Hz), 3.01 (1H, d, J=11.5 Hz), 3.25-3.50 (3H, m), 3.79 (1H, d, J=13.5 Hz), 4.00-4.10 (2H, m), 4.28 (2H, q, J=7 Hz), 4.60 (2H, s), 6.59 (1H, s), 6.70 (1H, s), 6.72 (1H, s), 7.30-7.45 (3H, m), 7.50-7.58 (4H, m), 7.84 (1H, s).
Yield: 90%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6.3 Hz), 1.31 (3H, t, J=7.2 Hz), 2.22-2.31 (1H, m), 2.32 (3H, s), 2.58-2.68 (1H, m), 2.83 (1H, dt, J=3.3, 12.3 Hz), 3.12-3.19 (2H, m), 3.34-3.43 (1H, m), 3.71 (1H, d, J=12.3 Hz), 3.86 (1H, d, J=10.5 Hz), 3.99 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7.2 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.75 (1H, s), 6.78 (1H, s), 7.23 (1H, d, J=2.4, 8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.55 (1H, d, J=2.4 Hz)
Yield: 70%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6.3 Hz), 1.30 (3H, t, J=7.2 Hz), 2.23-2.32 (1H, m), 2.32 (3H, s), 2.58-2.67 (1H, m), 2.80 (1H, d, J=3.3, 12.3 Hz), 3.12-3.19 (2H, m), 3.35-3.42 (1H, m), 3.71 (1H, dt, J=12.0 Hz), 3.86 (1H, dt, J=12.0 Hz), 3.99 (1H, d, J=13.2 Hz), 4.28 (2H, q, J=7.2 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.75 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J=2.1, 8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield: 89%, 1H-NMR (CDCl3): δ1.30 (3H, t, J=7 Hz), 1.43 (3H, d, J=6.5 Hz), 2.23 (1H, td, J=12, 3.5 Hz), 2.31 (3H, s), 2.31-2.40 (1H, m), 2.73 (1H, d, J=11 Hz), 2.91 (1H, d, J=11 Hz), 3.40 (1H, d, J=13 Hz), 3.46-3.51 (1H, m), 3.53 (1H, d, J=13 Hz), 3.85-3.95 (1H, m), 4.20-4.27 (1H, m), 4.28 (2H, q, J=7 Hz), 4.62 (2H, s), 6.65 (1H, s), 6.77 (1H, s), 6.79 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 84%, 1H-NMR (CDCl3): δ1.31 (3H, t, J=7.0 Hz), 1.43 (3H, d, J=6.5 Hz), 2.16-2.28 (1H, m), 2.30-2.39 (1H, m), 2.33 (3H, s), 2.70-2.78 (1H, m), 2.87-2.96 (1H, m), 3.40 (1H, d, J=13.5 Hz), 3.45-3.58 (2H, m), 3.86-3.97 (1H, m), 4.18-4.30 (1H, m), 4.28 (2H, q, J=7.0 Hz), 4.62 (2H, s), 6.65 (1H, s), 6.75-6.82 (2H, m), 7.48-7.60 (2H, m), 7.84 (1H, s).
Yield: 86%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.31 (3H, t, J=7 Hz), 1.57-1.78 (2H, m), 2.30-2.33 (1H, m), 2.34 (3H, s), 2.48-2.60 (1H, m), 2.78-2.90 (1H, m), 3.17 (1H, d, J=13.5 Hz), 3.37-3.58 (2H, m), 3.62-3.73 (1H, m), 3.79-3.88 (1H, m), 3.95 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield: 85%, 1H-NMR (CDCl3): δ1.02 (3H, t, J=7.5 Hz), 1.29 (3H, t, J=7 Hz), 1.58-1.78 (2H, m), 2.04 (3H, s), 2.05-2.15 (1H, m), 2.48-2.58 (1H, m), 2.79-2.89 (1H, m), 3.23 (1H, d, J=13.5 Hz), 3.42 (1H, dd, J=12.5, 8 Hz), 3.47-3.56 (1H, m), 3.63-3.72 (1H, m), 3.80-3.90 (1H, m), 3.95 (1H, d, J=13.5 Hz), 4.27 (2H, q, J=7 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.78 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield: 60%, 1H-NMR (CDCl3): δ0.95 (3H, t, J=7.0 Hz), 1.22-1.68 (4H, m), 1.31 (3H, t, J=7.0 Hz), 2.27-2.40 (1H, m), 2.32 (3H, s), 2.54-2.65 (1H, m), 2.76-2.89 (1H, m), 3.25 (1H, d, J=13.5 Hz), 3.41 (1H, dd, J=13.0, 7.5 Hz), 3.48-3.59 (1H, m), 3.60-3.71 (1H, m), 3.83 (1H, dd, J=12.5, 3.5 Hz), 3.93 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7.0 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield: 90%, 1H-NMR (CDCl3): δ0.95 (3H, t, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz), 1.33-1.62 (4H, m), 2.32 (3H, s), 2.32-2.38 (1H, m), 2.57-2.62 (1H, m), 2.79-2.86 (1H, m), 3.24 (1H, d, J=13.5 Hz), 3.41 (1H, dd, J=7.8, 12.6 Hz), 3.38-3.44 (1H, m), 3.64-3.69 (1H, m), 3.83 (1H, dd, J=3.0, 12.6 Hz), 3.93 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7.2 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.77 (2H, d, J=6.3 Hz), 7.53-7.55 (2H, m), 7.83 (1H, s)
Yield: 64%, 1H-NMR (CDCl3): δ0.93 (3H, t, J=7.0 Hz), 1.22-1.75 (6H, m), 1.31 (3H, t, J=7.0 Hz), 2.27-2.39 (1H, m), 2.32 (3H, s), 2.51-2.64 (1H, m), 2.76-2.88 (1H, m), 3.24 (1H, d, J=13.0 Hz), 3.41 (1H, dd, J=13.0, 7.5 Hz), 3.47-3.59 (1H, m), 3.61-3.72 (1H, m), 3.84 (1H, dd, J=13.0, 3.0 Hz), 3.94 (1H, d, J=13.0 Hz), 4.28 (2H, q, J=7.0 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield: 83%, 1H-NMR (CDCl3): δ0.91 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=6.5 Hz), 1.30 (3H, t, J=7 Hz), 1.35-1.45 (1H, m), 1.46-1.58 (1H, m), 1.65-1.80 (1H, m), 2.32 (3H, s), 2.33-2.44 (1H, m), 2.62-2.73 (1H, m), 2.75-2.86 (1H, m), 3.30 (1H, d, J=13.5 Hz), 3.35 (1H, dd, J=13, 6.5 Hz), 3.58 (2H, t, J=5 Hz), 3.75 (1H, dd, J=13, 6.5 Hz), 3.87 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7 Hz), 4.61 (2H, s), 6.62 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield: 68%, 1H-NMR (CDCl3): δ0.92 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=7.0 Hz), 1.20-1.44 (1H, m), 1.30 (3H, t, J=6.5 Hz), 1.45-1.80 (2H, m), 2.27-2.47 (1H, m), 2.32 (3H, s), 2.61-2.72 (1H, m), 2.75-2.88 (1H, m), 3.25-3.41 (2H, m), 3.58 (2H, t, J=5.0 Hz), 3.75 (1H, dd, J=12.5, 3.5 Hz), 3.87 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7.0 Hz), 4.61 (2H, s), 6.62 (1H, s), 6.76 (1H, s), 6.78 (1H, s), 7.23 (1H, dd, J=8.0, 2.0 Hz), 7.42 (1H, d, J=8.0 Hz), 7.54 (1H, d, J=2.0 Hz).
Yield: 85%, 1H-NMR (CDCl3): δ0.92 (3H, d, J=6.5 Hz), 0.95 (3H, d, J=6.5 Hz), 1.31 (3H, t, J=7 Hz), 1.34-1.45 (1H, m), 1.45-1.55 (1H, m), 1.65-1.80 (1H, m), 2.32 (3H, s), 2.35-2.46 (1H, m), 2.64-2.75 (1H, m), 2.78-2.88 (1H, m), 3.32 (1H, d, J=13.5 Hz), 3.42 (1H, dd, J=13, 6.5 Hz), 3.60-3.67 (2H, m), 3.79 (1H, dd, J=13, 3.5 Hz), 3.87 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7 Hz), 4.61 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.79 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield: 98%, 1H-NMR (CDCl3): δ1.21 (3H, d, J=6 Hz), 1.31 (3H, t, J=7 Hz), 2.20-2.32 (1H, m), 2.32 (3H, s), 2.59-2.70 (1H, m), 2.75-2.88 (1H, m), 3.16 (1H, d, J=13.5 Hz), 3.17-3.25 (1H, m), 3.48-3.50 (1H, m), 3.69-3.80 (1H, m), 3.85-3.95 (1H, m), 3.98 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7 Hz), 4.62 (2H, s), 6.63 (1H, s), 6.75 (1H, s), 6.78 (1H, s), 7.26 (1H, d, J=12 Hz), 7.74 (1H, d, J=7 Hz).
Yield: 69%, 1H-NMR (CDCl3): δ1.30 (3H, t, J=7.0 Hz), 1.96-2.08 (2H, m), 2.30 (3H, s), 2.63-2.71 (2H, m), 2.74-2.84 (2H, m), 3.57 (2H, s), 3.60-3.89 (4H, m), 4.27 (2H, q, J=7.0 Hz), 4.60 (2H, s), 6.62 (1H, s), 6.73 (1H, s), 6.75 (1H, s), 7.27 (1H, d, J=7.0 Hz), 7.75 (1H, d, J=11.5 Hz).
Yield: 75%, 1H-NMR (CDCl3): δ1.12 (6H, d, J=6.0 Hz), 1.30 (3H, t, J=7.0 Hz), 2.32 (3H, s), 2.72-2.86 (2H, m), 3.07 (1H, d, J=13.0 Hz), 3.11 (1H, d, J=13.0 Hz), 3.77 (2H, s), 3.89 (2H, d, J=11.0 Hz), 4.28 (2H, q, J=7.0 Hz), 4.60 (2H, s), 6.57 (1H, s), 6.78 (1H, s), 6.84 (1H, s), 7.27 (1H, d, J=11.5 Hz), 7.75 (1H, d, J=6.0 Hz).
Yield: 79%, 1H-NMR (CDCl3): δ1.01 (3H, t, J=7.5 Hz), 1.31 (3H, t, J=7.0 Hz), 1.50-1.80 (2H, m), 2.26-2.39 (1H, m), 2.32 (3H, s), 2.47-2.58 (1H, m), 2.77-2.88 (1H, m), 3.24 (1H, d, J=13.5 Hz), 3.36-3.57 (2H, m), 3.61-3.73 (1H, m), 3.77-3.88 (1H, m), 3.94 (1H, d, J=13.5 Hz), 4.28 (2H, q, J=7.0 Hz), 4.61 (2H, s), 6.62 (1H, s), 6.73-6.82 (2H, m), 7.26 (1H, d, J=11.5 Hz), 7.74 (1H, d, J=7.0 Hz)
Yield: 71%, 1H-NMR (CDCl3): δ1.29 (3H, t, J=7.0 Hz), 2.31 (3H, s), 2.54 (4H, t, J=5.0 Hz), 3.47 (2H, s), 3.52 (4H, t, J=5.0 Hz), 4.26 (2H, q, J=7.0 Hz), 4.60 (2H, s), 6.64 (1H, s), 6.74 (1H, s), 6.78 (1H, s), 7.18 (1H, tt, J=7.5, 1.5 Hz), 7.26-7.35 (2H, m), 7.37-7.44 (3H, m).
Yield: 74%, 1H-NMR (CDCl3): δ1.15 (6H, d, J=7.0 Hz), 1.30 (3H, t, J=7.0 Hz), 2.32 (3H, s), 2.68-2.83 (2H, m), 2.93 (1H, d, J=13.0 Hz), 2.96 (1H, d, J=13.0 Hz), 3.78 (2H, s), 4.26-4.38 (2H, m), 4.27 (2H, q, J=7.0 Hz), 4.61 (2H, s), 6.57 (1H, s), 6.80 (1H, s), 6.86 (1H, s), 7.34-7.43 (1H, m), 7.52-7.62 (1H, m), 7.67 (1H, dd, J=8.5, 1.5 Hz), 7.87 (1H, dd, J=8.5, 1.5 Hz), 8.56 (1H, s).
Yield: 79%, 1H-NMR (CDCl3): δ1.25 (3H, d, J=6.0 Hz), 1.31 (3H, t, J=7.0 Hz), 2.20-2.32 (1H, m), 2.33 (3H, s), 2.55-2.68 (1H, m), 2.85 (1H, dt, J=12.0, 3.5 Hz), 3.14 (1H, d, J=13.0 Hz), 3.16 (1H, d, J=13.5 Hz), 3.30-3.43 (1H, m), 4.02 (1H, d, J=13.0 Hz), 4.04-4.15 (1H, m), 4.17-4.26 (1H, m), 4.28 (2H, q, J=7.0 Hz), 4.62 (2H, s), 6.63 (1H, s), 6.77 (1H, s), 6.80 (1H, s), 7.34-7.42 (1H, m), 7.52-7.61 (1H, m), 7.67 (1H, dd, J=8.5, 1.5 Hz), 7.87 (1H, dd, J=8.5, 1.5 Hz), 8.55 (1H, s).
Yield: 74%, 1H-NMR (CDCl3): δ1.15 (6H, d, J=6.0 Hz), 1.30 (3H, t, J=7.0 Hz), 2.32 (3H, s), 2.67-2.81 (2H, m), 2.93 (1H, d, J=13.0 Hz), 2.97 (1H, d, J=13.0 Hz), 3.78 (2H, s), 4.24-4.35 (2H, m), 4.27 (2H, q, J=7.0 Hz), 4.61 (2H, s), 6.66 (1H, s), 6.79 (1H, s), 6.86 (1H, s), 7.50 (1H, dd, J=9.5, 2.0 Hz), 7.59 (1H, d, J=9.5 Hz), 7.85 (1H, d, J=2.0 Hz), 8.54 (1H, s).
Yield: 51%, 1H-NMR (CDCl3): δ1.15 (6H, d, J=6.0 Hz), 1.29 (3H, t, J=7.0 Hz), 2.31 (3H, s), 2.65-2.79 (2H, m), 2.95 (1H, d, J=13.0 Hz), 2.99 (1H, d, J=13.0 Hz), 3.76 (2H, s), 4.26 (2H, q, J=7.0 Hz), 4.35 (2H, d, J=12.0 Hz), 4.62 (2H, s), 6.58 (1H, s), 6.79 (1H, s), 6.86 (1H, s), 7.69 (1H, s), 7.70 (1H, s), 8.13 (1H, s), 8.59 (1H, s).
A mixture of acetic acid 4-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}phenyl ester (0.33 g; 0.834 mmol), lithium hydroxide (0.04 g; 0.831 mmol) and THF (8 ml) was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure. To the residue were added bromoethyl acetate (0.14 ml; 1.26 mmol), cesium carbonate (0.41 g; 1.26 mmol) and anhydrous N,N-dimethylformamide (4 ml). The mixture was stirred at room temperature for 17 hours. Water and ethyl acetate were added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give 4-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}phenoxyethyl acetate as colorless oil (0.35 g; 93%).
1H-NMR (CDCl3): δ1.31 (3H, t, J=7.2 Hz), 2.55 (4H, t, J=5.1 Hz), 3.50 (2H, s), 3.62 (4H, t, J=5.1 Hz), 4.28 (2H, q, J=7.2 Hz), 4.66 (2H, s), 6.88 (1H, d, J=8.1 Hz), 7.22-7.26 (4H, m), 7.43 (1H, d, J=8.1 Hz), 7.55 (1H, d, J=2.1 Hz).
A mixture of 3-chloro-5-[4-(2-methoxymethoxy-3-methylbenzyl)piperazine-1-yl]benzothiazole (0.15 g; 0.346 mmol) and 4N hydrochloric acid/dioxane solution (8.5 ml) was stirred at 60° C. for 2 hours. After cooling, the reaction solution was condensed under reduced pressure. To the residue were added bromoethyl acetate (0.05 ml; 0.451 mmol), cesium carbonate (0.50 g; 1.56 mmol) and anhydrous N,N-dimethylformamide (3 ml). The mixture was stirred at room temperature for 17 hours. Water and ethyl acetate were added to the reaction solution and extracted with etyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=2:1) to give 3-chloro-5-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}phenoxyethyl acetate as colorless oil (0.13 g; 77%).
1H-NMR (CDCl3): δ1.31 (3H, t, J=6.9 Hz), 2.56 (4H, t, J=5.1 Hz), 3.49 (2H, s), 3.63 (4H, t, J=5.1 Hz), 4.28 (2H, q, J=6.9 Hz), 4.61 (2H, s), 6.87 (1H, t, J=1.5 Hz), 6.84 (1H, s), 6.99 (1H, t, J=1.5 Hz), 7.24 (1H, dd, J=2.1, 8.7 Hz), 7.44 (1H, d, J=8.7 Hz), 7.55 (1H, dd, J=2.1 Hz)
The following compound was obtained by a similar method as Example 129 with a compound in Example 217 as a raw material.
Yield: 84%, 1H-NMR (CDCl3); δ1.31-1.50 (2H, m), 1.65 (1H, s), 1.74-1.96 (5H, m), 2.21 (3H, s), 3.07-3.20 (2H, m), 4.02-4.18 (4H, m), 4.65 (2H, d, J=5.5 Hz), 6.83 (1H, d, J=7.5 Hz), 6.86 (1H, s), 7.12 (1H, d, J=7.5 Hz), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.0 Hz).
The following compound was obtained by a similar method as Example 154 with a compound in Example 332 as a raw material.
Yield: 79%, 1H-NMR (CDCl3); δ1.33-1.52 (2H, m), 1.78-1.98 (5H, m), 2.21 (3H, s), 3.08-3.21 (2H, m), 4.03-4.17 (4H, m), 4.50 (2H, s), 6.82-6.90 (2H, m), 7.11 (1H, d, J=7.5 Hz), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.0 Hz).
The following compound was obtained by a similar method as Example 179 with a compound in Example 333 as a raw material.
Yield: 96%, 1H-NMR (CDCl3); δ1.34-1.52 (2H, m), 1.77-1.97 (5H, m), 2.21 (3H, s), 3.08-3.22 (2H, m), 3.72 (2H, s), 4.01-4.19 (4H, m), 6.75-6.81 (2H, m), 7.13 (1H, d, J=7.5 Hz), 7.23 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.0 Hz).
A mixture of Ethyl 3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}benzoate (0.30 g; 6.671 mmol), 2N-aqueous sodium hydroxide (1.5 ml) and methanol (3 ml) was stirred at 60° C. for 1 hour. The reaction solution was condensed under reduced pressure. To the residue were added water and 2N aqueous hydrochloric acid to be neutral. The precipitate was collected and washed with water and diisopropyl ether to give 3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}benzoic acid as colorless crystal (0.26 g; 93%).
1H-NMR (DMSO-d6): δ1.20-1.39 (2H, m), 1.66-1.93 (5H, m), 3.10-3.26 (2H, m), 3.94-4.16 (4H, m), 7.20 (1H, dd, J=8.5, 2.5 Hz), 7.27 (1H, d, J=8.5, 2.0 Hz), 7.36-7.47 (3H, m), 7.52 (1H, d, J=7.5 Hz), 7.89 (1H, d, J=2.0 Hz).
Compounds in Examples 336 to 489 were obtained by similar methods as Example 335.
Yield: 18%, 1H-NMR (DMSO-d6): δ1.68-1.84 (2H, m), 2.00-2.15 (2H, m), 3.50-3.64 (2H, m), 3.78-3.92 (2H, m), 4.68-4.81 (1H, m), 7.12-7.18 (1H, m), 7.26-7.39 (2H, m), 7.43 (1H, d, J=8.5 Hz), 7.48-7.55 (2H, m), 7.91 (1H, d, J=2.0 Hz).
Yield: 27%, 1H-NMR (DMSO-d6): δ1.66-1.83 (2H, m), 2.00-2.15 (2H, m), 3.48-3.64 (4H, m), 3.78-3.93 (2H, m), 4.62-4.75 (1H, m), 6.80-6.98 (3H, m), 7.19-7.28 (1H, m), 7.29 (1H, dd, J=8.5, 2.5 Hz), 7.44 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=2.5 Hz), 12.29 (1H, s).
Yield: 84%, 1H-NMR (DMSO-d6): δ1.35-1.55 (2H, m), 1.85-2.00 (2H, m), 2.00-2.20 (1H, m), 3.10-3.30 (2H, m), 3.94 (2H, d, J=6 Hz), 4.00-4.15 (2H, m), 6.98 (1H, t, J=7.5 Hz), 7.10 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8.5, 2 Hz), 7.41 (1H, d, J=8.5 Hz), 7.47 (1H, t, J=7.5 Hz), 7.61 (1H, d, J=7.5 Hz), 7.89 (1H, d, J=2 Hz), 12.50 (1H, brs).
Yield: 84%, 1H-NMR (DMSO-d6): δ1.30-1.50 (2H, m), 1.80-1.95 (2H, m), 2.00-2.15 (1H, m), 3.15-3.30 (2H, m), 3.93 (2H, d, J=6 Hz), 4.00-4.15 (2H, m), 7.20 (1H, dd, J=8, 2.5 Hz), 7.27 (1H, dd, J=8.5, 2 Hz), 7.35-7.45 (3H, m), 7.52 (1H, d, J=8 Hz), 7.88 (1H, d, J=2 Hz), 13.0 (1H, brs).
Yield: 59%, 1H-NMR (DMSO-d6): δ1.30-1.50 (2H, m), 1.85-1.95 (2H, m), 2.00-2.20 (1H, m), 3.00-3.20 (2H, m), 3.96 (2H, d, J=6.5 Hz), 4.04-4.14 (2H, m), 7.00 (2H, d, J=8 Hz), 7.28 (1H, dd, J=8.5, 1.5 Hz), 7.41 (1H, d, J=8.5 Hz), 7.87 (2H, d, J=8 Hz), 7.89 (1H, d, J=1.5 Hz).
Yield: 88%, 1H-NMR (DMSO-d6): δ1.20-1.45 (2H, m), 1.70-1.90 (1H, m), 1.90-2.05 (2H, m), 3.02 (2H, d, J=7 Hz), 3.10-3.25 (2H, m), 3.95-4.10 (2H, m), 7.70 (1H, dd, J=8.5, 2 Hz), 7.40 (1H, d, J=8.5 Hz), 7.44 (1H, t, J=7.5 Hz), 7.59 (1H, d, J=7.5 Hz), 7.73 (1H, d, J=7.5 Hz), 7.83 (1H, s), 7.88 (1H, d, J=2 Hz), 13.40 (1H, brs).
Yield: 32%, 1H-NMR (CDCl3); δ1.30-1.48 (2H, m), 1.70-1.90 (1H, m), 1.85-2.05 (2H, m), 2.88 (2H, d, J=7 Hz), 3.02-3.15 (2H, m), 3.63 (2H, s), 4.05-4.18 (2H, m), 7.05-7.15 (1H, m), 7.24 (1H, dd, J=8.5, 2 Hz), 7.25-7.30 (3H, m), 7.42 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2 Hz).
Yield: 88%, 1H-NMR (DMSO-d6): δ1.20-1.38 (2H, m), 1.71 (2H, q, J=6.0 Hz), 1.78-1.94 (3H, m), 3.09-3.23 (2H, m), 3.95-4.07 (2H, m), 4.10 (2H, t, J=6.0 Hz), 6.99 (1H, td, J=7.5, 1.5 Hz), 7.14 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.48 (1H, td, J=1.5, 7.5 Hz), 7.60 (1H, dd, J=7.5, 1.5 Hz), 7.88 (1H, d, J=2.0 Hz), 12.55 (1H, br).
Yield: 82%, 1H-NMR (DMSO-d6): δ1.20-1.39 (2H, m), 1.68-1.92 (5H, m), 3.10-3.26 (2H, m), 3.08-4.08 (2H, m), 4.12 (2H, t, J=6.0 Hz), 7.03 (2H, d, J=9.0 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz), 7.88 (2H, d, J=9.0 Hz), 12.62 (1H, br).
Yield: 75%, 1H-NMR (DMSO-d6): δ1.22-1.40 (2H, m), 1.70-1.92 (5H, m), 2.21 (3H, s), 3.12-3.24 (2H, m), 3.96-4.08 (2H, m), 4.09 (2H, t, J=6.0 Hz), 7.25 (1H, d, J=8.0 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.43 (2H, m), 7.88 (1H, d, J=2.0 Hz).
Yield: 78%, 1H-NMR (DMSO-d6): δ1.18-1.38 (2H, m), 1.64-1.91 (5H, m), 3.11-3.24 (2H, m), 3.52 (2H, s), 3.96-4.07 (4H, m), 6.78-6.87 (3H, m), 7.21 (1H, t, J=7.5 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz), 12.31 (1H, brs).
Yield: 84%, 1H-NMR (DMSO-d6): δ1.19-1.39 (2H, m), 1.64-1.92 (5H, m), 3.09-3.28 (2H, m), 3.47 (2H, s), 3.95-4.10 (4H, m), 6.80 (2H, d, J=8.5 Hz), 7.15 (2H, d, J=8.5 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz).
Yield: 35%, 1H-NMR (CDCl3); δ1.18-1.37 (2H, m), 1.68-1.91 (5H, m), 2.77 (2H, t, J=7.5 Hz), 3.09-3.43 (4H, m), 3.94-4.06 (4H, m), 6.71-6.83 (3H, m), 7.16 (1H, t, J=8.0 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz).
Yield: 27%, 1H-NMR (DMSO-d6): δ1.18-1.42 (2H, m), 1.68-1.94 (5H, m), 2.47 (2H, t, J=7.5 Hz), 2.80 (2H, t, J=7.5 Hz), 3.10-3.23 (2H, m), 3.96-4.10 (4H, m), 6.84 (1H, t, J=7.5 Hz), 6.96 (1H, d, J=7.5 Hz), 7.12-7.21 (2H, m), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz), 12.09 (1H, s).
Yield: 27%, 1H-NMR (DMSO-d6): δ1.14-1.31 (2H, m), 1.50-1.61 (2H, m), 1.64-1.86 (3H, m), 2.96-3.22 (4H, m), 3.93-4.03 (2H, m), 7.23-7.36 (3H, m), 7.39 (1H, d, J=8.5 Hz), 7.67 (1H, d, J=7.0 Hz), 7.81 (1H, s), 7.88 (1H, d, J=2.0 Hz).
Yield: 72%, 1H-NMR (DMSO-d6): δ1.12-1.32 (2H, m), 1.50-1.63 (2H, m), 1.64-1.87 (3H, m), 2.95-3.06 (2H, m), 3.07-3.22 (2H, m), 3.55 (2H, s), 3.92-4.08 (2H, m), 4.05 (1H, d, J=2.0 Hz), 7.17-7.31 (4H, m), 7.39 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=7.5 Hz), 12.36 (1H, brs).
Yield: 65%, 1H-NMR (CDCl3); δ1.33 (2H, m), 1.73-1.90 (5H, m), 2.31 (3H, s), 3.14 (2H, t, J=12.6 Hz), 3.58 (2H, s), 4.01 (2H, t, J=5.7 Hz), 4.11 (2H, d, J=14.1 Hz), 6.65 (2H, s), 6.70 (1H, s), 7.23 (1H, dd, J=8.4, 2.1 Hz), 7.43 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield: 90%, 1H-NMR (DMSO-d6): δ1.23-1.36 (2H, m), 1.72-1.87 (5H, m), 2.07 (3H, s), 3.15-3.23 (2H, m), 3.56 (2H, s), 4.01 (4H, t, J=5.7 Hz), 6.77 (1H, d, J=8.1 Hz), 6.87 (1H, d, J=8.1 Hz), 7.07 (1H, t, J=8.1 Hz), 7.28 (1H, dd, J=8.7, 2.1 Hz), 7.40 (1H, d, J=8.7 Hz), 7.89 (1H, d, J=2.1 Hz).
Yield: 65%, 1H-NMR (DMSO-d6): δ1.20-1.35 (1H, m), 1.65-1.90 (6H, m), 3.10-3.25 (2H, m), 3.54 (2H, s), 3.95-4.15 (4H, m), 6.75-6.85 (1H, m), 7.10 (1H, dd, J=8, 3.5 Hz), 7.14 (1H, d, J=8 Hz), 7.24 (1H, dd, J=8.5, 2 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2 Hz), 12.34 (1H, brs).
Yield: 36%, 1H-NMR (DMSO-d6): δ1.20-1.39 (2H, m), 1.66-1.93 (5H, m), 3.08-3.23 (2H, m), 3.40 (2H, s), 3.94-4.13 (4H, m), 6.76-6.84 (1H, m), 7.06 (1H, s), 7.23-7.32 (2H, m), 7.36-7.43 (1H, m), 7.87 (1H, d, J=2.0 Hz).
Yield: 59%, 1H-NMR (DMSO-d6): δ1.17-1.37 (2H, m), 1.62-1.91 (5H, m), 3.09-3.25 (2H, m), 3.34 (2H, s), 3.92-4.07 (4H, m), 6.75 (1H, dd, J=8.5, 3.0 Hz), 6.92 (1H, d, J=3.0 Hz), 7.21 (1H, d, J=8.5 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz).
Yield: 63%, 1H-NMR (DMSO-d6): δ2.69 (4H, t, J=4.5 Hz), 2.80 (2H, t, J=5.5 Hz), 3.56 (4H, t, J=4.5 Hz), 4.22 (2H, t, J=5.5 Hz), 7.01 (1H, t, J=7.5 Hz), 7.16 (1H, d, J=7.5 Hz), 7.29 (1H, dd, J=8.5, 2.0 Hz), 7.43 (1H, d, J=8.5 Hz), 7.48 (1H, t, J=7.5 Hz), 7.61 (1H, d, J=7.5 Hz), 7.91 (1H, d, J=2.0 Hz).
Yield: 31%, 1H-NMR (DMSO-d6): δ2.65 (4H, t, J=5.0 Hz), 2.80 (2H, t, J=5.5 Hz), 3.57 (4H, t, J=5.0 Hz), 4.15 (2H, t, J=5.5 Hz), 7.10 (1H, d, J=8.0 Hz), 7.27-7.36 (2H, m), 7.41-7.52 (3H, m), 7.91 (1H, d, J=2.2 Hz).
Yield: 50%, 1H-NMR (DMSO-d6): δ2.64 (4H, t, J=5.0 Hz), 2.80 (2H, t, J=5.5 Hz), 3.57 (4H, t, J=5.0 Hz), 4.20 (2H, t, J=5.5 Hz), 7.03 (2H, d, J=9 Hz), 7.29 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.87 (2H, d, J=9.0 Hz), 7.91 (1H, d, J=2.0 Hz).
Yield: 29%, 1H-NMR (DMSO-d6): δ1.18-1.36 (2H, m), 1.68-1.88 (5H, m), 3.00-3.25 (2H, m), 3.94-4.07 (2H, m), 4.20 (2H, t, J=6.0 Hz), 6.41 (1H, d, J=4.0 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.44 (1H, d, J=4.0 Hz), 7.88 (1H, d, J=2.0 Hz).
Yield: 64%, 1H-NMR (DMSO-d6): δ2.13 (3H, s), 2.68 (4H, t, J=5 Hz), 2.82 (2H, t, J=5.5 Hz), 3.47 (2H, s), 3.63 (4H, t, J=5 Hz), 4.10 (2H, t, J=5.5 Hz), 6.72 (1H, d, J=8 Hz), 6.86 (1H, s), 7.05 (1H, d, J=7.5 Hz), 7.57 (2H, s), 8.25 (1H, s), 12.50 (1H, brs).
Yield: 25%, 1H-NMR (DMSO-d6): δ1.88-1.94 (2H, m), 2.73-2.75 (2H, m), 2.87 (2H, t, J=5.1 Hz), 2.92-2.95 (2H, m), 3.25 (2H, s), 3.67-3.72 (4H, m), 4.01 (2H, t, J=5.7 Hz), 6.68-6.82 (3H, m), 7.10 (1H, t, J=7.5 Hz), 7.26 (1H, dd, J=8.7, 2.1 Hz), 7.40 (1H, d, J=8.7 Hz), 7.88 (1H, d, J=2.1 Hz).
Yield: 68%, 1H-NMR (DMSO-d6): δ1.85-1.95 (2H, m), 2.09 (3H, s), 2.75-2.82 (2H, m), 2.92 (2H, t, J=5.5 Hz), 2.95-3.02 (2H, m), 3.49 (2H, s), 3.60-3.75 (4H, m), 4.03 (2H, t, J=5.5 Hz), 6.71 (1H, d, J=7.5 Hz), 6.83 (1H, s), 7.03 (1H, d, J=7.5 Hz), 7.26 (1H, dd, J=8.5, 2 Hz), 7.39 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=2 Hz), 12.37 (1H, brs).
Yield: 67%, 1H-NMR (DMSO-d6): δ1.85-1.95 (2H, m), 2.75-2.85 (2H, m), 2.93 (2H, t, J=5.5 Hz), 2.95-3.05 (2H, m), 3.55 (2H, s), 3.60-3.80 (4H, m), 4.12 (2H, t, J=5.5 Hz), 6.83 (1H, dd, J=8, 1.5 Hz), 7.07 (1H, d, J=1.5 Hz), 7.25 (1H, dd, J=8.5, 2 Hz), 7.33 (1H, d, J=8 Hz), 7.39 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=2 Hz), 12.37 (1H, brs).
Yield: 45%, 1H-NMR (DMSO-d6): δ1.20-1.39 (2H, m), 1.65-1.94 (5H, m), 3.17-3.32 (2H, m), 3.99-4.12 (4H, m), 6.92-6.99 (1H, m), 7.23 (1H, t, J=7.5 Hz), 7.40-7.48 (2H, m), 7.51-7.59 (2H, m), 8.21 (1H, s).
Yield: 48%, 1H-NMR (DMSO-d6): δ1.18-1.38 (2H, m), 1.63-1.94 (5H, m), 3.13-3.30 (2H, m), 3.32 (2H, s), 3.93-4.13 (4H, m), 6.70-6.85 (3H, m), 7.13 (1H, t, J=8.0 Hz), 7.49-7.60 (2H, m), 8.21 (1H, s).
Yield: 82%, 1H-NMR (DMSO-d6): δ1.17-1.42 (2H, m), 1.68-1.96 (5H, m), 3.13-3.30 (2H, m), 3.43 (2H, s), 3.95-4.19 (4H, m), 6.81 (1H, d, J=7.5 Hz), 7.07 (1H, s), 7.28 (1H, d, J=7.5 Hz), 7.49-7.61 (2H, m), 8.21 (1H, s).
Yield: 77%, 1H-NMR (DMSO-d6): δ1.85-2.00 (2H, m), 2.68-2.81 (2H, m), 2.82-3.03 (4H, m), 3.51 (2H, s), 3.60-3.89 (4H, m), 3.97-4.09 (2H, m), 6.75-6.90 (3H, m), 7.19 (1H, t, J=8.0 Hz), 7.50-7.60 (2H, m), 8.22 (1H, s), 12.26 (1H, br).
Yield: 78%, 1H-NMR (DMSO-d6): δ1.84-1.98 (2H, m), 2.74-2.85 (2H, m), 2.86-3.07 (4H, m), 3.56 (2H, s), 3.60-3.85 (4H, m), 4.06-4.18 (2H, m), 6.83 (1H, dd, J=8.0, 2.0 Hz), 7.07 (1H, d, J=2.0 Hz), 7.33 (1H, d, J=8.0 Hz), 7.51-7.57 (2H, m), 8.22 (1H, s), 12.35 (1H, br).
Yield: 68%, 1H-NMR (CDCl3); δ1.19-1.39 (2H, m), 1.64-1.92 (5H, m), 3.12-3.27 (2H, m), 3.96-4.08 (4H, m), 6.80-6.87 (1H, m), 7.06 (1H, dd, J=8.0, 2.0 Hz), 7.15 (1H, t, J=8.0 Hz), 7.38-7.47 (3H, m), 7.76 (1H, d, J=8.0 Hz).
Yield: 87%, 1H-NMR (DMSO-d6): δ1.19-1.40 (2H, m), 1.63-1.92 (5H, m), 3.10-3.27 (2H, m), 3.51 (2H, s), 3.94-4.10 (4H, m), 6.77-6.86 (3H, m), 7.07 (1H, dd, J=8.5, 2.0 Hz), 7.20 (1H, t, J=7.5 Hz), 7.44 (1H, d, J=2.0 Hz), 7.76 (1H, d, J=8.5 Hz), 12.33 (1H, br).
Yield: 36%, 1H-NMR (DMSO-d6): δ1.20-1.39 (2H, m), 1.63-1.93 (5H, m), 3.12-3.28 (2H, m), 3.53 (2H, s), 3.95-4.12 (4H, m), 6.78-6.88 (3H, m), 7.13 (1H, dd, J=8.0, 1.0 Hz), 7.20 (1H, t, J=7.5 Hz), 7.31 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=8.0, 1.0 Hz), 12.31 (1H, s).
Yield: 89%, 1H-NMR (DMSO-d6): δ1.19-1.39 (2H, m), 1.65-1.93 (5H, m), 3.10-3.25 (2H, m), 3.96-4.09 (4H, m), 6.87-6.94 (1H, m), 7.20 (1H, t, J=8.0 Hz), 7.31-7.48 (4H, m), 8.00 (1H, d, J=2.0 Hz).
Yield: 58%, 1H-NMR (DMSO-d6): δ1.18-1.37 (2H, m), 1.63-1.91 (5H, m), 3.10-3.26 (4H, m), 3.92-4.07 (4H, m), 6.63-6.84 (3H, m), 7.08 (1H, t, J=8.0 Hz), 7.31-7.42 (2H, m), 7.99 (1H, d, J=2.0 Hz).
Yield: 46%, 1H-NMR (DMSO-d6): δ1.18-1.36 (2H, m), 1.61-1.90 (5H, m), 2.32 (3H, s), 3.04-3.19 (2H, m), 3.39 (2H, s), 3.91-4.07 (4H, m), 6.72-6.86 (3H, m), 7.06 (1H, d, J=8.5 Hz), 7.16 (1H, t, J=8.0 Hz), 7.31 (1H, d, J=8.5 Hz), 7.53 (1H, s).
Yield: 83%, 1H-NMR (DMSO-d6): δ1.18-1.39 (2H, m), 1.63-1.92 (5H, m), 3.07-3.24 (2H, m), 3.52 (2H, s), 3.93-4.09 (4H, m), 6.77-6.78 (3H, m), 7.10 (1H, td, J=9.0, 2.5 Hz), 7.21 (1H, t, J=8.0 Hz), 7.41 (1H, dd, J=9.0, 4.5 Hz), 7.69 (1H, dd, J=9.0, 2.5 Hz), 12.34 (1H, br).
Yield: 51%, 1H-NMR (DMSO-d6): δ1.18-1.35 (2H, m), 1.63-1.93 (5H, m), 3.09-3.26 (2H, m), 3.52 (2H, s), 3.95-4.13 (4H, m), 6.77-6.90 (3H, m), 7.20 (1H, t, J=8.0 Hz), 7.31 (1H, t, J=8.0 Hz), 7.43 (2H, t, J=8.0 Hz), 7.48 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.66 (2H, d, J=8.0 Hz), 8.07 (1H, s), 12.31 (1H, br).
Yield: 77%, 1H-NMR (DMSO-d6): δ1.19-1.40 (2H, m), 1.64-1.91 (5H, m), 2.98-3.14 (2H, m), 3.53 (2H, s), 3.86-4.10 (4H, m), 6.78-6.90 (3H, m), 7.16-7.26 (2H, m), 7.31-7.34 (2H, m), 7.44-7.50 (2H, m), 7.58 (1H, s), 12.30 (1H, s).
Yield: 76%, 1H-NMR (DMSO-d6): δ1.22-1.41 (2H, m), 1.68-1.90 (5H, m), 2.97-3.13 (2H, m), 3.56 (2H, s), 3.86-3.99 (2H, m), 4.06-4.16 (2H, m), 6.84 (1H, dd, J=8.0, 1.5 Hz), 7.09 (1H, d, J=1.5 Hz), 7.20 (1H, t, J=7.5 Hz), 7.31-7.41 (3H, m), 7.43-7.51 (2H, m), 7.58 (1H, s).
Yield: 69%, 1H-NMR (DMSO-d6): δ1.83-1.95 (2H, m), 2.73-2.83 (2H, m), 2.87-3.00 (4H, m), 3.52-3.71 (6H, m), 4.12 (2H, m), 6.83 (1H, d, J=7.0 Hz), 7.08 (1H, s), 7.18 (1H, t, J=7.5 Hz), 7.28-7.38 (3H, m), 7.40-7.47 (2H, m), 7.56 (1H, s).
Yield: 79%, 1H-NMR (DMSO-d6): δ1.20-1.41 (2H, m), 1.65-1.93 (5H, m), 3.05 (2H, m), 3.53 (2H, s), 3.90-4.10 (4H, m), 6.76-6.87 (3H, m), 7.16-7.32 (3H, m), 7.38 (2H, t, J=7.5 Hz), 7.85 (2H, d, J=7.5 Hz), 12.29 (1H, s).
Yield: 54%, 1H-NMR (CDCl3): 1.88-2.03 (2H, m), 2.73-3.04 (6H, m), 3.30 (2H, s), 3.47-3.84 (4H, m), 3.86-4.02 (2H, m), 6.59 (1H, d, J=8.0 Hz), 6.68 (1H, s), 7.07 (1H, d, J=8.0 Hz), 7.20 (1H, d, J=11.5 Hz), 7.68 (1H, d, J=7.0 Hz).
Yield 12%, 1H-NMR (DMSO-d6): δ2.25 (3H, s), 2.45-2.55 (4H, m), 3.44 (2H, s), 3.50-3.60 (4H, m), 4.47 (2H, s), 6.59 (1H, s), 6.65 (1H, s), 7.00 (1H, s), 7.28 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=2 Hz).
Yield 68%, 1H-NMR (CDCl3); δ1.60 (6H, s), 2.23 (3H, s), 2.65 (4H, t, J=5 Hz), 3.57 (2H, s), 3.62 (4H, t, J=5 Hz), 6.19 (1H, brs), 6.70-6.88 (3H, m), 7.24 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield 64%, 1H-NMR (DMSO-d6): δ2.24 (3H, s), 2.51 (4H, t, J=5.5 Hz), 3.43 (2H, s), 3.62 (4H, t, J=5.5 Hz), 4.10 (2H, s), 6.53 (1H, s), 6.61 (1H, s), 6.64 (1H, s), 7.57 (2H, s), 8.24 (1H, s).
Yield 96%, 1H-NMR (DMSO-d6): δ1.89-1.97 (2H, m), 2.23 (3H, s), 2.60 (2H, t, J=4.2 Hz), 2.74-2.77 (2H, m), 3.55 (2H, s), 3.68-3.70 (4H, m), 4.56 (2H, s), 6.58 (1H, s), 6.65 (1H, s), 6.70 (1H, s), 7.26 (1H, dd, J=9.0, 2.1 Hz), 7.39 (1H, d, J=8.7 Hz), 7.86 (1H, d, J=2.4 Hz).
Yield 98%, 1H-NMR (DMSO-d6): δ1.85-2.00 (2H, m), 2.20 (3H, s), 2.55-2.65 (2H, m), 2.70-2.83 (2H, m), 3.52 (2H, s), 3.55-3.85 (4H, m), 4.14 (2H, s), 6.52 (1H, s), 6.58-6.65 (2H, m), 7.55 (2H, s), 8.22 (1H, s).
Yield 59%, 1H-NMR (CD3OD): δ2.29 (3H, s), 2.60 (4H, t, J=5.0 Hz), 3.46-3.57 (6H, m), 4.36 (2H, s), 6.69 (1H, s), 6.75 (2H, s), 7.21 (1H, t, J=7.5 Hz), 7.33 (2H, t, J=7.5 Hz), 7.41 (1H, s), 7.45 (2H, d, J=7.5 Hz).
Yield 67%, 1H-NMR (CD3OD): δ1.98-2.12 (2H, m), 2.27 (3H, s), 2.70-2.81 (2H, m), 2.84-2.94 (2H, m), 3.65 (2H, s), 3.67-3.93 (4H, m), 4.39 (2H, s), 6.67 (1H, s), 6.73 (1H, s), 6.74 (1H, s), 7.27 (1H, d, J=12.0 Hz), 7.96 (1H, d, J=7.0 Hz).
Yield 97%, 1H-NMR (DMSO-d6): δ1.15 (3H, d, J=6 Hz), 2.18-2.33 (1H, m), 2.58-2.70 (1H, m), 2.70-2.83 (1H, m), 3.15-3.30 (2H, m), 3.35-3.50 (1H, m), 3.65-3.80 (1H, m), 3.83 (1H, d, J=11 Hz), 3.93 (1H, d, J=14 Hz), 4.65 (2H, s), 6.78 (1H, d, J=8 Hz), 6.90-6.95 (2H, m), 7.24 (1H, t, J=8 Hz), 7.56 (2H, s), 8.24 (1H, s), 13.0 (1H, brs).
Yield 86%, 1H-NMR (DMSO-d6): δ1.13 (3H, d, J=6 Hz), 2.17 (3H, s), 2.20-2.30 (1H, m), 2.55-2.65 (1H, m), 2.68-2.80 (1H, m), 3.15-3.50 (3H, m), 3.65-3.75 (1H, m), 3.82 (1H, d, J=9 Hz), 3.88 (1H, d, J=13.5 Hz), 4.68 (2H, s), 6.80 (1H, s), 6.83 (1H, d, J=7.5 Hz), 7.09 (1H, d, J=7.5 Hz), 7.56 (2H, s), 8.23 (1H, s), 12.30 (1H, brs).
Yield 86%, 1H-NMR (DMSO-d6): δ1.14 (3H, d, J=6 Hz), 2.20-2.25 (1H, m), 2.26 (3H, s), 2.55-2.65 (1H, m), 2.70-2.80 (1H, m), 3.10-3.50 (3H, m), 3.70-3.82 (3H, m), 4.63 (2H, s), 6.61 (1H, s), 6.70 (1H, s), 6.75 (1H, s), 7.55-7.59 (2H, m), 8.24 (1H, s), 12.9 (1H, brs).
Yield 73%, 1H-NMR (DMSO-d6): δ1.03 (6H, d, J=6 Hz), 2.25 (3H, s), 2.60-2.80 (2H, m), 2.95-3.10 (2H, m), 3.71 (2H, s), 3.80-3.85 (2H, m), 4.61 (2H, s), 6.55 (1H, s), 6.76 (2H, s), 7.28 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=2 Hz), 12.95 (1H, s).
Yield 82%, 1H-NMR (DMSO-d6): δ1.04 (6H, d, J=6 Hz), 2.25 (3H, s), 2.70-2.80 (2H, m), 2.95-3.15 (2H, m), 3.71 (2H, s), 3.80-3.95 (2H, m), 4.61 (2H, s), 6.55 (1H, s), 6.76 (2H, s), 7.57 (2H, s), 8.24 (1H, s), 12.94 (1H, brs).
Yield 72%, 1H-NMR (DMSO-d6): δ1.31 (3H, d, J=6.5 Hz), 2.02-2.24 (2H, m), 2.25 (3H, s), 2.70 (1H, d, J=11 Hz), 2.88 (1H, d, J=12 Hz), 3.20-3.35 (1H, m), 3.37 (1H, d, J=13.5 Hz), 3.51 (1H, d, J=13.5 Hz), 3.77 (1H, d, J=13 Hz), 4.10-4.25 (1H, m), 4.60 (2H, s), 6.61 (1H, s), 6.70 (1H, s), 6.73 (1H, s), 7.26 (1H, dd, J=8.5, 2 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2 Hz), 13.00 (1H, brs).
Yield 76%, 1H-NMR (DMSO-d6): δ1.34 (3H, d, J=6.5 Hz), 2.06-2.30 (5H, m), 2.73 (1H, d, J=10.5 Hz), 2.90 (1H, d, J=10.5 Hz), 3.30-3.56 (3H, m), 3.84 (1H, d, J=11.5 Hz), 4.19-4.32 (1H, m), 4.38 (2H, s), 6.58 (1H, s), 6.67 (1H, s), 6.70 (1H, s), 7.56 (2H, s), 8.24 (1H, s).
Yield 82%, 1H-NMR (CDCl3): δ0.97 (3H, t, J=7.5 Hz), 1.62-1.85 (2H, m), 2.28 (3H, s), 2.80-3.00 (3H, m), 3.55 (1H, d, J=13 Hz), 3.65-3.77 (1H, m), 3.77-3.90 (3H, m), 4.23 (1H, d, J=13 Hz), 4.65 (2H, s), 6.63 (1H, s), 6.80 (1H, s), 7.01 (1H, s), 7.53 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 92%, 1H-NMR (CDCl3): δ2.27 (3H, s), 2.27-2.40 (1H, m), 2.90 (1H, d, J=13.5 Hz), 3.06 (1H, d, J=11.5 Hz), 3.32-3.55 (3H, m), 3.80 (1H, d, J=13.5 Hz), 3.95-4.10 (2H, m), 5.30 (2H, s), 6.63 (1H, s), 6.66 (1H, s), 6.72 (1H, s), 7.30-7.45 (3H, m), 7.45-7.60 (4H, m), 7.82 (1H, s).
Yield 81%, 1H-NMR (CDCl3): δ1.32 (3H, d, J=6.6 Hz), 2.26 (3H, s), 2.76 (1H, s), 2.93-3.02 (2H, m), 3.37 (1H, d, J=12.9 Hz), 3.49-3.56 (1H, m), 3.70 (2H s), 3.87 (1H, d, J=10.8 Hz), 4.25 (1H, d, J=12.9 Hz), 4.63 (2H, s), 6.62 (1H, s), 6.77 (1H, s), 6.99 (1H, s), 7.24 (1H, dd, J=2.1, 8.7 Hz), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield 80%, 1H-NMR (CDCl3): δ1.33 (3H, d, J=6.0 Hz), 2.27 (3H, s), 2.76 (1H, br), 2.93-3.02 (2H, m), 3.38 (1H, d, J=12.6 Hz), 3.49-3.56 (1H, m), 3.71 (2H, s), 3.87 (1H, d, J=11.1 Hz), 4.25 (1H, d, J=12.6 Hz), 4.63 (2H, s), 6.62 (1H, s), 6.77 (1H, s), 6.99 (1H, s), 7.24 (1H, dd, J=1.8, 8.7 Hz), 7.42 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=1.8 Hz)
Yield 88%, 1H-NMR (CDCl3): δ1.41 (3H, d, J=6.5 Hz), 2.29 (3H, s), 2.35 (1H, td, J=12, 3.5 Hz), 2.48 (1H, dd, J=12, 4 Hz), 2.91 (1H, d, J=12 Hz), 3.26 (1H, d, J=11.5 Hz), 3.52 (1H, d, J=13 Hz), 3.54-3.65 (1H, m), 3.80 (1H, d, J=13 Hz), 3.89 (1H, d, J=13 Hz), 4.25-4.36 (1H, m), 4.62 (2H, s), 6.69 (1H, s), 6.75 (1H, s), 6.86 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield 94%, 1H-NMR (CDCl3): δ0.96 (3H, t, J=7 Hz), 1.60-1.86 (2H, m), 2.29 (3H, s), 2.75-2.86 (1H, m), 2.87-3.00 (1H, m), 3.00-3.10 (1H, m), 3.51 (1H, d, J=13 Hz), 3.65-3.80 (1H, m), 3.80-3.93 (3H, m), 4.28 (1H, d, J=13 Hz), 4.63 (1H, d, J=16.5 Hz), 4.71 (1H, d, J=16.5 Hz) 6.63 (1H, s), 6.81 (1H, s), 7.02 (1H, s), 7.53 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 86%, 1H-NMR (CDCl3): δ0.96 (3H, t, J=7.5 Hz), 1.62-1.86 (2H, m), 2.28 (3H, s), 2.76-2.88 (1H, m), 2.89-3.00 (1H, m), 3.01-3.13 (1H, m), 3.52 (1H, d, J=13 Hz), 3.65-3.93 (4H, m), 4.30 (1H, d, J=13 Hz), 4.63 (1H, d, J=16.5 Hz), 4.72 (1H, d, J=16.5 Hz), 6.63 (1H, s), 6.82 (1H, s), 7.03 (1H, s), 7.49-7.60 (2H, m), 7.84 (1H, s).
Yield 68%, 1H-NMR (DMSO-d6): δ0.89 (3H, t, J=7.0 Hz), 1.22-1.69 (4H, m), 2.22-2.37 (1H, m), 2.24 (3H, s), 2.49-2.62 (1H, m), 2.68-2.82 (1H, m), 3.28 (1H, d, J=13.5 Hz), 3.38-3.68 (3H, m), 3.69-3.80 (1H, m), 3.83 (1H, d, J=13.5 Hz), 4.28 (2H, s), 6.53 (1H, s), 6.64 (1H, s), 6.67 (1H, s), 7.53 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 8.22 (1H, s).
Yield 87%, 1H-NMR (CDCl3): δ0.90 (3H, t, J=7.2 Hz), 1.19-1.28 (1H, m), 1.45-1.52 (1H, m), 1.65 (2H, br), 2.78 (3H, s), 2.93 (2H, br), 3.05 (1H, br), 3.52 (1H, d, J=12.6 Hz), 3.67-3.74 (1H, m), 3.81-3.91 (3H, m), 4.30 (1H, d), 4.66 (2H, q, J=11.1 Hz), 6.62 (1H, s), 6.81 (1H, s), 7.03 (1H, s), 7.52-7.61 (2H, m), 7.84 (1H, s)
Yield 82%, 1H-NMR (DMSO-d6): δ0.88 (3H, t, J=6.5 Hz), 1.18-1.70 (6H, m), 2.23 (3H, s), 2.24-2.37 (1H, m), 2.48-2.60 (1H, m), 2.67-2.80 (1H, m), 3.27 (1H, d, J=13.5 Hz), 3.36-3.82 (4H, m), 3.83 (1H, d, J=13.5 Hz), 4.31 (2H, s), 6.54 (1H, s), 6.65 (1H, s), 6.67 (1H, s), 7.53 (1H, d, J=9.0 Hz), 7.56 (1H, d, J=9.0 Hz), 8.22 (1H, s).
Yield 70%, 1H-NMR (DMSO-d6): δ0.88 (6H, t, J=6.5 Hz), 1.21-1.35 (1H, m), 1.45-1.58 (1H, m), 1.58-1.73 (1H, m), 2.23 (3H, s), 2.32-2.43 (1H, m), 2.59-2.80 (2H, m), 3.35 (1H, d, J=13.5 Hz), 3.37-3.45 (1H, m), 3.45-3.60 (2H, m), 3.60-3.71 (1H, m), 3.77 (1H, d, J=13.5 Hz), 4.19 (2H, s), 6.51 (1H, s), 6.63 (1H, s), 6.66 (1H, s), 7.27 (1H, dd, J=8.5, 2 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2 Hz).
Yield 77%, 1H-NMR (DMSO-d6): δ0.87 (3H, d, J=6.5 Hz), 0.89 (3H, d, J=6.5 Hz), 1.21-1.36 (1H, m), 1.43-1.57 (1H, m), 1.58-1.73 (1H, m), 2.23 (3H, s), 2.30-2.43 (1H, m), 2.60-2.79 (2H, m), 3.34 (1H, d, J=13.5 Hz), 3.35-3.72 (4H, m), 3.77 (1H, d, J=13.5 Hz), 4.25 (2H, s), 6.53 (1H, s), 6.64 (1H, s), 6.70 (1H, s), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz).
Yield 76%, 1H-NMR (CDCl3): δ0.77 (3H, d, J=6.5 Hz), 0.92 (3H, d, J=6.5 Hz), 1.40-1.75 (3H, m), 2.25 (3H, s), 2.80-3.05 (3H, m), 3.46 (1H, d, J=13 Hz), 3.60-3.95 (4H, m), 4.22 (1H, d, J=13 Hz), 4.56 (1H, d, J=16 Hz), 4.65 (1H, d, J=16 Hz), 6.63 (1H, s), 6.77 (1H, s), 7.01 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.59 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield 79%, 1H-NMR (CDCl3): δ1.33 (3H, d, J=6.5 Hz), 2.28 (3H, s), 2.70-2.83 (1H, m), 2.92-3.08 (2H, m), 3.38 (1H, d, J=13 Hz), 3.54-3.65 (1H, m), 3.70-3.82 (2H, m), 3.87-3.97 (1H, m), 4.25 (1H, d, J=13 Hz), 4.60 (1H, d, J=16.5 Hz), 4.67 (1H, d, J=16.5 Hz), 6.64 (1H, s), 6.78 (1H, s), 6.99 (1H, s), 7.26 (1H, d, J=11.5 Hz), 7.74 (1H, d, J=7 Hz).
Yield 93%, 1H-NMR (CDCl3): δ0.92 (3H, t, J=7.0 Hz), 1.42-1.74 (2H, m), 2.13 (3H, s), 2.27-2.57 (2H, m), 2.62-2.82 (1H, m), 3.08-3.24 (1H, m), 3.35-3.77 (4H, m), 3.80-3.97 (1H, m), 4.37 (2H, s), 6.58 (1H, s), 6.63 (1H, s), 6.74 (1H, s), 7.20 (1H, d, J=11.5 Hz), 7.66 (1H, d, J=7.0 Hz).
Yield 80%, 1H-NMR (CDCl3): δ1.18 (6H, d, J=6.0 Hz), 2.25 (3H, s), 2.78-2.94 (2H, m), 3.13-3.29 (2H, m), 3.78-3.94 (4H, m), 4.54 (2H, s), 6.61 (1H, s), 6.74 (1H, s), 6.80 (1H, s), 7.24 (1H, d, J=11.5 Hz), 7.72 (1H, d, J=7.0 Hz).
Yield 82%, 1H-NMR (DMSO-d6): δ3.52 (2H, s), 3.57 (8H, s), 4.65 (2H, s), 6.87 (2H, s), 6.98 (1H, s), 7.29 (1H, d, J=8.7, 2.4 Hz), 7.42 (1H, dd, J=8.7 Hz), 7.91 (1H, d, J=2.4 Hz)
Yield 83%, 1H-NMR (DMSO-d6): δ2.40-2.55 (4H, m), 3.46 (2H, s), 3.53-3.56 (4H, m), 4.55 (2H, s), 6.85 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.28 (1H, dd, J=8.4, 2.4 Hz), 7.42 (1H, d, J=8.4 Hz), 7.90 (1H, d, J=2.4 Hz).
Yield 51%, 1H-NMR (DMSO-d6): δ2.16 (3H, s), 2.40-2.55 (4H, m), 3.47 (2H, s), 3.50-3.60 (4H, m), 4.67 (2H, s), 6.75-6.85 (2H, m), 7.08 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8.5, 1 Hz), 7.41 (1H, d, J=8 Hz), 7.88 (1H, d, J=2 Hz), 12.9 (1H, brs).
Yield 92%, 1H-NMR (DMSO-d6): δ2.19 (3H, s), 2.50-2.55 (4H, m), 3.52 (4H, s), 3.55-3.58 (4H, m), 6.76 (1H, d, J=8.4 Hz), 7.07 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.28 (1H, dd, 8.7, 1.5 Hz), 7.42 (1H, d, J=8.7 Hz), 7.90 (1H, d, J=1.5 Hz).
Yield 91%, 1H-NMR (DMSO-d6): δ1.90 (2H, m), 2.14 (3H, s), 2.58 (2H, m), 2.73 (2H, m), 3.50 (2H, s), 3.65-3.70 (4H, m), 4.49 (2H, s), 6.68 (1H, d, J=8.4 Hz), 7.01 (1H, d, J=8.4 Hz), 705 (1H, s), 7.26 (1H, dd, J=8.7, 2.1 Hz), 7.40 (1H, d, J=8.7 Hz), 7.88 (1H, d, J=2.1 Hz).
Yield 28%, 1H-NMR (CDCl3): δ1.33 (6H, d, J=6.0 Hz), 2.27 (3H, s), 2.87-3.04 (2H, m), 3.12-3.29 (2H, m), 4.02 (2H, s), 4.30 (2H, d, J=13.0 Hz), 4.59 (2H, s), 6.70 (2H, s), 6.83 (1H, s), 7.35-7.44 (1H, m), 7.52-7.61 (1H, m), 7.65 (1H, d, J=7.0 Hz), 7.86 (1H, d, J=7.0 Hz), 8.51 (1H, s).
Yield 37%, 1H-NMR (CDCl3): δ1.37 (3H, d, J=6.5 Hz), 2.26 (3H, s), 2.84-3.23 (3H, m), 3.45 (1H, d, J=13.0 Hz), 3.71-4.14 (4H, m), 4.34 (1H, d, J=13.0 Hz), 4.62 (1H, d, J=16.0 Hz), 4.69 (1H, d, J=16.0 Hz), 6.60 (1H, s), 6.81 (1H, s), 7.12 (1H, s), 7.37-7.47 (1H, m), 7.53-7.63 (1H, m), 7.67 (1H, d, J=8.0 Hz), 7.89 (1H, d, J=8.0 Hz), 8.52 (1H, s).
Yield 55%, 1H-NMR (CDCl3): δ1.24 (6H, d, J=6.0 Hz), 2.20 (3H, s), 2.77-2.92 (2H, m), 3.03-3.18 (2H, m), 3.89 (2H, s), 4.23 (2H, d, J=11.5 Hz), 4.48 (2H, s), 6.61 (1H, s), 6.69 (1H, s), 6.78 (1H, s), 7.46 (1H, dd, J=9.0, 2.0 Hz), 7.54 (1H, d, J=9.0 Hz), 7.81 (1H, d, J=2.0 Hz), 8.47 (1H, s).
Yield 60%, 1H-NMR (CDCl3): δ1.32 (6H, d, J=6.0 Hz), 2.27 (3H, s), 2.85-3.00 (2H, m), 3.16-3.30 (2H, m), 3.98 (2H, s), 4.29-4.41 (2H, m), 4.60 (2H, s), 6.67 (1H, s), 6.73 (1H, s), 6.83 (1H, s), 7.65-7.75 (2H, m), 8.12 (1H, s), 8.57 (1H, s).
Yield 46%, 1H-NMR (DMSO-d6): δ3.53 (2H, s), 3.54-3.74 (8H, m), 4.87 (2H, s), 6.79-6.90 (3H, m), 7.22 (1H, t, J=7.5 Hz), 7.32 (1H, dd, J=8.5, 2.0 Hz), 7.46 (1H, d, J=8.5 Hz), 7.94 (1H, d, J=2.0 Hz), 12.31 (1H, br).
Yield 21%, 1H-NMR (DMSO-d6): δ2.45-2.55 (4H, m), 3.33 (2H, s), 3.55-3.60 (4H, m), 6.50-6.60 (1H, m), 7.15-7.20 (1H, m), 7.29 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.92 (1H, d, J=2.5 Hz).
Yield 76%, 1H-NMR (DMSO-d6): δ2.58 (4H, s), 3.35 (2H, s), 3.59 (2H, s), 3.81 (2H, s), 7.06 (1H, d, J=3.6 Hz), 7.29 (1H, dd, J=8.7, 2.1 Hz), 7.43 (1H, d, J=8.4 Hz), 7.60 (1H, d, J=3.3 Hz), 7.91 (1H, d, J=2.1 Hz), 12.99 (1H, brs).
Yield 76%, 1H-NMR (DMSO-d6): δ1.25 (2H, m), 3.30 (2H, m), 3.62 (2H, m), 4.20 (2H, m), 4.45 (2H, brs), 7.33 (1H, dd, J=8.4, 1.8 Hz), 7.49 (1H, d, J=8.7 Hz), 7.69-7.71 (2H, m), 7.98 (1H, d, J=1.8 Hz), 8.02 (2H, d, J=8.1 Hz).
Yield 81%, 1H-NMR (DMSO-d6): δ2.45-2.50 (4H, m), 3.45-3.60 (8H, m), 7.15-7.35 (5H, m), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2 Hz), 12.31 (1H, brs).
Yield 94%, 1H-NMR (DMS-d6): δ2.50-2.55 (4H, m), 3.52 (4H, s), 3.57 (4H, s), 7.17 (1H, s), 7.24 (2H, s), 7.29 (1H, dd, J=2.1, 8.4 Hz), 7.42 (1H, d, J=8.4 Hz), 7.91 (1H, d, J=2.1 Hz)
Yield 86%, 1H-NMR (DMS-d6): δ1.92 (2H, s), 2.61 (2H, s), 2.77 (2H, s), 3.53 (2H, s), 3.61 (2H, s), 3.60-3.65 (4H, m), 7.15 (1H, s), 7.21 (1H, s), 7.22 (1H, s), 7.26 (1H, dd, J=8.4, 2.1 Hz), 7.40 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=2.1 Hz).
Yield 18%, 1H-NMR (DMSO-d6): δ1.85-2.00 (2H, m), 2.57-2.68 (2H, m), 2.74-2.85 (2H, m), 3.52 (2H, s), 3.61 (2H, s), 3.62-3.85 (4H, m), 7.09-7.31 (4H, m), 7.52-7.58 (2H, m), 8.22 (1H, s).
Yield 95%, 1H-NMR (DMSO-d6): δ1.05 (6H, d, J=6.5 Hz), 2.65-2.80 (2H, m), 3.04-3.15 (2H, m), 3.55 (2H, s), 3.79 (2H, s), 3.83-3.95 (2H, m), 7.05-7.15 (1H, m), 7.20-7.30 (3H, m), 7.57 (2H, s), 8.24 (1H, s), 12.27 (1H, brs).
Yield 61%, 1H-NMR (CDCl3): δ1.08 (6H, d, J=6.5 Hz), 2.74-2.86 (2H, m), 3.08 (1H, d, J=13 Hz), 3.12 (1H, d, J=13 Hz), 3.62 (2H, s), 3.78 (2H, s), 3.86-3.95 (2H, m), 7.16-7.18 (2H, m), 7.34 (1H, s), 7.52 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 87%, 1H-NMR (DMSO-d6): δ1.01 (3H, d, J=6.5 Hz), 1.33 (3H, d, J=6.5 Hz), 2.25-2.35 (1H, m), 2.75-2.85 (1H, m), 3.08-3.20 (1H, m), 3.49 (1H, d, J=14 Hz), 3.56 (2H, s), 3.63-3.75 (3H, m), 4.23-4.35 (1H, m), 7.10-7.20 (1H, m), 7.20-7.35 (3H, m), 7.50-7.60 (2H, m), 8.21 (1H, s), 12.23 (1H, brs).
Yield 87%, 1H-NMR (DMSO-d6): δ1.33 (3H, d, J=6.5 Hz), 2.10-2.30 (2H, m), 2.72 (1H, d, J=11.5 Hz), 2.94 (1H, d, J=12 Hz), 3.35-3.50 (2H, m), 3.57 (2H, s), 3.60 (1H, d, J=13.5 Hz), 3.75-3.90 (1H, m), 4.20-4.30 (1H, m), 7.15-7.32 (4H, m), 7.56 (2H, s), 8.22 (1H, s), 12.28 (1H, brs).
Yield 82%, 1H-NMR (DMSO-d6): δ1.16 (3H, d, J=6 Hz), 2.15-2.35 (1H, m), 2.55-2.68 (1H, m), 2.70-2.80 (1H, m), 3.15-3.30 (2H, m), 3.35-3.50 (1H, m), 3.56 (2H, s), 3.70-3.80 (1H, m), 3.80-3.90 (1H, m), 3.97 (1H, d, J=13.5 Hz), 7.10-7.35 (4H, m), 7.56 (2H, s), 8.23 (1H, s), 12.29 (1H, brs).
Yield 98%, 1H-NMR (CDCl3): δ1.00 (3H, t, J=7.5 Hz), 1.59-1.69 (1H, m), 1.73-1.80 (1H, m), 2.37-2.45 (1H, m), 2.54-2.59 (1H, m), 2.80-2.86 (1H, m), 3.34-3.54 (3H, m), 3.59-3.63 (1H, m), 3.63 (2H, s), 3.79 (1H, dd, J=2.7, 13.2 Hz), 4.04 (1H, d, J=13.2 Hz), 7.20-7.29 (5H, m), 7.42 (1H, d, J=8.7 Hz), 7.53 (1H, d, J=2.1 Hz)
Yield 96%, 1H-NMR (CDCl3): δ0.92 (6H, dd, J=6.3, 16.2 Hz), 1.38-1.47 (1H, m), 1.51-1.59 (1H, m), 1.64-1.75 (1H, m), 2.43-2.51 (1H, m), 2.71-2.76 (1H, m), 2.79-2.87 (1H, m), 3.40 (2H, dt, J=3.0, 13.2 Hz), 3.57-3.64 (2H, m), 3.63 (2H, s), 3.76 (1H, dd, J=3.0, 12.9 Hz), 3.99 (1H, d, J=13.2 Hz), 7.21-7.31 (5H, m), 7.43 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=2.4 Hz)
Yield 89%, 1H-NMR (CDCl3): δ1.25 (3H, d, J=6.0 Hz), 2.30-2.38 (1H, m), 2.68-2.74 (1H, m), 2.83 (1H, dt, J=3.9, 12.0 Hz), 3.18-3.28 (2H, m), 3.39-3.49 (1H, m), 3.63 (2H, s), 3.63-3.70 (1H, m), 3.86 (1H, dd, J=2.4, 12.0 Hz), 4.10 (1H, d, J=13.2 Hz), 7.19-7.30 (5H, m), 7.43 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=2.4 Hz)
Yield 91%, 1H-NMR (CDCl3): δ1.30 (3H, d, J=6.0 Hz), 2.40 (1H, t, J=9.6 Hz), 2.78 (1H, br), 2.88 (1H, br), 3.33 (2H, d, J=12.6 Hz), 3.48-3.54 (1H, m), 3.64 (2H, s), 3.72 (1H, d, J=13.2 Hz), 3.89 (1H, d, J=10.2 Hz), 4.16 (1H, d, J=13.2 Hz), 7.22-7.33 (5H, m), 7.43 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield 96%, 1H-NMR (CDCl3): δ1.26 (3H, d, J=6 Hz), 2.25-2.40 (4H, m), 2.65-2.75 (1H, m), 2.80-2.90 (1H, m), 3.20 (1H, d, J=13 Hz), 3.25-3.30 (1H, m), 3.45-3.53 (1H, m), 3.61 (2H, s), 3.68-3.80 (1H, m), 3.84-3.95 (1H, m), 4.07 (1H, d, J=13 Hz), 7.03 (2H, s), 7.10 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=8.5 Hz), 7.83 (1H, s)
Yield 67%, 1H-NMR (DMSO-d6): δ1.31 (3H, d, J=6.5 Hz), 2.03-2.25 (2H, m), 2.70 (1H, d, J=11.5 Hz), 2.91 (1H, d, J=12 Hz), 3.35-3.43 (2H, m), 3.56 (2H, s), 3.56-3.65 (1H, m), 3.79 (1H, d, J=11 Hz), 4.15-4.25 (1H, m), 7.15 (1H, d, J=7 Hz), 7.20-7.33 (4H, m), 7.41 (1H, d, J=8.5 Hz), 7.89 (1H, d, J=1.5 Hz), 12.30 (1H, brs).
Yield 86%, 1H-NMR (CDCl3): δ1.37 (3H, d, J=7.0 Hz), 2.23 (1H, td, J=11.0, 3.5 Hz), 2.31 (1H, dd, J=11.0, 3.5 Hz), 2.71 (1H, d, J=11.0 Hz), 2.91 (1H, d, J=11.0 Hz), 3.44 (1H, d, J=13.5 Hz), 3.47 (1H, td, J=12.5, 3.5 Hz), 3.60 (1H, d, J=11.0 Hz), 3.64 (2H, s), 3.83 (1H, d, J=12.5 Hz), 4.09-4.21 (1H, m), 7.14-7.33 (5H, m), 7.42 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2.0 Hz).
Yield 94%, 1H-NMR (CDCl3): δ1.37 (3H, d, J=6.5 Hz), 2.23 (1H, td, J=11.5, 3.5 Hz), 2.25-2.30 (1H, m), 2.32 (3H, s), 2.71 (1H, d, J=11.5 Hz), 2.91 (1H, d, J=11 Hz), 3.39 (1H, d, J=13.5 Hz), 3.45-3.54 (1H, m), 3.55 (1H, d, J=13.5 Hz), 3.60 (2H, s), 3.83 (1H, d, J=11.5 Hz), 4.10-4.20 (1H, m), 7.01 (1H, s), 7.06 (1H, s), 7.09 (1H, s), 7.23 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2 Hz).
Yield 82%, 1H-NMR (CDCl3): δ1.37 (3H, d, J=6.5 Hz), 2.13-2.36 (5H, m), 2.70 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.32-3.62 (5H, m), 3.76-3.87 (1H, m), 4.07-4.22 (1H, m), 6.99 (1H, s), 7.05 (1H, s), 7.07 (1H, s), 7.22 (1H, dd, J=8.5, 2.0 Hz), 7.42 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=2.0 Hz).
Yield 87%, 1H-NMR (DMSO-d6): δ1.33 (3H, d, J=6.5 Hz), 2.10-2.30 (2H, m), 2.72 (1H, d, J=11.5 Hz), 2.93 (1H, d, J=11.5 Hz), 3.30-3.50 (2H, m), 3.56 (2H, s), 3.59 (1H, d, J=13.5 Hz), 3.86 (1H, d, J=12.5 Hz), 4.20-4.30 (1H, m), 7.10-7.35 (4H, m), 7.56 (2H, s), 8.24 (1H, s), 12.43 (1H, brs).
Yield 96%, 1H-NMR (CDCl3): δ1.34 (3H, d, J=6.5 Hz), 2.14 (1H, td, J=11.5, 3.5 Hz), 2.25 (1H, dd, J=11.5, 3.5 Hz), 2.66 (1H, d, J=11.5 Hz), 2.83 (1H, d, J=11.5 Hz), 3.37 (1H, d, J=13.5 Hz), 3.38-3.55 (4H, m), 3.82 (1H, d, J=11.5 Hz), 4.08-4.22 (1H, m), 7.10 (1H, s), 7.14-7.23 (3H, m), 7.45-7.56 (2H, m), 7.81 (1H, s).
Yield 98%, 1H-NMR (CDCl3): δ1.39 (3H, d, J=6.5 Hz), 2.23 (1H, td, J=12, 3.5 Hz), 2.25-2.31 (1H, m), 2.32 (3H, s), 2.73 (1H, d, J=11.5 Hz), 2.92 (1H, d, J=12 Hz), 3.41 (1H, d, J=13 Hz), 3.45-3.55 (1H, m), 3.56 (1H, d, J=13 Hz), 3.59 (2H, s), 3.88 (1H, d, J=12 Hz), 4.17-4.28 (1H, m), 7.01 (1H, s), 7.06 (1H, s), 7.09 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 7.83 (1H, s).
Yield 72%, 1H-NMR (CDCl3): δ1.39 (3H, d, J=6.5 Hz), 2.13-2.34 (5H, m), 2.71 (1H, d, J=11.5 Hz), 2.90 (1H, d, J=11.5 Hz), 3.39 (1H, d, J=13.0 Hz), 3.43-3.60 (4H, m), 3.87 (1H, d, J=12.5 Hz), 4.13-4.26 (1H, m), 6.99 (1H, s), 7.05 (2H, s), 7.46-7.58 (2H, m), 7.83 (1H, s).
Yield 90%, 1H-NMR (CDCl3): δ1.40 (3H, d, J=6.5 Hz), 2.26 (1H, td, J=12, 3.5 Hz), 2.35 (1H, dd, J=11.5, 3.5 Hz), 2.72 (1H, d, J=11.5 Hz), 2.91 (1H, d, J=12 Hz), 3.43 (1H, d, J=13.5 Hz), 3.52 (1H, td, J=12.5, 3.5 Hz), 3.57 (1H, d, J=13.5 Hz), 3.64 (2H, s), 3.85-3.95 (1H, m), 4.19-4.30 (1H, m), 7.18 (1H, s), 7.21 (1H, s), 7.29 (1H, s), 7.51 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.84 (1H, s).
Yield 68%, 1H-NMR (CDCl3): δ0.85 (3H, t, J=7.5 Hz), 1.82-1.99 (2H, m), 2.17-2.29 (2H, m), 2.78-2.92 (2H, m), 3.37-3.51 (1H, m), 3.42 (1H, d, J=13.0 Hz), 3.59 (1H, d, J=13.0 Hz), 3.65 (2H, s), 3.76-3.87 (1H, m), 3.93-4.04 (1H, m), 7.16-7.34 (5H, m), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.0 Hz).
Yield 95%, 1H-NMR (DMSO-d6): δ0.79 (3H, t, J=7.5 Hz), 1.72-1.95 (2H, m), 2.07-2.20 (2H, m), 2.81 (1H, d, J=11 Hz), 2.89 (1H, d, J=11 Hz), 3.25-3.39 (2H, m), 3.40 (1H, d, J=13.5 Hz), 3.55 (2H, s), 3.59 (1H, d, J=13.5 Hz), 3.80-3.95 (1H, m), 7.13-7.34 (5H, m), 7.38 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=2 Hz), 12.45 (1H, brs).
Yield 96%, 1H-NMR (CDCl3): δ0.86 (3H, t, J=7.5 Hz), 1.80-2.00 (2H, m), 2.16-2.29 (2H, m), 2.33 (3H, s), 2.79-2.94 (2H, m), 3.38 (1H, d, J=13.5 Hz), 3.50 (1H, td, J=12.5, 3.5 Hz), 3.57 (1H, d, J=13.5 Hz), 3.61 (2H, s), 3.75-3.87 (1H, m), 3.93-4.03 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.21 (1H, dd, J=8.5, 2 Hz), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2 Hz).
Yield 77%, 1H-NMR (DMSO-d6): δ0.80 (3H, t, J=7.5 Hz), 1.67-1.97 (2H, m), 2.03-2.19 (2H, m), 2.28 (3H, s), 2.81 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.0 Hz), 3.27-3.44 (2H, m), 3.48 (2H, s), 3.55 (1H, d, J=13.5 Hz), 3.81-3.95 (2H, m), 6.96 (1H, s), 7.02 (2H, s), 7.26 (1H, dd, J=8.5, 2.0 Hz), 7.38 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=2.0 Hz).
Yield 96%, 1H-NMR (DMSO-d6): δ0.80 (3H, t, J=7.5 Hz), 1.76-1.96 (2H, m), 2.09-2.20 (2H, m), 2.82 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.30-3.42 (2H, m), 3.43 (1H, d, J=13.5 Hz), 3.56 (2H, s), 3.60 (1H, d, J=13.5 Hz), 3.88-4.00 (1H, m), 7.12-7.32 (4H, m), 7.51 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 8.21 (1H, s), 12.3 (1H, brs).
Yield 89%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7.5 Hz), 1.85-2.00 (2H, m), 2.23 (2H, td, J=12.5, 3.5 Hz), 2.34 (3H, s), 2.81-2.96 (2H, m), 3.38 (1H, d, J=13.5 Hz), 3.49 (1H, td, J=12.5, 3.5 Hz), 3.58 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 3.97-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.46-7.50 (2H, m), 7.81 (1H, s).
Yield 89%, 1H-NMR (CDCl3): δ0.88 (3H, t, J=7.5 Hz), 1.93 (2H, quant, J=7.5 Hz), 2.19-2.32 (2H, m), 2.78-2.93 (2H, m), 3.40 (1H, d, J=13.5 Hz), 3.49 (1H, td, J=12.5, 3.5 Hz), 3.57 (1H, d, J=13.5 Hz), 3.64 (2H, s), 3.84-3.95 (1H, m), 3.96-4.10 (1H, m), 7.16 (1H, s), 7.22 (1H, s), 7.28 (1H, s), 7.45-7.57 (2H, m), 7.82 (1H, s).
Yield 93%, 1H-NMR (CDCl3): δ0.86 (3H, t, J=7.5 Hz), 1.92 (2H, quant, J=7.5 Hz), 2.15-2.31 (2H, m), 2.80-2.96 (2H, m), 3.42 (1H, d, J=13 Hz), 3.48 (1H, td, J=12.5, 3 Hz), 3.61 (1H, d, J=13 Hz), 3.66 (2H, s), 3.80-3.95 (1H, m), 3.96-4.10 (1H, m), 7.15-7.33 (4H, m), 7.49 (1H, d, J=8.5 Hz), 7.50 (1H, d, J=8.5 Hz) 7.81 (1H, s).
Yield 96%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7.5 Hz), 1.85-2.00 (2H, m), 2.15-2.28 (2H, m), 2.34 (3H, s), 2.80-2.95 (2H, m), 3.39 (1H, d, J=13 Hz), 3.51 (1H, td, J=13, 3.5 Hz), 3.58 (1H, d, J=13 Hz), 3.62 (2H, s), 3.80-3.95 (1H, m), 3.96-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.08 (1H, s), 7.50 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=8.5 Hz) 7.81 (1H, s).
Yield 98%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7.5 Hz), 1.11-1.28 (2H, m), 1.68-1.88 (2H, m), 2.20-2.18 (2H, m), 2.64-2.79 (2H, m), 3.23-3.48 (5H, m), 3.74-3.96 (2H, m), 6.98-7.23 (5H, m), 7.35 (1H, d, J=8.5 Hz), 7.49 (1H, d, J=2.0 Hz).
Yield 98%, 1H-NMR (CDCl3): δ0.91 (3H, t, J=7.2 Hz), 1.19-1.29 (2H, m), 1.77-1.94 (2H, m), 2.18-2.28 (2H, m), 2.81 (1H, d, J=11.1 Hz), 2.89 (1H, d, J=11.1 Hz), 3.40-3.47 (2H, m), 3.61 (1H, d, J=13.2 Hz), 3.66 (2H, s), 3.90 (1H, s), 3.99 (1H, d, J=12.0 Hz), 7.20-7.31 (5H, m), 7.39 (1H, d, J=8.7 Hz), 7.52 (1H, d, J=2.1 Hz)
Yield 69%, 1H-NMR (CDCl3): δ0.92 (3H, t, J=7.0 Hz), 1.16-1.34 (2H, m), 1.68-2.00 (2H, m), 2.12-2.27 (2H, m), 2.32 (3H, s), 2.79 (1H, d, J=11.5 Hz), 2.86 (1H, d, J=11.5 Hz), 3.35 (1H, d, J=13.5 Hz), 3.39-3.62 (2H, m), 3.58 (2H, s), 3.82-4.03 (2H, m), 6.99 (1H, s), 7.03 (1H, s), 7.06 (1H, s), 7.21 (1H, dd, J=8.5, 2.0 Hz), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.0 Hz).
Yield 91%, 1H-NMR (CDCl3): δ0.92 (3H, t, J=7.2 Hz), 1.20-1.30 (2H, m), 1.75-1.84 (1H, m), 1.87-1.97 (1H, m), 2.18-2.28 (2H, m), 2.34 (3H, s), 2.86 (2H, dd, J=11.1 Hz), 3.37 (1H, d, J=13.2 Hz), 3.48 (1H, dt, J=3.3, 12.6 Hz), 3.61 (1H, d, J=12.1 Hz), 3.62 (2H, s), 3.90 (1H, s), 3.99 (1H, d, J=11.1 Hz), 7.02 (1H, s), 7.07 (2H, s), 7.22 (1H, dd, J=2.1, 8.7 Hz), 7.40 (1H, d, J=8.7 Hz), 7.52 (1H, d, J=2.1 Hz)
Yield 70%, 1H-NMR (CDCl3): δ0.92 (3H, t, J=7.0 Hz), 1.18-1.35 (2H, m), 1.75-1.98 (2H, m), 2.15-2.29 (2H, m), 2.81 (1H, d, J=11.5 Hz), 2.88 (1H, d, J=11.5 Hz), 3.41 (1H, d, J=13.0 Hz), 3.48 (1H, td, J=12.5, 3.0 Hz), 3.58 (1H, d, J=13.0 Hz), 3.62 (2H, s), 3.89-4.09 (2H, m), 7.14-7.32 (4H, m), 7.49 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=8.5 Hz), 7.81 (1H, s).
Yield 81%, 1H-NMR (CDCl3): δ0.92 (3H, t, J=7.2 Hz), 1.21-1.31 (2H, m), 1.80-1.94 (2H, m), 2.20-2.29 (2H, m), 2.82 (1H, d, J=11.4 Hz), 2.91 (1H, d, J=11.1 Hz), 3.43 (1H, d, J=13.2 Hz), 3.50 (1H, dt, J=3.0, 12.6 Hz), 3.61 (1H, d, J=13.2 Hz), 3.67 (2H, s), 3.99 (1H, d, J=14.1 Hz), 4.06 (1H, s), 7.20-7.34 (4H, m), 7.52 (2H, s), 7.82 (1H, s)
Yield 81%, 1H-NMR (CDCl3): δ0.86 (3H, t, J=7.5 Hz), 1.14-1.38 (4H, m), 1.74-1.99 (2H, m), 2.16-2.30 (2H, m), 2.81 (1H, d, J=11.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.42 (1H, d, J=13 Hz), 3.46 (1H, td, J=13.5, 3.5 Hz), 3.60 (1H, d, J=13 Hz), 3.66 (2H, s), 3.80-3.93 (1H, m), 3.95-4.06 (1H, m), 7.15-7.35 (5H, m), 7.40 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.5 Hz).
Yield 91%, 1H-NMR (CDCl3): δ0.86 (3H, t, J=7.5 Hz), 1.13-1.40 (4H, m), 1.74-2.00 (2H, m), 2.16-2.30 (2H, m), 2.82 (1H, d, J=12 Hz), 2.88 (1H, d, J=11.5 Hz), 3.41 (1H, d, J=13.5 Hz), 3.41-3.51 (1H, m), 3.60 (1H, d, J=13.5 Hz), 3.66 (2H, s), 3.80-3.92 (1H, m), 3.94-4.05 (1H, m), 7.16-7.34 (5H, m), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2 Hz).
Yield 81%, 1H-NMR (CDCl3): δ0.87 (3H, t, J=7.5 Hz), 1.17-1.39 (4H, m), 1.75-2.03 (2H, m), 2.17-2.30 (2H, m), 2.34 (3H, s), 2.83 (1H, d, J=11.5 Hz), 2.91 (1H, d, J=10.5 Hz), 3.38 (1H, d, J=13.5 Hz), 3.44-3.55 (1H, m), 3.58 (1H, d, J=13.5 Hz), 3.62 (2H, s), 3.85-3.97 (1H, m), 4.00-4.10 (1H, m), 7.02 (1H, s), 7.06 (1H, s), 7.07 (1H, s), 7.51 (2H, s), 7.82 (1H, s).
Yield 53%, 1H-NMR (DMSO-d6): δ0.87 (3H, d, J=6.5 Hz), 0.89 (3H, d, J=6.5 Hz), 2.02-2.25 (2H, m), 2.29 (3H, s), 2.45-3.05 (4H, m), 3.10 (1H, d, J=13.0 Hz), 3.35-3.58 (2H, m), 3.53 (2H, s), 4.01-4.22 (1H, m), 6.96 (1H, s), 7.00 (1H, s), 7.03 (1H, s), 7.49 (2H, s), 7.78 (1H, s).
Yield 70%, 1H-NMR (DMSO-d6): δ0.85 (6H, t, J=7.5 Hz), 2.00 (1H, d, J=11.5 Hz), 2.14 (1H, t, J=11.5 Hz), 2.28 (3H, s), 2.50-2.57 (1H, m), 2.93 (2H, t, J=11.5 Hz), 3.32 (1H, d, J=13.5 Hz), 3.32-3.48 (1H, m), 3.49 (2H, s), 3.57 (1H, d, J=13.5 Hz), 3.58-3.65 (1H, m), 3.95-4.10 (1H, m), 6.97 (1H, s), 7.02 (2H, s), 7.49 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.5 Hz), 8.18 (1H, s), 12.4 (1H, brs).
Yield 67%, 1H-NMR (DMSO-d6): δ0.88 (3H, d, J=6.5 Hz), 0.90 (3H, d, J=6.5 Hz), 1.32-1.58 (2H, m), 1.80-1.96 (1H, m), 2.05-2.23 (2H, m), 2.75 (1H, d, J=10.5 Hz), 2.89 (1H, d, J=11.5 Hz), 3.30-3.53 (2H, m), 3.48 (2H, s), 3.59 (1H, d, J=13.5 Hz), 3.80-4.08 (2H, m), 7.10-7.30 (5H, m), 7.38 (1H, d, J=8.5 Hz), 7.87 (1H, d, J=2.0 Hz).
Yield 88%, 1H-NMR (CDCl3): δ0.90 (6H, dd, J=6, 2 Hz), 1.30-1.59 (2H, m), 1.80-1.95 (1H, m), 2.08-2.24 (2H, m), 2.75 (1H, d, J=11.5 Hz), 2.91 (1H, d, J=11.5 Hz), 3.20-3.37 (1H, m), 3.38 (1H, d, J=13.5 Hz), 3.55 (2H, s), 3.62 (1H, d, J=13.5 Hz), 3.80-3.96 (1H, m), 3.97-4.10 (1H, m), 7.10-7.32 (5H, m), 7.38 (1H, d, J=8.5 Hz), 7.89 (1H, d, J=2 Hz), 12.43 (1H, brs).
Yield 62%, 1H-NMR (CDCl3): δ0.91 (3H, d, J=6.5 Hz), 0.93 (3H, d, J=6.5 Hz), 1.34-1.64 (2H, m), 1.85-2.00 (1H, m), 2.11-2.38 (2H, m), 2.31 (3H, s), 2.77 (1H, d, J=11.0 Hz), 2.86 (1H, d, J=10.5 Hz), 3.32 (1H, d, J=13.0 Hz), 3.38-3.64 (2H, m), 3.56 (2H, s), 3.83-4.07 (2H, m), 6.98 (1H, s), 7.01 (1H, s), 7.05 (1H, s), 7.21 (1H, dd, J=8.5, 2.0 Hz), 7.39 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=2.0 Hz).
Yield 92%, 1H-NMR (CDCl3): δ0.90 (6H, t, J=6 Hz), 1.42-1.53 (2H, m), 1.93-2.01 (1H, m), 2.02-2.12 (2H, m), 2.29 (3H, s), 2.75 (1H, d, J=11.5 Hz), 2.91 (1H, d, J=11.5 Hz), 3.31 (1H, d, J=13.5 Hz), 3.32-3.50 (1H, m), 3.51 (2H, s), 3.61 (1H, d, J=13.5 Hz), 3.87-4.04 (2H, m), 6.97 (1H, s), 7.02 (1H, s), 7.04 (1H, s), 7.27 (1H, dd, J=8.5, 2 Hz), 7.38 (1H, d, J=8.5 Hz), 7.89 (1H, d, J=2 Hz), 12.28 (1H, brs).
Yield 99%, 1H-NMR (CDCl3): δ0.90 (3H, d, J=6.0 Hz), 0.92 (3H, d, J=6.0 Hz), 1.34-1.64 (2H, m), 1.84-1.98 (1H, m), 2.07-2.30 (2H, m), 2.26 (3H, s), 2.74 (1H, d, J=11.0 Hz), 2.82 (1H, d, J=10.5 Hz), 3.28 (1H, d, J=13.5 Hz), 3.35-3.54 (4H, m), 3.87-4.07 (2H, m), 6.91 (1H, s), 6.93 (1H, s), 7.02 (1H, s), 7.50 (2H, s), 7.81 (1H, s).
Yield 98%, 1H-NMR (CDCl3): δ0.93 (6H, dd, J=3.6, 6.3 Hz), 1.42-1.50 (1H, m), 1.55-1.64 (1H, m), 1.90-1.99 (1H, m), 2.23 (2H, td, J=3.6, 11.4 Hz), 2.34 (3H, s), 2.81 (1H, d, J=11.4 Hz), 2.92 (1H, d, J=10.2 Hz), 3.37 (1H, d, J=13.2 Hz), 3.52 (1H, td, J=3.3, 12.9 Hz), 3.62 (1H, d, J=13.2 Hz), 3.62 (2H, s), 4.04 (2H, br), 7.02 (1H, s), 7.07 (2H, s), 7.52 (2H, s), 7.82 (1H, s)
Yield 62%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6.5 Hz), 1.38 (3H, d, J=6.5 Hz), 2.11-2.26 (1H, m), 2.65-2.89 (2H, m), 2.98-3.15 (1H, m), 3.35-3.52 (1H, m), 3.67 (2H, s), 3.68-3.82 (1H, m), 4.03-4.22 (2H, m), 7.17-7.36 (4H, m), 7.48-7.60 (2H, m), 7.83 (1H, s).
Yield 80%, 1H-NMR (DMSO-d6): δ2.43-2.58 (4H, m), 3.54 (2H, s), 3.57 (2H, s), 3.58-3.70 (4H, m), 7.13-7.34 (4H, m), 7.47 (1H, d, J=12.5 Hz), 8.27 (1H, d, J=7.5 Hz), 12.28 (1H, s).
Yield 92%, 1H-NMR (CDCl3): δ2.28 (3H, s), 2.50-2.62 (4H, m), 3.47 (2H, s), 3.52 (2H, s), 3.58-3.68 (4H, m), 6.97 (2H, s), 7.04 (1H, s), 7.25 (1H, d, J=11.5 Hz), 7.73 (1H, d, J=7.0 Hz).
Yield 59%, 1H-NMR (CD3OD): δ2.06-2.18 (2H, m), 2.31 (3H, s), 2.87-2.97 (2H, m), 2.99-3.08 (2H, m), 3.52 (2H, s), 3.70-3.98 (4H, m), 3.82 (2H, s), 7.07 (2H, s), 7.11 (1H, s), 7.29 (1H, d, J=12.0 Hz), 7.98 (1H, d, J=7.0 Hz).
Yield 85%, 1H-NMR (DMSO-d6): δ1.15 (3H, d, J=6 Hz), 2.16-2.27 (1H, m), 2.28 (3H, s), 2.55-2.68 (1H, m), 2.69-2.80 (1H, m), 3.17 (1H, d, J=13.5 Hz), 3.18-3.26 (1H, m), 3.35-3.48 (1H, m), 3.49 (2H, s), 3.65-3.79 (1H, m), 3.80-3.90 (1H, m), 3.92 (1H, d, J=13.5 Hz), 6.96 (1H, s), 7.00 (1H, s), 7.01 (1H, s), 7.45 (1H, d, J=12 Hz), 8.25 (1H, d, J=8 Hz), 12.40 (1H, brs).
Yield 67%, 1H-NMR (CDCl3): δ1.39 (3H, d, J=7.0 Hz), 2.14-2.35 (2H, m), 2.32 (3H, s), 2.72 (1H, d, J=11.0 Hz), 2.91 (1H, d, J=11.0 Hz), 3.40 (1H, d, J=14.0 Hz), 3.43-3.62 (2H, m), 3.58 (2H, s), 3.86 (1H, d, J=12.5 Hz), 4.12-4.28 (1H, m), 6.99 (1H, s), 7.02-7.10 (2H, m), 7.25 (1H, d, J=11.5 Hz), 7.73 (1H, d, J=7.0 Hz).
Yield 78%, 1H-NMR (CDCl3): δ1.38 (3H, d, J=7.0 Hz), 2.12-2.35 (2H, m), 2.30 (3H, s), 2.70 (1H, d, J=11.5 Hz), 2.88 (1H, d, J=11.5 Hz), 3.32-3.60 (5H, m), 3.84 (1H, d, J=11.5 Hz), 4.10-4.25 (1H, m), 6.97 (1H, s), 7.04 (2H, s), 7.24 (1H, d, J=12.0 Hz), 7.73 (1H, d, J=7.0 Hz).
Yield 82%, 1H-NMR (DMSO-d6): δ2.45-2.60 (4H, m), 3.48-3.63 (8H, m), 7.06 (1H, td, J=7.5, 1.0 Hz), 7.13-7.33 (5H, m), 7.45 (1H, d, J=7.5 Hz), 7.76 (1H, d, J=7.5 Hz), 12.32 (1H, brs).
Yield 60%, 1H-NMR (CDCl3): δ0.85 (3H, t, J=7.5 Hz), 1.80-2.00 (2H, m), 2.12-2.26 (2H, m), 2.31 (3H, s), 2.77-2.91 (2H, m), 3.36 (1H, d, J=13.5 Hz), 3.36-3.62 (2H, m), 3.57 (2H, s), 3.75-3.87 (1H, m), 3.88-4.02 (1H, m), 6.98 (1H, s), 7.04 (2H, s), 7.24 (1H, d, J=10.5 Hz), 7.51 (1H, d, J=7.0 Hz).
Yield 67%, 1H-NMR (CDCl3): δ2.75 (4H, t, J=5.0 Hz), 3.68 (4H, s), 3.85 (4H, t, J=5.0 Hz), 7.13-7.21 (1H, m), 7.22-7.34 (2H, m), 7.37-7.46 (2H, m), 7.54-7.64 (1H, m), 7.69 (1H, dd, J=8.0, 51.0 Hz), 7.89 (1H, dd, J=8.0, 1.0 Hz), 8.56 (1H, s).
Yield 57%, 1H-NMR (CDCl3): δ2.82 (4H, t, J=4.5 Hz), 3.66 (2H, s), 3.74 (2H, s), 3.83 (4H, t, J=4.5 Hz), 6.93 (1H, d, J=9.0 Hz), 7.07-7.15 (1H, m), 7.20-7.31 (3H, m), 7.47 (1H, s), 7.54 (1H, td, J=8.0, 1.5 Hz), 7.60 (1H, d, J=8.0), 7.70 (1H, d, J=8.0 Hz), 7.89 (1H, d, J=9.0 Hz).
Yield 42%, 1H-NMR (CDCl3): δ2.65-2.77 (4H, m), 3.64 (4H, s), 3.76-3.88 (4H, m), 7.13-7.32 (3H, m), 7.38 (1H, s), 7.50 (1H, dd, J=9.0, 2.0 Hz), 7.59 (1H, d, J=9.0 Hz), 7.86 (1H, d, J=2.0 Hz), 8.53 (1H, s).
Yield 81%, 1H-NMR (CDCl3): δ2.60-2.74 (4H, m), 2.63 (3H, s), 3.35-3.49 (4H, m), 3.52 (2H, s), 3.54 (2H, s), 7.05-7.23 (3H, m), 7.29 (1H, s), 7.69 (1H, d, J=9.0 Hz), 7.80 (1H, d, J=9.0 Hz), 8.14 (1H, s).
Yield 79%, 1H-NMR (CDCl3): δ1.35 (3H, d, J=6.5 Hz), 2.12-2.35 (5H, m), 2.79 (1H, d, J=11.5 Hz), 2.99 (1H, d, J=11.5 Hz), 3.27-3.43 (2H, m), 3.50-3.62 (3H, m), 4.35 (1H, d, J=12.5 Hz), 4.59-4.72 (1H, m), 6.98 (1H, s), 7.05 (1H, s), 7.08 (1H, s), 7.70 (2H, s), 8.13 (1H, s), 8.56 (1H, s).
Yield 76%, 1H-NMR (CD3OD): δ2.69-2.78 (4H, m), 3.52-3.60 (4H, m), 3.61 (2H, s), 3.71 (2H, s), 7.18-7.39 (7H, m), 7.42-7.50 (3H, m).
A mixture of {3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]phenyl}acetonitrile (0.35 g; 0.914 mmol), concentrated sulfuric acid (2 ml) and water (2 ml) was stirred at 80° C. for 2 hours. After air cooling, 5N-aqueous sodium hydroxide was added thereto to be alkaline. Ethyl acetate was added thereto and back-extracted. The water layer became neutral with 2N-aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to give 3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]phenyl acetic acid as colorless amorphous solid (0.08 g; 22%).
1H-NMR (DMSO-d6): δ2.45-2.50 (4H, m), 3.53 (2H, s), 3.53-3.65 (6H, m), 7.10-7.35 (5H, m), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2 Hz), 12.28 (1H, brs).
Compounds in Examples 491 to 512 were obtained by similar methods as Example 490.
Yield: 43%, 1H-NMR (DMSO-d6): δ1.90-1.96 (2H, m), 2.61 (2H, t, J=4.8 Hz), 2.77-2.80 (2H, m), 3.57-3.62 (4H, m), 3.62-3.71 (4H, m), 7.12-7.16 (2H, m), 7.21-7.28 (3H, m), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.4 Hz).
Yield: 78%, 1H-NMR (DMSO-d6): δ2.52 (4H, t, J=5 Hz), 3.54 (2H, s), 3.57 (2H, s), 3.63 (4H, t, J=5 Hz), 7.10-7.35 (4H, m), 7.57 (2H, s), 8.24 (1H, s), 12.31 (1H, s).
Yield: 18%, 1H-NMR (DMSO-d6): δ1.85-2.00 (2H, m), 2.57-2.68 (2H, m), 2.74-2.85 (2H, m), 3.52 (2H, s), 3.61 (2H, s), 3.62-3.85 (4H, m), 7.09-7.31 (4H, m), 7.52-7.58 (2H, m), 8.22 (2H, s).
Yield: 79%, 1H-NMR (DMSO-d6): δ1.31 (3H, d, J=6.5 Hz), 2.15 (1H, td, J=12, 3.5 Hz), 2.22 (1H, dd, J=11.5, 3.5 Hz), 2.70 (1H, d, J=11.5 Hz), 2.91 (1H, d, J=12 Hz), 3.41 (1H, td, J=12, 3.5 Hz), 3.44 (1H, d, J=13.5 Hz), 3.56 (2H, s), 3.59 (1H, d, J=13.5 Hz), 3.80 (1H, d, J=12 Hz), 4.10-4.30 (1H, m), 7.10-7.35 (5H, m), 7.41 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=2 Hz), 12.40 (1H, brs).
Yield: 69%, 1H-NMR (DMSO-d6): δ1.05-1.25 (3H, m), 2.15-2.30 (1H, s), 2.50-2.65 (1H, m), 2.65-2.80 (1H, m), 3.05-3.40 (3H, m), 3.57 (2H, s), 3.60-3.70 (1H, m), 3.70-3.85 (1H, m), 3.90-4.00 (1H, m), 7.05-7.35 (5H, m), 7.41 (1H, d, J=8.5 Hz), 7.90 (1H, s), 12.29 (1H, s).
Yield: 92%, 1H-NMR (DMSO-d6): δ1.04 (6H, d, J=6 Hz), 2.60-2.80 (2H, m), 2.95-3.10 (2H, m), 3.53 (2H, s), 3.77 (2H, s), 3.77-3.87 (2H, m), 7.00-7.10 (1H, m), 7.20-7.30 (4H, m), 7.42 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=2 Hz), 12.5 (1H, brs).
Yield: 76%, 1H-NMR (DMSO-d6): δ1.00 (3H, d, J=6 Hz), 1.30 (3H, d, J=6 Hz), 2.30 (1H, d, J=9.5 Hz), 2.70-2.85 (1H, m), 3.05-3.15 (1H, m), 3.40-3.45 (1H, m), 3.49 (2H, s), 3.62 (2H, s), 3.63-3.70 (1H, m), 4.10-4.30 (1H, m), 7.05-7.10 (1H, m), 7.20-7.35 (4H, m), 7.38 (1H, d, J=9 Hz), 7.87 (1H, d, J=2 Hz).
Yield: 42%, 1H-NMR (DMSO-d6): 2.31 (3H, s), 2.50 (4H, t, J=5 Hz), 3.47 (2H, s), 3.52 (2H, s), 3.55 (4H, t, J=5 Hz), 7.00-7.18 (3H, m), 7.28 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2 Hz), 12.25 (1H, brs).
Yield: 39%, 1H-NMR (DMSO-d6): δ2.58 (4H, t, J=5 Hz), 3.58 (4H, t, J=5 Hz), 3.61 (2H, s), 3.62 (2H, s), 7.19 (1H, dd, J=8, 2 Hz), 7.29 (1H, dd, J=8.5, 1.5 Hz), 7.39 (1H, d, J=8.5 Hz), 7.42 (1H, d, J=8 Hz), 7.43 (1H, d, J=1.5 Hz), 7.91 (1H, d, J=2 Hz), 12.41 (1H, brs).
Yield: 68%, 1H-NMR (CDCl3); δ2.32 (3H, s), 2.67 (4H, t, J=5 Hz), 3.59 (2H, s), 3.61 (2H, s), 3.67 (4H, t, J=5 Hz), 6.99 (1H, s), 7.04 (1H, s), 7.14 (1H, s), 7.24 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
Yield: 73%, 1H-NMR (DMSO-d6): δ1.88-1.94 (2H, m), 2.25 (3H, s), 2.60 (2H, t, J=4.5 Hz), 2.74-2.78 (2H, m), 3.48 (2H, s), 3.56 (2H, s), 3.66-3.73 (4H, m), 6.94-6.98 (3H, m), 7.26 (1H, dd, J=8.7, 2.1 Hz), 7.40 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=2.1 Hz).
Yield: 67%, 1H-NMR (CDCl3); δ2.71 (4H, t, J=5 Hz), 3.67 (4H, t, J=5 Hz), 3.78 (2H, s), 3.81 (2H, s), 6.78 (2H, s), 7.24 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.56 (1H, d, J=2 Hz).
Yield: 46%, 1H-NMR (CDCl3); δ2.16-2.20 (2H, m), 2.91-2.95 (2H, m), 3.03-3.06 (2H, m), 3.68 (2H, t, J=6.0 Hz), 3.79 (2H, s), 3.90-3.91 (2H, m), 3.97 (2H, s), 6.75 (1H, d, J=3.6 Hz), 6.77 (1H, d, J=3.3 Hz), 7.24 (1H, dd, J=9.0, 2.4 Hz), 7.43 (1H, d, J=9.0 Hz), 7.55 (1H, d, J=2.1 Hz).
Yield: 2%, 1H-NMR (DMSO-d6): δ2.40-2.50 (4H, m), 2.53 (2H, t, J=7.5 Hz), 2.81 (2H, t, J=7.5 Hz), 3.50 (2H, s), 3.55 (4H, t, J=5 Hz), 7.19 (2H, d, J=8 Hz), 7.23 (2H, d, J=8 Hz), 7.29 (1H, dd, J=8.5, 2 Hz), 7.41 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=2 Hz), 12.05 (1H, brs).
Yield: 70%, 1H-NMR (DMSO-d6): δ2.28 (3H, s), 2.45-2.55 (4H, m), 3.49 (2H, s), 3.51 (2H, s), 3.60-3.65 (4H, m), 6.97 (1H, s), 7.02 (2H, s), 7.57 (2H, s), 8.25 (1H, s), 12.4 (1H, brs).
Yield: 55%, 1H-NMR (DMSO-d6): δ1.85-2.00 (2H, m), 2.25 (3H, s), 2.55-2.70 (2H, m), 2.70-2.85 (2H, m), 3.49 (2H, s), 3.57 (2H, s), 3.60-3.85 (4H, m), 6.94 (1H, s), 6.99 (2H, s), 7.55 (2H, s), 8.22 (1H, s), 12.4 (1H, brs).
Yield 99%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.0 Hz), 2.26-2.33 (1H, m), 2.33 (3H, s), 2.64-2.71 (1H, m), 2.82 (1H, dt, J=3.6, 12.0 Hz), 3.19 (2H, d, J=12.9 Hz), 3.38-3.45 (1H, m), 3.61 (2H, s), 3.70 (1H, dt, J=3.6, 12.9 Hz), 3.86 (1H, dd, J=2.1, 11.7 Hz), 4.05 (1H, d, J=12.9 Hz), 7.03 (2H, d, J=4.5 Hz), 7.09 (1H, s), 7.23 (1H, dd, J=2.1, 8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield 93%, 1H-NMR (CDCl3): δ1.24 (3H, d, J=6.3 Hz), 2.27-2.37 (1H, m), 2.33 (3H, s), 2.56-2.71 (1H, m), 2.83 (1H, dt, J=3.3, 12.0 Hz), 3.19 (2H, d, J=13.2 Hz), 3.38-3.47 (1H, m), 3.60 (2H, s), 3.70 (1H, dt, J=4.8, 12.6 Hz), 3.86 (1H, dd, J=2.7, 12.6 Hz), 4.06 (1H, d, J=13.2 Hz), 7.03 (2H, s), 7.09 (1H, s), 7.23 (1H, dd, J=2.1, 8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz)
Yield 95%, 1H-NMR (DMSO-d6): δ1.04 (6H, d, J=6 Hz), 2.26 (3H, s), 2.60-2.80 (2H, m), 3.07 (1H, d, J=13 Hz), 3.09 (1H, d, J=13 Hz), 3.48 (2H, s), 3.73 (2H, s), 3.80-3.90 (2H, m), 6.88 (1H, s), 7.05 (2H, s), 7.55 (2H, s), 8.22 (1H, s), 12.21 (1H, brs).
Yield 82%, 1H-NMR (DMSO-d6): δ1.15 (3H, d, J=6.5 Hz), 2.18-2.25 (1H, m), 2.28 (3H, s), 2.55-2.68 (1H, m), 2.68-2.80 (1H, m), 3.15-3.48 (3H, m), 3.50 (2H, s), 3.70-3.76 (1H, m), 3.80-3.90 (1H, m), 3.93 (1H, d, J=13.5 Hz), 6.96 (1H, s), 7.02 (2H, s), 7.56 (2H, s), 8.23 (1H, s), 12.43 (1H, brs).
Yield 64%, 1H-NMR (CDCl3): δ1.23 (3H, d, J=6.5 Hz), 2.22-2.40 (4H, m), 2.60-2.74 (1H, m), 2.76-2.89 (1H, m), 3.10-3.31 (2H, m), 3.38-3.52 (1H, m), 3.59 (2H, s), 3.67-3.80 (1H, m), 3.84-3.96 (1H, m), 4.04 (1H, d, J=13.0 Hz), 6.97-7.12 (3H, m), 7.47-7.60 (2H, m), 7.83 (1H, s).
Yield 93%, 1H-NMR (DMSO-d6): δ1.33 (3H, d, J=6.5 Hz), 2.05-2.28 (2H, m), 2.29 (3H, s), 2.72 (1H, d, J=11 Hz), 2.93 (1H, d, J=11 Hz), 3.25-3.50 (2H, m), 3.51 (2H, s), 3.51-3.60 (1H, m), 3.86 (1H, d, J=11 Hz), 4.20-4.35 (1H, m), 6.97 (1H, s), 7.05 (2H, s), 7.56 (2H, s), 8.24 (1H, s), 12.43 (1H, brs).
To 2-{3-[4-(6-chlorobenzothiazole-2-yl)piperazine-1-ylmethyl]benzyl}diethyl malonate (0.38 g; 0.736 mmol) was added 6N-aqueous hydrochloric acid. The mixture was refluxed for 2 hours. After cooling, saturated aqueous sodium hydrogencarbonate was added thereto to become neutral. Ethyl acetate was added thereto and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was washed with diisopropyl ether to give 3-{3-[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}phenylpropionic acid as colorless crystal (0.08 g; 22%).
1H-NMR (DMSO-d6): δ2.50-2.52 (4H, m), 2.53 (2H, t, J=7.5 Hz), 2.82 (2H, t, J=7.5 Hz), 3.51 (2H, s), 3.57 (4H, t, J=5 Hz), 7.10-7.20 (3H, m), 7.24 (1H, d, J=7.5 Hz), 7.28 (1H, dd, J=8.5, 2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2 Hz), 12.15 (1H, brs).
A compound in Example 514 was obtained by a similar method as Example 513.
Yield: 55%, 1H-NMR (CDCl3): δ2.63 (4H, t, J=5 Hz), 2.72 (2H, t, J=7.5 Hz), 3.13 (2H, t, J=7.5 Hz), 3.64 (4H, t, J=5 Hz), 3.72 (2H, s), 6.68 (1H, d, J=3.5 Hz), 6.73 (1H, d, J=3.5 Hz), 7.24 (1H, dd, J=8.5, 2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2 Hz).
The following compound was obtained by a similar method as Reference Example 155.
Yield: 55%, 1H-NMR (DMSO-d6): δ2.50-2.55 (4H, m), 3.51 (2H, s), 3.55-3.65 (4H, m), 4.61 (2H, s), 6.75-7.00 (3H, m), 7.20-7.35 (2H, m), 7.42 (1H, d, J=8 Hz), 7.90 (1H, d, J=2 Hz).
A mixture of [3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}-4-methylphenyl]acetonitrile (1.14 g; 2.68 mmol), sodium hydroxide (0.54 g; 13.5 mmol), water (1.6 ml) and ethanol (21 ml) was stirred at 80° C. for 6 hours. The reaction solution was concentrated under reduced pressure and became pH=7 with 2N-aqueous hydrochloric acid. The precipitate was collected to give 3-{2-[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethoxy}-4-methylphenyl acetic acid as colorless crystal (0.63 g; 53%).
1H-NMR (DMSO-d6): δ1.20-1.38 (2H, m), 1.67-1.91 (5H, m), 2.09 (3H, s), 3.10-3.25 (4H, m), 3.93-4.06 (4H, m), 6.54 (1H, d, J=7.5 Hz), 6.82 (1H, s), 6.92 (1H, d, J=7.5 Hz), 7.27 (1H, dd, J=8.5, 2.0 Hz), 7.40 (1H, d, J=8.5 Hz), 7.88 (1H, d, J=2.0 Hz).
The present invention includes the following compounds synthesized by similar methods.
m/z=461 (M+H)+
m/z=431 (M+H)+
m/z=447 (M+H)+
m/z=435 (M+H)+
Rf=0.49 (AcOEt)
1H NMR (DMSO-d6): d 12.9 (br, 1H), 7.86 (s, 1H), 7.39 (d, 1H, J=6.3 Hz), 7.25 (d, 1H, J=6.3 Hz), 6.88 (s, 1H), 6.87 (d, 1H, J=6.0 Hz), 6.77 (d, 1H, J=6.0 Hz), 4.01 (m, 2H), 3.72 (s, 3H), 3.67 (br, 4H), 3.46 (s, 2H), 2.94 (s, 2H), 2.87 (t, 2H, J=4.2 Hz), 2.75 (br, 2H), 1.90 (s, 2H).
m/z=461 (M+H)+
m/z=475 (M+H)+
m/z=505 (M+H)+
m/z=493 (M+H)+
MS (ESI) m/e calcd. for C24H25ClFN2O3S2 (MH)+ 507.1, found 507
MS (ESI) m/e calcd. for C24H26ClN2O2S2 (MH)+ 473.1, found 473
MS (ESI) m/e calcd. for C23H23Cl2N2O2S2 (MH)+ 493.1, found 493
MS (ESI) m/e calcd. for C25H26ClN2O3S2 (MH+) 501.1, found 501.4
MS (ESI) m/e calcd. for C25H26ClN2O2S3 (MH+) 517.1, found 517.4
MS (ESI) m/e calcd. for C24H25 ClN3O2S2 (MH+) 486.1, found 486.4
m/z=489 (M+H)+
m/z=445 (M+H)+
MS (ESI) m/e calcd. for C24H29 ClN3O3S (MH+) 474.2, found 474.4
MS (ESI) m/e calcd. for C26H29ClN3O3S (MH)+ 498.2, found 498
m/z=460 (M+H)+
m/z=461 (M+H)+
MS (ESI) m/e calcd. for C25H26ClN2O4S (MH+) 485.1, found 485.2
MS (ESI) m/e calcd. for C24H28ClN2O3S (MH+) 459.2, found 459.4
m/z=479 (M+H)+
m/z=493 (M+H)+
MS (ESI) m/z 438 [M+H]+
MS (ESI) m/z 438 [M+H]+
m/z=446 (M+H)+
m/z=466 (M+H)+
m/z=482 (M+H)+
m/z=430 (M+H)+
m/z=444 (M+H)+
m/z=494 (M+H)+
m/z=474 (M+H)+
m/z=402 (M+H)+
m/z=431 (M+H)+
m/z=451 (M+H)+
m/z=462 (M+H)+
m/z=478 (M+H)+
m/z=478 (M+H)+
A mixture of 2,5-dibromothiazole (29.5 g), 2,6-dimethyl piperazine (13.8 g), potassium carbonate (20.1 g) and dimethylformamide (150 mL) was stirred at 60° C. for 6 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give the title compound (21.5 g). Yield: 64%.
1H-NMR (CDCl3) δ: 1.14 (6H, d, J=6.3 Hz), 2.05 (1H, br), 2.59-2.63 (2H, m), 2.98-3.02 (2H, m), 3.70-3.74 (2H, m), 7.06 (1H, s).
A mixture of 1-(5-bromothiazole-2-yl)-3,5-dimethyl piperazine (21.5 g), bromo acetic acid methyl ester (8.8 mL), potassium carbonate (12.9 g) and dimethylformamide (150 mL) was stirred at 60° C. for 2.5 hours. To the reaction solution was added water and 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 to give the title compound (20.1 g). Yield: 74%.
1H-NMR (CDCl3) δ: 1.17 (6H, d, J=6.0 Hz), 2.80-2.84 (2H, m), 3.13-3.16 (2H, m), 3.65 (2H, s), 3.65-3.68 (2H, m), 3.73 (3H, s), 7.08 (1H, s).
To a solution of [4-(5-bromothiazole-2-yl)-2,6-dimethyl piperazine-1-yl]acetic acid methyl ester (20.1 g) in tetrahydrofuran (300 mL) was added dropwise diisobutyl aluminium hydride (1M toluene solution, 200 mL) at −78° C. The mixture was stirred at −78° C. for 3.5 hours. To the reaction solution were added aqueous ammonium chloride solution (150 mL) and diethyl ether (45 mL). The insoluble material was filtrated. The filtrate was extracted diethyl ether. 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 to give the title compound (13.2 g). Yield: 71%.
1H-NMR (CDCl3) δ: 1.17 (6H, d, J=5.8 Hz), 2.44 (1H, br), 2.84 (6H, dd, J=16.9, 11.1 Hz), 3.60-3.64 (4H, m), 7.06 (1H, s).
To a mixture of 2-[4-(5-bromothiazole-2-yl)-2,6-dimethyl piperazine-1-yl]ethanol (9.87 g), triethylamine (8.6 mL) and methylene chloride (100 mL) was added dropwise methanesulfonyl chloride (2.9 mL) at 0° C. After stirring at 0° C. for 0.5 hour, to the reaction solution was added water and extracted with chloroform. 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 dissolved in acetonitrile (100 mL). (3-hydroxy-4-methylphenyl)acetic acid methyl ester (5.0 g) and cesium carbonate (12.0 g) were added thereto and stirred at 60° C. for 1 hour. The reaction solution was diluted with ethyl acetate and the insoluble material was filtrated. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel to give the title compound (8.49 g). Yield: 57%.
1H-NMR (CDCl3) δ: 1.27 (6H, d, J=6.6 Hz), 2.20 (3H, s), 2.87-2.91 (4H, m), 3.25-3.27 (2H, m), 3.60 (2H, s), 3.68 (2H, brm), 3.71 (3H, s), 4.03-4.05 (2H, m), 6.75 (1H, d, J=1.4 Hz), 6.79 (1H, dd, J=7.7, 1.4 Hz), 7.07 (1H, s), 7.10 (1H, d, J=7.7 Hz).
A mixture of [3-[2-[4-(5-bromothiazole-2-yl)-2,6-dimethyl piperazine-1-yl]ethoxy]-4-methylphenyl]acetic acid methyl ester (8.49 g), 2N aqueous sodium hydroxide solution (22 mL), methanol (50 mL) and tetrahydrofuran (50 mL) was stirred at room temperature for 1.5 hours. To the reaction solution were added water and brine. The mixture was washed with ethyl acetate. The water layer was neutralized with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was washed with diisopropyl ether to give the title compound (5.81 g).
Yield: 71%.
1H-NMR (DMSO-d6) δ: 1.16 (6H, d, J=5.5 Hz), 2.13 (3H, s), 2.71-2.83 (4H, m), 3.12-3.14 (2H, m), 3.52 (2H, s), 3.65-3.68 (2H, m), 3.99-4.01 (2H, m), 6.74 (1H, d, J=7.4 Hz), 6.87 (1H, s), 7.07 (1H, d, J=7.4 Hz), 8.34 (1H, s).
A mixture of [3-[2-[4-(5-bromothiazole-2-yl)-2,6-dimethyl piperazine-1-yl]ethoxy]-4-methylphenyl]acetic acid (400 mg), 2,5-difluorophenyl boronic acid (270 mg), tetrakis(triphenylphosphine) palladium (100 mg), 1M sodium carbonate (4.3 mL) and dimethylformamide (8 mL) was reacted with a microwave reaction device at 180° C. for 5 minutes. To the reaction solution was added water and extracted with chloroform. 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 to give the title compound (369 mg). Yield: 87%.
MS (ESI) m/z 502 [M+H]
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 508 [M+]
MS (ESI) m/z 508 [M+]
MS (ESI) m/z 515, 517 [M+H]+
MS (ESI) m/z 501, 503 [M+H]+
MS (ESI) m/z 579, 581 [+H]+
MS (ESI) m/z 529, 531 [M+H]+
1H-NMR (DMSO-d6) δ: 1.11 (6H, d, J=5.1 Hz), 2.60-2.70 (2H, m), 3.00-3.05 (2H, m), 3.55 (2H, s), 3.96-4.05 (2H, m), 4.32-4.45 (2H, m), 6.80-6.96 (3H, m), 8.44 (2H, s).
1H-NMR (DMSO-d6) δ: 1.17 (6H, d, J=4.9 Hz), 2.64-2.74 (4H, m), 3.09-3.18 (2H, m), 3.55 (2H, s), 4.03-4.10 (2H, m), 4.48-4.60 (2H, m), 6.83 (1H, dd, J=8.0, 0.8 Hz), 7.09 (1H, d, J=1.1 Hz), 7.33 (1H, d, J=8.0 Hz), 7.47-7.83 (3H, m), 8.71 (2H, s).
1H-NMR (DMSO-d6) δ: 1.17 (6H, d, J=4.4 Hz), 2.64-2.76 (4H, m), 3.10-3.18 (2H, m), 3.56 (2H, s), 4.04-4.11 (2H, m), 4.49-4.60 (2H, m), 6.83 (1H, d, J=8.0 Hz), 7.07-7.59 (5H, m), 8.59 (2H, s).
1H-NMR (CDCl3) δ: 1.31 (6H, d, J=5.8 Hz), 2.40 (3H, s), 2.90-3.08 (4H, m), 3.35-3.42 (2H, m), 3.54 (2H, s), 4.08-4.16 (2H, m), 4.52-4.67 (2H, m), 6.79-7.34 (7H, m), 8.52 (2H, s).
1H-NMR (Acetone) δ: 8.62 (2.0H, s), 7.61-7.59 (2.0H, m), 7.45 (2.0H, dd, J=7.55, 7.55 Hz), 7.37-7.28 (2.0H, m), 7.14 (1.0H, d, J=1.89 Hz), 6.89 (1.0H, dd, J=8.10, 1.89 Hz), 4.64 (2.0H, d, J=11.81 Hz), 4.16 (2.0H, dd, J=6.11, 6.11 Hz), 3.59 (2.0H, s), 3.24 (2.0H, dd, J=6.11, 6.11 Hz), 2.93-2.64 (4.0H, m), 1.25 (6.0H, d, J=6.04 Hz).
MS (ESI) m/z 508 [M+H]+
1H-NMR (DMSO-d6)) d: 7.81 (1H, s), 7.67 (1H, s), 7.32-7.29 (2H, m), 7.07 (1H, s), 6.81 (1H, d, J=8.8 Hz), 6.75 (1H, s), 4.06-4.03 (2H, m), 3.67 (2H, d, J=10.8 Hz), 3.52 (2H, s), 3.12-3.09 (2H, m), 2.82-2.69 (4H, m), 1.13 (6H, d, J=5.7 Hz).
MS (ESI) m/z 525 [M+H]+
1H-NMR (DMSO-d6) δ: 7.79 (1.0H, s), 7.70-7.64 (4.0H, m), 7.03 (1.0H, d, J=7.56 Hz), 6.85 (1.0H, s), 6.71 (1.0H, d, J=7.56 Hz), 3.99 (2.0H, dd, J=5.49, 5.49 Hz), 3.79 (2.0H, d, J=9.06 Hz), 3.47 (2.0H, s), 3.15-3.11 (2.0H, m), 2.89-2.78 (4.0H, m), 2.11 (3.0H, s), 1.17 (6.0H, d, J=5.22 Hz).
1H-NMR (DMSO-d6) δ: 7.83-7.70 (3.0H, m), 7.63-7.50 (2.0H, m), 7.03 (1.0H, d, J=7.69 Hz), 6.85 (1.0H, s), 6.70 (1.0H, d, J=7.69 Hz), 4.02-3.96 (2.0H, m), 3.79 (2.0H, d, J=9.06 Hz), 3.47 (2.0H, s), 3.17-3.10 (2.0H, m), 2.91-2.76 (4.0H, m), 2.12 (3.0H, s), 1.26-1.11 (6.0H, d, J=6.0 Hz).
1H-NMR (DMSO-d6) δ: 7.58 (1.0H, s), 7.46 (2.0H, d, J=7.42 Hz), 7.35 (2.0H, dd, J=7.42, 7.42 Hz), 7.21 (1.0H, dd, J=7.42, 7.42 Hz), 7.03 (1.0H, d, J=7.80 Hz), 6.85 (1.0H, s), 6.70 (1.0H, d, J=7.80 Hz), 4.01-3.97 (2.0H, m), 3.76 (2.0H, d, J=10.99 Hz), 3.45 (2.0H, s), 3.14-3.11 (2.0H, m), 2.89-2.74 (4.0H, m), 2.11 (3.0H, s), 1.17 (6.0H, d, J=5.49 Hz).
1H-NMR (CDCl3) δ 1.17 (6H, m), 2.12 (3H, s), 2.82 (4H, m), 2.13 (2H, br), 3.30 (3H, d, J=2.1 Hz), 3.49 (2H, s), 3.77 (2H, d, J=10.2 Hz), 3.99 (2H, br), 4.41 (2H, s), 6.71 (1H, brd), 6.85 (1H, brd), 7.04 (1H, brd), 7.15 (1H, brd), 7.30-7.41 (3H, m), 7.60 (1H, d, 1.8 Hz)
1H-NMR (DMSO-d6) δ 1.16 (6H, d, J=6.0 Hz), 1.33 (3H, t, J=6.9 Hz), 2.12 (3H, s), 2.74-2.90 (4H, m), 3.13 (2H, t, J=5.1 Hz), 3.49 (2H, s), 3.76 (2H, d, J=10.5 Hz), 3.97-4.08 (4H, m), 6.72 (1H, d, J=7.8 Hz), 6.78 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.85 (1H, s), 6.98-7.06 (3H, m), 7.24 (1H, t, J=8.1 Hz), 7.61 (1H, s)
1H-NMR (DMSO-d6) δ 1.16 (6H, d, J=5.7 Hz), 2.12 (3H, s), 2.72-2.91 (4H, m), 2.91 (6H, s), 3.12 (2H, brs), 3.49 (2H, s), 3.76 (2H, d, J=10.5 Hz), 3.99 (2H, brs), 6.57-6.61 (1H, m), 6.70-6.77 (3H, m), 6.85 (1H, s), 7.05 (1H, d, J=7.5 Hz), 7.15 (1H, t, J=7.8 Hz), 7.54 (1H, s)
1H-NMR (Acetone) δ: 8.62 (2.0H, s), 7.61-7.59 (2.0H, m), 7.45 (2.0H, dd, J=7.55, 7.55 Hz), 7.37-7.28 (2.0H, m), 7.14 (1.0H, d, J=1.89 Hz), 6.89 (1.0H, dd, J=8.10, 1.89 Hz), 4.64 (2.0H, d, J=11.81 Hz), 4.16 (2.0H, dd, J=6.11, 6.11 Hz), 3.59 (2.0H, s), 3.24 (2.0H, dd, J=6.11, 6.11 Hz), 2.93-2.64 (4.0H, m), 1.25 (6.0H, d, J=6.04 Hz).
1H-NMR (DMSO-d6) δ: 8.69 (2.0H, s), 7.63 (2.0H, d, J=7.42 Hz), 7.45 (2.0H, dd, J=7.42, 7.42 Hz), 7.35 (1.0H, d, J=7.42 Hz), 6.62 (3.0H, s), 4.53 (2.0H, d, J=8.79 Hz), 3.96 (2.0H, dd, J=6.48, 6.48 Hz), 3.45 (2.0H, s), 3.03 (2.0H, dd, J=6.48, 6.48 Hz), 2.67 (4.0H, d, J=7.97 Hz), 2.23 (3.0H, s), 1.14 (6.0H, d, J=4.94 Hz).
1H-NMR (DMSO-d6) δ: 8.65 (2.0H, s), 7.32 (1.0H, d, J=8.23 Hz), 7.23 (1.0H, dd, J=8.10, 8.10 Hz), 7.09 (1.0H, d, J=1.65 Hz), 6.87-6.81 (3.0H, m), 6.72-6.67 (1.0H, m), 4.52 (2.0H, d, J=9.61 Hz), 4.07 (2.0H, dd, J=5.40, 5.40 Hz), 3.55 (2.0H, s), 3.13 (2.0H, dd, J=5.40, 5.40 Hz), 2.93 (6.0H, s), 2.73-2.62 (4.0H, m), 1.18 (6.0H, d, J=6.04 Hz).
To a mixture of 2,6-dimethyl piperazine (10.0 g) in methylene chloride (200 mL) was added di-t-butyldicarbonate (19.1 g) under ice-cooling. After stirring at room temperature for 17 hours, to the reaction solution was added water and extracted with methylene chloride. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the title compound (18.7 g). Yield: 100%.
1H-NMR (CDCl3) δ 1.15 (6H, d, J=6.3), 1.32 (2H, m), 1.49 (9H, s), 2.43 (1H, m), 2.85 (2H, m), 3.99 (1H, m).
A mixture of 3,5-dimethyl carbonyl piperazine-1-carboxylic acid t-butyl ester (18.7 g), potassium carbonate (14.5 g), bromo acetic acid methyl ester (14.7 g), DMF (90 mL) was stirred at 60° C. for 3 hours. To the reaction solution was added water and 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 to give the title compound. This compound was provided to the next reaction without further purification.
3,5-Dimethyl carbonyl piperazine-1-carboxylic acid t-butyl ester derived from the above reaction was dissolved in THF (300 mL) and lithium aluminium hydride (3.31 g) was added thereto under ice-cooling. After stirring at 0° C. for 1 hour, water and 2N aqueous sodium hydroxide solution was sequentially added. After filtration of the insoluble material, the filtrate was concentrated under reduced pressure to give the title compound (20.3 g). Yield: 90%.
A mixture of 4-(2-hydroxyethyl)-3,5-dimethyl piperazine-1-carboxylic acid t-butyl ester (3.0 g), triethylamine (1.76 g), mesyl chloride (1.60 g) and methylene chloride (60 mL) was stirred at under ice-cooling for 1.5 hours. To the reaction solution was added water and 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 dissolved in acetonitrile (60 mL), and (4-chloro-3-hydroxyphenyl)acetic acid methyl ester (2.33 g) and cesium carbonate (4.54 g) were added thereto. The mixture was stirred at 60° C. for 5 hours. After filtration of the insoluble material, the filtrate was concentrated and the obtained residue was purified by column chromatograph on silica gel to give the title compound (3.58 g). Yield: 70%.
1H-NMR (DMSO-d6) δ: 1.09 (6H, d, J=6.0), 1.40 (9H, s), 2.40-2.50 (2H, m), 2.52-2.61 (2H, m), 3.08-3.12 (2H, m), 3.64 (3H, s), 3.71 (2H, 2), 3.77 (2H, m), 4.02-4.09 (2H, m), 6.87 (1H, d, J=8.0), 7.13 (1H, s), 7.37 (1H, d, J=8.0)
A solution of 4-[2-(5-carbonyl methyl-2-chlorophenoxy)ethyl]-3,5-dimethyl piperazine-1-1-carboxylic acid t-butyl ester (400 mg) in 4N hydrochloric acid-dioxane (4 mL) was stirred at room temperature for 2 hours. To the reaction solution were added water and ethyl acetate. The mixture was neutralized with sodium carbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with brine. The solvent was evaporated under reduced pressure to give the title compound (291 mg). Yield: 94%.
1H-NMR (DMSO-d6) δ: 1.02 (3H, d, J=6.3), 2.22-2.29 (2H, m), 2.50-2.54 (2H, m), 2.72-2.76 (2H, m), 3.03-3.07 (2H, m), 4.03-4.07 (2H, m), 6.87 (1H, d, J=8.2), 7.13 (1H, s), 7.37 (1H, d, J=8.2)
A mixture of [4-chloro-3-[2-(2,6-dimethyl piperazine-1-yl)ethoxy]phenyl]acetic acid methyl ester (50 mg), phenylisocyanate (19 mg), potassium carbonate (41 mg) and methylene chloride (2 mL) was stirred at room temperature for 3 hours. After filtration of the insoluble material, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatograph on silica gel to give the title compound (52 m). Yield: 77%.
1H-NMR (DMSO-d6) δ: 1.15 (6H, d, J=5.8), 2.11 (2H, brm), 2.57 (2H, brm), 2.67 (2H, brm), 3.13 (2H, brm), 3.64 (3H, s), 3.71 (2H, s), 4.04-4.09 (2H, m), 6.86-6.97 (2H, m), 7.14 (1H, s), 7.22-7.25 (2H, m), 7.36-7.47 (3H, m), 8.48 (1H, s).
A mixture of [4-chloro-3-[2-(2,6-dimethyl-4-phenyl carbamoyl piperazine-1-yl)ethoxy]phenyl]acetic acid methyl ester (50 mg), 2N sodium hydroxide (0.1 mL) and tetrahydrofuran (1 mL) was stirred at room temperature for 4 hours. After neutralizing with 2N hydrochloric acid, 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 residue was purified by column chromatograph on silica gel to give the title compound (18 mg). Yield: 37%.
1H-NMR (DMSO-d6) δ: 1.12 (6H, d, J=5.8 Hz), 2.42-2.70 (4H, m), 3.06-3.16 (2H, m), 3.56 (2H, s), 3.93-4.11 (4H, m), 6.81-7.47 (6H, m), 8.46 (1H, s).
The following compound was obtained by a similar method as above.
1H-NMR (DMSO-d6) δ: 1.10-1.29 (2H, m), 1.70-1.83 (4H, m), 2.73-2.87 (2H, m), 3.59 (2H, s), 4.07-4.20 (4H, m), 6.83-7.51 (6H, m), 8.46 (1H, s).
To a solution of cis-2,6-dimethyl piperazine (247 mg) in tetrahydrofuran (5 mL) was added n-BuLi (2.67 M hexane solution, 1.62 mL) at −78° C. The mixture was stirred at room temperature for 30 minutes, and trimethyl silyl chloride (0.27 mL) was added thereto. After stirring for 40 minutes, a solution of 2-chloro-6-trifluoromethyl benzothiazole (500 mg) in tetrahydrofuran (2 mL) was added thereto and the mixture was stirred for 2 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium carbonate. The residue was purified by column chromatograph on silica gel to give the title compound (367 mg). Yield: 54%.
1H-NMR (CDCl3) δ: 1.47 (6H, d, J=6.87 Hz), 2.13 (2H, s), 2.91-3.10 (4H, m), 4.14-4.23 (2H, m), 7.51-7.59 (2H, m), 7.85 (1H, s).
A mixture of 2-(2,6-dimethyl piperazine-1-yl)-6-trifluoromethyl benzothiazole (360 mg), (2-bromoethoxy)-t-butyldimethyl silane (257 uL), potassium carbonate (157 mg) and dimethylformamide (2 mL) was stirred at 60° C. for 20 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium carbonate. After evaporating the solvent, the residue was purified by column chromatograph on silica gel to give the title compound (265 mg). Yield: 65%.
1H-NMR (CDCl3) δ: 1.53 (6H, d, J=6.59 Hz), 2.54-2.57 (2H, br m), 2.67-2.70 (2H, br m), 2.80-2.90 (2H, br m), 3.74-3.77 (2H, br m), 4.29-4.32 (2H, br m), 7.52-7.61 (2H, m), 7.87 (1H, s).
To a solution of 2-[3,5-dimethyl-4-(6-trifluoromethylbenzothiazole-2-yl)piperazine-1-yl]ethanol (138 mg) in methylene chloride (3 mL) were added methanesulfonyl chloride (45 μL) and triethylamine (107 μL). The mixture was stirred at room temperature for 1 hour. To the reaction solution was added water and extracted with chloroform. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure. To the obtained residue were added dimethylformamide (2 mL), cesium carbonate (248 mg) and (4-chloro-3-hydroxyphenyl)acetic acid methyl ester (92 mg). The mixture was stirred at 60° C. for 2 hours. To the reaction solution was added 2N hydrochloric acid to neutralize and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulphate. The residue was purified by column chromatograph on silica gel to give the title compound (178 mg). Yield: 89%.
A mixture of [4-chloro-3-[2-[3,5-dimethyl-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1-yl]ethoxy]phenyl]acetic acid methyl ester (178 mg), 2N aqueous sodium hydroxide (0.66 mL), tetrahydrofuran (2 mL) and methanol (2 mL) was stirred at room temperature for 2 hours. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (83 mg). Yield: 48%.
MS (ESI) m/z 528 [M+H]+
The following compound was obtained by a similar method as above.
MS (ESI) m/z 508 [M+H]+
A mixture of 2-(2,6-dimethyl piperazine-1-yl)-6-trifluoromethyl benzothiazole (163 mg), (3-bromomethylphenyl)acetic acid methyl ester (126 mg), potassium carbonate (75 mg) and dimethylformamide (4 mL) was stirred at room temperature for 18 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (171 mg). Yield: 65%.
A mixture of [3-[3,5-dimethyl-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1-ylmethyl]phenyl]acetic acid methyl ester (171 mg), 2N sodium hydroxide (1 mL) and methanol (2 mL) was stirred at room temperature for 1 hour. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (82 mg). Yield: 52%.
MS (ESI) m/z 464 [M+H]+
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 494 [M+H]+
MS (ESI) m/z 475 [M+H]+
MS (ESI) m/z 478 [M+H]+
To a suspension of sodium hydride (4.02 g) in tetrahydrofuran (300 mL) was added phosphonoacetic acid trimethyl at 0° C. After stirring at 0° C. for 1 hours, a solution of 1-Boc-4-piperidone (20 g) in tetrahydrofuran (150 mL) was added thereto. After stirring at 50° C. for 1.5 hours, to the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (27.0 g). Yield: 100%.
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.27-2.29 (2H, m), 2.93-2.94 (2H, m), 3.47-3.51 (4H, m), 3.70 (3H, s), 5.72 (1H, s).
A solution of 4-carboxylmethylene piperidine-1-carboxylic acid t-butyl ester (8.00 g) in 4N hydrochloric acid/dioxane (80 mL) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in dimethylformamide (60 mL). Potassium carbonate (8.65 g) and 2,6-dichlorobenzothiazole (6.39 g) were added thereto at 0° C. After stirring at 50° C. for 1 hour and at 60° C. for 3 hours, water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (9.48 g). Yield: 94%.
1H-NMR (CDCl3) δ: 2.47-2.49 (2H, m), 3.14-3.19 (2H, m), 3.72 (3H, s), 3.70-3.77 (4H, m), 5.81 (1H, s), 7.25 (1H, dd, J=8.5, 2.2 Hz), 7.46 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=2.2 Hz).
Copper iodide (1.77 g) was suspended in tetrahydrofuran (18 mL), and ethyl magnesium bromide (1.0 M tetrahydrofuran solution, 18.6 mL) was added thereto at −30° C. After stirring at −25° C. for 0.5 hour, the reaction solution was cooled to −78° C. To the mixture was added dropwise a solution of [1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylidene]acetic acid methyl ester (1.00 g) in tetrahydrofuran (10 mL), and then added trimethylsilyl trifluoromethansulfonate (1.12 mL). After stirring at −78° C. for 2 hours, aqueous sodium hydrogencarbonate solution was added thereto. After filtration of the insoluble material, the filtrate 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 and the residue was purified by column chromatograph on silica gel to give the title compound (979 mg). Yield: 90%.
1H-NMR (CDCl3) δ: 0.93 (3H, t, J=7.6 Hz), 1.67-1.75 (6H, m), 2.42 (2H, s), 3.57-3.68 (4H, m), 3.70 (3H, s), 7.26 (1H, dd, J=8.5, 2.2 Hz), 7.47 (1H, d, J=8.5 Hz), 7.58 (1H, d, J=2.2 Hz).
Lithium aluminium hydride (202 mg) was suspended in tetrahydrofuran (10 mL). A solution of [1-(6-chlorobenzothiazole-2-yl)-4-ethyl piperidine-4-yl]acetic acid methyl ester (940 mg) in tetrahydrofuran (10 mL) was added thereto at 0° C. After stirring at 0° C. for 1 hour, to the reaction solution were sequentially added water (0.2 mL), 10% sodium hydroxide (0.2 mL) and water (0.6 mL). The insoluble material was filtrated and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (790 mg). Yield: 91%.
1H-NMR (CDCl3) δ: 0.87 (3H, t, J=7.5 Hz), 1.44 (2H, q, J=7.5 Hz), 1.58-1.60 (4H, m), 1.68 (2H, t, J=7.5 Hz), 1.81 (1H, br), 3.60-3.62 (4H, m), 3.71-3.74 (2H, m), 7.23 (1H, dd, J=8.8, 2.2 Hz), 7.44 (1H, d, J=8.8 Hz), 7.55 (1H, d, J=2.2 Hz).
A mixture of 2-[1-(6-chlorobenzothiazole-2-yl)-4-ethyl piperidine-4-yl]ethanol (764 mg) and thionyl chloride (4 mL) were stirred at 60° C. for 1.5 hours. To the reaction solution was added ice and extracted with ethyl acetate. The organic layer was washed with sodium hydrogencarbonate and brine and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (739 mg). Yield: 92%.
1H-NMR (CDCl3) δ: 0.91 (3H, t, J=7.6 Hz), 1.47 (2H, q, J=7.6 Hz), 1.60-1.63 (4H, m), 1.92-1.94 (2H, m), 3.53-3.56 (2H, m), 3.62-3.65 (4H, m), 7.26 (1H, dd, J=8.5, 2.2 Hz), 7.47 (1H, d, J=8.5 Hz), 7.58 (1H, d, J=2.2 Hz).
A mixture of 6-chloro-2-[4-(2-chloroethyl)-4-ethyl piperidine-1-yl]benzothiazole (150 mg), (4-chloro-3-hydroxyphenyl)acetic acid methyl ester (176 mg), cesium carbonate (285 mg) and dimethylformamide (2 mL) was stirred at 75° C. for 24 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (174 mg). Yield: 79%.
1H-NMR (CDCl3) δ: 0.94 (3H, t, J=7.6 Hz), 1.52-1.78 (8H, m), 3.59 (2H, s), 3.60-3.63 (2H, m), 3.68-3.70 (2H, m), 3.72 (3H, s), 4.09-4.18 (2H, m), 6.80-6.88 (2H, m), 6.98-6.98 (1H, m), 7.27-7.32 (1H, m), 7.48 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=1.9 Hz).
A mixture of [4-Chloro-3-[2-[1-(6-chlorobenzothiazole-2-yl)-4-ethyl piperidine-4-yl]ethoxy]phenyl]acetic acid methyl ester (152 mg), 2N aqueous sodium hydroxide (0.45 mL), tetrahydrofuran (1 mL) and methanol (1 mL) was stirred at room temperature for 2 hours. The reaction solution was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (53 mg). Yield: 36%.
MS (ESI) m/z 493 [M+H]+
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 479 [M+H]+
MS (ESI) m/z 459 [M+H]+
MS (ESI) m/z 507 [M+H]+
MS (ESI) m/z 547 [M+H]+
MS (ESI) m/z 564 [M+H]+
1H-NMR (Acetone-d6) δ: 8.65 (1H, s), 7.60-7.63 (2H, m), 7.48 (2H, t, J=7.55 Hz), 7.36 (1H, t, J=7.55 Hz), 7.20-7.25 (1H, m), 6.97 (1H, s), 6.84-6.87 (2H, m), 4.19-4.27 (2H, m), 4.14 (2H, t, J=7.42 Hz), 3.65-3.72 (2H, m), 3.62 (2H, s), 2.05-2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).
1H-NMR (Acetone-d6) δ: 8.65 (1H, s), 7.62-7.65 (2H, m), 7.48 (2H, t, J=7.55 Hz), 7.36 (1H, t, J=7.55 Hz), 6.76 (1H, s), 6.72 (2H, s), 4.19-4.27 (2H, m), 4.14 (2H, t, J=7.42 Hz), 3.65-3.72 (2H, m), 3.62 (2H, s), 2.25 (3H, s), 2.05-2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).
1H-NMR (Acetone) δ: 8.65 (1H, s), 7.62-7.65 (2H, m), 7.48 (2H, t, J=7.55 Hz), 7.36 (1H, t, J=7.55 Hz), 6.76 (1H, s), 6.72 (2H, s), 4.19-4.27 (2H, m), 4.14 (2H, t, J=7.42 Hz), 3.65-3.72 (2H, m), 3.62 (2H, s), 2.05-2.10 (2H, m), 1.57-1.79 (7H, m), 0.96-1.00 (6H, m).
MS (ESI) m/z 547 [M+H]+
1H-NMR (CDCl3) δ: 0.87-1.98 (15H, m), 3.44-3.78 (6H, m), 4.03 (3H, t, J=7.1 Hz), 6.78-7.45 (7H, m), 7.54 (1H, d, J=1.9 Hz).
1H-NMR (CDCl3) δ: 0.83-1.99 (15H, m), 2.30 (3H, s), 3.47-3.79 (6H, m), 4.02 (2H, t, J=7.1 Hz), 6.62 (2H, s), 6.69 (1H, s), 7.22-7.26 (1H, m), 7.46 (1H, d, J=9.1 Hz), 7.54 (1H, d, J=2.2 Hz).
1H-NMR (CDCl3) δ: 7.42 (1.0H, s), 7.29-7.24 (1.0H, m), 7.17 (1.0H, ddd, J=7.97, 1.30, 1.30 Hz), 7.10 (1.0H, ddd, J=9.89, 2.13, 2.13 Hz), 6.93-6.85 (2.0H, m), 6.80 (1.0H, dd, J=1.92, 1.92 Hz), 6.72 (1.0H, dd, J=1.79, 1.79 Hz), 4.03 (2.0H, dd, J=7.14, 7.14 Hz), 3.67-3.57 (4.0H, m), 3.47-3.39 (2.0H, m), 1.93 (2.0H, dd, J=7.14, 7.14 Hz), 1.82-1.77 (2.0H, m), 1.67-1.54 (4.0H, m), 1.50-1.42 (1.0H, m), 0.98-0.90 (6.0H, m).
1H-NMR (CDCl3) δ: 7.42 (1.0H, s), 7.30 (1.0H, dd, J=5.63, 2.06 Hz), 7.17 (1.0H, d, J=8.79 Hz), 7.12-7.07 (1.0H, m), 6.92-6.85 (1.0H, m), 6.69 (1.0H, s), 6.63 (2.0H, d, J=4.67 Hz), 4.04 (2.0H, dd, J=7.00, 7.00 Hz), 3.68-3.57 (4.0H, m), 3.47-3.39 (2.0H, m), 2.31 (3.0H, s), 1.95-1.54 (8.0H, m), 1.49-1.42 (1.0H, m), 0.97-0.90 (6.0H, m).
1H-NMR (Acetone) δ: 7.60 (1.0H, d, J=1.65 Hz), 7.42-7.33 (1.0H, m), 7.30-7.18 (3.0H, m), 6.99-6.92 (2.0H, m), 6.89-6.83 (2.0H, m), 4.15-4.09 (2.0H, m), 3.72-3.47 (6.0H, m), 1.85-1.56 (6.0H, m), 1.31-1.27 (3.0H, m), 0.99-0.92 (6.0H, m).
1H-NMR (DMSO-d6) δ 1.25 (2H, br), 1.46-1.64 (10H, m), 1.94 (2H, t, J=6.9 Hz), 2.12 (1H, m), 3.43-3.52 (2H, m), 3.56 (2H, s), 3.70-3.80 (2H, br), 4.02 (3H, 2H, J=6.9 Hz), 6.83 (1H, s), 6.90 (1H, s), 6.96 (1H, s), 7.25-7.29 (1H, m), 7.40 (1H, d, J=8.7 Hz), 7.89 (1H, d, J=2.4 Hz)
A mixture of 2,6-dichlorobenzothiazole (2.00 g), 2-(trifluoroacetamide)pyrrolidine hydrochloride (2.14 g), potassium carbonate (4.06 g) and dimethylformamide (15 mL) was stirred at 60° C. for 2 hours. To the reaction solution was added water and 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 and the residue was washed with n-hexane. The obtained purified product was dissolved in tetrahydrofuran (20 mL) and methanol (10 mL). 2N sodium hydroxide was added thereto and the mixture was stirred for 2.5 hours. The solvent was evaporated under reduced pressure. Water was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give the title compound (2.49 g). Yield: 100%.
1H-NMR (DMSO-d6) δ: 1.72-1.80 (2H, m), 3.45-3.63 (5H, m), 7.26 (1H, dd, H=2.0, 8.0), 7.41 (1H, d, J=8.5), 7.88 (1H, d, J=2.0)
A mixture of 1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamine (2.49 g), 2-nitrobenzenesulphonyl chloride (2.40 g), triethylamine (3.02 mL) and dimethylformamide (15 mL) was stirred at 60° C. for 3 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (2.01 g). Yield: 47
1H-NMR (DMSO-d6) δ: 1.99-2.03 (1H, m), 2.19-2.23 (1H, m), 3.55-3.63 (4H, m), 4.07-4.09 (1H, m), 7.30 (1H, dd, J=8.5, 2.2 Hz), 7.45 (1H, d, J=8.8 Hz), 7.90-7.94 (3H, m), 8.01-8.10 (2H, m).
N-[1(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]-2-nitrobenzenesulfonamide (500 mg) was dissolved in dimethylformamide (5 mL). Sodium hydride (60%, oil, 50 mg) was added thereto and the mixture was stirred at room temperature for 1 hour. (3-bromomethylphenyl)acetic acid methyl ester (305 mg) was added thereto and the mixture was stirred for 16 hours. To the reaction solution was added water and 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 and the residue was purified by column chromatograph on silica gel to give the title compound (412 mg). Yield: 60%.
1H-NMR (CDCl3) δ: 2.11-2.19 (1H, m), 2.34-2.37 (1H, m), 3.53-3.59 (6H, m), 3.69 (3H, s), 3.78-3.81 (1H, m), 4.53-4.63 (2H, m), 7.07-7.19 (4H, m), 7.25-7.32 (1H, m), 7.50-7.58 (3H, m), 7.65-7.67 (2H, m), 7.85 (1H, d, J=7.7 Hz).
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]-(2-nitrobenzensulphonyl)amino]methyl]phenyl]acetic acid methyl ester (412 mg), mercaptoacetic acid (95 mL), 1,8-diazabicyclo [5,4,0]-7-undecene (4 mL) and dimethylformamide (4 mL) was stirred at room temperature for 1 hour. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (204 mg). Yield: 71%.
1H-NMR (CDCl3) δ: 2.11-2.14 (1H, m), 2.27-2.32 (1H, m), 3.49-3.59 (2H, m), 3.63 (2H, s), 3.70 (3H, s), 3.74-3.82 (2H, m), 3.89 (2H, s), 7.23 (2H, dd, J=8.5, 2.2 Hz), 7.31-7.33 (3H, m), 7.45 (1H, d, J=8.5 Hz), 7.46 (1H, s), 7.54 (1H, d, J=2.2 Hz), 8.02 (1H, brs).
A mixture of [3-[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamino]methyl]phenyl]acetic acid methyl ester (68 mg), 1-iodobutane (37 μL), potassium carbonate (45 mg) and dimethylformamide (1 mL) was stirred at 80° C. for 3.5 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The residue was purified by column chromatograph on silica gel to give the title compound (28 mg). Yield: 36%.
1H-NMR (CDCl3) δ: 0.90 (3H, t, J=7.3 Hz), 1.24-1.36 (2H, m), 1.47-1.50 (2H, m), 2.54-2.56 (2H, m), 3.51-3.71 (14H, m), 7.21-7.29 (5H, m), 7.50 (1H, d, J=8.8 Hz), 7.58 (1H, d, J=2.2 Hz).
A mixture of [3-[[butyl[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]amino]methyl]phenyl]acetic acid methyl ester (28 mg), 2N sodium hydroxide (0.15 mL), tetrahydrofuran (1 mL) and methanol (0.5 mL) was stirred at room temperature for 1 hour. The mixture was neutralized with 2N hydrochloric acid and concentrated under reduced pressure. The solution was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate to give the title compound (19 mg). Yield: 68%.
MS (ESI) m/z 458 [M+H]+
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 430 [M+H]+
MS (ESI) m/z 416 [M+H]+
MS (ESI) m/z 480 [M+H]+
MS (ESI) m/z 402 [M+H]+
A mixture of 4-Boc-amino piperidine (3.23 g), 2,6-dichlorobenzothiazole (3.29 g), potassium carbonate (6.68 g) and dimethylformamide (20 mL) was stirred at 60° C. for 16 hours. Water was added to the reaction solution. The precipitate was collected and the obtained title compound was provided to the next reaction without purification.
[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]carbamic acid tert-butyl ester obtained from the above reaction was dissolved in chloroform. 4N solution of hydrochloric acid/dioxane was added thereto and the mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure. Water was added thereto and washed with ethyl acetate. The water layer was neutralized with 2N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with magnesium sulphate and the solvent was evaporated under reduced pressure to give the title compound (3.31 g). Yield: 77%.
1H-NMR (DMSO-d6) δ: 1.24-1.33 (4H, m), 3.20-3.30 (3H, m), 3.90-3.95 (2H, m), 7.27 (1H, dd, J=8.5, 2.2 Hz), 7.40 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=2.2 Hz).
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (500 mg), (3-bromomethylphenyl)acetic acid methyl ester (454 mg), potassium carbonate (284 mg) and dimethylformamide (6 mL) was stirred at room temperature for 1 hour. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (434 mg). Yield: 55%.
A mixture of [3-[[1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamino]methyl]phenyl]acetic acid methyl ester (110 mg), methyl iodide (800 mg), potassium carbonate (71 mg) and dimethylformamide (2 mL) was stirred at 80° C. for 5 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (65 mg). Yield: 56%.
1H-NMR (CDCl3) δ: 1.03-1.07 (3H, br m), 1.63-1.66 (2H, br m), 1.89-1.92 (2H, br m), 2.58-2.62 (1H, br m), 2.91 (2H, s), 2.98 (2H, s), 3.09-3.13 (2H, m), 3.64-3.67 (2H, br m), 3.71 (3H, s), 4.20-4.23 (2H, br m), 7.25-7.28 (5H, m), 7.44 (1H, d, J=8.5 Hz), 7.57 (1H, d, J=10.0 Hz).
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]ethylamino]methyl]phenyl]acetic acid methyl ester (65 mg), 2N sodium hydroxide (0.36 mL), tetrahydrofuran (1 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. The solution was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the obtained residue was washed with the mixed solvent of ethyl acetate and n-hexane to give the title compound (19 mg). Yield: 30%.
MS (ESI) m/z 444 [M+H]+
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 472 [M+H]+
MS (ESI) m/z 472 [M+H]+
MS (ESI) m/z 494 [M+H]+
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (335 mg), acetone (92 ul), acetic acid (0.1 mL) and methanol (3 mL) was stirred at room temperature for 5 minutes. To the reaction solution was added triacetoxy sodium boron hydride (332 mg). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. Aqueous sodium hydrogencarbonate was added thereto and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (160 mg). Yield: 41%.
1H-NMR (CDCl3) δ: 1.11 (6H, d, J=6.3 Hz), 1.48-1.51 (2H, m), 2.01-2.05 (2H, m), 2.84-2.91 (1H, m), 3.00-3.08 (1H, m), 3.14-3.24 (2H, m), 4.08-4.16 (2H, m), 7.23 (1H, dd, J=8.5, 2.2 Hz), 7.42 (1H, d, J=8.5 Hz), 7.55 (1H, d, J=2.2 Hz).
A mixture of [1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]isopropylamine (159 mg), (3-bromomethylphenyl)acetic acid methyl ester (138 mg), potassium carbonate (107 mg) and dimethylformamide (2 mL) was stirred at 80° C. for 8 hours. To the reaction solution was added water and 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 and the residue was purified by column chromatograph on silica gel to give the title compound (90 mg). Yield: 37%.
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]isopropylamino]methyl]phenyl]acetic acid methyl ester (90 mg), 2N sodium hydroxide (0.5 mL), tetrahydrofuran (2 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. After neutralizing with 2N hydrochloric acid, the reaction solution was concentrated under reduced pressure and 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 and the residue was purified by column chromatograph on silica gel to give the title compound (28 mg).
Yield: 32%.
MS (ESI) m/z 458 [M+H]+
A mixture of 1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamine (190 mg), [3-(2-bromoethoxy)phenyl]acetic acid methyl ester (205 mg) and potassium carbonate (114 mg) was stirred at 80° C. for 2 hours. To the reaction solution, was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (174 mg). Yield: 52%.
1H-NMR (CDCl3) δ: 2.01-2.06 (1H, m), 2.31-2.36 (1H, m), 3.09 (2H, t, J=4.9 Hz), 3.48-3.50 (1H, m), 3.62 (2H, s), 3.64-3.80 (4H, m), 3.72 (3H, s), 4.12 (2H, t, J=4.9 Hz), 6.83-6.91 (3H, m), 7.24-7.28 (3H, m), 7.50 (1H, d, J=8.5 Hz), 7.59 (1H, d, J=1.9 Hz).
A mixture of [3-[2-[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamino]ethoxy]phenyl]acetic acid methyl ester (174 mg), ethyl iodide (68 uL), potassium carbonate (81 mg) and dimethylformamide (2 mL) was stirred at 80° C. for 6.5 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (101 mg). Yield: 55%.
1H-NMR (CDCl3) δ: 1.14 (3H, t, J=6.7 Hz), 2.08-2.11 (1H, m), 2.29-2.32 (1H, m), 2.79-2.81 (2H, m), 2.98-3.03 (2H, m), 3.46-3.86 (5H, m), 3.62 (2H, s), 3.71 (3H, s), 4.05-4.08 (2H, m), 6.82-6.90 (3H, m), 7.23-7.29 (2H, m), 7.50 (1H, d, J=8.8 Hz), 7.59 (1H, d, J=1.9 Hz).
A mixture of [3-[2-[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]ethylamino]ethoxy]phenyl]acetic acid methyl ester (101 mg), 2N aqueous sodium hydroxide (0.535 mL), tetrahydrofuran (1 mL) and methanol (0.5 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was washed with ethyl acetate/n-hexane to give the title compound (13 mg). Yield: 14%.
MS (ESI) m/z 459 [M+H]+
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 487 [M+H]+
MS (ESI) m/z 473 [M+H]+
MS (ESI) m/z 516 [M+H]+
MS (ESI) m/z 548 [M+H]+
MS (ESI) m/z 528 [M+H]+
MS (ESI) m/z 508 [M+H]+
A mixture of 1-benzyl-4-piperidone (3 mL), pyrrolidine (6.95 mL) and toluene (30 mL) was refluxed for 1 hour. The solvent was evaporated under reduced pressure. To the residue was added acetic acid (0.96 mL). The mixture was stirred at room temperature for 5 minutes. To the reaction solution were added zinc (1.37 g) and bromo acetic acid methyl ester (2.17 mL). The mixture was stirred at room temperature for 2 hours. To the reaction solution was added aqueous sodium carbonate solution (20 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (2.77 g). Yield: 52%.
1H-NMR (CDCl3) δ: 1.71-1.73 (4H, m), 1.81-1.84 (4H, m), 2.45-2.56 (10H, m), 3.55-3.58 (2H, m), 3.69 (3H, s), 7.26-7.36 (5H, m).
Lithium aluminium hydride (324 mg) was suspended in tetrahydrofuran (25 mL). A solution of (1-benzyl-4-pyrrolidine-1-ylpiperidine-4-yl)acetic acid methyl ester (2.70 g) in tetrahydrofuran (25 mL) was added thereto at 0° C. After stirring at 0° C. for 1 hour, to the reaction solution were sequentially added with water (0.35 mL), 10% aqueous sodium hydroxide (0.35 mL) and water (1.05 mL). The insoluble material was filtrated and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give the title compound. The obtained objective substance was provided to the next reaction without further purification.
1H-NMR (CDCl3) δ: 1.74-1.76 (6H, m), 1.89-1.94 (4H, m), 2.06-2.17 (2H, m), 2.80-2.83 (6H, m), 3.54 (3H, s), 3.85-3.87 (2H, m), 7.33 (5H, t, J=3.6 Hz).
2-(1-Benzyl-4-pyrrolidine-1-ylpiperidine-4-yl) ethanol obtained above was dissolved in methanol (60 mL). Pd/C (600 mg) was added thereto and the mixture was stirred under a hydrogen atmosphere for 19 hours. The insoluble material was filtrated and the filtrate was concentrated under reduced pressure. To the obtained residue were added dimethylformamide (30 mL), potassium carbonate (1.24 g) and 2,6-dichlorobenzothiazole (1.83 g). The mixture was stirred at 60° C. for 21 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (2.58 g).
Yield: 83%.
1H-NMR (CDCl3) δ: 1.83-1.86 (4H, m), 2.00-2.01 (6H, m), 2.91-2.98 (4H, m), 3.29-3.38 (2H, m), 3.92-4.05 (4H, m), 7.26 (1H, d, J=2.2 Hz), 7.45 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=2.2 Hz).
A mixture of 2-[1-(6-chlorobenzothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethanol (1.60 g), tri-n-butylphosphine (1.15 mL), 1,1′-(azodicarbonyl)dipiperidine (1.16 g) and tetrahydrofuran (25 mL) was stirred at room temperature for 1 hour. The insoluble material was filtrated. To the filtrate was added aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (874 mg).
Yield: 36%.
1H-NMR (CDCl3) δ: 1.77-1.81 (6H, m), 1.94-2.03 (4H, m), 2.69-2.72 (4H, m), 3.53-3.77 (4H, m), 3.56 (2H, s), 3.72 (3H, s), 4.01 (2H, m), 6.75-6.84 (3H, m), 7.25 (1H, dd, J=8.7, 2.1 Hz), 7.44 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=2.2 Hz).
A mixture of [3-chloro-5-[2-[1-(6-chlorobenzothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethanol]phenyl]acetic acid methyl ester (851 mg), 2N sodium hydroxide (2.33 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at room temperature for 0.5 hour. The mixture was neutralized with 2N hydrochloric acid and 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 and the residue was washed with hexane to give the title compound (725 mg). Yield: 88%.
MS (ESI) m/z 534 [M+H]+
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 568 [M+H]+
MS (ESI) m/z 534 [M+H]+
MS (ESI) m/z 568 [M+H]+
MS (ESI) m/z 520 [M+H]+
MS (ESI) m/z 548 [M+H]+
MS (ESI) m/z 582 [M+H]+
MS (ESI) m/z 582 [M+H]+
MS (ESI) m/z 514 [M+H]+
MS (ESI) m/z 514 [M+H]+
MS (ESI) m/z 584 [M+H]+
MS (ESI) m/z 584 [M+H]+
MS (ESI) m/z 550 [M+H]+
MS (ESI) m/z 612 [M+H]+
MS (ESI) m/z 612 [M+H]+
MS (ESI) m/z 612 [M+H]+
MS (ESI) m/z 612 [M+H]+
MS (ESI) m/z 578 [M+H]+
MS (ESI) m/z 578 [M+H]+
1H-NMR (CDCl3) δ: 1.08 (6H, t, J=7.1 Hz), 1.65-1.77 (2H, m), 1.92-2.05 (4H, m), 2.65 (4H, q, J=7.1 Hz), 3.54-3.77 (6H, m), 4.01 (2H, t, J=6.6 Hz), 6.70 (1H, s), 6.78 (1H, s), 6.87 (1H, s), 7.22 (1H, dd, J=8.5, 2.2 Hz), 7.43 (1H, d, J=8.5 Hz), 7.54 (1H, d, J=2.2 Hz).
1H-NMR (CDCl3) δ: 1.07 (6H, t, J=7.0 Hz), 1.70-2.10 (6H, m), 2.66 (4H, q, J=7.0 Hz), 3.56-3.79 (6H, m), 4.05-4.13 (2H, m), 6.76-6.85 (2H, m), 7.19-7.30 (2H, m), 7.42 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=1.6 Hz).
1H-NMR (CDCl3) δ: 1.08 (3H, t, J=6.9 Hz), 1.64-2.03 (6H, m), 2.26 (3H, s), 2.53 (2H, q, J=6.9 Hz), 3.52-3.68 (6H, m), 3.96-4.03 (2H, m), 6.68-6.88 (3H, m), 7.22 (1H, dd, J=8.5, 2.2 Hz), 7.43 (1H, d, J=8.8 Hz), 7.54 (1H, d, J=2.2 Hz).
1H-NMR (CDCl3) δ: 1.05 (3H, t, J=7.1 Hz), 1.64-2.03 (6H, m), 2.23 (3H, s), 2.44-2.56 (2H, m), 3.45-3.68 (6H, m), 3.98-4.08 (2H, m), 6.68-6.85 (2H, m), 7.18-7.25 (2H, m), 7.41 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=1.4 Hz).
1H-NMR (CDCl3) δ: 1.08 (3H, t, J=7.1 Hz), 1.64-2.06 (6H, m), 2.26 (3H, s), 2.52 (2H, q, J=7.1 Hz), 3.56 (2H, s), 3.60-3.80 (4H, m), 4.00 (2H, t, J=6.7 Hz), 6.68-6.89 (3H, m), 7.49-7.58 (2H, m), 7.83 (1H, s).
1H-NMR (CDCl3) δ: 1.07 (3H, t, J=6.9 Hz), 1.70-2.07 (6H, m), 2.25 (3H, s), 2.52 (2H, q, J=6.9 Hz), 3.53 (2H, s), 3.59-3.76 (5H, m), 4.03-4.10 (2H, m), 6.74-6.84 (2H, m), 7.23-7.28 (1H, m), 7.47-7.57 (2H, m), 7.82 (1H, s).
1H-NMR (CDCl3) δ: 7.54 (1.0H, d, J=1.92 Hz), 7.42 (1.0H, d, J=8.79 Hz), 7.31-7.29 (1.0H, m), 7.24-7.21 (1.0H, m), 6.85-6.79 (2.0H, m), 4.09 (2.0H, dd, J=7.14, 7.14 Hz), 3.78-3.58 (6.0H, m), 2.79-2.73 (4.0H, br m), 2.10-1.52 (14.0H, m).
1H-NMR (CDCl3) δ: 7.54 (1.0H, d, J=2.20 Hz), 7.43 (1.0H, d, J=8.24 Hz), 7.25-7.20 (1.0H, m), 6.87 (1.0H, s), 6.78 (1.0H, s), 6.70 (1.0H, s), 3.99 (2.0H, dd, J=7.00, 7.00 Hz), 3.77-3.56 (6.0H, m), 2.76-2.72 (4.0H, m), 2.13-1.91 (10.0H, m), 1.73-1.56 (4.0H, m).
1H-NMR (CDCl3) δ: 7.53 (1.0H, d, J=1.92 Hz), 7.41 (1.0H, d, J=8.79 Hz), 7.26-7.20 (2.0H, m), 6.86 (1.0H, s), 6.76 (1.0H, d, J=8.52 Hz), 4.17-4.10 (2.0H, m), 3.92-3.84 (1.0H, m), 3.81-3.40 (4.0H, m), 3.33-3.24 (2.0H, m), 2.97-2.89 (1.0H, m), 2.76-2.66 (1.0H, m), 2.19-1.61 (8.0H, m), 1.54-1.42 (2.0H, m), 1.04 (3.0H, d, J=6.30 Hz).
MS (ESI) m/z 548 [M+H]+
MS (ESI) m/z 525 [M+H]+
1H-NMR (CDCl3) δ: 7.83 (1.0H, d, J=1.24 Hz), 7.55 (1.0H, d, J=8.51 Hz), 7.50 (1.0H, dd, J=8.78, 1.24 Hz), 7.30 (1.0H, d, J=8.10 Hz), 6.85 (1.0H, d, J=1.78 Hz), 6.80 (1.0H, dd, J=8.10, 1.78 Hz), 4.15-4.10 (2.0H, m), 3.79-3.61 (6.0H, m), 3.47 (2.0H, t, J=6.45 Hz), 3.36 (3.0H, s), 2.71 (4.0H, t, J=6.45 Hz), 2.07-1.98 (4.0H, m), 1.82-1.71 (2.0H, m).
1H-NMR (CDCl3) δ: 7.83 (1.0H, d, J=0.89 Hz), 7.56 (1.0H, d, J=8.85 Hz), 7.51 (1.0H, dd, J=8.85, 0.89 Hz), 6.88-6.87 (1.0H, m), 6.79 (1.0H, dd, J=1.92, 0.96 Hz), 6.71-6.69 (1.0H, m), 4.02 (2.0H, t, J=6.31 Hz), 3.79-3.63 (4.0H, m), 3.57 (2.0H, s), 3.46 (2.0H, t, J=6.24 Hz), 3.35 (3.0H, s), 2.68 (3.0H, t, J=6.24 Hz), 2.31 (3.0H, s), 2.07-1.91 (4.0H, m), 1.77-1.64 (2.0H, m).
A mixture of 2-(1-benzyl-4-pyrrolidine-1-ylpiperidine-4-yl)ethanol (9.28 g), 10% Pd/C (1.86 g) and methanol (100 mL) was stirred under hydrogen (4 atm) for 3 days. The insoluble material was filtrated and the filtrate was concentrated to give the title compound (6.30 g).
Yield: 99%.
1H-NMR (DMSO-d6) δ: 1.76-1.79 (6H, m), 1.88-1.91 (4H, m), 2.77-2.80 (4H, m), 3.02-3.05 (2H, br m), 3.15-3.18 (2H, br m), 3.53-3.55 (2H, br m).
A mixture of 2-(4-pyrrolidine-1-ylpiperidine-4-yl)ethanol (4.11 g), 2,5-dibromothiazole (5.03 g), potassium carbonate (3.43 g) and dimethylformamide (75 mL) was stirred at 60° C. for 16 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and washed with magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (3.88 g). Yield: 52%.
A mixture of 2-[1-(5-bromothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethanol (1.30 g), (3-chloro-5-hydroxy phenyl)acetic acid (796 mg), tri-n-butylphosphine (0.99 mL), 1,1′-(azodicarbonyl)dipiperidine (1.00 g) and tetrahydrofuran (20 mL) was stirred at room temperature for 4 hours. To the reaction solution was added water and 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 and the residue was purified by column chromatograph on silica gel to give the title compound (1.45 g). Yield: 74%.
1H-NMR (CDCl3) δ: 1.71-1.85 (8H, m), 2.09-2.10 (2H, m), 2.69-2.71 (4H, br m), 3.48-3.53 (4H, m), 3.61 (2H, s), 3.71 (3H, s), 4.12-4.16 (2H, m), 6.83 (2H, dd, J=8.0, 2.2 Hz), 7.07 (1H, d, J=2.2 Hz), 7.31 (1H, d, J=8.0 Hz).
A mixture of [3-[2-[1-(5-bromothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethoxy]-5-chlorophenyl]acetic acid methyl ester (1.45 g), 2N sodium hydroxide (3.3 mL), tetrahydrofuran (15 mL) and methanol (15 mL) was stirred at room temperature for 3 hours. To the reaction solution was added water and washed with chloroform. The water layer was neutralized with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (916 mg). Yield: 65%.
1H-NMR (DMSO-d6) δ: 1.75-1.89 (10H, m), 2.64-2.67 (4H, m), 3.33-3.36 (2H, m), 3.34 (2H, s) 3.51-3.55 (2H, m), 4.11-4.14 (2H, m), 6.85 (1H, dd, J=7.8, 2.1 Hz), 7.10 (1H, d, J=2.1 Hz), 7.19 (1H, s), 7.34 (1H, d, J=7.8 Hz).
A mixture of [3-[2-[1-(5-bromothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethoxy]-5-chlorophenyl]acetic acid (60 mg), 3-fluorophenyl boronic acid (32 mg), tetrakis (triphenylphosphine) palladium (13 mg), 1M sodium carbonate (0.55 mL) and dimethylformamide (1 mL) was reacted with a microwave reaction device at 180° C. for 5 minutes. The insoluble material was filtrated. To the filtrate was added formic acid. The solvent was evaporated under reduced pressure and the residue was purified by high performance liquid chromatography to give the title compound (14.4 mg). Yield: 24%.
1H-NMR (DMSO-d6)) δ: 8.18 (1H, s), 7.69 (1H, s), 7.39-7.26 (3H, m), 7.01 (1H, m), 6.90 (1H, d, J=10.8 Hz), 6.82 (1H, s), 4.53 (2H, m), 3.58-3.54 (4H, m), 2.64 (2H, s), 1.94-1.69 (8H, m)
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 584[M+]
MS (ESI) m/z 586 [M+]
MS (ESI) m/z 569[M+]
MS (ESI) m/z 584 [M+]
MS (ESI) m/z 586 [M+]
MS (ESI) m/z 569 [M+]
MS (ESI) m/z 546 [M+H]+
1H-NMR (DMSO-d6)) d: 8.18 (1H, s), 7.69 (1H, s), 7.39-7.26 (3H, m), 7.01 (1H, m), 6.90 (1H, d, J=10.8 Hz), 6.82 (1H, s), 4.53 (2H, m), 3.58-3.54 (4H, m), 2.64 (2H, s), 1.94-1.69 (8H, m).
MS (ESI) m/z 540 [M+H]+
1H-NMR (CDCl3) δ 2.93-3.18 (4H, m), 3.29 (1H, td, J=12.0, 3.2 Hz), 3.35-3.42 (1H, m), 3.39 (3H, s), 3.48 (1H, dd, J=9.2, 3.6 Hz), 3.91 (1H, d, J=12.0 Hz), 3.99 (1H, d, J=12.0 Hz), 7.24 (1H, dd, J=8.8, 2.4 Hz), 7.44 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=2.4 Hz).
1H-NMR (CDCl3) δ 1.22 (3H, t, J=7.2 Hz), 2.92-3.02 (2H, m), 3.04-3.11 (1H, m), 3.12-3.17 (1H, m), 3.26 (1H, td, J=12.0, 3.2 Hz), 3.39 (1H, dd, J=9.2, 7.2 Hz), 3.48-3.59 (3H, m), 3.91 (1H, brd, J=12.0 Hz), 3.98 (1H, brd, J=12.0 Hz), 7.24 (1H, dd, J=8.8, 2.0 Hz), 7.44 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=2.0 Hz).
TLC Rf 0.13 (MeOH—CHCl3, 1:10)
mp 109-112
mp 92-98
TLC Rf 0.15 (MeOH—CHCl3, 1:10)
TLC Rf 0.23 (MeOH—CHCl3, 1:10)
Rf 0.12 (MeOH—CHCl3, 1:10)
Rf 0.24 (MeOH—CHCl3, 1:10)
MS (ESI) m/z 480 [M+H]+
MS (ESI) m/z 480 [M+H]+
MS (ESI) m/z 479 [M+H]+
MS (ESI) m/z 514, 516 [M+H]+
MS (ESI) m/z 514, 516 [M+H]+
MS (ESI) m/z 494 [M+H]+
MS (ESI) m/z 494 [M+H]+
MS (ESI) m/z 528, 530 [M+H]+
MS (ESI) m/z 528, 530 [M+H]+
MS (ESI) m/z 508 [M+H]+
MS (ESI) m/z 508 [M+H]+
MS (ESI) m/z 480 [M+H]+
1H-NMR (300 MHz, CDCl3): 1.46 (3H, d, J=6.9 Hz), 2.53-2.60 (1H, m), 2.73-2.77 (1H, m), 3.06 (2H, s), 3.16-3.20 (1H, m), 3.27-3.31 (1H, m), 3.55-3.60 (1H, m), 3.60 (2H, s), 3.89-3.94 (1H, m), 4.29 (3H, m), 6.84 (1H, d, J=8.1 Hz), 6.87 (1H, s), 7.25 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.31 (1H, d, J=8.1 Hz), 7.44 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.1 Hz)
MS (ESI) m/z 494 [M+H]+
MS (ESI) m/z 528 [M+H]+
MS (ESI) m/z 508 [M+H]+
MS (ESI) m/z 528 [M+H]+
MS (ESI) m/z 474, 476, 478 [M+H]+
1H-NMR (DMSO-d6) δ: 1.18 (6H, d, J=4.7 Hz), 2.80-2.95 (4H, m), 3.10-3.19 (2H, m), 3.55 (2H, s), 3.85 (2H, d, J=9.9 Hz), 4.03-4.11 (2H, m), 6.83 (1H, d, J=8.2 Hz), 7.02-7.11 (2H, m), 7.22-7.48 (3H, m), 7.75 (1H, d, J=8.0 Hz).
1H-NMR (DMSO-d6) δ: 1.16 (6H, d, J=5.8 Hz), 2.61-2.85 (5H, m), 3.07-3.16 (3H, m), 3.55 (2H, s), 3.89-4.11 (5H, m), 6.79-7.36 (8H, m).
1H-NMR (DMSO-d6) δ: 1.22 (6H, d, J=6.0 Hz), 2.58-2.84 (4H, m), 3.09-3.19 (2H, m), 3.52 (2H, s), 4.06-4.14 (2H, m), 4.34-4.46 (2H, m), 6.84 (1H, d, J=8.2 Hz), 7.09-7.74 (7H, m), 8.03 (1H, d, J=9.1 Hz).
1H-NMR (Acetone) δ: 8.38-8.35 (1.0H, m), 7.71 (1.0H, dd, J=9.34, 2.20 Hz), 7.31 (1.0H, dd, J=7.97, 1.65 Hz), 7.13 (1.0H, d, J=1.92 Hz), 6.97-6.87 (2.0H, m), 4.33 (2.0H, d, J=12.64 Hz), 4.17 (2.0H, dd, J=5.91, 5.91 Hz), 3.61 (2.0H, s), 3.25-3.23 (2.0H, m), 2.83-2.67 (4.0H, m), 1.24 (6.0H, d, J=6.00 Hz).
1H-NMR (DMSO-d6) δ: 8.66 (1.0H, d, J=4.94 Hz), 7.31 (1.0H, d, J=8.10 Hz), 7.08 (1.0H, s), 6.99 (1.0H, d, J=4.94 Hz), 6.82 (1.0H, d, J=8.10 Hz), 4.45 (2.0H, d, J=8.24 Hz), 4.08-3.99 (3.0H, m), 3.53 (2.0H, s), 3.13 (2.0H, dd, J=5.63, 5.63 Hz), 2.76-2.65 (4.0H, m), 1.16 (6.0H, d, J=6.32 Hz).
1H-NMR (Acetone) δ: 8.14 (1.0H, d, J=2.54 Hz), 7.60 (1.0H, dd, J=9.13, 2.54 Hz), 7.40 (1.0H, s), 7.34 (1.0H, d, J=7.69 Hz), 7.25 (1.0H, dd, J=7.69, 7.69 Hz), 7.15 (1.0H, d, J=7.69 Hz), 6.81 (1.0H, d, J=9.13 Hz), 4.13 (2.0H, d, J=11.54 Hz), 3.81 (2.0H, s), 3.62 (2.0H, s), 2.76-2.62 (4.0H, m), 1.07 (6.0H, d, J=5.77 Hz).
1H-NMR (DMSO-d6) δ: 1.14 (6H, d, J=5.1 Hz), 2.60-2.76 (2H, m), 3.00-3.10 (2H, m), 3.55 (2H, s), 3.97-4.06 (2H, m), 4.46-4.60 (2H, m), 6.80-6.96 (3H, m), 7.30-7.67 (3H, m), 8.69 (2H, s).
1H-NMR (DMSO-d6) δ: 7.18-7.18 (1.0H, m), 7.04 (1.0H, d, J=7.28 Hz), 6.84 (1.0H, s), 6.71 (1.0H, d, J=7.28 Hz), 3.98 (2.0H, dd, J=5.10, 5.10 Hz), 3.64 (2.0H, d, J=10.99 Hz), 3.48 (2.0H, s), 3.10 (2.0H, dd, J=5.10, 5.10 Hz), 2.84-2.69 (4.0H, m), 2.11 (3.0H, s), 1.14 (6.0H, d, J=5.77 Hz).
1H-NMR (Acetone) δ: 8.12 (1.0H, d, J=2.68 Hz), 7.59 (1.0H, dd, J=9.13, 2.68 Hz), 7.32 (1.0H, d, J=8.11 Hz), 7.13 (1.0H, d, J=1.92 Hz), 6.90 (1.0H, dd, J=8.11, 1.92 Hz), 6.80 (1.0H, d, J=9.13 Hz), 4.18-4.13 (4.0H, m), 3.63 (2.0H, s), 3.22 (2.0H, dd, J=6.04, 6.04 Hz), 2.85-2.78 (2.0H, m), 2.62-2.53 (2.0H, m), 1.23 (6.0H, d, J=6.04 Hz).
1H-NMR (Acetone) δ: 8.34 (2.0H, s), 7.30 (1.0H, d, J=8.04 Hz), 7.13 (1.0H, d, J=1.65 Hz), 6.90 (1.0H, dd, J=8.04, 1.65 Hz), 4.49 (2.0H, d, J=12.36 Hz), 4.15 (2.0H, dd, J=5.91, 5.91 Hz), 3.60 (2.0H, s), 3.23 (2.0H, dd, J=6.04, 6.04 Hz), 2.82-2.60 (4.0H, m), 1.22 (6.0H, d, J=6.04 Hz).
1H-NMR (DMSO-d6) δ: 8.44 (2.0H, s), 6.61 (3.0H, s), 4.43-4.33 (2.0H, m), 3.95 (2.0H, dd, J=6.59, 6.59 Hz), 3.43 (2.0H, s), 3.03 (2.0H, dd, J=6.00, 6.00 Hz), 2.63 (4.0H, d, J=6.90 Hz), 2.23 (3.0H, s), 1.12 (6.0H, d, J=5.22 Hz).
1H-NMR (DMSO-d6) δ: 1.23-1.41 (2H, m), 1.70-1.92 (5H, m), 3.09-3.23 (2H, m), 3.57 (2H, s), 3.98-4.15 (4H, m), 6.81-7.46 (6H, m), 7.74 (1H, d, J=8.0 Hz).
1H-NMR (Acetone) δ: 8.37 (1.0H, s), 7.71 (1.0H, dd, J=9.06, 2.47 Hz), 7.33 (1.0H, d, J=7.97 Hz), 7.12 (1.0H, d, J=1.65 Hz), 6.93-6.89 (2.0H, m), 4.55-4.50 (2.0H, m), 4.19 (2.0H, dd, J=6.32, 6.32 Hz), 3.62 (2.0H, s), 2.96-2.92 (3.0H, m), 1.96-1.79 (4.0H, m), 1.37-1.24 (2.0H, m).
1H-NMR (DMSO-d6) δ: 8.65 (1.0H, d, J=4.67 Hz), 7.33 (1.0H, d, J=8.11 Hz), 7.08 (1.0H, s), 6.95 (1.0H, d, J=4.67 Hz), 6.83 (1.0H, d, J=8.11 Hz), 4.64 (2.0H, d, J=12.42 Hz), 4.10 (2.0H, dd, J=6.59, 6.59 Hz), 3.55 (2.0H, s), 3.40-3.25 (1.0H, m), 2.96 (2.0H, dd, J=12.42, 12.42 Hz), 1.91-1.72 (4.0H, m), 1.24-1.15 (2.0H, m).
1H-NMR (DMSO-d6) δ: 1.13-1.36 (2H, m), 1.67-1.87 (5H, m), 2.86-3.00 (2H, m), 3.56 (2H, s), 4.05-4.16 (5H, m), 6.80-7.36 (7H, m).
1H-NMR (300 MHz, CDCl3): 1.40 (6H, m), 3.27-3.44 (6H, m), 3.93-3.98 (2H, m), 4.14 (2H, m), 4.53 (2H, s), 6.47-6.55 (3H, m), 7.13-7.26 (2H, m), 7.43 (1H, d, J=8.1 Hz), 7.55 (1H, s).
1H-NMR (300 MHz, CDCl3): 1.98-2.17 (5H, m), 3.21-3.29 (2H, m), 3.84 (2H, d, J=6.0 Hz), 4.23 (2H, m), 4.65 (2H, s), 6.49-6.56 (3H, m), 7.20 (1H, t, J=8.1 Hz), 7.26-7.29 (2H, m), 7.55 (1H, d, J=2.1 Hz)
1H-NMR (300 MHz, CDCl3): 1.28 (6H, m), 2.64 (2H, t, J=7.5 Hz), 2.91 (2H, t, J=7.5 Hz), 2.99 (4H, m), 3.24 (2H, m), 3.87-3.91 (2H, m), 4.05 (2H, m), 6.70-6.73 (2H, m), 6.80 (1H, d, J=7.5 Hz), 7.19 (1H, t, J=7.5 Hz), 7.22-7.25 (1H, m), 7.43 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=2.1 Hz).
1H-NMR (300 MHz, CDCl3): 1.27 (6H, m), 2.99 (4H, m), 3.23 (2H, m), 3.89-3.93 (2H, m), 4.09 (2H, m), 6.43 (1H, d, J=15.9 Hz), 6.92 (1H, dd, J=8.1 Hz, 2.1 Hz), 7.04 (1H, s), 7.14 (1H, d, J=8.1 Hz), 7.24 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.31 (1H, t, J=8.1 Hz), 7.44 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.1 Hz), 7.71 (1H, d, J=15.9 Hz).
1H-NMR (300 MHz, CDCl3): 1.35 (6H, m), 2.53 (4H, m), 3.15 (2H, m), 3.71 (3H, s), 3.90-3.94 (2H, m), 4.14 (2H, m), 6.81 (1H, dd, J=8.7 Hz, 2.1 Hz), 7.01-7.02 (2H, m), 7.14 (1H, d, J=8.7 Hz), 7.24 (1H, dd, J=8.7 Hz), 7.44 (1H, d, J=8.7 Hz), 7.54 (1H, d, J=2.1 Hz).
TLC Rf 0.13 (MeOH—CHCl3, 1:10)
TLC Rf 0.20 (MeOH—CHCl3, 1:10)
TLC Rf 0.30 (MeOH—CHCl3, 1:10)
TLC Rf 0.31 (MeOH—CHCl3, 1:10)
TLC Rf 0.23 (MeOH—CHCl3, 1:5)
MS (ESI) m/z 495 [M+H]+
MS (ESI) m/z 564 [M+H]+
MS (ESI) m/z 564 [M+H]+
MS (ESI) m/z 602 [M+H]+
MS (ESI) m/z 585 [M+H]+
MS (ESI) m/z 600 [M+H]+
MS (ESI) m/z 534 [M+H]+
MS (ESI) m/z 539 [M+H]+
MS (ESI) m/z 555 [M+H]+
MS (ESI) m/z 544 [M+H]+
MS (ESI) m/z 537 [M+H]+
MS (ESI) m/z 527 [M+H]+
MS (ESI) m/z 560 [M+H]+
MS (ESI) m/z 542 [M+H]+
MS (ESI) m/z 532 [M+H]+
MS (ESI) m/z 528 [M+H]+
MS (ESI) m/z 578 [M+H]+
MS (ESI) m/z 584 [M+H]+
MS (ESI) m/z 512 [M+H]+
MS (ESI) m/z 512 [M+H]+
MS (ESI) m/z 569 [M+H]+
MS (ESI) m/z 569 [M+H]+
TLC: (SiO2) CHCl3-MeOH (10:1) Rf=0.1
1H-NMR (DMSO-d6) δ: 7.56 (1.0H, d, J=1.92 Hz), 7.26 (1.0H, d, J=8.51 Hz), 7.19 (1.0H, dd, J=8.51, 4.25 Hz), 7.04 (1.0H, d, J=7.41 Hz), 6.86 (1.0H, s), 6.71 (1.0H, d, J=7.41 Hz), 4.06-4.03 (2.0H, m), 3.84-3.80 (2.0H, m), 3.65-3.48 (2.0H, m), 2.68 (4.0H, br s), 2.10 (2.0H, s), 2.03-1.67 (6.0H, m), 1.06 (3.0H, d, J=6.04 Hz).
1H-NMR (CDCl3) δ: 7.84-7.82 (1.0H, m), 7.64-7.49 (2.0H, m), 6.93-6.76 (3.0H, m), 4.22-4.11 (1.0H, m), 3.99-3.37 (9.0H, m), 3.31 (3.0H, s), 3.09-2.95 (1.0H, m), 2.89-2.64 (3.0H, m), 2.31-1.12 (8.0H, m).
1H-NMR (CDCl3) δ: 7.86-7.82 (1.0H, m), 7.59-7.48 (2.0H, m), 6.89-6.85 (1.0H, m), 6.80-6.77 (1.0H, m), 6.73-6.69 (1.0H, m), 4.05 (2.0H, dd, J=6.59, 6.59 Hz), 3.95-3.87 (1.0H, m), 3.79-3.60 (4.0H, m), 3.56 (2.0H, s), 3.31 (3.0H, s), 3.01 (1.0H, dd, J=7.68, 5.49 Hz), 2.83-2.69 (3.0H, m), 2.07-1.68 (8.0H, m).
1H-NMR (CDCl3) δ: 7.83 (1.0H, s), 7.58-7.48 (2.0H, m), 7.07 (1.0H, d, J=7.41 Hz), 6.79-6.70 (2.0H, m), 4.04 (2.0H, dd, J=6.59, 6.59 Hz), 3.83-3.56 (6.0H, m), 3.47 (2.0H, dd, J=6.59, 6.59 Hz), 3.36 (3.0H, s), 2.70 (2.0H, dd, J=6.59, 6.59 Hz), 2.33 (3.0H, s), 2.17 (3.0H, s), 2.06-1.95 (4.0H, m), 1.84-1.70 (2.0H, m).
1H-NMR (CDCl3) δ: 7.83 (1.0H, br s), 7.57-7.48 (2.0H, m), 6.68 (1.0H, s), 6.62-6.58 (2.0H, m), 4.00 (2.0H, dd, J=6.59, 6.59 Hz), 3.82-3.61 (4.0H, m), 3.55 (2.0H, s), 3.47 (2.0H, dd, J=6.31, 6.31 Hz), 3.35 (3.0H, s), 2.68 (2.0H, dd, J=6.31, 6.31 Hz), 2.31 (3.0H, s), 2.29 (3.0H, s), 2.04-1.91 (4.0H, m), 1.80-1.66 (2.0H, m).
1H-NMR (CDCl3) δ: 7.31 (1.0H, d, J=8.23 Hz), 7.08 (1.0H, s), 6.93-6.87 (1.0H, m), 6.83 (1.0H, dd, J=8.23, 1.65 Hz), 4.30-4.07 (2.0H, m), 3.89-3.66 (4.0H, m), 3.65-3.55 (4.0H, m), 3.53-3.34 (4.0H, m), 2.87-2.52 (4.0H, m), 2.32-1.62 (6.0H, m).
1H-NMR (CDCl3) δ: 7.55-7.44 (2.0H, m), 7.31 (1.0H, d, J=8.23 Hz), 7.19-7.13 (1.0H, m), 6.93-6.80 (2.0H, m), 4.32-4.08 (2.0H, m), 3.91-3.57 (10.0H, m), 2.91-2.51 (4.0H, m), 2.33-1.61 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.52 (2.0H, m), 7.13 (1.0H, dd, J=8.51, 8.51 Hz), 6.54-6.49 (1.0H, m), 6.46-6.41 (3.0H, m), 4.57-4.47 (2.0H, m), 4.00 (2.0H, dd, J=7.14, 7.14 Hz), 3.82-3.67 (2.0H, m), 3.63-3.44 (6.0H, m), 2.60-2.53 (4.0H, m), 2.01 (2.0H, d, J=12.90 Hz), 1.90 (2.0H, dd, J=7.14, 7.14 Hz), 1.77-1.63 (2.0H, m).
1H-NMR (DMSO-d6) δ: 7.55 (1.0H, d, J=2.20 Hz), 7.30 (1.0H, d, J=8.23 Hz), 7.24 (1.0H, d, J=8.23 Hz), 7.20-7.14 (1.0H, m), 7.07 (1.0H, s), 6.82 (1.0H, d, J=9.61 Hz), 4.12-4.00 (2.0H, m), 3.83-3.71 (2.0H, m), 3.63-3.51 (8.0H, m), 2.58-2.53 (4.0H, m), 2.03-1.89 (4.0H, m), 1.77-1.65 (2.0H, m).
1H-NMR (DMSO-d6) δ: 12.36 (1.0H, br s), 7.59 (1.0H, s), 7.46 (2.0H, d, J=7.41 Hz), 7.38-7.31 (3.0H, m), 7.20 (1.0H, dd, J=7.41, 7.41 Hz), 7.10 (1.0H, d, J=1.65 Hz), 6.83 (1.0H, dd, J=7.41, 1.65 Hz), 4.11 (2.0H, dd, J=6.59, 6.59 Hz), 3.63-3.53 (8.0H, m), 3.47-3.39 (2.0H, m), 2.60-2.53 (4.0H, m), 2.05-1.90 (4.0H, m), 1.80-1.66 (2.0H, m).
1H-NMR (DMSO-d6) δ: 7.70 (1.0H, s), 7.42-7.30 (3.0H, m), 7.25 (1.0H, d, J=8.23 Hz), 7.10 (1.0H, d, J=1.92 Hz), 7.06-6.97 (1.0H, m), 6.83 (1.0H, dd, J=8.23, 1.92 Hz), 4.11 (2.0H, dd, J=6.59, 6.59 Hz), 3.63-3.54 (8.0H, m), 3.47-3.40 (2.0H, m), 2.60-2.53 (4.0H, m), 2.06-1.90 (4.0H, m), 1.80-1.66 (2.0H, m).
1H-NMR (CDCl3) δ: 8.29 (2.0H, s), 7.31 (1.0H, d, J=8.23 Hz), 6.91 (1.0H, s), 6.85-6.82 (1.0H, m), 4.31-4.16 (2.0H, m), 4.00-3.70 (6.0H, m), 3.69-3.60 (4.0H, m), 2.98-2.69 (4.0H, m), 2.29-1.60 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J=7.41 Hz), 7.44 (1.0H, d, J=12.35 Hz), 7.31 (1.0H, d, J=8.23 Hz), 7.08 (1.0H, d, J=2.20 Hz), 6.82 (1.0H, dd, J=8.23, 2.20 Hz), 4.10 (2.0H, dd, J=7.14, 7.14 Hz), 3.65-3.50 (6.0H, m), 3.49-3.12 (4.0H, m), 2.60-2.53 (4.0H, m), 2.10-1.89 (4.0H, m), 1.82-1.68 (2.0H, m).
1H-NMR (DMSO-d6) δ: 7.86 (1.0H, d, J=8.51 Hz), 7.76 (1.0H, d, J=8.51 Hz), 7.31 (1.0H, d, J=7.96 Hz), 7.08 (1.0H, d, J=1.92 Hz), 6.83 (1.0H, dd, J=7.96, 1.92 Hz), 4.10 (2.0H, dd, J=6.86, 6.86 Hz), 3.67-3.52 (6.0H, m), 3.44-3.22 (4.0H, m), 2.62-2.54 (4.0H, m), 2.10-1.92 (4.0H, m), 1.83-1.68 (2.0H, m).
1H-NMR (DMSO-d6) δ: 7.83 (1.0H, s), 7.71-7.67 (1.0H, m), 7.33-7.31 (2.0H, m), 7.09 (1.0H, s), 6.83 (1.0H, d, J=7.96 Hz), 6.78 (1.0H, s), 4.10 (2.0H, dd, J=6.86, 6.86 Hz), 3.63-3.46 (6.0H, m), 3.45-3.24 (4.0H, m), 2.61-2.52 (4.0H, m), 2.03-1.89 (4.0H, m), 1.78-1.65 (2.0H, m), 1.04 (2.7H, d, J=6.04 Hz).
1H-NMR (DMSO-d6) δ: 12.37 (1.0H, br s), 8.61 (2.0H, s), 8.10 (1.0H, s), 7.75-7.72 (1.0H, m), 7.32 (1.0H, d, J=8.23 Hz), 7.08 (1.0H, s), 6.93 (1.0H, s), 6.82 (1.0H, d, J=8.23 Hz), 4.16-3.96 (4.0H, m), 3.64-3.47 (8.0H, m), 2.62-2.53 (4.0H, m), 2.00-1.86 (4.0H, m), 1.67-1.52 (2.0H, m).
1H-NMR (DMSO-d6) δ: 12.40 (1.0H, br s), 8.69 (2.0H, s), 7.63 (2.0H, d, J=7.72 Hz), 7.43 (2.0H, dd, J=7.72, 7.72 Hz), 7.34-7.31 (2.0H, m), 7.08 (1.0H, d, J=1.85 Hz), 6.82 (1.0H, dd, J=8.23, 1.85 Hz), 4.20-4.06 (4.0H, m), 3.63-3.52 (8.0H, m), 2.62-2.54 (4.0H, m), 2.02-1.87 (4.0H, m), 1.68-1.54 (2.0H, m).
1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.57-7.42 (3.0H, m), 7.31 (1.0H, d, J=8.23 Hz), 7.19-7.07 (2.0H, m), 6.82 (1.0H, d, J=8.23 Hz), 4.20-4.06 (4.0H, m), 3.63-3.51 (8.0H, m), 2.63-2.55 (4.0H, m), 2.01-1.87 (4.0H, m), 1.67-1.54 (2.0H, m).
1H-NMR (DMSO-d6) δ: 8.21 (1.0H, s), 7.58-7.51 (2.0H, m), 7.12 (1.0H, dd, J=8.56, 8.56 Hz), 6.54-6.40 (2.0H, m), 4.56-4.41 (1.0H, m), 4.08-3.97 (3.0H, m), 3.84-3.69 (2.0H, m), 3.59-3.46 (2.0H, m), 2.71-2.60 (4.0H, m), 2.00-1.81 (4.0H, m), 1.79-1.65 (6.0H, m).
1H-NMR (CDCl3) δ: 7.85 (1.0H, s), 7.62-7.49 (2.0H, m), 7.31-7.20 (1.0H, m), 6.94-6.76 (3.0H, m), 4.14-3.95 (2.0H, m), 3.84-3.58 (8.0H, m), 2.72-2.55 (4.0H, m), 2.12-1.90 (4.0H, m), 1.88-1.69 (2.0H, m).
4-Cyanopiperidine-1-carboxylic acid t-butyl ester (5.35 g) was added to trifluoroacetic acid (20 mL) and the mixture was stirred at room temperature for 10 minutes. Trifluoroacetic acid was evaporated under reduced pressure to give the title compound as colorless crystal (5.62 g). Yield: 99%.
1H-NMR (DMSO-d6) δ: 1.83-1.96 (2H, m), 2.08-2.14 (2H, m), 3.00-3.08 (2H, m), 3.14-3.26 (2H, m), 3.41 (1H, br s).
2-Chloro-6-trifluorobenzothiazole (5.84 g), piperidine-4-carbonitrile trifluoroacetate (5.62 g), potassium carbonate (10.39 g) and dimethyl sulfoxide (50 mL) were stirred at 60° C. for 6 hours. To the reaction solution was added water and 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 and the residue was washed with isopropylether to give the title compound as colorless crystal (6.84 g). Yield: 89%.
1H-NMR (CDCl3) δ: 1.99-2.17 (4H, m), 2.97-3.05 (1H, m), 3.68-3.76 (2H, m), 3.87-3.95 (2H, m), 7.55-7.63 (2H, m), 7.89-7.90 (1H, m).
To a solution of 1-(6-trifluoromethyl benzothiazole-2-yl)piperidine-4-carbonitrile (1.00 g) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (3.21 mL) at −15° C. To the reaction solution was added (2-bromoethoxy)-t-butyldimethyl silane (689 μL). The mixture was stirred at 0° C. for 3 hours. To the reaction solution was added brine and 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 and the obtained residue was purified by column chromatograph on silica gel to give the title compound (1.23 g). Yield: 82%.
1H-NMR (CDCl3) δ: 0.10 (6H, s), 0.93 (9H, s), 1.71-1.81 (2H, m), 1.88 (2H, t, J=6.0 Hz), 2.17-2.21 (2H, m), 3.49-3.59 (2H, m), 3.94 (2H, t, J=6.0 Hz), 4.11-4.23 (2H, m), 7.55-7.62 (2H, m), 7.89-7.89 (1H, m).
To 4-[2-(t-butyldimethyl silyloxy)ethyl]-1-(6-trifluoromethyl benzothiazole-2-yl)piperidine-4-carbonitrile (510 mg) was added tetramethylammonium fluoride (1 M tetrahydrofuran solution, 1.63 mL). The mixture was stirred at 0° C. for 0.5 hour. To the reaction solution was added aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (366 mg). Yield: 95%.
1H-NMR (Acetone) δ: 1.82-1.99 (4H, m), 2.20-2.25 (2H, m), 3.44-3.54 (2H, m), 3.89 (2H, t, J=5.9 Hz), 4.25-4.29 (2H, m), 7.62-7.63 (2H, m), 8.13-8.16 (1H, br m).
The above compound was synthesized from 4-(2-hydroxyethyl)-1-(6-trifluoromethyl benzothiazole-2-yl)piperidine-4-carbonitrile according to the methods of Example 585 and 586.
MS (ESI) m/z 524 [M+H]+
The following compound was obtained by a similar method as above.
MS (ESI) m/z 524 [M+H]+
To a solution of 4-[2-(t-butyldimethyl silyloxy)ethyl]-1-(6-trifluoromethyl benzothiazole-2-yl)piperidine-4-carbonitrile (600 mg) in 1,2-dimethoxyethane (12 mL) was added diisobutylaluminum hydride (1.0 M toluene solution, 6.39 mL) at 0° C. The mixture was stirred for 4 hours. To the reaction solution was added aqueous citric acid solution and extracted with ethyl acetate. The organic layer was sequentially washed with aqueous citric acid solution, water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (526 mg). Yield: 87%.
1H-NMR (CDCl3) δ: 0.05 (6H, s), 0.90 (9H, s), 1.64-1.74 (2H, m), 1.85 (2H, t, J=5.8 Hz), 2.13-2.19 (2H, m), 3.40-3.50 (2H, m), 3.68 (2H, t, J=5.8 Hz), 3.93-4.00 (2H, m), 7.52-7.59 (2H, m), 7.85-7.88 (1H, br m), 9.57-9.60 (1H, br m).
To a solution of 4-[2-(t-butyldimethyl silanyloxy)ethyl]-1-(6-trifluoromethyl benzothiazole-2-yl)piperidine-4-carboxaldehyde (500 mg) in tetrahydrofuran (20 mL) was added ethoxy aminehydrochloride (124 mg). The mixture was stirred at 60° C. for 4 hours. The solvent was evaporated under reduced pressure. To the residue was added tetrabuthyl ammonium fluoride (1M tetrahydrofuran solution, 1.59 mL). The mixture was stirred at 0° C. for 0.5 hour, at room temperature for 1 hour and at 40° C. for 2 hours. To the reaction solution was added aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (394 mg). Yield: 93%.
1H-NMR (CDCl3) δ: 1.28 (3H, t, J=7.0 Hz), 1.68-1.77 (2H, m), 1.80 (2H, t, J=6.7 Hz), 2.03-2.10 (2H, m), 3.47-3.56 (2H, m), 3.74-3.80 (2H, m), 3.92-3.99 (2H, m), 4.13 (2H, q, J=7.0 Hz), 7.33-7.36 (1H, br m), 7.52-7.59 (2H, m), 7.84-7.88 (1H, br m).
The above compound was synthesized from N-[4-(2-hydroxyethyl)-1-(6-trifluoromethylbenzothiazole-2-yl)piperidine-4-yl]formimido ethyl ester according to the methods of Example 585 and 586.
MS (ESI) m/z 570 [M+H]+
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 570 [M+H]+
MS (FABMS) m/z 582 [M+H]+
TLC_Rf=0.61 (MeOH:CHCl3=1:15)
TLC_Rf=0.63 (MeOH:CHCl3=1:15)
MS (ESI) m/z 547 [M+H]+
MS (ESI) m/z 521 [M+H]+
MS (ESI) m/z 507 [M+H]+
MS (ESI) m/z 521 [M+H]+
MS (ESI) m/z 521 [M+H]+
MS (ESI) m/z 555 [M+H]+
MS (ESI) m/z 508 [M+H]+
MS (ESI) m/z 493 [M+H]+
MS (ESI) m/z 479 [M+H]+
1H-NMR (DMSO-d6) δ: 7.88 (1.0H, d, J=8.51 Hz), 7.78 (1.0H, d, J=8.51 Hz), 7.05 (2.0H, d, J=5.21 Hz), 7.00 (1.0H, s), 4.22-3.91 (1.0H, m), 3.65-3.36 (4.0H, m), 2.97 (1.0H, d, J=11.53 Hz), 2.83 (1.0H, d, J=11.53 Hz), 2.31 (3.0H, s), 2.21-2.16 (3.0H, m), 2.02-1.93 (1.0H, m), 1.83-1.78 (1.0H, m), 1.38-1.16 (4.0H, m), 0.86 (3.0H, t, J=7.27 Hz).
1H-NMR (DMSO-d6) δ: 7.88 (1.0H, d, J=8.23 Hz), 7.78 (1.0H, d, J=8.23 Hz), 7.34-7.18 (4.0H, m), 4.06 (1.0H, br s), 3.61-3.41 (5.0H, m), 2.96 (1.0H, d, J=11.80 Hz), 2.84 (1.0H, d, J=11.80 Hz), 2.19-2.17 (2.0H, m), 1.92-1.84 (2.0H, m), 1.32-1.21 (4.0H, m), 0.86 (3.0H, t, J=7.27 Hz).
1H-NMR (DMSO-d6) δ: 12.32 (1.0H, br s), 8.26 (1.0H, d, J=7.41 Hz), 7.46 (1.0H, d, J=12.08 Hz), 7.05 (2.0H, d, J=5.76 Hz), 7.00 (1.0H, s), 4.07-4.04 (1.0H, m), 3.58-3.40 (5.0H, m), 2.95 (1.0H, d, J=12.08 Hz), 2.82 (1.0H, d, J=12.08 Hz), 2.31 (3.0H, s), 2.22-2.11 (2.0H, m), 2.02-1.92 (1.0H, m), 1.78-1.74 (1.0H, m), 1.30-1.22 (4.0H, m), 0.86 (3.0H, t, J=7.27 Hz).
1H-NMR (300 MHz, DMSO-d6): δ 0.83 (3H, t, J=7.2 Hz), 1.13-1.20 (2H, m), 1.27-1.34 (2H, m), 1.71-1.94 (2H, m), 2.09-2.19 (2H, m), 2.28 (3H, s), 2.78-2.94 (2H, m), 3.32-3.61 (5H, m), 3.99 (2H, m), 6.97-7.02 (3H, m), 7.50-7.57 (2H, m), 8.22 (1H, s)
1H-NMR (300 MHz, DMSO-d6): δ 0.83 (3H, t, J=7.2 Hz), 1.13-1.20 (2H, m), 1.27-1.36 (2H, m), 1.72-1.94 (2H, m), 2.12-2.15 (2H, m), 2.78-2.92 (2H, m), 3.37-3.61 (5H, m), 3.99 (2H, m), 7.16-7.29 (4H, m), 7.50-7.57 (2H, m), 8.21 (1H, s)
1H-NMR (300 MHz, DMSO-d6): δ 0.81 (3H, t, J=7.2 Hz), 1.07-1.17 (2H, m), 1.25-1.32 (2H, m), 1.68-1.77 (2H, m), 2.09-2.18 (2H, m), 2.26 (3H, s), 2.75-2.93 (2H, m), 3.26-3.42 (3H, m), 3.48 (2H, s), 3.57 (1H, d, J=13.5 Hz), 3.97 (1H, m), 6.95-7.02 (3H, m), 7.41 (1H, d, J=12.3 Hz), 8.22 (1H, d, J=6.6 Hz), 12.24 (1H, br)
1H-NMR (300 MHz, DMSO-d6): δ 0.81 (3H, t, J=7.2 Hz), 1.13-1.31 (4H, m), 1.75-1.95 (2H, m), 2.10-2.13 (2H, m), 2.76-2.90 (1H, m), 3.21-4.37 (8H, m), 7.15-7.59 (5H, m), 8.21-8.30 (1H, m), 12.34 (1H, br)
1H-NMR (300 MHz, CDCl3): δ 0.88 (3H, t, J=7.2 Hz), 1.21-1.39 (4H, m), 1.94 (2H, m), 2.27 (2H, m), 2.36 (3H, s), 2.91 (2H, m), 3.45 (3H, m), 3.64 (2H, s). 4.11 (2H, m), 7.06-7.11 (3H, m), 7.58 (1H, d, J=8.4 Hz), 7.71 (1H, d, J=8.4 Hz)
1H-NMR (DMSO-d6) δ: 8.24 (1H, s), 7.58-7.55 (2H, m), 7.06 (2H, s), 7.00 (1H, s), 4.09-3.95 (2H, m), 3.64-3.32 (2H, m), 3.53 (2H, s), 2.94 (1H, d, J=11.2 Hz), 2.82 (1H, d, J=11.4 Hz), 2.31 (3H, s), 2.19-2.14 (2H, m), 1.98-1.89 (1H, m), 1.80-1.71 (1H, m), 1.27-1.19 (2H, m), 0.92 (3H, t, J=7.3 Hz).
1H-NMR (300 MHz, CDCl3): δ 0.87 (3H, t, J=7.2 Hz), 1.20-1.38 (4H, m), 1.92 (2H, m), 2.27 (2H, m), 2.89 (2H, m), 3.50 (3H, m), 3.67 (2H, s). 4.11 (2H, m), 7.31 (4H, m), 7.57 (1H, d, J=8.4 Hz), 7.70 (1H, d, J=8.4 Hz)
1H-NMR (DMSO-d6) δ: 7.55 (1H, d, J=2.0 Hz), 7.26-7.17 (2H, m), 7.04 (1H, s), 7.02 (1H, s), 6.97 (1H, s), 4.13 (1H, s), 3.95 (1H, d, J=12.3 Hz), 3.50 (2H, s), 3.48 (2H, dd, J=58.3, 14.7 Hz), 2.90 (1H, d, J=12.1 Hz), 2.76 (1H, d, J=12.1 Hz), 2.28 (3H, s), 2.15-2.09 (2H, m), 1.92-1.83 (1H, m), 1.79-1.70 (1H, m), 1.31-1.26 (2H, m), 1.16-1.10 (2H, m), 0.83 (3H, t, J=7.3 Hz).
1H-NMR (DMSO-d6) δ: 7.88 (1H, s), 7.45 (1H, d, J=8.8 Hz), 7.24 (1H, d, J=9.1 Hz), 7.03 (1H, s), 7.01 (1H, s), 6.97 (1H, s), 3.99-3.90 (2H, m), 3.50 (2H, s), 3.49 (2H, dd, J=58.4, 12.7 Hz), 2.91 (1H, d, J=11.5 Hz), 2.79 (1H, d, J=11.5 Hz), 2.28 (3H, s), 2.15-2.09 (2H, m), 1.97-1.91 (1H, m), 1.73-1.67 (1H, m), 1.32-1.26 (2H, m), 1.19-1.13 (2H, m), 0.84 (3H, t, J=7.1 Hz).
1H-NMR (DMSO-d6) δ: 8.40 (1H, s), 7.77 (1H, dd, J=9.3, 2.6 Hz), 7.05 (2H, d, J=6.2 Hz), 6.99 (1H, s), 6.88 (1H, d, J=9.1 Hz), 4.41 (1H, s), 4.25 (1H, d, J=10.0 Hz), 3.63-3.29 (2H, m), 3.51 (2H, s), 3.14 (1H, t, J=11.3 Hz), 2.93 (1H, d, J=10.2 Hz), 2.81 (1H, d, J=11.8 Hz), 2.30 (3H, s), 2.11-1.88 (3H, m), 1.53-1.48 (1H, m), 1.32-1.23 (2H, m), 1.16-1.06 (2H, m), 0.84 (3H, t, J=7.3 Hz).
1H-NMR (DMSO-d6) δ: 8.37 (1H, s), 7.74 (1H, dd, J=9.1, 2.5 Hz), 7.03 (2H, d, J=6.6 Hz), 6.97 (1H, s), 6.85 (1H, d, J=9.3 Hz), 4.38 (1H, s), 4.22 (1H, d, J=11.6 Hz), 3.50 (2H, s), 3.44 (2H, dd, J=87.8, 13.2 Hz), 3.12 (1H, t, J=11.3 Hz), 2.91 (1H, d, J=11.0 Hz), 2.79 (1H, d, J=11.3 Hz), 2.28 (3H, s), 1.51-1.45 (1H, m), 1.28-1.21 (2H, m), 1.13-1.06 (2H, m), 0.81 (3H, t, J=7.3 Hz).
1H-NMR (DMSO-d6) δ: 7.87 (1H, d, J=8.6 Hz), 7.78 (1H, d, J=8.6 Hz), 7.05 (2H, s), 7.00 (1H, s), 4.13-4.02 (2H, m), 3.63-3.34 (2H, m), 3.51 (2H, s), 2.96 (1H, d, J=11.4 Hz), 2.83 (1H, d, J=11.9 Hz), 2.31 (3H, s), 2.21-2.15 (2H, m), 1.95-1.87 (1H, m), 1.84-1.76 (1H, m), 1.27-1.18 (2H, m), 0.92 (3H, t, J=7.3 Hz).
1H-NMR (CDCl3) δ: 7.71 (1.0H, d, J=8.23 Hz), 7.58 (1.0H, d, J=8.23 Hz), 7.17-7.00 (3.0H, m), 4.22-4.01 (2.0H, m), 3.67-3.29 (5.0H, m), 3.07-2.72 (2.0H, m), 2.38-2.19 (5.0H, m), 2.03-1.90 (1.0H, m), 1.75-1.56 (2.0H, m), 1.55-1.40 (1.0H, m), 1.02-0.88 (6.0H, m).
1H-NMR (CDCl3) δ: 7.70 (1.0H, d, J=8.51 Hz), 7.57 (1.0H, d, J=8.51 Hz), 7.37-7.20 (4.0H, m), 4.22-4.03 (2.0H, m), 3.74-3.38 (5.0H, m), 3.13-2.74 (2.0H, m), 2.43-2.18 (2.0H, m), 2.00-1.85 (1.0H, m), 1.80-1.58 (1.0H, m), 1.50-1.41 (1.0H, m), 0.98-0.89 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.25 (1.0H, d, J=7.41 Hz), 7.42 (1.0H, d, J=12.90 Hz), 7.05-6.95 (3.0H, m), 4.17-3.88 (2.0H, m), 3.59 (2.0H, d, J=14.00 Hz), 3.49 (2.0H, s), 3.45-3.19 (2.0H, m), 2.93 (1.0H, d, J=11.53 Hz), 2.76 (1.0H, d, J=11.53 Hz), 2.28 (3.0H, s), 2.23-2.07 (2.0H, m), 1.98-1.87 (1.0H, m), 1.59-1.34 (1.6H, m), 0.93-0.87 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J=7.41 Hz), 7.42 (1.0H, d, J=12.62 Hz), 7.32-7.13 (4.0H, m), 4.24-3.82 (2.0H, m), 3.63 (1.0H, d, J=13.72 Hz), 3.56 (2.0H, s), 3.53-3.36 (3.0H, m), 2.93 (1.0H, d, J=11.53 Hz), 2.77 (1.0H, d, J=11.53 Hz), 2.23-2.11 (2.0H, m), 1.95-1.80 (1.0H, m), 1.64-1.50 (1.0H, m), 1.48-1.32 (1.0H, m), 0.94-0.86 (6.0H, m).
1H-NMR (CDCl3) δ: 7.29-7.19 (3.0H, m), 7.17-7.02 (3.0H, m), 4.43-4.25 (1.0H, m), 4.16-4.01 (1.0H, m), 3.67-3.35 (4.0H, m), 3.11-2.69 (2.0H, m), 2.41-2.16 (5.0H, m), 1.85-1.70 (2.0H, m), 1.53-1.39 (1.0H, m), 0.98-0.86 (6.0H, m).
1H-NMR (CDCl3) δ: 7.40-7.19 (6.0H, m), 7.14 (1.0H, dd, J=8.51, 1.92 Hz), 4.49-4.24 (1.0H, m), 4.22-4.01 (1.0H, m), 3.71-3.39 (4.0H, m), 2.99-2.71 (2.0H, m), 2.53-1.69 (4.0H, m), 1.55-1.39 (1.0H, m), 0.96-0.89 (6.0H, m).
TLC_Rf=0.55 (MeOH:CHCl3=1:10)
2-Chloro-6-trifluoromethyl benzothiazole (2.79 g), (S)-4-N-Boc-piperazine carboxylic acid methyl ester (3.10 g), potassium carbonate (1.95 g) and dimethylformamide (20 mL) were stirred at 55° C. for 16 hours and at 90° C. for 7 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (1.40 g).
Yield: 27%.
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.97-3.18 (1H, m), 3.20-3.38 (1H, m), 3.58-3.81 (2H, m), 3.76 (3H, s), 4.09-4.37 (1H, m), 4.61-4.77 (1H, m), 5.06 (1H, brs), 7.55 (1H, d, J=8.4, 1.2 Hz), 7.61 (1H, d, J=8.4 Hz), 7.90 (1H, d, J=1.2 Hz).
Reference Example 265
To a solution of (S)-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1,3-dicarboxylic acid-1-t-butyl ester-3-methyl ester (1.18 g) in tetrahydrofuran (10 mL) was added lithium borohydride (65.7 mg). The mixture was stirred for 20 hours. To the reaction solution was added aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (840 mg). Yield: 76%.
1H-NMR (CDCl3) δ: 1.50 (9H, s), 3.03-3.30 (2H, m), 3.35-3.55 (1H, m), 3.68-4.00 (3H, m), 4.00-4.43 (3H, m), 7.51-7.59 (2H, m), 7.87 (1H, d, J=0.8 Hz).
To a solution of (S)-3-hydroxymethyl-4-(6-trifluoromethyl benzothiazole-2-yl) piperazine-1-carboxylic acid t-butyl ester (209 mg) in dimethylformamide (2 mL) were sequentially added methyl iodide (0.5 mL) and sodium hydride (62.4 mg). The mixture was stirred at room temperature for 24 hours. To the reaction solution was added ice water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (167 mg).
Yield: 77%.
1H-NMR (CDCl3) δ: 1.50 (9H, s), 2.96-3.19 (2H, m), 3.34-3.45 (1H, m), 3.38 (3H, s), 3.57 (2H, d, J=6.9 Hz), 3.94-4.06 (1H, m), 4.20-4.33 (3H, m), 7.53 (1H, dd, J=8.7, 1.5 Hz), 7.58 (1H, d, J=8.7 Hz), 7.86 (1H, d, J=1.5 Hz).
To a solution of (S)-3-methoxymethyl-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1-carboxylic acid t-butyl ester (167 mg) in methylene chloride (1.5 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate solution was added thereto and 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 the title compound (123 mg). Yield: 96%.
1H-NMR (CDCl3) δ: 2.84-2.96 (3H, m), 3.01 (1H, dd, J=12.0, 3.9 Hz), 3.06-3.16 (1H, m), 3.26 (1H, d, J=12.9 Hz), 3.39 (1H, s), 3.46 (1H, dd, J=12.0, 3.3 Hz), 3.66 (1H, dd, J=12.4, 5.1 Hz), 3.91 (1H, dd, J=12.4, 7.2 Hz), 3.90-3.96 (1H, m), 4.12-4.21 (1H, m), 7.52 (1H, dd, J=8.4, 2.1 Hz), 7.56 (1H, d, J=8.4 Hz), 7.85 (1H, d, J=2.1 Hz).
A mixture of 2-((S)-2-methoxymethylpiperazine-1-yl)-6-trifluoromethyl benzothiazole (123 mg), (3-bromomethylphenyl)ethyl acetate ester (104 mg), potassium carbonate (259 mg) and dimethylformamide (1.5 mL) was stirred at room temperature for 2 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (169 mg). Yield: 90%.
1H-NMR (CDCl3) δ: 1.26 (3H, t, J=7.2 Hz), 2.20-2.32 (2H, m), 2.90 (1H, brd, J=10.8 Hz), 3.04 (1H, d, J=11.7 Hz), 3.36 (3H, s), 3.39-3.64 (3H, m), 3.62 (2H, s), 3.70 (1H, dd, J=9.0, 6.0 Hz), 3.83 (1H, t, J=9.0 Hz), 4.03 (1H, brd, J=12.6 Hz), 4.16 (2H, q, J=7.2 Hz), 4.13-4.24 (1H, m), 7.18-7.33 (4H, m), 7.51 (1H, dd, J=8.4, 1.8 Hz), 7.56 (1H, d, J=8.4 Hz), 7.83 (1H, d, J=1.8 Hz).
A mixture of [3-[(S)-3-methoxymethyl-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1-ylmethyl]phenyl]ethyl acetate ester (167 mg), 2N aqueous sodium hydroxide solution (0.8 mL), tetrahydrofuran (1.2 mL) and methanol (1.2 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. To the residue was added 2N hydrochloric acid and 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 the title compound (153 mg). Yield: 97%.
TLC_Rf=0.40 (MeOH:CHCl3=1:10)
The following compounds were obtained by similar methods as above.
TLC_Rf=0.33 (MeOH:CHCl3=1:10)
TLC_Rf=0.52 (MeOH:CHCl3=1:15)
TLC_Rf=0.088 (MeOH:CHCl3=1:5)
TLC_Rf=0.17 (MeOH:CHCl3=1:15)
TLC_Rf=0.29 (MeOH:CHCl3=1:15)
TLC_Rf=0.23 (MeOH:CHCl3=1:15)
TLC_Rf=0.28 (MeOH:CHCl3=1:15)
MS (ESI); m/z 463 [M+H]+
MS (ESI); m/z 445 [M+H]+
MS (ESI); m/z 449 [M+H]+
MS (ESI); m/z 431 [M+H]+
TLC: (SiO2) AcOEt-Hexane (3:1) Rf=0.21
TLC: (SiO2) AcOEt Rf=0.46
TLC: (SiO2) AcOEt Rf=0.45
TLC: (SiO2) AcOEt Rf=0.67
TLC: (SiO2) AcOEt Rf=0.60
TLC: (SiO2) AcOEt-Hexane (1:1) Rf=0.18
TLC: (SiO2) AcOEt-Hexane (1:1) Rf=0.25
TLC: (SiO2) AcOEt-Hexane (1:1) Rf=0.34
TLC: (SiO2) AcOEt Rf=0.29
TLC: (SiO2) AcOEt Rf=0.25
MS (ESI) m/z 468 [M+H]+
MS (ESI) m/z 477 [M+H]+
MS (ESI) m/z 449 [M+H]+
MS (ESI) m/z 463 [M+H]+
MS (ESI) m/z 435 [M+H]+
MS (ESI) m/z 483 [M+H]+
MS (ESI) m/z 465 [M+H]+
1H-NMR (DMSO-d6) δ: 8.17 (1.0H, s), 7.78 (1.0H, d, J=2.01 Hz), 7.33-7.17 (4.0H, m), 6.91 (1.0H, s), 6.83 (1.0H, d, J=2.01 Hz), 4.06-0.29 (0.0H, m), 3.67-3.32 (4.0H, m), 3.19-3.16 (1.0H, m), 2.81 (1.0H, d, J=11.58 Hz), 2.67 (1.0H, d, J=11.58 Hz), 2.28-2.24 (2.0H, m), 1.95-1.92 (1.0H, br m), 1.45-1.42 (1.0H, br m), 1.28-1.08 (4.0H, m), 0.83 (3.0H, t, J=7.22 Hz).
1H-NMR (300 MHz, DMSO-d6): δ 0.84 (3H, t, J=7.5 Hz), 1.12-1.34 (4H, m), 1.83-1.93 (2H, m), 2.34 (3H, s), 2.99-3.14 (2H, m), 3.14-3.57 (5H, m), 4.21-4.35 (2H, m), 4.81-4.86 (1H, m), 5.05-5.06 (1H, m), 7.15-7.63 (7H, m), 8.82 (2H, s), 10.52 (2H, br), 12.41 (1H, br)
1H-NMR (300 MHz, DMSO-d6): δ0.83 (3H, t, J=7.2 Hz), 1.12-1.32 (4H, m), 1.82-1.95 (2H, m), 3.00-3.15 (2H, m), 3.24-3.39 (3H, m), 3.62 (2H, s), 4.25-4.40 (2H, m), 4.81-4.86 (1H, m), 5.05 (1H, m), 7.18 (1H, m), 7.39-7.60 (7H, m), 8.82 (2H, s), 10.62 (2H, br), 12.45 (1H, br)
1H-NMR (DMSO-d6) δ: 8.72 (2H, s), 7.52-7.48 (3H, m), 7.14-7.11 (1H, m), 7.03 (2H, s), 6.96 (1H, s), 4.73 (1H, s), 4.56 (1H, d, J=12.3 Hz), 3.56-3.31 (2H, m), 3.51 (2H, s), 3.19-3.15 (1H, m), 2.90 (1H, d, J=9.9 Hz), 2.79 (1H, d, J=11.0 Hz), 2.29 (3H, s), 2.03 (2H, s), 1.86-1.83 (1H, m), 1.65-1.62 (1H, m), 1.18-1.15 (2H, m), 0.88 (3H, t, J=7.1 Hz).
1H-NMR (DMSO-d6) δ: 8.65 (2H, s), 7.23 (1H, t, J=8.2 Hz), 7.03 (2H, s), 6.96 (1H, s), 6.88 (1H, s), 6.87 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=9.3 Hz), 4.72 (1H, s), 4.54 (1H, d, J=10.0 Hz), 3.59-3.32 (2H, m), 3.51 (2H, s), 3.15 (1H, t, J=10.0 Hz), 2.94 (6H, s), 2.91-2.88 (1H, m), 2.77 (1H, t, J=11.0 Hz), 2.29 (3H, s), 2.05-1.97 (2H, m), 1.89-1.81 (1H, m), 1.65-1.58 (1H, m), 1.18-1.14 (2H, m), 0.88 (3H, t, J=7.3 Hz).
1H-NMR (DMSO-d6) δ: 8.42 (1H, d, J=2.7 Hz), 7.82 (1H, dd, J=8.9, 2.6 Hz), 7.62 (1H, d, J=1.4 Hz), 7.59 (1H, s), 7.42 (2H, t, J=7.5 Hz), 7.29 (1H, d, J=7.4 Hz), 7.04 (2H, d, J=8.8 Hz), 6.97 (1H, s), 6.81 (1H, d, J=9.1 Hz), 4.31 (1H, s), 4.14 (1H, d, J=10.9 Hz), 3.62-3.33 (2H, m), 3.50 (2H, s), 3.14-3.06 (1H, m), 2.91 (1H, d, J=10.0 Hz), 2.80 (1H, d, J=10.0 Hz), 2.29 (3H, s), 2.09 (1H, t, J=10.0 Hz), 2.01-1.92 (2H, m), 1.47-1.38 (1H, m), 1.29-1.23 (2H, m), 1.15-1.07 (2H, m), 0.82 (3H, t, J=7.1 Hz).
1H-NMR (DMSO-d6) δ: 8.47 (1H, d, J=2.5 Hz), 7.87 (1H, dd, J=8.9, 2.7 Hz), 7.46 (3H, t, J=8.8 Hz), 7.05 (1H, s), 7.02 (1H, s), 6.97 (1H, s), 6.81 (1H, d, J=9.1 Hz), 4.32 (1H, s), 4.16 (1H, d, J=12.6 Hz), 3.63-3.28 (2H, m), 3.50 (2H, s), 3.10 (1H, t, J=12.6 Hz), 2.92 (1H, d, J=9.9 Hz), 2.80 (1H, d, J=10.9 Hz), 2.29 (3H, s), 2.09 (1H, t, J=9.4 Hz), 1.98-1.91 (2H, m), 1.44-1.39 (1H, m), 1.31-1.22 (2H, m), 1.15-1.06 (2H, m), 0.82 (3H, t, J=7.2 Hz).
MS (ESI); m/z 445 [M+H]+
MS (ESI) m/z 459 [M+H]+
MS (ESI) m/z 426 [M−H]−
MS (ESI) m/z 440 [M−H]−
1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J=6.0 Hz), 2.27 (3H, s), 2.63-2.80 (2H, m), 2.85-2.97 (2H, m), 3.49 (2H, s), 3.69-3.78 (4H, m), 6.86-7.61 (9H, m).
TLC Rf 0.64 (hexane:AcOEt=1:1)
TLC Rf 0.70 (hexane:AcOEt=1:1)
TLC: (SiO2) AcOEt-Hexane (1:1) Rf=0.34
The above compound was synthesized with 2-chloro-6-trifluoromethyl benzothiazole and piperazine-1-carboxylic acid t-butyl ester as starting materials by a similar method of Reference Example 84 or 155.
1H-NMR (DMSO-d6) δ: 0.90 (3H, t, J=7.0 Hz), 1.31-1.37 (4H, m), 1.85-1.95 (2H, m), 3.03-3.18 (1H, m), 3.25-3.39 (3H, m), 3.42-3.55 (1H, m), 4.13-4.33 (2H, m), 7.31 (1H, dd, J=8.5, 1.8 Hz), 7.54 (1H, d, J=8.5 Hz), 7.99 (1H, d, J=1.8 Hz), 9.14 (1H, br s), 9.57 (1H, br s).
A mixture of 2-((R)-2-butylpiperazine-1-yl)-6-trifluoromethoxybenzothiazole dihydrochloride (170 mg), (3-chloromethyl-5-methylphenoxy)acetic acid methyl ester (108 mg), potassium carbonate (270 mg), potassium iodide (65 mg) and dimethylformamide (4 mL) was stirred at room temperature for 24 hours. To the reaction solution was added water and 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 and the residue was purified by column chromatograph on silica gel to give the title compound (203 mg). Yield: 94%.
A mixture of [3-[(R)-3-butyl-4-(6-trifluoromethoxybenzothiazole-2-yl)-piperazine-1-ylmethyl]-5-methylpheno xy]acetic acid methyl ester (203 mg), 2N sodium hydroxide (0.46 mL), tetrahydrofuran (2 mL) and methanol (2 mL) was stirred at room temperature for 16 hours. To the reaction solution were added water and chloroform. The mixture was neutralized with 2N hydrochloric acid. The reaction solution was extracted with chloroform. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the title compound (182 mg). Yield: 91%.
1H-NMR (DMSO-d6) δ: 7.90 (1.0H, d, J=1.65 Hz), 7.48 (1.0H, d, J=8.78 Hz), 7.25 (1.0H, dd, J=8.78, 1.65 Hz), 6.74 (1.0H, s), 6.67 (1.0H, s), 6.61 (1.0H, s), 4.48 (2.0H, s), 4.06-3.80 (1.0H, m), 3.72-3.20 (3.0H, m), 2.90 (1.0H, d, J=12.62 Hz), 2.81
The following compounds were obtained by similar methods as above.
MS (ESI) m/z 508 [M+H]+
1H-NMR (DMSO-d6) δ: 8.23 (1.0H, s), 7.58-7.54 (2.0H, m), 6.74 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.48 (2.0H, s), 4.11-3.87 (1.0H, m), 3.58-3.33 (3.0H, m), 2.94 (1.0H, d, J=12.42 Hz), 2.83 (1.0H, d, J=12.42 Hz), 2.27 (3.0H, s), 2.16-2.12 (2.0H, m), 2.01-1.92 (1.0H, m), 1.80-1.76 (1.0H, m), 1.34-1.21 (4.0H, m), 0.86 (3.0H, t, J=7.22 Hz).
1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.49 (2.0H, m), 7.24 (1.0H, dd, J=7.72, 7.72 Hz), 6.95-6.87 (2.0H, m), 6.82-6.76 (1.0H, m), 4.60 (2.0H, s), 4.20-3.89 (2.0H, m), 3.57 (1.0H, d, J=13.76 Hz), 3.47-3.22 (2.0H, m), 2.96-2.70 (2.0H, m), 2.24-2.08 (2.0H, m), 1.93-1.79 (1.5H, br m), 1.70-1.56 (1.2H, br m), 1.52-1.37 (1.4H, br m), 0.92 (6.0H, d, J=6.55 Hz).
1H-NMR (DMSO-d6) δ: 8.22 (1.0H, s), 7.59-7.49 (2.0H, m), 6.75 (1.0H, s), 6.68 (1.0H, s), 6.64-6.61 (1.0H, m), 4.61 (2.0H, s), 4.18-3.89 (2.0H, m), 3.55 (1.0H, d, J=13.26 Hz), 3.51-3.17 (2.0H, m), 2.90 (1.0H, d, J=9.90 Hz), 2.83-2.71 (1.0H, m), 2.26 (3.0H, s), 2.22-2.09 (2.3H, m), 1.96-1.84 (1.0H, m), 1.65-1.52 (1.0H, m), 1.52-1.39 (1.0H, m), 0.98-0.88 (6.0H, m).
MS (ESI) m/z 492 [M−H]−
MS (ESI) m/z 506 [M−H]−
1H-NMR (300 MHz, DMSO-d6) δ 0.85 (3H, t, J=7.2 Hz), 1.16-1.36 (4H, m), 1.79-1.95 (2H, m), 2.15-2.19 (2H, m), 2.81-2.92 (2H, m), 3.34-3.60 (3H, m), 4.03 (2H, m), 4.66 (2H, s), 6.82 (1H, dd, J=7.8 Hz, 1.8 Hz), 6.91 (1H, s), 6.94 (1H, d, J=7.8 Hz), 7.26 (1H, t, J=7.8 Hz), 7.51-7.58 (2H, m), 8.22 (1H, s), 13.00 (1H, br s)
1H-NMR (300 MHz, DMSO-d6) δ 0.84 (3H, t, J=7.2 Hz), 1.15-1.36 (4H, m), 1.73-1.97 (2H, m), 2.11-2.16 (2H, m), 2.27 (3H, s), 2.79-2.92 (2H, m), 3.33-3.57 (3H, m), 4.02 (2H, m), 4.62 (2H, s), 6.63 (1H, s), 6.69 (1H, s), 6.76 (1H, s), 7.51-7.58 (2H, m), 8.22 (1H, s), 12.98 (1H, br s)
MS (ESI) 492[M−H]−
MS (ESI) 506[M−H]−
1H-NMR (300 MHz, DMSO-d6) δ 0.84 (3H, t, J=7.2 Hz), 1.15-1.35 (4H, m), 1.77-1.95 (2H, m), 2.10-2.18 (2H, m), 2.80-2.92 (2H, m), 3.25-3.59 (3H, m), 4.01 (2H, m), 4.61 (2H, s), 6.80 (1H, d, J=7.8 Hz), 6.89 (1H, s), 6.92 (1H, d, J=7.8 Hz), 7.25 (1H, t, J=7.8 Hz), 7.43 (1H, d, J=12.3 Hz), 8.23 (1H, d, J=7.5 Hz)
1H-NMR (300 MHz, DMSO-d6) δ 0.84 (3H, t, J=7.2 Hz), 1.15-1.35 (4H, m), 1.74-1.99 (2H, m), 2.11-2.14 (2H, m), 2.26 (3H, s), 2.79-2.92 (2H, m), 3.33-3.57 (3H, m), 3.99 (2H, m), 4.61 (2H, s), 6.63 (1H, s), 6.69 (1H, s), 6.75 (1H, s), 7.43 (1H, d, J=12.3 Hz), 8.23 (1H, d, J=7.5 Hz)
1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J=7.72 Hz), 7.42 (1.0H, d, J=12.59 Hz), 7.24 (1.0H, dd, J=7.72, 7.72 Hz), 6.95-6.86 (2.0H, m), 6.82-6.75 (1.0H, m), 4.55 (2.0H, s), 4.11-3.86 (2.0H, m), 3.60-3.20 (3.0H, m), 2.90 (1.0H, d, J=12.25 Hz), 2.77 (1.0H, d, J=12.25 Hz), 2.25-2.06 (2.0H, m), 1.92-1.76 (1.0H, m), 1.70-1.54 (1.0H, m), 1.53-1.35 (1.0H, m), 0.95-0.88 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.24 (1.0H, d, J=7.39 Hz), 7.42 (1.0H, d, J=12.59 Hz), 6.75 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.61 (2.0H, s), 4.19-3.89 (2.0H, m), 3.59-3.21 (3.0H, m), 2.90 (1.0H, d, J=10.74 Hz), 2.83-2.71 (1.0H, m), 2.26 (3.0H, s), 2.21-2.08 (2.0H, m), 1.96-1.83 (1.0H, m), 1.65-1.52 (1.0H, m), 1.51-1.36 (1.0H, m), 0.95-0.88 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J=7.39 Hz), 7.43 (1.0H, d, J=12.42 Hz), 7.25 (1.0H, dd, J=7.72, 7.72 Hz), 6.96-6.88 (2.0H, m), 6.80 (1.0H, dd, J=8.31, 2.27 Hz), 4.64 (2.0H, s), 4.15-3.89 (2.0H, m), 3.60-3.22 (3.0H, m), 2.89 (1.0H, d, J=11.92 Hz), 2.82 (2.0H, d, J=11.92 Hz), 2.23-2.07 (2.0H, m), 1.90-1.76 (2.0H, m), 1.31-1.14 (2.0H, m), 0.90 (3.0H, t, J=7.30 Hz).
1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J=7.22 Hz), 7.43 (1.0H, d, J=12.42 Hz), 6.75 (1.0H, s), 6.69 (1.0H, s), 6.63 (1.0H, s), 4.62 (2.0H, s), 4.17-3.86 (2.0H, m), 3.57-3.22 (3.0H, m), 2.89 (1.0H, d, J=11.58 Hz), 2.81 (1.0H, d, J=11.58 Hz), 2.26 (3.0H, s), 2.19-2.07 (2.0H, m), 1.97-1.71 (2.0H, m), 1.31-1.15 (2.0H, m), 0.90 (3.0H, t, J=7.30 Hz).
1H-NMR (DMSO-d6) δ: 7.87 (1.0H, d, J=8.73 Hz), 7.77 (1.0H, d, J=8.39 Hz), 6.71 (1.0H, s), 6.64 (1.0H, s), 6.57 (1.0H, s), 4.28 (2.0H, s), 3.53-3.39 (6.0H, m), 3.00-2.71 (2.0H, m), 2.30-2.26 (3.0H, m), 2.18-2.15 (2.0H, m), 1.36-1.17 (4.0H, m), 0.87 (3.0H, t, J=7.13 Hz).
MS (ESI) 493 [M−H]−
MS (ESI) 507 [M−H]−
MS (ESI) m/z 493 [M−H]−
MS (ESI) m/z 507 [M−H]−
MS (ESI) m/z 524 [M+H]+
1H-NMR (DMSO-d6) δ: 7.89 (1.0H, d, J=2.18 Hz), 7.45 (1.0H, d, J=8.73 Hz), 7.29-7.20 (2.0H, m), 6.95-6.88 (2.0H, m), 6.80 (1.0H, dd, J=8.73, 2.18 Hz), 4.64 (2.0H, s), 4.11-4.01 (1.0H, m), 3.97-3.85 (1.0H, m), 3.56 (1.0H, d, J=13.76 Hz), 3.44-3.29 (2.0H, m), 2.88 (1.0H, d, J=10.74 Hz), 2.78 (1.0H, d, J=10.74 Hz), 2.22-2.06 (2.0H, m), 1.90-1.76 (1.0H, m), 1.67-1.54 (1.0H, m), 1.50-1.37 (1.0H, m), 0.91 (6.0H, d, J=6.55 Hz).
1H-NMR (DMSO-d6) δ: 7.89 (1.0H, d, J=2.18 Hz), 7.45 (1.0H, d, J=8.73 Hz), 7.23 (1.0H, dd, J=8.73, 2.18 Hz), 6.75 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.61 (2.0H, s), 4.09-4.00 (1.0H, m), 3.96-3.86 (1.0H, m), 3.55 (2.0H, d, J=13.26 Hz), 3.50-3.14 (1.0H, m), 2.89 (1.0H, d, J=11.92 Hz), 2.77 (1.0H, d, J=11.92 Hz), 2.26 (3.0H, s), 2.21-2.08 (2.0H, m), 1.96-1.83 (1.0H, m), 1.62-1.36 (2.0H, m), 0.94-0.88 (6.0H, m).
1H-NMR (300 MHz, DMSO-d6) δ0.90 (3H, t, J=7.2 Hz), 1.14-1.28 (2H, m), 1.72-1.90 (2H, m), 2.12-2.18 (2H, m), 2.79-2.89 (2H, m), 3.33-3.58 (3H, m), 3.89-4.00 (2H, m), 4.66 (2H, s), 6.80 (1H, dd, J=8.1 Hz, 1.8 Hz), 6.90-6.94 (2H, m), 7.22-7.28 (2H, m), 7.45 (1H, d, J=8.7 Hz), 7.88 (1H, s), 12.98 (1H, br s)
1H-NMR (300 MHz, DMSO-d6) δ0.88 (3H, t, J=7.5 Hz), 1.21 (2H, m), 1.71-1.91 (2H, m), 2.10-2.13 (2H, m), 2.24 (3H, s), 2.76-2.88 (2H, m), 3.30-3.53 (3H, m), 3.87-3.98 (2H, m), 4.60 (2H, s), 6.61 (1H, s), 6.67 (1H, s), 6.73 (1H, s), 7.21 (1H, d, J=8.7 Hz), 7.43 (1H, d, J=8.7 Hz), 7.85 (1H, s), 13.02 (1H, br s)
1H-NMR (DMSO-d6) δ: 7.54 (1H, s), 7.28-7.15 (2H, m), 6.74 (1H, s), 6.94-6.89 (2H, m), 6.80 (1H, d, J=7.8 Hz), 4.64 (2H, s), 4.13 (1H, s), 3.95 (1H, m), 3.57-3.32 (3H, m), 2.90-2.76 (2H, m), 2.19-2.11 (2H, m), 1.85-1.80 (2.0H, m), 1.28 (2H, q, J=7.2 Hz), 1.13 (2H, q, J=7.5 Hz), 0.83 (3H, t, J=7.2 Hz).
1H-NMR (DMSO-d6) δ: 7.54 (1H, d, J=1.85 Hz), 7.20 (2H, d, J=8.4 Hz), 6.74 (1H, s), 6.68 (1H, s), 6.62 (1H, s), 4.62 (2H, s), 4.14-3.92 (2H, m), 3.52 (1H, d, J=13.8 Hz), 2.90-2.75 2H, m), 2.26 (3H, s), 2.15-2.11 (2H, m), 1.80 (2.0H, m), 1.26 (2H, t, J=7.2 Hz), 0.85 (7.0H, t, J=5.96 Hz).
1H-NMR (DMSO-d6) δ: 7.54 (1.0H, d, J=2.18 Hz), 7.28-7.21 (2.0H, m), 7.17 (1.0H, dd, J=8.23, 2.18 Hz), 6.94-6.87 (2.0H, m), 6.79 (1.0H, dd, J=8.23, 2.18 Hz), 4.63 (2.0H, s), 4.29-4.21 (1.0H, m), 3.94 (1.0H, d, J=13.93 Hz), 3.54 (1.0H, d, J=13.93 Hz), 3.45-3.24 (2.0H, m), 2.86 (1.0H, d, J=10.74 Hz), 2.75 (1.3H, d, J=10.74 Hz), 2.30-2.05 (2.0H, m), 1.81-1.62 (2.0H, m), 1.47-1.35 (1.0H, m), 0.93-0.86 (6.0H, m).
1H-NMR (DMSO-d6) δ: 7.54 (1.0H, d, J=1.85 Hz), 7.24 (1.0H, d, J=8.56 Hz), 7.17 (1.0H, dd, J=8.56, 1.85 Hz), 6.74 (1.0H, s), 6.68 (1.0H, s), 6.62 (1.0H, s), 4.62 (2.0H, s), 4.29-4.20 (1.0H, m), 3.94 (1.0H, d, J=12.25 Hz), 3.52 (1.0H, d, J=13.76 Hz), 3.45-3.36 (2.0H, m), 2.87 (1.0H, d, J=10.58 Hz), 2.74 (1.0H, d, J=10.58 Hz), 2.26 (3.0H, s), 2.20-2.05 (2.0H, m), 1.80-1.62 (2.0H, m), 1.49-1.34 (1.0H, m), 0.90 (7.0H, t, J=5.96 Hz).
MS (ESI) m/z 442 [M−H]−
MS (ESI) m/z 456[M−H]−
MS (ESI) m/z 442[M−H]−
MS (ESI) m/z 456[M−H]−
1H-NMR (DMSO-d6) δ: 8.74 (2H, s), 7.55-7.45 (3H, m), 7.24 (1H, t, J=8.1 Hz), 7.14 (1H, m), 6.95-6.90 (2H, m), 6.80 (1H, dd, J=8.1, 2.4 Hz), 4.74 (1H, s), 4.64 (2H, s), 4.55 (1H, m), 3.57-3.53 (2H, m), 3.15 (1H, m), 2.89-2.79 (2H, m), 2.06-2.01 (2H, m), 1.84 (1H, m), 1.68 (1H, m), 127 (2H, q, J=7.2 Hz), 117 (2H, q, J=7.2 Hz), 0.82 (3H, t, J=7.1 Hz).
1H-NMR (DMSO-d6) δ: 8.74 (2H, s), 7.55-7.45 (3H, m), 7.24 (1H, t, J=8.1 Hz), 6.75 (1H, s), 6.68 (1H, s), 6.62 (1H, s), 4.74 (1H, s), 4.64 (2H, s), 4.55 (1H, m), 3.57-3.53 (2H, m), 3.15 (1H, m), 2.89-2.79 (2H, m), 2.25 (3H, s), 2.06-2.01 (2H, m), 1.84 (1H, m), 1.68 (1H, m), 127 (2H, q, J=7.2 Hz), 117 (2H, q, J=7.2 Hz), 0.82 (3H, t, J=7.1 Hz).
1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.57-7.42 (3.0H, m), 7.25 (1.0H, dd, J=7.89, 7.89 Hz), 7.18-7.09 (1.0H, m), 6.96-6.87 (2.0H, m), 6.80 (1.0H, dd, J=7.89, 2.52 Hz), 4.92-4.83 (1.0H, m), 4.66-4.52 (3.0H, m), 3.53 (1.0H, d, J=13.60 Hz), 3.48-3.07 (2.0H, m), 2.86 (1.0H, d, J=11.25 Hz), 2.77 (1.0H, d, J=11.25 Hz), 2.11-1.94 (2.0H, m), 1.74-1.61 (2.0H, m), 1.46-1.34 (1.0H, m), 0.93-0.86 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.73 (2.0H, s), 7.58-7.42 (3.0H, m), 7.18-7.09 (1.0H, m), 6.76 (1.0H, s), 6.69 (1.0H, s), 6.62 (1.0H, s), 4.91-4.81 (1.0H, m), 4.64-4.52 (3.0H, m), 3.51 (1.0H, d, J=13.60 Hz), 3.47-3.09 (2.0H, m), 2.92-2.82 (1.0H, m), 2.80-2.71 (1.0H, m), 2.26 (3.0H, s), 2.08-1.95 (2.0H, m), 1.81-1.69 (1.0H, m), 1.66-1.53 (1.0H, m), 1.49-1.35 (1.0H, m), 0.93-0.86 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.74 (2H, s), 7.55-7.45 (3H, m), 7.25 (1H, t, J=8.0 Hz), 7.14 (1H, m), 6.94-6.90 (2H, m), 6.79 (1H, dd, J=8.1, 2.4 Hz), 4.78 (1H, s), 4.64 (2H, s), 4.59 (1H, m), 3.57-3.10 (3H, m), 2.89-2.79 (2H, m), 2.08-2.04 (2H, m), 1.77 (2H, m), 1.17 (2H, q, J=7.2 Hz), 0.87 (3H, t, J=7.1 Hz).
1H-NMR (DMSO-d6) δ: 8.74 (2H, s), 7.55-7.45 (3H, m), 7.25 (1H, t, J=8.0 Hz), 6.75 (1H, s), 6.68 (1H, s), 6.62 (1H, s), 4.78 (1H, s), 4.64 (2H, s), 4.59 (1H, m), 3.57-3.10 (3H, m), 2.89-2.79 (2H, m), 2.26 (3H, s), 2.08-2.04 (2H, m), 1.77 (2H, m), 1.17 (2H, q, J=7.2 Hz), 0.87 (3H, t, J=7.1 Hz).
1H-NMR (300 MHz, DMSO-d6) δ0.83 (3H, t, J=7.2 Hz), 1.13-1.33 (4H, m), 1.62-1.91 (2H, m), 1.98-2.04 (2H, m), 2.79-2.90 (2H, m), 3.12-3.56 (3H, m), 4.52-4.57 (3H, m), 4.74 (1H, m), 6.77 (1H, d, J=7.8 Hz), 6.88 (1H, s), 6.91 (1H, d, J=7.8 Hz), 7.11-7.16 (1H, m), 7.23 (1H, t, J=7.8 Hz), 7.43-7.55 (3H, m), 8.73 (2H, s)
1H-NMR (300 MHz, DMSO-d6) δ0.83 (3H, t, J=7.2 Hz), 1.06-1.33 (4H, m), 1.61-1.91 (2H, m), 1.98-2.05 (2H, m), 2.26 (3H, s), 2.78-2.90 (2H, m), 3.11-3.55 (3H, m), 4.55 (1H, d, =12.3 Hz), 4.61 (2H, s), 4.72 (1H, m), 6.62 (1H, s), 6.69 (1H, s), 6.76 (1H, s), 7.14 (1H, m), 7.45-7.55 (3H, m), 8.73 (2H, s), 12.94 (1H, br s)
TLC: (SiO2) AcOEt Rf=0.29
1H-NMR (DMSO-d6) δ: 8.42 (2.0H, s), 7.24 (1.0H, dd, J=7.72, 7.72 Hz), 6.94-6.86 (2.0H, m), 6.79 (1.0H, dd, J=8.56, 1.85 Hz), 4.76-4.67 (1.0H, m), 4.64 (2.0H, s), 4.40 (1.0H, d, J=12.93 Hz), 3.51 (1.0H, d, J=13.60 Hz), 3.42-3.21 (1.0H, m), 3.18-3.05 (1.0H, m), 2.83 (1.0H, d, J=11.25 Hz), 2.74 (1.0H, d, J=11.25 Hz), 2.09-1.90 (2.0H, m), 1.72-1.52 (2.0H, m), 1.41-1.30 (1.0H, m), 0.89-0.83 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.42 (2.0H, s), 6.74 (1.0H, s), 6.67 (1.0H, s), 6.61 (1.0H, s), 4.76-4.66 (1.0H, br m), 4.60 (2.0H, s), 4.40 (1.0H, d, J=13.26 Hz), 3.49 (1.0H, d, J=13.93 Hz), 3.45-3.20 (1.0H, m), 3.18-3.05 (1.0H, m), 2.83 (1.0H, d, J=12.09 Hz), 2.77-2.69 (1.0H, m), 2.25 (3.0H, s), 2.04-1.96 (2.0H, m), 1.77-1.65 (1.0H, m), 1.60-1.47 (1.0H, m), 1.44-1.28 (1.0H, m), 0.90-0.83 (6.0H, m).
1H-NMR (DMSO-d6) δ: 8.22 (1H, s), 7.59-7.53 (2H, m), 6.75 (1H, s), 6.68 (1H, s), 6.54 (1H, s), 4.21-3.89 (2H, m), 3.55-3.30 (3H, m), 2.92-2.75 (2H, m), 2.24 (3H, s), 2.18-2.02 (2H, m), 1.83 (1H, m), 1.65-1.38 (2H, m), 1.51 (6H, s), 0.93-0.91 (6H, m).
MS (ESI) m/z 442 [M+H]+
MS (ESI) m/z 462 [M+H]+
MS (ESI) m/z 442 [M+H]+
1H-NMR (DMSO-d6) δ: 1.01 (6H, d, J=5.5 Hz), 2.70-2.87 (4H, m), 3.22 (3H, s), 3.47 (2H, d, J=10.2 Hz), 3.55 (2H, s), 3.71-3.83 (4H, m), 4.15-4.24 (2H, m), 7.04-7.45 (8H, m).
1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J=5.2 Hz), 2.70-2.88 (4H, m), 3.45 (2H, d, J=11.0 Hz), 3.55 (2H, s), 3.60 (3H, s), 3.81 (2H, s), 7.04-7.42 (8H, m).
1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J=6.0 Hz), 2.66-2.79 (2H, m), 3.01 (2H, t, J=11.7 Hz), 3.54 (3H, s), 3.76-3.88 (4H, m), 7.02-7.31 (6H, m), 7.44 (1H, d, J=8.0 Hz), 7.75 (1H, d, J=7.7 Hz).
1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J=6.0 Hz), 2.63-2.76 (2H, m), 2.93-3.04 (2H, m), 3.53 (2H, s), 3.78 (2H, s), 3.90-3.98 (2H, m), 6.98-7.41 (8H, m).
1H-NMR (DMSO-d6) δ: 1.01 (6H, d, J=6.0 Hz), 2.50-2.58 (2H, m), 2.80 (2H, dd, J=12.6, 10.4 Hz), 3.52 (2H, s), 3.75 (2H, s), 4.34 (2H, dd, J=12.6, 1.6 Hz), 7.05-7.27 (4H, m), 8.44 (2H, s).
1H-NMR (DMSO-d6) δ: 1.02 (6H, d, J=6.0 Hz), 2.47-2.55 (2H, m), 2.61-2.74 (2H, m), 3.52 (2H, s), 3.60-3.67 (2H, m), 3.76 (2H, s), 7.07-7.45 (6H, m), 8.07 (1H, d, J=3.3 Hz).
1H-NMR Acetone) δ: 7.76 (1.0H, s), 7.50 (1.0H, d, J=9.06 Hz), 7.41 (1.0H, s), 7.35 (1.0H, d, J=7.42 Hz), 7.30-7.22 (2.0H, m), 7.16 (1.0H, d, J=7.42 Hz), 3.94 (2.0H, dd, J=12.71, 2.33 Hz), 3.86 (2.0H, s), 3.62 (2.0H, s), 3.10 (2.0H, dd, J=12.71, 10.16 Hz), 2.87-2.77 (2.0H, m), 1.12 (6.0H, d, J=6.00 Hz).
1H-NMR Acetone) δ: 8.27 (1.0H, d, J=1.80 Hz), 7.82 (1.0H, dd, J=8.46, 1.80 Hz), 7.58 (1.0H, d, J=8.46 Hz), 7.41 (1.0H, s), 7.35 (1.0H, d, J=7.42 Hz), 7.27 (1.0H, dd, J=7.42, 7.42 Hz), 7.17 (1.0H, d, J=7.42 Hz), 4.00 (2.0H, d, J=12.64 Hz), 3.87 (2.0H, s), 3.63 (2.0H, s), 3.21-3.07 (5.0H, m), 2.89-2.78 (2.0H, m), 1.13 (6.0H, d, J=6.32 Hz).
1H-NMR Acetone) δ: 7.81 (1.0H, s), 7.47-7.33 (4.0H, m), 7.26 (1.0H, dd, J=7.54, 7.54 Hz), 7.16 (1.0H, d, J=7.54 Hz), 3.96 (2.0H, d, J=12.91 Hz), 3.86 (2.0H, s), 3.62 (2.0H, s), 3.15-3.01 (8.0H, m), 2.92-2.78 (2.0H, m), 1.12 (6.0H, d, J=6.04 Hz).
1H-NMR (Acetone) δ: 8.23 (1.0H, s), 7.82 (1.0H, d, J=8.52 Hz), 7.64 (1.0H, br s), 7.48-7.23 (4.0H, m), 7.16 (1.0H, d, J=7.14 Hz), 3.96 (2.0H, d, J=12.64 Hz), 3.86 (2.0H, s), 3.62 (2.0H, s), 3.11 (2.0H, dd, J=11.40, 11.40 Hz), 2.93-2.76 (5.0H, m), 1.12 (6.0H, d, J=6.32 Hz).
1H-NMR Acetone) δ: 7.42-7.31 (4.0H, m), 7.26 (1.0H, dd, J=7.42, 7.42 Hz), 7.16 (1.0H, d, J=7.42 Hz), 6.90 (1.0H, dd, J=8.79, 2.75 Hz), 3.90-3.84 (4.0H, m), 3.80 (3.0H, s), 3.60 (2.0H, s), 3.01 (2.0H, dd, J=12.77, 10.30 Hz), 2.83-2.72 (2.0H, m), 1.11 (6.0H, d, J=6.00 Hz).
1H-NMR Acetone) δ: 7.83 (1.0H, d, J=8.24 Hz), 7.73 (1.0H, d, J=8.24 Hz), 7.42 (1.0H, s), 7.36 (1.0H, d, J=7.55 Hz), 7.27 (1.0H, dd, J=7.55, 7.55 Hz), 7.17 (1.0H, d, J=7.55 Hz), 4.05 (2.0H, d, J=13.05 Hz), 3.88 (2.0H, s), 3.63 (2.0H, s), 3.21 (2.0H, dd, J=13.05, 10.30 Hz), 1.14 (6.0H, d, J=6.32 Hz).
1H-NMR (DMSO-d6) δ: 7.70 (1.0H, dd, J=8.52, 2.75 Hz), 7.43 (1.0H, dd, J=9.06, 4.94 Hz), 7.28-7.20 (3.0H, m), 7.16-7.05 (2.0H, m), 3.83-3.78 (4.0H, m), 3.52 (2.0H, s), 3.01 (2.0H, dd, J=11.54, 11.54 Hz), 2.77-2.69 (2.0H, m), 1.04 (6.0H, d, J=6.04 Hz).
1H-NMR (Acetone) δ: 8.30 (1.0H, d, J=5.22 Hz), 7.31 (1.0H, d, J=7.97 Hz), 7.13 (1.0H, d, J=1.92 Hz), 7.05 (1.0H, s), 6.89 (1.0H, dd, J=7.97, 1.92 Hz), 6.80 (1.0H, d, J=5.22 Hz), 4.32 (2.0H, d, J=13.73 Hz), 4.16 (2.0H, dd, J=6.04, 6.04 Hz), 3.23 (2.0H, dd, J=6.04, 6.04 Hz), 2.89-2.79 (2.0H, m), 2.70-2.61 (2.0H, m), 1.25 (6.0H, d, J=6.04 Hz).
1H-NMR (DMSO-d6) δ: 1.05 (7H, d, J=6.0 Hz), 2.58-2.87 (4H, m), 3.54 (2H, s), 3.77 (2H, s), 4.23-4.34 (2H, m), 7.05-7.53 (8H, m), 7.90-8.06 (3H, m).
1H-NMR (Acetone) δ: 7.50 (1.0H, dd, J=7.97, 7.97 Hz), 7.40 (1.0H, s), 7.34 (1.0H, d, J=7.42 Hz), 7.25 (1.0H, dd, J=7.42, 7.42 Hz), 7.15 (1.0H, d, J=7.42 Hz), 6.75 (1.0H, d, J=7.97 Hz), 6.59 (1.0H, d, J=7.97 Hz), 4.13 (2.0H, d, J=11.54 Hz), 3.82 (2.0H, s), 3.61 (2.0H, s), 2.80-2.62 (4.0H, m), 1.08 (6.0H, d, J=5.77 Hz).
MS (ESI) m/z 428 [M+H]+
1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J=6.0 Hz), 2.27 (3H, s), 2.63-2.80 (2H, m), 2.85-2.97 (2H, m), 3.49 (2H, s), 3.69-3.78 (4H, m), 6.86-7.61 (9H, m).
1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J=6.0 Hz), 2.52-2.62 (2H, m), 2.84 (2H, dd, J=12.9, 10.4 Hz), 3.54 (2H, s), 3.77 (2H, s), 4.44-4.52 (2H, m), 7.07-7.64 (9H, m), 8.69 (2H, s).
1H-NMR (DMSO-d6)) δ: 7.77 (1H, s), 7.59-7.53 (1H, m), 7.37-7.29 (1H, m), 7.14-7.06 (3H, m), 6.89 (1H, s), 3.78-3.73 (4H, m), 3.49 (2H, s), 2.94 (2H, t, J=12.6 Hz), 2.74-2.68 (2H, m), 2.27 (3H, s), 1.0.3 (6H, d, J=6.3 Hz).
1H-NMR (DMSO-d6)) δ: 7.77 (1H, s), 7.59-7.53 (1H, m), 7.37-7.29 (1H, m), 7.14-7.06 (3H, m), 6.76 (2H, s), 6.54 (1H, s), 4.60 (2H, s), 3.79-3.70 (4H, m), 2.93 (2H, t, J=10.5 Hz), 2.70 (2H, brs), 2.25 (3H, s), 1.02 (6H, d, J=6.0 Hz).
1H-NMR (Acetone) δ: 8.43 (1.0H, d, J=2.54 Hz), 7.81 (1.0H, dd, J=9.00, 2.54 Hz), 7.61-7.58 (2.0H, m), 7.45-7.24 (6.0H, m), 7.16 (1.0H, d, J=7.69 Hz), 6.91 (1.0H, d, J=9.00 Hz), 4.25 (2.0H, d, J=11.81 Hz), 3.84 (2.0H, s), 3.63 (2.0H, s), 2.90-2.63 (4.0H, m), 1.10 (6.0H, d, J=5.22 Hz).
1H-NMR (Acetone) δ: 8.09-8.07 (2.0H, m), 7.60 (1.0H, dd, J=7.76, 7.76 Hz), 7.48-7.34 (5.0H, m), 7.26 (1.0H, dd, J=7.76, 7.76 Hz), 7.20-7.13 (2.0H, m), 6.79 (1.0H, d, J=8.79 Hz), 4.32 (2.0H, d, J=11.81 Hz), 3.83 (2.0H, s), 3.62 (2.0H, s), 2.93-2.67 (4.0H, m), 1.10 (2.0H, d, J=5.70 Hz).
1H-NMR (DMSO-d6) δ: 1.00 (6H, d, J=6.0 Hz), 2.35 (3H, t, J=10.7 Hz), 2.61-2.73 (2H, m), 3.53 (2H, s), 3.75 (2H, s), 5.90 (2H, s), 6.32 (1H, dd, J=8.5, 1.6 Hz), 6.65-6.78 (2H, m), 7.05-7.28 (4H, m).
1H-NMR (DMSO-d6) δ: 1.03 (7H, d, J=6.0 Hz), 2.35-2.46 (2H, m), 2.68-2.81 (2H, m), 3.55 (2H, s), 3.72 (3H, s), 3.79 (2H, s), 6.27 (1H, d, J=2.2 Hz), 6.90-7.31 (8H, m).
1H-NMR (DMSO-d6) δ: 1.03 (6H, d, J=5.2 Hz), 2.61-2.76 (4H, m), 2.92-3.00 (2H, m), 3.53 (2H, s), 3.75 (2H, s), 3.83 (2H, d, J=10.7 Hz), 6.93-7.28 (6H, m), 7.42 (1H, d, J=8.5 Hz).
1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J=6.0 Hz), 2.50-2.58 (2H, m), 2.66-2.78 (2H, m), 3.54 (2H, s), 3.66 (2H, d, J=11.5 Hz), 3.78 (2H, s), 7.06-7.31 (5H, m), 7.59 (1H, d, J=2.2 Hz), 7.87 (1H, d, J=9.1 Hz), 9.07 (1H, s).
1H-NMR (DMSO-d6) δ: 1.04 (6H, d, J=6.0 Hz), 2.45-2.75 (7H, m), 3.54 (2H, s), 3.61 (2H, d, J=10.7 Hz), 3.78 (2H, s), 7.06-7.39 (6H, m), 7.78 (1H, d, J=8.8 Hz).
1H-NMR (Acetone) δ: 7.49 (2.0H, d, J=8.66 Hz), 7.40 (1.0H, s), 7.35 (1.0H, d, J=7.42 Hz), 7.26 (1.0H, dd, J=7.42, 7.42 Hz), 7.16 (1.0H, d, J=7.42 Hz), 7.08 (2.0H, d, J=8.66 Hz), 3.83 (2.0H, s), 3.75 (2.0H, d, J=10.71 Hz), 3.62 (2.0H, s), 2.84-2.66 (4.0H, m), 1.09 (6.0H, d, J=5.77 Hz).
1H-NMR (Acetone) δ: 7.53-7.49 (2.0H, m), 7.41 (1.0H, s), 7.37-7.32 (3.0H, m), 7.29 (1.0H, d, J=4.39 Hz), 7.25 (1.0H, d, J=7.42 Hz), 7.20-7.13 (3.0H, m), 6.17 (1.0H, d, J=3.85 Hz), 3.85 (2.0H, s), 3.63 (2.0H, s), 3.43 (2.0H, d, J=9.61 Hz), 2.86-2.83 (2.0H, m), 2.70-2.66 (2.0H, m), 1.09 (6.0H, d, J=6.32 Hz).
1H-NMR (DMSO-d6) δ: 8.72 (2H, s), 7.59-7.40 (2H, m), 7.13 (1H, t, J=8.1 Hz), 6.75 (1H, s), 6.66 (1H, s), 6.54 (1H, s), 4.86 (1H, br-s), 4.56 (1H, d, J=12.9 Hz), 3.48-3.13 (3H, m), 2.86-2.72 (2H, m), 2.23 (3H, s), 2.10-1.90 (2H, m), 1.39 (1H, m), 0.91-0.87 (6H, m).
1H-NMR (DMSO-d6) δ: 8.72 (2H, s), 6.75 (1H, s), 6.66 (1H, s), 6.54 (1H, s), 4.86 (1H, br-s), 4.56 (1H, d, J=12.9 Hz), 3.48-3.13 (3H, m), 2.86-2.72 (2H, m), 2.23 (3H, s), 2.10-1.90 (2H, m), 1.39 (1H, m), 0.91-0.87 (6H, m).
1H-NMR (DMSO-d6) δ: 8.23 (1.0H, d, J=7.22 Hz), 7.42 (1.0H, d, J=12.42 Hz), 6.73 (1.0H, s), 6.65 (1.0H, s), 6.54 (1.0H, s), 4.15-3.86 (2.0H, m), 3.53-3.20 (3.0H, m), 2.92-2.75 (2.0H, m), 2.24 (3.0H, s), 2.20-2.05 (2.0H, m), 1.92-1.70 (2.0H, m), 1.52-1.48 (6.0H, m), 1.30-1.14 (2.0H, m), 0.90 (3.0H, t, J=7.30 Hz).
MS (ESI) 534[M−H]−
MS (ESI) 494[M−H]−
MS (ESI) 508[M−H]−
MS (ESI) 536[M−H]−
1H-NMR (300 MHz, DMSO-d6) δ 0.85 (3H, t, J=7.2 Hz), 1.13-1.35 (4H, m), 1.50 (6H, s), 1.75-1.94 (2H, m), 2.12-2.17 (2H, m), 2.24 (3H, s), 2.78-2.90 (2H, m), 3.33-3.53 (3H, m), 4.02 (2H, m), 6.54 (1H, s), 6.65 (1H, s), 6.74 (1H, s), 7.43 (1H, d, J=12.0 Hz), 8.23 (1H, d, J=7.2 Hz), 12.97 (1H, br s)
MS (ESI) m/z 428 [M+H]+
TLC_Rf=0.55 (MeOH:CHCl3=1:10)
1H-NMR (300 MHz, DMSO-d6) δ 0.83 (3H, t, J=7.2 Hz), 1.06-1.33 (4H, m), 1.51 (6H, s), 1.61-1.91 (2H, m), 1.98-2.05 (2H, m), 2.26 (3H, s), 2.78-2.90 (2H, m), 3.11-3.55 (3H, m), 4.55 (1H, d, =12.3 Hz), 4.72 (1H, m), 6.54 (1H, s), 6.66 (1H, s), 6.75 (1H, s), 7.14 (1H, m), 7.45-7.55 (3H, m), 8.72 (2H, s)
The present invention includes the following compounds synthesized by similar methods as above.
Compound I-1
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 a (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. pG5luc vector (Promega) was used as a reporter plasmid.
Cell culturing and transfection: CHO cells were cultured in 10% FBS-aMEM. 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 CO2 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 9.
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 (14C 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-position 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 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.
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.
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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2005-246297 | Aug 2005 | JP | national |
| 2006-154607 | Jun 2006 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2006/316564 | 8/24/2006 | WO | 00 | 4/8/2008 |
