ZA200507365B - Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient - Google Patents

Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient Download PDF

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ZA200507365B
ZA200507365B ZA200507365A ZA200507365A ZA200507365B ZA 200507365 B ZA200507365 B ZA 200507365B ZA 200507365 A ZA200507365 A ZA 200507365A ZA 200507365 A ZA200507365 A ZA 200507365A ZA 200507365 B ZA200507365 B ZA 200507365B
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South Africa
Prior art keywords
amino
group
phenoxy
methanol
methyl
Prior art date
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ZA200507365A
Inventor
Rena Nishizawa
Shiro Shibayama
Yoshikazu Takaoka
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Ono Pharmaceutical Co
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Publication of ZA200507365B publication Critical patent/ZA200507365B/en

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oO
DESCRIPTION
NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVES AND
DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT
TECHNICAL FIELD
The present invention relates to (1) compounds represented by formula (I)
CL
X
(wherein all symbols have the same meanings as described hereinafter), salts thereof or solvates thereof, or prodrugs thereof, and (2) treatment and/or prevention for diseases through the intervention of CCR5 comprising compounds represented by formula (I), salts thereof or solvates thereof, or prodrugs thereof, as an active ingredient.
BACKGROUND ART
Chemokine is known as a basic protein having endogeneous leukocyte chemotactic and activating abilities and strong heparin-binding abilities. At present, it is considered that chemokine is related to not only the control of infiltration of specific leukocyte at the time of inflammations and immune responses but also the development and homing of lymphocyte under physiological conditions and migration of hemocyte precursor cells and somatic cells.
Differentiation, proliferation and cell death of hemocytes are controlled by various types of cytokine. In the living body, inflammations are found topically and differentiation, maturation and the like of lymphocytes are carried out at certain specified sites. That is, various necessary cells migrate into certain specified sites and accumulate therein to cause a series of inflammations and immune responses. Accordingly, migration of cells is also an indispensable phenomenon in addition to differentiation, proliferation and death of cells.
Migration of hemocytes in the living body starts firstly in the development stage by the shift of hematopoiesis started in the AGM region into permanent hematopoiesis in bone marrow via fetal liver. Furthermore, precursor cells of T cells and thymus dendritic cells migrate from the fetal liver into the bone marrow and then into the thymus gland and cytodifferentiate under thymus environment. The T cell which — received clone selection migrates into secondary lymphoid tissues and takes part in an immune response in the periphery. The Langerhans’ cell of the skin activated and differentiated by capturing an antigen migrates into the T cell region of a topical lymph
CW | 9005. C7057 node and activates naive T cell therein as a dendritic cell. The memory T cell performs its homing again into the lymph node via lymphatic and blood vessels. Also, B cell, T cell in the intestinal epithelium, v8 T cell, NKT cell and dendritic cell migrate from bone marrow without passing through the thymus gland and differentiate to take part in an immune response.
Chemokine deeply takes part in the migration of such various cells. Chemokine receptors are greatly related to the control of inflammation and immune responses through a mechanism in which they are expressed at certain specified periods in variously specific cells and the effector cells are accumulated in a region where chemokine is produced.
Acquired immunodeficiency syndrome (called AIDS) which is induced by human immunodeficiency virus (hereinafter referred to as "HIV") is one of the diseases of which their therapeutic methods are most eamestly desired in recent years. Once infection with HIV is completed in a CD4-positive cell which is a principal target cell, HIV repeats its proliferation in the body of the patient and, sooner or later, completely destroys
T cell which takes charge of the immunological function. During this process, the immunological function is gradually reduced to cause fever, diarrhea, lymph node enlargement and the like various immunodeficiency conditions which are apt to cause complications with pneumocystis carinii pneumonia and the like various opportunistic infections. Such conditions are the onset of AIDS, and it is well known that they induce and worsen Kaposi sarcoma and the like malignant tumors.
As the recent preventive and therapeutic methods for AIDS, attempts have been made to, e.g., (1) inhibit growth of HIV by the administration of a reverse transcriptase inhibitor or a protease inhibitor and (2) prevent or alleviate opportunistic infections by the administration of a drug having immunopotentiation activity.
Helper T cells which take charge of the central of immune system are mainly infected with HIV. It is known since 1985 that HIV uses the membrane protein CD4 expressing on the membrane of T cells in the infection (Cell, 52, 631 (1985)). The CD4 molecule is composed of 433 amino acid residues, and its expression can be found in macrophages, some B cells, vascular endothelial cells, Langerhans’ cells in skin tissues, dendritic cells in lymphoid tissues, glia cells of the central nervous system and the like, in addition to the mature helper T cells. However, since it has been revealed that the infection with HIV is not completed by the CD4 molecule alone, a possibility has been suggested on the presence of factors other than the CD4 molecule, which are related to the infection of cells with HIV.
CCRS, which is a receptor of RANTES, MIP-1a and MIP-18, is also used at — the time of the infection with a macrophage tropic (R5) HIV (Science, 272, 1955 (1996)).
Accordingly, substances which can compete with CCR5 for HIV, or which can bind to HIV virus thus causing the virus unable to bind to CCRS, could become HIV infection inhibitors.
Based on the above, it is considered that CCRS receptors are deeply related to the inflammation, immune disease or HIV infection. For example, it is considered that they are related to various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, ulcerative colitis and the like), immunologic diseases (autoimmune diseases, rejection in organ transplantation, immunosuppression, psoriasis, multiple sclerosis and the like), infection with human immunodeficiency virus (acquired immunodeficiency syndrome and the like), allergic diseases (atopic dermatitis, uticaria, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis and the like), ischemic reperfusion injury, acute respiratory distress syndrome, shock accompanying bacterial infection, diabetes mellitus, or cancer metastasis and the like.
It is reported that the aminopiperidine derivatives represented by formula (a)
AN
R12 nN" (a) 2a ah R haa (wherein R'* is hydrogen atom or Cl-12 alkyl, R* and R*® are each independently hydrogen atom or C1-12 alkyl, X* is nitrogen atom or oxygen atom, A* is
DS ST yr and Re
R52 Ra (wherein R* is hydrogen atom, C1-12 alkyl, C3-8 cycloalkyl, aryl, substituted aryl, aryl-
C(=0)- or aryl-CH(OH)-, R** is hydrogen, C1-12 alkyl, C1-4 alkoxy, halogen or COR, R** is hydrogen, C1-12 alkyl or substituted C1-4 alkyl. With the proviso that the definition of each symbol is a excerpt partially.) are useful as inhibitors of the chemokine receptors (ref. - specification of WO02/79186).
It is described that the sulfonic acid derivatives represented by formula (b) -3- h
LIN
SO;H 0 (R®),
Fe AA x
La PE (b) (R™)q oN F (R*) are selective antagonists of CCR1 receptors (ref. specification of W002/102787).
Moreover, 1-(4-pyridyl)-piperazine derivatives are described as CCRS antagonists (ref. specification of US6,391,865).
On the other hand, it is reported that triazaspiro[5.5]Jundecane derivatives, quaternary ammonium salts thereof or N-oxides thereof, or pharmacologically acceptable salts thereof regulate the effect of chemokine/chemokine receptor, so they are used for prevention and/or treatment of various inflammatory diseases, asthma, atopic dermatitis, urticaria, allergic diseases (allergic bronchopulmonary aspergillosis or allergic eosinophilic gastroenteritis efc.), nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, psoriasis, rhinitis, conjunctivitis, ischemic reperfusion disorder, multiple sclerosis, ulcerative colitis, acute respiratory distress syndrome, cytotoxic shock, diabetes, autoimmune disease, in transplanted organ rejection reactions, immunosuppression, cancer metastasis and acquired immune deficiency syndrome (ref. specification of W001/40227).
It is described that the compounds represented by formula (c) (0)
J nc
D°—N (eee (c)
Rc R2e me (wherein mc and nc, which are the same or different, is each zero or the integer 1 or 2,
Alk™* is a covalent bond or a straight or branched C1-6 alkylene chain, R!® and R*, which are the same or different, is each a hydrogen atom or a straight or branched C1-6 alkyl group, Df is an optionally substituted aromatic or heteroaromatic group, Eis an optionally substituted C7-10 cycloalkyl, C7-10 cycloalkenyl or C7-10 polycycloaliphatic group.) are modulators of CXCR3 (ref. specification of W003/070242).
DISCLOSURE OF THE INVENTION
The compound which regulates CCRS5 receptor is used as prevention and - treatment for diseases through the intervention of CCRS receptor. Therefore it is desired that safety CCRS regulators, especially CCRS antagonists, are developed.
PCT/JP2004/003333 ®
In order to find a compound binding and regulating CCRS receptor specifically, the present inventors have conducted intensive studies and found, as a result, that the objects can be accomplished by the compound represented by formula (I), and thus the present invention has been accomplished.
The present invention relates to 1. a compound represented by formula (I):
RSYISECHE
X wherein R' represents a hydrogen atom or an acidic group which may be protected;
X and Y each independently represents a bond or a spacer containing 1 to 3 atoms as a main chain; ring A and ring B, which are the same or different, each represents a 3- to 15- membered homocyclic group or heterocyclic group which may have a substituent(s); ring D represents a 3- to 15-membered nitrogen-containing heterocyclic group which may have a substituent(s);
R? represents (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent(s), (3) a cyano group, (4) a hydroxy group which may be protected, (5) an amino group which may have a substituent(s), (6) an oxo group, (7) a 3- to 15-membered heterocyclic group which may have a substituent(s) or (8) =N-OR®, wherein R® represents a hydrogen atom or C1-4 alkyl, a salt thereof or a solvate thereof, or a prodrug thereof, 2. the compound according to the above-described 1, wherein R' is an acidic group which may be protected, = : a 3. the compound according to the above-described 2, wherein the acidic group is carboxy or sulfonamide, 4. the compound according to the above-described 1, wherein X and Y are each independently a bond or a divalent group selected from (1)-CR’R®-, (2)-NR’-, (3)-CO-, (4)-0-, (5)-S-, (6)-SO-, (7)-SO;- and (8)-C(=N-OR'®)-, wherein R’ and R® each independently represents a hydrogen atom, C1-4 alkyl, -OR" or phenyl; R’ represents a hydrogen atom Cl-4 alkyl, or phenyl; R'® and R'' each independently represents a hydrogen atom or C1-4 alkyl, 5. the compound according to the above-described 4, wherein X is a bond, -O- or -CH,-, 6. the compound according to the above-described 1, wherein Y is C1-3 alkylene, -5-
AMENDED SHEET
PCT/IP2004/003333 ® 7. the compound according to the above-described 1, wherein ring D is a S- to 10- membered nitrogen-containing heterocyclic group which may have a substituents), 8. the compound according to the above-described 1, wherein ring A and ring B, which are the same or different, are each a 5- to 10-membered homocyclic group or heterocyclic group which may have a substituent(s), 9. the compound according to the above-described 1, wherein ring A and ring B, which are the same or different, are each a 5- or 6-membered aromatic ring which may have a substituent(s), 10. the compound according to the above-described 1, wherein R? is 0) ~~ PY _R%
N
RS? R52 wherein the arrow represents a binding position to ring D; R*, R*? and R* each independently represents (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent(s), (3) a 3- to 15-membered heterocyclic group which may have a substituent(s), (4) a C1-4 alkoxy group which may have a substituent(s), (5) a phenoxy group which may have a substituent(s) or (6) a benzyloxy group which may have a substituent(s), 11. the compound according to the above-described 1, which is represented by formula (Ia): (SIORC
R1 N D1a}-R2 (1a)
X wherein ring D'* is piperidine or piperazine which may have a substituent(s) and other symbols have the same meanings as those described in the above-described 1, 12. the compound according to the above-described 1, which is selected from the group consisting of (1) N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide, (2) N-[4-(4-{[4-(butyl{[(6-methyl-3-pyridinyl)amino]carbonyl }amino)-1- piperidinyl]methyl } phenoxy)phenyl]Jmethanesulfonamide, 3) N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)piperidin-1- yl]lmethyl}-3,5-dimethyl-1H-pyrazol-1-yl)phenylJmethanesulfonamide, 4) N-[4-(4-{[4-(butyl{[(1-methyl-1H-pyrazol-4- yl)amino]carbonyl}amino)piperidin-1-yl]methyl}phenoxy)phenyl]methanesulfonamide, -6-
AMENDED SHEET
0 (5) 3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]Jamino} carbonyl)amino]benzamide, (6) N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(phenyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide, 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl )piperidin-4- yl]lamino} carbonyl)amino]-2-fluorobenzamide, (8) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl )piperidin-4- yl]amino} carbonyl)amino]-2,4-difluorobenzamide, )) N-[4-(4-{[4-(butyl {[(3-cyano-4- fluorophenyl)amino]carbonyl}amino)piperidin-1- yl]methyl } phenoxy)phenylJmethanesulfonamide, and (10) N-[4-(4-{[4-(butyl{[(3-hydroxycyclohexyl)amino]carbonyl}amino)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide, and
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(1,3-thiazol-4- ylmethyl)amino]piperidin-1-yl} methyl)phenoxy]phenyl} methanesulfonamide, 13. a CCRS regulator comprising the compound according to the above-described 1, a salt thereof or a solvate thereof, or a prodrug thereof, 14. the CCRS5 regulator according to the above-described 13, which is a CCRS antagonist, 15. the CCRS5 regulator according to the above-described 13, which is an agent for treatment and/or prevention for a disease through the intervention of CCRS, 16. the CCRS regulator according to the above-described 15, wherein the disease through the intervention of CCRS is infection with human immunodeficiency virus, 17. the CCRS regulator according to the above-described 16, wherein the infection with human immunodeficiency virus is acquired immune deficiency syndrome, 18. the CCRS regulator according to the above-described 15, wherein the disease through the intervention of CCRS is immunological diseases, 19. the CCRS regulator according to the above-described 18, wherein the immunological disease is rejection in organ transplantation, 20. the CCRS5 regulator according to the above-described 15, wherein the disease through the intervention of CCRS is inflammatory diseases, 21. the CCRS regulator according to the above-described 20, wherein the inflammatory disease is asthma, 22. an agent for prevention and/or treatment for infection with human immunodeficiency virus, immunological diseases or inflammatory diseases, which -— comprises the compound represented by formula (I) according to the above-described 1, a salt thereof or a solvate thereof, or a prodrug thereof,
PCT/JP2004/003333 ® 23. a pharmaceutical composition, which comprises the compound represented by formula (I) according to the above-described 1, a salt thereof or a solvate thereof, or a prodrug thereof, 24. a medicament which comprises the compound represented by formula (I) according to the above-described 1, a salt thereof or a solvate thereof, or a prodrug thereof, in combination with one or at least two of a reverse transferase inhibitor, a protease inhibitor, a CCR2 antagonist, a CCR3 antagonist, a CCR4 antagonist, a CCRS5 antagonist, a
CXCR4 antagonist, a fusion inhibitor, an antibody against a surface antigen of HIV-1, and a vaccine of HIV-1, 25. a method for treating or preventing a disease through the intervention of CCR5 in a mammal, which comprises administering to a mammal an effective amount of a compound represented by formula (I):
X wherein R' represents a hydrogen atom or an acidic group which may be 1S protected,
X and Y each independently represents a bond or a spacer containing 1 to 3 atoms as a main chain; ring A and ring B, which are the same or different, each represents a 3- to 15- membered homocyclic group or heterocyclic group which may have a substituent(s); ring D represents a 3- to 15-membered nitrogen-containing heterocyclic group which may have a substituent(s);
R? represents (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent(s), (3) a cyano group, (4) a hydroxy group which may be protected,..(5) an amino group which may have a substituent(s), (6) an oxo group, (7) a 3- to 15-membered heterocyclic group which may have a substituent(s) or (8) =N-OR®, wherein R® represents a hydrogen atom or C1-4 alkyl, a salt thereof or a solvate thereof, or a prodrug thereof, 26. use of a compound represented by formula (I): (Te
X wherein R! represents a hydrogen atom or an acidic group which may be protected, -8-
AMENDED SHEET
PCT/JP2004/003333
X and Y each independently represents a bond or a spacer containing 1 to 3 atoms as a main chain; ring A and ring B, which are the same or different, each independently represents a 3- to 15-membered homocyclic group or heterocyclic group which may have a substituent(s); ring D represents a 3- to 15-membered nitrogen-containing heterocyclic group which may have a substituent(s);
R? represents (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent(s), (3) a cyano group, (4) a hydroxy group which may be protected, (5) an amino group which may have a substituent(s), (6) an oxo group, (7) a 3- to 15-membered heterocyclic group which may have a substituent(s) or (8) =N-OR®, wherein R® represents a hydrogen atom or C1-4 alkyl, a salt thereof or a solvate thereof, or a prodrug thereof for the manufacture of an agent for prevention and/or treatment for a disease through the intervention of CCRS.
The "acidic group which may be protected" represented by R! represents the "acidic group" which may be protected by a "protecting group". Examples of the "acidic group" include hydroxy, alkoxy, carboxy (-COOH), sulfo (-SOsH), sulfino (-SO.H), sulfonamide (-SO,NH, or -NR'*!'SOsH (R'®! is hydrogen atom or hydrocarbon group which may have a substituent(s).)), phosphono (-PO(OH);), phenol (-C¢H4sOH) or various types of Br¢nsted acid such as a nitrogen-containing ring residue having hydrogen from which can be removed as proton. The "Brgnsted acid" means a substance which gives hydrogen ion to other substance. Examples of the "nitrogen-containing ring residue having hydrogen from which can be removed as proton” include: ~N N 0) 0 - N
N\ HNN hg \ HN y — — [ N—
Pu ’ ’ HN - + N= ’ o” N oo ° o ~
CH,
S ) 0 0 ) N \
An Ay "07° N Ny © H SH H H jo] 0 o jo]
Te ! + HN / o” 8 Ao Ao o -9-
AMENDED SHEET
PCT/JP2004/003333 _
Preferred as "acidic group" is carboxy or sulfonamide. More preferred is sulfonamide.
Examples of the "protecting group" include hydrocarbon group which may have a substituent(s), C1-6 alkoxy, amino group which may have a substituent(s), — or —~N The "hydrocarbon group" in the "hydrocarbon group __/ which may have a substituent(s)" includes, for example, C1-15 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl etc.; C3-8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.; C2-10 alkenyl such as vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, 3-octenyl efc.; C2-10 alkynyl such as ethynyl, 2-propynyl, 3-hexynyl etc.; C3-10 cycloalkenyl such as cyclopropenyl, cyclopentenyl, cyclohexenyl efc.; C6-14 aryl such as phenyl, naphthyl etc., C7-16 aralkyl such as benzyl, phenylethyl etc ; (C3-8 cycloalkyl)-(C1-4 alkyl) such as cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, 1- methyl-1-cyclohexylmethyl, cyclopropylethyl etc.
The "substituents" in the "hydrocarbon group which may have a substituent(s)" include, for example, (1) nitro, (2) hydroxy group, (3) oxo, (4) thioxo, (5) cyano, (6) carbamoyl, (7) aminocarbonyl substituted by C1-8 hydrocarbon etc. (e.g, N- butylaminocarbonyl, N-cyclohexylmethylaminocarbonyl, N-butyl-N- cyclohexylmethylaminocarbonyl, N-cyclohexylaminocarbonyl, phenylaminocarbonyl efc.), (8) carboxy, (9) Cl1-4 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl ezc., (10)sulfo, (11) halogen such as fluorine, chlorine, bromine or iodine, (12) C1-4 lower alkoxy which may be substituted by halogen (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, difluoromethoxy or trifluoro,ethoxy), (13) phenoxy, (14) halogenophenoxy such as o-, m- or p-chlorophenoxy, or o-, m- or p-bromophenoxy etc., (15) C1-4 lower alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio efc., (16) phenylthio, (17) C1-4 lower alkylsulfinyl such as methylsulfinyl or ethylsulfinyl etc., (18) C1-4 lower alkylsulfonyl such as methylsulfonyl or ethylsulfonyl efc., (19) amino, (20) C1-6 lower acylamino such as acetylamino or propionylamino efc., (21) primary or secondary amino substituted by hydrocarbon group (e.g, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, cyclohexylamino, 1-carbamoyl-2-cyclohexylethylamino, N- butyl-N-cyclohexylmethylamino or phenylamino erc.), (the "hydrocarbon group" has the same meanings as above "hydrocarbon group" and may be substituted by oxo, amino which may be substituted by optional substituents (e.g., hydrocarbon), carbamoyl, halogen or hydroxy group efc.), (22) C1-4 lower acyl such as formyl or acetyl ezc., (23) benzoyl, (24) 5 or 6 membered heterocyclic group such as 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5- pyrazolyl, 4-tetrahydopyranyl, 2-, 4- or 5-thiazolyl, 3-, 4- or S-isothiazolyl, 2-, 4- or 5- oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H- -10-
AMENDED SHEET
PCT/JP2004/003333 ® tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or S-pyromidinyl, 3- or 4-pyridazinyl, quinolyl, isoquinoly! or indolyl etc. which includes 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen besides carbon atom, and optionally has 1 to 4 substituents selected from (a) halogen such as bromine, chlorine, or fluorine, (b) hydrocarbon such as methyl, ethyl, propyl, isopropyl, benzyl, cyclohexyl, cyclohexylmethyl or cyclohexylethyl ezc. optionally substituted by oxo or hydroxy group efc., (the "hydrocarbon group" has the same meanings as above "hydrocarbon group"), (c) halogenophenoxy such as o-, m- or p-chlorophenoxy, or o-, m- or p-bromophenoxy efc., and (d) oxo efc., (25) C1-10 haloalkyl such as difluoromethyl, trifluoromethyl, trifluoroethyl or trichloroethyl etc., (26) hydroxyimino, (27) alkyloxyimino such as methyloxyimino or ethyloxyimino etc, (28) alkylsulfonylamino such as methylsulfonylamino, ethylsulfonylamino or benzylsulfonylamino efc., or (29) arylsulfonylamino such as phenylsulfonylamino or p- toluenesulfonylamino etc. The "hydrocarbon group which may have a substituent(s)" can have 1 to 10 of substituents selected from above (1) to (29). If the "hydrocarbon group"
IS is cycloalkyl, cycloalkenyl, aryl or aralkyl, it may have 1 to 4 of C1-4 lower alkyl such as methyl, ethyl, propyl, isopropyl or butyl efc. as substituent. When the number of substituents is two or more, each substituent may be same or different.
The substituents of amino group in the "amino group which may have a substituent(s)" in the "protecting group" includes the above-described "hydrocarbon group”.
The "C1-6 alkoxy” in the "protecting group" includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy etc.
Preferred as the "protecting group" in R' is hydrocarbon group which may have a substituent(s), and more preferred is C1-4 alkyl etc.
The "acidic group which may be protected” represented by R' includes, for example, ester such as methoxycarbonyl or ethoxycarbonyl or amide such as carbamoyl.
Preferred as R' is -SO.NR'”R'® or -NR'*'SO,R'*, -COOR'”, -CONR'*R'” (wherein R'“2-R'” is hydrogen atom or the above described protecting group and other symbols have the same meanings as described above.) and more preferred is -
SO,NR!2R!® or NR!SO,R!%*
The "spacer containing 1 to 3 atoms as a main chain" represented by X and Y means a space formed by 1 to 3 continued atoms of a main chain. In this case, the "number of atoms as a main chain" should be counted such that atoms as a main chain become minimum. The "spacer having from 1 to 3 atoms as a main chain" include, for example, a bivalent group comprising 1 to 3 selected from -CR'R®-, -NR’-, -CO-, -O-, -S-, -SO-, -SO;- and -C(=N-OR'®)- (wherein R’ and R® are each independently hydrogen atom,
C1-4 alkyl, -OR"" or phenyl, R® is hydrogen atom, C1-4 alkyl or phenyl, R'" and R" are each independently hydrogen atom or C1-4 alkyl.). In the case, the "C1-4 alkyl" includes methyl, ethyl, propyl or butyl ezc. Concretely, the "spacer having from 1 to 3 atoms as a - 11 -
AMENDED SHEET
PCT/JP2004/003333 main chain" include, for example, -CR'R®-, -NR’-, -CO-, -O-, -S-, -C(=N-OR'%)-, -
NR’CO-, -CONR’-, -NR’COCR’R®- or -CONR’CR'R®- (wherein R’-R'® have the same meanings as described above.). Preferably spacer in "spacer having from 1 to 3 atoms as a main chain" represented by X is -CR'R®., -NR’-, -CO-, -O-, -S-, -SO-, -SO,- or -C(=N-
OR')- (wherein R” and R® are each independently hydrogen atom, C1-4 alkyl, -OR'' or phenyl, R’ is hydrogen atom, C1-4 alkyl or phenyl, R'” and R"' are each independently hydrogen atom or C1-4 alkyl.) etc.
Preferred as X is a bond, -O- or -CH;- etc.
Preferred as the "spacer having from 1 to 3 atoms as a main chain" represented by Yis "Cl1-3 alkylene". "C1-3 alkylene" includes methylene, ethylene or propylene etc.
More preferably, Y is methylene.
The "3- to 15-membered homocycle" in the "3- to 15-membered homocyclic group or heterocyclic group which may have a substituent(s)" represented by ring A and ring B includes, for example, a "cyclic hydrocarbon" etc. The "cyclic hydrocarbon" includes, for example, a "unsaturated cyclic hydrocarbon" or a "saturated cyclic hydrocarbon". The "saturated cyclic hydrocarbon" includes, for example, cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane or cyclopentadecane etc; perhydropentalene; perhydroazulene; perhydroindene; perhydronaphthalene; perhydroheptalene; spiro[4.4]nonane; spiro[4.5]decane; spiro[5.5]undecane; bicyclo[2.2.1]heptane; bicyclo[3.1.1]heptane; bicyclo[2.2.2]octane; adamantane; noradamantane etc. The "unsaturated cyclic hydrocarbon” includes, for example, cycloalkene such as cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene or cyclooctadiene efc, benzene; pentalene, azulene, indene; indan, naphthalene; dihydronaphthalene; - tetrahydronaphthalene; heptalene; biphenylene; as-indacene; s- indacene; acenaphthene; acenaphthylene; fluorene; phenalene; phenanthrene; anthracene; bicyclo[2.2.1]hept-2-ene; bicyclo[3.1.1]hept-2-ene; bicyclo[2.2.2]oct-2-ene etc.
The "3- to 15-membered heterocycle" in the "3- to 15-membered homocyclic group or heterocyclic group which may have a substituent(s)" represented by ring A and ring B includes a "3- to 15-membered unsaturated heterocycle" or a "3- to 15-membered saturated heterocycle".
The "3- to 15-membered unsaturated heterocycle" includes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, -12-
AMENDED SHEET oO dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzoxepine, benzoxazepine, benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, beta-carboline, acridine, phenazine, dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine, phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine, pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine, dihydroazepine, tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrofuran, dihydropyran, dihydrooxepine, tetrahydrooxepine, dihydrothiophene, dihydrothiopyran, dihydrothiepine, tetrahydrothiepine, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazan, dihydrooxadiazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene, dihydroindazole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, ~~ benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, dihydroacridine, tetrahydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, dioxaindan, benzodioxane, chroman, benzodithiolane, benzodithiane efc.
The "3- to 15-membered saturated heterocycle” includes, for example, aziridine, azetidine, azocane, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, perhydrooxepine, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, perhydrothiepine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine),
tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, : tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, perhydrothiazepine, perhydrothiadiazepine,
oO morpholine, thiomorpholine, oxathiane, perhydrobenzofuran, perhydroisobenzofuran, perhydrobenzothiophene, perhydroisobenzothiophene, perhydroindazole, perhydroquinoline, perhydroisoquinoline, perhydrophthalazine, perhydronaphthyridine, perhydroquinoxaline, perhydroquinazoline, perhydrocinnoline, perhydrobenzoxazole, perhydrobenzothiazole, perhydrobenzimidazole, perhydrocarbazole, perhydroacridine, perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane in) , in) , wn () ; w , or nf \ erc.
Preferred as the "3- to 15-membered homocyclic group or heterocyclic group" represented by ring A and ring B is a "S- to 10-membered homocyclic group or heterocyclic group”. Concretely, the "5- to 10-membered homocyclic group" includes, for example, C5-10 saturated cyclic hydrocarbon such as C5-10 cycloalkane (e.g, cyclopentane, cyclohexane or cycloheptane) or C5-10 unsaturated cyclic hydrocarbon such as C5-10 cycloalkene (e.g, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene or cyclooctadiene); benzene; naphthalene; indene etc. The "5- to 10-membered heterocyclic group" includes 5- to 10- membered unsaturated heterocyclic group such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine, dihydroazepine, tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrofuran, dihydropyran, dihydrooxepine, tetrahydrooxepine, dihydrothiophene, dihydrothiopyran, dihydrothiepine, tetrahydrothiepine, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazan, dihydrooxadiazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene, dihydroindazole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline,
PCT/JP2004/003333 ® dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzimidazole, dioxaindan, benzodioxane, chroman, benzodithiolane or benzodithiane; or 5- to 10-membered saturated heterocyclic group such as pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, tetrahydrofuran, tetrahydropyran, perhydrooxepine, tetrahydrothiophene, tetrahydrothiopyran, perhydrothiepine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, perhydrobenzofuran, perhydroisobenzofuran, perhydrobenzothiophene, perhydroisobenzothiophene, perhydroindazole, perhydroquinoline, perhydroisoquinoline, perhydrophthalazine, perhydronaphthyridine, perhydroquinoxaline, perhydroquinazoline, perhydrocinnoline, perhydrobenzoxazole, perhydrobenzothiazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane etc. o> m3) mm) vor elc.
More preferably, ring A or ring B is a "5- tolO-membered unsaturated homocyclic group or heterocyclic group”. The "S- tolO-membered unsaturated homocyclic group or heterocyclic group" is a "S- tolO-membered unsaturated cyclic hydrocarbon" or "5- tol10-membered unsaturated heterocyclic group”. More preferred is 5- or 6-aromatic ring such as benzene, = : -- : pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole or thiadiazole etc.
The "substituents" in the "3- to 15-membered homocyclic group or heterocyclic group which may have a substituent(s)" represented by ring A or ring B includes, for example, (1) hydrocarbon group which may have a substituent(s) (the "hydrocarbon group which may have a substituent(s)" has a same meanings as the above-described "hydrocarbon group which may have a substituent(s)".), (2) C1-6 alkoxy group which may be substituted by halogen atom (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or triflucromethoxy), (3) (C1-4 alkoxy)-(C1-4 alkyl) group such as methoxyethyl etc, (4) phenoxy group, (5) C1-8 alkanoyl group such as formyl, acetyl, propyonyl, n-butyryl, iso- butyryl or cyclohexyl carbonyl efc., (6) benzoyl group, (7) C1-8 alkanoyloxy group such as -15-
AMENDED SHEET oO formyloxy, acetyloxy, propyonyloxy, n-butyryloxy, iso-butyryloxy or cyclohexyl carbonyloxy efc., or benzoyloxy group, (8) carboxy group, (9) C2-7 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n- butoxycarbonyl, isobutoxycabonyl, tert-butoxycabonyl group erc.) (10) carbamoyl group, (11) N-mono-C1-4 alkylcarbamoy! group such as N-methylcarbamoyl, N-ethylcarbamyl,
N-propylcarbamoyl, N-isopropylcarbamoyl or N-butylcarbamoyl efc., (12) N,N-di-C1-4 alkylcarbamoyl group such as N,N-dimethylcarbamoyl, N N-diethylcarbamoyl, N,N- dipropylcarbamoy! or N,N-dibutylcarbamoyl etc. (13) cyclic aminocarbonyl such as 1- aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N- methylpiperazinylcarbonyl, morpholinocarbonyl ezc., (14) halogen atom such as fluorine, chlorine, bromine or iodine, (15) mono-, di- or tri-halogeno-C1-4alkyl group such as chloromethyl, dichloromethyl, trifluoromethyl or trifluoroethyl ezc. (16) oxo group, (17) amidino group, (18) imino group, (19) amino group, (20) mono-C1-4alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino or butylamino efc., (21) di-Cl-4alkylamino group such as dimethylamino, diethylamino, dipropylamino, diisopropylamino or dibutylamino etc., (22) 3- to 6-membered cyclic amino group which includes carbon atom and 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen besides one nitrogen atom (e.g., aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidino, morpholino, dihydropyridyl, pyridyl, N- methylpiperazinyl or N-ethylpiperadiny!l etc), (23) C1-8 alkanoylamide group such as formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide, cyclohexylcarbonylamino etc., (24) benzamide group, (25) carbamoylamino group, (26) N-
C1-4 alkylcarbamoylamino group such as N-methylcarbamoylamino, N- ethylcarbamoylamino, = N-propylcarbamoylamino, N-isopropylcarbamoylamino, N- butylcarbamoylamino efc., (27) N,N-di-C1-4 alkylcarbamoylamino group such as N,N- dimethylcarbamoylamino, N,N-diethylcarbamoylamino, N,N-dipropylcarbamoylamino,
N,N-dibutylcarbamoylamino efc. (28) C1-3 alkylenedioxy group such as methylenedioxy or ethylenedioxy efc. (29) -B(OH),, (30) hydroxy group, (31) epoxy group, (32) nitro group, (33) cyano group, (34) mercapto group, (35) sulfo group, (36) sulfino group, (37) phosphono group, (38) sulfamoyl group, (39) C1-6 monoalkylsulfamoyl such as N- methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl or N- butylsulfamoyl etc., (40) di-C1-4 alkylsulfamoyl group such as N,N-dimethylsulfamoyl,
N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl or N,N-dibutylsulfamoyl erc., (41) C1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec- butylthio or tert-butylhioerc., (42) phenylthio group, (43) C1-6 alkylsulfinyl group such as methylsulfinyl, ethylsulfinyl, propylsulfinyl or butylsulfinyl erc., (44) phenylsulfinyl, (45)
C1-6 alkylsulfony! such as methylsulfonyl, ethylsulfonyl, propylsulfonyl or butylsulfony! etc., (46) phenylsulfonyl group, or (47) azide group efc. 1 to 10 of the above-described
PCT/JP2004/003333 ® substituents may be substituted at replaceable positions in ring A and ring B. When the number of substituents is two or more, each substituent are the same or different.
Preferred as substituents in ring A and ring B is hydrocarbon group which may have a substituent(s), alkoxy group, carboxy group or alkanoylamide group efc., and more preferred is hydrocarbon group or alkoxy group.
The "nitrogen-containing heterocycle" in the "3- to 15-membered nitrogen- containing heterocyclic group which may have a substituent(s)" represented by ring D refers to a heterocycle which may contain, in addition to at least one nitrogen atom besides carbon atom, 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms. The "3- to 15-membered nitrogen-containing heterocycle” includes a "3- to 15-membered nitrogen-containing unsaturated heterocycle" and "3- to 15-membered nitrogen-containing saturated heterocycle".
The "3- to 15-membered nitrogen-containing unsaturated heterocycle" includes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, indole, isoindole, indazole, purine, benzimidazole, benzazepine, benzodiazepine, benzotriazole, carbazole, beta- carboline, phenothiazine, phenoxazine, perimidine, pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, ~~ dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine, dihydroazepine, tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazan, dihydrooxadiazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine, dihydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, indoline, isoindoline, 2S dihydroindazole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine; dihydronaphthyridine, tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, dihydroacridine, tetrahydroacridine etc. The "3- to 15-membered nitrogen-containing saturated heterocycle" includes, for example, aziridine, azetidine, azocane, pyrrolidine, imidazolidine, tnazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, -17-
AMENDED SHEET
0 tetrahydrooxadiazole ~~ (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, tetrahydrothiazepine, perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, perhydroindazole, perhydroquinoline, perhydroisoquinoline, perhydrophthalazine, perhydronaphthyridine, perhydroquinoxaline, perhydroquinazoline, perhydrocinnoline, perhydrobenzoxazole, perhydrobenzothiazole, perhydrobenzimidazole, perhydrocarbazole, perhydroacridine, mn) , mw J) , an () ’ mw () , Or in \ elc.
Preferred as the "3- to 15-membered nitrogen-containing heterocycle" is a "5- {6 10-membered nitrogen-containing heterocycle". A "5- to 10-membered nitrogen- containing unsaturated heterocycle" includes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, indole, isoindole, indazole, purine, benzimidazole, benzotriazole, pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, ~~ dihydropyridazine, tetrahydropyridazine, dihydroazepine, tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrofurazan, dihydrooxadiazole, dihydrooxazine, dihydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, dihydrothiadiazole, dihydrothiazine, dihydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, indoline, isoindoline, dihydroindazole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzimidazole etc. A "S- to 10- membered nitrogen-containing saturated heterocycle" includes, for example, azocane, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, perhydroazepine, perhydrodiazepine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazan, tetrahydrooxadiazole ~~ (oxadiazolidine), tetrahydrooxazine, tetrahydrooxadiazine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, tetrahydrothiadiazine, perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, perhydroindazole, perhydroquinoline, perhydroisoquinoline, perhydrophthalazine, perhydronaphthyridine, perhydroquinoxaline, perhydroquinazoline,
PCT/JP2004/003333
J perhydrocinnoline, perhydrobenzoxazole, perhydrobenzothiazole, perhydrobenzimidazole, nd) , mw) ) , w () , mw [) , or |e etc.
Moreover, preferred as "nitrogen-containing heterocycle" is piperidine or piperazine. More preferred is piperidine.
The "substituents" in "3- to 15-membered nitrogen-containing heterocyclic group which may have a substituent(s)" represented by ring D have the same meanings as the above-described "substituents" in "3- to 15-membered homocyclic group or heterocyclic group which may have "substituents" represented by ring A and ring B.
Preferably, ring D has no substituent or is substituted by hydrocarbon group have a substituent(s), mono-C1-4 alkylamino group or di-C1-4 alkylamino group etc.
More preferably, ring D has no substituent.
The "hydrocarbon group" in the "hydrocarbon group which may have a substituent(s)" represented by R* has a same meaning as the "hydrocarbon group which may have a substituent(s)" defined in the "protecting group" of the "acidic group which may be protected” represented by R'. Preferred as the "hydrocarbon group which may have a substituent(s)" represented by R? is alkyl group substituted by oxo group or (C3-8 cycloalkyl)-(C1-4 alkyl) group substituted by oxo group.
Among R?, the "hydroxy group which may be protected" is the "hydroxy group" which may be protected by a "protecting group”. The "protecting group" of hydroxy group includes, for example, (1) C1-6 alkyl group (e.g., methyl, ethyl or n-propyl etc.) which may have 1 to 4 of substituents selected from halogen atom such as chlorine, bromine or fluorine efc.; C6-10 aryl such as phenyl or naphthyl efc.; C7-12 aralkyl group such as benzyl or phenylethyl efc.; and nitro group etc., (2) C6-10 aryl (e.g., phenyl or naphthyl etc.) which may have 1 to 4 of substituents selected from halogen atom such as chlorine, bromine or fluorine etc.; C1-6 alkyl graup such as methyl, ethyl or n-propyl etc;
C6-10 aryl such as phenyl or naphthyl etc; C7-12 aralkyl group such as benzyl or phenylethy! etc.; and nitro group etc., (3) C7-12 aralkyl group (e.g., benzyl, phenylethyl or naphthylmethyl etc.) which may have 1 to 4 of substituents selected from halogen atom such as chlorine, bromine or fluorine etc.; C1-6 alkyl group such as methyl, ethyl or n- propyl etc; C6-10 aryl such as phenyl or naphthyl efc.; C7-12 aralkyl group such as benzyl or phenylethyl efc.; and nitro group efc., (4) formyl, (5) C1-6 alkyl-carbonyl group (e.g., acetyl or propionyl! etc.) which may have 1 to 4 of substituents selected from halogen atom such as chlorine, bromine or fluorine efc.; C1-6 alkyl group such as methyl, ethyl or n- propyl etc.; C6-10 aryl such as phenyl or naphthyl efc.; C7-12 aralkyl group such as benzyl or phenylethyl efc; and nitro group efc, (6) C6-10 aryl-oxycarbonyl group (e.g, phenyloxycarbony! or naphthyloxycarbonyl efc.) which may have 1 to 4 of substituents selected from halogen atom such as chlorine, bromine or fluorine ezc.; C1-6 alkyl group -19-
AMENDED SHEET
PCT/JP2004/003333 ® such as methyl, ethyl or n-propyl efc.; C6-10 aryl such as phenyl or naphthyl ezc.; C7-12 aralkyl group such as benzyl or phenylethyl etc.; and nitro group etc., (7) C6-10 aryl- carbonyl group (e.g, benzoyl or naphthyicarbonyl etc.) which may have 1 to 4 of substituents selected from halogen atom such as chlorine, bromine or fluorine efc.; C1-6 alkyl group such as methyl, ethyl or n-propyl etc.; C6-10 aryl such as phenyl or naphthyl etc.; C7-12 aralkyl group such as benzyl or phenylethyl efc.; and nitro group etc. (8) C7- 12 aralkyl-carbonyl group (e.g., benzylcarbonyl or phenethylcarbonyl etc.) which may have 1 to 4 of substituents selected from halogen atom such as chlorine, bromine or fluorine efc.; C1-6 alkyl group such as methyl, ethyl or n-propyl etc.; C6-10 aryl such as phenyl or naphthyl etc.; C7-12 aralkyl group such as benzyl or phenylethyl efc.; and nitro group etc, (9) pyranyl or furanyl which may have 1 to 4 of substituents selected from halogen atom such as chlorine, bromine or fluorine efc.; C1-6 alkyl group such as methyl, ethyl or n-propyl etc.; C6-10 aryl such as phenyl or naphthyl efc.; C7-12 aralkyl group such as benzyl or phenylethyl efc.; and nitro group etc., or (10) tri-C1-4 alkylsilyl such as trimethylsilyl or triethylsilyl ezc.
The "substituents" in the "amino group which may have a substituent(s)" represented by R? includes hydrocarbon group which may have a substituent(s), -SO,R™", =NR?** OR? (wherein R*'-R?®? is hydrocarbon group which may have a substituent(s)) etc. The "hydrocarbon group which may have a substituent(s)" has the same meaning as the "hydrocarbon group which may have a substituent(s)" defined in the "protecting group" of the "acidic group which may be protected" represented by R'. Preferred as the "substituents" in the "amino group which may have a substituent(s)" represented by R? is the "hydrocarbon group which may have a substituent(s)".
The "3- to 15-membered heterocyclic group which may have a substituent(s)" represented by R? has the same meanings as the "3- to 15-membered heterocyclic group which may have a substituent(s)" represented by ring A or ring B. = Preferred as the "3- to 15-membered heterocyclic group which may have a substituent(s)" represented by R? is piperidine or piperazine which may have a substituent(s) and more preferred is
RY!
TT
32
R34 (wherein the arrow represents a binding position to ring D, and R*', R”, R* and R* each independently have the same meanings as the "substituents" of the "3- to 15-membered heterocyclic group which may have a substituent(s)" represented by ring A or ring B.) etc. -20-
AMENDED SHEET
PCT/JP2004/003333
Preferred as R? is, for example, hydrocarbon group which may have a substituent(s) or amino group which may have a substituent(s) etc., and more preferred is 0] 0 oO
LW. “y : NR or ge
RS! R52 R52 R52 (wherein the arrow represents a binding position to ring D, and R*, R*2, R* and R** are each independently hydrogen atom, hydrocarbon group which may have a substituent(s), 3- to 15-membered heterocyclic group which may have a substituent(s), C1-4 alkoxy group which may have a substituent(s), phenoxy which may have a substituent(s) or benzyloxy which may have a substituent(s).) etc. The "hydrocarbon group which may have a substituent(s)" and "3- to 15-membered heterocyclic group which may have a substituent(s)" have the same meanings as described above respectively. Cl-4 alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s- butoxy or t-butoxy etc. Cl1-4 alkoxy group, phenoxy group or benzyloxy group may have optional substituents. The substituents of Cl-4 alkoxy group, phenoxy group or benzyloxy group include, for example, the above-described "substituents" of the "hydrocarbon group which may have a substituent(s)".
Preferably, R*!, R*2, R* or R* is hydrogen atom, hydrocarbon group which may have a substituent(s) or 3- to 15-membered heterocyclic group which may have a substituent(s) etc. Moreover, the compound wherein either among R*? and R™ is hydrogen atom is preferred.
In the present invention, the compound represented by formula (I) including the combination of the above-described preferable group and ring is preferred. For example, a compound wherein ring D is piperidine or piperazine and Y is methylene group, i.e., a compound represented by formula (Ia)
H,
R? ““N pre)-ge
D—+R la (wherein ring D" is piperidine or piperazine which may have a substituent(s) and other symbols have the same meanings as described above.), a compound wherein ring D is piperidine or piperazine, R? is
Oo
PLS i N°
RS! R32 221 -
AMENDED SHEET
PCT/JP2004/003333 i.e., a compound represented by formula (Ib) 0)
Y<
R? N pita R8 (Ib
LoL og yew
RS! R52 (wherein all symbols have the same meanings as described above.); a compound wherein
R'is -SO,NR!2R!® or .NR'*!SO,R'* X is a bond, -CR’R®-, -NR’-, -CO-, -O-, -S-, -SO-, -SO;-, -C(=N-OR'%)- (wherein R” and R® are each independently hydrogen atom, C1-4 alkyl, -OR" or phenyl, R® is hydrogen atom, C1-4 alkyl or phenyl, R'® and R'' are each independently hydrogen atom or C1-4 alkyl), Y is methylene, ring A and ring B are each independently benzene which may have a substituent(s), ring D is piperidine and R? is oO
AEN _R%® ly
RS R52 ie. a compound represented by formula (Ic)
H,
Cc. wa] Vou) 0
Xa ALR (lc)
RS! R52 (wherein R'? is -SO,NR'?R'® or -NR'!SO,R'* X'* is a bond, -CR’R®-, -NR’-, -CO-, -
O-, -S-, -SO-, -SO;-, -C(=N-OR'%)- (wherein R’ and R® are each independently hydrogen atom, C1-4 alkyl, -OR" or phenyl, R® is hydrogen atom, C1-4 alkyl or phenyl, R'® and R"! are each independently hydrogen atom or Cl1-4 alkyl), ring A'* and ring B'* are each independently benzene which may have a substituent(s), ring D'® is piperidine which may have a substituent(s) and other symbols have the same meanings as described above.); or a compound wherein R! is -SO,NR'®R!'® or -NR''SO,R'* X is a bond, -CR’R-, -NR’-, -
CO-, -O-, -S-, -SO-, -S0,-, -C(=N-OR'%)- (wherein R” and R® are each independently hydrogen atom, Cl1-4 alkyl, -OR" or phenyl, R’ is hydrogen atom, C1-4 alkyl or phenyl,
R! and R'! are each independently hydrogen atom or C1-4 alkyl), Y is methylene, ring A and ring B are each independently benzene or unsaturated mono-heterocyclic group which may have a substituent(s), ring D is piperidine or piperazine, R?is -22-
AMENDED SHEET
PCT/JP2004/003333 x ~
RS" R™, i.e., a compound represented by formula (Id)
J
Ria B®] 'N pa Id
Can) A
R51 R52 (wherein ring A'® and ring B" are each independently benzene or 5- or 6-membered aromatic ring which may have a substituent(s) and other symbols have the same meanings as described above.) esc. is preferred.
Concretely, the compound of the present invention includes the compound described in Example, or 2-[3-methyl-4-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperazin-1-yl]-
N-phenylhexanamide,
N-{4-[4-({4-[(anilinocarbonyl)(butyl)amino]-4'-methyl-1,4'-bipiperidin-1'- yl} methyl)phenoxy]phenyl } methanesulfonamide,
N-[4-(4-{[3-[(anilinocarbony!)(butyl)amino]-4-(3-fluoropheny!)pyrrolidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide,
N-[4-(4-{[3-(butylamino)-4-(3-fluorophenyl)pyrrolidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide,
N-butyl-N-(1-{3-ethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4- yl} piperidin-4-yl)-N'-phenylurea, Co oo
N-butyl-N-[1-({4-methyl-2-[4-(trifluoromethyl)phenyl]}-1H-imidazol-5- yl}methyl)piperidin-4-yl]-N'-phenylurea,
N-{4-[4-({3-[(anilinocarbonyl)(butyl)amino]-8-azabicyclo[3.2.1]oct-8- yl} methyl)phenoxy]phenyl } methanesulfonamide,
N-[4-(4-{[4-(3-isopropyl-5-methyl-4H-1,2 4-triazol-4-yl)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide,
N-[4-(4-{[4-(2-methyl-1H-benzimidazoll-yl)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide,
N-[4-(4-{[4-[(anilinocarbonyl)(butyl)amino]-3,4-dihydroquinolin-1(2H)- yl]methyl} phenoxy)phenyl]methanesulfonamide,
N-[4-(4-{[4-(2-0x0-3-phenyl-6-propyltetrahydropyrimidin-1(2H)-yl)piperidin- 1-yl]methyl}phenoxy)phenyl]methanesulfonamide, -23-
AMENDED SHEET oO
N-(4-{4-[(3-butyl-2-0x0-1,2,3,3a,4,5-hexahydro-6H-pyrido[4,3,2- de]quinazolin-6-yl)methyl]phenoxy } phenyl)methanesulfonamide,
N-(4-{4-[(1-butyl-2-ox0-4-phenyloctahydropyrido[4,3-d]pyrimidin-6(2H)- yl)methyl]phenoxy} phenyl)methanesulfonamide,
N-{4-[4-({8-[(anilinocarbonyl)(butyl)amino]-3-azabicyclo[3.2.1]oct-3- yl} methyl)phenoxy]phenyl } methanesulfonamide,
N-[4-(4-{[(2Z)-1-butyl-2-(phenylimino)hexahydro-2H-pyrido[4,3- d][1,3]oxazin-6(4H)-ylJmethyl } phenoxy)phenyl]methanesulfonamide or
N-[7-({4-[(anilinocarbonyl)(butyl)amino]piperidin-1-yl} methyl)-9H-xanthen- 2-yl]methanesulfonamide etc.
Particularly preferred are compounds described in Example, salts thereof and solvates thereof], and prodrugs thereof.
More preferred are
N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1- piperidinyl}jmethyl}phenoxy)phenyljmethanesulfonamide,
N-[4-(4-{[4-(butyl{ [(6-methyl-3-pyridinyl)amino]carbonyl }amino)-1- piperidinyl]methyl}phenoxy)phenyl]Jmethanesulfonamide,
N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- ylJmethyl}-3,5-dimethyl-1H-pyrazol-1-yl)phenylJmethanesulfonamide,
N-[4-(4-{[4-(butyl{[(1-methyl-1H-pyrazol-4- yl)amino]carbony! }amino)piperidin-1-ylJmethyl} phenoxy)phenyl]methanesulfonamide, 3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)piperidin-4- yl]amino}carbonyl)amino]benzamide,
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(phenyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide, 5-[({butyl[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)piperidin-4- yl]amino}carbonyl)amino]-2-fluorobenzamide, 5-[({butyl[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl )piperidin-4- yl]amino}carbonyl)amino}-2,4-difluorobenzamide,
N-[4-(4-{[4-(butyl{[(3-cyano-4- fluorophenyl)amino]carbonyl }amino)piperidin-1- ylJmethyl } phenoxy)phenyl]methanesulfonamide,
N-[4-(4-{[4-(butyl{[(3-hydroxycyclohexyl)amino]carbonyl }amino)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide or
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(1,3-thiazol-4- ylmethyl)amino]piperidin-1-yl} methyl)phenoxy]phenyl } methanesulfonamide, salts thereof and solvates thereof, and prodrugs thereof.
(IN
Unless otherwise specifically mentioned, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene include straight chain and branched ones. Moreover, all of isomers due to double bond, ring and fused ring (E-, Z-, cis- and trans-forms), isomers due to presence of asymmetric carbon(s) etc. (R-, S-, a- and B-configuration, enantiomer and diastereomer), optically active substances having optical rotation (D-, L-, d- and l-forms), polar compound by chromatographic separation (more polar compound and less polar compound), equilibrium compounds, rotational isomers, a mixture thereof in any proportion and a racemic mixture are included in the present invention.
According to the present invention, unless otherwise indicated and as is apparent for those skilled in the art, symbol _ indicates that it is bound to the opposite side of the sheet (namely a-configuration), symbol 7 indicates that it is bound to the front side of the sheet (namely B-configuration), and symbol ~~ indicates that it is a mixture of a.-configuration and B-configuration.
The compound of the present invention can be converted into a salt by known methods. The salt is preferably a pharmacological acceptable salt.
The salt includes salt with alkaline metal, salt with alkaline earth metal, ammonium salt, amine salt or acid addition salt etc.
The salt is preferably water-soluble. The suitable salt is, for example, salt with alkaline metal (such as potassium and sodium), salt with alkaline earth metal (such as calcium and magnesium), ammonium salt and salt with pharmacological acceptable organic amine (such as tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylaminomethane, lysine, arginine and N-methyl- D-glucamine).
The acid addition salt is preferably water-soluble. The suitable acid addition salt is, for example, inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate; or organic acid salt such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isothionate, glucuronate and gluconate; efc.
The compound represented by formula (I) and the salt thereof can be converted into the solvates.
The solvate is preferably non toxic and water-soluble. The suitable solvate is, for example, solvate of water or alcohol (e.g., ethanol).
All of the compound represented by formula (I) or the pharmacological acceptable salt thereof are preferred; concretely, compounds described in Example or pharmacological acceptable salts thereof are preferred.
oO
Moreover, the salt includes a quaternary ammonium salt. The quaternary ammonium salt of the compound represented by formula (I) is the compound where nitrogen of the compounds represented by formula (I) is quarternalized by RC.
The RC is C1-8 alkyl or C1-8 alkyl substituted by phenyl.
The compound of the present invention can be converted into an N-oxide by known methods. The N-oxide is the compound where nitrogen of the compound represented by formula (I) is oxidized.
A prodrug of the compound of formula (I) means a compound which is converted to the compound of formula (I) by reaction with an enzyme, gastric acid or the like in the living body. For example, with regard to a prodrug of the compound of formula (I), when the compound of formula (I) has an amino group, compounds in which the amino group is, for example, acylated, alkylated or phosphorylated (e.g., compounds in which the amino group of the compound of formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-0x0-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated, erc.); when the compound of formula (I) has a hydroxyl group, compounds where the hydroxyl group is, for example, acylated, alkylated, phosphorylated or borated (e.g., compounds in which the hydroxyl group of the compound of formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated), and that the carboxyl group of the compound of formula (I) is, for example, esterified or amidated (e.g., compounds in which the carboxyl group of the compound of formula (I) is made into ethyl ester, phenyl ester, phenylethyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethy! ester, phthalidyl ester, (5-methyl-2-oxo0-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester or methylamide). Those compounds may be produced by a known method per se. The prodrug of the compound of formula (I) may be either a hydrate or a non-hydrate. A prodrug of the compound of formula (I) may also be a compound which is converted to the compound of formula (I) under physiologic condition as described in "Iyakuhin no kaihatsu, Vol.7 (Bunshi-sekkei), pp.163-198 (Hirokawa-Shoten), 1990". And the compound of formula (I) may also be labeled by a radio isotope (such as *H, '*C, ’S, '%[, etc,).
Processes for the preparation of the compound of the present invention:
The compound of the present invention represented by formula (I) can be prepared by methods which properly improved and combined known methods, such as .- methods described below, methods described in Examples or methods described in
Comprehensive Organic Transformations:A Guide to Functional Group Preparations, 2nd
Edition (Richard C. Larock, John Wiley & Sons Inc, 1999). In each method described
0 below, a starting material can be used as a salt thereof. An example of the salt includes a salt of compound of formula (I) described above.
Among the compounds represented by formula (I), 2 compound wherein a spacer which is adjacent with ring D is -CHa-, -CO- or -SO,- can be prepared by alkylation, amidation or sulfonamidation by a compound represented by formula (IT)
Y'—vy?—z {nr 0)
X' (wherein Z is hydroxy group or a leaving group (e.g., halogen atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoro methanesulfonyloxy group etc.), Y" is a bond or a spacer containing 1 or 2 atoms as a main chain, Y* is -CHa-, -CO- or -SO,-, and R"",
X, ring A' and ring B' have the same meanings as R!, X, ring A and ring B respectively.
With proviso that, carboxy group, hydroxy group, amino group or thiol group in R", X', ring A’ or ring B' may be protected, if necessary. Other symbols have the same meaning as described above.) and a compound represented by formula (III) 0 (im) (wherein R* and ring D' have the same meanings as R” and D respectively. With proviso that, carboxy group, hydroxy group, amino group or thiol group in R* or ring D' may be protected, if necessary.), if necessary, followed by removal of the protecting group.
The alkylation 1s well known. For example, it may be carried out in an organic solvent (e.g., dimethylsulfoxide), in the presence of alkaline (e.g., potassium carbonate or sodium carbonate), and sodium iodide or potassium iodide at 0 to 150°C.
The amidation is known. For example, it includes the method ¢)) via an acyl halide, 2) via a mixed acid anhydride, 3) using a condensing agent.
These methods are explained as follows. (1) The method via an acyl halide may be carried out, for example, by reacting carboxylic acid with an acyl halide (e.g., oxalyl chloride or thionyl chloride) in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether or tetrahydrofuran) or without a solvent at -20°C to reflux temperature. And then the obtained acyl halide derivative may To be reacted with amine in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether or tetrahydrofuran) in the presence of a base (e.g, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine erc.) at 0 to 40°C. As oO an alternative, the obtained acyl halide derivative may be reacted with amine in an organic solvent (e.g., dioxane, tetrahydrofuran) using an alkaline aqueous solution (e.g., sodium bicarbonate, sodium hydroxide) at 0 to 40°C. (2) The method via a mixed acid anhydride may be carried out, for example, by reacting carboxylic acid with an acyl halide (e.g., pivaloyl! chloride, tosyl chloride or mesyl chloride) or an acid derivative (e.g., ethyl chloroformate or isobutyl chloroformate) in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or without a solvent, in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or diisopropylethylamine) at 0 to 40°C. And then the obtained mixed acid anhydride derivative may be reacted with amine in an organic solvent (e.g, chloroform, methylene chloride, diethyl ether or tetrahydrofuran), at 0 to 40°C. (3) The method using a condensing agent may be carried out, for example, by reacting carboxylic acid with amine in an organic solvent (e.g, chloroform, dichloromethane, dimethylformamide, diethyl ether or tetrahydrofuran) or without a solvent, in the presence or absence of a base (e.g., pyridine, triethylamine, dimethylaniline or dimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide (EDC), 1,1'-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, or 1-propanephosphonic acid cyclic anhydride (PPA)), in the presence or absence of 1-hydroxybenzotiazole (HOB), at O to 40°C.
The reaction described in (1), (2) and (3) may be carried out under an inert gas (e.g., argon, nitrogen) to avoid water in order to obtain a preferable result.
The sulfoneamidation is well known. For example, it may be carried out by reacting sulfonic acid with acyl halide (e.g., oxalyl chloride or thionyl chloride, phosphorus pentachloride or phosphorus trichloride) in an organic solvent (e.g., chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran or methyl t-butyl ether) or without a solvent at-20°C to reflux temperature. And then the obtained sulfonyl halide derivative may be reacted with amine in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether or tetrahydrofuran) in the presence of a base (e.g, diisopropylethylamine, pyridine, triethylamine, dimethylaniline or dimethylaminopyridine ere.) at0to 40°C.
The removal of the protecting group is known and may be carried out by following method.
The carboxyl-protective group includes, for example, methyl, ethyl, allyl, t- butyl, trichloroethyl, benzyl (Bn) or phenacyl etc.
The protecting group of hydroxy includes, for example, methyl, trityl : methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2- tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl oO (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p- methoxybenzyl, allyloxycarbonyl (Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc) efc.
The protecting group of amino includes such as benzyloxycarbonyl, t- butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl, = benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM) or 2-(trimethylsilyl)ethoxymethyl (SEM) efc.
The protective group of thiol includes, for example, benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), diphenylmethyl and acetyl (Ac) efc.
With regard to the protective group for carboxyl, hydroxyl, amino and thiol, there is no particular limitation to the above ones so far as it is a group which is able to be easily and selectively detached. For example, a deprotection reaction may be carried out by a method mentioned in "I. W. Greene, Protective Groups in Organic Synthesis, John
Wiley & Sons Inc, 1999".
The reaction for removing the protective group for carboxyl, hydroxyl, amino or thiol is known and its examples are as follows. (1) a hydrolyzing reaction with an alkali; (2) a deprotection reaction under an acidic condition; (3) a deprotection reaction by hydrogenolysis; (4) a deprotection reaction of silyl; (5) a deprotection reaction using a metal; and (6) a deprotection reaction using metal complex.
Those methods will be specifically illustrated as follows. (1) A deprotection reaction using an alkali is carried out, for example, at 0 to 40°C using a hydroxide of alkaline metal (such as sodium hydroxide, potassium hydroxide and lithium hydroxide), a hydroxide of alkaline earth metal (such as barium hydroxide and calcium hydroxide), a carbonate (such as sodium carbonate and potassium carbonate), an aqueous solution thereof or a mixture thereof in an organic solvent (such as methanol, tetrahydrofuran and dioxane efc.). (2) A deprotection reaction under an acidic condition is carried out, for example, at 0 to 100°C in an organic acid (e.g, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-tosylate), an inorganic acid (e.g., hydrochloric acid and sulfuric acid) or a mixture thereof (such as hydrogen bromide/acetic acid) in an organic solvent (such as dichloromethane, chloroform, dioxane, ethyl acetate and anisole erc.). (3) A deprotection reaction by hydrogenolysis is carried out, for example, at 0 to 200°C in a hydrogen atmosphere of ordinary pressure or high pressure or in the presence of ammonium formate in the presence of a catalyst (such as palladium-carbon, palladium black, palladium hydroxide, platinum oxide and Raney nickel) in a solvent [such as an ether type (such as tetrahydrofuran, dioxane, dimethoxyethane and diethyl ether), an
PCT/JP2004/003333 ® alcohol type (such as methanol and ethanol), a benzene type (such as benzene and toluene), a ketone type (such as acetone and methyl ethyl ketone), a nitrile type (such as acetonitrile), an amide type (such as dimethylformamide), water, ethyl acetate, acetic acid or a mixed solvent comprising two or more thereof]. (4) A deprotection reaction of silyl is carried out, for example, at 0 to 40°C using tetrabutylammonium fluoride in an organic solvent miscible with water (such as tetrahydrofuran and acetonitrile efc.). (5) A deprotection reaction using metal is carried out, for example, at 0 to 40°C with or without ultrasonic wave in the presence of powdery zinc in an acidic solvent (such as acetic acid, a buffer of pH 4.2 to 7.2 and a mixed solution of a solution thereof with an organic solvent such as tetrahydrofuran). (6) A deprotection reaction using a metal complex is carried out, for example, at 0 to 40°C using a metal complex [such as tetrakistriphenylphosphine palladium (0), bis(triphenylphosphine) palladium (II) dichloride, palladium (II) acetate and tris(triphenylphosphine) rhodium (I) chloride] in the presence or absence of a phosphine agent (such as triphenyl phosphine) in the presence of a trap reagent (such as tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine and pyrrolidine), an organic acid (such as acetic acid, formic acid and 2-ethylhexanoic acid) and/or an organic acid salt (such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate) in an organic solvent (such as dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane and ethanol), water or a mixed solvent thereof.
Apart from the above, the deprotection may also be effected, for example, according to the methods described in TW. Greene, Protective Groups in Organic
Synthesis, Wiley, New York, 1999.
As persons skilled in the art can easily understand that the aimed compound of the present invention is able to be easily produced by using appropriate ones among those - deprotection reactions.
Among the compounds represented by formula (I), a compound wherein R? is amino group which may have a substituent(s), i.e., a compound represented by formula (I- a)
COAT
R* ND R%' (l-a)
X
(wherein R*"' is amino group which may have a substituent(s) and other symbols have the same meanings as described above.) can be prepared by reductive amination of a compound represented by formula (IV) -30 -
AMENDED SHEET
PCT/JP2004/003333 . Y.
R , N D Oo (IV)
X
(wherein all symbols have the same meanings as described above.) and a compound represented by formula (V)
R301 7
HN oz (V) (wherein R*' and R*2 which are the same or different, are hydrogen atom or have the same meanings as the "substituents" of the above-described "amino group which may have a substituent(s)", and other symbols have the same meanings as described above. With proviso that, carboxy group, hydroxy group, amino group or thiol group in R**! or R3® may be protected, if necessary.), if necessary, followed by removal of the protecting group.
The reductive amination is well known. For example, it may be carried out in an organic solvent (e.g., dichloroethane, dichloromethane or dimethylformamide) in the presence of tertiary amine (e.g., triethylamine or diisopropylethylamine) and reducing agent (e.g., sodium triacetoxyborohydride or sodium cyanoborohydride) at 0 to 40°C,
The removal of the protecting group may be carried out by the above described method.
Among the compounds represented by formula (I), a compound wherein R? is
R304
N (0) (0) N
H R
(wherein R*®, R*® and R3%, which are the same or different, have the same meanings as the “substituents” of the above-described "3- to 15-mrembered homocyclic group or heterocyclic group which may have a substituent(s)" represented by ring A and ring B, and other symbols have the same meanings as described above.), i.e., a compound represented by formula (I-b)
R304
N o 305
Y R
R' “ND “ (I-b)
X N CRS
H oO -31-
AMENDED SHEET
(wherein all symbols have the same meanings as described above) can be prepared by cyclization of a compound represented by formula (VI)
R39" p30
R304 \ Da
RY YN " o \
N oO 7 (wherein T is C1-4 alkyl group, C5-6 mono-carbocycle, or C1-4 alkyl substituted by C5-6 mono-carbocycle or 5- or 6-membered mono-heterocycle containing 1 or 2 nitrogen atoms and/or one oxygen atom, R¥* R3%' and R*® are the same meanings as R** R*® and R** respectively and other symbols are the same meanings as described above. With proviso that, carboxy group, hydroxy group, amino group or thiol group in R¥ R33 apd R¥® may be protected, if necessary.), if necessary, followed by removal of the protecting group.
The cyclization is well known. For example, it may be carried out in an organic solvent (e.g., dichloroethane or toluene), with tertiary amine (e.g, triethylamine or diisopropylethylamine) or acid (e.g, acetic acid or trifluoroacetic acid), or without tertiary amine or acid at 60 to 120°C. This cyclization reaction is carried out with the cleavage of T group.
The removal of the protecting group may be carried out by the above described method.
Among the compounds represented by formula (I), a compound wherein R%is 0)
NPS
Ng!
Oo ? i.e., a compound represented by formula (I-c) 0 o) i Y. \
R? N D N N (i-c) :
X \— /
(wherein all symbols have the same meanings as described above.) can be prepared by cyclization of a compound represented by formula (VII) 0)
D’ N VII " ¥ A
H.C. _CH, O 3 (0) (0) 3 (wherein all symbols have the same meanings as described above.), if necessary, followed by removal of the protecting group.
The cyclization is well known. For example, it may be carried out in an organic solvent (e.g., dichloroethane or toluene) with acid (e.g., hydrochloric acid, sulfuric acid or p-toluenesulfonic acid) at 60 to 120°C.
The removal of the protecting group may be carried out by the above described method.
Among the compound represented by formula (I), a compound wherein R? is x oy
RS! R% i.e., a compound represented by formula (I-d) oO
Y
R? ND I-d £2), Le) 0 (re)
RS" RS? (wherein all symbols have the same meanings as described above.) can be prepared by a below reaction using a compound represented by formula (IX)
J Yo
R? N D' —N—RS" (IX)
X' H (wherein R>" has the same meaning as R’! and other symbols have the same meanings as described above. With proviso that, carboxy group, hydroxy group, amino group or thiol group in R*!" may be protected, if necessary.) and a compound represented by (X)
R%—COOH (X) (wherein R** has the same meaning as R*? and other symbols have the same meanings as described above. With proviso that, carboxy group, hydroxy group, amino group or thiol group in R** may be protected, if necessary.), if necessary, followed by removal of the protecting group.
The reaction is well known. For example, it may be carried out in an organic solvent (e.g., N,N-dimetylformamide, toluene or tetrahydrofuran) with base (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine or diisopropylethylamine) at 20 to 120°C.
The removal of the protecting group may be carried out by the above described method.
Moreover, the compound represented by formula (I-d) can be prepared by a below reaction using the compound represented by formula (IX) and a compound represented by formula (XI)
R¥—NH, (XI) (wherein the symbol has the same meaning as described above.), if necessary, followed by removal of the protecting group.
The reaction is well known. For example, it may be carried out in an organic solvent (e.g., tetrahydrofuran or N,N-dimetylformamiden) in the presence of triphosgene with base (e.g, triethylamine) at 0 to 40°C. Moreover, it may be carried out in an organic solvent (e.g, methylene chloride or N,N-dimetylformamiden) in the presence of 1,1'- carbonylbis-1H-imidazole (CDI) with base (e.g., triethylamine or N-methylmorpholine) or without base at 0 to 80°C.
The removal of the protecting group may be carried out by the above described method.
Among a compound represented by formula (I), a compound wherein Y is methylene, i.e., a compound represented by formula (I-e) oz
X
(wherein all symbols have the same meanings as described above) can be prepared by - reductive amination of a compound represented by formula (XII)
PCT/JP2004/003333
RY CHO (XI)
X' (wherein all symbols have the same meanings as described above.) and the compound represented by formula (III), if necessary, followed by removal of the protecting group.
The reductive amination is well known. For example, it may be carried out in an organic solvent (e.g., dichloroethane, dichloromethane, dimethylformamide, acetic acid or a mixture of them) in the presence of reducing agent (e.g, sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride) at 0 to 40°C.
The removal of the protecting group may be carrie! out by the above described method.
Among the compounds represented by formula (I), a compound wherein at least one nitrogen atom is quaternary ammonium salt, 7.e., a compounds of formula (I-2) 1-2 2 Ya
R'- x2 B N2 D2—+-R2?2 (1-2)
Q
(wherein RZ R*? XY? ring Al ring B? and ring D? have the same meanings as R! R%
X,Y, ring A, ring B and ring D respectively, and N? is nitrogen atom. With the proviso that, at least one nitrogen atom is quaternary ammonium salt, and Q is halogen.) can be prepared by reacting the compound of formula (I) with the compounds of formula (VIII)
R’—Qq (Vii (wherein R° is C1-4 alkyl or C1-4 alkyl substituted by phenyl, and Q is halogen.). - The reaction is well known, and it may be carried out, for example, in an organic solvent (acetone, dimethylformamide or methyl ethyl ketone etc.) at 0 to 40°C.
Among the compounds of formula (I), a compound where at least one nitrogen is N-oxide, i.e., a compound of formula (I-3) 13 3 4 3 Yi. a
R A x3 B N3 D3 —+R23 (I-3) (wherein R'? R*? X°, Y?, ring A?, ring B® and ring D* have the same meanings as R', R?,
X,Y, ring A, ring B and ring D respectively and N? is nitrogen atom. With the proviso that, at least one nitrogen represents N-oxide.) can be prepared by an oxidation of a compound of formula (I). -35-
AMENDED SHEET oO
The oxidation is well known and it may be carried out, for example, in a suitable organic solvent (e.g, dichloromethane, chloroform, benzene, hexane or t- butylalcohol) in the presence of an excessive oxidizing reagent (hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peroxidized acid (for example, 3- chloroperbenzoic acid or peracetic acid efc.), OXONE (brand name, OXONE is an abbreviation for potassium peroxymonosulfate.), potassium permanganate or chromic acid etc.) at 20 to 60°C.
The compound of the present invention can be prepared by these reactions or reactions modified a part of them.
Among the compound represented by formula (I), other compounds than the above-described can be prepared easily by combination of known methods, for example the methods described in Comprehensive Organic Transformations: A Guide to Functional
Group Preparations, 2nd Edition (Richard C. Larock, John Willey & Sons Inc, 1999).
Other starting compounds or compounds used as reagent are known compounds can be prepared easily by combination of known methods, for example the methods described in Comprehensive Organic Transformations: A Guide to Functional
Group Preparations, 2nd Edition (Richard C. Larock, John Willey & Sons Inc, 1999) or
Elmer J Rauckman ef al., J. Org. Chem., vol.41, No.3, 1976, p564-565 etc
In each reaction of the specification, the reactions with heating, as will be apparent to those skilled in the art, it may be carried with water bath, oil bath, sand bath and microwave.
In each reaction of the specification, it may be used a solid phase reagent which is supported by polymer (for example, polystyrene, polyacrylamide, polypropylene or polyethyleneglycol efc.).
In each reaction of the specification, the obtained products may be purified by conventional techniques. For example, the purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography with silica gel or magnesium silicate, by thin layer chromatography, by ion-exchange resin, by scavenger resin, by column chromatography, by washing or by recrystallization. The purification may be done each reaction or after several reactions.
Toxicity:
The toxicity of the compounds of the present invention is very low and therefore the compounds may be considered safe for pharmaceutical use.
Application to pharmaceuticals:
The compounds of the present invention represented by formula (I) regulate the effect of CCRS receptor in animal included human, especially human, so they are used for oO prevention and/or treatment of various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, ulcerative colitis, efc.), immunological diseases (autoimmune diseases, rejection In organ transplantation, immunosuppression, psoriasis, multiple sclerosis, efc.), infection with human immunodeficiency virus (acquired immunodeficiency syndrome, efc.), allergic diseases (atopic dermatitis, urticaria, allergic bronchoplumonary aspergillosis, allergic eosinophilic gastroenteritis, efc.), ischemic reperfusion injury, acute respiratory distress syndrome, shock accompanying bacterial infection, diabetes, cancer metastasis and so on.
For the purpose above described, the compounds of the present invention by formula (I), salts thereof or solvates salts, or prodrugs thereof may be normally administered systemically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person are generally from 1 mg to 1000 mg, by oral administration, up to several times per day, and from 1 mg to 100 mg, by parenteral administration (preferably intravenous administration), up to several times per day, or continuous administration from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions.
Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered for example, in the form of solid for oral administration, liquid forms for oral administration, injections, liniments or suppositories for parenteral administration.
Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules include hard capsules and soft capsules.
In such solid forms, one or more of the active compound(s) may be admixed with vehicles (such as lactose, mannitol, glucose, microcrystalline cellulose or starch), binders (such as hydroxypropyl! cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate), disintegrants (such as cellulose calcium glycolate), lubricants (such as magnesium stearate), stabilizing agents, and solution adjuvants (such as glutamic acid or aspartic acid) and prepared according to methods well known in normal pharmaceutical practice. The solid forms may, if desired, be coated with coating agents (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs. In such forms, one or more of the active compound(s) may be dissolved, suspended or emulsified into diluent(s) commonly used in the art (such as purified water, ethanol or a mixture thereof). Besides such liquid forms may also comprise some additives, such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservative or buffering agent.
Injections for parenteral administration include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent(s) for injection immediately before use. In injections, one or more of the active compound(s) may be dissolved, suspended or emulsified into solvent(s). The solvents may include distilled water for injection, saline, vegetable oil, propylene glycol, polyethylene glycol, alcohol such as ethanol, or a mixture thereof. Injections may comprise some additives, such as stabilizing agents, solution adjuvants (such as glutamic acid, aspartic acid or
POLYSORBATES80 (registered trade mark)), suspending agents, emulsifying agents, soothing agent, buffering agents, preservative. They may be sterilized at a final step, or may be prepared according to sterile methods. They may also be manufactured in the form of sterile solid forms such as freeze-dried products, which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
Other forms for parenteral administration include liquids for external use, ointments and endermic liniments, inhalations, sprays, suppositories and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by methods known per se.
Sprays may comprise additional substances other than diluents, such as stabilizing agents, such as sodium sulfate, isotonic buffers, such as sodium chloride, sodium citrate or citric acid. For preparation of such sprays, for example, the method described in the United States Patent No. 2,868,691 or 3,095,355 may be used.
The compounds of the present invention represented by formula (I), salts thereof or solvates thereof, or prodrugs thereof may be used together with other drugs, for example, preventive and/or treating agent(s) for HIV infection (particularly agents for prevention and/or treatment for AIDS). In that case, the drug as such may be mixed with pharmacologically acceptable excipient, binder, disintegrating agent, lubricant, stabilizer, solubilizer, diluent, efc. either separately or simultaneously to make into a pharmaceutical preparation and that can be administered either orally or parenterally as a pharmaceutical composition for prevention and/or treatment of HIV infection.
The compounds of the present invention represented by formula (I), salts thereof or solvates thereof, or prodrugs thereof have an infection inhibiting activity to HIV-
I which acquired resistance to other agents for preventive and/or treating HIV infection - (particularly agents for prevention and/or treatment for AIDS). Therefore, it is also able to be used for HIV-infected patients to whom other agents for preventive and/or treating
HIV infection are no longer effective. In that case, although the compound of the present oO invention may be used solely, it may be also used together with agents for preventive and/or treating HIV infection where infected HIV-1 strain acquired resistance or with other drugs.
The present invention covers the case where the compounds represented by formula (I), salts thereof or solvates thereof, or prodrugs thereof is combined with drugs which do not inhibit the HIV infection whereby preventive and/or treating effect for HIV infection is enhanced as compared with a single preparation.
Examples of other agent for preventive and/or treating HIV infection used for a combination with the compounds of the present invention represented by formula (I), salts thereof or solvates thereof, or prodrugs thereof are reverse transcriptase inhibitor, protease inhibitor, chemokine antagonist (such as CCR2 antagonist, CCR3 antagonist, CCR4 antagonist, CCRS antagonist and CXCR4 antagonist), fusion inhibitor, antibody to surface antigen of HIV-1 and vaccine of HIV-1.
Reverse transcriptase inhibitors are concretely (1) nucleoside/nucleotide reverse transcriptase inhibitors: zidovudine (brand name: Retrovir), didanosine (brand name: Videx), zalcitabine (brand name: HIVID), stavudine (brand name: Zerit), lamivudine (brand name: Epivir), abacavir (brand name: Ziagen), adefovir, adefovir dipivoxil, emtricitabine (brand name: Coviracil) or PMPA (brand name: Tenofovir) etc. and (2) nonnucleoside reverse transcriptase inhibitors : nevirapine (brand name: Viramune), delavirdine (brand name: Rescriptor), efavirenz (brand name: Sustiva, Stocklin) or capravirine (AG1549) etc.
Protease inhibitors are concretely indinavir (brand name: Crixivan), ritonavir (brand name: Norvir), nelfinavir (brand name: Viracept), saquinavir (brand name: Invirase,
Fortovase), amprenavir (brand name: Agenerase), lopinavir (brand name: Kaletra) or tipranavir efc.
As chemokine antagonists, internal ligand of chemokine receptor, its derivatives, its non-peptide low molecular compound or antibody of chemokine receptor are included.
The examples of internal ligand of chemokine receptor are concretely, MIP-1a,
MIP-1B, RANTES, SDF-1a, SDF-13, MCP-1, MCP-2, MCP-4, Eotaxin and MDC etc.
The derivatives of internal ligand are concretely, AOP-RANTES, Met-SDF-1a,
Met- SDF-1f efc.
Antibodies of chemokine receptor are concretely, Pro-140 ezc.
CCR2 antagonists are concretely written in specification of W099/07351, W099/40913, W000/46195, WO000/46196, WO00/46197, WO00/46198, WO00/46199,
W000/69432 or WO00/69815 or in Bioorg. Med. Chem. Lett., 10, 1803 (2000) etc.
CCR3 antagonists are concretely written in specification of DE19837386,
W099/55324, W099/55330, W000/04003, WO00/27800, WO00/27835, WO00/27843,
oO
WO000/29377, WO000/31032, WO00/31033, WO00/34278, WO000/35449, WO00/35451,
WO000/35452, WO00/35453, WO00/35454, W0O00/35876, WOO00/35877, WO00/41685,
WO000/51607, WO00/51608, WO00/51609, WO00/51610, WO00/53172, WO00/53600,
WO000/58305, W0O00/59497, WO00/59498, WO000/59502, WO00/59503, W000/62814, WO000/73327 or WO01/09088 etc.
CCRS5 antagonists are concretely TAK-779, SCH-351125 (SCH-C), SCH- 417690(SCH-D), UK-427857, GW873140A(ONO-4128), TAK-220 efc. Moreover, it includes compounds written in specification of W099/17773, W099/32100, WO00/06085,
WO000/06146, WOQ00/10965, WO000/06153, WO000/21916, WO00/37455, EP1013276, 'WO00/38680, WO00/39125, WO00/40239, W000/42045, WO00/53175, WO000/42852,
WO000/66551, WO00/66558, WO00/66559, WO00/66141, W0O00/68203, JP2000309598,
WO000/51607, WO00/51608, WO00/51609, WO00/51610, WO00/56729, W0O00/59497,
W000/59498, WO00/59502, WO00/59503, WO00/76933, W0O98/25605 or W0O99/04794,
W099/38514 or in Bioorg. Med. Chem. Lett., 10, 1803 (2000) etc.
CXCR4 antagonists are concretely AMD-3100, AMD-070, T-22, KRH-1120,
KRH-1636 or the compounds written in specification of WO00/66112 erc.
Fusion Inhibitors are concretely, T-20 (Pentafuside) and T-1249 etc.
The examples of combination agents written above are intended to illustrate the present invention, but do not limit them.
The typical examples of the usual the dosage level in clinical trials of reverse transcriptase inhibitors or protease inhibitors written below are intended to illustrate the present invention, but do not limit them.
Zidovudine: 100 mg capsule, 200 mg per dose, 3 times per day, 300 mg tablet, 300 mg per dose, twice per day; didanosine: 25-200 mg tablet, 125-200 mg per dose, twice per day; zalcitabine: 0.375-0.75 mg tablet, 0.75 mg per dose, 3 times per day; stavudine: 15-40 mg capsule, 30-40 mg per dose, twice per day, lamivudine: 150 mg tablet, 150 mg per dose, twice per day; abacavir: 300 mg tablet, 300 mg per dose, twice per day; nevirapine: 200 mg tablet, 200 mg per dose, once per day for 14 days and then twice per day; delavirdine: 100 mg tablet, 400 mg per dose, 3 times per day; efavirenz: 50-200 mg capsule, 600 mg per dose, once per day; indinavir: 200-400 mg capsule, 800 mg per dose, 3 times per day; ritonavir: 100 mg capsule, 600 mg per dose, twice per day; . nelfinavir: 250 mg tablet, 750 mg per dose, 3 times per day; saquinavir: 200 mg capsule, 1,200 mg per dose, 3 times per day; amprenavir: 50-150 mg tablet, 1,200 mg per dose, twice per day.
oO
Effect of the invention
The compounds of the present invention represented by formula (I) has CCRS antagonistic action, so they are useful as prevention and/or treatment for diseases through
S the intervention of CCRS receptor.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is explained below in detail based on Reference
Examples, Examples, Biological Examples or Formulation Examples, but the present invention is not limited thereto.
In chromatographic separations and TLC, the solvents in parenthesis show the eluting and developing solvents and the ratios of the solvents used are by volume.
Unless otherwise specified, NMR data is "H-NMR data.
The solvents in parenthesis in NMR show the solvents used for measurement.
All the compounds described in the present specification were named using
ACD/Name (registered trademark, ver. 6.0, Advanced Chemistry Development Inc.) or
ACD/Name Batch (registered trademark, ver. 4.5, Advanced Chemistry Development Inc.), or named according to IUPAC nomenclature system. For example, a compound represented by
Oo
H,C-5°° CH, no
SPRY.
N
OM
+ HCI was named N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperidin-4- yl]cyclohexanecarboxamide hydrochloride.
Example 1: 1-(4-(4-methylsulfonylaminophenoxy)benzyl)piperidin-4-ol
To a solution of 4-(4-methylsulfonylaminophenoxy)benzaldehyde (2.50 g) in dimethyl formamide (25 mL) were added 4-hydroxypiperidine (1.74 g) and acetic acid (2.5 mL), and the solution was stirred. To the reaction solution was added sodium - triacetoxyborohydride (2.18 g) and the solution was stirred for 2 days. After finishing the reaction, the reaction solution was neutralized with 2N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine,
oO dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride : methanol=10:1) to give the title compound (1.90 g) having the following physical data.
TLC:Rf 0.48(chloroform:methanol=5:1);
NMR (DMSO-d): & 1.29-1.42 (m, 2H), 1.63-1.73 (m, 2H), 1.95-2.05 (m, 2H), 2.59-2.68 (m, 2H), 2.95 (s, 3H), 3.38 (s, 2H), 3.43 (m, 1H), 4.51 (d, J=4.5 Hz, 1H), 6.91 (d, J=8.5 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 7.21 (d, J=9.0 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 9.59 (br s, IH).
Example 2: 1-(4-(4-methylsulfonylaminophenoxy)benzyl)piperidin-4-one 0) (0)
OO
H,C~ °N
H
To a solution of the compound prepared in Example 1 (1.79 g) in dimethylsulfoxide (5 mL) was added triethylamine (3 mL). To the reaction solution was added sulfur trioxide pyridine complex (1.52 g) under cooling with ice and the solution was stirred for one hour. After finishing the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride : methanol=20:1) to give the title compound (1.76 g) having the following physical data.
TLC:Rf0.51(chloroform:methanol=10:1);
NMR (DMSO-de): § 2.33 (t, J=6.0 Hz, 4H), 2.66 (t, J=6.0 Hz, 4H), 2.95 (s, 3H), 3.57 (s, 2H), 6.94 (d, J=8.5 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 7.22 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.5
Hz, 2H), 9.59 (s, 1H).
Example 3:
N-[4-(4-{[4-(butylamino)piperidin- 1-ylJmethyl} phenoxy)phenyl] methanesulfonamide dihydrochloride
0
J oO NH
BY 9 To 91
HC” °N N
H -2HCI
To a solution of the compound prepared in Example 2 (400 mg) in dimethylformamide (5 mL) were added n-butylamine (0.2 mL) and triethylamine (0.2 mL) and the solution was stirred. To the reaction solution was added sodium triacetoxyborohydride (440 mg) and the solution was stirred for 20 hours. After finishing the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride : methanol=5:1). 4N hydrogen chloride/ethyl acetate solution was added to the reaction mixture, which was concentrated to give the compound of the present invention (267 mg) having the following physical data.
TLC Rf 0.22(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.99 (t, J=7.5 Hz, 3H), 1.38-1.51 (m, 2H), 1.63-1.74 (m, 2H), 1.97-2.10 (m, 2H), 2.31-2.41 (m, 2H), 2.95 (s, 3H), 3.02-3.08 (m, 2H), 3.10-3.18 (m, 2H), 3.45 (m, 1H), 3.55-3.65 (m, 2H), 4.31 (s, 2H), 7.03 (d, J=9.0 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H).
Example 4:
N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)piperidin-4-yl]-2- (tetrahydro-2H-pyran-4-yl)acetamide hydrochloride
J
0) N 00 \"4
HsC N
H HCI -
To a solution of the compound prepared in Example 3 (183 mg) in dimethylformamide (3 mL) were added 4-tetrahydropyranylacetic acid (70 mg), 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg) and dimethylaminopyridine oO (155 mg) and the solution was stirred over night. After finishing the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride : methanol=25:1). 4N hydrogen chloride/ethyl acetate solution was added to the reaction mixture, which was concentrated to give the compound of the present invention (79 mg) having the following physical data.
TLC:Rf 0.49(chloroform:methanol=10:1);
NMR (CDs;OD): 6 0.98 (t, J=7.0 Hz, 3H), 1.24-1.69 (m, 8H), 1.87-2.40 (m, 7H), 2.95 (s, 3H), 3.02-3.48 (m, 6H), 3.49-3.61 (m, 2H), 3.87-3.95 (m, 2H), 4.12 (m, 1H), 4.27-4.30 (m, 2H), 7.03 (d, J=9.0 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.49 (d, J=8.5
Hz, 2H).
Example 4(1): 2-cyclohexyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4-yl]-N- propylacetamide hydrochloride
By the same procedure as described in Example 3—>Example 4, using n- propylamine and a corresponding cyclohexylacetic acid instead of n-butylamine and 4- tetrahydropyranylacetic acid respectively, the compound of the present invention having the following physical data was obtained.
TLC:Rf 0.40(chloroform:methanol=10:1),
NMR (CD;OD): 4 0.86-1.39 (m, SH), 1.48-2.14 (m, 9H), 2.22 (d, J=7.0 Hz, 2H), 2.27-2.39 (m, 2H), 2.95 (s, 3H), 3.02-3.25 (m, 4H), 3.49-3.61 (m, 2H), 4.13 (m, 1H), 4.27-4.29 (m, 2H), 7.03 (d, J=9.0 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.49 (d, J=8.5
Hz, 2H).
Reference Example 1: 1-t-butoxycarbonyl-4-butylaminopiperidine
To a solution of I-t-butoxycarbonylpyperidin-4-one (10.0 g) in dimethylformamide (200 mL) were added n-butylamine (6.0 mL) and triethylamine (7.0 mL) and the solution was stirred. To the reaction solution was added sodium triacetxyborohydride (16.0 g) and the solution was stirred for 1.5 hours. After finishing the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the title compound having the following physical data.
TLC Rf 0.28(chloroform:methanol=10:1);
NMR (CDCls): 6 0.92 (t, J = 7.0 Hz, 3H), 1.19-1.53 (m, 6H), 1.45 (s, 9H), 1.82-1.87 (m, 2H), 2.55-2.66 (m, 3H), 2.74-2.82 (m, 2H), 4.00-4.10 (m, 2H).
oO
Reference Example 2: 1-t-butoxycarbonyl-4-(N-cyclohexylcarbonyl-N-butylamino)piperidine
To a solution of the compound prepared in Reference Example 1 in methylene chloride (100 mL) were added cyclohexylacetic acid (7.5 g), 1-ethyl-3-[3- (dimethylamino)propyljcarbodiimide =~ hydrochloride ~~ (14.5 g) and 4-N,N- dimethylaminopyridine (9.2 g) and the solution was stirred overnight. After finishing the reaction, water was added to the reaction solution, which was extracted with ethyl acetate.
The organic layer was washed with brine, dried over magnesium sulfate and concentrated.
The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=1:1) to give the title compound (8.97 g) having the following physical data.
TLC:Rf 0.50(hexane: ethyl acetate=2:1),
NMR (CDCl): § 0.87-1.01 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H), 1.05-1.81 (m, 16H), 1.46 (s,
SH), 1.89 (m, 1H), 2.16 (d, J = 7.0 Hz, 2H), 2.68-2.85 (m, 2H), 3.08-3.18 (m, 2H), 4.09- 4.35 (m, 2H), 4.52 (m, 1H).
Reference Example 3: 4-[(N-cyclohexylcarbonyl-N-butyl)amino]piperidine hydrochloride
To a solution of the compound prepared in Reference Example 2 (8.92 g) in methylene chloride (20 mL) was added trifluoroacetic acid (20 mL) and the solution was stirred for 30 minutes. After finishing the reaction, the reaction solution was alkalinized with IN aqueous solution of sodium hydroxide and was extracted with methylene chloride.
The organic layer was washed with brine, dried over magnesium sulfate and concentrated. 4N hydrogen chloride/ethyl acetate solution was added to the obtained residue, which was concentrated to give the title compound (7.98 g) having the following physical data.
TLC:Rf 0.35(chloroform:methanol=5:1);
NMR (CD;0D): & 0.92-1.08 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H), 1.15-2.36 (m, 17H), 2.23 (d,
J =17.0 Hz, 2H), 3.01-3.30 (m, 4H), 3.41-3.53 (m, 2H), 4.15 (m, 1H).
Example 5(1)-Example 5(54)
By the same procedure as described in Example 1 and the conversion to hydrochloride salt by a conventional method, using the compound prepared in Reference
Example 3 or a corresponding amine derivative instead of 4-hydroxypiperidine, and using 4-(4-methylsulfonylaminophenoxy)benzaldehyde or a corresponding aldehyde derivative, the following compounds of the present invention were obtained.
oO
Example 5(1):
N-butyl-2-cyclohexyl-N-[1-(4-{2-methoxy-4- [(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4-yl]acetamide hydrochloride
CH; jon N
WTO
4
HC S\N N oO
H “HCI TLC:Rf 0.49(chloroform:methanol=10:1);
NMR (CDCls): 3 0.87-1.01 (m, 2H), 0.93 (t, J=7.0 Hz, 3H), 1.07-2.06 (m, 15H), 2.19 (d,
J=7.0 Hz, 2H), 2.49-2.84 (m, 4H), 3.02 (s, 3H), 3.17-3.27 (m, 2H), 3.49-3.59 (m, 2H), 3.81 (s, 3H), 4.10 (br s, 2H), 4.72 (m, 1H), 6.88-6.93 (m, 3H), 6.99 (d, J=8.5 Hz, 1H), 7.13 (d,
J=2.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.94 (br s, 1H), 12.14 (s, 1H).
Example 5(2):
N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]cyclohexanecarboxamide hydrochloride
TLC:Rf 0.62(methylene chloride:methanol=10:1);
NMR (CD;OD): § 7.55-7.46 (m, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.10-7.00 (m, 4H), 4.33- 4.25 (m, 2H), 4.19 (m, 1H), 3.62-3.48 (m, 2H), 3.30-3.02 (m, 4H), 2.95 (s, 3H), 2.48 (m, 1H), 2.35-2.08 (m, 2H), 1.98-1.63 (m, 7H), 1.63-1.18 (m, 9H), 1.03-0.88 (m, 3H).
Example 5(3): N-butyl-2-cyclohexyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]acetamide hydrochloride
TLC:Rf 0.62(methylene chloride:methanol=10:1);
NMR (CD;OD): 8 7.55-7.46 (m, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.10-7.00 (m, 4H), 4.32- 4.24 (m, 2H), 4.16 (m, 1H), 3.63-3.48 (m, 2H), 3.30-3.01 (m, 4H), 2.95 (s, 3H), 2.40-2.08 (m, 4H), 2.00-1.60 (m, 8H), 1.60-1.10 (m, 7H), 1.10-0.90 (m, SH).
Example 5(4): N
N-butyl-3-cyclohexyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]propanamide hydrochloride
TLC:Rf0.64(methylene chloride:methanol=10:1);
oO
NMR (CD;OD): 6 7.56-7.46 (m, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.10-7.00 (m, 4H), 4.32- 4.23 (m, 2H), 4.16 (m, 1H), 3.62-3.47 (m, 2H), 3.30-3.00 (m, 4H), 2.95 (s, 3H), 2.50-2.03 (m, 4H), 2.02-1.84 (m, 2H), 1.82-1.60 (m, 5H), 1.60-1.10 (m, 10H), 1.05-0.83 (m, SH).
Example 5(5):
N-butyl-2-cyclohexyl-N-{1-[(3,5-dimethyl-1-{4-[(methylsulfonyl)amino]phenyl}-1H- pyrazol-4-yl)methyl]piperidin-4-yl} acetamide hydrochloride
TLC:Rf 0.41(chloroform:methanol=10:1);
NMR (CD;OD): 8 0.91-1.06 (m, 2H), 0.98 (t, J=7.5 Hz, 3H), 1.14-1.83 (m, 13H), 1.89- 1.97 (m, 2H), 2.23 (d, J=6.5 Hz, 2H), 2.32-2.40 (m, 2H), 2.36 (s, 3H), 2.39 (s, 3H), 3.04 (s, 3H), 3.12-3.29 (m, 4H), 3.61-3.71 (m, 2H), 4.25 (s, 2H), 4.27 (m, 1H), 7.41 (d, J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H).
Example 5(6):
N-(1-{4-[4-(aminosulfonyl)phenoxy]benzyl} piperidin-4-yl)-N-butyl-2- cyclohexylacetamide hydrochloride
TLC:Rf 0.37(chloroform:methanol=10:1);
NMR (CD;0D): § 0.91-1.04 (m, 2H), 0.98 (t, J=7.0 Hz, 3H), 1.12-1.99 (m, 15H), 2.22 (d,
J=6.5 Hz, 2H), 2.25-2.36 (m, 2H), 2.97-3.30 (m, 4H), 3.46-3.60 (m, 2H), 4.10 (m, 1H), 4.29 (s, 2H), 7.13 (d, J=9.0 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.90 (d, J=9.0 Hz, 2H).
Example 5(7):
N-butyl-2-cyclohexyl-N-[1-({4'-[ (methylsulfonyl)amino]biphenyl-3-yl } methyl)piperidin- 4-yl]acetamide hydrochloride
TLC:Rf 0.50(chloroform:methanol=10:1);
NMR (CD;OD): 6 0.87-1.05 (m, 2H), 0.96 (t, J=7.0 Hz, 3H), 1.13-2.14 (m, 15H), 2.21 (d,
J=7.0 Hz, 2H), 2.25-2.38 (m, 2H), 2.99 (s, 3H), 3.08-3.28 (m, 4H), 3.54-3.65 (m, 2H), 4.15 (m, 1H), 4.37-4.39 (m, 2H), 7.36 (d, J=9.0 Hz, 2H), 7.47 (d, J=7.5 Hz, 1H), 7.57 (1, J=7.5
Hz 1H), 7.67 (d, J=9.0 Hz, 2H), 7.74-7.82 (m, 2H).
Example 5(8):
N-{4-[4-({4-[butyl(2-cyclohexylethyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride
TLC:Rf0.32(chloroform:methanol=10:1);
NMR (CD;0D): 6 0.94 (t, J=7.0 Hz, 3H), 0.98-1.08 (m, 2H), 1.18-1.41 (m, 7H), 1.53-1.80 (m, 8H), 2.24-2.49 (m, 4H), 2.96 (s, 3H), 3.05-3.21 (m, 6H), 3.70-3.81 (m, 3H), 4.32 (d,
oO
J=13.0 Hz, 1H), 4.53 (d, J=13.0 Hz, 1H), 7.04 (d, J=9.0 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 7.30 (d, J=9.0 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H).
Example 5(9):
N-[(1S)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]-1-(4-{4- [(methylsulfonyl)amino]phenoxy } benzyl)piperidine-4-carboxamide hydrochloride
TLC:Rf 0.34(chloroform:methanol=4:1);
NMR (CD;0D): § 0.84-1.06 (m, 2H), 1.13-1.41 (m, 4H), 1.55-2.14 (m, 11H), 2.59 (m, 1H), 2.95 (s, 3H), 2.97-3.09 (m, 2H), 3.50-3.59 (m, 2H), 4.29 (s, 2H), 4.39 (dd, J=9.5, 5.5 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.49 (d, J=9.0
Hz, 2H).
Example 5(10):
N-{4-[4-({4-[(3S)-3-(cyclohexylmethyl)-2,5-dioxopiperazin-1-yl]piperidin-1- yl}methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.73(chloroform:methanol=5:1);
NMR (CD;0D): 6 7.49 (brd, J = 8.7 Hz, 2H), 7.29 (brd, J = 9.0 Hz, 2H), 7.07 (brd, J = 8.7
Hz, 2H), 7.03 (brd, J = 9.0 Hz, 2H), 4.44 (m, 1H), 4.29 (s, 2H), 4.04 (d, J = 16.8 Hz, 1H), 3.96 (t, J = 6.6 Hz, 1H), 3.83 (d, J = 16.8 Hz, 1H), 3.64-3.52 (m, 2H), 3.15 (m, 2H), 2.95 (s, 3H), 2.20-1.60 (m, 10H), 1.49 (m, 1H), 1.39-1.10 (m, 4H), 1.09-0.80 (m, 2H).
Example 5(11):
N-{4-[4-({4-[4-(cyclohexylcarbonyl)-2-oxopiperazin-1-yl]piperidin-1- yl}methyl)phenoxy]phenyl } methanesulfonamide hydrochloride TLC:0.45(methylene chloride: methanol=10:1);
NMR (CD;0D): § 7.50 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.05 (d, J] = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 4.50 (m, 1H), 4.26 (m, 1H), 4.23 (s, 2H), 4.14 (m, 1H), 3.82- 3.76 (m, 2H), 3.53-3.33 (m, 4H), 3.09-3.01 (m, 2H), 2.95 (s, 3H), 2.65 (m, 1H), 2.19-1.88 (m, 4H), 1.79-1.70 (m, 5H), 1.49-1.21 (m, SH).
Example 5(12):
N-butyl-2-cyclohexyl-N-[1-(4-{2-methoxy-4- [(methylsulfonyl)amino]phenoxy } benzyl)piperidin-3-ylJacetamide hydrochloride
TLC:Rf 0.49(chloroform:methanol=10:1),
NMR (CDCl): 8 0.87-1.00 (m, 2H), 0.94 (t, J=7.5 Hz, 3H), 1.08-1.93 (m, 16H), 2.11 (d, : 1=7.0 Hz, 2H), 2.25 (m, 1H), 2.45-2.64 (m, 2H), 3.02 (s, 3H), 3.18-3.37 (m, 4H), 3.80 (s, 3H), 3.86-4.00 (m, 2H), 4.20 (dd, J=13.0, 4.0 Hz, 1H), 6.87-6.92 (m, 3H), 6.99 (d, J=8.5
Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.83 (br 5, 1H), 11.87 (s, 1H).
0
Example 5(13):
N-butyl-2-cyclohexyl-N-[1-(4-{[(4-methylphenyl)sulfonyl]amino } benzyl)piperidin-4- yl]acetamide hydrochloride TLC:Rf 0.45(chloroform:methanol=10:1);
NMR (CD;0D): 8 0.89-1.06 (m, 2H), 0.96 (t, J=7.0 Hz, 3H), 1.12-2.09 (m, 15H), 2.21 (d,
J=7.0 Hz, 2H), 2.22-2.32 (m, 2H), 2.36 (s, 3H), 2.97-3.27 (m, 4H), 3.41-3.54 (m, 2H), 4.11 (m, 1H), 4.18-4.20 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 7.36 (d, I=8.5
Hz, 2H), 7.69 (d, J=8.5 Hz, 2H).
Example 5(14): 1-(4-(4-(N-cyclohexylmethylcarbonyl-N-methylsulfonylamino)phenoxy)benzyl)-4-(N- propyl-N-cyclohexylmethylcarbonylamino)piperidine hydrochloride
TLC:Rf 0.82(chloroform:methanol=10:1);
NMR (CD;0D): 8 0.77-1.39 (m, 13H), 1.47-1.96 (m, 16H), 2.05 (d, J=7.0 Hz, 2H), 2.22 (d,
J=7.0 Hz, 2H), 2.24-2.41 (m, 2H), 3.04-3.26 (m, 4H), 3.48 (s, 3H), 3.51-3.65 (m, 2H), 4.13 (m, 1H), 4.31-4.33 (m, 2H), 7.13 (d, J=9.0 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.38 (d, J=9.0
Hz, 2H), 7.56 (d, J=8.5 Hz, 2H).
Example 5(15): 4-(4-{[4-(4-bromobenzoy!)piperidin-1-ylJmethyl} phenoxy)benzoic acid hydrochloride
TLC:Rf 0.35(chloroform:methanol=10:1);
NMR (DMSO-d¢): 8 1.83-2.15 (m, 4H), 2.94-3.09 (m, 2H), 3.39-3.50 (m, 2H), 3.65 (s, 1H), 4.31 (br s, 2H), 7.09 (d, J=9.0 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.76 (d, J=8.5 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 7.97 (d, J=9.0 Hz, 2H), 10.52 (br s, 1H), 12.86 (br s, 1H).
Example 5(16): 4-[4-({4-[(3S)-3-(cyclohexylmethyl)-2,5-dioxopiperazin-1-yl]piperidin-1- yl}methyl)phenoxy]benzoic acid hydrochloride
TLC:Rf 0.65(chloroform:methanol=5:1),
NMR (CD;0D): & 8.04 (brd, J = 8.7 Hz, 2H), 7.59 (brd, J = 8.1 Hz, 2H), 7.17 (brd, J = 8.1
Hz, 2H), 7.07 (brd, J = 8.7 Hz, 2H), 4.46 (m, 1H), 4.34 (s, 2H), 4.05 (d, J = 17.1 Hz, 1H), 3.97 (dd, J = 6.6, 5.4 Hz, 1H), 3.85 (d, J = 17.1 Hz, 1H), 3.68-3.53 (m, 2H), 3.17 (m, 2H), 224-2.04 (m, 2H), 1.94 (m, 1H), 1.84-1.56 (m, 7H), 1.48 (m, 1H), 1.38-1.08 (m, 4H), : 1.08-0.80 (m, 2H).
LI
Example 5(17): 5-chloro-2-{4-[1-(3,4-dimethoxybenzyl)piperidin-4-yl]benzyl }- 1H-isoindole-1,3(2H)- dione hydrochloride
TLC Rf 0.48(methylene chloride:methanol=10:1);
NMR (CD;OD): & 7.86-7.81 (m, 2H), 7.33(d, J = 8.0 Hz, 2H), 7.23(d, J = 8.0 Hz, 2H), 7.14(s, 1H), 7.06-7.01 (m, 3H), 4.78(s, 2H), 4.26(s, 2H), 3.88(s, 3H), 3.85(s, 3H), 3.58- 3.54 (m, 2H), 3.10-3.00 (m, 2H), 2.90(m, 1H), 2.10-1.90 (m, 4H).
Example 5(18):
N-butyl-2-cyclohexyl-N-[1-(4-phenoxybenzyl)piperidin-4-yl]acetamide hydrochloride
TLC:Rf 0.82(methylene chloride:methanol=10:1);
NMR (CD;OD): § 7.50-7.37 (m, 4H), 7.18(t, J = 7.2 Hz, 1H), 7.07-7.02(m, 4H), 4.27(s, 2H), 4.15(m, 1H), 3.60-3.50 (m, 2H), 3.30-3.00 (m, 4H), 2.20-2.00 (m, 4H), 2.00-1.80 (m, 2H), 1.80-1.40 (m, 8H), 1.40-1.10 (m, SH), 1.00-0.90 (m, 2H), 0.97(t, J = 7.4 Hz, 3H).
Example 5(19): 4-[4-({4-[butyl(cyclohexylacetyl)amino]piperidin-1-yl} methyl)phenoxy]benzoic acid hydrochloride
TLC:Rf 0.43(methylene chloride: methanol=10:1),
NMR (CDsOD): & 8.04(d, J = 8.3 Hz, 2H), 7.56(d, J = 8.3 Hz, 2H), 7.17(d, J = 8.3 Hz, 2H), 7.07(d, J = 8.3 Hz, 2H), 4.31(s, 2H), 4.16(m, 1H), 3.60-3.50 (m, 2H), 3.30-3.00 (m, 4H), 2.20-2.00 (m, 4H), 2.00-1.80 (m, 2H), 1.80-1.40 (m, 8H), 1.40-1.10 (m, SH), 1.00-0.90 (m, 2H), 0.97(t, J = 7.0 Hz, 3H).
Example 5(20):
N-butyl-2-cyclohexyl-N-{1-[(3,5-dimethyl-1 -phenyl-1H-pyrazol-4-yl)methyl]piperidin-4- yl}acetamide dihydrochloride
TLC:Rf 0.47(methylene chloride:methanol=10:1);
NMR (CD;0D): 8 7.58-7.45(m, SH), 4.24(s, 2H), 4.15(m, 1H), 3.60-3.50 (m, 2H), 3.30- 3.00 (m, 4H), 2.37(s, 3H), 2.36(s, 3H), 2.40-2.10 (m, 4H), 2.00-1.80 (m, 2H), 1.80-1.40 (m, 8H), 1.40-1.10 (m, 5H), 1.00-0.90 (m, 2H), 0.98(t, J = 7.4 Hz, 3H).
Example 5(21):
N-butyl-2-cyclohexyl-N-(1-{[1-(4-hydroxyphenyl)-3, 5-dimethyl-1H-pyrazol-4- yl]methyl}piperidin-4-yl)acetamide dihydrochloride BN
TLC:Rf 0.37(methylene chloride: methanol=10:1);
NMR (CD;0D): § 7.26(d, J = 9.0 Hz, 2H), 6.92(d, J = 9.0 Hz, 2H), 4.24(s, 2H), 4.15(m, 1H), 3.70-3.60 (m, 2H), 3.30-3.00 (m, 4H), 2.37(s, 3H), 2.32(s, 3H), 2.40-2.20 (m, 4H),
oO 2.00-1.80 (m, 2H), 1.80-1.40 (m, 8H), 1.40-1.10 (m, SH), 1.00-0.90 (m, 2H), 0.98(t, J = 7.4
Hz, 3H).
Example 5(22):
N-{4-[4-({4-[4-(cyclohexylcarbonyl)piperazin-1-yl]piperidin-1- yl}methyl)phenoxy]phenyl } methanesulfonamide dihydrochloride
TLC:Rf 0.59(methylene chloride: methanol=5:1);
NMR (CD;0D): § 1.21-1.49 (m, 6H), 1.70-1.98 (m, 10H), 2.20-2.35 (m, 2H), 2.60-2.70 (m, 2H), 2.95 (s, 3H), 2.95-3.23 (m, 4H), 3.55-3.80 (m, 4H), 4.28 (s, 2H), 7.03 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H).
Example 5(23):
N-{4-[4-({4-[5-(cyclohexylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]piperidin-1- yl}methyl)phenoxy]phenyl } methanesulfonamide dihydrochloride TLC:Rf 0.46(methylene chloride:methanol=5:1);
NMR (CD;O0D): 6 1.15-1.49 (m, 6H), 1.60-1.98 (m, 10H), 2.35-2.88 (m, 6H), 2.95 (s, 3H), 3.08-3.72 (m, 4H), 3.89 (d, J = 9.5 Hz, 1H), 4.04 (s, 2H), 4.62 (d, J = 22.5 Hz, 1H), 7.01 (d,
J=18.7 Hz, 2H), 7.02 (d, J] = 8.7 Hz, 2H), 7.28 (d, ] = 8.7 Hz, 2H), 7.42 (d, J] = 8.7 Hz, 2H).
Example 5(24): 2-cyclohexyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]acetamide hydrochloride
TLC:Rf 0.46(methylene chloride: methanol=10:1);
NMR (CDs0OD): § 0.89-1.00 (m, 2H), 1.21-1.29 (m, 3H), 1.68-1.71 (m, 8H), 2.03 (d, J = 6.9 Hz, 2H), 2.11-2.16 (m, 2H), 2.95 (s, 3H), 3.06-3.14 (m, 2H), 3.49-3.53 (m, 2H), 3.90 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] =8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H).
Example 5(25): 2-cyclohexyl-N-[1-(4-phenoxybenzyl)piperidin-4-yl]acetamide hydrochloride
TLC:Rf 0.62(methylene chloride: methanol=10:1);
NMR (CD;0D): § 0.90-1.00 (m, 2H), 1.13-1.29 (m, 3H), 1.67-1.78 (m, 8H), 2.03 (d, J = 6.9 Hz, 2H), 2.12-2.15 (m, 2H), 3.05-3.13 (m, 2H), 3.49-3.53 (m, 2H), 3.90 (m, 1H), 4.27 (s, 2H), 7.02-7.08 (m, 4H), 7.18 (m, 1H), 7.37-7.42 (m, 2H), 7.46-7.50 (m, 2H). -
Example 5(26): 2-cyclohexyl-N-{1-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]piperidin-4- yl}acetamide dihydrochloride oO
TLC:Rf 0.40(methylene chloride: methanol=10:1);
NMR (CD;0D): 6 0.91-1.02 (m, 2H), 1.14-1.34 (m, 3H), 1.69-1.85 (m, 8H), 2.05(d, J = 6.9 Hz, 2H), 2.13-2.19 (m, 2H), 2.36 (s, 3H), 2.38 (s, 3H), 3.14-3.24 (m, 2H), 3.61-3.66 (m, 2H), 3.93 (m, 1H), 4.25 (s, 2H), 7.45-7.60 (m, SH).
Example 5(27):
N-{4-[4-({4-[(5S)-5-(cyclohexylmethyl)-1-isopropyl-3,6-dioxopiperazin-2-yl]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.69(chloroform:methanol=5:1);
NMR (CD3;OD): & 0.80-2.36 (m, 24H), 2.95 (s, 3H), 3.04 (m, 1H), 3.46-3.69 (m, 3H), 3.78-4.12 (m, 3H), 4.26 (brs, 2H), 7.00-7.18 (m, 4H), 7.26-7.34 (m, 2H), 7.40-7.48 (m, 2H).
Example 5(28):
N-{4-[4-({4-[(5S)-5-(cyclohexylmethyl)-1-(2-methoxyethyl)-3,6-dioxopiperazin-2- yl]piperidin-1-yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.67(chloroform:methanol=5:1);
NMR (CD3OD): 6 0.80-2.32 (m, 21H), 2.95 (s, 3H), 2.84-3.02 (m, 3H), 3.40-3.60 (m, 4H), 3.80-4.14 (m, 3H), 4.26 (brs, 2H), 7.00-7.14 (m, 4H), 7.21-7.32 (m, 2H), 7.41-7.52 (m, 2H).
Example 5(29):
N-{4-[4-({4-[(5S)-5-(cyclohexylmethyl)-1-methyl-3,6-dioxopiperazin-2-yl]piperidin-1- yl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC Rf 0.64(chloroform:methanol=5:1);
NMR (CD;O0D): 6 0.96 (m, 1H), 1.12-1.36 (m, 3H), 1.44-2.38 (m, 14H), 2.95 (s, 3H), 2.98 (m, 2H), 3.36 (brs, 3H), 3.42-3.60 (m, 2H), 3.86-4.34 (m, 2H), 4.25 (brs, 2H), 6.98-7.08 (m, 4H), 7.24-7.30 (m, 2H), 7.40-7.52 (m, 2H).
Example 5(30):
N-{4-[4-({4-[(5S)-1-benzyl-5-(cyclohexylmethyl)-3,6-dioxopiperazin-2-yl]piperidin-1- yl}methyl)phenoxy]phenyl}methanesulfonamide hydrochloride
TLC:Rf 0.78(chloroform:methanol=5:1);
NMR (CD;O0D): § 0.80-2.40 (m, 18H), 2.95 (s, 3H), 3.44-3.56 (m, 3H), 3.79 (m, 1H), 4.02-4.30 (m, 4H), 5.22 (m, 2H), 7.00-7.08 (m, 4H), 7.24-7.40 (m, 6H), 7.40-7.50 (m, 3H).
Example 5(31): — (3S)-3-(cyclohexylmethyl)-1-isopropyl-6-[ 1-(4-phenoxybenzyl)piperidin-4-yl]piperazine- 2,5-dione hydrochloride
TLC:Rf 0.84(chloroform:methanol=5:1);
oO
NMR (CD30D): 6 0.80-2.38 (m, 24H), 3.03 (m, 2H), 3.46-3.70 (m, 3H), 3.76-4.10 (m, 2H), 4.26 (brs, 2H), 7.00-7.06 (m, 4H), 7.19 (m, 1H), 7.36-7.58 (m, 4H).
Example 5(32): (3S)-3-(cyclohexylmethyl)-1-(2-methoxyethyl)-6-[ 1-(4-phenoxybenzyl)piperidin-4- yl]piperazine-2,5-dione hydrochloride
TLC:Rf 0.77(chloroform:methanol=5:1);
NMR (CD30D): § 0.80-1.10 (m, 2H), 1.12-2.10 (m, 16H), 2.16-2.62 (m, 2H), 2.98-4.14 (m, 11H), 4.26 (brs, 2H), 7.00-7.10 (m, 4H), 7.18 (m, 1H), 7.30-7.54 (m, 4H).
Example 5(33): (3S)-1-benzyl-3-(cyclohexylmethyl)-6-[ 1 -(4-phenoxybenzyl)piperidin-4-yl]piperazine-2,5- dione hydrochloride
TLC:Rf 0.86(chloroform:methanol=5:1);
NMR (CD;OD): § 0.84-2.40 (m, 18H), 2.76-3.04 (m, 2H), 3.42-3.60 (m, 2H), 3.78 (m, 1H), 4.10 (m, 1H), 4.16-4.34 (m, 3H), 5.20 (m, 1H), 6.98-7.14 (m, 4H), 7.19 (m, 1H), 7.20-7.52 (m, 9H).
Example 5(34): (3S)-3-(cyclohexylmethyl)-6-{1-[(3,5-dimethyl-1-phenyl- 1H-pyrazol-4- yl)methyl]piperidin-4-yl}-1-isopropylpiperazine-2,5-dione hydrochloride
TLC:Rf 0.74(chloroform:methanol=5:1);
NMR (CD;OD): 6 0.84-2.36 (m, 24H), 2.36 (brs, 3H), 2.38 (brs, 3H), 3.04-3.24 (m, 2H), 3.60-4.10 (m, 5H), 4.25 (brs, 2H), 7.40-7.60 (m, SH).
Example 5(35): (3S)-3-(cyclohexylmethyl)-6-{ 1-[(3,5-dimethyl-1-phenyl- 1H-pyrazol-4- yl)methyl]piperidin-4-yl}-1-methylpiperazine-2,5-dione hydrochloride
TLC:Rf 0.74(chloroform:methanol=5:1);
NMR (CD;OD): 8 0.84-2.40 (m, 18H), 2.35 (m, 6H), 3.00 (brs, 3H), 3.09 (m, 2H), 3.56- 3.70 (m, 2H), 3.82-4.12 (m, 2H), 4.24 (brs, 2H), 7.40-7.60 (m, SH).
Example 5(36): (3S)-3-(cyclohexylmethyl)-6-{1-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl}-1-(2-methoxyethyl)piperazine-2,5-dione hydrochloride -
TLC:Rf 0.74(chloroform:methanol=5:1);
NMR (CD;O0D): 8 0.80-2.40 (m, 18H), 2.35 (brs, 3H), 2.38 (brs, 3H), 3.00-3.20 (m, 3H), 3.33 (s, 3H), 3.49-3.72 (m, 4H), 3.88-4.16 (m, 3H), 4.25 (brs, 2H), 7.40-7.62 (m, SH).
oO
Example 5(37):
N-butyl-1-(4-phenoxybenzyl)piperidine-4-carboxamide hydrochloride
TLC:Rf 0.58(chloroform:methanol=10:1);
NMR (CDsOD): 3 0.92 (t, J = 7.2 Hz, 3H), 1.28-1.52 (m, 4H), 1.82-2.05 (m, 4H), 2.49 (m, 1H), 2.98-3.07 (m, 2H), 3.16 (t, J = 7.0 Hz, 2H), 3.52-3.56 (m, 2H), 4.28 (s, 2H), 7.02-7.06 (m, 4H), 7.18 (t, J = 7.5 Hz, 1H), 7,37-7.42 (m, 2H), 7.48 (d, J = 8.7 Hz, 2H).
Example 5(38):
N-(cyclohexylmethyl)-1-(4-phenoxybenzyl)piperidine-4-carboxamide hydrochloride
TLC:Rf 0.64(chloroform:methanol=10:1);
NMR (CD;0D): 6 0.86-0.97 (m, 2H), 1.15-1.28 (m, 4H), 1.46 (m, 1H), 1.60-1.78 (m, 4H), 1.89-2.05 (m, 4H), 2.52 (m, 1H), 3.00 (d, J] = 7.2 Hz, 2H), 3.00-3.07 (m, 2H), 3.51-3.56 (m, 2H), 4.29 (s, 2H), 7.01-7.06 (m, 4H), 7.18 (m, 1H), 7.37-7.42 (m, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 5(39):
N-butyl-N-(cyclohexylmethyl)-1-(4-phenoxybenzyl)piperidine-4-carboxamide hydrochloride TLC:Rf0.71(chloroform:methanol=10:1);
NMR (CD;OD): § 0.89-1.00 (m, SH), 1.18-1.71 (m, 13H), 1.92-2.00 (m, SH), 2.92-3.55 (m, 6H), 3.51-3.55 (m, 2H), 4.28 (s, 2H), 7.02-7.07 (m, 4H), 7.18 (t, J = 7.2 Hz, 1H), 7.37- 7.42 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H).
Example 5(40): 1-benzyl-4-{[ 1-(4-phenoxybenzyl)piperidin-4-yl]carbonyl} piperazine dihydrochloride
TLC:Rf 0.59(chloroform:methanol=10:1);
NMR (CD30D): § 1.90-2.10 (m, 4H), 3.00-3.60 (m, 12H), 4.30 (s, 2H), 4.39 (s, 2H), 4.63 (m, 1H), 7.02-7.06 (m, 4H), 7.18 (t, ] = 7.0 Hz, 1H), 7.37-7.42 (m, 2H), 7.48-7.58 (m, 7H).
Example 5(41): 1-(cyclohexylmethyl)-4-{[1-(4-phenoxybenzyl)piperidin-4-yl]carbonyl} piperazine dihydrochloride
TLC:Rf 0.62(chloroform:methanol=10:1);
NMR (CDs;OD): 6 1.02-1.43 (m, SH), 1.70-2.01 (m, 10H), 3.03(d, J = 6.6 Hz, 2H), 3.03- = 3.69 (m, 12H), 431 (s, 2H), 4.59 (m, 1H), 7.02-7.07 (m, 4H), 7.18 (t, J = 7.5 Hz, 1H), 7.37-7.42 (m, 2H), 7.50 (d, J = 8.7 Hz, 2H).
oO
Example 5(42):
N-butyl-1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperidine-4-carboxamide hydrochloride
TLC:Rf 0.26(chloroform:methanol=10:1);
NMR (CD;0D): § 0.92 (t, J = 7.2 Hz, 3H), 1.30-1.52 (m, 4H), 1.84-2.04 (m, 4H), 2.48 (m, 1H), 2.95 (s, 3H), 2.95-3.07 (m, 2H), 3.16 (t, J = 7.2 Hz, 2H), 3.51-3.56 (m, 2H), 4.28 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J =9.0 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H).
Example 5(43): N-(cyclohexylmethyl)-1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidine-4- carboxamide hydrochloride
TLC:Rf 0.28(chloroform:methanol=10:1);
NMR (CD;0D): § 0.85-1.00 (m, 2H), 1.15-1.46 (m, 5H), 1.65-2.13 (m, 8H), 2.49 (m, 1H), 2.95 (s, 3H), 3.00 (d, J = 7.0 Hz, 2H), 3.00-3.06 (m, 2H), 3.52-3.56 (m, 2H), 4.28 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H).
Example 5(44):
N-butyl-N-(cyclohexylmethyl)-1-(4-{4- [(methylsulfonyl)amino]phenoxy } benzyl)piperidine-4-carboxamide hydrochloride TLC:Rf 0.45(chloroform:methanol=10:1);
NMR (CD;0D): § 0.89-1.00 (m, SH), 1.21-2.00 (m, 18H), 2.95 (s, 3H), 3.00-3.36 (m, 6H), 3.51-3.54 (m, 2H), 4.27 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H).
Example 5(45):
N-{4-[4-({4-[(4-benzylpiperazin-1-yl)carbonyl]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride
TLC:Rf 0.28(chloroform:methanol=10:1);
NMR (CD;OD): § 1.90-2.10 (m, 4H), 2.95 (s, 3H), 3.05-3.56 (m, 12H), 4.30 (s, 2H), 4.39 (s, 2H), 4.63 (m, 1H), 7.02-7.08 (m, 4H), 7.29 (d, J = 9.0 Hz, 2H), 7.47-7.55 (m, 7H).
Example 5(46):
N-(4-{4-[(4-{[4-(cyclohexylmethyl)piperazin-1-yl]carbonyl}piperidin-1- yl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride TLC:Rf0.30(chloroform:methanol=10:1); B
NMR (CD;OD): § 1.05-1.43 (m, 5H), 1.70-2.01 (m, 10H), 2.95 (s, 3H), 3.03 (d, J = 6.9 Hz, 2H), 3.03-3.63 (m, 12H), 4.31 (s, 2H), 4.59 (m, 1H), 7.02-7.08 (m, 4H), 7.29 (d, J =9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
oo 0
Example 5(47): 1-(cyclohexylmethyl)-4-[ 1-(4-phenoxybenzyl)piperidin-4-yl]piperazine-2-carboxylic acid trihydrochloride TLC:Rf 0.07(chloroform:methanol:acetic acid=10:1:1),
NMR (CD;OD): § 1.01-1.11 (m, 2H), 1.19-1.41 (m, 4H), 1.66-2.02 (m, 8H), 2.19-2.31 (m, 2H), 2.97-3.37 (m, 8H), 3.45-3.64 (m, 3H), 3.80 (m, 1H), 4.29 (s, 2H), 4.35 (s, 1H), 7.01- 7.06 (m, 4H), 7.18 (t, J=8.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H).
Example 5(48): 1-benzyl-4-[ 1-(4-phenoxybenzyl)piperidin-4-yl]piperazine-2-carboxylic acid trihydrochloride
TLC:Rf 0.05(chloroform: methanol acetic acid=10:1:1);
NMR (CDsOD): § 1.86-2.03 (m, 2H), 2.15-2.27 (m, 2H), 2.86-3.62 (m, 11H), 4.13-4.35 (m, 4H), 4.57 (d, J=12.5 Hz, 1H), 7.01-7.06 (m, 4H), 7.18 (t, J=7.5 Hz, 1H), 7.39 (t, J=8.0 Hz, 2H), 7.45-7.56 (m, 7H).
Example 5(49): 1-(cyclohexylcarbonyl)-4-[1-(4-phenoxybenzyl)piperidin-4-yl]piperazine-2-carboxylic acid dihydrochloride
TLC:Rf 0.14(chloroform:methanol acetic acid=10:1:1),
NMR (CD;OD): § 1.22-1.57 (m, SH), 1.67-1.85 (m, SH), 2.06-2.78 (m, SH), 2.96-3 23 (m, 4H), 3.46-3.70 (m, SH), 4.08 (m, 1H), 4.31 (m, 1H), 4.33 (s, 2H), 5.53 (s, 1H), 7.02-7.07 (m, 4H), 7.18 (t, J=7.5 Hz, 1H), 7.36-7.42 (m, 2H), 7.54 (d, J=8.5 Hz, 2H).
Example 5(50): 1-benzoyl-4-[1-(4-phenoxybenzyl)piperidin-4-yl]piperazine-2-carboxylic acid dihydrochloride
TLC:Rf 0.09(chloroform:methanol:acetic acid=10:1:1);
NMR (CD;OD): 6 1.92-2.41 (m, 4H), 2.87-3.95 (m, 11H), 4.31 (s, 2H), 5.53 (s, 1H), 7.02- 7.07 (m, 4H), 7.18 (t, J=7.5 Hz, 1H), 7.36-7.42 (m, 2H), 7.45-7.54 (m, 7TH).
Example 5(51): 4-(cyclohexylmethyl)-2-methyl-1-[1-(4-phenoxybenzyl)piperidin-4-yl]piperazine - 35 trihydrochloride
TLC:Rf 0.18(chloroform:methanol=10:1);
oO
NMR (CD3OD): § 0.97-1.13 (m, 2H), 1.20-1.44 (m, 3H), 1.55 (d, J=6.5 Hz, 3H), 1.65-1.95 (m, 6H), 2.08-2.47 (m, 4H), 3.10-3.28 (m, 4H), 3.40-4.21 (m, 10H), 4.33 (s, 2H), 7.02-7.07 (m, 4H), 7.18 (t, J=7.5 Hz, 1H), 7.37-7.42 (m, 2H), 7.53 (d, J=8.5 Hz, 2H).
Example 5(52): 4-benzyl-2-methyl-1-[ 1-(4-phenoxybenzyl)piperidin-4-yl]piperazine trihydrochloride
TLC:Rf 0.20(chloroform:methanol=10:1);
NMR (CD3;0D): § 1.48 (d, J=6.5 Hz, 3H), 2.01-2.38 (m, 4H), 3.12-3.25 (m, 2H), 3.38-3.72 (m, 8H), 3.92 (br s, 2H), 4.31 (s, 2H), 4.41 (d, J=13.0 Hz, 1H), 4.47 (d, J=13.0 Hz, 1H), 7.01-7.06 (m, 4H), 7.18 (t, J=7.5 Hz, 1H), 7.36-7.42 (m, 2H), 7.49-7.53 (m, 5H), 7.58-7.62 (m, 2H).
Example 5(53): 4-(cyclohexylcarbonyl)-2-methyl-1-[1-(4-phenoxybenzyl)piperidin-4-yl]piperazine dihydrochloride
TLC:Rf 0.38(chloroform:methanol=10:1);
NMR (CD;0D): 8 1.16-1.57 (m, 8H), 1.66-1.84 (m, SH), 2.05-2.75 (m, 5H), 3.00-4.73 (m, 12H), 4.33 (s, 2H), 7.01-7.07 (m, 4H), 7.18 (t, J=7.5 Hz, 1H), 7.36-7.42 (m, 2H), 7.53 (d,
J=8.5 Hz, 2H).
Example 5(54): 4-benzoyl-2-methyl-1-[1-(4-phenoxybenzyl)piperidin-4-yl]piperazine dihydrochloride
TLC:Rf 0.40(chloroform:methanol=10:1);
NMR (CDs0D): § 1.29-1.55 (br, 3 H, -Me), 2.07-2.54 (m, 4H), 3.09-4.17 (m, 12H), 4.33 (s, 2H), 7.01-7.07 (m, 4H), 7.18 (t, J=7.5 Hz, 1H), 7.36-7.42 (m, 2H), 7.46-7.55 (m, 7H).
Reference Example 4:
N-(4-(4-bis(2-chloroethyl)aminomethylphenoxy)phenyl)methanesulfonamide
To a solution of 4-(4-methylsulfonylaminophenoxy)benzaldehyde (1.27 g) in dimethylformamide (5 mL)/acetic acid (0.5 mL) was added N,N-bis(2-chloroethyl)amine (856 mg) and the solution was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (31.39 g) was added to the solution, which was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate three times. The extract was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The obtained residue purified by column - chromatography on silica gel (hexane : ethyl acetate=5:1) to give the title compound (790 mg) having the following physical data.
TLC:Rf 0.60(chloroform:methanol=9:1),
0
NMR (CDCl3): § 7.32 (brd, J = 8.4 Hz, 2H), 7.22 (brd, J = 8.7 Hz, 2H), 7.01 (brd, J = 8.7
Hz, 2H), 6.96 (brd, J = 8.4 Hz, 2H), 3.72 (s, 2H), 3.51 (t, J = 7.2 Hz, 4H), 3.00 (s, 3H), 2.93 (t,J=7.2 Hz, 4H).
Example 6: 1-(4-(4-methylsulfonylaminophenoxy)benzyl)-4-(1-methoxycarbonylpentyl)piperazine
To a solution of the compound prepared in Reference Example 2 (266 mg) in dimethylformamide (3 mL) was added DL-norleucine methyl ester hydrochloride (117 mg).
To the obtained solution was triethylamine (0.267 mL) and catalytic amount of sodium iodide and the solution was stirred at 60°C overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate three times. The extract was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give the compound of the present invention (210 mg) having the following physical data.
TLC:Rf 0.67(chloroform: methanol=9:1);
NMR (CDCl): 8 7.32-7.24 (m, 2H), 7.20 (brd, J = 9.0 Hz, 2H), 6.98 (brd, J = 9.0 Hz, 2H), 6.94 (brd, J = 9.0 Hz, 2H), 3.72 (s, 2H), 3.69 (s, 3H), 3.15 (dd, J = 4.8, 3.6 Hz, 1H), 3.00 (s, 3H), 2.70-2.36 (m, 8H), 1.80-1.18 (m, 6H), 0.89 (t, J = 5.4 Hz, 3H).
Example 7: 2-[4-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperazin-1-yl]hexanoic acid dihydrochloride
CH3
SOROS
HaC S\N N 0)
H -2HCI
To a solution of the compound obtained in Example 6 (210 mg) in ethanol (5 mL) was added 2N aqueous solution of sodium hydroxide (0.215 mL) and the solution was stirred at 40°C overnight. The reaction mixture was concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=8:1) and converted to hydrochloride salt by a conventional method to give the compound of the B present invention (141.6 mg) having the following physical data.
TLC:Rf 0.55(chloroform:methanol=5:1);
® Oo
NMR (CD;OD): § 7.53 (brd, J = 8.7 Hz, 2H), 7.29 (brd, J = 9.0 Hz, 2H), 7.06 (brd, ] = 8.7
Hz, 2H), 7.03 (brd, J = 9.0 Hz, 2H), 4.37 (s, 2H), 3.75 (brt, J = 6.3 Hz, 1H), 3.56-3.34 (m, 8H), 2.95 (s, 3H), 1.92-1.80 (m, 2H), 1.48-1.32 (m, 4H), 1.00-0.86 (m, 3H).
Example 8:
N-cyclohexyl-2-[4-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)piperazin-1- ylJhexanamide dihydrochloride
To a solution of the compound prepared in Example 7 (46.7 mg) in dimethylformamide (2 mL) were added cyclohexylamine (16.8 nL), 1-ethyl-3-[3- (dimethylamino)propyl]carbodiimide hydrochloride (28.2 mg) and 1-hydroxybenztriazol (19.87 mg) and the solution was stirred at room temperature overnight. The reaction mixture was concentrated. The obtained residue was purified by column chromatography on silica gel (chloroform : methanol=9:1) and converted to hydrochloride salt by a conventional method to give the compound of the present invention (22.7 mg) having the following physical data.
TLC:Rf 0.75(chloroform:methanol=5:1);
NMR (CD;0D): 6 7.49 (brd, J = 8.7 Hz, 2H), 7.29 (brd, J = 9.0 Hz, 2H), 7.05 (brd, J= 9.0
Hz, 2H), 7.02 (brd, J = 8.7 Hz, 2H), 4.30 (s, 2H), 3.68 (m, 1H), 3.50-3.00 (m, 8H), 2.95 (s, 3H), 1.90-1.58 (m, 8H), 1.44 -1.12 (m, SH), 0.92 (brt, J = 7.5 Hz, 3H).
Example 9(1)-Example 9(3)
By the same procedure as described in Reference Example 4—Example 6—>Example 7—>Example 8, using 4-(4-methylsulfonylaminophenoxy)benzamide, DL- norleucine methyl ester and cyclohexylamine, or using a corresponding aldehyde derivative, amino acid derivative and amine derivative instead of them respectively, the following compounds of the present invention were obtained.
Example 9(1):
N-(cyclohexylmethyl)-2-[4-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperazin-1- yl]hexanamide dihydrochloride
TLC:Rf 0.82(chloroform:methanol=5:1);
NMR (CD;OD): § 7.53 (brd, J = 8.7 Hz, 2H), 7.29 (brd, J = 9.0 Hz, 2H), 7.06 (brd, J=9.0
Hz, 2H), 7.03 (brd, J = 8.7 Hz, 2H), 4.37 (s, 2H), 3.61 (m, 1H), 3.60-3.28 (m, 8H), 3.15 (dd,
J=175,15.0 Hz, 1H), 2.99 (dd, J = 7.5, 15.0 Hz, 1H), 2.95 (s, 3H), 1.90-1.62 (m, 6H), 1.5 8-1.16 (m, 9H), 1.04-0.88 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).
oO
Example 9(2):
N-cyclohexyl-2-[4-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)piperazin-1- yl]pentanamide dihydrochloride
TLC:Rf 0.78(chloroform:methanol=5:1);
NMR (CD;OD): § 7.52 (brd, J = 6.6 Hz, 2H), 7.29 (brd, J = 8.4 Hz, 2H), 7.10-7.01 (m, 4H), 4.36 (brs, J = 2H), 3.69 (m, 1H), 3.60-3.20 (m, 9H), 2.95 (s, 3H), 1.92-1.70 (m, 6H), 1.65 (m, 1H), 1.46-1.14 (m, 7H), 0.97 (t, J = 7.5 Hz, 3H).
Example 9(3): 2-(4-{4-[4-(aminosulfonyl)phenoxy]benzyl} piperazin-1-yl)-N-cyclohexylhexanamide dihydrochloride
TLC:Rf 0.84(chloroform:methanol=5:1),
NMR (CD;0D): 8 7.90 (brd, J = 9.3 Hz, 2H), 7.63 (brd, J = 11.4 Hz, 2H), 7.18 (brd, J = 11.4 Hz, 2H), 7.13 (brd, J = 9.3 Hz, 2H), 4.45 (s, 2H), 3.80-3.42 (m, 9H), 1.96-1.56 (m, 7H), 1.46-1.18 (m, 10H), 0.93 (t, J = 7.2 Hz, 3H).
Reference Example 5: t-butyl 1-benzyloxycarbonyl-4-cyclohexylmethylaminocarbonylpiperidin-4-ylcarbamate
To a solution of 1-benzyloxycarbonyl-4-(t-butoxycarbonylamino)piperidin-4- carboxylic acid (297 mg) in dimethylformamide (2.5 mL) were added 1-ethyl-3-[3- (dimethylamino)propyl]carbodiimide hydrochloride (226 mg), 4-N,N- dimethylaminopiperidine (144 mg) and cyclohexylmethylamine (0.15 mL) and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=40:1-10:1) to give the title compound having the following physical data.
TLC:Rf 0.18(dichloromethane:methanol=5:1).
Reference Example 6: t-butyl 4-cyclohexylmethylaminocarbonylpiperidin-4-ylcarbamate
To a solution of the compound prepared in Reference Example S in methanol (3 mL) was added 5% palladium-carbon (15 mg). The reaction mixture was stirred at room temperature for 2 hours under an atmosphere of hydrogen. Under an atmosphere of argon, the reaction mixture was filtrated through CELITE (brand name). The filtrate was : concentrated and the obtained residue was used in the next reaction without purification.
0
Example 10: 1 -(4-(4-methylsulfonylaminophenoxy)benzyl)-4-cyclohexylmethylaminocarbonyl-4-(t- butoxycarbonylamino)piperidine dihydrochloride
To a solution of the compound prepared in Reference Example 6 in dimethylformamide (5 mL) and acetic acid (0.2 mL) were added 4-(4- methylsulfonylaminophenoxy)benzaldehyde (274 mg) and sodium triacetoxyborohydride (249 mg), and the solution was stirred at room temperature overnight. The reaction mixture was concentrated, purified by column chromatography on silica gel (ethyl acetate : methanol=50:1-40:1) and converted to hydrochloride salt by a conventional method to give the title compound (190 mg) having the following physical data.
TLC:Rf 0.49(dichloromethane:methanol=10:1);
NMR (CDsOD): § 7.35 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 6.98 (d, J] = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.69 (s, 2H), 3.01-2.99 (m, 2H), 2.93 (s, 3H), 2.88-2.85 (m, 2H), 2.53-2.44 (m, 2H), 2.16-2.02 (m, 4H), 1.75-1.64 (m, 6H), 1.43 (s, 9H), 1.28-1.18 (m, 3H), 0.96-0.89 (m, 2H).
Example 11: 1 -(4-(4-methylsulfonylaminophenoxy)benzyl)-4-cyclohexylmethylaminocarbonyl-4- aminopiperidine dihydrochloride
To a solution of the compound prepared in Example 10 (190 mg) in tetrahydrofuran (3 mL) and dioxane (3 mL) was added 4N hydrogen chloride/ethyl acetate solution (9 mL) and the solution was stirred at room temperature overnight. The reaction mixture was concentrated to give the compound of the present invention having the following physical data. The compound was used in the next reaction without purification.
TLC:Rf 0.35(methylene chloride: methanol=10:1).
Example 12(1) and Example 12(2)
To a solution of the compound prepared in Example 11 in dimethylformamide (3 mL) and acetic acid (0.1 mL) were added butanal (0.03 mL) and sodium triacetoxyborohydride (103 mg), and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=50:1) and high performance thin layer chromatography -- (dichloromethane : methanol=10:1), and converted to hydrochloride salt by a conventional method to give the compound of the present invention having the following physical data.
oO Luub/07383
Example 12(1): 4-(butylamino)-N-(cyclohexylmethyl)-1-(4-{4- [(methylsulfonyl)amino]phenoxy }benzyl)piperidine-4-carboxamide dihydrochloride
CH,
J oO H \Y4
HC” ON N 0)
H
-2HCI TLC:Rf 0.48(methylene chloride:methanol=10:1);
NMR (CD;OD): & 7.52 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 4.34 (s, 2H), 3.70-3.56 (m, 3H), 3.20-2.79 (m, 7H), 2.95 (s, 3H), 2.46-2.30 (m, 2H), 1.73-1.58 (m, 8H), 1.46-1.38 (m, 2H), 1.28-1.15 (m, 3H), 1.05- 0.95 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).
Example 12(2):
N-(cyclohexylmethyl)-4-(dibutylamino)-1-(4-{4- [(methylsulfonyl)amino]phenoxy } benzyl)piperidine-4-carboxamide dihydrochloride
TLC:Rf 0.46(methylene chloride: methanol=10:1);
NMR (CD;OD): & 7.54 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 4.33 (s, 2H), 3.67-3.63 (m, 2H), 3.37-3.00 (m, 8H), 2.95 (s, 3H), 2.84-2.80 (m, 2H), 2.64-2.51 (m, 2H), 1.84-1.57 (m, 10H), 1.46-1.17 (m, 7H), 1.05- 0.92 (m, 2H), 0.98 (t, J = 7.2 Hz, 6H).
Example 13: methyl (25)-2-{[4-[(butylamino)carbonyl]-1-(4-{4- [(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4-yl]Jamino}-3-cyclohexylpropanoate hydrochloride oO
GH
TO
HN” 0) H
QAP ry Tl (he
SJ N
HC N oO
H -2HCI
To a solution of the compound prepared in Example 2 (200 mg) in methanol (5.3 mL) were added L-cyclohexylalanin (91.4 mg), n-butylisocyanide (50.8 pL) and triethylamine (74.5 pL), and the solution was stirred at 65°C for 12 hours. After cooling at 0°C, 4N hydrogen chloride/ethyl acetate solution (0.3 mL) was added thereto. The solution was stirred and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=8:1) and converted to hydrochloride salt by a conventional method to give the compound of the present invention (102.2 mg) having the following physical data. TLC:Rf 0.55(chloroform:methanol=9:1);
NMR (CD;OD): § 7.60-7.44 (m, 2H), 7.29 (brd, J = 9.0 Hz, 2H), 7.09-6.96 (m, 4H), 4.31 (brs, 2H), 3.80-3.62 (m, 5H), 3.52-3.02 (m, SH), 2.95 (s, 3H), 2.30-1.82 (m, 2H), 1.80-1.40 (m, 11H), 1.40-1.10 (m, 6H), 1.04 -0.80 (m, SH).
Example 14: 1-(4-(4-methylsulfonylaminophenoxy)benzyl)piperidin-4-ylmethanol
To a solution of 4-piperidylmethanol (1.0 g) and 4-(4- methylsulfonylaminophenoxy)benzaldehyde (2.53 g) in dimethylformamide (10 mL) was added acetic acid (1.0 mL) and the solution was stirred at room temperature for 5 min.
Sodium triacetoxyborohydride (2.75 g) was added to the reaction solution, which was stirred for 12 hours. Water (20 mL) and ethyl acetate (30 mL) were added to the reaction mixture, which was stirred and extracted with ethyl acetate three times. The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and concentrated.
The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=1:1) to give the compound of the present invention (2.40 g) having the following physical data.
TLC:Rf 0.16(chloroform:methanol=5:1); BN
NMR (CDCl): 6 7.31-7.26 (m, 2H), 7.23-7.00 (m, 2H), 7.02-6.92 (m, 4H), 3.50 (d, J = 6.3
Hz, 2H), 3.47 (s, 2H), 3.00 (s, 3H), 2.98-2.86 (m, 2H), 1.97 (td, J = 11.7, 2.7 Hz, 2H), 1.79- 1.64 (m, 2H), 1.50 (m, 1H), 1.36-1.20 (m, 2H).
oOo
Example 15: 1-(4-(4-methylsulfonylaminophenoxy)benzy!)-4-piperidinylcarboxaldehyde
To a solution of the compound prepared in Example 14 (2.40 g) in methylene chloride (20 mL) were added triethylamine (3.43 mL) and dimethylsulfoxide (1.99 mL).
Sulfur trioxide pyridine complex (1.96 g) was added to the reaction mixture, which was stirred at room temperature for 5 hours. Water was added to the reaction mixture, which was extracted with methylene chloride three times. The organic layer was wash with brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=1:1) to give the compound of the present invention (3.04 g) having the following physical data.
TLC:Rf 0.32(chloroform:methanol=5:1);
NMR (CDCl): 8 9.65 (d, J = 1.2 Hz, 1H), 7.32-7.24 (m, 2H), 7.24-7.18 (m, 2H), 7.02-6.90 (m, 4H), 3.47 (s, 2H), 3.00 (s, 3H), 2.82 (m, 2H), 2.26 (m, 2H), 2.11 (m, 2H), 1.90 (m, 2H), 1.71 (m, 2H).
Example 16:
N-{4-[4-({4-[(55)-1-butyl-5-(cyclohexylmethyl)-3,6-dioxopiperazin-2-yl]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride 0) a 0 NH
Ww TTL
HC” oN N ©
H
HCI
A solution of the compound prepared in Example 15 (500 mg), N-(t- butoxycarbonyl)-L-cyclohexylalanin (396 mg), n-butylamine (0.140 mL) and 2- morpholinoethylisocyanide (0.179 mL) in methanol (13 mL) was stirred at 65°C for 12 hours. Concentrated hydrochloric acid (0.5 mL) was added to the reaction solution, which was stirred for 2 hours and concentrated. Methylene chloride (15 mL) and sodium hydrogen carbonate solution (15 mL) were thereto. The solution was stirred and extracted with methylene chloride twice. The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and concentrated. To the obtained residue was added 1.25M acetic acid/ethyl acetate solution (20 mL) and the solution was stirred at N 70°C for 12 hours. Ethyl acetate was added to the reaction solution, which was washed with water. Sodium hydrogen carbonate (15 mL) was added thereto, and the solution was stirred and extracted with ethyl acetate twice. The organic layer was washed with brine oO (15 mL), dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=8:1) and converted to hydrochloride salt by a conventional method to give the compound of the present invention (470.4 mg) having the following physical data. TLC:Rf0.58(chloroform:methanol=5:1);
NMR (CD;OD): 6 7.48 (brd, J = 8.7 Hz, 2H), 7.29 (brd, J = 8.7 Hz, 2H), 7.08-7.00 (m, 4H), 4.26 (s, 2H), 4.12 (m, 1:2H), 4.04-3.92 (m, 1H), 3.88 (d, J = 5.2 Hz, 1:2H), 3.82 (d, J = 6.0
Hz, 1:2Hz), 3.80 (m, 1:2H ), 3.60-3.48 (m, 2H), 3.08-2.78 (m, 3H), 2.95 (s, 3H), 2.34-2.10 (m, 1H), 2.10-1.44 (m, 13H), 1.40-1.12 (m, 6H), 1.10-0.84 (m, 2H), 0.94 (t, J = 7.2 Hz, 3:2H), 0.93 (1, ] = 7.2 Hz, 3:2H).
Example 16(1)-(3)
By the same procedure as described in Example 14—Example 15—Example 16 using a corresponding carboxylic acid and aldehyde instead of N-(t-butoxycarbonyl)-L- cyclohexylalanine and 4-(4-methylsulfonylaminophenoxy)benzaldehyde respectively, the compounds of the present invention having the following physical data were obtained.
Example 16(1):
N-(4-{4-[(4-{(5R)-1-butyl-5-[(R)-cyclohexyl(hydroxy)methyl]-3,6-dioxopiperazin-2- yl}piperidin-1-yl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.51(chloroform:methanol=5:1);
NMR (CD30D): 6 7.47 (brd, J = 9.0 Hz, 2H), 7.29 (brd, J = 9.0 Hz, 2H), 7.07-7.00 (m, 4H), 4.25 (s, 2H), 4.18(m, 1H), 3.98-3.72 (m, 2H), 3.57-3.45 (m, 2H), 3.26 (m, 1H), 3.06-2.78 (m, 3H), 2.95 (5, 3H), 2.46-2.18 (m, 1H), 2.14-1.86 (m, 4H), 1.86-1.48 (m, 7H), 1.44-0.82 (m, 8H), 0.94 (t, J =7.2 Hz, 3H).
Example 16(2): 4-[4-({4-[(5S)-1-butyl-5-(cyclohexylmethyl)-3,6-dioxopiperazin-2-yl]piperidin-1- yl} methyl)phenoxy]benzoic acid hydrochloride
TLC:Rf0.53(chloroform:methanol=5:1);
NMR (CD;0D): 8.04 (brd, J = 8.7 Hz, 2H), 7.54 (brd, J = 8.7 Hz, 2H), 7.16 (brd, J = 8.7
Hz, 2H), 7.06 (brd, J = 8.7 Hz, 2H), 4.30 (s, 2H), 4.12 (m, 1/2H), 4.05-3.92 (m, 1H), 3.92- 3.76 (m, 3/2H), 3.61-3.46 (m, 2H), 3.10-2.78 (m, 3H), 2.36-1.92 (m, 5H), 1.90-1.44 (m, 10H), 1.40-1.14 (m, 5H), 1.04-0.82 (m, SH). _
Example 16(3): 4-{4-[(4-{(5R)-1-butyl-5-[(R)-cyclohexyl(hydroxy)methyl]-3,6-dioxopiperazin-2- yl} piperidin-1-yl)methyl]phenoxy } benzoic acid hydrochloride oO
TLC:Rf 0.39(chloroform:methanol=5:1);
NMR (CD3OD): & 8.07-8.00 (m, 2H), 7.60-7.46 (m, 2H), 7.17 (brd, J = 8.7 Hz, 2H), 7.10- 7.00 (m, 2H), 4.30 (s, 2H), 4.21-4.14 (m, 1H), 4.00-3.74 (m, 2H), 3.72-3.46 (m, 2H), 3.26 (m, 1H), 3.09-2.84 (m, 3H), 2.50-2.20 (m, 2H), 2.16-1.88 (m, SH), 1.88-1.48 (m, 6H), 1.44-0.84 (m, 10H).
Reference Example 7 1-benzyl-4-[N-(2-dimethoxyethyl)amino]piperidine
To a solution of 4-amino-1-benzylpiperidine (5 g) in dimethylformamide (100 mL) were added to dimethoxyacetoaldehyde (5.5 mL), sodium triacetoxyborohydride (8.36 g) and acetic acid (1.5 mL), and the solution was stirred overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=40:1-1:1) to give the title compound (2.74 g) having the following physical data.
TLC:Rf 0.27 (dichloromethane: methanol=5:1)
NMR (CDCl): & 7.31-7.20 (m, 5H), 4.46 (t, ] = 5.5 Hz, 1H), 3.50 (s, 2H), 3.38 (s, 6H), 2.87-2.83 (m, 2H), 2.74 (d, J = 5.5 Hz, 2H), 2.45 (m, 1H), 2.07-1.98 (m, 2H), 1.86-1.82 (m, 2H), 1.46-1.34 (m, 2H).
Reference Example 8 1-benzyl-4-(N-(2-dimethoxyethyl)-N-(2-cyclohexylcarbonylaminoacetyl)amino)piperidine
To a solution of the compound prepared in Reference Example 7 (2.74 g) in dimethylformamide (30 mL) were added 1-ethyl-3-[3- (dimethylamino)propyl]carbodiimide hydrochloride (2.82 g), 4-N,N-dimetylaminopyridine (2.4 g) and N-cyclohexylcarbonylglycin (2.0 g), and the solution was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=10:1) to give the title compound (1.45 g) having the following physical data.
TLC:Rf 0.36(ethyl acetate:methanol=10:1).
Reference Example 9: 4-(N-(2-dimethoxyethyl)-N-(2-cyclohexylcarbonylaminoacetyl)amino)piperidine --
To a solution of the compound prepared in Reference Example 7 (900 mg) in methanol (8 mL) was added palladium hydroxide on carbon (200 mg) and the solution was stirred at 50°C for 3 hours under an atmosphere of hydrogen. After cooling, the reaction
0 mixture was filtrated through CELITE (brand name) and the filtrate was concentrated to give the title compound. The compound was used in the next reaction without purification.
Example 17: 1-(4-(4-methylsulfonylaminophenoxy)benzyl)-4-(N-(2-dimethoxyethyl)-N-(2- cyclohexylcarbonylaminoacetyl)amino)piperidine
To a solution of the compound prepared in Reference Example 9 (300 mL) in dimethylformamide (5 mL)/acetic acid (02 mL) were added 4-(4- methylsulfonylaminophenoxy)benzaldehyde (270 mg) and sodium triacetoxyborohydride (268 mg) and the solution was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate : methanol=30:1-10:1) to give the title compound (223 mg) having the following physical data. TLC:Rf 0.41(ethyl acetate: methanol=10:1);
NMR (CDCl): 6 7.29-7.21 (m, 4H), 6.99 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 4.60 (t, J = 5.5 Hz, 1H), 4.20 (m, 1H), 4.13 (dd, J = 16.5, 4.0 Hz, 2H), 3.56-3.33 (m, 6H), 3.40 (s, 6H), 3.05-2.96 (m, 2H), 2.19-1.22 (m, 15H).
Example 18:
N-{4-[4-({4-[4-(cyclohexylcarbonyl)-2-0x0-3,4-dihydropyrazin-1(2H)-yl]piperidin-1- yl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
Oo oO
Ty : SAS
WT
J
HCO N N
H -HCI
To a suspension of the compound prepared in Example 17 in toluene (9 mL) was added p-toluenesulfonic acid (20 mg) and the suspension was stirred and heated at 100°C for 3 hours. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and - concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=30:1) and high performance thin layer chromatography (dichloromethane : methanol=15:1), and converted to hydrochloride salt by a conventional oO method to give the compound of the present invention (20 mg) having the following physical data.
TLC:Rf 0.78(methylene chloride: methanol=10:1);
NMR (CD;0D): 4 7.50 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.60 (d, J = 6.0 Hz, 1H), 5.86 (d, J] = 6.0 Hz, 1H), 4.58 (m, 1H), 4.30 (s, 2H), 4.27 (s, 2H), 3.61-3.57 (m, 2H), 3.20-3.12 (m, 2H), 2.95 (s, 3H), 2.26- 1.21 (m, 15H).
Example 18(1): 1-(1-benzylpiperidin-4-yl)-4-(cyclohexylcarbonyl)-3,4-dihydropyrazin-2(1H)-one hydrochloride
By the same procedure as described in Example 18 using the compound prepared in Reference Example 8 instead of the compound prepared in Reference Example 17, the compound of the present invention having the following physical data was obtained.
TLC:Rf 0.53(methylene chloride:methanol=10:1);
NMR (CDsOD): & 7.52 (s, 5H), 6.60 (d, J] = 6.0 Hz, 1H), 5.84 (d, J = 6.0 Hz, 1H), 4.58 (m, 1H), 4.33 (s, 2H), 4.27 (s, 2H), 3.6-3.56 (m, 2H), 3.22-3.14 (m, 2H), 2.69 (m, 1H), 2.19- 1.29 (m, 14H).
Example 19:
E-form: 4-[4-({4-[(E)-(4-bromophenyl)(ethoxyimino)methyl]piperidin-1- yl} methyl)phenoxy]benzoic acid hydrochloride
Z-form: 4-[4-({4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]piperidin-1- yl} methyl)phenoxy]benzoic acid hydrochloride
To a solution of the compound prepared in Example 5(15) (912 mg) in ethanol (10 mL) were added pyridine (5 mL) and O-ethylhydroxyamine hydrochloride (340 mg) and the solution was refluxed for 3 hours. After finishing the reaction, the reaction solution was concentrated. Water and 2N hydrochloric acid were added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=25:1) and 4N hydrogen chloride/ethy! acetate solution was added to the obtained residue, which was concentrated to give the compound of the present invention (E-form: 409 mg, Z-form: 500 mg) having the following physical data.
E-form:
TLC:Rf0.37(chloroform:methanol=10:1); _
NMR (CDsOD): 8 1.29 (t, J=7.0 Hz, 3H), 1.90-2.00 (m, 2H), 2.14-2.28 (m, 2H), 2.86-2.96 (m, 2H), 3.38-3.48 (m, 3H), 4.16 (s, 2H), 4.18 (q, J=7.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H),
oO 7.11 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 7.50 (d, J=9.0 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 8.00 (d, J=9.0 Hz, 2H).
Z-form:
TLC Rf 0.35(chloroform:methanol=10:1); : > NMR (CD;OD): 5 1.16 (t, J=7.0 Hz, 3H), 1.76-1.91 (m, 2H), 2.03-2.14 (m, 2H), 2.89 (m, 1H), 3.02-3.11 (m, 2H), 3.50-3.58 (m, 2H), 4.03 (q, J=7.0 Hz, 2H), 4.31 (s, 2H), 7.06 (d,
J=9.0 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H), 7.55 (d, J=9.0 Hz, 2H), 7.57 (d, J=9.0 Hz, 2H), 8.03 (d, J=9.0 Hz, 2H).
Example 20(1)-Example 20(79)
By the same procedure as described in Example 1 and the conversion to hydrochloride salt by a conventional method, using a corresponding amine derivative instead of 4-hydroxypiperidine, and using 4-(4- methylsulfonylaminophenoxy)benzaldehyde or a corresponding aldehyde derivative instead of it, the following compounds of the present invention were obtained.
Example 20(1):
N-benzyl-1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4-piperidinecarboxamide hydrochloride
H
CL N Ny Ars
CL Oyo
Ny J eX 0 0 - HCI
TLC:Rf 0.67(methylene chloride:methanol=5:1);
NMR (CD;0D): 4 1.92-2.03 (m, 4H), 2.51 (m, 1H), 2.82-2.92 (m, 2H), 2.95 (s, 3H), 3.40- 3.44 (m, 2H), 4.15 (s, 2H), 4.35 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.23-7.33 (m, 7H), 7.45 (d, J = 8.7 Hz, 2H).
Example 20(2): 4-[4-({4-[(cyclohexylacetyl)amino]-1-piperidinyl} methyl)phenoxy]benzoic acid hydrochloride
TLC:Rf 0.37(methylene chloride: methanol=5:1);
NMR (CD;0D): 6 0.94-1.00 (m, 2H), 1.14-1.30 (m, 4H), 1.60-1.80 (m, 6H), 1.99-2.17 (m, 5H), 3.08-3.16 (m, 2H), 3.52-3.56 (m, 2H), 3.92 (m, 1H), 4.31 (s, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.7 Hz, 2H).
® O
Example 20(3): 4-[4-({4-[(benzylamino)carbonyl]-1-piperidinyl} methyl)phenoxy]benzoic acid hydrochloride TLC:Rf 0.26(methylene chloride: methanol=5:1);
NMR (CD;0D): § 1.90-2.08 (m, 4H), 2.56 (m, 1H), 2.99-3.07 (m, 2H), 3.48-3.53 (m, 2H), 4.28 (s, 2H), 4.36 (s, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.16 (d, ] = 8.4 Hz, 2H), 7.21-7.34 (m,
SH), 7.54 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H).
Example 20(4): 4-[4-({4-[(butylamino)carbonyl]-1-piperidinyl } methyl)phenoxy]benzoic acid hydrochloride
TLC:Rf 0.20(methylene chloride: methanol=5:1);
NMR (CD;0D): 4 0.93 (t, J = 7.2 Hz, 3H), 1.28-1.53 (m, 4H), 1.95-2.00 (m, 4H), 2.51 (m, 1H), 3.06-3.20 (m, 4H), 3.51-3.53 (m, 2H), 4.32 (s, 2H), 7.07 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.55 (d, J] = 8.5 Hz, 2H), 8.04 (d, J = 9.0 Hz, 2H).
Example 20(5): 4-{4-[(4-{[(cyclohexylmethyl)amino]carbonyl}-1-piperidinyl)methyl]phenoxy } benzoic acid hydrochloride
TLC:Rf 0.21(methylene chloride: methanol=5:1);
NMR (CDsOD): & 0.87 (m, 2H), 1.19 -1.31 (m, 3H), 1.46 (m, 1H), 1.64-1.73 (m, SH), 1.90-2.06 (m, 4H), 2.52 (m, 1H), 3.00-3.09 (m, 4H), 3.53-3.58 (m, 2H), 4.33 (5, 2H), 7.07 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 9.0 Hz, 2H).
Example 20(6):
N-(cyclohexylmethyl)-4-hydroxy-1-(4- {4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinecarboxamide hydrochloride
TLC:Rf0.36(chloroform:methanol=5:1);
NMR (CDsOD): 6 0.82-1.02 (m, 2H), 1.12-1.36 (m, 4H), 1.49 (m, 1H), 1.60-1.88 (m, 6H), 2.31 (m, 2H), 2.95 (s, 3H), 3.04 (brt, J = 6.6 Hz, 2H), 3.22-3.45 (m, 4H), 4.32 (s, 2H), 6.98-7.01 (m, 4H), 7.29 (brd, J = 9.0 Hz, 2H), 7.50 (brd, J = 9.0 Hz, 2H), 8.09 (m, 1H).
Example 20(7): -
N-(cyclohexylmethyl)-4-methoxy-1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinecarboxamide hydrochloride
TLC:Rf 0.50(chloroform:methanol=5:1);
(I
NMR (CD;OD): § 0.80-1.04 (m, 2H), 1.18-1.40 (m, 4H), 1.50 (m, 1H), 1.60-1.90 (m, 6H), 2.30 (m, 2H), 2.91 (s, 3H), 3.04 (m, 2H), 3.20-3.52 (m, 7H), 4.33 (s, 2H), 7.02-7.18 (m, 4H), 7.45 (brt, J=9.0 Hz, 2H), 7.53 (brt, J = 8.7 Hz, 2H), 8.08 (m, 1H).
Example 20(8):
N-[4-(4-{[4-(cyclohexylcarbonyl)-1- piperazinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.89(chloroform:methanol=5:1);
NMR (CD3;0D): 6 1.18-1.56 (m, SH), 1.64-1.85 (m, 5H), 2.65 (m, 1H), 2.95 (m, 3H), 2.90- 3.20 (m, 3H), 3.32-3.58 (m, 3H), 4.28 (m, 1H), 4.35 (s, 2H), 4.67 (m, 1H), 7.00-7.12 (m, 4H), 7.29 (brd, J =9.0 Hz, 2H), 7.5 2 (brd, J = 8.7 Hz 2H).
Example 20(9):
N-[4-(4-{[4-(cyclohexylacetyl)-1- piperazinyl]methyl }phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.85(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.90-1.06 (m, 2H), 1.08-1.40 (m, 3H), 1.60-1.80 (m, 6H), 2.31 (brd, J = 6.0 Hz, 2H), 2.95 (s, 3H), 2.86-3.18 (m, 3H), 3.36-3.60 (m, 3H), 4.21 (m, 1H), 4.35 (s, 2H), 4.69 (m, 1H), 7.00-7.12 (m, 4H), 7.29 (brd, J = 9.0 Hz, 2H), 7.51 (brd, J = 8.7 Hz, 2H).
Example 20(10):
N-(cyclohexylmethyl)-4-methyl-1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinecarboxamide hydrochloride
TLC:Rf 0.67(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.80-1.00 (m, 2H), 1.12-1.32 (m, 4H), 1.49 (m, 1H), 1.62-1.80 (m, 6H), 2.22-2.34 (m, 2H), 2.95 (s, 6H), 2.96-3.08 (m, 2H), 3.24-3.38 (m, 4H), 4.22 (s, 2H), 6.98- 7.10 (m, 4H), 7.29 (brd, J = 9.3 Hz, 2H), 7.46 (brd, J] = 8.7 Hz, 2H), 7.81 (m, 1H).
Example 20(11): 4-butoxy-N-(cyclohexylmethyl)-1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4- piperidinecarboxamide hydrochloride
TLC:Rf 0.87(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.95 (t, J = 7.2 Hz, 3H), 0.82-1.04 (m, 2H), 1.10-1.58 (m, 7H), 1.58- 1.78 (m, 6H), 2.06-2.24 (m, 4H), 2.95 (s, 3H), 3.05 (t, J = 3.0 Hz, 2H), 3.08-3.44 (m, 6H), 4.32 (s, 2H), 7.00-7.12 (m, 4H), 7.29 (brd, J = 8.7 Hz, 2H), 7.50(brd, J = 8.7 Hz, 2H), 8.00 — (m, 1H).
(I
Example 20(12):
N-cyclohexyl-4-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)- 1-piperazinecarboxamide hydrochloride
TLC:Rf 0.77(chloroform:methanol=5:1);
NMR (CD;OD): § 1.08-1.44 (m, SH), 1.58-1.92 (m, 5H), 2.95 (s, 3H), 2.95-3.60 (m, SH), 4.31 (s, 2H), 7.00-7.12 (m, 4H), 7.29 (brd, J = 9.3 Hz, 2H), 7.49 (brd, J = 8.4 Hz, 2H).
Example 20(13):
N-benzyl-4-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-1-piperazinecarboxamide hydrochloride
TLC:Rf 0.73(chloroform:methanol=5:1);
NMR (CD;0D): 6 2.95 (s, 3H), 3.22 (m, 4H), 3.70 (m, 4H), 4.28 (s, 2H), 4.35 (s, 2H), 7.00-7.08 (m, 4H), 7.18-7.36 (m, 7H), 7.44-7.56 (m, 2H).
Example 20(14): 4-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-N-phenyl-1-piperazinecarboxamide hydrochloride
TLC:Rf 0.73(chloroform:methanol=5:1);
NMR (CD;0D): § 2.95 (s, 3H), 3.10-3.42 (m, 8H), 4.29 (s, 2H), 7.00-7.10 (m, SH), 7.21- 7.40 (m, 6H), 7.49 (brd, J = 8.4 Hz, 2H).
Example 20(15):
N-[4-(4-{[4-(cyclohexylacetyl)-1- piperidinyl}methyl} phenoxy)phenyllmethanesulfonamide hydrochloride TLC:Rf 0.59(chloroform:methanol=5:1);
NMR (CD;O0D): 4 0.80-1.02 (m, 2H), 1.08-1.40 (m, 3H), 1.60-1.90 (m, 8H), 2.04-2.20 (m, 2H), 2.41 (d, J = 6.9 Hz, 2H), 2.72 (m, 1H), 2.95 (s, 3H), 3.05 (m, 2H), 3.48 (m, 2H), 4.27 (s, 2H), 7.00-7.10 (m, 4H), 7.29 (brd, J = 9.0 Hz, 2H), 7.48 (brd, J = 9.0 Hz, 2H),
Example 20(16):
N-(4-{4-[(4-hydroxy-1-piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.38(methylene chloride:methanol=5:1);
NMR (CD;OD): 6 1.71-2.16 (m, 4H), 2.95 (s, 3H), 3.06-3.53 (m, 4H), 4.08 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 9,0 Hz, 2H), 7.06 (d, J] = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.48 (d, =
J=9.0 Hz, 2H).
® Oo
Example 20(17): 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4-piperidinecarboxamide hydrochloride
TLC:Rf 0.36(methylene chloride: methanol=5:1);
NMR (CD;OD): 6 1.83-2.21 (m, 4H), 2.54 (m, 1H), 2.95 (s, 3H), 2.98-3.06 (m, 2H), 3.52- 3.56 (m, 2H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H).
Example 20(18): benzyl 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4-piperidinecarboxylate hydrochloride
TLC:Rf 0.36(methylene chloride: methanol=10:1);
NMR (CD;OD): & 1.85-1.94 (m, 2H), 2.06-2.12 (m, 2H), 2.60-2.78 (m, 3H), 2.94 (s, 3H), 3.20-3.25 (m, 2H), 3.99 (s, 2H), 5.14 (s, 2H), 6.99-7.02 (m, 4H), 7.27 (4, J = 8.7 Hz, 2H), 7.32-7.36 (m, SH), 7.40 (d, J = 8.7 Hz, 2H).
Example 20(19): t-butyl 1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinylcarbamate
TLC:Rf 0.35(methylene chloride:methanol=10:1);
NMR (CD;OD): 6 1.42 (s, 9H), 1.42-1.53 (m, 2H), 1.81-1.85 (m, 2H), 2.07-2.14 (m, 2H), 2.83-2.87 (m, 2H), 2.93 (s, 3H), 3.30-3.36 (m, 1H), 3.49 (s, 2H), 6.93 (d, J] = 8.7 Hz, 2H), 6.97 (d, J =8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H).
Example 20(20):
N-{4-[4-(1-piperidinylmethyl)phenoxy]phenyl } methanesulfonamide hydrochloride TLC:Rf0.34(methylene chloride:methanol=10:1);
NMR (CD3;OD): 6 1.48-1.97 (m, 6H), 2.90-2.99 (m, 2H), 2.95 (s, 3H), 3.42-3.46 (m, 2H), 4.25 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.47 (d, J =8.7 Hz, 2H).
Example 20(21):
N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)-4-piperidinyl}-2-tetrahydro-2H- pyran-4-ylacetamide hydrochloride
TLC:Rf0.17(ethyl acetate:methanol=5:1);
NMR (CD3OD): 6 1.20-1.40 (m, 2H), 1.54-1.64 (m, 2H), 1.67-1.84 (m, 2H), 1.88-2.21 (m,
SH), 2.95 (s, 3H), 3.06-3.18 (m, 2H), 3.30-3.46 (m, 2H), 3.46-3.56 (m, 2H), 3.85-3.97 (m, - 3H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
oO
Example 20(22): 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-N-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinecarboxamide hydrochloride
TLC:Rf 0.18(ethyl acetate:methanol=5:1);
NMR (CDs;OD): 8 1.18-1.32 (m, 2H), 1.56-1.64 (m, 2H), 1.73 (m, 1H), 1.84-2.10 (m, 4H), 2.53 (m, 1H), 2.95 (s, 3H), 2.96-3.11 (m, 4H), 3.28-3.42 (m, 2H), 3.49-3.58 (m, 2H), 3.87- 3.96 (m, 2H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J =8.7 Hz, 2H).
Example 20(23): 4-methyl-N-[1-(4- {4-[(methylsulfonyl)amino]phenoxy }benzyl)-4- piperidinyl]benzenesulfonamide hydrochloride
TLC:Rf 0.65(chloroform:methanol=5:1);
NMR (CD;OD): § 1.56-1.76 (m, 2H), 1.84-2.04 (m, 2H), 2.41 (s, 3H), 2.95 (s, 3H), 3.00 (m, 1H), 3.14-3.45 (m, 4H), 4.20 (s, 2H), 6.98-7.10 (m, 4H), 7.22-7.34 (m, 2H), 7.38-7.52 (m, 4H), 7.72-7.80 (m, 2H).
Example 20(24):
N-{[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]carbonyl }benzenesulfonamide hydrochloride
TLC:Rf 0.44(chloroform:methanol=5:1);
NMR (CD30D): 6 1.68-1.86 (m, 2H), 1.92-2.10 (m, 2H), 2.53 (m, 1H), 2.95 (s, 3H), 2.90- 3.04 (m, 2H), 3.42-3.54 (m, 2H), 4.26 (s, 2H), 6.98-7.06 (m, 4H), 7.22-7.36 (m, 2H), 7.40- 7.50 (m, 2H), 7.52-7.62 (m, 2H), 7.6 8 (m, 1H), 8.00 (brd, J = 7.5 Hz, 2H).
Example 20(25):
N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinylJmethanesulfonamide hydrochloride
TLC:Rf 0.78(chloroform:methanol=5:1);
NMR (CD;OD): & 1.70-1.92 (m, 2H), 2.08-2.26 (m, 2H), 2.95 (s, 3H), 2.98 (s, 3H), 3.00- 3.18 (m, 2H), 3.28 -3.46 (m, 2H), 3.54 (m, 1H), 4.22 (s, 2H), 6.98-7.10 (m, 4H), 7.26-7.34 (m, 2H), 7.42-7.56 (m, 2H).
Example 20(26): 4-[(cyclohexylcarbonyl)amino]-1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)-4- -- piperidinecarboxylic acid hydrochloride
TLC:Rf 0.20(chloroform:methanol acetic acid=20:4:1);
I
NMR (CD;0D): & 1.18-1.48 (m, 6H), 1.63-1.86 (m, 4H), 2.16-2.42 (m, 5H), 2.95 (s, 3H), 3.00-3.14 (m, 2H), 3.26-3.41 (m, 2H), 4.23 (s, 2H), 7.00-7.10 (m, 4H), 7.28 (brd, J = 9.0
Hz, 2H), 7.47 (brd, J = 8.7 Hz, 2H) .
Example 20(27): 4-cyclohexyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]butanamide hydrochloride
TLC:Rf 0.58(methanol: methylene chloride=1:8);
NMR (CD;0D): 8 0.80-0.96 (m, 2H), 1.12-1.30 (m, 6H), 1.54-1.84 (m, 9H), 2.00-2.18 (m, 4H), 2.95 (s, 3H), 3.03-3.14 (m, 2H), 3.46-3.56 (m, 2H), 3.89 (m, 1H), 4.28 (s, 2H), 7.03 (d,
J=87Hz 2H), 7.05 (d, J= 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 20(28): 3-cyclohexyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]propanamide hydrochloride
TLC:Rf 0.52(methanol: methylene chloride=1:8);
NMR (CD;OD): § 0.83-0.98 (m, 2H), 1.12-1.53 (m, 4H), 1.48 (dd, J = 6.6, 15.0 Hz, 2H), 1.60-1.78 (m, 7H), 2.04-2.24 (m, 4H), 2.95 (s, 3H), 3.02-3.24 (m, 2H), 3.35-3.58 (m, 2H), 3.90 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d,J = 8.7 Hz, 2H), 7.29(d, J = 8.7 Hz 2H), 7.48 (d, J =8.7 Hz, 2H).
Example 20(29):
N-[1-({ 1-[4-(aminosulfonyl)phenyl]-3,5-dimethyl- 1H-pyrazol-4-yl } methyl)-4- piperidinyl]-2-cyclohexylacetamide dihydrochloride
TLC:Rf0.30(methylene chloride:methanol=10:1);
NMR (CD;OD): 6 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.90 (m, 8H), 2.05 (d, J = 6.6 Hz, 2H) 2.10-2.20 (m, 2H), 2.39 (s, 3H), 2.44 (s, 3H), 3.10-3.30 (m, 2H), 3.60-3.70 (m, 2H), 3.90 (m, 1H), 4.26 (s, 2H), 7.70 (d, J = 7.7 Hz, 2H), 8.07 (d, J = 7.7 Hz, 2H).
Example 20(30): 2-cyclohexyl-N-{1-[(1-{4-[(cyclohexylamino)sulfonyl}phenyl}-3,5-dimethyl-1H-pyrazol- 4-yl)ymethyl]-4-piperidinyl } acetamide dihydrochloride
TLC:Rf 0.46(methylene chloride: methanol=10:1);
NMR (CD;OD): 8 0.90-1.10 (m, 2H), 1.10-1.40 (m, 8H), 1.60-1.90 (m, 13H), 2.05(d, J = 7.2 Hz, 2H) 2.10-2.30 (m, 2H), 2.39 (s, 3H), 2.44 (s, 3H), 3.00-3.20 (m, 3H), 3.60-3.70 (m, -- 2H), 3.93 (m, 1H), 4.26 (s, 2H), 7.71 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H).
oO
Example 20(31): 2-cyclohexyl-N-[1-({ 1-[4-({[2-(dimethylamino)ethyl]Jamino } sulfonyl)phenyl]-3,5- dimethyl-1H-pyrazol-4-y!} methyl)-4-piperidinyl]acetamide trihydrochloride
TLC:Rf 0.08(methylene chloride: methanol=10:1),
NMR (CD;OD): § 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.90 (m, 8H), 2.05 (d, J = 6.9 Hz, 2H) 2.10-2.30 (m, 2H), 2.39 (s, 3H), 2.47 (s, 3H), 2.95 (s, 6H), 3.10-3.20 (m, 6H), 3.60-3.70 (m, 2H), 3.90 (m, 1H), 4.26 (s, 2H), 7.78 (d, J = 8.9 Hz, 2H), 8.07 (d, J = 8.9 Hz, 2H).
Example 20(32): 2-cyclohexyl-N-[1-({3,5-dimethy!-1-[4-({[2-(4- morpholinyl)ethyl]amino} sulfonyl)phenyl]-1H-pyrazol-4-yl } methyl)-4- piperidinyl]acetamide trihydrochloride
TLC:Rf 0.39(methylene chloride: methanol=10:1);
NMR (CD;OD): § 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.90 (m, 8H), 2.05 (d, J = 7.2 Hz, 2H) 2.10-2.30 (m, 2H), 2.39 (s, 3H), 2.46 (s, 3H), 3.10-3.40 (m, 8H), 3.50-3.70 (m, 4H), 3.80-3.90 (m, 3H), 4.10-4.20 (m, 2H), 4.26 (s, 2H), 7.77 (d, J] = 8.7 Hz, 2H), 8.07 (d, J =8.7 Hz, 2H).
Example 20(33): 2-cyclohexyl-N-{1-[(1-{4-[(dimethylamino)sulfonyl]phenyl}-3,5-dimethyl-1H-pyrazol-4- yl)methyl]-4-piperidinyl }acetamide dihydrochloride
TLC:Rf 0.53(methylene chloride: methanol=10:1);
NMR (CD3;OD): 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.90 (m, 8H), 2.05(d, J = 6.9 Hz, 2H) 2.10-2.30 (m, 2H), 2.39 (s, 3H), 2.46 (s, 3H), 2.74 (s, 6H), 3.10-3.20 (m, 2H), 3.60-3.70 (m, 2H), 3.90 (m, 1H), 4.26 (s, 2H), 7.76-7.80 (m, 2H), 7.94-7.97 (m, 2H).
Example 20(34): 2-cyclohexyl-N-(1-{[1-(4-{[(2-hydroxyethyl)(methyl)amino]sulfonyl } phenyl)-3,5- dimethyl-1H-pyrazol-4-yl]methyl}-4-piperidinyl)acetamide dihydrochloride
TLC:Rf 0.43(methylene chloride: methanol=10:1);
NMR (CD;OD): § 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.90 (m, 8H), 2.05 (d, J = 6.9 Hz, 2H) 2.10-2.30 (m, 2H), 2.39 (s, 3H), 2.45 (s, 3H), 2.87 (s, 3H), 3.10-3.20 (m, 2H), 3.19 (t, J = 5.9 Hz, 2H), 3.60-3.80 (m, 2H), 3.69 (t, J = 5.9 Hz, 2H), 3.93 (m, 1H), 4.26 (5, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H). :
(I
Example 20(35): 2-cyclohexyl-N-{1-[(1-{4-[(diethylamino)sulfonyl]phenyl }-3,5-dimethyl-1H-pyrazol-4- yl)methyl]-4-piperidinyl }acetamide dihydrochloride
TLC:Rf 0.53(methylene chloride: methanol=10:1);
NMR (CDsOD): § 0.90-1.10 (m, 2H), 1.15 (t, J = 7.1 Hz, 6H), 1.10-1.40 (m, 3H), 1.60- 1.75 (m, 6H), 1.75-1.90 (m, 2H), 2.05 (d, J = 7.2 Hz, 2H), 2.10-2.30 (m, 2H), 2.40 (s, 3H), 2.45 (s, 3H), 3.10-3.20 (m, 2H), 3.20-3.40 (m, 4H), 3.60-3.80 (m, 2H), 3.94 (m, 1H), 4.26 (s, 2H), 7.73 (d, J = 8.6 Hz, 2H), 7.99 (d, J] = 8.6 Hz, 2H).
Example 20(36): 2-cyclohexyl-N-[1-({3,5-dimethyl-1-[4-(4-morpholinylsulfonyl)phenyl]-1H-pyrazol-4- yl}methyl)-4-piperidinyl]acetamide dihydrochloride
TLC Rf 0.50(methylene chloride: methanol=10:1);
NMR (CD;0D): § 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.75 (m, 6H), 1.75-1.90 (m, 2H), 2.06 (d, J = 7.2 Hz, 2H), 2.10-2.30 (m, 2H), 2.40 (s, 3H), 2.48 (s, 3H), 3.02 (t,] = 4.7
Hz, 4H), 3.10-3.20 (m, 2H), 3.60-3.80 (m, 2H), 3.71 (t, J = 4.7 Hz, 4H), 3.94 (m, 1H), 4.27 (s, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.6 Hz, 2H).
Example 20(37): 2-cyclohexyl-N-{1-[(3,5-dimethyl-1-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl }-1H- pyrazol-4-yl)methyl]-4-piperidinyl }acetamide dihydrochloride
TLC:Rf 0.48(methylene chloride:methanol=10:1);
NMR (CD;0D): § 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 6H), 1.80-2.00 (m, 2H), 2.06 (d, J = 6.9 Hz, 2H), 2.10-2.30 (m, 2H), 2.40 (s, 3H), 2.48 (s, 3H), 2.80-3.00 (m, 2H), 2.90 (s, 3H), 3.10-3.40 (m, 4H), 3.50-3.80 (m, 4H), 3.90-4.10 (m, 3H), 4.27 (s, 2H), 7.84 (d, J=8.6 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H).
Example 20(38): ethyl [4-({4-[4-({4-[(cyclohexylacetyl)amino]-1-piperidinyl } methyl)-3,5-dimethyl-1H- pyrazol-1-yl]phenyl}sulfonyl)-1-piperazinyl]acetate trihydrochloride
TLC:Rf 0.43(methylene chloride: methanol=10:1);
NMR (CD;OD): & 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.30 (t, J] = 7.1 Hz, 3H), 1.60- 1.90 (m, 8H), 2.05 (d, J = 6.9 Hz, 2H), 2.10-2.30 (m, 2H), 2.40 (s, 3H), 2.49 (s, 3H), 3.10- 3.20 (m, 2H), 3.40-4.00 (m, 11H), 4.22 (s, 2H), 4.27 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 7.84 (d,J=8.6 Hz 2H), 8.02 (d, J = 8.6 Hz, 2H).
oO
Example 20(39): 2-cyclohexyl-N-{1-[(3,5-dimethyl-1-{4-[(methylsulfonyl)amino]phenyl }-1H-pyrazol-4- yl)methyl]-4-piperidinyl }acetamide dihydrochloride
TLC:Rf 0.45(methylene chloride: methanol=10:1);
NMR (CD;OD): § 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.90 (m, 8H), 2.05 (d, J = 7.2 Hz, 2H), 2.10-2.30 (m, 2H), 2.36 (s, 3H), 2.37 (s, 3H), 3.03 (s, 3H), 3.10-3.20 (m, 2H), 3.60-3.70 (m, 2H), 3.90 (m, 1H), 4.24 (s, 2H), 7.39-7.46 (m, 4H).
Example 20(40): 2-cyclohexyl-N-[1-(4-{2,6-dimethyl-4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyljacetamide hydrochloride
TLC:Rf 0.46(methylene chloride: methanol=10:1);
NMR (CD;0D): 6 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.03 (d, J = 6.9 Hz, 2H), 2.07 (s, 6H), 2.10-2.20 (m, 2H), 2.97 (s, 3H), 3.00-3.10 (m, 2H), 3.40-3.60 (m, 2H), 3.90 (m, 1H), 4.24 (s, 2H), 6.84 (d, J =3.9 Hz, 2H), 7.04 (s, 2H), 7.45 (d, ] = 8.7 Hz, 2H).
Example 20(41):
N-(1-{4-[4-(aminosulfonyl)phenoxy]benzyl }-4-piperidinyl)-2-cyclohexylacetamide hydrochloride
TLC:Rf 0.33(methylene chloride:methanol=10:1);
NMR (CD;0D): 8 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.04 (d, J = 7.2 Hz, 2H), 2.10-2.20 (m, 2H), 3.00-3.10 (m, 2H), 3.50-3.60 (m, 2H), 3.92 (m, 1H), 4.32 (s, 2H), 7.11-7.19 (m, 4H), 7.58-7.62 (m, 2H), 7.88-7.93 (m, 2H).
Example 20(42): 2-cyclohexyl-N-(1-{4-[4-(methylsulfonyl)phenoxy Jbenzyl}-4-piperidinyl)acetamide hydrochloride
TLC:Rf 0.43(methylene chloride:methanol=10:1);
NMR (CD;0D): 6 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.05 (d, J = 6.9 Hz, 2H), 2.10-2.20 (m, 2H), 3.00-3.10 (m, 2H), 3.12 (s, 3H), 3.50-3.60 (m, 2H), 3.91 (m, 1H), 4.33 (s, 2H), 7.19-7.23 (m, 4H), 7.59 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.6 Hz, 2H).
Example 20(43): 2-cyclohexyl-N-[1-({4'-[(methylsulfonyl)amino]-1, 1'-biphenyl-3-yl} methyl)-4- - piperidinyl]Jacetamide hydrochloride
TLC:Rf 0.38(methylene chloride:methanol=10:1),
oO
NMR (CDs;0D): & 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.02 (d, J = 6.9 Hz, 2H), 2.10-2.20 (m, 2H), 2.99 (s, 3H), 3.00-3.10 (m, 2H), 3.50-3.60 (m, 2H), 3.90 (m, 1H), 4.37 (s, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.45-7.60 (m, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.70-7.80 (m, 2H).
Example 20(44): 2-cyclohexyl-N-(1-{4-[4-(methylsulfanyl)phenoxy]benzyl}-4-piperidinyl)acetamide hydrochloride
TLC:Rf 0.60(methylene chloride:methanol=10:1);
NMR (CD;OD): § 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.03 (d, J = 7.2 Hz, 2H), 2.10-2.20 (m, 2H), 2.47 (s, 3H), 3.00-3.10 (m, 2H), 3.50-3.60 (m, 2H), 3.90 (m, 1H), 4.27 (s, 2H), 6.99 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H) 7.32 (d, J) = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H).
Example 20(45):
N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)-4-piperidinyl]propanamide hydrochloride
TLC:Rf 0.34(methylene chloride: methanol=10:1);
NMR (CD;OD): 4 0.97 (t, J] = 7.2 Hz, 3H), 1.10 (t, J = 7.4 Hz, 3H), 1.20-1.70 (m, 4H), 1.80-2.10 (m, 2H), 2.20-2.50 (m, 2H), 2.35 (q, J = 7.6 Hz, 2H), 2.95 (s, 3H), 3.00-3 40 (m, 4H), 3.40-3.60 (m, 2H), 4.11 (m, 1H), 4.26 (s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.06 (d, J] = 8.9 Hz, 2H) 7.29 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 8.9 Hz, 2H).
Example 20(46): N-benzyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]propanamide hydrochloride
TLC:Rf 0.44(methylene chloride:methanol=10:1);
NMR (CD;OD): & 1.08 (t, J = 7.5 Hz, 3H), 1.80-2.00 (m, 2H), 2.00-2.20 (m, 2H), 2.37 (q,
J =17.5 Hz, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.40-3.60 (m, 2H), 4.22 (s, 2H), 4.40 (m, 1H), 4.61 (s, 2H), 7.00-7.05 (m, 4H), 7.22-7.46 (m, 7H), 7.45 (d, J = 8.4 Hz, 2H).
Example 20(47):
N-(2-methoxyethyl)-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]propanamide hydrochloride
TLC:Rf0.43(methylene chloride:methanol=10:1);
NMR (CD;OD): § 1.07 (t, ] = 7.4 Hz, 3H), 1.90-2.00 (m, 2H), 2.42 (q, J = 7.4 Hz, 2H), 2.40-2.60 (m, 2H), 2.96 (s, 3H), 3.00-3.20 (m, 2H), 3.34 (s, 3H), 3.40-3.60 (m, 4H), 4.05 (m, 1H), 4.28 (s, 2H), 7.01-7.06 (m, 4H), 7.28-7.31 (m, 2H), 7.51-7.56 (m, 2H).
(I
Example 20(48):
N-(3-hydroxybuty!)-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]propanamide hydrochloride TLC:Rf0.43(methylene chloride: methanol=10:1);
NMR (CD;0D): 8 1.10 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 6.0 Hz, 2H), 1.60-1.80 (m, 2H), 1.80-2.40 (m, 6H), 2.41 (q, J = 7.4 Hz, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.40-3.60 (m, 4H), 3.80 (m, 1H), 4.05 (m, 1H), 4.28 (s, 2H), 7.03 (t, J = 8.7 Hz, 2H), 7.05 (t, J = 7.4 Hz, 2H), 7.29 (1, J = 7.4 Hz, 2H), 7.50 (t, J = 8.7 Hz, 2H).
Example 20(49):
N-(cyclohexylmethyl)-N-[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]propanamide hydrochloride
TLC:Rf 0.54(methylene chloride: methanol=10:1);
NMR (CD;OD): § 0.87-0.91 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H), 1.10-1.40 (m, 5H), 1.60- 1.80 (m, 4H), 1.80-2.00 (m, 2H), 2.36 (q, J = 7.2 Hz, 2H), 2.40-2.60 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.16 (d, J = 7.5 Hz, 2H), 3.40-3.60 (m, 2H), 3.80 (m, 1H), 4.26 (s, 2H), 7.03 (d, J =8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7
Hz, 2H).
Example 20(50): 4-(acetylamino)-N-(cyclohexylmethyl)-1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)- 4-piperidinecarboxamide hydrochloride
TLC:Rf 0.39(chloroform:methanol=9:1);
NMR (CD;0D): § 0.80-1.00 (m, 2H), 1.08-1.32 (m, 4H), 1.48 (m, 1H), 1.60-1.78 (m, 4H), 2.05 (brs, 3H), 2.10-2.50 (m, 4H), 2.95 (s, 3H), 3.00 (t, J = 6.3 Hz, 2H), 3.04-3.50 (m, 4H), 4.30 (s, 2H), 6.98-7.08 (m, 4H), 7.28 (brd, J = 9.0 Hz, 2H), 7.49 (brd, J = 8.7 Hz, 2H).
Example 20(51): 4-[4-({4-[(cyclohexylacetyl)amino]-1-piperidinyl } methyl)phenoxy]phenyl methanesulfonate hydrochloride
TLC:Rf 0.50(methylene chloride: methanol=10:1);
NMR (CD;OD): 6 0.90-1.10 (m, 2H), 1.20-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.04 (d, J = 7.2 Hz, 2H), 2.10-2.20 (m, 2H), 3.10-3.20 (m, 2H), 3.23 (s, 3H), 3.40-3.60 (m, 2H), 3.91 (m, 1H), 4.29 (s, 2H), 7.08-7.14 (m, 4H), 7.34 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), -
( I
Example 20(52):
N-(cyclopropylmethyl)-N-[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]propanamide hydrochloride
TLC:Rf 0.43(methylene chloride:methanol=10:1);
NMR (CD;OD): & 0.30-0.40 (m, 2H), 0.60-0.70 (m, 2H), 0.95 (m, 1H), 1.10 (t, J = 7.4 Hz, 3H), 1.90-2.10 (m, 2H), 2.40-2.60 (m, 2H), 2.43 (q, ] = 7.2 Hz, 2H), 2.95 (s, 3H), 3.00- 3.20 (m, 2H), 3.22 (d, J = 6.3 Hz, 2H), 3.45-3.60 (m, 2H), 4.00 (m, 1H), 4.28 (s, 2H), 7.02- 7.08 (m, 4H), 7.27-7.32 (m, 2H), 7.50 (t, J = 8.1 Hz, 2H).
Example 20(53):
N-(2-cyclohexylethyl)-1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinecarboxamide hydrochloride
TLC:Rf 0.64(methylene chloride: methanol=10:1);
NMR (CDsOD): 6 0.89-0.97 (m, 2H), 1.18-1.41 (m, 7H), 1.60-1.74 (m, 4H), 1.87-2.04 (m, 4H), 2.47 (m, 1H), 2.95 (s, 3H), 2.95-3.04 (m, 2H), 3.16-3.21 (m, 2H), 3.52-3.56 (m, 2H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.47 (d, J =8.7 Hz, 2H).
Example 20(54): 2-cyclohexyl-N-(1-{4-[4-(methylsulfinyl)phenoxy ]benzyl}-4-piperidinyl)acetamide hydrochloride
TLC:Rf 0.21(chloroform:methanol=10:1);
NMR (CD;0D): 6 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.04 (d, J = 6.9 Hz, 2H), 2.10-2.20 (m, 2H), 2.80 (s, 3H), 3.10-3.20 (m, 2H), 3.50-3.60 (m, 2H), 3.90 (m, 1H), 4.31 (s, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H).
Example 20(55):
N-[2-(ethylsulfanyl)ethyl]-1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinecarboxamide hydrochloride
TLC:Rf 0.30(methylene chloride: methanol=10:1);
NMR (CDs;OD): & 1.23 (t, J = 7.5 Hz, 3H), 1.88-2.08 (m, 4H), 2.46-2.67 (m, SH), 2.94- 3.07 (m, 2H), 2.95 (s, 3H), 3.37 (t, J = 7.0 Hz, 2H), 3.52-3.56 (m, 2H), 4.28 (s, 2H), 7.03 (d,
J=9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H). -
Example 20(56): 2-cyclohexyl-N-[1-(4-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]acetamide hydrochloride oO
TLC:Rf 0.30(chloroform:methanol=10:1);
NMR (CD;0D): & 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.03 (d, J = 6.9 Hz, 2H), 2.10-2.20 (m, 2H), 2.99 (s, 3H), 3.00-3.20 (m, 2H), 3.40-3.60 (m, 2H), 3.72 (s, 3H), 3.89 (m, 1H), 4.31 (s, 2H), 6.83-6.94 (m, 3H), 6.99-7.05 (m, 2H), 7.39-7.45 (m, 2H).
Example 20(57): 2-cyclohexyl-N-[1-(4-{3-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]acetamide hydrochloride
TLC:Rf 0.30(chloroform:methanol=10:1),
NMR (CD;0OD): 8 0.90-1.10 (m, 2H), 1.10-1.40 (m, 3H), 1.60-1.80 (m, 8H), 2.04 (d, J = 6.9 Hz, 2H), 2.10-2.20 (m, 2H), 2.96 (s, 3H), 3.00-3.20 (m, 2H), 3.40-3.60 (m, 2H), 3.90 (m, 1H), 4.29 (s, 2H), 6.79 (dd, J = 7.5, 2.4 Hz, 1H), 6.95-7.01 (m, 2H), 7.08-7.11 (m, 2H), 7.31-7.34 (m, 1H), 7.51-7.54 (m, 2H).
Example 20(58):
N-[4-(4-{[4-(cyclohexylacetyl)-3-methyl-1- piperazinyljmethyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.72(chloroform:methanol=5:1);
NMR (CD;0OD): 4 0.82-1.44 (m, 8H), 1.60-1.85 (m, 6H), 2.30-2.42 (m, 2H), 2.95 (s, 3H), 2.95-3.65 (m, 5H), 4.10-5.15 (m, 4H), 7.00-7.12 (m, 4H), 7.24-7.38 (m, 2H), 7.52 (brd, J = 8.7 Hz, 2H).
Example 20(59): 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4-piperidinyl cyclohexylcarbamate hydrochloride
TLC:Rf 0.69(ethyl acetate:methanol=10:1);
NMR (CD;OD): 6 1.06-1.42 (m, 6H), 1.54-1.92 (m, 6H), 1.95-2.17 (m, 2H), 2.26 (m, 1H), 2.95 (s, 3H), 3.05-3.58 (m, SH), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (dd, J = 4.2, 8.7 Hz, 2H).
Example 20(60): (2R,3R)-3-cyclohexyl-3-hydroxy-2-({[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)- 4-piperidinyl]carbonyl}amino)propanoic acid hydrochloride
TLC:Rf 0.23(methylene chloride:methanol=8:2),
NMR (CD;0D): 8 1.00-1.34 (m, 5H), 1.48 (m, 1H), 1.58-1.80 (m, 4H), 1.83-2.11 (m, SH), -- 2.58 (m, 1H), 2.95 (s, 3H), 2.87-3.00 (m, 2H), 3.40-3.49 (m, 2H), 3.51 (t, ] = 6.0 Hz, 1H), 4.18 (s, 2H), 439 (d,J=6.0 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.46 (d, ] = 8.7 Hz, 2H).
0
Example 20(61):
N-butyl-2-cyclohexyl-N-[1-(4-{3-[(methylsulfonyl )amino]phenoxy }benzyl)-4- piperidinyl]acetamide hydrochloride TLC:Rf 0.32(chloroform:methanol=10:1);
NMR (CD;OD): § 0.80-1.10 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 1.20-1.40 (m, 5H), 1.40- 1.60 (m, 2H), 1.60-2.00 (m, 8H), 2.30-2.40 (m, 2H), 2.32 (d, J = 7.2 Hz, 2H), 2.96 (s, 3H), 3.10-3.30 (m, 4H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.30 (s, 2H), 6.80 (m, 1H), 6.95 (m, 1H), 7.00 (m, 1H), 7.08 (d, J = 8.7 Hz, 2H), 7.33 (t, J = 8.1 Hz, 1H), 7.55-7.61 (m, 2H).
Example 20(62): 4-[4-({4-[butyl(hexanoyl)amino]-1-piperidinyl } methyl)phenoxy]benzoic acid hydrochloride
TLC:Rf 0.34(chloroform:methanol=10:1);
NMR (CD;0D): 8 0.90-1.00 (m, 3H), 0.97 (t, J = 7.4 Hz, 3H), 1.20-1.40 (m, 6H), 1.50- 1.70 (m, 4H), 1.80-2.00 (m, 2H), 2.20-2.40 (m, 4H), 3.00-3.20 (m, 4H), 3.50-3.70 (m, 2H), 4.10 (m, 1H), 4.31 (s, 2H), 7.07 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 8.04 (d, J =9.0 Hz, 2H).
Example 20(63): 4-[4-({4-[benzyl(hexanoyl)amino]-1-piperidinyl } methyl)phenoxy]benzoic acid hydrochloride
TLC:Rf 0.40(chloroform:methanol=10:1);
NMR (CD;OD): 6 0.86 (t, J = 7.2 Hz, 3H), 1.20-1.50 (m, 4H), 1.50-1.70 (m, 2H), 1.88- 1.95 (m, 2H), 2.00-2.20 (m, 2H), 2.30-2.40 (m, 2H), 3.00-3.20 (m, 2H), 3.50-3.60 (m, 2H), 4.27 (s, 2H), 4.45 (m, 1H), 4.62 (s, 2H), 7.03-7.07 (m, 2H), 7.13-7.37 (m, 7TH), 7.52 (d, J = 8.4 Hz, 2H), 8.01-8.04 (m, 2H).
Example 20(64): N-butyl-2-cyclohexyl-N-[1-(4-{2-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]acetamide hydrochloride
TLC:Rf 0.50(chloroform:methanol=10:1);
NMR (CD;0D): 6 0.90-1.00 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 1.20-1.40 (m, 5H), 1.40- 1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.21 (d, J = 6.9 Hz, 2H), 2.30-2.40 (m, 2H), 2.98 (s, 3H), 3.00-3.30 (m, 4H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.28 (s, 2H), 6.98 (m, 1H), 7.12 (d, J = = 8.7 Hz, 2H), 7.18-7.21 (m, 2H), 7.52-7.54 (m, 3H).
(I
Example 20(65): benzyl butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinyl]carbamate hydrochloride
TLC:Rf 0.77(ethyl acetate:methanol=10:1);
NMR (CD;0OD): 6 0.90 (t, J = 7.2 Hz, 3H), 1.21-1.36 (m, 2H), 1.42-1.58 (m, 2H), 1.88- 2.00 (m, 2H), 2.09-2.34 (m, 2H), 2.95 (s, 3H), 3.00-3.14 (m, 2H), 3.17-3.28 (m, 2H), 3.43- 3.58 (m, 2H), 3.93 (m, 1H), 4.25 (s, 2H), 5.12 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.05(d, J = 8.7 Hz, 2H), 7.24-7.38 (m, 7H), 7.47 (d, J = 8.7 Hz, 2H).
Example 20(66): benzyl allyl [1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinyl]carbamate hydrochloride
TLC:Rf 0.75(ethyl acetate:methanol=10:1);
NMR (CD30D): § 1.90-2.01 (m, 2H), 2.09-2.19 (m, 2H), 2.95 (s, 3H), 3.01-3.12 (m, 2H), 3.44-3.55 (m, 2H), 3.89 (d, J = 5.5 Hz, 2H), 4.03 (mm, 1H), 4.25 (s, 2H), 5.09-5.21 (m, 2H), 5.13 (s, 2H), 5.83 (ddd, J=225, 10.2, 5.4 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.05(d, J = 8.7 Hz, 2H), 7.25-7.38 (m, 7TH), 7.47(d, J = 8.7 Hz, 2H).
Example 20(67): benzyl 2-butynyl [1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]carbamate hydrochloride
TLC:Rf 0.76(ethyl acetate:methanol=10:1);
NMR (CD;0D): 6 1.75 (t, J = 2.1 Hz, 3H), 1.95-2.08 (m, 2H), 2.18-2.36 (m, 2H), 2.95 (s, 3H), 3.03-3.18 (m, 2H), 3.47-3.57 (m, 2H), 4.03 (d, J = 2.1 Hz, 2H), 4.07 (m, 1H), 4.26 (s, 2H), 5.16 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.25-7.41 (m, 7H), 7.47 (d, J = 8.7 Hz, 2H).
Example 20(68):
N-butyl-2-cyclohexyl-N-(1-{3-[(methylsulfonyl)amino]-4-phenoxybenzyl}-4- piperidinyl)acetamide hydrochloride
TLC:Rf 0.48(chloroform:methanol:acetic acid=20:2:1);
NMR (CD;0D): & 0.90-1.00 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 1.10-1.40 (m, 5H), 1.50- 1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.21 (d, J = 6.9 Hz, 2H), 2.30-2.40 (m, 2H), 3.04 (s, 3H), 3.05-3.30 (m, 4H), 3.50-3.70 (m, 2H), 4.14 (m, 1H), 4.28 (s, 2H), 6.89 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 7.5 Hz, 2H), 7.20-7.29 (m, 2H), 7.40-7.46 (m, 2H), 7.68 (d, J = 2.1 Hz, 1H). .
oO
Example 20(69):
N-butyl-2-cyclohexyl-N-{ 1-[4-(4-nitrophenoxy)benzyl]-4-piperidinyl } acetamide hydrochloride
TLC:Rf 0.54(chloroform:methanol acetic acid=20:2:1);
NMR (CD;0OD): & 0.90-1.00 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 1.10-1.40 (m, SH), 1.50- 1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.22 (d, J = 6.6 Hz, 2H), 2.30-2.40 (m, 2H), 3.10-3.30 (m, 4H), 3.50-3.60 (m, 2H), 4.19 (m, 1H), 4.34 (s, 2H), 7.16 (d, J = 9.1 Hz, 2H), 7.24(d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 8.27 (d, J = 9.1 Hz, 2H).
Example 20(70): 4-[4-({4-[butyl(cyclohexylacetyl)amino]-1-piperidinyl } methyl)phenoxy]phenyl methanesulfonate hydrochloride
TLC:Rf 0.79(chloroform:methanol=10:1);
NMR (CD;OD): § 0.90-1.00 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 1.10-1.40 (m, SH), 1.40- 1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.21 (d, J = 6.9 Hz, 2H), 2.30-2.40 (m, 2H), 3.00-3.20 (m, 4H), 3.23 (s, 3H), 3.50-3.60 (m, 2H), 4.18 (m, 1H), 4.29 (s, 2H), 7.11 (d, J = 9.0 Hz, 4H), 7.35 (d, J=9.0 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H).
Example 20(71): N-butyl-2-cyclohexyl-N-[1-(4-{2-methyl-4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyi]acetamide hydrochloride
TLC:Rf 0.44(chloroform:methanol=10:1);
NMR (CD;OD): § 0.90-1.00 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 1.10-1.40 (m, SH), 1.40- 1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.16 (s, 3H), 2.21 (d, J = 6.9 Hz, 2H), 2.30-2.40 (m, 2H), 2.96 (s, 3H), 3.00-3.20 (m, 4H), 3.50-3.60 (m, 2H), 4.10 (m, 1H), 4.25 (s, 2H), 6.91-6.98 (m, 3H), 7.13 (dd, J = 8.6, 2.6 Hz, 1H), 7.20 (m, 1H), 7.44-7.49 (m, 2H).
Example 20(72):
N-butyl-2-cyclohexyl-N-[ 1-(4-{2,6-dimethyl-4-[(methylsulfonyl)amino] phenoxy } benzyl)- 4-piperidinyl]acetamide hydrochloride
TLC:Rf 0.33(chloroform:methanol=10:1);
NMR (CD;0OD): 8 0.90-1.00 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 1.10-1.40 (m, SH), 1.40- 1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.07 (s, 6H), 2.21 (d, J = 6.6 Hz, 2H), 2.30-2.40 (m, 2H), 2.97 (s, 3H), 3.00-3.20 (m, 4H), 3.50-3.60 (m, 2H), 4.17 (m, 1H), 4.24 (s, 2H), 6.86 (d, J = 8.7 Hz 2H), 7.04 (s, 2H), 7.45 (d, J = 8.7 Hz, 2H). -
® O°
Example 20(73):
N-butyl-N-[1-(4-{2-chloro-4-[(methylsulfonyl)amino]}phenoxy} benzyl)-4-piperidinyl]-2- cyclohexylacetamide hydrochloride
TLC:Rf 0.60(chloroform:methanol=10:1);
NMR (CD;0D): 6 0.90-1.00 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H), 1.20-1.40 (m, SH), 1.40- 1.60 (m, 2H), 1.60-2.00 (m, 8H), 2.21 (d, J = 6.6 Hz, 2H), 2.30-2.40 (m, 2H), 3.01 (s, 3H), 3.10-3.30 (m, 4H), 3.50-3.60 (m, 2H), 4.10 (m, 1H), 4.27 (s, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.13 (d, J=9.0Hz, 1H), 7.24 (dd, J = 9.0, 2.6 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.48-7.52 (m, 2H).
Example 20(74): (2R)-2-cyclohexyl-2-hydroxy-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]acetamide hydrochloride
TLC:Rf 0.48(ethyl acetate:methanol=10:1);
NMR (CD;OD): § 1.06-1.38 (m, SH), 1.45-1.94 (m, 8H), 2.05-2.16 (m, 2H), 2.95 (s, 3H), 3.03-3.17 (m, 2H), 3.48-3.57 (m, 2H), 3.79 (d, J = 4.0 Hz, 1H), 3.96 (m, 1H), 4.28 (s, 2H), 7.03 (d, J =8.7H z, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.51 (d,] = 8.7
Hz, 2H).
Example 20(75): (2S)-2-cyclohexyl-2-hydroxy-N-[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]acetamide hydrochloride
TLC:Rf 0.48(ethyl acetate:methanol=10:1);
NMR (CD;OD): 6 1.06-1.38 (m, 5H), 1.45-1.94 (m, 8H), 2.05-2.16 (m, 2H), 2.95 (s, 3H), 3.03-3.17 (m, 2H), 3.48-3.57 (m, 2H), 3.79 (d, J] = 4.0 Hz, 1H), 3.96 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7H z, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.51 (d,] = 8.7
Hz, 2H).
Example 20(76): methyl 2-[4-({4-[butyl(cyclohexylacetyl)amino]-1-piperidinyl } methyl)phenoxy]-5- [(methylsulfonyl)amino]benzoate hydrochloride
TLC:Rf 0.50(methylene chloride: methanol=10:1);
NMR (CD;0D): 6 0.90-1.00 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 1.10-1.40 (m, 5H), 1.50- 1.60 (m, 2H), 1.65-1.80 (m, 6H), 1.80-2.00 (m, 2H), 2.21 (d, J = 6.9 Hz, 2H), 2.30-2.40 (m, - 35 2H), 3.00 (s, 3H), 3.10-3.30 (m, 4H), 3.50-3.60 (m, 2H), 3.74 (s, 3H), 4.10 (m, 1H), 4.26 (5, -- 2H), 6.98 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 1H), 7.45-7.52 (m, 3H), 7.79 (d,J = 3.0
Hz, 1H).
oOo
Example 20(77): 2-[4-({4-[butyl(cyclohexylacetyl)amino]-1-piperidinyl } methyl)phenoxy]-5- [(methylsulfonyl)amino]benzoic acid hydrochloride
TLC:Rf 0.40(methylene chloride:methanol=10:1);
NMR (CD;OD): & 0.95-1.05 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H), 1.10-1.40 (m, SH), 1.50- 1.80 (m, 8H), 1.80-2.00 (m, 2H), 2.21 (d, J = 6.9 Hz, 2H), 2.30-2.40 (m, 2H), 3.01 (s, 3H), 3.05-3.25 (m, 4H), 3.50-3.60 (m, 2H), 4.10 (m, 1H), 4.26 (s, 2H), 6.95 (d, J = 8.7 Hz, 2H), 7.09 (d, J =8.7Hz, 1H), 7.46-7.51 (m, 3H), 7.83 (d, J =2.7 Hz, 1H).
Example 20(78): (2R)-N-butyl-2-cyclohexyl-2-hydroxy-N-[1-(4-{4- [(methylsulfonyl)amino]phenoxy } benzyl)-4-piperidinyl]acetamide hydrochloride
TLC:Rf 0.55(methylene chloride:methanol=9:1);
NMR (CD30D): & 0.90-2.58 (m, 22H), 2.95 (s, 3H), 3.02-3.35 (m, 4H), 3.50-3.60 (m, 2H), 3.94-4.17 (m, 2H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d,
J=28.7 Hz, 2H), 7.45-7.54 (m, 2H).
Example 20(79): (2S)-N-butyl-2-cyclohexyl-2-hydroxy-N-[1-(4-{4- [(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinyl]acetamide hydrochloride
TLC:Rf 0.55(methylene chloride:methanol=9:1),
NMR (CDs0D): § 0.90-2.58 (m, 22H), 2.95 (s, 3H), 3.02-3.35 (m, 4H), 3.50-3.60 (m, 2H), 3.94-4.17 (m, 2H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d,
J=28.7 Hz, 2H), 7.45-7.54 (m, 2H).
Example 20(80): (3,4-trans)-N-(cyclohexylmethyl)-3-methyl-1-(4- {4- [(methylsulfonyl)amino]phenoxy } benzyl)-4-piperidinecarboxamide hydrochloride
TLC Rf 0.40(chloroform:methanol=9:1),
NMR (CD;0D): & 0.84-1.04 (m, 2H), 0.93 (d, J = 6.0 Hz, 3H), 1.14-1.34 (m, 4H), 1.48 (m, 1H), 1.60-1.80 (m, 4H), 1.88-2.04 (m, 2H), 2.06-2.18 (m, 2H), 2.72 (m, 1H), 2.88-3.12 (m, 3H), 2.95 (s, 3H), 3.22-3.60 (m, 2H), 4.28 (brs, 2H), 7.00-7.18 (m, 4H), 7.29 (brd, J = 9.0
Hz, 2H), 7.48 (brd, J = 8.7 Hz, 2H).
Example 20(81): i; (3,4-cis)-N-(cyclohexylmethyl)-3-methyl-1-(4-{4- [(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinecarboxamide hydrochloride
TLC:Rf 0.25(chloroform:methanol=9:1);
oO
NMR (CD;0D): 8 0.82-1.06 (m, 2H), 1.00 (d, J = 6.9 Hz, 3H), 1.13-1.34 (m, 4H), 1.46 (m, 1H), 1.62-1.80 (m, 4H), 1.92-2.24 (m, 3H), 2.55 (m, 1H), 2.90-3.12 (m, 2H), 2.95 (s, 3H), 3.13-3.62 (m, 4H), 4.29 (brs, 2H), 6.98-7.10 (m, 4H), 7.29 (brd, J = 9.0 Hz, 2H), 7.51 (brd,
J =8.7 Hz, 2H).
Example 20(82):
N-(cyclohexylmethyl)- 1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)-3- azetidinecarboxamide hydrochloride
TLC:Rf 0.73(chloroform:methanol=5:1);
NMR (CD;OD): § 0.80-1.02 (m, 2H), 1.19-1.35 (m, 4H), 1.49 (m, 1H), 1.60-1.80 (m, 4H), 2.95 (s, 3H), 3.06 (m, 2H), 3.61 (m, 1H), 4.12-4.32 (m, 4H), 4.39 (s, 2H), 6.98-7.06 (m, 4H), 7.29 (brd, J = 9.0 Hz, 2H), 7.4 5 (brd, J] = 8.7 Hz, 2H).
Example 20(83): (1R,3s,5S)-N-(cyclohexylmethyl)-8-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-8- azabicyclo[3.2.1]octane-3-carboxamide hydrochloride 0 H. NP bs aeWers (JV 0 - HCI
TLC:Rf 0.53(chloroform:methanol=5:1);
NMR (CD;OD): 5 0.85-1.04 (m, 2H), 1.20-1.36 (m, 4H), 1.46 (m, 1H), 1.60-1.78 (m, 4H), 1.85-1.90 (m, 2H), 2.08-2.16 (m, 4H), 2.38-2.50 (m, 2H), 2.88 (m, 1H), 2.95 (s, 3H), 3.00 (d, J = 6.9 Hz, 2H), 3.96 (mm, 2H), 4.16 (s, 2H), 7.00-7.10 (m, 4H), 7.24-7.32 (m, 2H), 7.53 (brd, 1 = 8.7 Hz, 2H).
Example 20(84): (3aR,5s,6aS)-N-(cyclohexylmethyl)-2-(4-{4- [(methylsulfonyl)amino]phenoxy }benzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide hydrochloride oO
Sane ° ] .
H N NS
H O
+ HCI oo
TLC:Rf 0.55(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.80-1.02 (m, 2H), 1.04-1.36 (m, 3H), 1.46 (m, 1H), 1.60-2.18 (m, 9H), 2.76-3.04 (m, 7H), 2.95 (s, 3H), 3.60-3.78 (m, 2H), 4.35 (s, 2H), 7.00-7.19 (m, 4H), 7.24- 7.32 (m, 2H), 7.42-7.58 (m, 2H).
Example 20(85): (3aR, 5r1,6aS)-N-(cyclohexylmethyl)-2-(4-{4- [(methylsulfonyl)amino]phenoxy }benzyl)octahydrocyclopenta[c]pyrrole-5-carboxamide hydrochloride 0)
J
HH Ir Rg (0 “«-CH, es vS,
H O
+ HCI
TLC:Rf 0.39(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.80-1.00 (m, 2H), 1.10-1.36 (m, 3H), 1.42 (m, 1H), 1.60-1.82 (m, 6H), 2.18 (m, 1H), 2.24-2.38 (m, 2H), 2.78-3.40 (m, 9H), 2.95 (s, 3H), 4.30 (s, 2H), 7.00-7.10 (m, 4H), 7.22-7.38 (m, 2H), 7.42-7.5 8 (m, 2H).
Example 21(1)-(11)
By the same procedure as described in Example 14—Example 15—>Example 16, using N-(t-butoxycarbonyl)-L-cyclohexylalanine or a corresponding carboxylic acid derivative instead of it; a corresponding aldehyde derivative instead of 4-(4- methylsulfonylaminophenoxy)benzaldehyde; and n-butylamine or a corresponding amine derivative instead of it, the compounds of the present invention having the following physical data were obtained.
Example 21(1): (3S)-1-benzyl-3-(cyclohexylmethyl)-6-{1-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4- yl)methyl]-4-piperidinyl}-2,5-piperazinedione hydrochloride
0
CH,
CEO
HN ne N
Pr ) - HCI
TLC:Rf 0.73(chloroform:methanol=5:1);
NMR (CD;0D): § 0.82-2.42 (m, 24H), 2.80-3.12 (m, 2H), 3.56-3.70 (m, 2H), 3.79 (m, 1H), 4.02-4.16 (m, 4H), 5.12-5.38 (m, 1H), 7.20-7.62 (m, 10H).
Example 21(2): (3S)-1-butyl-3-(cyclohexylmethyl)-6-[ 1-(4-phenoxybenzyl)-4-piperidinyl]-2,5- piperazinedione hydrochloride
TLC:Rf 0.73(chloroform:methanol=5:1);
NMR (CD;0D): § 0.80-1.08 (m, SH), 1.10-1.42 (m, 6H), 1.42-2.38 (m, 14H), 2.78-3.08 (m, 3H), 3.44-3.60 (m, 2H), 3.62-4.14 (m, 3H), 4.26 (brs, 2H), 7.00-7.06 (m, 4H), 7.18 (m, 1H), 7.38-7.52 (m, 4H).
Example 21(3): (3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-6-[ 1-(4-phenoxybenzyl)-4-piperidinyl]- 2,5-piperazinedione hydrochloride
TLC:Rf 0.62(chloroform:methanol=5:1);
NMR (CD;OD): § 0.86-2.48 (m, 23H), 2.81-3.08 (m, 3H), 3.27 (m, 1H), 3.45-3.58 (m, 2H), 3.64-4.00 (m, 2H), 4.18 (m, 1H), 4.25 (brs, 2H), 7.00-7.07 (m, 4H), 7.18 (m, 1H), 7.28- 7.52 (m, 4H).
Example 21(4): (3S)-3-benzyl-1-butyl-6-[ 1-(4-phenoxybenzyl)-4-piperidinyl]-2,5-piperazinedione hydrochloride TLC:Rf 0.65(chloroform:methanol=5:1);
NMR (CD;O0D): 6 0.78-2.30 (m, 12H), 2.52-3.96 (m, SH), 4.14-4.28 (m, 2H), 4.38 (m, 1H), 6.98-7.52 (m, 14H). -
O°
Example 21(5): (35)-1-butyl-3-cyclohexyl-6-[ 1-(4-phenoxybenzyl)-4-piperidinyl]-2,5-piperazinedione hydrochloride
TLC:Rf 0.65(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.78-1.00 (m, 3H), 1.00-2.38 (m, 20H), 2.78-3.08 (m, 3H), 3.48-4.04 (m, 5H), 4.26 (m, 2H), 6.98-7.10 (m, 4H), 7.18 (m, 1H), 7.39-7.54 (m, 4H).
Example 21(6): (3S)-1-butyl-3-(hydroxymethyl)-6-[ 1-(4-phenoxybenzyl)-4-piperidinyl]-2,5- piperazinedione hydrochloride
TLC:Rf 0.46(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.76-1.01 (m, 3H), 1.22-1.42 (m, 2H), 1.44-1.72 (m, 3H), 1.86-2.38 (m, 4H), 2.80-3.08 (m, 3H), 3.44-3.60 (m, 2H), 3.64-4.12 (m, SH), 4.26 (brs, 2H), 6.96-7.10 (m, 4H), 7.18 (m, 1H), 7.36-7.52 (m, 4H).
Example 21(7): (3S)-1-butyl-3-(cyclohexylmethyl)-6-{ 1-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4- yl)methyl]-4-piperidinyl}-2,5-piperazinedione hydrochloride
TLC:Rf 0.68(chloroform:methanol=5:1);
NMR (CD;OD): § 0.86-1.08 (m, 5H), 1.16-2.12 (m, 20H), 2.39 (m, 6H), 2.78-3.16 (m, 3H), 3.56-3.70 (m, 2H), 3.76-4.14 (m, 3H), 4.24 (brs, 2H), 7.47-7.56 (m, 5H).
Example 21(8): (3R)-1-butyl-3-[(R)-cyciohexyl(hydroxy)methyl]-6-{ 1-[(3,5-dimethyl-1-phenyl-1H- pyrazol-4-yl)methyl]-4-piperidinyl}-2,5-piperazinedione hydrochloride
TLC:Rf 0.67(chloroform:methanol=5:1);
NMR (CDs0D): § 0.90-2.14 (m, 23H), 2.32-2.40 (m, 6H), 2.80-3.14 (m, 3H), 3.28 (m, 1H), 3.56-3.68 (m, 2H), 3.68-4.00 (m, 2H), 4.19 (m, 1H), 4.24 (brs, 2H), 7.42-7.60 (m, SH).
Example 21(9): (3S)-3-benzyl-1-butyl-6-{ 1-[(3,5-dimethyl-1-phenyl- 1H-pyrazol-4-yl)methyl]-4- piperidinyl}-2,5-piperazinedione hydrochloride
TLC:Rf 0.74(chloroform:methanol=5:1});
NMR (CD;0D): § 0.78-2.40 (m, 12H), 2.32-2.40 (m, 6H), 2.32-3.95 (m, 8H), 4.12-4.44 (m, 4H), 7.10-7.28 (m, SH), 7.40-7.61 (m, SH).
oO
Example 21(10): (3S)-1-butyl-3-cyclohexyl-6-{ 1-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]-4- piperidinyl}-2,5-piperazinedione hydrochloride
TLC:Rf 0.74(chloroform:methanol=5:1);
NMR (CD;OD): § 0.80-1.00 (m, 3H), 1.02-2.22 (m, 20H), 2.32-2.40 (m, 6H), 2.80-3.18 (m, 3H), 3.58-4.08 (m, SH), 4.24 (brs, 2H), 7.40-7.60 (m, SH).
Example 21(11): (3S)-1-butyl-3-(cyclohexylmethyl)-6-[1-(4-phenoxybenzyl)-4-piperidinyl]-2-piperazinone dihydrochloride
TLC:Rf 0.82(chloroform:methanol=5:1);
NMR (CD;OD): § 0.95 (t, J = 7.5 Hz, 3H), 0.85-1.10 (m, 2H), 1.16-1.42 (m, 6H), 1.46- 2.10 (m, 13H), 2.21 (m, 1H), 2.81 (m, 1H), 3.00-3.20 (m, 2H), 3.34-3.72 (m, 5H), 3.92- 4.08 (m, 2H), 4.30 (s, 2H), 7.00-7.10 (m, 4H), 7.18 (m, 1H), 7.36-7.44 (m, 2H), 7.54 (brd,
J=284Hz 2H).
Example 22:
Mixture of N-{4-[4-({4-[(1E)-2-cyclohexyl-N-ethoxyethaneimidyl]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride and N-{4-[4-({4- [(1Z)-2-cyclohexyl-N-ethoxyethaneimidyl]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
N..2 (0) 3 o
N + HCI
CH,
NP
N = S.
EY TOLL Fe oO
N + HCI i»
O°
By the same procedure as described in Example 19, using the compound prepared in Example 20(15) instead of the compound prepared in Example 5(15), the compounds of the present invention having the following physical data were obtained.
TLC:Rf 0.67, 0.73(chloroform:methanol=9:1);
NMR (CD;OD): § 0.84-1.06 (m, 2H), 1.08-1.36 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H), 1.58- 2.18 (m, 9H), 2.23 (d, J = 7.2 Hz, 2H), 2.42 (m, 1H), 2.95 (s, 3H), 3.02 (m, 2H), 3.38-3.56 (m, 2H), 4.00 (q, J = 7.2 Hz, 2H), 4 .26 (s, 2H), 7.00-7.10 (m, 4H), 7.22-7.36 (m, 2H), 7.47 (brd, J = 8.4 Hz, 2H).
Example 23:
N-[4-(4-{[4-(butyl{[(1-methylcyclohexyl)amino]carbonyl}amino)-1- piperidinyl]methyl }phenoxy)phenyl]methanesulfonamide hydrochloride
H
0 N Nog CHs
SRN NOASWELL
N N Oo
H,C . HCI
H,C
To a solution of the compound prepared in Example 3 (117 mg) in N,N- dimethylformamide (3 mL) and triethylamine(0.1 mL) were added 1- methylcyclohexanecarboxylic acid (S50 mg) and diphenylphosphorylazide (0.077 mL) and the solution was stirred at 80°C for 2 hours. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The obtained residue was purified by column chromatography on silica gel (ethyl acetate) and high performance thin layer chromatography, and converted to hydrochloride salt by a conventional method to give the compound of the present invention (58 mg) having the following physical data.
TLC:Rf 0.60(ethyl acetate);
NMR (CD;OD): 6 0.96 (t, J = 7.2 Hz, 3H), 1.30-1.60 (m, 12H), 1.32 (s, 3H), 1.87-2.07 (m, 6H), 2.95 (s, 3H), 3.05-3.15 (m, 4H), 3.52-3.56 (m, 2H), 4.19 (m, 1H), 4.28 (s, 2H), 7.03 (d,
J =9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H).
Example 23(1)-(151)
By the same procedure as described in Example 23, using the compound prepared in Example 3 or a corresponding amine derivative, and using 1-
O° methylcyclohexanecarboxylic acid or a corresponding carboxylic acid derivative, the following compounds of the present invention were obtained.
Example 23(1): 3-[({[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]amino}carbonyl)amino]benzoic acid hydrochloride
TLC:Rf 0.75(n-butanol:acetic acid: water=4:2:1);
NMR (CD;0D): § 1.70-1.96 (m, 2H), 2.10-2.30 (m, 2H), 2.96 (s, 3H), 3.07-3.20 (m, 2H), 3.46-3.60 (m, 2H), 3.84 (m, 1H), 4.31 (s, 2H), 7.02-7.08 (m, 4H), 7.30 (d, J = 8.7 Hz, 2H), 7.35(,J=78Hz 1H), 7.51 (d, J =8.7 Hz, 2H), 7.59-7.66 (m, 2H), 8.04 (s, 1H).
Example 23(2):
N-(4-{4-[(4-{butyl[(butylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf0.51(ethyl acetate:methanol=5:1);
NMR (CD;OD): 6 0.92 (t, J] = 6.9 Hz, 3H), 0.94 (t, J = 6.9 Hz, 3H), 1.40-1.26 (m, 4H), 1.56-1.42 (m, 4H), 1.95-1.83 (m, 2H), 2.20-2.02(m, 2H), 2.95 (s, 3H), 3.17-3.05 (m, 6H), 3.60-3.50(m, 2H), 4.13 (m, 1H), 4.27 (s, 2H), 7.03(d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(3):
N-(4-{4-[(4-{butyl[(t-butylamino)carbonylJamino }-1- piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.65(ethyl acetate:methanol=5:1);
NMR (CD;OD): 6 0.95 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H), 1.40-1.25 (m, 2H), 1.58-1.44 (m, 2H), 1.92-1.83 (m, 2H), 2.10-1.97 (m, 2H), 2.95 (s, 3H), 3.15-3.02 (m, 4H), 3.58-3.50 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.30 (d,
J=9.0Hz 2H), 7.50 (d, ] = 8.7 Hz, 2H).
Example 23(4):
N-(4-{4-[(4-{butyl[(cyclohexylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.62(ethyl acetate:methanol=5:1);
NMR (CD;0D): 6 0.94 (t, J = 7.2 Hz, 3H), 1.95-1.10 (m, 18H), 2.20-2.02 (m, 2H), 2.95 (5s, 3H), 3.18-3.02 (m, 4H), 3.60-3.50 (m, 3H), 4.18 (m, 1H), 4.27 (s, 2H), 7.03 (d, ] = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
( IN
Example 23(5):
N-(4-{4-[(4-{benzyl[(butylamino)carbonyl]amino}-1- piperidinyl)methy!]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.71(ethyl acetate:methanol=5:1),
NMR (CD;OD): 8 0.84-0.95 (m, 3H), 1.14-1.50 (m, 4H), 1.86-2.09 (m, 4H), 2.95 (s, 3H), 3.01-3.12 (m, 2H), 3.13 (t, J = 6.9 Hz, 2H), 3.44-3.52 (m, 2H), 4.24 (s, 2H), 4.35 (m, 1H), 4.46 (s, 2H), 7.02 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.20-7.35 (m, 7H), 7.46 (d,
J =9.0 Hz, 2H).
Example 23(6):
N-(4-{4-[(4-{benzyl[(cyclohexylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.70(ethyl acetate:methanol=5:1);
NMR (CD;0D): § 1.02-1.40 (m, 6H), 1.52-2.08 (m, 8H), 2.95 (s, 3H), 3.02-3.13 (m, 2H), 3.44-3.60 (m, 3H), 4.22 (s, 2H), 4.39 (m, 1H), 4.43 (s, 2H), 7.02 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.20-7.36 (m, 7H), 7.46 (d, J = 9.0 Hz, 2H).
Example 23(7):
N-(4-{4-[(4-{benzyl[(ethylamino)carbonyl]amino }-1- piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.42(ethyl acetate. methanol=5:1);
NMR (CD;OD): § 1.02-1.13(m, 3H), 1.84-2.08 (m, 4H), 2.95 (s, 3H), 3.00-3.12 (m, 2H), 3.15-3.21(m, 2H), 3.42-3.52 (m, 2H), 4.23 (s, 2H), 4.32 (m, 1H), 4.46 (s, 2H), 7.01 (dJ= 9.0 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.20-7.34 (m, 7H), 7.46 (d, J] = 8.7 Hz, 2H).
Example 23(8):
N-{4-[4-({4-[[(cyclohexylamino)carbonyl](2-methoxyethyl)amino]-1- piperidinyl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC: Rf 0.55(ethyl acetate:methanol=5:1);
NMR (CD;OD): § 1.12-1.44 (m, 6H), 1.54-2.13 (m, 8H), 2.95 (s, 3H), 3.02-3.14 (m, 2H), 3.28-3.40 (m, 2H), 3.37 (5, 3H), 3.42-3.58 (m, SH), 4.13 (m, 1H), 4.27 (s, 2H), 7.03(d, J = 8.7 Hz, 2H), 7.0 6 (d, J= 8.7 Hz, 2H), 7.29 (d, } = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(9): 4-[({[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- ] piperidinylJamino}carbonyl)amino]benzoic acid hydrochloride
TLC:Rf 0.30(methylene chloride:methanol=5:1);
(I
NMR (CD;OD): 8 1.71-1.82 (m, 2H), 2.21-2.26 (m, 2H), 2.96 (s, 3H), 2.99-3.17 (m, 2H), 3.52-3.57 (m, 2H), 3.84 (m, 1H), 4.30 (s, 2H), 7.03-7.08 (m, 4H), 7.30 (d, J = 8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H).
Example 23(10):
N-[4-(4-{[4-(2,4-diox0-1,4-dihydro-3(2H)-quinazolinyl)-1- piperidinyl]methyl}phenoxy)phenyl]jmethanesulfonamide hydrochloride
TLC:Rf 0.62(ethyl acetate: methanol=5:1);
NMR (CD;0D): 6 1.93-1.97 (m, 2H), 2.95 (s, 3H), 2.96-3.30 (m, 4H), 3.55-3.59 (m, 2H), 4.31 (s, 2H), 5.19 (m, 1H), 7.04 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.13 (m, 1H), 7.22 (m, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.63 (m, 1H), 8.02 (m, 1H).
Example 23(11):
N-{4-[4-({4-[(anilinocarbonyl)(butyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl}methanesulfonamide hydrochloride
TLC:Rf 0.71(ethyl acetate:methanol=5:1);
NMR (CD;OD): § 0.97 (t, J = 7.5 Hz, 3H), 1.30-1.45 (m, 2H), 1.54-1.66 (m, 2H), 1.94- 2.04 (m, 2H), 2.14-2.32 (m, 2H), 2.95 (s, 3H), 3.05-3.18 (m, 2H), 3.24-3.34 (m, 2H), 3.51- 3.63 (m, 2H), 4.19 (m, 1H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.23-7.34 (m, 7H), 7.51 (d, J = 8.7 Hz, 2H).
Example 23(12):
N-[4-(4-{[4-(butyl {[(2-phenylethyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.75(ethyl acetate: methanol=5:1);
NMR (CD;OD): 6 0.90 (t, J = 7.2 Hz, 3H), 1.20-1.46 (m, 4H), 1.84-1.93 (m, 2H), 2.00- 2.18 (m, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.95 (s, 3H), 2.99-3.12 (m, 4H), 3.39 (t, J = 7.2 Hz, 2H), 3.48-3.57 (m, 2H), 4.06 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.13-7.27 (m, 5H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(13):
N-[4-(4-{[4-(butyl{[(4-fluorophenyl)amino]carbonyl}amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.78(ethyl acetate: methanol=5:1);
NMR (CD;OD): 8 0.97 (t, ] = 7.5 Hz, 3H), 1.33-1.44 (m, 2H), 1.55-1.66 (m, 2H), 1.94- _ 2.02 (m, 2H), 2.14-2.30 (m, 2H), 2.95 (s, 3H), 3.04-3.14 (m, 2H), 3.22-3.32 (m, 2H), 3.52- 3.62 (m, 2H), 4.17 (m, 1H), 4.29 (s, 2H), 6.97-7.08 (m, 6H), 7.27-7.33 (m, 4H), 7.50 (d, J = 8.7 Hz, ZH).
oO
Example 23(14):
N-[4-(4-{[4-(butyl {[(2,5-dimethylphenyl)amino]carbonyl}amino)-1- piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride TLC:Rf0.79(ethyl acetate:methanol=5:1);
NMR (CD;0D): 8 0.99 (t, J = 7.2 Hz, 3H), 1.34-1.48 (m, 2H), 1.60-1.71 (m, 2H), 1.95- 2.04 (m, 2H), 2.14-2.30 (m, 2H), 2.16 (s, 3H), 2.27 (s, 3H), 2.95 (s, 3H), 3.04-3.16 (m, 2H), 3.24-3.34 (m, 2H), 3.52-3.60 (m, 2H), 4.15(m, 1H), 4.28 (s, 2H), 6.91-7.10 (m, 7H), 7.29 (d, J =8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(15):
N-[4-(4-{[4-(benzyl {[(4-fluorophenyl)amino]carbonyl }amino)-1- piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.82(ethyl acetate:methanol=5:1);
NMR (CD;OD): § 1.94-2.20 (m, 4H), 2.95 (s, 3H), 3.02-3.14 (m, 2H), 3.44-3.55 (m, 2H), 4.25 (s, 2H), 4.36 (m, 1H), 4.64 (s, 2H), 6.97 (d, J = 8.7 Hz, 2H), 7.02 (d, J =8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.24-7.41 (m, 9H), 7.46 (d, J = 8.7 Hz, 2H).
Example 23(16): N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl} (2-methoxyethyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.50(ethyl acetate:methanol=5:1);
NMR (CD;0D): § 1.98-2.08 (m, 2H), 2.10-2.26 (m, 2H), 2.95 (s, 3H), 3.02-3.18 (m, 2H), 3.47 (s, 3H), 3.44-3.64 (m, 6H), 4.14 (m, 1H), 4.29 (s, 2H), 6.98-7.06 (m, 2H), 7.03 (d, J = 8.7 Hz 2H), 7.07 (d, J=8.7 Hz, 2H), 7.22-7.28 (m, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d,
J=8.7 Hz, 2H).
Example 23(17):
N-{4-[4-({4-[butyl({[3 -(methylsulfanyl)phenyl]amino }carbonyl)amino]-1- piperidinyl } methyl)phenoxy phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.73 (ethyl acetate: methanol=5: 1);
NMR (CD;OD): 5 0.98 (t, J = 7.2 Hz, 3H), 1.33-1.46 (m, 2H), 1.54-1.66 (m, 2H), 1.93 2.04 (m, 2H), 2.14-2.24 (m, 2H), 2.46 (s, 3H), 2.95 (s, 3H), 3.04-3.18 (m, 2H), 3.24-3.34 (m, 2H), 3.48-3.60 (m, 2H), 4.16 (m, 1H), 4.29 (s, 2H), 6.76 (m, 1H), 7.00-7.22 (m, 7H), 7.30(d, J =8.7Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
oO
Example 23(18):
N-{4-[4-({4-[benzyl({[3-(methylsulfanyl)phenyl]amino}carbonyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.76(ethyl acetate:methanol=5:1);
NMR (CD;0D): § 1.90-2.02 (m, 2H), 2.04-2.20 (m, 2H), 2.43 (s, 3H), 2.95 (s, 3H), 3.00- 3.15 (m, 2H), 3.42-3.54 (m, 2H), 4.23(s, 2H), 4.36 (m, 1H), 4.66 (s, 2H), 6.92 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 7.25-7.39 (m, 9H), 7.45 (d, J = 8.7 Hz, 2H).
Example 23(19):
N-[4-(4-{[4-(butyl{[(2-chloro-6-methylphenyl)amino]carbonyi}amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.77(ethyl acetate:methanol=5:1);
NMR (CD;0D): 6 0.98 (t, J = 7.2 Hz, 3H), 1.34-1.48 (m, 2H), 1.65-1.75 (m, 2H), 1.96- 2.06 (m, 2H), 2.16-2.32 (m, 2H), 2.26 (s, 3H), 2.95 (s, 3H), 3.04-3.16 (m, 2H), 3.26-3.34 (m, 2H), 3.51-3.60 (m, 2H), 4.16 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.14-7.21 (m, 2H), 7.28-7.31 (m, 3H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(20): N-(4-{4-[(4-{butyl[(mesitylamino)carbonyl]amino }piperidin-1- yl)methyl]phenoxy} phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.77(ethyl acetate:methanol=5:1);
NMR (CD;OD): 3 0.98 (t, J = 7.2 Hz, 3H), 1.34-1.46 (m, 2H), 1.61-1.73 (m, 2H), 1.94- 2.04 (m, 2H), 2.13-2.30 (m, 2H), 2.15 (s, 6H), 2.23 (s, 3H), 2.95 (s, 3H), 3.04-3.16 (m, 2H), 3.24-3.32 (m, 2H), 3.52-3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 6.87 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J =8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, ] = 8.7 Hz, 2H).
Example 23(21):
N-{4-[4-({4-[{[(3-acetylphenyl)amino]carbonyl }(butyl)amino]-1- piperidinyl }methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.79(ethyl acetate:methanol=5:1);
NMR (CDs;OD): 8 0.97 (t, J = 7.2 Hz, 3H), 1.33-1.45 (m, 2H), 1.55-1.68 (m, 2H), 1.96- 2.06 (m, 2H), 2.15-2.32 (m, 2H), 2.58 (s, 3H), 2.95 (s, 3H), 3.06-3.19 (m, 2H), 3.25-3.35 (m, 2H), 3.53-3.62 (m, 2H), 4.19 (m, 1H), 4.30 (s, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.07(d, J =8.7 Hz 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), y 7.62 (ddd, J = 8.0, 2.1, 1.2 Hz, 1H), 7.68 (ddd, J = 8.0, 1.5, 1.2 Hz, 1H), 8.00 (m, 1H).
oO
Example 23(22):
N-{4-[4-({4-[[(benzylamino)carbonyl](butyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.73(ethyl acetate:methanol=5:1);
NMR (CDs;OD): § 0.94 (t, J = 7.2 Hz, 3H), 1.26-1.40 (m, 2H), 1.47-1.60 (m, 2H), 1.87- 1.98 (m, 2H), 2.06-2.21 (m, 2H), 2.95 (s, 3H), 3.02-3.18 (m, 4H), 3.49-3.59 (m, 2H), 4.15 (m, 1H),4.27 (s, 2H) 4.36 (s, 2H), 7.03 (d, J =8.7 Hz, 2H), 7.06 (J = 8.7 Hz, 2H), 7.23-7.31 (m, 7TH), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(23):
N-{4-[4-({4-[[(1-adamantylamino)carbonyl](3-hydroxybutyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.66(ethyl acetate: methanol=5:1);
NMR (CD;OD): 6 1.18 (d, J = 6.3 Hz, 3H), 1.38-1.50 (m, 2H), 1.64-1.80 (m, 7H), 1.80- 1.94 (m, 2H), 1.95-2.12 (m, 10H), 2.95 (s, 3H), 3.00-3.54 (m, 4H), 3.48-3.57 (m, 2H), 3.74 (m, 1H), 4.12 (m, 1H), 4.27 (s, 2H), 7.03 (d, J] = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(24): N-[4-(4-{[4-(butyl{[(2-cyclohexylethyl)amino]carbonyl }amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.52(ethyl acetate:methanol=10:1);
NMR (CD;0D): 8 0.95 (t, J = 7.2 Hz, 3H), 0.85-1.02 (m, 2H), 1.13-1.58 (m, 10H), 1.61- 1.80 (m, SH), 1.83-1.95 (m, 2H), 2.03-2.19 (m, 2H), 2.95 (s, 3H), 3.02-3.13 (m, 6H), 3.48- 3.58 (m, 2H), 4.14 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J =8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(25):
N-[4-(4-{[4-({[(2-cyclohexylethyl)amino]}carbonyl } amino)-1- piperidinyl]Jmethyl}phenoxy)phenyllmethanesulfonamide hydrochloride
TLC:Rf 0.24(ethyl acetate:methanol=10:1);
NMR (CD;OD): & 0.85-1.00 (m, 2H), 1.10-1.40 (m, 7H), 1.60-1.78 (m, 6H), 2.08-2.20 (m, 2H), 2.95 (s, 3H), 3.02-3.18 (m, 4H), 3.45-3.55 (m, 2H), 3.72 (m, 1H), 4.27 (s, 2H), 7.03 (d,
J=8.7 Hz, 2H), 7.05 (d, ] = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H). -
Example 23(26):
N-{4-[4-({4-[{[(2-cyclohexylethyl)amino]carbonyl } (methyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl }methanesulfonamide hydrochloride
® O°
TLC:Rf 0.29(ethyl acetate:methanol=10:1);
NMR (CD;OD): & 0.84-1.00 (m, 2H), 1.15-1.44 (m, 7H), 1.60-1.78 (m, 6H), 1.97-2.13 (m, 2H), 2.74 (s, 3H), 2.95 (s, 3H), 3.03-3.20 (m, 4H), 3.51-3.60 (m, 2H), 4.28 (s, 2H),4.30(m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J =8.7Hz 2H).
Example 23(27):
N-{4-[4-({4-[{[(2-cyclohexylethyl)amino]carbonyl}(ethyl)amino]-1- piperidinyl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf0.57(ethyl acetate:methanol=10:1),
NMR (CD;0D): § 0.84-1.01 (m, 2H), 1.12 (t, ] = 6.9 Hz, 3H), 1.08-1.45 (m, 6H), 1.58- 1.80 (m, SH), 1.85-1.94 (m, 2H), 1.97-2.18 (m, 2H), 2.95 (s, 3H), 3.02-3.14 (m, 6H), 3.48- 3.59 (m, 2H), 4.20 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J] = 8.7 Hz, 2H).
Example 23(28):
N-{4-[4-({4-[{[(2-cyclohexylethyl)amino]carbony! }(propyl)amino]-1- piperidinyl}methyl)phenoxy]pheny!} methanesulfonamide hydrochloride
TLC:Rf 0.69(ethyl acetate: methanol=10:1),
NMR (CD;OD): 5 0.91 (t, J = 7.5 Hz, 3H), 0.82-1.00 (m, 2H), 1.15-1.40 (m, 6H), 1.42- 1.80 (m, 6H), 1.80-2.20 (m, SH), 2.95 (s, 3H), 2.98-3.22 (m, 6H), 3.42-3.58 (m, 2H), 4.12 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.30 (d, J =8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(29):
N-{4-[4-({4-[{[(2-cyclohexylethyl)amino]carbonyl} (2-methoxyethyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.64(ethyl acetate: methanol=10:1);
NMR (CD;0D): 8 0.85-1.00 (m, 2H), 1.08-1.40 (m, 6H), 1.60-1.80 (m, 5H), 1.87-2.18 (m, 4H), 2.95 (s, 3H), 3.02-3.18 (m, 2H), 3.15 (t, J = 6.2 Hz, 2H), 3.29-3.38 (m, 2H),3.36 (s, 3H), 3.45-3.57 (m, 4H), 4.08 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H).
Example 23(30): N-[4-(4-{[4-(benzyl{[(2-cyclohexylethyl)amino]carbonyl }amino)-1- - piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.73(ethyl acetate:methanol=10:1);
oOo
NMR (CD;OD): § 0.78-0.93 (m, 2H), 1.02-1.33 (m, 6H), 1.56-1.70 (m, SH), 1.85-2.03 (m, 4H), 2.95 (s, 3H), 2.98-3.20 (m, 4H), 3.42-3.53 (m, 2H), 4.23 (s, 2H), 4.36 (m, 1H), 4.45 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.15-7.38 (m, 7H), 7.45 (d, J = 8.7
Hz, 2H).
Example 23(31):
N-{4-[4-({4-[{[(2-cyclohexylethyl)amino]carbonyl}(cyclohexylmethyl)amino]-1- piperidinyl } methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.71(ethyl acetate:methanol=10:1);
NMR (CD;0OD): 6 0.83-1.12 (m, 4H), 1.15-1.41 (m, 10H), 1.52-1.80 (m, 10H), 1.87-1.95 (m, 2H), 2.18-2.30 (m, 2H), 2.95 (s, 3H), 3.02-3.14 (m, 4H), 3.17 (t, ] = 6.2 Hz, 2H), 3.48- 3.57 (m, 2H), 3.91 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(32):
N-[4-(4-{[4-(butyl {[(cyclohexylmethyl)amino]carbonyl}amino)-1- piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.69(ethyl acetate:methanol=10:1);
NMR (CDsOD): 8 0.95 (t, J = 7.2 Hz, 3H), 0.82-1.05 (m, 2H), 1.14-1.42 (m, SH), 1.43- 1.58 (m, 3H), 1.62-1.81 (m, SH), 1.85-1.98 (m, 2H), 1.99-2.22 (m, 2H), 2.95 (s, 3H), 2.99 (d, J = 6.9 Hz, 2H), 3 .02-3.17 (m, 4H), 3.48-3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 7.03 (d, J=8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(33):
N-[4-(4-{[4-({[(cyclohexylmethyl)amino]carbonyl }amino)-1- piperidinyl]Jmethyl}phenoxy)phenyljmethanesulfonamide hydrochloride
TLC Rf 0.48(ethyl acetate:methanol=10:1);
NMR (CD;0D): 6 0.83-1.02 (m, 2H), 1.12-1.33 (m, 4H), 1.58-1.80 (m, 6H), 2.03 (m, 1H), 2.09-2.11 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3.50-3.58 (m, 2H), 3.72 (m, 1H), 4.27 (s, 2H), 7.03 (d,J =8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H).
Example 23(34): N-{4-[4-({4-[{[(cyclohexylmethyl)amino]carbonyl}(methyl)amino]-1- : piperidinyl } methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.52(ethyl acetate:methanol=10:1);
® Oo
NMR (CD;0D): 8 0.81-1.00 (m, 2H), 1.13-1.32 (m, 4H), 1.48 (m, 1H), 1.60-1.90 (m, 6H), 1.93-2.12 (m, 2H), 2.75 (s, 3H), 2.95 (s, 3H), 2.98 (d, J = 6.9 Hz, 2H), 3.04-3.19 (m, 2H), 3.49-3.60 (m, 2H), 4.28 (s, 2H), 4.33 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(35):
N-{4-[4-({4-[{[(cyclohexylmethyl)amino]carbonyl }(ethyl)amino]-1- piperidinyl } methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.55(ethyl acetate:methanol=10:1);
NMR (CD;0D): 6 0.83-0.99 (m, 2H), 1.14 (t, J = 6.9 Hz, 3H), 1.08-1.32 (m, 2H), 1.47 (m, 1H), 1.60-1.79 (m, 6H), 1.86-1.95 (m, 2H), 2.00-2.17 (m, 2H), 2.95 (s, 3H), 2.98 (dd, J = 7.2, 2.0 Hz, 2H), 3.02-3.25 (m, 4H), 3.49-3.58 (m, 2H), 4.22 (m, 1H), 4.28 (s, 2H), 7.03 (d,
J=8.7Hz 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(36):
N-{4-[4-({4-[{[(cyclohexylmethyl)amino]carbonyl}(propyl)amino]-1- piperidinyl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.59(ethyl acetate:methanol=10:1),
NMR (CDs;OD): 6 0.91 (t, J = 7.2 Hz, 3H), 0.83-0.99 (m, 2H), 1.10-1.33 (m, 4H), 1.40- 1.80 (m, 7H), 1.85-1.96 (m, 2H), 2.02-2.20 (m, 2H), 2.95 (s, 3H), 2.98 (d, J = 7.2 Hz, 2H), 3.00-3.17 (m, 4H), 3 .50-3.58 (m, 2H), 4.14 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(37): N-{4-[4-({4-[{[(cyclohexylmethy])amino]carbonyl}(2-methoxyethyl)amino]-1- piperidinyl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.57(ethyl acetate: methanol=10:1),
NMR (CD;0D): 6 0.85-1.00 (m, 2H), 1.15-1.35 (m, 3H), 1.43 (m, 1H), 1.63-1.80 (m, SH), 1.88-2.18 (m, 4H), 2.95 (s, 3H), 2.95 (d, J = 6.6 Hz, 2H), 3.02-3.15 (m, 2H), 3.25-3.38 (m, 2H), 3.36 (s, 3H), 3.46-3.58 (m, 4H), 4.10 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J= 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, ] = 8.7 Hz, 2H).
Example 23(38):
N-[4-(4-{[4-(benzyl{[(cyclohexylmethyl)amino]carbonyl }amino)-1- piperidinyl]methyl}phenoxy)phenyljmethanesulfonamide hydrochloride -
TLC:Rf 070(ethyl acetate: methanol=10:1);
NMR (CD;0D): 6 0.72-0.85 (m, 2H), 1.08-1.40 (m, 4H), 1.50-1.79 (m, 5H), 1.90-2.08 (m, 4H), 2.95 (s, 3H), 2.96 (d, J = 6.9 Hz, 2H), 3.02-3.17 (m, 2H), 3.44-3.56 (m, 2H), 4.24 (s,
(IN 2H), 4.38 (m, 1H), 4.46 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.20- 7.38 (m, 7TH), 7.46 (d, J = 8.7 Hz, 2H).
Example 23(39): N-[4-(4-{[4-((cyclohexylmethyl){ [(cyclohexylmethyl)amino]carbonyl}amino)-1- piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.72(ethyl acetate:methanol=10:1);
NMR (CD3OD): & 0.82-1.05 (m, 4H), 1.13-1.35 (m, 6H), 1.46 (m, 1H), 1.60-1.85 (m, 11H), 1.87-1.98 (m, 2H), 2.15-2.31 (m, 2H), 2.95 (s, 3H), 2.98 (d, J = 6.6 Hz, 2H), 2.94-3.13 (m, 4H), 3.50-3.59 (m, 2H), 3.89 (m, 1H), 4.26 (s, 2H), 7.03 (d, J =8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H).
Example 23(40):
N-{4-[4-({4-[[(cyclohexylamino)carbonyl](ethyl)amino}-1- piperidinyl} methyl)phenoxy phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.44(ethyl acetate: methanol=10:1);
NMR (CD;OD): § 1.12 (t, J = 7.0 Hz, 3H), 1.07-1.43 (m, 5H), 1.59-1.96 (m, 7H), 1.97- 2.18 (m, 2H), 2.95 (s, 3H), 3.03-3.26 (m, 4H), 3.48-3.61 (m, 3H), 4.21 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.50 (d, J =8.7 Hz, 2H).
Example 23(41):
N-{4-[4-({4-[(anilinocarbonyl)(ethyl)amino]-1- piperidinyl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride TLC:Rf0.56(ethyl acetate:methanol=10:1);
NMR (CD;0D): § 1.23 (t, J = 7.0 Hz, 3H), 1.94-2.04 (m, 2H), 2.10-2.29 (m, 2H), 2.95 (s, 3H), 3.05-3.19 (m, 2H), 3.38 (q, J = 7.0 Hz, 2H), 3.52-3.61 (m, 2H), 4.25 (m, 1H), 4.30 (s, 2H), 7.04 (d,J] =8.7Hz 2H), 7.07(d, J =8.7 Hz, 2H), 7.24-7.38 (m, 7TH), 7.50 (d, J = 8.7
Hz, 2H).
Example 23(42):
N- {4-[4-({4-[[(benzylamino)carbonyl](ethyl)amino]- 1- piperidinyl} methyl)phenoxy]pheny!} methanesulfonamide hydrochloride
TLC Rf 0.52(ethyl acetate: methanol=10:1);
NMR (CDsOD): 8 1.16 (t, J = 7.0 Hz, 3H), 1.89-1.97 (m, 2H), 2.02-2.18 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 2H), 3.25 (q, J = 7.0 Hz, 2H), 3.50-3.58 (m, 2H), 4.21 (m, 1H), 4.28 (, 2H), 4.36 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.18-7.30 (m, 7H), 7.49 (d, J = 8.7 Hz, 2H).
(I
Example 23(43):
N-[4-(4-{[4-(ethyl{[(2-phenylethyl)amino]carbonyl }amino)-1- piperidinylJmethyl } phenoxy)phenyljmethanesulfonamide hydrochloride TLC:Rf0.67(ethyl acetate:methanol=10:1);
NMR (CD3;OD): § 1.06 (t, J = 7.0 Hz, 3H), 1.84-1.93 (m, 2H), 1.98-2.15 (m, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.95 (s, 3H), 3.01-3.20 (m, 4H), 3.38 (t, J = 7.5 Hz, 2H), 3.50-3.59 (m, 2H), 4.19 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.12-7.33 (m, 7H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(44):
N-(4-{4-[(4-{ethyl[(ethylamino)carbonyl]Jamino}-1- piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.20(ethy! acetate:methanol=10:1);
NMR (CDsOD): 8 1.09 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H), 1.85-1.95 (m, 2H), 1.98-2.18 (m, 2H), 2.95 (s, 3H), 3.03-3.24 (m, 6H), 3.50-3.59 (m, 2H), 4.21 (m, 1H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.50 (d,
J=28.7Hz, 2H).
Example 23(45):
N-{4-[4-({4-[[(t-butylamino)carbonyl](ethyl)amino]-1- piperidinyl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.41(ethyl acetate:methanol=10:1);
NMR (CD;OD): 5 1.13 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H), 1.82-1.93 (m, 2H), 1.95-2.11 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 2H), 3.18 (t, J = 7.2 Hz, 2H), 3.49-3.59 (m, 2H), 4.22 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(46): N-{4-[4-({4-[[(butylamino)carbonyl](ethyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.37(ethyl acetate: methanol=10:1);
NMR (CD;0D): 8 0.93 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H), 1.26-1.40 (m, 2H), 1.42-1.54 (m, 2H), 1.85-1.96 (m, 2H), 1.98-2.15 (m, 2H), 2.95 (s, 3H), 3.02-3.24 (m, 6H), 3.49-3.58 (m, 2H), 4 .21 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J =8.7 Hz, : 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
oO
Example 23(47):
N-{4-[4-({4-[[(cyclohexylamino)carbonyl](propyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.67(ethyl acetate:methanol=10:1),
NMR (CD;OD): 8 0.93 (t, J = 7.2 Hz, 3H), 1.13-1.41 (m, 5H), 1.48-1.67 (m, 3H), 1.71- 1.92 (m, 6H), 2.03-2.20 (m, 2H), 2.95 (s, 3H), 3.03-3.14 (m, 4H), 3.50-3.59 (m, 3H), 4.10 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, ] = 8.7 Hz, 2H), 7.29 (d, 1 = 8.7
Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(48):
N-{4-[4-({4-[(anilinocarbonyl)(propyl)amino]-1- piperidinyl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.73 (ethyl acetate:methanol=10:1);
NMR (CD;OD): § 0.96 (t, J = 7.2 Hz, 3H), 1.59-1.72 (m, 2H), 1.95-2.06 (m, 2H), 2.15- 2.31 (m, 2H), 2.95 (s, 3H), 3.05-3.18 (m, 2H), 3.22-3.32 (m, 2H), 3.52-3.61 (m, 2H), 4.18 (m, 1H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.23-7.37 (m, 7H), 7.50 (d, J =8.7 Hz, 2H).
Example 23(49): N-{4-[4-({4-[[(benzylamino)carbonyl](propyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC Rf 0.74(ethyl acetate:methanol=10:1);
NMR (CD;0D): 3 0.91 (t, J = 7.0 Hz, 3H), 1.50-1.66 (m, 2H), 1.87-1.98 (m, 2H), 2.04- 2.21 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3.49-3.58 (m, 2H), 4.14 (m, 1H), 4.27 (s, 2H), 4.36 (s, 2H), 7.0 3 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.15-7.32 (m, TH), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(50):
N-{4-[4-({4-[{[(2-phenylethyl)amino]carbonyl}(propyl)amino]-1- piperidinyl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.72(ethyl acetate:methanol=10:1);
NMR (CD;OD): 8 0.85 (t, J = 7.2 Hz, 3H), 1.38-1.51 (m, 2H), 1.84-1.93 (m, 2H), 2.00- 2.19 (m, 2H), 2.75-2.82 (m, 2H), 2.95 (s, 3H), 2.94-3.15 (m, 4H), 3.33-3.41 (m, 2H), 3.48- 3.58 (m, 2H), 4.11 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.13-7.31 (m, 7H), 7.49 (d, J = 8.7 Hz, 2H). ]
O°
Example 23(51):
N-{4-[4-({4-[[(ethylamino)carbonyl](propyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.56(ethyl acetate: methanol=10:1);
NMR (CD;OD): 8 0.91 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H), 1.46-1.60 (m, 2H), 1.86-1.95 (m, 2H), 2.03-2.19 (m, 2H), 2.95 (s, 3H), 3.00-3.22 (m, 6H), 3.50-3.59 (m, 2H), 4.13 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29(d, J = i 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(52):
N-{4-[4-({4-[[(t-butylamino)carbonyl](propyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.68(ethyl acetate:methanol=10:1);
NMR (CDsOD): 8 0.91 (t, J = 7.2 Hz, 3H), 1.32 (s, 9H), 1.47-1.61 (m, 2H), 1.84-194 (m, 2H), 1.95-2.11 (m, 2H), 2.95 (s, 3H), 3.01-3.15 (m, 4H), 3.50-3.57 (m, 2H), 4.16 (m, 1H), 4.28 (s, 2H), 7.0 3 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(53): N-{4-[4-({4-[[(butylamino)carbonyl](propyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.74(ethyl acetate:methanol=10:1);
NMR (CD;0D): & 091 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H), 1.27-1.39 (m, 2H), 1.41-1.59 (m, 4H), 1.85-1.96 (m, 2H), 2.03-2.20 (m, 2H), 2.95 (s, 3H), 3.02-3.22 (m, 6H), 3.50-3.58 (m, 2H), 4 .13 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J =8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(54):
N-(4-{4-[(4-{butyl[(pentylamino)carbonyl]Jamino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.69(ethyl acetate:methanol=10:1);
NMR (CD;0D): 8 0.91 (t, J = 7.2 Hz, 3H), 0.95 (t, ] = 7.2 Hz, 3H), 1.23-1.41 (m, 6H), 1.44-1.58 (m, 4H), 1.86-1.95 (m, 2H), 2.03-2.20 (m, 2H), 2.95 (s, 3H), 3.02-3.17 (m, 6H), 3.48-3.58 (m, 2H), 4.14 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J =8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H). :
O°
Example 23(55):
N-(4-{4-[(4-{benzyl[(pentylamino)carbonylJamino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.71(ethyl acetate:methanol=10:1);
NMR (CD;OD): & 0.86 (t, J = 7.2 Hz, 3H), 1.10-1.50 (m, 6H), 1.88-2.09 (m, 4H), 2.95 (s, 3H), 3.01-3.17 (m, 2H), 3.13 (t, J = 7.0 Hz, 2H), 3.44-3.52 (m, 2H), 4.24 (s, 2H), 4.35 (m, 1H), 4.46 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.20-7.36 (m, TH), 7.45 (d, J =8.7 Hz, 2H).
Example 23(56):
N-(4-{4-[(4-{(2-methoxyethyl)[(pentylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.29(ethyl acetate:methanol=10:1),
NMR (CD;OD): 8 0.91 (t, J = 7.0 Hz, 3H), 1.22-1.38 (m, 4H), 1.41-1.54 (m, 2H), 1.87- 2.19 (m, 4H), 2.95 (s, 3H), 3.02-3.16 (m, 2H), 3.11 (t, J = 7.0 Hz, 2H), 3.28-3.38 (m, 2H), 3.36 (s, 3H), 3.45- 3.58 (m, 4H), 4.10 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(57): N-(4-{4-[(4-{butyl[(isopropylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.65(ethyl acetate: methanol=10:1);
NMR (CD;OD): 8 0.91 (t, J = 7.2 Hz, 3H), 1.13 (d, J = 6.6 Hz, 6H), 1.28-1.40 (m, 2H), 1.43-1.57 (m, 2H), 1.85-1.96 (m, 2H), 2.02-2.19 (m, 2H), 2.95 (s, 3H), 3.03-3.15 (m, 4H), 3.48-3.58 (m, 2H), 3 .91 (m, 1H), 4.13 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J =8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(58):
N-(4-{4-[(4-{benzyl[(isopropylamino)carbonyl]Jamino}-1- piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.70(ethyl acetate: methanol=10:1);
NMR (CD;0D): 8 1.05 (d, J = 6.6 Hz, 6H), 1.86-2.10 (m, 4H), 2.95 (s, 3H), 3.02-3.15 (m, 2H), 3.44-3.53 (m, 2H), 3.91 (m, 1H), 4.24 (s, 2H), 4.35 (m, 1H), 4.47 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.0 4 (d, J = 8.7 Hz, 2H), 7.21-7.39 (m, 7H), 7.46 (d, J = 8.7 Hz, 2H).
Example 23(59):
N-{4-[4-({4-[[(butylamino)carbonyl](2-methoxyethyl)amino]-1- piperidinyl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride oO
TLC:Rf 0.33(ethyl acetate:methanol=10:1);
NMR (CDsOD): § 0.93 (t, J = 7.2 Hz, 3H), 1.26-1.51 (m, 4H), 1.87-1.98 (m, 2H), 2.00- 2.18 (m, 2H), 2.95 (s, 3H), 3.01-3.16 (m, 2H), 3.12 (t, J = 7.0 Hz, 2H), 3.28-3.37 (m, 2H), 3.36 (s, 3H), 3.45- 3.58 (m, 4H), 4.10 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d,J=87Hz 2H), 7.29 (d, J =8.7 Hz, 2H), 7.49 (d, J] = 8.7 Hz, 2H).
Example 23(60):
N-[4-(4-{[4-({[(2-methoxyphenyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf0.39(methylene chloride: methanol=10:1);
NMR (CD;0D): 8 1.66-1.73 (m, 2H), 2.22-2.26 (m, 2H), 2.95 (s, 3H), 3.08-3.17 (m, 2H), 3.51-3.55 (m, 2H), 3.80 (m, 1H), 3.86 (s, 3H), 4.29 (s, 2H), 6.86 (m, 1H), 6.94 (m, 2H), 7.04 (d, J =9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.49 (d,] = 9.0
Hz, 2H), 7.96 (m, 1H).
Example 23(61):
N-[4-(4-{[4-({[(3-methoxyphenyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.30(methylene chloride:methanol=10:1);
NMR (CD;OD): § 1.67-1.79 (m, 2H), 2.20-2.24 (m, 2H), 2.96 (s, 3H), 3.08-3.16 (m, 2H), 3.51-3.55 (m, 2H), 3.75 (s, 3H), 3.81 (m, 1H), 4.29 (5, 2H), 6.56 (m, 1H), 6.82 (m, 1H), 7.02-7.16 (m, 6H), 7.30 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H).
Example 23(62): N-[4-(4-{[4-({[(4-methoxyphenyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.25(methylene chloride:methanol=10:1);
NMR (ds-DMSO): 8 1.66-1.75 (m, 2H), 1.99-2.23 (m, 2H), 2.97 (s, 3H), 2.97-3.05 (m, 2H), 3.31-3.35 (m, 2H), 3.64 (m, 1H), 3.67 (s, 3H), 4.22 (d, J = 4.8 Hz, 2H), 6.38 (br-d, J] = 7.2
Hz 1H), 6.79 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 7.25 (d,
J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H), 8.24 (s, 1H), 9.70 (s, 1H).
Example 23(63): N-(4-{4-[(4-{[(cyclohexylamino)carbonyl]amino}-1- : piperidinyl)methyl]phenoxy} phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.25(ethyl acetate: methanol=10:1);
(I
NMR (CD;0D): § 1.06-1.41 (m, 5H), 1.53-1.88 (m, 6H), 2.01 (m, 1H), 2.09-2.18 (m, 2H), 2.95 (s, 3H), 3.02-3.12 (m, 2H), 3.40-3.55 (m, 3H), 3.72 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7Hz,2H), 705 (d,J=8.7Hz 2H), 7.29 (d, J=8.7 Hz, 2H), 7.49 (d, J] = 8.7 Hz, 2H).
Example 23(64):
N-{4-[4-({4-[(anilinocarbonyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.26(ethyl acetate:methanol=10:1);
NMR (CD;O0D): 8 1.64-1.89 (m, 2H), 2.10-2.25 (m, 2H), 2.95 (s, 3H), 3.03-3.25 (m, 2H), 3.36-3.57 (m, 2H), 3.85 (m, 1H), 4.29 (s, 2H), 6.97 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.20-7.38 (m, 6H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(65):
N-(4-{4-[(4-{butyl[(cyclopropylamino)carbonylJamino}-1- piperidinyl)methyl]jphenoxy }phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.46(ethyl acetate:methanol=10:1);
NMR (CD;OD): 8 0.42-0.50 (m, 2H), 0.62-0.71 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H), 1.23- 1.37 (m, 2H), 1.41-1.53 (m, 2H), 1.84-1.96 (m, 2H), 2.04-2.23 (m, 2H), 2.51 (m, 1H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3.49-3.59 (m, 2H), 4.09 (m, 1H), 4.28 (s, 2H), 7.03 (d, ] = 8.7
Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(66):
N-(4-{4-[(4-{butyl[(cyclobutylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide hydrochloride TLC:Rf0.58(ethyl acetate:methanol=10:1);
NMR (CD;OD): & 0.95 (t, J = 7.2 Hz, 3H), 1.26-1.41 (m, 2H), 1.44-1.56 (m, 2H), 1.60- 1.73 (m, 2H), 1.84-2.30 (m, 8H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3.48-3.59 (m, 2H), 4.10 (m, 1H), 4.20 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J=8.7Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(67):
N-(4-{4-[(4-{butyl[(cyclopentylamino)carbonylJamino}-1- piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.60(ethyl acetate: methanol=10:1);,
NMR (CD;0D): 6 0.94 (t, J] = 7.2 Hz, 3H), 1.25-1.76 (m, 10H), 1.85-1.98 (m, 4H), 2.02- 2.21 (m, 2H), 2.95 (s, 3H), 3.02-3.16 (m, 4H), 3.48-3.59 (m, 2H), 4.03 (m, 1H), 4.14 (m, 1H), 4.28 (s, 2H), 7.0 3 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
oO
Example 23(68):
N-(4-{4-[(4-{butyl[(tetrahydro-2H-pyran-4-ylamino)carbonylJamino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride TLC:Rf0.31(ethyl acetate:methanol=10:1);
NMR (CD;OD): & 0.95 (t, J = 7.2 Hz, 3H), 1.26-1.64 (m, 6H), 1.72-1.95 (m, 4H), 2.03- 2.21 (m, 2H), 2.95 (s, 3H), 3.02-3.17 (m, 4H), 3.38-3.59 (m, 4H), 3.78 (m, 1H), 3.86-3.96 (m, 2H), 4.13 (m, 1H), 4.28 (s, 2H), 7.03 (d, J =8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J =8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(69):
N-(4-{4-[(4- {butyl[(cycloheptylamino)carbonylJamino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.67(ethyl acetate:methanol=10:1);
NMR (CD;OD): § 0.94 (t, J = 7.2 Hz, 3H),1.26-1.72 (m, 14H), 1.78-1.94 (m, 4H), 2.03- 2.20 (m, 2H), 2.95 (s, 3H), 3.02-3.16 (m, 4H), 3.49-3.59 (m, 2H), 3.74 (m, 1H), 4.14 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(70):
N-{4-[4-({4-[(anilinocarbonyl)(pentyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.76(ethyl acetate: methanol=10:1);
NMR (CD;0D): 8 0.92 (t, J = 7.2 Hz, 3H), 1.28-1.44 (m, 4H), 1.55-1.69 (m, 2H), 1.93- 2.04 (m, 2H), 2.12-2.30 (m, 2H), 2.95 (s, 3H), 3.03-3.18 (m, 2H), 3.23-3.32 (m, 2H), 3.51- 3.60 (m, 2H), 4.19 (m, 1H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.22-7.35 (m, 5H), 7.41 (d, J=7.5 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(71):
N-{4-[4-({4-[[(cyclohexylamino)carbonyl](pentyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.78(ethyl acetate:methanol=10:1),
NMR (CD;OD): 5 0.91 (t, J = 7.2 Hz, 3H), 1.12-1.41 (m, 9H), 1.46-1.93 (m, SH), 2.02- 2.19 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3.48-3.60 (m, 3H), 4.13 (m, 1H), 4.28 (s, 2H), 7.03 (d,J=8.7Hz 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
oO
Example 23(72):
N-(4-{4-[(4-{allyl[(cyclohexylamino)carbonyl]Jamino }-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.74(ethyl acetate: methanol=10:1);
NMR (CD;OD): § 1.08-1.42 (m, 6H), 1.55-2.12 (m, 8H), 2.95 (s, 3H), 3.03-3.16 (m, 2H), 3.47-3.59 (m, 3H), 3.81 (d, J = 5.0 Hz, 2H), 4.27 (s, 2H), 4.32 (m, 1H), 5.18 (dd, J = 10.5, 1.5 Hz, 1H), 5.20 (dd J = 20.2, 1.5 Hz, 1H), 5.83 (ddd, J = 20.2, 10.5, 5.0 Hz, IH), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 87 Hz, 2H).
Example 23(73):
N-(4-{4-[(4-{2-butynyl[(cyclohexylamino)carbonyl]lamino }-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.75(ethyl acetate:methanol=10:1);
NMR (CD;OD): 8 1.15-1.43 (m, 5H), 1.77 (t, J = 2.4 Hz, 3H), 1.58-2.00 (m, 7H), 2.05- 2.20 (m, 2H), 2.95 (s, 3H), 3.03-3.18 (m, 2H), 3.50-3.62 (m, 3H), 3.92 (d, J = 2.4 Hz, 2H), 4.23 (m, 1H), 4.28 (s, 2H), 7.03 (d, J] = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 d,J= 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(74):
N-(4-{4-[(4-{butyl[(propylamino)carbonyl]Jamino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.71(ethyl acetate:methanol=10:1);
NMR (CD;OD): 5 0.89 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H), 1.26-1.41 (m, 2H), 1.45-1.58 (m, 4H), 1.85-1.95 (m, 2H), 2.04-2.22 (m, 2H), 2.95 (s, 3H), 3.03-3.16 (m, 6H), 3.48-3.59 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(75): N-(4-{4-[(4-{pentyl[(propylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.73(ethyl acetate:methanol=10:1);
NMR (CD;OD): § 0.89 (t, J = 7.2 Hz, 3H), 0.92 (t, J] = 7.0 Hz, 3H), 1.23-1.40 (m, 4H), 1.44-1.59 (m, 4H), 1.85-1.95 (m, 2H), 2.03-2.21 (m, 2H), 2.95 (s, 3H), 3.04-3.15 (m, 6H), 3.49-3.58 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, : 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
oo °
Example 23(76):
N-{4-[4-({4-[[(butylamino)carbonyl]}(pentyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.75(ethyl acetate: methanol=10:1);
NMR (CD:0D): § 0.91 (d, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H), 1.24-1.41 (m, 6H), 1.43-1.59 (m, 4H), 1.85-1.96 (m, 2H), 2.03-2.21 (m, 2H), 2.95 (s, 3H), 3.03-3.20 (m, 6H), 3.49-3.58 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(77):
N-{4-[4-({4-[[(butylamino)carbonyl](cyclohexylmethyl)amino]-1- piperidinyl} methyl)phenoxy]pheny!} methanesulfonamide hydrochloride
TLC:Rf 0.74(ethyl acetate: methanol=10:1);
NMR (CD;0D): 8 0.92 (t, J = 7.2 Hz, 3H), 0.83-1.00 (m, 2H), 1.15-1.80 (m, 13H), 1.87- 1.98 (m, 2H), 2.13-2.32 (m, 2H), 2.95 (s, 3H), 3.00-3.17 (m, 6H), 3.48-3.57 (m, 2H), 3.89 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] =8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(78): N-(4-{4-[(4-{butyl[(hexylamino)carbonyl]Jamino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.72(ethyl acetate: methanol=10:1);
NMR (CD;OD): 8 0.89 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H), 1.22-1.39 (m, 8H), 1.41-1.56 (m, 4H), 1.85-1.94 (m, 2H), 2.03-2.21 (m, 2H), 2.95 (s, 3H), 3.02-3.19 (m, 6H), 3.49-3.58 (m, 2H), 4 .15 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, ] =8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J] = 8.7 Hz, 2H).
Example 23(79):
N-(4-{4-[(4-{pentyl[(pentylamino)carbonyl]Jamino }-1- piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.71(ethyl acetate:methanol=10:1);
NMR (CDs;OD): 4 0.90 (t, J = 7.2 Hz, 3H), 0.92 (t, J] = 7.2 Hz, 3H), 1.23-1.40 (m, 8H), 1.44-1.60 (m, 4H), 1.86-1.95 (m, 2H), 2.03-2.20 (m, 2H), 2.95 (s, 3H), 3.02-3.20 (m, 6H), 3.49-3.58 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
oO
Example 23(80):
N-(4-{4-[(4- {benzyl[(t-butylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy} phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.69(ethy! acetate: methanol=10:1);
NMR (CD;OD): 6 1.18 (s, 9H), 1.90-2.09 (m, 4H), 2.95 (s, 3H), 3.05-3.17 (m, 2H), 3.47- 3.56 (m, 2H), 4.26 (s, 2H), 4.42 (s, 2H), 4.45 (m, 1H), 7.02 (d, J=8.7Hz, 2H), 7.05(d, J = 8.7 Hz, 2H), 7.2 3-7.39 (m, 7H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(81): N-[4-(4-{[4-({[(2-hydroxyphenyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.53(methylene chloride:methanol=10:1);
NMR (CD;O0D): 8 1.65-1.77 (m, 2H), 2.20-2.25 (m, 2H), 2.95 (s, 3H), 3.07-3.15 (m, 2H), 3.50-3.55 (m, 2H), 3.81 (m, 1H), 4.29 (s, 2H), 6.72-6.85 (m, 3H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J=8.7Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.69 (m, 1H).
Example 23(82):
N-[4-(4-{[(3aR,6aS)-5- {butyl[(cyclohexylamino)carbonyl]amino } hexahydrocyclopenta[c]pyrrol-2(1H)- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
H N..° ¢ NTO
CL BQ 5 0 °c
N N H
HoT + HCI
TLC:Rf 0.50(chloroform:methanol=5:1);
NMR (CD;OD): & 0.88-1.00 (m, 3H), 1.14-1.84 (m, 16H), 2.00-2.22 (m, 2H), 2.70-3.79 (m, 9H), 2.95 (s, 3H), 4.08 (m, 1H), 4.35 (m, 2H), 7.00-7.10 (m, 4H), 7.22-7.34 (m, 2H), 7.45- 7.58 (m, 2H).
Example 23(83):
N-[4-(4-{[4-(butyl{[(2-methoxyethyl)amino]carbonyl }amino)-1- piperidinyl]Jmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride :
TLC:Rf0.27(ethyl acetate:methanol=10:1);
NMR (CDs;OD): 6 0.95 (t, J = 7.2 Hz, 3H), 1.27-1.41 (m, 2H), 1.45-1.59 (m, 2H), 1.87- 1.97 (m, 2H), 2.03-2.20 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3.33 (s, 3H), 3.32-3.36
(I (m, 2H), 3.40-3.47 (m, 2H), 3.51-3.58 (m, 2H), 4.14 (m, 1H), 4,28 (s, 2H), 7.03 (d, J = 8.7
Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(84): N-[4-(4-{[4-(butyl{[(4-hydroxyphenyl)amino]carbonyl }amino)-1- piperidinyljmethyl} phenoxy)phenylJmethanesulfonamide hydrochloride
TLC:Rf 0.64(chloroform:methanol=5:1);
NMR (CD;O0D): & 0.97 (t, J = 7.5 Hz, 3H), 1.39 (m, 2H), 1.62 (m, 2H), 1.92 (m, 2H), 2.22 (m, 2H), 2.95 (s, 3H), 3.18 (m, 2H), 3.25 (m, 2H), 3.52 (m, 2H), 4.14 (m, 1H), 4.27 (s, 2H), 6.68-6.78 (m, 2H), 7.00-7.10 ( m, 6H), 7.24-7.34 (m, 2H), 7.49 (brd, J = 8.4 Hz, 2H).
Example 23(85):
N-[4-(4-{[4-(butyl{[(3-hydroxyphenyl)amino]carbonyl }amino)-1- piperidinyl]methy!} phenoxy)phenyl]methanesulfonamide hydrochloride TLC:Rf 0.64(chloroform:methanol=5:1);
NMR (CD;OD): § 0.96 (t, J = 7.5 Hz, 3H), 1.39 (m, 2H), 1.60 (m, 2H), 1.98 (m, 2H), 2.21 (m, 2H), 2.95 (s, 3H), 3.11 (m, 2H), 3.28 (m, 2H), 3.58 (m, 2H), 4.18 (m, 1H), 4.28 (s, 2H), 6.48 (m, 1H), 6.78 (m, 1H), 6.8 4 (m, 1H), 7.0 0-7.12 (m, 5H), 7.22-7.40 (m, 2H), 7.50 (brd, J = 8.7 Hz, 2H).
Example 23(86):
N-[4-(4-{[4-({[(4-hydroxyphenyl)amino]carbonyl } amino)-1- piperidinyl]methyl}phenoxy)phenyl}methanesulfonamide hydrochloride
TLC:Rf 0.44(chloroform:methanol=5:1);
NMR (CD:;0D): 8 1.70 (m, 2H), 2.19 (m, 2H), 2.95 (s, 3H), 3.08 (m, 2H), 3.48 (m, 2H), 3.78 (m, 1H), 4.25 (s, 2H), 6.62-6.78 (m, 2H), 7.00-7.36 (m, 8H), 7.47 (brd, J = 8.4 Hz, 2H).
Example 23(87):
N-[4-(4-{[4-({[(3-hydroxyphenyl)amino]carbonyl} amino)-1- piperidinyl]methyl }phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.51(chloroform:methanol=5:1);
NMR (CD;O0D): § 1.52 (m, 2H), 1.95 (m, 2H), 2.24 (m, 2H), 2.89 (m, 2H), 2.93 (s, 3H), 3.56 (s, 2H), 3.60 (m, 1H), 6.39 (m, 1H), 6.71 (m, 1H), 6.90-7.08 (m, SH), 7.18-7.38 (m,
SH).
oO
Example 23(88):
N-[4-(4-{[4-(butyl {[(4-methoxyphenyl)amino]carbonyl } amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.71(chloroform:methanol=5:1);,
NMR (CD;OD): § 0.96 (t, J = 7.2 Hz, 3H), 1.26-1.44 (m, 2H), 1.52-1.80 (m, 6H), 2.28 (m, 2H), 2.93 (s, 3H), 3.02 (m, 2H), 3.22 (m, 2H), 3.54 (s, 2H), 3.75 (s, 3H), 4.04 (m, 1H), 6.80-6.88 (m, 2H), 6.90-7.02 (m, 4H), 7.18-7.38 (m, 6H).
Example 23(89): N-{4-[4-({4-[butyl({[4-(trifluoromethyl)phenylJamino}carbonyl)amino}-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.78(chloroform:methanol=5:1};
NMR (CDsOD): § 0.97 (t, J = 7.5 Hz, 3H), 1.32-1.50 (m, 2H), 1.53-1.68 (m, 2H), 1.94- 2.06 (m, 2H), 2.08-2.34 (m, 2H), 2.95 (s, 3H), 3.12 (m, 2H), 3.32 (m, 2H), 3.58 (m, 2H), 4.18 (m, 1H), 4.30 (s, 2H), 7.00-7.12 ( m, 4H), 7.22-7 .38 (m, 2H), 7.42-7.60 (m, 6H).
Example 23(90):
N-{4-[4-({4-[(aminocarbonyl)(butyl)amino]-1- piperidinyl } methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf0.15(ethyl acetate:methanol=10:1);
NMR (CDs;OD): 8 0.95 (t, J = 7.2 Hz, 3H), 1.27-1.42 (m, 2H), 1.50-1.63 (m, 2H), 1.81- 2.02 (m, 2H), 2.11-2.30 (m, 2H), 2.95 (s, 3H), 3.05-3.21 (m, 4H), 3.51-3.60 (m, 2H), 4.13 (m, 1H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H).
Example 23(91):
N-[4-(4-{[4-(buty]{[(4-hydroxycyclohexyl)amino]carbonyl }amino)-1- piperidinyljmethy!} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC Rf 0.19(ethyl acetate: methanol=10:1);
NMR (CD;OD): § 0.95 (t, J = 7.2 Hz, 3H), 1.27-1.41 (m, 2H), 1.45-1.79 (m, 10H), 1.86- 1.95 (m, 2H), 2.03-2.22 (m, 2H), 2.95 (s, 3H), 3.02-3.17 (m, 4H), 3.48-3.65 (m, 3H), 3.87 (m, 1H), 4.15 (m, 1H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 He, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(92):
N-[4-(4-{[4-(butyl{[(2-fluorophenyl)amino]carbonyl }amino)-1- piperidinyl]methyl }phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.73 (ethyl acetate:methanol=10:1);
oO
NMR (CD;OD): 8 0.98 (t, J = 7.2 Hz, 3H), 1.32-1.48 (m, 2H), 1.58-1.72 (m, 2H), 1.95- 2.06 (m, 2H), 2.14-2.33 (m, 2H), 2.95 (s, 3H), 3.03-3.18 (m, 2H), 3.25-3.35 (m, 2H), 3.52- 3.61 (m, 2H), 4.17 (m, 1H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.10-7.18 (m, 3H), 7.29 (d, J = 8.7 Hz, 2H), 7.45 (dt, J = 2.4, 72 Hz, 1H), 7.51 (d,T = 8.7
Hz, 2H).
Example 23(93):
N-[4-(4-{[4-(butyl {[(3-fluorophenyl)amino]carbonyl}amino)-1- piperidinyl]methyl }phenoxy)phenyl]methanesulfonamide hydrochloride TLC:Rf0.73(ethyl acetate:methanol=10:1),
NMR (CD;0D): 8 0.97 (t, J = 7.2 He, 3H), 1.33-1.46 (m, 2H), 1.54-1.67 (m, 2H), 1.93- 2.06 (m, 2H), 2.15-2.32 (m, 2H), 2.95 (s, 3H), 3.05-3.18 (m, 2H), 3.26-3.35 (m, 2H), 3.52- 3.62 (m, 2H), 4.18 (m, 1H), 4.29 (s, 2H), 6.74 (dt, J = 2.4, 8.1 Hz, 1H), 7.04 (d, ] =8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 4.0 Hz, 1H), 7.20-7.31 (m, 2H), 7.29 (d, J = 8.7
Hz, 2H), 7.51 (d, J=8.7 Hz, 2H).
Example 23(94):
N-(4-{4-[(4-{butyl[(4-pyridinylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy} phenyl)methanesulfonamide dihydrochloride
TLC:Rf0.53(chloroform:methanol=10:1);
NMR (CDsOD): 8 0.96 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.00- 2.10 (m, 2H), 2.30-2.40 (m, 2H), 2.95 (s, 3H), 3.10-3.30 (m, 2H), 3.40-3.50 (m, 2H), 3.50- 3.60 (m, 2H), 4.30 (m, 1H), 4.31 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 7.5 Hz, 2H), 8.47 (d, J = 7.5 Hz, 2H).
Example 23(95):
N-(4-{4-[(4-{butyl[(3-pyridinylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.50(chloroform: methanol=10:1);
NMR (CD;OD): § 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.00- 2.10 (m, 2H), 2.30-2.40 (m, 2H), 2.95 (s, 3H), 3.10-3.30 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.70 (m, 2H), 4.30 (m, 1H), 4.31 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 9.0 Hz, 2H), 7.53 (d, J =9.0 Hz, 2H), 7.95 (dd, J = 8.5, 2.4 Hz, 1H), 8.43 (d, J=85Hz, 1H), 8.61 (d,J=8.5
Hz, 1H), 9.20 (d, J = 2.4 Hz, 1H).
Example 23(96): 2-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinylJamino} carbonyl)amino]benzoic acid hydrochloride oO
TLC:Rf 0.36(methylene chloride: methanol=9:1);
NMR (CD;OD): § 0.97 (t, J = 7.5 Hz, 3H), 1.35-1.51 (m, 2H), 1.60-1.72 (m, 2H), 1.92- 2.04 (m, 2H), 2.16-2.35 (m, 2H), 2.95 (s, 3H), 3.08-3.11 (m, 2H), 3.23-3.35 (m, 2H), 3.52- 3.63 (m, 2H), 4.22-4.36 (m, 3H), 7.02 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d,
J=87Hz 2H), 7.29 (d,] =8.7Hz, 2H), 7.49 (dt, J = 1.8, 7.8 Hz, 1H), 7.54 (d, ] =8.7 Hz, 2H), 8.05(dd, J=7.8,18Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H).
Example 23(97): 3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinylJamino }carbonyl)amino]}benzoic acid hydrochloride
TLC:Rf 0.30(methylene chloride: methanol=9:1);
NMR (CD;OD): 0.95 (t, J] = 7.5 Hz, 3H), 1.30-1.44 (m, 2H), 1.53-1.64 (m, 2H), 1.90- 2.03 (m, 2H), 2.20-2.38 (m, 2H), 2.95 (s, 3H), 3.05-3.19 (m, 2H), 3.25-3.36 (m, 2H), 3.49- 3.59 (m, 2H), 4.23 (m, 1H), 4.29 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.60 (ddd, J = 7.8,2.4, 1.8 Hz, 1H), 7.69 (dt, J= 7.8, 2.4 Hz, 1H), 8.04 (t, J = 1.8 Hz, 1H).
Example 23(98): 4-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]amino }carbonyl)amino]benzoic acid hydrochloride
TLC:Rf 0.34(methylene chloride: methanol=9:1),
NMR (CD;OD): 8 0.97 (t, J = 7.2 Hz, 3H), 1.33-1.46 (m, 2H), 1.54-1.66 (m, 2H), 1.94- 2.05 (m, 2H), 2.20-2.38 (m, 2H), 2.95 (s, 3H), 3.06-3.20 (m, 2H), 3.25-3.37 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.03 (d, J] = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29(d,J=8.7Hz 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 8.5
Hz, 2H).
Example 23(99): [({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]Jamino }carbonyl)amino]acetic acid hydrochloride
TLC:Rf 0.41(methylene chloride: methanol=4:1);
NMR (CD;0D): 6 0.94 (t, J = 7.2 Hz, 3H), 1.27-1.41 (m, 2H), 1.48-1.62 (m, 2H), 1.84- 1.95 (m, 2H), 2.08-2.26 (m, 2H), 2.95 (s, 3H), 2.98-3.18 (m, 4H), 3.44-3.53 (m, 2H), 3.80 (s, 2H), 4.15 (m, 1H), 4.25 (s, 2H), 7.02 (d, J] = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H). -
oO
Example 23(100):
N-{4-[4-({4-[[(cyclohexylamino)carbonyl](3-hydroxypropyl)amino]-1- piperidinyl } methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.43(methylene chloride: methanol=10:1);
NMR (CD;OD): § 1.10-1.50 (m, 6H), 1.60-1.80 (m, 4H), 1.80-2.00 (m, 4H), 2.00-2.20 (m, 2H), 2.95 (s, 3H), 3.00-3.15 (m, 2H), 3.20-3.30 (m, 2H), 3.40-3.70 (m, SH), 4.10 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H).
Example 23(101):
N-{4-[4-({4-[[(cyclohexylamino)carbonyl}(4-hydroxybutyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.42(methylene chloride: methanol=10:1);
NMR (CDsOD): § 1.10-1.40 (m, 6H), 1.40-1.70 (m, 5H), 1.70-2.00 (m, 6H), 2.00-2.20 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 4H), 3.50-3.60 (m, 2H), 3.59 (t, J = 6.0 Hz, 2H), 4.10 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H).
Example 23(102): N-{4-[4-({4-[[(cyclohexylamino)carbonyl]}(3-hydroxybutyl)amino]-1- piperidinyl}methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.43(methylene chloride:methanol=10:1);
NMR (CD3OD): 6 1.10-1.50 (m, 6H), 1.17 (d, J = 6.3 Hz, 3H), 1.70-2.00 (m, 9H), 2.00- 2.20 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 4H), 3.50-3.60 (m, 2H), 3.70 (m, 1H), 4.10 (m, 1H), 4.27 (s, 2H), 7.02-7.07 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H).
Example 23(103):
N-{4-[4-({ 4-[[(cyclohexylamino)carbonyl](2-hydroxybutyl)amino]-1- piperidinyl }methyl)phenoxy phenyl} methanesulfonamide hydrochloride
TLC:Rf0.44(methylene chloride: methanol=10:1);
NMR (CD3OD): § 0.97 (t, J = 7.4 Hz, 3H), 1.10-2.20 (m, 16H), 2.99 (s, 3H), 3.10-3.20 (m, 4H), 3.40-3.60 (m, 4H), 4.10 (m, 1H), 4.27 (s, 2H), 7.01-7.08 (m, 4H), 7.28-7.31 (m, 2H), 7.48 (d, J = 8.7 Hz, 2H).
Example 23(104): 4-[({butyl[1 ~(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinylJamino }carbonyl)amino]butanoic acid hydrochloride
TLC:Rf 0.73(methylene chloride: methanol=4:1),
® O°
NMR (CDsOD): § 0.95 (t, J = 7.5 Hz, 3H), 1.28-1.41 (m, 2H), 1.44-1.59 (m, 2H), 1.74 1.85 (m, 2H), 1.87-1.97 (m, 2H), 2.03-2.20 (m, 2H), 2.31 (t, J = 6.9 Hz, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3 .20 (t, J] = 6.9 Hz, 2H), 3.50-3.58 (m, 2H), 4.13 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.50(d, ] = 8.7
Hz 2H).
Example 23(105):
N-[4-(4-{[4-(butyl{[(4-chlorophenyl)amino]carbonyl}amino)-1- piperidinyl]methyl} phenoxy)phenyl]lmethanesulfonamide hydrochloride
TLC:Rf0.53(chloroform:methanol=10:1);
NMR (CD;0OD): 6 0.96 (t, J] = 7.2 Hz, 3H), 1.30-1.40 (m, 2H), 1.55-1.60 (m, 2H), 1.95- 2.00 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.01-7.08 (m, 4H), 7.23-7.40 (m, 6H), 7.51 (d, J = 8.4 Hz, 2H).
Example 23(106):
N-[4-(4-{[4-(butyl{[(3-chlorophenyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.53(chloroform:methanol=10:1);
NMR (CDsOD): 6 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.55-1.65 (m, 2H), 1.95- 2.05 (m, 2H), 2.20-2.30 (m, 2H), 2.96 (s, 3H), 3.10-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 7.00-7.09 (m, SH), 7.23-7.31 (m, 4H), 7.48-7.51 (m, 3H).
Example 23(107):
N-[4-(4-{[4-(butyl{[(2-chlorophenyl)amino]carbonyl}amino)-1- piperidinyl]Jmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.53(chloroform:methanol=10:1);
NMR (CD;OD): 8 0.99 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 2.00- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.10 (m, 4H), 7.14 (dd, J = 7.5, 1.5 Hz, 1H), 7.27-7.31 (m, 3H), 7.42 (dd, J = 7.5, 1.5 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 7.5, 1.5 Hz, 1H).
Example 23(108):
N-[4-(4-{[4-(buty]{[(4-methylphenyl)amino]carbonyl}amino)-1- piperidinylJmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.53(chloroform:methanol=10:1);
(I
NMR (CD;0D): 6 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.55-1.65 (m, 2H), 1.95- 2.05 (m, 2H), 2.20-2.30 (m, 2H), 2.28 (s, 3H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.20-3.30 (m, 2H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.10 (m, 6H), 7.19 (d, J = 8.4
Hz, 2H), 7.29 (d, J =9.0 Hz, 2H), 7.50 (d, ] = 9.0 Hz, 2H).
Example 23(109):
N-[4-(4-{[4-(butyl {[(3-methylphenyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]Jmethanesulfonamide hydrochloride
TLC:Rf 0.59(chloroform:methanol=10:1);
NMR (CD;0D): & 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.30 (s, 3H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.10 (m, 1H), 4.29 (s, 2H), 6.87 (d, J = 6.6 Hz, 1H), 7.01-7.15 (m, 7H), 7.29 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H).
Example 23(110):
N-[4-(4-{[4-(butyl{[(2-methylphenyl)amino]carbonyl }amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.50(chloroform:methanol=10:1);
NMR (CD;OD): 6 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.22 (s, 3H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.14 (m, 1H), 4.28 (s, 2H), 7.02-7.15 (m, 7H), 7.19 (m, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(111): N-[4-(4-{[4-(butyl{[(3-methoxyphenyl)amino]carbonyl}amino)-1- piperidinyl]Jmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.53(chloroform:methanol=10:1),
NMR (CD;0D): § 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 3.76 (s, 3H), 4.15 (m, 1H), 4.29 (s, 2H), 6.63 (m, 1H), 6.91 (m, 1H), 7.01- 7.08 (m, SH), 7.16 (m, 1H), 7.29 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H).
Example 23(112):
N-[4-(4-{[4-(butyl{ [(2-methoxyphenyl)amino]carbonyl}amino)-1- piperidinylJmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.55(chloroform:methanol=10:1);
NMR (CDs;OD): & 1.02 (t, J = 7.4 Hz, 3H), 1.40-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50-
oO 3.60 (m, 2H), 3.87 (s, 3H), 4.26 (m, 1H), 4.29 (s, 2H), 6.89 (m, 1H), 6.99-7.08 (m, 6H), 7.29 (d, J =8.7 Hz, 2H), 7.51 (d, J= 8.7 Hz, 2H), 7.76 (dd, ] = 7.8, 1.5 Hz, 1H).
Example 23(113): N-{4-[4-({4-[butyl({[3-(trifluoromethyl)phenyl]amino } carbonyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.55(chloroform:methanol=10:1),
NMR (CD;0D): 6 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 7.27-7.31 (m, 3H), 7.45 (m, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H).
Example 23(114):
N-[4-(4-{[4-({ [(4-hydroxycyclohexyl)amino]carbonyl }amino)-1- piperidinyljmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.19(ethyl acetate:methanol=5:1);
NMR (CD;0D): 8 1.52-1.72 (m, 9H), 2.01 (m, 1H), 2.10-2.21 (m, 2H), 2.95 (s, 3H), 3.02- 3.14 (m, 2H), 3.47-3.62 (m, 3H), 3.72 (m, 1H), 3.78 (m, 1H), 4.27 (s, 2H), 7.03 (d, ] = 8.7
Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8. 7 Hz, 2H).
Example 23(115): 2-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4- piperidinyl]amino } carbonyl)amino]-4-methylpentanoic acid hydrochloride
TLC:Rf 0.39(methylene chloride: methanol=4:1),
NMR (CD;OD): 4 0.93 (d, J = 6.0 Hz, 6H), 0.95 (t, J = 7.5 Hz, 3H), 1.28-1.42 (m, 2H), 1.48-1.79 (m, 5H), 1.82-1.95 (m, 2H), 1.97-2.19 (m, 2H), 2.95 (s, 3H), 2.90-3.05 (m, 2H), 3.08-3.25 (m, 2H), 3 .42-3.52 (m, 2H), 4.13 (m, 1H), 4.19 (s, 2H), 4.32 (dd, J = 9.0, 6.0 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H).
Example 23(116):
N-{3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)-4- piperidinyl]amino }carbonyl)amino]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.32(chloroform:methanol=10:1);
NMR (CD;OD): & 0.96 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 2.96 (s, 3H), 3.05-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.23 (m, 1H), 4.29 (s, 2H), 6.90 (m, 1H), 6.99-7.08 (m, 4H),
oO 7.11 (m, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.29 (d, J] = 9.0 Hz, 2H), 7.38 (t, J] = 2.1 Hz, 1H), 7.53 (d, J =9.0 Hz, 2H).
Example 23(117):
N-{4-[({buty][1-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)-4- piperidinyl]Jamino}carbonyl)amino]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.50(methylene chloride:methanol=10:1);
NMR (CDsOD): 8 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.90 (s, 3H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 7.18 (t, J = 9.0
Hz, 2H), 7.28-7.33 (m, 4H), 7.55 (d, J = 9.0 Hz, 2H).
Example 23(118):
N-[4-(4-{[4-(butyl{[(3-hydroxypropyl)amino]carbonyl }amino)-1- piperidinylJmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.70(methylene chloride: methanol=4:1);
NMR (CD;OD): § 0.95 (t, J = 7.2 Hz, 3H), 1.26-1.41 (m, 2H), 1.45-1.58 (m, 2H), 1.65- 1.77 (m, 2H), 1.86-1.97 (m, 2H), 2.03-2.22 (m, 2H), 2.95 (s, 3H), 3.03-3.15 (m, 4H), 3.27 (t, J = 6.3 Hz, 2H), 3 .59 (t, J = 6.3 Hz, 2H),3.50-3.65 (m, 2H), 4.14 (m, 1H), 4.25 (s, 2H), 7.03 (d,J=8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.50 (d, J = 8.7
Hz, 2H).
Example 23(119):
N-[4-(4-{[4-({[(3-hydroxypropyl)amino]carbonyl } amino)-1- piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.32(methylene chloride:methanol=4:1);
NMR (CD;0D): § 1.60-1.84 (m, 3H), 2.02 (m, 1H), 2.09-2.20 (m, 2H), 2.95 (s, 3H), 3.02- 3.15 (m, 2H), 3.20 (t, J = 6.5 Hz, 2H), 3.45-3.61 (m, 2H), 3.57 (t, J = 6.5 Hz, 2H), 3.72 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J =8.7 Hz, 2H).
Example 23(120):
N-(4-{4-[(4-{butyl[(3-thienylamino)carbonylJamino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf0.31(methylene chloride:methanol=10:1),
NMR (CD;0D): 3 0.96 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.05-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-
0 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.11 (m, 5H), 7.18 (t, J = 3.3, 1.5 Hz, 1H), 7.25-7.31 (m, 3H), 7.51 (d, J = 8.7 Hz, 2H).
Example 23(121):N-(4-{4-[(4-{butyl[(2-thienylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide
TLC:Rf 0.3 1(methylene chloride: methanol=10:1);
NMR (CD;OD): § 0.95 (t, J] = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.60 (m, 2H), 1.60- 1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.10-2.20 (m, 2H), 2.91 (s, 3H), 2.95-3.05 (m, 2H), 3.20- 3.30 (m, 2H), 3.51 (s, 2H), 4.00 (m, 1H), 6.65 (m, 1H), 6.77-6.79 (m, 2H), 6.92-6.96 (m, 4H), 7.21-7.24 (m, 2H), 7.31 (d, J = 8.7 Hz, 2H).
Example 23(122):
N-(4-{4-[(4-{butyl[(2,3-dihydro-1,4-benzodioxin-6-ylamino)carbonylJamino }-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride TLC:Rf0.40(methylene chloride:methanol=10:1);
NMR (CD;0D): § 0.96 (t, J = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.10 (m, 1H), 4.20 (s, 4H), 4.28 (s, 2H), 6.72 (s, 2H), 6.85 (t, J = 1.4 Hz, 1H), 7.02-7.11 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.48 (d, J] = 8.9 Hz, 2H).
Example 23(123):
N-[4-(4-{[4-(butyl{[(3,5-difluorophenyl)amino]carbonyl }amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.40(methylene chloride: methanol=10:1),
NMR (CD;OD): § 0.96 (t, J = 7.2 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.30 (s, 2H), 6.55 (m, 1H), 7.02-7.11 (m, 6H), 7.29 (d, J = 8.4
Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H).
Example 23(124):
N-[4-(4-{[4-(butyl {[(3,4-difluorophenyl)amino]carbonyl }amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.44(methylene chloride:methanol=10:1),
NMR (CD;OD): 8 0.97 (t, J = 7.5 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 7.02-7.16 (m, 6H), 7.29 (d, J = 8.6 Hz, 2H), 7.40 (m, 1H), 7.55 (d, J = 8.6 Hz, 2H).
(I
Example 23(125):
N-[4-(4-{[4-(butyl {[(1-0xido-3-pyridinyl)amino]carbonyl }amino)-1- piperidinylJmethy!} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.69(methylene chloride: methanol=5:1);
NMR (CD;0OD): & 0.96 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.30-2.40 (m, 2H), 2.95 (s, 3H), 3.10-3.30 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.31 (s, 2H), 4.35 (m, 1H), 7.02-7.07 (m, 4H), 7.29 (d, J = 8.6 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H) 7.88 (dd, J = 8.9, 3.5 Hz, 1H), 8.39 (d, J =2.7 Hz, 1H), 8.50 (d, J = 2.7
Hz, 1H), 9.39 (s, 1H).
Example 23(126):
N-[4-(4-{[4-(butyl {[(2,4-difluorophenyl)amino]carbony! }amino)-1- piperidinylJmethyl}phenoxy)phenyl]methanesuifonamide hydrochloride
TLC:Rf 0.58(chloroform:methanol=10:1);
NMR (CD;0D): & 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.17 (m, 1H), 4.29 (s, 2H), 6.92-7.00 (m, 2H), 7.02-7.08 (m, 4H), 7.26-7.41 (m, 3H), 7.49-7.52 (m, 2H), amorphous; softening point :about 196-198°C.
Example 23(127):
N-{4-[4-({4-[{[(4-bromophenyl)amino]carbonyl}(butyl)amino]-1- piperidinyl } methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf0.57(chloroform:methanol=10:1);
NMR (CDs;OD): 4 0.96 (t, J = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.60 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.05-3.20 (m, 2H), 3.20-3.30 (m, 2H), 3.50- 3.60 (m, 2H), 4.19 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 7.27-7.31 (m, 4H), 7.39 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H).
Example 23(128):
N-(4-{4-[(4-{butyl[(isobutylamino)carbonyl]amino }-1- piperidinyl)methyl}phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.51(chloroform:methanol=10:1);
NMR (CDsOD): 6 0.87 (d, J = 6.6 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.60 (m, 2H), 1.76 (m, 1H), 1.80-2.00 (m, 2H), 2.00-2.20 (m, 2H), 2.96 (s, 3H), 2.96 (d, J = 7.5 Hz, 2H), 3.00-3.40 (m, 4H), 3.50-3.60 (m, 2H), 4.16 (m, 1H), 4.28 (s, 2H), 7.02- 7.08 (m, 4H), 7.29 (d, J] = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H).
(IN
Example 23(129):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(3-methyl-2-butenyl)amino]-1- piperidinyl} methyl )phenoxy phenyl} methanesulfonamide hydrochloride TLC:Rf 0.62(methylene chloride:methanol=9:1),
NMR (CD;O0D): § 1.75 (s, 6H), 1.92-2.03 (m, 2H), 2.07-2.23 (m, 2H), 2.95 (s, 3H), 3.05- 3.19 (m, 2H), 3.50-3.60 (m, 2H), 3.94-4.02 (m, 2H), 4.20-4.35 (m, 3H), 5.18 (m, 1H), 6.98-7.10 (m, 6H), 7.26 -7.34 (m, 4H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(130):
N-[4-(4-{[4-(3-butynyl {[(4-fluorophenyl)amino]carbonyl }amino)-1- piperidinylJmethyl } phenoxy )phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.61(methylene chloride:methanol=9:1),
NMR (CD;OD): § 1.97-2.10 (m, 2H), 2.19-2.20 (m, 2H), 2.43 (m, 1H), 2.49-2.58 (m, 2H), 2.95 (s, 3H), 3.02-3.19 (m, 2H), 3.46-3.61 (m, 4H), 4.08 (m, 1H), 4.29 (s, 2H), 6.98-7.10 (m, 6H), 7.26-7.34 (m, 4H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(131):
N-[4-(4-{[4-(3-butenyl{[(4-fluorophenyl)amino]carbonyl }amino)-1- piperidinyl]methyl}phenoxy)phenyljmethanesulfonamide hydrochloride
TLC:Rf 0.61(methylene chloride: methanol=9:1);
NMR (CD;0D): § 1.95-2.06 (m, 2H), 2.15-2.44 (m, 4H), 2.95 (s, 3H), 3.03-3.18 (m, 2H), 3.28-3.41 (m, 2H), 3.50-3.61 (m, 2H), 4.13 (m, 1H), 4.29 (s, 2H), 5.08 (d, J] = 10.2 Hz, 1H), 5.14 (d, J = 17.1 Hz, 1H), 5.86 (m, 1H), 6.98-7.10 (m, 6H), 7.26-7.35 (m, 4H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(132):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(2-hydroxybutyl)amino]-1- piperidinyl } methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf0.59(methylene chloride:methanol=9:1),
NMR (CD3;OD): § 1.02 (t, J = 7.5 Hz, 3H), 1.44-1.60 (m, 2H), 1.95-2.28 (m, 4H), 2.95 (s, 3H), 3.01-3.36 (m, 4H), 3.47-3.60 (m, 2H), 3.66 (m, 1H), 4.10 (m, 1H), 4.28 (s, 2H), 6.98- 7.10 (m, 6H), 7.2 2-7.34 (m, 4H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(133): :
N-{4-[4-({4-[[(1,3-benzodioxol-5-ylamino)carbonyl](butyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.29(chloroform:methanol=10:1),
oO
NMR (CD;OD): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.95 (s, 3H), 3.05-3.20 (m, 2H), 3.20-3.30 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 5.90 (s, 2H), 6.70-6.71 (m, 2H), 6.89 (d, J] = 1.8
Hz, 1H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(134):
N-[4-(4-{[4-((4-fluorobenzyl){[(4-fluorophenyl)amino]carbonyl }amino)-1- piperidinyl]Jmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC Rf 0.59(chloroform:methanol=9:1),
NMR (CD:OD): 6 7.46 (brd, J = 8.4 Hz, 2H), 7.40-7.24 (m, 6H), 7.14-6.80 (m, 8H), 4.62 (s, 2H), 4.32 (m, 1H), 4.24 (s, 2H), 3.48 (m, 2H), 3.06 (m, 2H), 2.95 (s, 3H), 2.20-1.88 (m, 4H).
Example 23(135): N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(2-methoxybenzyl)amino]-1- piperidinyl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.62(chloroform:methanol=9:1),
NMR (CD;0D): § 7.45 (brd, J = 8.7 Hz, 2H), 7.30-7.19 (m, 6H), 7.16-6.90 (m, 8H), 4.59 (s, 2H), 4.32 (m, 1H), 4.23 (s, 2H), 3.88 (s, 3H), 3.47 (m, 2H), 3.08 (m, 2H), 2.95 (s, 3H), 2.18-1.88 (m, 4H).
Example 23(136):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(2-methylbenzyl)amino]-1- piperidinyl } methyl)phenoxy phenyl} methanesulfonamide hydrochloride TLC:Rf 0.68(chloroform:methanol=9:1);
NMR (CD;0D): § 7.45 (brd, J = 8.7 Hz, 2H), 7.30-7.10 (m, 8H), 7.08-6.90 (m, 6H), 4.56 (s, 2H), 4.43 (m, 1H), 4.24 (s, 2H), 3.49 (m, 2H), 3.07 (m, 2H), 2.95 (s, 3H), 2.35 (5, 3H), 2.16-1.86 (m, 4H).
Example 23(137):
N-[4-(4-{[4-(butyl{[(3-hydroxy-4-methylphenyl)amino]carbonyl }amino)-1- piperidinylJmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.42(chloroform:methanol=10:1);
NMR (CD;0D): § 0.96 (t, J = 7.2 Hz, 3H), 1.20-1.40 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.00 (m, 2H), 2.10-2.30 (m, 2H), 2.12 (s, 3H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.16 (m, 1H), 4.28 (s, 2H), 6.64 (dd, J =8.0, 2.0 Hz, 1H), 6.83 (d, J =2.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H).
I
Example 23(138):
N-[4-(4-{[4-(butyl{[(3,5-dihydroxyphenyl)amino]carbonyl }amino)-1- piperidinylJmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride TLCRf0.75(methylene chloride:methanol=5:1);
NMR (d¢-DMSO): 8 0.88 (t, J = 7.2 Hz, 3H), 1.20-1.40 (m, 2H), 1.40-1.50 (m, 2H), 1.70- 1.80 (m, 2H), 2.10-2.30 (m, 2H), 3.16 (s, 3H), 3.30-3.40 (m, 2H), 3.60-3.90 (m, 4H), 4.14 (m, 1H), 4.22 (d, ] = 4.8 Hz, 2H), 5.83 (t, J = 2.1 Hz, 1H), 6.37 (d, J = 2.1 Hz, 2H), 7.02- 7.08 (m, 4H), 7.25 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.88 (s, 1H), 9.71 (s, 1H), 10.51 (s, 1H).
Example 23(139):
N-[4-(4-{[4-(butyl{[(2-hydroxy-2-methylpropyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.50(methylene chloride:methanol=9:1);
NMR (CD;0D): 8 0.96 (t, J = 7.2 Hz, 3H), 1.15 (s, 6H), 1.28-1.44 (m, 2H), 1.50162 (m, 2H), 1.88-1.98 (m, 2H), 2.08-2.25 (m, 2H), 2.95 (s, 3H), 3.02-3.22 (m, 6H), 3.50-3.60 (m, 2H), 4.16 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d,
J =8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(140):
N-[4-(4-{[4-({[(2-hydroxy-2-methylpropyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.15(methylene chloride:methanol=9:1);
NMR (CDs;OD): & 1.15 (s, 6H), 1.60-1.78 (m, 2H), 2.00-2.21 (m, 2H), 2.95 (s, 3H), 3.01- 3.15 (m, 4H), 3.44-3.55 (m, 2H), 3.73 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J=8.7Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 23(141): N-[4-(4-{[4-((cyclopropylmethyl){[(4-fluorophenyl)amino]carbonyl }amino)-1- piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.43(methylene chloride:methanol=9:1),
NMR (CD;0D): 4 0.32-0.37 (m, 2H), 0.57-0.63 (m, 2H), 1.06 (m, 1H), 1.97-2.10 (m, 2H), 2.25-2.42 (m, 2H), 2.95 (s, 3H), 3.05-3.18 (m, 2H), 3.25 (d, J = 6.6 Hz, 2H), 3.51-3.62 (m, 2H), 4.06 (m, 1H), 4.29 (s, 2H), 6.98-7.10 (in, 6H), 7.27-7.35 (m, 4H), 7.50 (d, J = 8.7 Hz, a 2H).
oO
Example 23(142):
N-[4-(4-{[4-((cyclobutylmethyl){[(4-fluorophenyl)amino]carbonyl}amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.43(methylene chloride:methanol=9:1);
NMR (CD;OD): 6 1.75-2.14 (m, 8H), 2.23-2.40 (m, 2H), 2.62 (m, 1H), 2.95 (s, 3H), 3.03- 3.15 (m, 2H), 3.36 (d, J = 6.9 Hz, 2H), 3.50-3.60 (m, 2H), 3.95 (m, 1H), 4.28 (s, 2H), 6.98- 7.08 (m, 6H), 7.2 7-7.32 (m, 4H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(143): N-(4-{4-[(4-{{[(4-flucrophenyl)amino]carbonyl }[(1-oxido-3-pyridinyl)methyl]Jamino}-1- piperidinyl)methyl]phenoxy}phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.14(methylene chloride:methanol=9:1);,
NMR (CD;0D): 6 1.98-2.32 (m, 4H), 2.95 (s, 3H), 3.09-3.21 (m, 2H), 3.50-3.60 (m, 2H), 4.30 (s, 2H), 4.40 (m, 1H), 4.72 (s, 2H), 6.97-7.10 (m, 6H), 7.29 (d, J = 8.7 Hz, 2H), 7.37 (dd, J=9.0, 5.1 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.84 (t, J = 7.0 Hz, 1H), 8.08 (d,] = 7.0
Hz, 1H), 8.62 (d, J = 7.0 Hz, 1H), 8.69 (s, 1H).
Example 23(144):
N-[4-(4-{[4-((3-fluorobenzyl){[(4-fluorophenyl)amino]carbonyl } amino)-1- piperidiny!]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.65(chloroform:methanol=5:1);
NMR (CDsOD): § 7.47 (m, 2H), 7.40-7.22 (m, 5H), 7.16 (m, 1H), 7.10-6.96 (m, 8H), 4.65 (s, 2H), 4.37 (m, 1H), 4.24 (s, 2H), 3.50 (m, 2H), 3.09 (m, 2H), 2.95 (s, 3H), 2.20-1.90 (m, 4H).
Example 23(145):
N-[4-(4-{[4-((2-fluorobenzyl){[(4-fluorophenyl)amino]carbonyl} amino)-1- piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.65(chloroform:methanol=5:1);
NMR (CD;OD): 8 7.46 (brd, J = 8.7 Hz, 2H), 7.40-7.22 (m, 6H), 7.20-6.92 (m, 8H), 4.69 (s, 2H), 4.39 (m, 1H), 4.25 (s, 2H), 3.51 (m, 2H), 3.10 (m, 2H), 2.95 (s, 3H), 2.20-1.89 (m, 4H).
Example 23(146): N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(4-methoxybenzyl)amino]-1- a piperidinyl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.69(chloroform:methanol=5:1);
oO
NMR (CD3OD): & 7.45 (brd, J = 8.7 Hz, 2H), 7.40-7.20 (m, 6H), 7.10-6.88 (m, 8H), 4.57 (s, 2H), 4.29 (m, 1H), 4.23 (s, 2H), 3.76 (s, 3H), 3.49 (m, 2H), 3.08 (m, 2H), 2.95 (s, 3H), 2.22-1.86 (m, 4H).
Example 23(147):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbony!}(3-methoxybenzyl)amino]-1- piperidinyl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.81(chloroform:methanol=5:1);
NMR (CD;0D): § 7.46 (brd, J = 9.0 Hz, 2H), 7.30-7.20 (m, 5H), 7.08-6.94 (m, 6H), 6.92- 6.76 (m, 3H), 4.62 (s, 2H), 4.35 (m, 1H), 4.24 (s, 2H), 3.77 (s, 3H), 3.49 (m, 2H), 3.08 (m, 2H), 2.95 (s, 3H), 2.20-1.90 (m, 4H).
Example 23(148):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(3-methylbenzyl)amino]-1- piperidinyl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.85(chloroform:methanol=5:1);
NMR (CD3;OD): & 7.47 (brd, J = 9.0 Hz, 2H), 7.34-7.18 (m, 6H), 7.16-6.92 (m, 8H), 4.61 (s, 2H), 4.36 (m, 1H), 4.25 (s, 2H), 3.49 (m, 2H), 3.08 (m, 2H), 2.95 (s, 3H) 2.32 (s, 3H), 2.22-1.90 (m, 4H).
Example 23(149): 4-{{{(4-fluorophenyhamino]carbony!}[1-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)- 4-piperidinyl}amino } butanoic acid hydrochloride
TLC:Rf 0.18(methylene chloride:methanol=9:1),
NMR (CD3;OD): § 1.82-2.02 (m, 4H), 2.10-2.30 (m, 2H), 2.43 (t, J = 6.3 Hz, 2H), 2.95 (s, 3H), 3.04-3.18 (m, 2H), 3.25-3.35 (m, 2H), 3.50-3.60 (m, 2H), 4.22-4.35 (m, 3H), 7.00 (dd,
J=17.1,9.0 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.42-7.55 (m, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 23(150):
N-[4-(4-{[4-(butyl{[(3,5-dimethyl-4-isoxazolyl)amino]carbonyl }amino)-1- piperidinylJmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.53(methylene chloride:methanol=9:1);
NMR (CDs;OD): 6 0.98 (t, J] = 7.2 Hz, 3H), 1.32-1.47 (m, 2H), 1.58-1.70 (m, 2H), 1.95- 2.03 (m, 2H), 2.12 (s, 3H), 2.26 (s, 3H), 2.15-2.25 (m, 2H), 2.95 (s, 3H), 3.03-3.17 (m, 2H), 3.21-3.32 (m, 2H), 3.50-3.60 (m, 2H), 4.10 (m, 1H), 4.29 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J=8.7Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
oO
Example 23(151):
N-[4-(4-{[4-(butyl {[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1- piperidinylJmethyl} phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.51 (methylene chloride:methanol=9:1);
NMR (CDsOD): § 0.97 (t, J = 7.2 Hz, 3H), 1.31-1.45 (m, 2H), 1.57-1.67 (m, 2H), 1.97- 2.08 (m, 2H), 2.22-2.38 (m, 2H), 2.70 (s, 3H), 2.95 (s, 3H), 3.10-3.25 (m, 2H), 3.28-3.36 (m, 2H), 3.52-3.62 (m, 2H), 4.30 (m, 1H), 4.31 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 8.7 Hz, 1H), 8.49 (dd, J = 8.7, 2.7 Hz, 1H), 9.02 (s, 1H).
Example 24:
N-[4-(4-{[4-(butyl {[(cyclohexylmethyl)amino]carbonothioyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
H
S N Nog CH;
OTL CT
SRB ae
I - HCI
H,C
To a solution of the compound prepared in Example 3 (70 mg) in dimethylformamide (1 mL) was added triethylamine (38 pL). The solution was added dropwise to a solution of cyclohexylmethyl isothiocyanate (43 mg) in dimethylformamide (0.5 mL) and the mixture was stirred for 1 hour. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=10:1), and converted to hydrochloride salt by a conventional method to give the compound of the present invention (81.9 mg) having the following physical data.
TLC:Rf 0.69(ethy! acetate:methanol=10:1);
NMR (CD;OD): 6 0.88-1.03 (m, 2H), 0.96 (t, J] = 7.2 Hz, 3H), 1.14-1.44 (m, SH), 1.47- 1.60 (m, 2H), 1.62-1.82 (m, 6H), 1.93-2.08 (m, 4H), 2.95 (s, 3H), 3.05-3.20 (m, 2H), 3.24- 3.36 (m, 2H), 3.47 (d, J] = 6.6 Hz, 2H), 3.50-3.60 (m, 2H), 4.29 (s, 2H), 5.66 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H).
0
Example 24(1) and Example 24(2)
By the same procedure as described in Example 24, using a corresponding amine derivative instead of the compound prepared in Example 3, the compounds of the present invention having the following physical data were obtained.
Example 24(1):
N-[4-(4-{[4-({[(cyclohexylmethyl)amino]carbonothioyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.62(ethyl acetate:methanol=10:1);
NMR (CD;OD): 8 0.88-1.05 (m, 2H), 1.13-1.34 (m, 3H), 1.50-1.83 (m, 8H), 2.22-2.35 (m, 2H), 2.95 (s, 3H), 3.05-3.18 (m, 2H), 3.21-3.42 (m, 2H), 3.47-3.58 (m, 2H), 4.28 (s, 2H), 4.42 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J= 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 24(2):
N-[4-(4-{[4-(benzyl{[(cyclohexylmethyl)amino]carbonothioyl }amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.67(ethyl acetate:methanol=10:1);
NMR (CD3;0D): § 0.62-0.78 (m, 2H), 1.00-1.14 (m, 3H), 1.30-1.62 (m, 6H), 1.89-2.13 (m, 4H), 2.95 (s, 3H), 3.09-3.21 (m, 2H), 3.36 (d, J = 6.6 Hz, 2H), 3.45-3.56 (m, 2H), 4.27 (s, 2H), 4.71 (s, 2H), 5.87 (m, 1H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.17- 7.38 (m, 7H), 7.48 (d, J = 8.7 Hz, 2H).
Example 25: N-[4-(4-{[4-(butyl{[(3-hydroxybutyl)amino]carbonyl }amino)-1- piperidinyl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
H
OH 0 YL rds: me (0 ©
H, A + HCI
To a solution of (3-{[t-butyl(dimethyl)silyl]Joxy }butyl)amine (72.3 mg) in tetrahydrofuran (1 mL) were added triethylamine (97 pL) and triphosgen (44.1 mg) under : cooling with ice and stirring, and then the solution was stirred at room temperature for 1 hour. A solution of the compound prepared in Example 3 (100 mg) and triethylamine (55 uL) in N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture, which was stirred for 15 minutes. A saturated aqueous solution of sodium hydrogen carbonate oO was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. A solution of 4N hydrochloric acid in ethyl acetate was added to the obtained residue. The reaction mixture was stirred for 15 minutes and concentrated. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=10:1), and converted to hydrochloride salt by a conventional method to give the compound of the present invention (99.6 mg) having the following physical data.
TLC:Rf 0.46(methylene chloride: methanol=9:1);
NMR (CD;0D): 0.95 (t, J = 7.2 Hz, 3H), 1.16 (d, J = 6.0 Hz, 3H), 1.26-1.41 (m, 2H), 1.44-1.70 (m, 4H), 1.85-1.97 (m, 2H), 2.05-2.21 (m, 2H), 2.95 (s, 3H), 3.03-3.13 (m, 4H), 3.17-3.38 (m, 2H), 3.50-3.58 (m, 2H), 3.78 (m, 1H), 4.13 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 25(1)-Example 25(10)
By the same procedure as described in Example 25, using (3-{[t- butyl(dimethyl)silylJoxy }butyl)amine or a corresponding amine derivative, and using the compound prepared in Example 3 or a corresponding amine derivative, the compounds of the present invention having the following physical data were obtained.
Example 25(1):
N-{4-[4-({4-[butyl({[(1R,2R)-2-hydroxycyclohexyl]amino } carbonyl )amino}-1- piperidinyl } methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.29(ethyl acetate:methanol=10:1);
NMR (CD;OD): 6 0.95 (t, J = 7.2 Hz, 3H), 1.23-1.42 (m, 6H), 1.47-1.61 (m, 2H), 1.65- 1.77 (m, 2H), 1.88-2.05 (m, 4H), 2.05-2.22 (m, 2H), 2.95 (s, 3H), 3.02-3.20 (m, 4H), 3.34- 3.48 (m, 2H), 3.50-3.59 (m, 2H), 4.14 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J =8.7Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 25(2):
N-{4-[4-({4-[butyl({[(1S,25)-2-hydroxycyclohexyl]amino }carbonyl)amino]-1- piperidinyl } methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.29(ethyl acetate: methanol=10:1);
NMR (CD;0D): 6 0.95 (t, J = 7.2 Hz, 3H), 1.23-1.42 (m, 6H), 1.47-1.61 (m, 2H), 1.65- 1.77 (m, 2H), 1.88-2.05 (m, 4H), 2.05-2.22 (m, 2H), 2.95 (s, 3H), 3.02-3.20 (m, 4H), 3.34- 3.48 (m, 2H), 3.50-3.59 (m, 2H), 4.14 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J=8.7Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J] = 8.7 Hz, 2H).
LI J
Example 25(3):
N-{4-[4-({4-[({[(1-hydroxycyclohexy!)methyl]amino } carbonyl)amino]-1- piperidinyl} methyl)phenoxy]pheny!} methanesulfonamide hydrochloride
TLC:Rf 0.23(ethyl acetate:methanol=5:1);
NMR (CD;0D): 8 1.26-1.75 (m, 11H), 2.02(m, 1H), 2.10-2.21 (m, 2H), 2.95 (s, 3H), 3.03- 3.16 (m, 4H), 3.45-3.55 (m, 2H), 3.72 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.05 (d, T=8.7Hz, 2H), 7.29(d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 25(4):
N-{4-[4-({4-[({[(1R,2R)-2-hydroxycyclohexyl]amino } carbonyl)amino]-1- piperidinyl } methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.64(methylene chloride:methanol=4:1),
NMR (CD;0D): 6 1.12-1.40 (m, 4H), 1.59-1.76 (m, 3H), 1.88-2.06 (m, 3H), 2.11-2.21 (m, 2H), 2.95 (s, 3H), 3.02-3.14 (m, 2H), 3.18-3.38 (m, 2H), 3.46-3.55 (m, 2H), 3.73 (m, 1H), 4.27 (s, 2H), 7.03 (d, J =8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 25(5):
N-{4-[4-({4-[({[(1S,2S)-2-hydroxycyclohexyl]amino } carbonyl)amino]-1- piperidinyl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.64(methylene chloride: methanol=4:1),
NMR (CD;0D): § 1.12-1.40 (m, 4H), 1.59-1.76 (m, 3H), 1.88-2.06 (m, 3H), 2.11-2.21 (m, 2H), 2.95 (s, 3H), 3.02-3.14 (m, 2H), 3.18-3.38 (m, 2H), 3.46-3.55 (m, 2H), 3.73 (m, 1H), 4.27 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d,J=8.7Hz, 2H).
Example 25(6):
N-(4-{4-[(4-{butyl[(4-piperidinylamino)carbonyl]Jamino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf0.24(n-butanol:acetic acid: water=4:2:1);
NMR (CDs;0D): & 0.95 (t, J = 7.2 Hz, 3H), 1.30-1.40 (m, 2H), 1.40-1.50 (m, 2H), 1.70- 1.80 (m, 2H), 1.80-2.00 (m, 2H), 2.00-2.20 (m, 4H), 2.95 (s, 3H), 3.00-3.20 (m, 6H), 3.30- 3.50 (m, 2H), 3.50-3.60 (m, 2H), 3.80 (m, 1H), 4.10 (m, 1H), 4.28 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 25(7):
N-[4-(4-{[4-({[(2-hydroxybutyl)amino]carbonyl}amino)-1- piperidinylJmethy! }phenoxy)phenyl]methanesulfonamide hydrochloride oO
TLC:Rf 0.48(methylene chloride: methanol=4:1);
NMR (CDsOD): 6 0.94 (t, J = 7.2 Hz, 3H), 1.32-1.52 (m, 2H), 1.58-1.75 (m, 1.6H), 1.98- 2.08 (m, 0.4H), 2.10-2.20 (m, 2H), 2.95 (s, 3H), 3.00-3.14 (m, 2H), 3.16-3.40 (m, 2.6H), 3.45-3.54 (m, 2.4H), 3.68-3.78 (m, 0.8H), 3.90-3.95 (m, 0.2H), 4.27 (s, 1.6H), 4.33 (s, 04H), 7.03 (d, J=8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 25(8):
N-[4-(4-{[4-({[(3-hydroxybutyl)amino]carbonyl }amino)-1- piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.33(methylene chloride:methanol=4:1);
NMR (CD3;OD): 6 1.16 (d, J = 6.3 Hz, 2.4H), 1.17 (d, J = 6.3 Hz, 0.6H), 1.48-1.75 (m, 3.6H), 1.98-2.05 (m, 0.4H), 2.10-2.20 (m, 2H), 2.95 (s, 3H), 3.02-3.30 (m, 4H), 3.48-3.55 (m, 2H), 3.65-3.83 (m, 2H), 4.27 (s, 1.6H), 4.32 (s, 0.4H), 7.03 (d, J = 8.7 Hz, 2H), 7.05 (d,
J=8.7Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 25(9):
N-[4-(4-{[4-(butyl {[(2-hydroxybutyl)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride TLC:Rf 0.48(methylene chloride:methanol=9:1);
NMR (CD3;OD): 8 0.95 (t, J] = 7.2 Hz, 6H), 1.28-1.61 (m, 6H), 1.88-1.97 (m, 2H), 2.04- 2.22 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3.22-3.32 (m, 2H), 3.48-3.59 (m, 3H), 4.14 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7
Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 25(10):
N-{4-[4-({4-[butyl({[(1-hydroxycyclohexyl)methyl]jamino }carbonyl)amino]}-1- piperidinyl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
H
0
SAD. = 0 AN Oo ho HCI
TLC:Rf0.56(ethyl acetate: methanol=10:1);
NMR (CD3;0D): 6 0.96 (t, J = 7.5 Hz, 3H), 1.27-1.70 (m, 14H), 1.88-1.97 (m, 2H), 2.04- 2.21 (m, 2H), 2.95 (s, 3H), 3.02-3.18 (m, 4H), 3.20 (s, 2H), 3.48-3.60 (m, 2H), 4.15 (m,
oO 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J] = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 26:
N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy} benzyl)-4-piperidinyl]-1- piperidinecarboxamide hydrochloride
N..0 0 N SC
INGRAGWE FL en, - HCl
Under an atmosphere of argon, to a solution of the compound prepared in
Example 3 (50.0 mg) in N,N-dimethylformamide (1 mL) were triethylamine (30.0 pL) and piperidine-1-carbonylchloride (13.4 pL) and the solution was stirred at 40°C for 12 hours.
The reaction mixture was diluted with ethyl acetate. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous and concentrated. The obtained residue was purified by column chromatography on silica gel (chloroform : methanol=7:1), and converted to hydrochloride salt by a conventional method to give the compound of the present invention (14.9 mg) having the following physical data.
TLC:Rf 0.61(chloroform:methanol=5:1);
NMR (CDsOD): 8 0.92 (t, J = 7.5 Hz, 3H), 1.20-1.70 (m, 10H), 1.90-2.05 (m, 2H), 2.06- 2.24 (m, 2H), 2.95 (s, 3H), 3.02-3.18 (m, 4H), 3.18-3.38 (m, 4H), 3.45-3.62 (m, 3H), 4.27 (s, 2H), 7.00-7.12 (m, 4H), 7.24-7.3 4 (m, 2H), 7.44-7.58 (m, 2H).
Example 26(1)-Example 26(4)
By the same procedure as described in Example 26, using a corresponding acid chloride derivative instead of piperidine-1-carbonylchloride, the compounds of the present invention having the following physical data were obtained.
Example 26(1):
N-butyl-N-[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)-4-piperidinyl]-4- morpholinecarboxamide hydrochloride
TLC:Rf0.64(chloroform:methanol=5:1);
NMR (CD;OD): 6 0.93 (t, J = 7.2 Hz, 3H), 1.20-1.40 (m, 2H), 1.42-1.56 (m, 2H), 1.88- 2.02 (m, 2H), 2.06-2.30 (m, 2H), 2.95 (s, 3H), 3.02-3.16 (m, 4H), 3.21-3.34 (m, 3H), 3.44-
0 3.70 (m, 8H), 4.23 (s, 2H), 7.00-7.10 (m, 4H), 7.12-7.38 (m, 2H), 7.49 (brd, J = 8.7 Hz, 2H).
Example 26(2):
N-(4-{4-[(4-{[(dibutylamino)carbonyl]amino}-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.55(chloroform:methanol=5:1);
NMR (CDs0D): 6 0.93 (t, J = 7.5 Hz, 6H), 1.31 (m, 4H), 1.49 (m, 4H), 1.70-1.88 (m, 2H), 2.04-2.14 (m, 2H), 2.95 (s, 3H), 3.08 (m, 2H), 3.14-3.35 (m, 4H), 3.50 (m, 2H), 3.79 (m, 1H), 4.27 (s, 2H), 7.00-7.10 (m, 4H ), 7.22-7.34 (m, 2H), 7.49 (brd, J = 8.7 Hz, 2H).
Example 26(3):
N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]-1- pyrrolidinecarboxamide hydrochloride TLC:Rf0.63(chloroform:methanol=5:1),
NMR (CDs;0OD): 8 0.92 (t, J = 7.5 Hz, 3H), 1.22-1.36 (m, 2H), 1.38-1.52 (m, 2H), 1.80- 2.02 (m, 6H), 2.04-2.24 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 4H), 3.26-3.38 (m, 4H), 3.52 (m, 2H), 3.72 (m, 1H), 4.26 (s, 2H), 7.00-7.10 (m, 4H), 7.22-7.36 (m, 2H), 7.42-7.56 (m, 2H).
Example 26(4):
N-(4-{4-[(4-{butyl[(dibutylamino)carbonyl]amino }-1- piperidinyl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.59(chloroform:methanol=5:1);
NMR (CD;0OD): § 0.80-1.02 (m, 9H), 1.20-1.60 (m, 12H), 1.92-2.20 (m, 4H), 2.95 (s, 3H), 3.00-3.40 (m, 7H), 3.44-3.68 (m, 4H), 4.26 (s 2H), 7.00-7.12 (m, 4H), 7.29 (brd, J =9.0 Hz, 2H), 7.48 (brd, J = 8.4 Hz, 2H).
Example 27: N-[4-(4-{[4-({[(benzyloxy)amino]carbonyl }amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
H
0 N x N. g- CHa le 8 LY TL LT 6%
N N "0
H H
- HCI oO
Under cooling with ice and stirring, 1,1'-carbonylbis-1H-imidazole (CDI) (129 mg) in tetrahydrofuran (6.5 mL) was added dropwise to a solution of O- benzylhydroxyamine (100 mg) in tetrahydrofuran (2.5 mL). After stirring for 30 minutes,
N-(4-{4-[(4-aminopiperidin-1-yl)methyl]phenoxy } phenyl)methanesulfonamide (200 mg) prepared by a method based on Example 1 was added thereto, and the solution was stirred at 55°C for 24 hours. Distilled water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : methanol=10:1), and converted to hydrochloride salt by a conventional method to give the compound of the present invention (144.3 mg) having the following physical data.
TLC:Rf 0.42(ethy! acetate: methanol=5:1);
NMR (CD3;0D): & 1.63-1.79 (m, 2H), 1.96-2.07 (m, 2H), 2.96 (s, 3H), 3.00-3.12 (m, 2H), 3.44-3.54 (m, 2H), 3.74 (m, 1H), 4.26 (s, 2H), 4.76 (s, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.06 (d, J=8.7Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.33-7.43 (m, SH), 7.48 (d, J = 8.7 Hz, 2H).
Example 28: 4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl } phenoxy)benzoic acid hydrochloride
F 0 CL or
NN (0)
FH I + HCl
N-t-butoxycarbonylpiperidin-4-one and n-buthylamine were subjected to reductive alkylation in acetic acid and dimethylformamide at room temperature using sodium triacetoxyborohydride. The obtained 1-t-butoxycarbonyl-4-aminopiperidine was reacted with 2 4difluorobenzenisocyanate in dimethylformamide in the presence of triethylamine. The reaction mixture was deprotected by treatment with Hydrochloric acid to give N-butyl-N'-(2,4-difluorophenyl)-N-piperidin-4-ylurea hydrochloride. By the same procedure as described in Example 1 and the conversion to hydrochloride salt by a conventional method, using N-butyl-N'-(2,4-difluorophenyl)-N-piperidin-4-ylurea and 4- (4-formylphenoxy)benzoic acid, the compound of the present invention (48 mg) having the following physical data was obtained.
TLC:Rf 0.78(methylene chloride: methanol=5:1);
oO
NMR (CD;OD): § 0.98 (t, J = 7.2 Hz, 3H), 1.36-1.43 (m, 2H), 1.60-1.70 (m, 2H), 1.99- 2.04 (m, 2H), 2.16-2.28 (m, 2H), 3.08-3.17 (m, 2H), 3.24-3.30 (m, 2H), 3.56-3.61 (m, 2H), 4.15 (m, 1H), 4.32 (s, 2H), 6.90-7.05 (m, 2H), 7.07 (d, J =8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.37 (m, 1H), 7.56 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.7 Hz, 2H).
Example 28(1)-Example 28(18)
By the same procedure as described in Example 28, using N-butyl-N'-(2,4- difluorophenyl)-N-piperidin-4-ylurea or a corresponding piperidine derivative, and using a corresponding aldehyde derivative instead of 4-(4-formylphenoxy)benzoic acid, the following compounds of the present invention data were obtained.
Example 28(1): 4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)benzenesulfonamide hydrochloride TLC:Rf 0.89(methylene chloride: methanol=5:1);
NMR (CD;0OD): 6 0.98 (t, J = 7.2 Hz, 3H), 1.36-1.45 (m, 2H), 1.59-1.70 (m, 2H), 1.99- 2.03 (m, 2H), 2.17-2.30 (m, 2H), 3.08-3.17 (m, 2H), 3.23-3.30 (m, 2H), 3.56-3.60 (m, 2H), 4.15 (m, 1H), 4.32 (s, 2H), 6.90-7.03 (m, 2H), 7.14 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.37 (m, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.7 Hz, 2H).
Example 28(2):
N-butyl-N'-(2,4-difluorophenyl)-N-[1-({3,5-dimethyl-1-[ 1-(methylsulfonyl)piperidin-4- yl]-1H-pyrazol-4-yl} methyl)piperidin-4-ylJurea dihydrochloride
TLC:Rf 0.12(ethyl acetate:methanol=10:1);
NMR (CD;OD): § 0.98 (t, J = 7.5 Hz, 3H), 1.33-1.45 (m, 2H), 1.59-1.70 (m, 2H), 1.98- 2.01 (m, 4H), 2.12-2.30 (m, 4H), 2.33 (s, 3H), 2.43 (s, 3H), 2.89 (s, 3H), 2.93-3.01 (m, 2H), 3.09-3.17 (m, 2H), 3.25-3.30 (m, 2H), 3.58-3.63 (m, 2H), 3.86-3.90 (m, 2H), 4.19 (s, 2H), 4.19 (m, 1H), 4.39 (m, 1H), 6.89-7.03 (m, 2H), 7.37 (m, 1H).
Example 28(3):
N-(3'-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl } amino)piperidin-1-ylJmethyl}-1,1'- biphenyl-4-yl)methanesulfonamide hydrochloride
TLC:Rf 0.78(ethyl acetate:methanol=10:1);
NMR (CD;O0D): 6 0.97 (t, J] = 7.5 Hz, 3H), 1.34-1.44 (m, 2H), 1.58-1.68 (m, 2H), 1.98- 2.01 (m, 2H), 2.19-2.32 (m, 2H), 2.99 (s, 3H), 3.12-3.30 (m, 4H), 3.58-3.63 (m, 2H), 4.19 (m, 1H), 4.39 (s, 2H), 6.89-7.02 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.37 (m, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.68 (d, ] = 8.4 Hz, 2H), 7.76 (d, ] = 7.5 Hz, 1H), 7.82 (s, 1H).
(IN
Example 28(4):
N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)piperidin-1-ylJmethyl }- 3,5-dimethyl-1H-pyrazol-1-yl)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.29(ethyl acetate: methanol=10:1);
NMR (CD;OD): 6 0.98 (t, J = 7.5 Hz, 3H), 1.36-1.44 (m, 2H), 1.60-1.70 (m, 2H), 1.98- 2.00 (m, 2H), 2.20-2.35 (m, 2H), 2.35 (s, 3H), 2.35 (s, 3H), 3.03 (s, 3H), 3.03-3.13 (m, 2H), 3.27-3.30 (m, 2H), 3.58-3.62 (m, 2H), 4.17 (m, 1H), 4.17 (s, 2H), 6.90-7.03 (m, 2H), 7.35- 7.45 (m, SH).
Example 28(5): 4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl } amino)piperidin-1-ylJmethyl}-N-{4- [(methylsulfonyl)amino]benzyl } benzamide hydrochloride
TLC:Rf 0.36(methylene chloride:methanol=10:1);
NMR (CDs;0OD): 6 0.96 (t, J = 7.5 Hz, 3H), 1.28-1.40 (m, 2H), 1.69-1.89 (m, 4H), 2.11- 2.18 (m, 2H), 2.92 (s, 3H), 2.96-3.00 (m, 2H), 3.22-3.37 (m, 4H), 3.59 (s, 2H), 4.02 (m, 1H), 4.53 (s, 2H), 6.87-7.01 (m, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.38 (m, 1H), 7.44 (d, J =8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H).
Example 28(6):
N-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)piperidin-1- yl]methyl } phenyl)-2-{4-[(methylsulfonyl)amino]phenyl }acetamide hydrochloride
TLC:Rf 0.26(methylene chloride: methanol=10:1);
NMR (CD3;0D): 6 0.97 (t, J = 7.5 Hz, 3H), 1.28-1.41 (m, 2H), 1.58-1.69 (m, 2H), 1.96- 2.01 (m, 2H), 2.11-2.26 (m, 2H), 2.93 (s, 3H), 3.05-3.26 (m, 2H), 3.23-3.26 (m, 2H), 3.53- 3.56 (m, 2H), 3.67 (s, 2H), 4.13 (m, 1H), 4.26 (s, 2H), 6.89-7.02 (m, 2H), 7.21 (d, J = 8.7
Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.38 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.70(d, J = 8.4 Hz, 2H).
Example 28(7):
N-{4-[(4-{[4-(butyl {[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl }benzyl)oxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.40(methylene chloride:methanol=10:1);
NMR (CDs;OD): 6 0.97 (t, J = 7.5 Hz, 3H), 1.34-1.42 (m, 2H), 1.55-1.60 (m, 2H), 1.94- 2.00 (m, 2H), 2.12-2.20 (m, 2H), 2.99 (s, 3H), 3.03-3.12 (m, 2H), 3.23-3.25 (m, 2H), 3.47- 3.51 (m, 2H), 4.13 (m, 1H), 4.25 (s, 2H), 4.85 (s, 2H), 6.68 (d, J = 8.7 Hz, 2H), 6.89-7.03 (m, 2H), 7.13 (d, J = 8.7 Hz, 2H), 7.36 (m, 1H), 7.42 (s, 4H).
(I
Example 28(8): 4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1-ylJmethyl }-3,5- dimethyl-1H-pyrazol-1-yl)-N-methylbenzenesulfonamide dihydrochloride
TLC:Rf 0.38(methylene chloride:methanol=10:1);
NMR (CD;OD): 6 0.98 (t, J = 7.5 Hz, 3H), 1.36-1.44 (m, 2H), 1.63-1.68 (m, 2H), 1.97- 2.04 (m, 2H), 2.29-2.34 (m, 2H), 2.39 (s, 3H), 2.46 (s, 3H), 2.58 (s, 3H), 3.16-3.36 (m, 4H), 3.66-3.70 (m, 2H), 4.23 (m, 1H), 4.27 (s, 2H), 6.89-7.03 (m, 2H), 7.38 (m, 1H), 7.73 (d, ] = 8.7 Hz, 2H), 8.00 (d, J = 8.7 Hz, 2H).
Example 28(9):
N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- yllmethyl} phenoxy)benzylJmethanesulfonamide hydrochloride
TLC:Rf 0.30(ethyl acetate);
NMR (CD;0D): 6 0.98 (t, J = 7.5 Hz, 3H), 1.33-1.45 (m, 2H), 1.59-1.69 (m, 2H), 1.98- 2.02 (m, 2H), 2.15-2.28 (m, 2H), 2.88 (s, 3H), 3.06-3.15 (m, 2H), 3.24-3.30 (m, 2H), 3.54- 3.59 (m, 2H), 4.14 (m, 1H), 4.24 (s, 2H), 4.28 (s, 2H), 6.89-7.03 (m, 2H), 7.03 (d, J = 8.7
Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.37 (m, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.49 (d, ] = 8.7
Hz, 2H).
Example 28(10):
N-{4-[(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- yllmethyl}phenoxy)methyl]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.27(ethyl acetate);
NMR (CD;OD): § 0.97 (t, J = 7.5 Hz, 3H), 1.34-1.42 (m, 2H), 1.60-1.66 (m, 2H), 1.96- 2.01 (m, 2H), 2.12-2.20 (m, 2H), 2.95 (s, 3H), 3.04-3.11 (m, 2H), 3.23-3.30 (m, 2H), 3.52- 3.56 (m, 2H), 4.12 (m, 1H), 4.24 (s, 2H), 5.10 (s, 2H), 6.86-7.03 (m, 2H), 7.10 (d, J = 8.7
Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.36 (m, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.42 (d, ] = 8.7
Hz, 2H).
Example 28(11):
N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenyl]acetamide hydrochloride
TLC:Rf 0.28(ethyl acetate);
NMR (CDsOD): 6 0.98 (t, J = 7.5 Hz, 3H), 1.35-1.45 (m, 2H), 1.58-1.69 (m, 2H), 1.98- 2.02 (m, 2H), 2.12 (s, 3H), 2.15-2.27 (m, 2H), 3.06-3.14 (m, 2H), 3.24-3.30 (m, 2H), 3.54- 3.58 (m, 2H), 4.14 (m, 1H), 4.28 (s, 2H), 6.89-7.03 (m, 2H), 7.00 (d, J = 8.7 Hz, 2H), 7.04 (d, J =8.7 Hz, 2H), 7.36 (m, 1H), 7.47 (d, ] = 8.7 Hz, 2H), 7.57 (d, ] = 8.7 Hz, 2H).
o®
Example 28(12):
N-[4-(4-{[4-({ butyl[(cyclohexylamino)carbonyl]amino} methyl)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.47(chloroform:methanol=5:1);
NMR (CD;OD): & 0.94 (t, ] = 7.5 Hz, 3H), 2.00-1.06 (m, 19H), 2.95 (s, 3H), 3.02-2.88 m, 2H), 3.30-3.16 (m, 4H), 3.56-3.44 (m, 3H), 4.25 (s, 2H), 7.10-7.00 (m, 4H), 7.29 (brd, J = 9.0 Hz, 2H), 7.48 (brd, J = 8.4 Hz, 2H).
Example 28(13): 4-[4-({4-[(N-acetylleucyl)(butyl)amino]piperidin-1-yl} methyl)phenoxy]benzoic acid hydrochloride
TLC:Rf 0.24(ethyl acetate: methanol=10:1);
NMR (CD;OD): 68.04 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 4.75 (m, 1H), 4.40-4.10 (m, 3H), 3.70-3.05 (m, 6H), 2.40- 1.30 (m, 14H), 1.01-0.93 (m, 9H).
Example 28(14): 4-[4-({4-[(N-acetyl-3-cyclohexylalanyl)(butyl)amino]piperidin-1- yl}methyl)phenoxy]benzoic acid hydrochloride TLC:Rf0.27(ethyl acetate:methanol=10:1);
NMR (CD;OD): & 8.04 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.17 (d, ] = 8.7 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 4.75 (m, 1H), 4.40-4.10 (m, 3H), 3.70-3.00 (m, 6H), 2.40- 0.80 (m, 27H).
Example 28(15):
N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbony! }amino)piperidin-1- ylJmethyl}benzyl)phenyl]Jmethanesulfonamide hydrochloride
TLC:Rf 0.68(methylene chloride:methanol=10:1),
NMR (CD3OD): 6 0.97 (t, J = 7.2 Hz, 3H), 1.34-1.41 (m, 2H), 1.58-1.69 (m, 2H), 1.96- 2.00 (m, 2H), 2.12-2.23 (m, 2H), 2.91 (s, 3H), 3.05-3.13 (m, 2H), 3.23-3.30 (m, 2H), 3.53- 3.56 (m, 2H), 3.99 (s, 2H), 4.10 (m, 1H), 4.27 (s, 2H), 6.89-7.03 (m, 2H), 7.16 (d, ] = 8.7
Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 7.35 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0
Hz, 2H).
Example 28(16):
N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl } amino)piperidin-1- yl]methyl} phenoxy)-3-chlorophenyl]methanesulfonamide hydrochloride
TLC:Rf 0.63(methylene chloride:methanol=10:1);
oe
NMR (CD;OD): 6 0.97 (t, J = 7.2 Hz, 3H), 1.32-1.45 (m, 2H), 1.59-1.69 (m, 2H), 1.98- 2.01 (m, 2H), 2.13-2.26 (m, 2H), 3.01 (s, 3H), 3.06-3.14 (m, 2H), 3.24-3.30 (m, 2H), 3.54- 3.58 (m, 2H), 4.13 (m, 1H), 4.28 (s, 2H), 6.90-7.05 (m, 2H), 7.00 (d, J = 8.7 Hz, 2H), 7.13 (d, J =8.7 Hz, 1H), 7.24 (dd, J = 8.7, 2.7 Hz, 1H), 7.36 (dt, ] = 8.7, 6.0 Hz, 1H), 7.43 (4, J =27Hz 1H), 7.48 (d, J= 8.7 Hz, 2H).
Example 28(17):
N-butyl-N'-(2,4-difluorophenyl)-N-[1-({3,5-dimethyl-1-[4-(trifluoromethyl)phenyl]-1H- pyrazol-4-yl} methyl)piperidin-4-yljurea dihydrochloride
TLC:Rf 0.74(methylene chloride: methanol=10:1);
NMR (CDs0OD): 4 0.99 (t, J = 7.5 Hz, 3H), 1.36-1.44 (m, 2H), 1.61-1.71 (m, 2H), 2.00- 2.05 (m, 2H), 2.23-2.37 (m, 2H), 2.39 (s, 3H), 2.44 (s, 3H), 3.16-3.24 (m, 2H), 3.27-3.32 (m, 2H), 3.66-3.70 (m, 2H), 4.20 (m, 1H), 4.27 (s, 2H), 6.89-7.03 (m, 2H), 7.38 (dt, ] = 9.0, 6.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H).
Example 28(18):
N-{4-[(5-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)piperidin-1- yl]methyl } pyridin-2-yl)oxy]phenyl } methanesulfonamide dihydrochloride
TLC:Rf 0.31(chloroform:methanol=10:1);
NMR (CD;OD): § 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.98 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.35 (s, 2H), 6.86-7.05 (m, 2H), 7.10-7.17 (m, 3H), 7.32-7.38 (m, 3H), 8.09 (dd, J = 8.7, 2.2 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H).
Example 29(1)-Example 29(131)
By the same procedure as described in Example 23 and if necessary, the hydrolysis, deprotection or oxydation by a conventional method, using the compound prepared in Example 3 or a corresponding amine derivative, and using a corresponding carboxylic acid derivative instead of 1-methylcyclohexylcarboxylic acid, the following compounds of the present invention were obtained.
Example 29(1):
N-(4-{4-[(4-{butyl[(pyrimidin-5-ylamino)carbonyl Jamino} piperidin-1- yl)methyl]phenoxy} phenyl)methanesulfonamide dihydrochloride oe
H
SHNSASWerS
NSS ON 0) ©0
H
Is + 2HCI
H1C
TLC:Rf 0.44(methylene chloride:methanol=9:1);
NMR (CD;OD): 8 0.98 (t, J = 7.2 Hz, 3H), 1.32-1.48 (m, 2H), 1.55-1.70 (m, 2H), 1.97- 2.08 (m, 2H), 2.23-2.40 (m, 2H), 2.95 (s, 3H), 3.10-3.23 (m, 2H), 3.29-3.38 (m, 2H), 3.50- 3.62 (m, 2H), 4.25 (m, 1H), 4.31 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 9.03 (s, 1H), 9.27 (s, 2H).
Example 29(2):
N-(4-{4-[(4-{butyl[(pyridazin-4-ylamino)carbonyl]Jamino } piperidin-1- yl)methyl]phenoxy }phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.45(methylene chloride: methanol=9:1),
NMR (CD;0D): 8 0.97 (t, J = 7.5 Hz, 3H), 1.32-1.47 (m, 2H), 1.55-1.69 (m, 2H), 2.00- 2.10 (m, 2H), 2.27-2.45 (m, 2H), 2.95 (s, 3H), 3.12-3.27 (m, 2H), 3.33-3.45 (m, 2H), 3.50- 3.62 (m, 2H), 4.24-4.35 (m, 3H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d,
J=8.7Hz 2H), 7.53 (d,J =8.7 Hz, 2H), 8.49 (dd, J=7.2,2.7Hz, 1H), 9.13 (d, J = 7.2 Hz, 1H), 9.49 (d, J = 2.7 Hz, 1H).
Example 29(3):
N-{4-[4-({4-[{[(6-azidopyridin-3-yl)amino]carbony! }(butyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.47(methylene chloride: methanol=9:1);
NMR (CD;0D): 6 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.45 (m, 2H), 1.55-1.70 (m, 2H), 1.97- 2.08(m, 2H), 2.24-2.41 (m, 2H), 2.95 (s, 3H), 3.05-3.20 (m, 2H), 3.25-3.38 (m, 2H), 3.55- 3.65 (m, 2H), 4.19 (m, 1H), 4.31 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.29(d,J=8.7Hz, 2H), 7.51 (d, ] = 8.7 Hz, 2H), 7.88 (dd, J = 9.6, 1.5 Hz, 1H), 7.99 (dd, J =96,1.5Hz 1H), 9.42(d, J=1.5 Hz, 1H).
Example 29(4):
N-{4-[4-({4-[butyl({[3-(trifluoromethoxy)phenylJamino } carbonyl)aminoJpiperidin-1- : yl}methyl)phenoxylphenyl} methanesulfonamide hydrochloride
TLC:Rf 0.49(chloroform:methanol=10:1);
©
NMR (CD3;OD): 6 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.00- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.17 (m, 1H), 4.29 (s, 2H), 6.93 (m, 1H), 7.02-7.08 (m, 4H), 7.27-7.34 (m, 4H), 7.45 (m, 1H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(5):
N-{4-[4-({4-[{[(4-acetylphenyl)amino]carbonyl } (butyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.42(chloroform:methanol=10:1),
NMR (CD;OD): § 0.96 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.00- 2.10 (m, ZH), 2.20-2.40 (m, 2H), 2.55 (s, 3H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.10 (m, 1H), 4.30 (s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H).
Example 29(6):
N-{4-[4-({4-[butyl({[2-(trifluoromethoxy)phenyl]amino } carbonyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.51(chloroform:methanol=10:1);
NMR (CD;OD): 4 0.98 (t, J = 7.2 Hz, 3H), 1.35-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.40- 3.60 (m, 2H), 4.16 (mn, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 7.19-7.34 (m, SH), 7.48-7.51 (m, 2H), 7.60 (m, 1H).
Example 29(7):
N-{4-[4-({4-[[(benzoylamino)carbonyl](butyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl}methanesulfonamide hydrochloride
TLC:Rf 0.60(chloroform:methanol=10:1);
NMR (CDsOD): 8 0.92 (t, J = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.60-1.70 (m, 2H), 2.00- 2.10 (m, 2H), 2.30-2.40 (m, 2H), 2.95 (s, 3H), 3.05-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.10 (m, 1H), 4.27 (s, 2H), 7.02-7.06 (m, 4H), 7.29 (d, J = 9.0 Hz, 2H), 7.48- 7.53 (m, 4H), 7.61 (m, 1H), 7.87 (d, J = 7.2 Hz, 2H).
Example 29(8): N-[4-(4-{[4-(butyl{[(2,6-difluorophenyl)amino]carbonyl }amino)piperidin-1- a yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.56(chloroform:methanol=10:1);
eo O°
NMR (CD;OD): 6 0.98 (t, J] = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.30 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 6.97-7.08 (m, 6H), 7.28-7.31 (m, 3H), 7.49-7.52 (m, 2H).
Example 29(9):
N-{4-[4-({4-[butyl({[4-(trifluoromethoxy)phenyl]Jamino } carbonyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.47(chloroform:methanol=10:1);
NMR (CD;OD): 6 0.97 (t, J] = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.05-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.01-7.08 (m, 4H), 7.18 (d, J = 9.0 Hz, 2H), 7.29 (d, J =93 Hz, 2H), 7.43 (d, J = 9.3 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H).
Example 29(10):
N-(4-{4-[(4-{butyl[(quinolin-3-ylamino)carbonyl]amino } piperidin-1- yl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.40(chloroform:methanol=10:1);
NMR (CD;OD): 4 0.99 (t, J = 7.4 Hz, 3H), 1.40-1.50 (m, 2H), 1.60-1.70 (m, 2H), 2.00- 2.10 (m, 2H), 2.30-2.40 (m, 2H), 2.95 (s, 3H), 3.20-3.30 (m, 2H), 3.20-3.40 (m, 2H), 3.55- 3.65 (m, 2H), 4.30 (m, 1H), 4.32 (s, 2H), 7.02-7.09 (m, 4H), 7.30 (d, J = 8.9 Hz, 2H), 7.54 (d, J=8.9 Hz 2H), 7.91 (td, J= 7.2, 1.2 Hz, 1H), 8.02 (td, J =7.2, 1.2 Hz, 1H), 8.14 (d, J =8.4 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 9.05 (d, J =2.4 Hz, 1H), 9.53 (d, J = 2.4 Hz, 1H).
Example 29(11):
N-(4-{4-[(4-{butyl[(cyclopent-3-en-1-ylamino)carbonylJamino } piperidin-1- yl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.72(chloroform:methanol=5:1);
NMR (CD;OD): 8 0.93 (t, J = 7.2 Hz, 3H), 1.20-1.40 (m, 2H), 1.40-1.60 (m, 2H), 1.80- 2.00 (m, 2H), 2.00-2.20 (m, 2H), 2.24 (dd, J = 14.6, 5.6 Hz, 2H) 2.69 (dd, J = 14.6, 8.0 Hz, 2H) 2.95 (s, 3H), 3.00-3.20 (m, 4H), 3.50-3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 4.39 (m, 1H), 5.69 (s, 2H), 7.02-7.07 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 8.9 Hz, 2H).
Example 29(12): N-[4-(4-{[4-(butyl{[(4-chloro-3-hydroxyphenyl)amino]carbonyl }amino)piperidin-1- yl]methyl } phenoxy)phenyljmethanesulfonamide hydrochloride
TLC:Rf 0.41(chloroform:methanol=10:1);
©
NMR (CD3OD): 6 0.96 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.00 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 6.77 (dd, J = 8.9, 2.4 Hz, 1H), 7.02-7.08 (m, 5H), 7.15 (d, J =9.0 Hz, 1H), 7.29-7.31 (m, 2H), 7.47-7.51 (m, 2H).
Example 29(13):
N-[4-(4-{[4-(butyl{[(4-fluoro-3-hydroxyphenyl)amino]carbonyl }amino)piperidin-1- yllmethyl} phenoxy)phenyllmethanesulfonamide hydrochloride
TLC:Rf 0.40(chloroform:methanol=10:1),
NMR (CD;OD): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 6.70 (m, 1H), 6.90-7.00 (m, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 8.9 Hz, 2H).
Example 29(14):
N-(4-{4-[(4-{butyl[(quinolin-6-ylamino)carbonyl]amino } piperidin-1- yl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.44(chloroform:methanol=10:1),
NMR (CD;OD): § 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 2.00- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.10-3.30 (m, 2H), 3.30-3.50 (m, 2H), 3.50- 3.70 (m, 2H), 4.30 (m, 1H), 4.32 (s, 2H), 7.02-7.09 (m, 4H), 7.30 (d, J = 8.9 Hz, 2H), 7.53 (d, J =8.9 Hz, 2H), 8.01 (dd, J = 8.6, 5.6 Hz, 1H), 8.15 (d, J = 9.3 Hz, 1H), 8.31 (dd, J = 9.3, 2.4 Hz, 1H), 8.42 (m, 1H), 9.01-9.05 (m, 2H).
Example 29(15):
N-{4-[4-({4-[butyl({[2-(trifluoromethyl)phenyl]amino }carbonyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl } methanesulfonamide
TLC:Rf 0.69(chloroform:methanol=10:1);
NMR (CD;OD): 6 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.90 (m, 4H), 2.00- 2.20 (m, 2H), 2.93 (s, 3H), 2.95-3.05 (m, 2H), 3.20-3.40 (m, 4H), 3.51 (s, 2H), 4.05 (m, 1H), 6.93-6.98 (m, 4H), 7.24 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.34 (m, 1H), 7.58-7.60 (m, 2H), 7.66 (d, J = 7.8 Hz, 1H).
Example 29(16): N-[4-(4-{[4-(butyl{[(6-0x0-1,6-dihydropyridin-3-yl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.45(methylene chloride:methanol=4:1),
® ©
NMR (CD;0D): § 0.96 (t, J = 7.2 Hz, 3H), 1.30-1.45 (m, 2H), 1.50-1.65 (m, 2H), 1.92- 2.05 (m, 2H), 2.18-2.35 (m, 2H), 2.95 (s, 3H), 3.08-3.35 (m, 4H), 3.50-3.60 (m, 2H), 4.21 (m, TH), 4.30 (s, 2H), 6.68 (d, J = 9.6 Hz, 1H), 7.03 (d, ] = 8.7 Hz, 2H), 7.06 (d,J=8.7Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 3.0 Hz, 1H), 7.79 (dd, J 5S =9.6,3.0Hg, 1H).
Example 29(17):
N-[4-(4-{[4-(butyl{[(4-oxocyclohexyl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.47(methylene chloride: methanol=9:1);
NMR (CDsOD): § 0.94 (t, J = 7.2 Hz, 3H), 1.26-1.58 (m, 7H), 1.70-1.80 (m, 2H), 1.85- 2.20 (m, 7H), 2.95 (s, 3H), 3.02-3.17 (m, 4H), 3.48-3.65 (m, 3H), 4.13 (m, 1H), 4.28 (s, 2H), 7.03 (d, J = 8.7H z, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J] = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(18):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(3 -hydroxybenzyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.80(chloroform:methanol=5:1);
NMR (CD;OD): § 1.88-2.24 (m, 4H), 2.95 (s, 3H), 3.08 (m, 2H), 3.48 (m, 2H), 4.24 (s, 2H), 4.34 (m, 1H), 4.58 (s, 2H), 6.60-6.84 (m, 3H), 6.90-7.10 (m, 6H), 7.16 (m, 1H), 7.22- 7.38 (m, 4H), 7.38-7.52 (m, 2H).
Example 29(19): N-[4-(4-{[4-(butyl{[(2,6-dimethylphenyl)amino]carbony! }amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.59(chloroform:methanol=10:1);
NMR (CDs;OD): 4 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.20 (s, 6H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.28 (s, 2H), 7.02-7.07 (m, 7H), 7.29 (d, = 8.9
Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H).
Example 29(20):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(2-methoxybutyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.34(methylene chloride: methanol=9:1);
NMR (CDsOD): 4 1.00 (t, J = 7.5 Hz, 3H), 1.57-1.70 (m, 2H), 1.93-2.30 (m, 4H), 2.95 (s, 3H), 3.02-3.20 (m, 3H), 3.35-3.45 (m, 2H), 3.50 (s, 3H), 3.50-3.60 (m, 2H), 4.10 (m, 1H),
® © 4.28 (s, 2H), 6.97-7.10 (m, 6H), 7.21-7.33 (m, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(21):
N-{4-[4-({4-[4-ethyl-3-(4-fluorophenyl)-2-ox0-2,3-dihydro-1H-imidazol-1-yl]piperidin-1- yl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.33(methylene chloride:methanol=9:1);
NMR (CD;OD): 6 1.02 (t, J = 7.5 Hz, 3H), 2.15-2.25 (m, 4H), 2.28 (q, J = 7.5 Hz, 2H), 2.96 (s, 3H), 3.13-3.29 (m, 2H), 3.58-3.70 (m, 2H), 4.26 (m, 1H), 4.33 (s, 2H), 6.39 (s, 1H), 7.04 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.20-7.35 (m, 6H), 7.52 (d, J = 8.7 Hz, 2H).
Example 29(22):
N-[4-(4-{[4-({[(4-fluorophenyl)amino]carbonyl} { 2- [(methylsulfonyl)amino]butyl}amino)piperidin-1- yl]methyl} phenoxy)phenylJmethanesulfonamide hydrochloride
TLC:Rf 0.31(methylene chloride:methanol=9:1);
NMR (CD;0D): 6 1.06 (t, J = 7.5 Hz, 3H), 1.48 (m, 1H), 1.69 (m, 1H), 2.05-2.18 (m, 2H), 2.21-2.43 (m, 2H), 2.95 (s, 3H), 2.97 (s, 3H), 3.03-3.14 (m, 2H), 3.34 (d, J = 7.5 Hz, 2H), 3.42-3.61 (m, 3H), 3.95 (m, 1H), 4.28 (s, 2H), 6.96-7.10 (m, 6H), 7.26-7.40 (m, 4H), 7.50 (d, J=8.7 Hz, 2H).
Example 29(23):
N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl } [(2S)-2-methylbutyl Jamino } piperidin-1- yDmethyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.39(methylene chloride:methanol=9:1),
NMR (CDs;OD): 6 0.94 (d, J = 7.5 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H), 1.16 (m, 1H), 1.50 (m, 1H), 1.74 (m, 1H), 1.95-2.07 (m, 2H), 2.28-2.47 (m, 2H), 2.95 (s, 3H), 3.02-3.24 (m, 4H), 3.50-3.60 (m, 2H ), 3.90 (m, 1H), 4.28 (s, 2H), 6.96-7.10 (m, 6H), 7.25-7.32 (m, 2H), 7.29 (d,J=8.7Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(24):
N-[4-(4-{[4-((2-ethylbutyl){[(4-fluorophenyl)amino]carbonyl } amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.39(methylene chloride:methanol=9:1),
NMR (CD;0D): 8 0.93 (t, J = 7.5 Hz, 6H), 1.27-1.50 (m, 4H), 1.60 (m, 1H), 1.97-2.08 (m, 2H), 2.30-2.50 (m, 2H), 2.95 (s, 3H), 3.03-3.18 (m, 2H), 3.26 (d, J = 7.5 Hz, 2H), 3.50-
®o © 3.60 (m, 2H), 3.87 (mm, 1H), 4.28 (s, 2H), 6.96-7.10 (m, 6H), 7.24-7.33 (m, 4H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(25):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl } (thien-2-ylmethyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.34(methylene chloride: methanol=9:1);
NMR (CD;0D): 6 1.94-2.05 (m, 2H), 2.12-2.30 (m, 2H), 2.95 (s, 3H), 3.02-3.17 (m, 2H), 3.50-3.58 (m, 2H), 4.26 (s, 2H), 4.27 (m, 1H), 4.79 (s, 2H), 6.94-7.08 (m, 8H), 7.26-7.34 (m, SH), 7.48 (d, J = 8.7 Hz, 2H).
Example 29(26):
N-{3-[({butyl[1-(4- {4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino} carbonyl)amino]phenyl}acetamide hydrochloride TLC:Rf 0.73(ethyl acetate:methanol=5:1);
NMR (CD;0D): 6 0.97 (t, J = 7.2 Hz, 3H), 1.28-1.45 (m, 2H), 1.56-1.67 (m, 2H), 1.98- 2.02 (m, 2H), 2.11 (s, 3H), 2.16-2.28 (m, 2H), 2.96 (s, 3H), 3.07-3.15 (m, 2H), 3.26-3.30 (m, 2H), 3.55-3.59 (m, 2H), 4.16 (m, 1H), 4.29 (s, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.10-7.23 (m, 3H), 7.30 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.69 (m, 1H).
Example 29(27):
N-{4-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperidin-4- yl]Jamino} carbonyl)amino]phenyl }acetamide hydrochloride TLC:Rf0.70(ethyl acetate:methanol=5:1);
NMR (CD;0D): 8 0.97 (t, J = 7.5 Hz, 3H), 1.29-1.42 (m, 2H), 1.55-1.67 (m, 2H), 1.98- 2.02 (m, 2H), 2.10 (s, 3H), 2.13-2.28 (m, 2H), 2.96 (s, 3H), 3.03-3.15 (m, 2H), 3.25-3.30 (m, 2H), 3.55-3.59 (m, 2H), 4.16 (m, 1H), 4.29 (s, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H) 7.46 (d, J = 8.7 Hz, 2H), 7.50(d,J=8.7Hz, 2H).
Example 29(28):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(2,2,3,3,4,4,4- heptafluorobutyl)amino]piperidin-1-yl} methyl )phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.57(methylene chloride:methanol=9:1);
® ©
NMR (CD;0OD): 6 2.08-2.38 (m, 4H), 2.95 (s, 3H), 3.08-3.11 (m, 2H), 3.52-3.65 (m, 2H), 4.04 (m, 1H), 4.18-4.35 (m, 4H), 6.99-7.08 (m, 6H), 7.26-7.37 (m, 4H), 7.50 (d, J =8.7 Hz, 2H).
Example 29(29):
N-{4-[4-({4-[ {[(4-fluorophenyl)amino]carbonyl}(isopentyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.52(methylene chloride:methanol=9:1);
NMR (CD;OD): 6 0.96 (d, J = 6.6 Hz, 6H), 1.45-1.55 (m, 2H), 1.65 (m, 1H), 1.95-2.05 (m, 2H), 2.12-2.30 (m, 2H), 2.95 (s, 3H), 3.05-3.10 (m, 2H), 3.22-3.33 (m, 2H), 3.51-3.61 (m, 2H), 4.19 (m, 1H), 4.29 (s, 2H), 6.97-7.10 (m, 6H), 7.26-7.33 (m, 4H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(30): N-[4-(4-{[4-((2,6-difluorobenzyl){[(4-fluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.54(methylene chloride:methanol=9:1);
NMR (CD;0D): & 1.88-1.99 (m, 2H), 2.19-2.34 (m, 2H), 2.95 (s, 3H), 2.99-3.12 (m, 2H), 3.44-3.52 (m, 2H), 3.98 (m, 1H), 4.24 (s, 2H), 4.75 (s, 2H), 6.95-7.08 (m, 8H), 7.25-7.40 (m, SH), 7.45 (d, J =8.7 Hz, 2H).
Example 29(31):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(pyridin-2-ylmethyl)amino]piperidin-1- yl }methyl)phenoxy]phenyl } methanesulfonamide dihydrochloride TLC:Rf0.56(methylene chloride:methanol=9:1);
NMR (CDsOD): § 2.03-2.36 (m, 4H), 2.95 (s, 3H), 3.13-3.26 (m, 2H), 3.54-3.64 (m, 2H), 4.32 (s, 2H), 4.45 (m, 1H), 4.87 (s, 2H), 7.00 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.05 (d, J =8.7Hz 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.39 (dd, J = 9.0, 5.0 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.94 (t, ] = 6.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.54 (dt, J = 1.8, 8.0 Hz, 1H), 8.75(dd,J=6.0, 1.8 Hz, 1H).
Example 29(32):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(pyridin-3-ylmethyl)amino}piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride
TLC:Rf0.47(methylene chloride:methanol=9:1);
NMR (CD;OD): 6 1.98-2.10 (m, 2H), 2.18-2.35 (m, 2H), 2.95 (s, 3H), 3.10-3.23 (m, 2H), 3.50-3.60 (m, 2H), 4.30 (s, 2H), 4.43 (m, 1H), 4.80 (s, 2H), 7.00 (d, J = 9.0 Hz, 2H), 7.02 (d, J =8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.38 (dd, J = 9.0, 5.0
® ©
Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 8.05 (dd, J = 8.4, 5.7 Hz, 1H), 8.59 (d, J] = 8.4 Hz, 1H), 8.75 (d, J=5.7 Hz, 1H), 8.84 (s, 1H).
Example 29(33):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(pyridin-4-ylmethyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl }methanesulfonamide dihydrochloride
TLC:Rf 0.47(methylene chloride:methanol=9:1);
NMR (CD;0D): 6 2.02-2.30 (m, 4H), 2.95 (s, 3H), 3.10-3.23 (m, 2H), 3.50-3.60 (m, 2H), 4.30 (s, 2H), 4.48 (m, 1H), 4.88 (s, 2H), 6.99 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.05(d, J =8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.36 (dd, J = 9.0, 5.0 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 6.6 Hz, 2H), 8.77 (d, J = 6.6 Hz, 2H).
Example 29(34):
N-(4-{4-[(4-{butyl[(methylamino)carbonyl]amino} piperidin-1- yl)methyl]phenoxy}phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.50(chloroform:methanol=10:1);
NMR (CD;OD): 6 0.94 (t, J = 7.5 Hz, 3H), 1.30-1.40 (m, 2H), 1.40-1.60 (m, 2H), 1.80- 2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.72 (s, 3H), 2.95 (s, 3H), 3.00-3.15 (m, 4H), 3.50-3.60 (m, 2H), 4.12 (m, 1H), 4.27 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.49 (d, J =8.9 Hz 2H).
Example 29(35):
N-[4-(4-{[4-(butyl {[(5-hydroxypyridin-3-yl)amino]carbonyl }amino)piperidin-1- yl]methyl } phenoxy)phenyl Jmethanesulfonamide dihydrochloride
TLC:Rf0.50(chloroform:methanol=5:1);
NMR (CDs;OD): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.10-3.30 (m, 4H), 3.50-3.60 (m, 2H), 4.30 (m, 1H), 4.31 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.9 Hz, 2H), 7.93 (d,J=2.1Hz, 1H) 8.12(d,J=2.1Hz 1H), 8.68 (d, J = 1.5 Hz, 1H).
Example 29(36):
N-[4-(4-{[4-(butyl{[(1-1sopropyl-1H-1,2,3-benzotriazol-5- yl)amino]carbonyl }amino)piperidin-1-ylJmethyl} phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf0.65(chloroform:methanol=5:1);
NMR (CDs;OD): 6 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.74 (d,
J = 6.6 Hz, 6H), 2.00-2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.96 (s, 3H), 3.10-3.30 (m, 2H), 3.30-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.30 (m, 1H), 4.32 (s, 2H), 5.34 (m, 1H), 7.02-7.08 oo (m, 4H), 7.30 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.9 Hz, 2H), 7.77 (dd, J = 9.0, 1.5 Hz, 1H) 7.95(d,J=9.0Hz, 1H), 8.17 (d, J= 1.5 Hz, 1H).
Example 29(37): 5S N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl }[(6-methylpyridin-2- yl)methylJamino} piperidin-1-yl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.50(methylene chloride: methanol=9:1);
NMR (CD;OD): 6 2.08-2.18 (m, 2H), 2.20-2.38 (m, 2H), 2.80 (s, 3H), 2.95 (s, 3H), 3.14- 3.26 (m, 2H), 3.52-3.62 (m, 2H), 4.32 (s, 2H), 4.47 (m, 1H), 4.83 (s, 2H), 7.00 (d, ] = 9.0
Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.29 (d, J] = 8.7 Hz, 2H), 7.37 (dd, 7=19.0, 5.0 Hz, 2H), 7.57 (d, ] = 8.7 Hz, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0
Hz, 1H), 8.40 (t, ] = 8.0 Hz, 1H).
Example 29(38):
N-[4-(4-{[4-(butyl{[(3-cyanophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.52(methylene chloride: methanol=10:1);
NMR (CD;OD): 6 0.97 (t, J] = 7.2 Hz, 3H), 1.28-1.44 (m, 2H), 1.55-1.66 (m, 2H), 1.98- 2.03 (m, 2H), 2.20-2.33 (m, 2H), 2.95 (s, 3H), 3.09-3.17 (m, 2H), 3.30-3.40 (m, 2H), 3.55- 3.59 (m, 2H), 4.17 (m, 1H), 4.30 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.36 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.64 (m, 1H), 7.82 (m, 1H).
Example 29(39):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(tetrahydro-2H-pyran-4- ylmethyl)amino]piperidin-1-yl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.57(methylene chloride:methanol=9:1),
NMR (CD;OD): 6 1.27-1.42 (m, 2H), 1.60-1.70 (m, 2H), 1.87-2.08 (m, 3H), 2.25-2.42 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 2H), 3.19-3.28 (m, 2H), 3.31-3.42 (m, 2H), 3.48-3.60 (m, 2H), 3.88-4.00 (m, 3H), 4.28 (s, 2H), 6.97-7.10 (m, 6H), 7.25-7.33 (m, 4H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(40):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(2-phenylethyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC Rf 0.68(methylene chloride: methanol=9:1);
® ©
NMR (CD;0D): & 1.82-2.92 (m, 2H), 2.10-2.28 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.95 (s, 3H), 3.00-3.12 (m, 2H), 3.49-3.59 (m, 4H), 4.10 (m, 1H), 4.27 (s, 2H), 6.97-7.10 (m, 6H), 7.18-7.37 (m, 9H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(41):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(2-pyridin-2-ylethyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride
TLC:Rf 0.59(methylene chloride: methanol=9:1);
NMR (CD;OD): 6 1.98-2.10 (m, 2H), 2.28-2.44 (m, 2H), 2.95 (s, 3H), 3.09-3.22 (m, 2H), 3.34 (t, J=7.2 Hz, 2H), 3.55-3.63 (m, 2H), 3.75 (t, ] = 7.2 Hz, 2H), 4.25 (m, 1H), 4.33 (s, 2H), 6.97-7.10 (m, 6H), 7.26-7.33 (m, 4H), 7.57 (d, J = 8.7 Hz, 2H), 7.92 (ddd, J = 8.1, 5.7, 1.8 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.53 (dt, J = 1.8, 8.1 Hz, 1H), 8.74 (d, J = 5.7 Hz, 1H).
Example 29(42):
N-[4-(4-{[4-(butyl{[(4-methyl-1,2 3-thiadiazol-5-yl)amino]carbonyl }amino)piperidin-1- yljmethyl}phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.78(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.99 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.30-2.40 (m, 2H), 2.68 (s, 3H), 2.96 (s, 3H), 3.10-3.20 (m, 2H), 3.40-3.50 (m, 2H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.31 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, ] = 8.9
Hz, 2H), 7.53 (d, J = 8.9 Hz, 2H).
Example 29(43): N-[4-(4-{[4-(butyl{[(2-chloro-4-fluorophenyl)amino]carbonyl }amino)piperidin-1- ylmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.72(chloroform:methanol=5:1),
NMR (CD;0D): 8 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 2.00- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, SH), 7.27 (m, 1H), 7.29 (d, 1=9.0
Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 7.51 (m, 1H).
Example 29(44): :
N-[4-(4-{[4-(butyl{[(4-cyanophenyl)amino]carbonyl}amino)piperidin-1- yllmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride -
TLC:Rf 0.71(methylene chloride:methanol=10:1);
NMR (CD;OD): 6 0.96 (t, J = 7.2 Hz, 3H), 1.34-1.41 (m, 2H), 1.57-1.62 (m, 2H), 1.98- 2.01 (m, 2H), 2.20-2.33 (m, 2H), 2.95 (s, 3H), 3.08-3.16 (m, 2H), 3.30-3.40 (m, 2H), 3.55-
® © 3.59 (m, 2H), 4.17 (m, 1H), 4.29 (s, 2H), 7.04 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.61 (d,J = 9.0
Hz, 2H).
Example 29(45):
N-[4-(4-{[4-(butyl {[(2,2-difluoro-1,3-benzodioxol-5-yl)amino]carbonyl }amino)piperidin- 1-yl]methyl} phenoxy)phenyl]Jmethanesulfonamide hydrochloride
TLC:Rf 0.64(methylene chloride: methanol=10:1);
NMR (CD;0OD): 6 0.97 (t, J] = 7.2 Hz, 3H), 1.34-1.42 (m, 2H), 1.55-1.65 (m, 2H), 1.98- 2.03 (m, 2H), 2.15-2.25 (m, 2H), 2.95 (s, 3H), 3.07-3.15 (m, 2H), 3.25-3.30 (m, 2H), 3.55- 3.59 (m, 2H), 4.14 (m, 1H), 4.29 (s, 2H), 7.02-7.11 (m, 6H), 7.29 (d, J = 8.7 Hz, 2H), 7.33 (m, 1H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(46):
N-[4-(4-{[4-(butyl{[(4-chloro-2-fluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC: Rf 0.46(chloroform:methanol=10:1),
NMR (CD;OD): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 7.15 (m, 1H), 7.22 (dd, 1 = 6.3, 2.1 Hz, 1H), 7.29 (d, J =8.9 Hz, 2H), 7.43 (m, 1H), 7.43 (d, J = 8.9 Hz, 2H).
Example 29(47):
N-[4-(4-{[4-(butyl {[(1-methyl-1H-1,2,3-benzotriazol-5- yl)amino]carbonyl}amino)piperidin-1-yl]methyl } phenoxy)phenyl]methanesulfonamide dihydrochloride :
TLC:Rf 0.40(chloroform:methanol=10:1),
NMR (CD;OD): & 0.98 (1, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 2.00- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.30 (m, 1H), 4.31 (s, 2H), 4.39 (s, 3H), 7.02-7.08 (m, 4H), 7.29 (d, J = 9.0
Hz, 2H), 7.53 (d, J = 9.0 Hz, 2H), 7.69 (dd, J = 9.0, 1.8 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H).
Example 29(48): 2-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperidin-4- - yl]amino}carbonyl)amino]benzamide
TLC:Rf 0.60(methylene chloride: methanol=10:1);
® ©
NMR (CD;0D): § 0.96 (t, J = 7.2 Hz, 3H), 1.37-1.44 (m, 2H), 1.59-1.91 (m, 6H), 2.15- 2.22 (m, 2H), 2.93 (s, 3H), 3.00-3.04 (m, 2H), 3.22-3.27 (m, 2H), 3.54 (s, 2H), 4.05 (m, 1H), 6.93-7.02 (m, SH), 7.25 (d, J = 8.7 Hz, 2H), 7.32 (d, ] = 8.7 Hz, 2H), 7.42 (, ] = 8.3
Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H).
Example 29(49):
N-[4-(4-{[4-(butyl{[(2,4-dimethylpyridin-3-yl)amino]carbonyl }amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.45(methylene chloride:methanol=10:1),
NMR (CD;OD): 8 1.00 (t, J = 7.5 Hz, 3H), 1.39-1.46 (m, 2H), 1.63-1.70 (m, 2H), 2.01- 2.06 (m, 2H), 2.22-2.35 (m, 2H), 2.52 (s, 3H), 2.64 (s, 3H), 2.95 (s, 3H), 3.12-3.20 (m, 2H), 3.30-3.37 (m, 2H), 3.56-3.60(m, 2H), 4.24 (m, 1H), 4.30 (s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.06 (d, J=8.9 Hz, 2H), 7.29 (d, J = 89 Hz, 2H), 7.52 (d, J = 89 Hz, 2H), 7.83 (d, J = 6.3
Hz, 1H), 8.48 (d, J = 6.3 Hz, 1H).
Example 29(50):
N-[4-(4-{[4-(butyl{[(4-fluoro-2-hydroxyphenyl)amino]carbonyl}amino)piperidin-1- yl]Jmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.50(chloroform:methanol=10:1);
NMR (CD;0D): 8 0.99 (t, J = 7.5 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 6.53-6.60 (m, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.7 Hz, 2H), 7.46 (m, 1H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(51):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(2-hydroxy-3- methylbutyl)amino]piperidin-1-yl} methyl)phenoxyJphenyl }methanesulfonamide hydrochloride
TLC:Rf 0.45(methylene chloride: methanol=9:1);
NMR (CD;OD): § 0.99 (d, ] = 6.9 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 1.74 (m, 1H), 1.95- 2.25 (m, 4H), 2.95 (s, 3H), 3.07-3.20 (m, 2H), 3.25-3.42 (m, 2H), 3.47-3.62 (m, 3H), 4.16 (m, 1H), 4.29 (s, 2H), 6.99 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7
Hz, 2H), 7.24 (dd, J =9.0, 5.0 Hz, 2H), 7.29 (d, J 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(52):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(3-hydroxy-3- methylbutyl)amino]piperidin-1-yl} methyl)phenoxy Jphenyl }methanesulfonamide hydrochloride
® ©
TLC:Rf 0.44(methylene chloride:methanol=9:1),
NMR (CD;0D): 8 1.25 (s, 6H), 1.79 (t, J = 7.5 Hz, 2H), 1.92-2.02 (m, 2H), 2.08-2.23 (m, 2H), 2.95 (s, 3H), 3.08-3.18 (m, 2H), 3.40 (t, J = 7.5 Hz, 2H), 3.52-3.62 (m, 2H), 4.26-4.36 (m, 3H), 6.98 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d,J87Hz 2H), 7.36 (dd, J =9.0, 5.0 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(53):
N-[4-(4- {[4-(butyl{[(2,4-dimethyl-1-0xidopyridin-3-yl)amino] carbonyl }amino)piperidin- 1-yljmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride TLC:Rf 0.43(methylene chloride:methanol=5:1),
NMR (CD;OD): § 1.00 (t, J = 7.2 Hz, 3H), 1.39-1.46 (m, 2H), 1.63-1.75 (m, 2H), 1.97- 2.05 (m, 2H), 2.23-2.35 (m, 2H), 2.43 (s, 3H), 2.59 (s, 3H), 2.96 (s, 3H), 3.10-3.20 (m, 2H), 3.30-3.38 (m, 2H), 3.53-3.59 (m, 2H), 4.21 (m, 1H), 4.30 (s, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.07 (d, J= 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.66 (d,] = 6.9
Hz 1H), 8.59 (d, J = 6.9 Hz, 1H).
Example 29(54):
N-[4-(4-{[4-(buty!{[(1-oxidopyridin-4-yl)amino]carbonyl }amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride TLC:Rf 0.35(methylene chloride:methanol=5:1);
NMR (CD;OD): 8 0.96 (t, J = 7.2 Hz, 3H), 1.34-1.44 (m, 2H), 1.55-1.65 (m, 2H), 1.98- 2.05 (m, 2H), 2.26-2.38 (m, 2H), 2.95 (s, 3H), 3.13-3.21 (m, 2H), 3.33-3.38 (m, 2H), 3.56- 3.60 (m, 2H), 4.24 (m, 1H), 4.31 (s, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 7.0 Hz, 2H), 8.59 (d,J = 7.0
Hz 2H).
Example 29(55):
N-[4-(4- {[4-(butyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl } amino)piperidin-1- yl]methy!}phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.40(chloroform:methanol=10:1);
NMR (CD;OD): & 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.10-3.30 (m, 4H), 3.50-3.60 (m, 2H), 3.97 (s, 3H), 4.20 (m, 1H), 4.30 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.88 (s, 1H), 7.99 (s, 1H); amorphous; : softening point :about 156-159°C.
® ©
Example 29(56):
N-{4-[4-({4-[{[(2,4-difluorophenyl)amino}carbonyl}(2-hydroxybutyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl }methanesulfonamide hydrochloride
TLC:Rf 0.51 (methylene chloride: methanol=9:1);
NMR (CD;OD): § 1.00 (t, J = 7.5 Hz, 3H), 1.40-1.60 (m, 2H), 1.97-2.31 (m, 4H), 2.95 (s, 3H), 3.02-3.41 (m, 4H), 3.50-3.71 (m, 3H), 4.12 (m, 1H), 4.28 (s, 2H), 6.83-7.02 (m, 2H), 7.03 (d, J=8.7H z, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7
Hz, 2H), 7.63 (dt, J=5.7, 9.0 Hz, 1H).
Example 29(57):
N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbony! }[(3-methylpyridin-2- yl)methyl]amino} piperidin-1-yl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.56(methylene chloride: methanol=9:1);
NMR (CDs;0D): 6 2.01-2.30 (m, 4H), 2.62 (s, 3H), 2.95 (s, 3H), 3.16-3.30 (m, 2H), 3.50- 3.61 (m, 2H), 4.31 (s, 2H), 4.51 (m, 1H), 4.88 (s, 2H), 6.98-7.08 (m, 6H), 7.28 (d, ] = 8.7
Hz, 2H), 7.42-7.5 0 (m, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.86 (t, J = 6.5 Hz, 1H), 8.39 (d, J = 6.5 Hz, 1H), 8.54 (d, J = 6.5 Hz, 1H).
Example 29(58):
N-[4-(4-{[4-((cyclopentylmethyl){[(4-fluorophenyl)amino]carbonyl }amino)piperidin-1- ylJmethyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.57(methylene chloride: methanol=9:1);,
NMR (CDs0OD): & 1.20-1.35 (m, 2H), 1.52-1.87 (m, 6H), 1.98-2.07 (m, 2H), 2.22 (m, 1H), 2.30-2.48 (m, 2H), 2.95 (s, 3H), 3.03-3.18 (m, 2H), 3.28-3.33 (m, 2H), 3.50-3.60 (m, 2H), 3.88 (m, 1H), 4.28 (s, 2H), 6.98-7.08 (m, 6H), 7.24-7.32 (m, 4H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(59):
N-[4-(4-{[4-(butyl{[(2-fluoro-5-methoxyphenyl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.52(chloroform:methanol=10:1),
NMR (CD;OD): 8 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 3.75 (s, 3H), 4.20 (m, 1H), 4.29 (s, 2H), 6.67 (m, 1H), 7.02-7.12 (m, 6H), 7.29(d, J=8.9Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H).
® ©O
Example 29(60):
N-[4-(4-{[4-(butyl {[(2-fluoro-3-methoxyphenyl)amino]carbonyl }amino)piperidin-1- yl]Jmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.52(chloroform:methanol=10:1);
NMR (CD;OD): § 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 3.85 (s, 3H), 4.20 (m, 1H), 4.29 (s, 2H), 6.89 (m, 1H), 7.02-7.08 (m, 6H), 7.29 (d, J =9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H).
Example 29(61):
N-[4-(4-{[4-(butyl{[(2-fluoro-4-methylphenyl)amino]jcarbonyl }amino)piperidin-1- ylJmethyl} phenoxy)phenylJmethanesulfonamide hydrochloride
TLC:Rf 0.56(chloroform:methanol=10:1);
NMR (CD;0D): 6 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.40 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.31 (s, 3H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 6.90-7.00 (m, 2H), 7.02-7.08 (m, 4H), 7.26-7.31 (m, 3H), 7.50 (d, J = 9.0 Hz, 2H).
Example 29(62):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbony!}(1,3-thiazol-2-ylmethyl)amino]piperidin- 1-yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC Rf 0.63(chloroform:methanol=5:1),
NMR (CD;0D): 6 2.00-2.13 (m, 2H), 2.13-2.31 (m, 2H), 2.95 (s, 3H), 3.16 (m, 2H), 3.58 (m, 2H), 4.31 (s, 2H), 4.38 (m, 1H), 4.93 (s, 2H), 6.98-7.18 (m, 6H), 7.24-7.42 (m, 4H), 7.52 (brd, J=8.7 Hz, 2H), 7.75 (d, ] =3.6 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H).
Example 29(63): 3-[({butyl[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- ylJamino } carbonyl)amino]-N-methylbenzamide hydrochloride
TLC:Rf0.34(chloroform:methanol=10:1);
NMR (CD;0D): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.90 (s, 3H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.7
Hz, 2H), 7.30-7.50 (m, 3H), 7.50 (d, ] = 8.7 Hz, 2H), 7.79 (s, 1H). :
Example 29(64):
N-{4-[4-({4-[butyl({ [3-(dimethylamino)phenylJamino } carbonyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride
® ©
TLC:Rf 0.50(chloroform:methanol=10:1);
NMR (CD3;OD): & 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.10-3.40 (m, 4H), 3.28 (s, 6H), 3.50-3.60 (m, 2H), 4.30 (m, 1H), 4.31 (s, 2H), 7.02-7.08 (m, 4H), 7.28-7.31 (m, 3H), 7.48-7.54 (m, 4H), 7.90 (m, 1H).
Example 29(65):
N-[4-(4-{[4-(butyl{[(4-fluoro-2-methylphenyl)amino]carbonyl}amino)piperidin-1- yl]lmethyl} phenoxy)phenyl]methanesulfonamide hydrochloride TLC:Rf 0.47(chloroform:methanol=10:1);
NMR (CD;OD): 6 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.21 (s, 3H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.28 (s, 2H), 6.88 (m, 1H), 6.94-7.14 (m, 6H), 7.29 (d, J =8.7Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H).
Example 29(66):
N-[4-(4-{[4-(butyl{[(2-fluoro-4-methoxyphenyl)amino]carbonyl }amino)piperidin-1- yllmethyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.63(chloroform:methanol=10:1),
NMR (CDs;OD): 6 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 3.77 (s, 3H), 4.15 (m, 1H), 4.28 (s, 2H), 6.70-6.75 (m, 2H), 7.02-7.08 (m, 4H), 7.22 (m, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(67):
N-[4-(4-{[4-(butyl {[(3-ethylphenyl)amino]carbonyl }amino)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.58(chloroform:methanol=10:1);
NMR (CD;OD): 8 0.97 (t, J = 7.4 Hz, 3H), 1.22 (t, J = 7.5 He, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90-2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.60 (q, J = 7.1 Hz, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.19 (m, 1H), 4.29 (s, 2H), 6.89 (m, 1H), 7.01-7.08 (m, 4H), 7.12-7.20 (m, 3H), 7.29-7.32 (m, 2H), 7.49-7.52 (m, 2H).
Example 29(68): N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl}[(1-oxidopyridin-2- : yl)methyl]amino } piperidin-1-yl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC Rf 0.14(methylene chloride: methanol=9:1),
® ©O
NMR (CD;0D): 8 2.02-2.30 (m, 4H), 2.95 (s, 3H), 3.12-3.25 (m, 2H), 3.50-3.60 (m, 2H), 4.30 (s, 2H), 4.43 (m, 1H), 6.95-7.08 (m, 6H), 7.29 (d, J = 8.7 Hz, 2H), 7.35 (dd, J = 9.0, 5.0 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.73 (t, ] = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 8.01 (t, J=7.5Hz, 1H), 8.68 (d, J =7.5 Hz, 1H).
Example 29(69):
N-[4-(4-{[4-(butyl{[(2-fluoro-4-hydroxyphenyl)amino]carbonyl } amino)piperidin-1- yllmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.44(chloroform:methanol=10:1);
NMR (CD;OD): 8 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 6.52-6.56 (m, 2H), 7.02-7.09 (m, 6H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(70):
N-[4-(4-{[4-(butyl{[(1-methyl-1H-indol-3-yl)amino]carbonyl } amino)piperidin-1- yllmethyl }phenoxy)phenyllmethanesulfonamide dihydrochloride
TLC:Rf 0.42(chloroform:methanol=10:1);
NMR (CDsOD): 8 0.99 (t, J = 7.4 Hz, 3H), 1.40-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 3.76 (s, 3H), 4.25 (m, 1H), 4.26 (s, 2H), 7.02-7.07 (m, 5H), 7.10-7.20 (m, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.30 (m, 1H), 7.45 (m, 1H), 7.49 (d, J = 9.0 Hz, 2H),
Example 29(71): N-{4-[4-({4-[butyl({[3-(methylsulfonyl)phenyl]amino}carbonyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.26(chloroform:methanol=10:1),
NMR (CD;0D): & 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.10 (s, 3H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.10 (m, 1H), 4.30 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.3
Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H) 7.54-7.59 (m, 2H), 7.69 (m, 1H), 8.07 (m, 1H).
Example 29(72):
N-[4-(4-{[4-(butyl{[(3-chloro-1-methyl-1H-pyrazol-4- yl)amino]carbonyl}amino)piperidin-1-yl]methyl} phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.42(chloroform:methanol=10:1),
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NMR (CDsOD): 6 0.97 (t, J] = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 3.81 (s, 3H), 4.10 (m, 1H), 4.28 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.7
Hz, 2H), 7.45 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(73):
N-[4-(4-{[4-((2,6-dimethylbenzyl){[(4-fluorophenyl)amino]carbonyl }amino)piperidin-1- yllmethyl}phenoxy)phenyl]methanesulfonamide
TLC:Rf 0.50(methylene chloride:methanol=9:1);
NMR (CD;OD): § 1.40-1.49 (m, 2H), 1.79-1.90 (m, 2H), 2.15-2.32 (m, 2H), 2.39 (s, 6H), 2.80-2.90 (m, 2H), 2.92 (s, 3H), 3.14 (m, 1H), 3.40 (s, 2H), 4.68 (s, 2H), 6.87-7.15 (m, 10H), 7.20-7.32 (m, SH).
Example 29(74): N-[4-(4-{[4-((2-cyclopropylethyl){[(4-fluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl }phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.56(methylene chloride:methanol=9:1);
NMR (CD;0D): 8 0.10-0.16 (m, 2H), 0.44-0.53 (m, 2H), 0.74 (m, 1H), 1.48-1.60 (m, 2H), 1.95-2.07 (m, 2H), 2.12-2.30 (m, 2H), 2.95 (s, 3H), 3.07-3.19 (m, 2H), 3.35-3.43 (m, 2H), 3.51-3.62 (m, 2H), 4.17 (m, 1H), 4.29 (s, 2H), 6.97-7.10 (m, 6H), 7.26-7.37 (m, 4H), 7.50 (d, J=8.7 Hz, 2H).
Example 29(75):
N-{4-[4-({4-[{[(2,4-difluorophenyl)amino]carbonyl}(pyridin-2-ylmethyl)amino]piperidin- 1-yl}methyl)phenoxy]phenyl}methanesulfonamide dihydrochloride
TLC:Rf 0.71(chloroform:methanol=5:1);
NMR (CD;OD): 6 2.06-2.38 (m, 4H), 2.95 (s, 3H), 3.18 (m, 2H), 3.59 (m, 2H), 4.32 (s, 2H), 4.40 (m, 1H), 4.88 (s, 2H), 6.88-7.08 (m, 6H), 7.21-7.34 (m, 2H), 7.41 (m, 1H), 7.56 (brd, J = 8.4 Hz, 2H), 7.91 (m, 1H), 8.00 (m, 1H), 8.52 (m, 1H), 8.76 (brd, J] = 5.4 Hz, 1H).
Example 29(76):
N-[4-(4-{[4-(but-3-enyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.82(chloroform:methanol=5:1);
NMR (CD;OD): § 2.01 (m, 2H), 2.25 (m, 2H), 2.42 (m, 2H), 2.95 (s, 3H), 3.10 (m, 2H), 3.37 (m, 2H), 3.56 (m, 2H), 4.12 (m, 1H), 4.28 (m, 2H), 5.09 (brd, J = 9.9 Hz, 1H), 5.16 (brd, J = 17.1 Hz, 1H), 5.88 (m, 1H), 6.88-7.12 (m, 6H), 7.22-7.42 (m, 3H), 7.42-7.52 (m, 2H).
Oo
Example 29(77): 3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- ylJamino}carbonyl)amino]benzamide hydrochloride
TLC:Rf 0.45(chloroform:methanol=5:1);
NMR (CDs;OD): & 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.30 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 9.0 Hz, 2H), 7.38 (m, 1H), 7.49-7.52 (m, 4H), 7.84 (m, 1H).
Example 29(78):
N-(4-{4-[(4-{butyl[(1H-pyrazol-4-ylamino)carbonyl]amino } piperidin-1- yl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.47(chloroform:methanol=5:1);
NMR (CDsOD): 6 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.30 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 9.0 Hz, 2H), 7.52 (d, J =9.0 Hz, 2H), 8.10 (s, 2H).
Example 29(79):
N-{4-[4-({4-[butyl({[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4- ylJamino} carbonyl)amino]piperidin-1-yl} methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride
TLC:Rf 0.88(chloroform:methanol=5:1);
NMR (CDs;OD): 6 0.97 (t, J] = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.30 (m, 2H), 3.50- 3.60 (m, 2H), 3.90 (s, 3H), 4.10 (m, 1H), 4.28 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 9.0
Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H), 7.71 (s, 1H).
Example 29(80):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(1H-tetrazol-5-ylmethyl)amino]piperidin- 1-yl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.29(n-butanol:acetic acid:water=20:4:1);
NMR (CD;OD): § 1.98-2.25 (m, 4H), 2.95 (s, 3H), 3.15 (m, 2H), 3.58 (m, 2H), 4.30 (s, 2H), 4.34 (m, 1H), 4.84 (s, 2H), 6.98-7.08 (m, 6H), 7.24-7.41 (m, 4H), 7.51 (brd, J = 8.7
Hz, 2H).
® Oo
Example 29(81):
N-[4-(4-{[4-(but-3-enyl{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl }amino)piperidin-1- yl]lmethyl} phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.75(chloroform:methanol=5:1),
NMR (CD;0D): 6 1.98 (m, 2H), 2.21 (m, 2H), 2.35 (m, 2H), 2.95 (s, 3H), 3.12 (m, 2H), 3.24-3.38 (m, 2H), 3.57 (m, 2H), 3.87 (s, 3H), 4.12 (m, 1H), 4.29 (s, 2H), 5.00-5.20 (m, 2H), 5.76-5.94 (m, 1H), 7.00-7.10 (m, 4H), 7.22-7.34 (m, 2H), 7.42-7.60 (m, 3H), 7.73 (m, 1H).
Example 29(82):
N-{4-[4-({4-[{[(6-methylpyridin-3-yl)amino]carbonyl } (pyridin-2- ylmethyl)amino]piperidin-1-yl} methyl)phenoxy}phenyl } methanesulfonamide trihydrochloride
TLC:Rf 0.68(chloroform:methanol=5:1),
NMR (CD;0OD): 6 2.00 (m, 2H), 2.22 (m, 2H), 2.70 (s, 3H), 2.95 (s, 3H), 3.17 (m, 2H), 3.55 (m, 2H), 4.30 (s, 2H), 4.48 (m, 1H), 4.75 (s, 2H), 6.98-7.10 (m, 4H), 7.29 (brd, J = 9.0
Hz, 2H), 7.48-7.56 (m, 3H), 7.62 (m, 1H), 7.80 (d, J = 8.7 Hz, 1H), 8.02 (m, 1H), 842 (m, 1H), 8.63 (m, 1H), 9.02 (d, J] = 1.8 Hz, 1H).
Example 29(83):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl} (phenyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.49(methylene chloride:methanol=9:1);
NMR (CD;0D): & 1.60-1.80 (m, 2H), 2.12-2.21 (m, 2H), 2.95 (s, 3H), 3.10-3.21 (m, 2H), 3.42-3.52 (m, 2H), 4.22 (s, 2H), 4.66 (m, 1H), 6.95 (t, J = 9.0 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.19-7.35 (m, 6H), 7.42 (d, J = 8.7 Hz, 2H), 7.46-7.57 (m, 3H).
Example 29(84): N-(4-{4-[(4-{butyl[(1H-indol-5-ylamino)carbonyl]amino }piperidin-1- yl)methyl]phenoxy} phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.65(chloroform:methanol=5:1);
NMR (CD;0D): & 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.00 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.25 (s, 2H), 7.02-7.07 (m, 6H), 7.21 (s, 1H), 7.28-7.32 (m, 3H), 7.44 (m, 1H), 7.50 (d, J = 9.0 Hz, 2H).
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Example 29(85):
N-{4-[4-({4-[butyl({[1-methy]-3-(trifluoromethyl)- 1H-pyrazol-4- yl]amino} carbonyl)amino]piperidin-1-yl }methyl)phenoxy]pheny!} methanesulfonamide dihydrochloride
TLC:Rf0.84(chloroform:methanol=5:1);
NMR (CDs;0D): 6 0.96 (t, J = 7.2 Hz, 3H), 1.30-1.40 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.00 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 3.90 (s, 3H), 4.15 (m, 1H), 4.28 (s, 2H), 7.02-7.07 (m, 4H), 7.29 (d, J] =9.0
Hz, 2H) 7.51 (d, J = 9.0 Hz, 2H), 7.71 (s, 1H).
Example 29(86):
N-[4-(4-{[4-(butyl{[(2-fluoro-5-hydroxyphenyl)amino]carbonyl}amino)piperidin-1- yllmethyl } phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.82(chloroform:methanol=5:1);
NMR (CDsOD): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.00 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 6.52 (m, 1H), 6.88 (m, 1H), 6.95 (m, 1H), 7.02- 7.08 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 8.9 Hz, 2H).
Example 29(87):
N-{4-[4-({4-[[(cyclobutylamino)carbonyl}(1,3-thiazol-2-ylmethyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.68(chloroform:methanol=5:1);
NMR (CD;OD): § 1.60-1.78 (m, 2H), 1.84-2.36 (m, 8H), 2.95 (s, 3H), 3.12 (m, 2H), 3.56 (m, 2H), 4.16-4.30 (m, 2H), 4.29 (s, 2H), 4.81 (m, 2H), 7.00-7.12 (m, 4H), 7.29 (bid, J = 8.7 Hz, 2H), 7.52 (brd, J = 8.7 Hz, 2H), 7.77 (brd, J = 3.6 Hz, 1H), 7.92 (brd, J = 3.6 Hz, 1H).
Example 29(88): N-{4-[4-({4-[{[(6-methylpyridin-3-yl)amino]carbonyl}(1,3-thiazol-2- ylmethyl)amino]piperidin-1-yl} methyl)phenoxy ]phenyl} methanesulfonamide dihydrochloride
TLC:Rf 0.61(chloroform:methanol=5:1);
NMR (CD;OD): § 2.00-2.18 (m, 2H), 2.18-2.40 (m, 2H), 2.71 (s, 3H), 2.95 (s, 3H), 3.29 (m, 2H), 3.57 (m, 2H), 4.32 (s, 2H), 4.59 (m, 1H), 5.00 (s, 2H), 7.00-7.12 (m, 4H), 7.29 (brd, J = 9.0 Hz, 2H), 7.55 (brd, J] = 8.4 Hz, 2H), 7.77 (m, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.94 (brd, J = 2.1 Hz, 1H), 8.58 (m, 1H), 9.08 (brd, J = 2.1 Hz, 1H).
® 0
Example 29(89):
N-{4-[4-({4-[{[(2,4-difluorophenyl)amino]carbony!}(1,3-thiazol-2- ylmethyl)amino]piperidin-1-yl} methyl)phenoxy]pheny!} methanesulfonamide hydrochloride TLC:Rf0.73(chloroform:methanol=5:1);
NMR (CD;OD): § 2.00-2.32 (m, 4H), 2.95 (s, 3H), 3.12 (m, 2H), 3.57 (m, 2H), 429 (s, 2H), 4.32 (m, 1H), 4.91 (s, 2H), 6.90-7.12 (m, 6H), 7.29 (brd, J = 9.0 Hz, 2H), 7.39-7.60 (m, 3H), 7.70 (brd, J = 3.3 Hz, 1H), 7.88 (brd, J = 3.3 Hz, 1H).
Example 29(90):
N-(4-{4-[(4-{ {[(4-fluorophenyl)amino]carbonyl} [(2-methylpyridin-3- yl)methyl]amino } piperidin-1-yl)methyl}phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.67(chloroform:methanol=5:1);
NMR (CD;OD): § 2.00-2.11 (m, 2H), 2.12-2.38 (m, 2H), 2.82 (s, 3H), 2.95 (5, 3H), 3.13 (m, 2H), 3.54 (m, 2H), 4.29 (s, 2H), 4.49 (m, 1H), 4.69 (s, 2H), 6.96-7.10 (m, 6H), 7.14- 738 (m, 4H), 7.54 (brd, J = 8.4 Hz, 2H), 7.82 (m, 1H), 8.32 (m, 1H), 8.56 (d, ] = 5.4 Hz, 1H).
Example 29(91):
N-(4-{4-[(4-{ {[(2,4-difluorophenyl)amino]carbonyl} [(3-methylpyridin-2- yl)methyl]amino} piperidin-1-yl)methy!]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.55(methylene chloride: methanol=9:1),
NMR (CD;OD): § 2.08-2.35 (m, 4H), 2.62 (s, 3H), 2.95 (s, 3H), 3.12-3.25 (m, 2H), 3.52- 3.61 (m, 2H), 4.31 (s, 2H), 4.47 (m, 1H), 4.92 (s, 2H), 6.90-7.00 (m, 2H), 7.02 (d, 1 =8.7
Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.47 (dt, J = 6.0, 9.0 Hz, 1H), 7.56 (d, J =8.7 Hz, 2H), 7.89 (dd, J = 7.5, 5.7 Hz, 1H), 8.44 (d, J = 7.5 Hz, 1H), 8.57(d, J = 5.7 Hz, 1H).
Example 29(92):
N-(4-{4-[(4-{[(cyclobutylamino)carbonyl][(3-methylpyridin-2-yl)methylJamino } piperidin- 1-yl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.50(methylene chloride:methanol=9:1);
NMR (CD;OD): § 1.63-1.75 (m, 2H), 1.95-2.30 (m, 8H), 2.59 (s, 3H), 2.95 (s, 3H), 3.10- 3.22 (m, 2H), 3.49-3.58 (m, 2H), 4.20-4.37 (m, 4H), 4.74 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J=8.7H z, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.54 (d, J=8.7Hz, 2H), 7.86 (dd, J = 17.5, 6.0 Hz, 1H), 8.40 (d, J =7.5 Hz, 1H), 8.51 (d, J = 6.0 Hz, 1H).
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Example 29(93):
N-(4-{4-[(4-{{[(6-methylpyridin-3-yl)amino]carbonyl }[(3-methylpyridin-2- yl)methyl]amino}piperidin-1-yl)methyl]phenoxy } phenyl)methanesulfonamide trihydrochloride
TLC:Rf 0.47(methylene chloride: methanol=9:1);
NMR (CD;OD): § 2.10-2.39 (m, 4H), 2.64 (s, 3H), 2.71 (s, 3H), 2.95 (s, 3H), 3.22-3.35 (m, 2H), 3.50-3.60 (m, 2H), 4.32 (s, 2H), 4.75 (m, 1H), 4.96 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.28 (d, J =8.7 Hz, 2H), 7.57 (d, ] = 8.7 Hz, 2H), 7.83 (d, J = 8.7
Hz 1H), 7.89 (dd, J = 7.5, 5.1 Hz, 1H), 8.44 (d, J = 7.5 Hz, 1H), 8.57 (d, J = 5.1 Hz, 1H), 8.68 (dd, J=8.7, 2.4 Hz, 1H), 9.12 (d, J = 2.4 Hz, 1H).
Example 29(94):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbony!} (pyrimidin-2-ylmethyl)amino ]piperidin- 1-yl}methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride
TLC Rf 0.40(methylene chloride:methanol=9:1);
NMR (DMSO-ds): 6 1.80-1.89 (m, 2H), 2.10-2.30 (m, 2H), 2.96 (s, 3H), 2.97-3.10 (m, 2H), 4.21 (s, 2H), 4.36 (m, 1H), 4.70 (s, 2H), 6.98-7.07 (m, 6H), 7.28 (d, J = 8.7 Hz, 2H), 7.35- 7.43 (m, 3H), 7.55 (d, J = 8.7 Hz, 2H), 8.60 (m, 1H), 8.78 (d, J = 5.1 Hz, 2H), 9.35 (m, 1H).
Example 29(95):
N-[4-(4-{[4-(butyl {[(2,4,6-trifluorophenyl)amino]carbonyl }amino)piperidin-1- ylJmethyl }phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.71(chloroform:methanol=5:1);
NMR (CD;OD): 6 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 6.88-6.94 (m, 2H), 7.02-7.07 (m, 4H), 7.29 (d, J = 9.2 Hz, 2H), 7.51 (d, J =9.2 Hz, 2H).
Example 29(96):
N-(4-{4-[(4-{{[(2-hydroxybutyl)amino]carbonyl }[ (3-methylpyridin-2- yl)methylJamino} piperidin-1-yl)methyl]phenoxy } phenyl)methanesulfonamide dihydrochloride
TLC:Rf 0.39(methylene chloride: methanol=9:1);
NMR (CD;OD): 6 0.96 (t, J = 7.2 Hz, 3H), 1.37-1.58 (m, 2H), 1.97-2.25 (m, 4H), 2.60 (s, 3H), 2.95 (s, 3H), 3.10-3.23 (m, 4H), 3.50-3.67 (m, 3H), 4.27-4.38 (m, 3H), 4.80 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.55 (d, ] = 8.7
Hz, 2H), 7.88 (dd, J = 7.8, 6.0 Hz, 1H), 8.42 (d, J= 7.8 Hz, 1H), 8.54 (d, J = 6.0 Hz, 1H).
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Example 29(97):
N-{4-[4-({4-[[(cyclobutylamino)carbonyl](pyridin-2-ylmethyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride TLC:RfO0.54(chloroform:methanol=5:1),
NMR (CD;OD): § 1.60-1.74 (m, 2H), 1.90-2.30 (m, 8H), 2.95 (s, 3H), 3.11 (m, 2H), 3.56 (m, 2H), 4.18-4.32 (m, 2H), 4.30 (s, 2H), 4.72 (s, 2H), 7.00-7.10 (m, 4H), 7.29 (brd, J = 9.0
Hz, 2H), 7.53 (brd, J = 8.7 Hz, 2H), 7.80-7.92 (m, 2H), 8.44 (m, 1H), 8.71 (brd, J = 5.4 Hz, 1H).
Example 29(98):
N-{4-[4-({4-[{[(2-hydroxybutyl)amino]carbonyl } (2-methylbenzyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl}methanesulfonamide hydrochloride
TLC:Rf 0.61 (chloroform methanol=5:1);
NMR (CDsOD): 8 0.90 (t, J = 7.5 Hz, 3H), 1.20-1.50 (m, 2H), 1.90-2.02 (m, 4H), 2.32 (s, 3H), 2.95 (s, 3H), 3.00-3.34 (m, 4H), 3.42-3.51 (m, 3H), 4.24 (s, 2H), 4.39 (s, 2H), 4.41 (m, 1H), 6.98-7.04 (m, 4H), 7.08-7.20 (m, 4H), 7.28 (brd, 9.0 Hz, 2H), 7.45 (brd, J = 8.4 Hz, 2H).
Example 29(99): 5-[({butyl{1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino } carbonyl)amino]-2-fluorobenzamide hydrochloride
TLC:Rf 0.67(chloroform:methanol=5:1);
NMR (CD;OD): 8 0.97 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 7.02-7.07 (m, 4H), 7.13 (m, 1H), 7.29 (d,J =9.0
Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 7.52 (m, 1H), 7.78 (m, 1H).
Example 29(100): 3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperidin-4- yl]amino} carbonyl)amino]-2,6-difluorobenzamide hydrochloride
TLC:Rf 0.64(chloroform:methanol=5:1),
NMR (CD;OD): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.20 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 7.02-7.07 (m, SH), 7.29 (d, J = 8.7 Hz, 2H), 7.44 (m, 1H), 7.49 (d, J = 8.7 Hz, 2H).
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Example 29(101): 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino }carbonyl)amino]-2,4-difluorobenzamide hydrochloride
TLC:Rf 0.65(chloroform:methanol=5:1),
NMR (CD;OD): 8 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.10 (m, 1H), 4.28 (s, 2H), 7.02-7.07 (m, 4H), 7.17 (t, J = 10.5 Hz, 1H), 7.29 (d, J =9.0 Hz, 2H), 7.49 (d, ] = 9.0 Hz, 2H), 7.85 (m, 1H).
Example 29(102):
N-[4-(4-{[4-(butyl {[(3-cyano-4-fluorophenyl)amino]carbonyl } amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.66(chloroform:methanol=5:1);
NMR (CD;0D): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3 20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 7.02-7.07 (m, 4H), 7.23-7.31 (m, 3H), 7.50 (d, J = 8.7 Hz, 2H), 7.66 (m, 1H), 7.91 (m, 1H).
Example 29(103): N-[4-(4-{[4-(butyl{[(5-cyano-2,4-difluorophenyl)amino]carbonyl } amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.64(chloroform:methanol=5:1);
NMR (CD;OD): 6 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3 20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.10 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.35 (m, 1H) 7.49 (d, ] = 8.9 Hz, 2H), 7.87 (m, 1H).
Example 29(104):
N-[4-(4-{[4-((2-fluorophenyl){[(4-fluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.51(methylene chloride: methanol=9:1),
NMR (CD;OD): § 1.55-1.80 (m, 2H), 2.16-2.23 (m, 2H), 2.95 (s, 3H), 3.10-3.22 (m, 2H), 3.47-3.56 (m, 2H), 4.23 (s, 2H), 4.64 (m, 1H), 6.93-7.06 (m, 6H), 7.20-7.45 (m, 9H), 7.51 (m, 1H).
Example 29(105):
N-[4-(4-{[4-((3-fluorophenyl){[(4-fluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl } phenoxy)phenylJmethanesulfonamide hydrochloride
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TLC:Rf 0.52(methylene chloride: methanol=9:1),
NMR (CD;0D): § 1.63-1.82 (m, 2H), 2.1202.23 (m, 2H), 2.95 (s, 3H), 3.10-3.21 (m, 2H), 3.44-3.55 (m, 2H), 4.23 (s, 2H), 4.64 (m, 1H), 6.93-7.07 (m, 6H), 7.15 (d, J = 6.9 Hz, 2H), 7.20-7.32 (m, SH), 7.42 (d, J = 8.7 Hz, 2H), 7.54 (q, J = 6.9 Hz, 1H).
Example 29(106):
N-[4-(4-{[4-((4-fluorophenyl){ [(4-fluorophenyl)amino]carbonyl } amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.54(methylene chloride:methanol=9:1),
NMR (CD;OD): 5 1.59-1.79 (m, 2H), 2.10-2.20 (m, 2H), 2.95 (s, 3H), 3.09-3.21 (m, 2H), 3.45-3.54 (m, 2H), 4.22 (s, 2H), 4.64 (m, 1H), 6.91-7.05 (m, 6H), 7.20-7.38 (m, 8H), 7.43 (d, J =8.7 Hz, 2H).
Example 29(107): N-[4-(4-{[4-(butyl{[(4-cyano-2-fluorophenyl)amino]carbonyl } amino)piperidin-1- ylJmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.81(chloroform:methanol=5:1);
NMR (CD;OD): 8 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.07 (m, 4H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (m, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.56 (dd, J = 10.5, 1.8 Hz, 1H), 7.83 (m, 1H).
Example 29(108):
N-{4-[4-({4-[ {[(4-fluorophenyl)amino]carbonyl} (pyridin-3-yl)amino]piperidin-1- yl}methyl)phenoxy]phenyl}methanesulfonamide dihydrochloride
TLC:Rf 0.46(methylene chloride: methanol=9:1);
NMR (CD;0D): 8 1.95-2.10 (m, 2H), 2.18-2.24 (m, 2H), 2.95 (s, 3H), 3.11-3.23 (m, 2H), 3.49-3.58 (m, 2H), 4.26 (s, 2H), 4.64 (m, 1H), 6.97-7.07 (m, 6H), 7.26-7.35 (m, 4H), 7.50 (d, J = 8.7 Hz, 2H), 8.15 (dd, J = 8.7, 5.7 Hz, 1H), 8.58 (dq, J = 8.7, 2.4 Hz, 1H), 8.89 (d, J =5.7Hz 1H), 904 (d,J=2.4 Hz 1H).
Example 29(109):
N-{4-[4-({4-[ {[(4-fluorophenyl)amino]carbonyl }(2-methylphenyl)amino]piperidin-1- yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride TLC:Rf0.57(methylene chloride: methanol=9:1); :
NMR (CD;0D): 6 1.62 (m, 1H), 1.97-2.10 (m, 2H), 2.28-2.40 (m, 4H), 2.95 (s, 3H), 3.07- 3.20 (m, 2H), 3.40-3.57 (m, 2H), 4.22 (s, 2H), 4.55 (m, 1H), 6.95 (t, J = 9.0 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.08-7.47 (m, 10H).
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Example 29(110):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(3-methylphenyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride TLC:Rf0.57(methylene chloride:methanol=9:1);
NMR (CD;OD): & 1.62-1.80 (m, 2H), 2.11-2.20 (m, 2H), 2.40 (s, 3H), 2.95 (s, 3H), 3.09- 3.21 (m, 2H), 3.45-3.54 (m, 2H), 4.23(s, 2H), 4.63 (m, 1H), 6.95 (t, J = 9.0 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 7.5 Hz, 1H), 7.15 (s, 1H), 7.21 (dd, J=9.0, 5.0 Hz, 2H), 7.25-7.35 (m, 3H), 7.40 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H).
Example 29(111):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(4-methylphenyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf0.58(methylene chloride:methanol=9:1),
NMR (CD;OD): § 1.59-1.78 (m, 2H), 2.10-2.20 (m, 2H), 2.40 (s, 3H), 2.95 (s, 3H), 3.08- 3.20 (m, 2H), 3.44-3.50 (m, 2H), 4.21 (s, 2H), 4.67 (m, 1H), 6.95 (t, J] = 9.0 Hz, 2H), 6.98- 7.08 (m, 4H), 7.18-7.23 (m, 4H), 7.29 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.42 (d,
J =8.7 Hz, 2H).
Example 29(112):
N-[4-(4-{[4-(butyl{[(2-hydroxyphenyl)amino]carbonyl}amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.63(ethyl acetate);
NMR (CDs;0D): 8 1.00 (t, J = 7.2 Hz, 3H), 1.37-1.49 (m, 2H), 1.63-1.71 (m, 2H), 1.98- 2.03 (m, 2H), 2.14-2.27 (m, 2H), 2.96 (s, 3H), 3.09-3.17 (m, 2H), 3.25-3.30 (m, 2H), 3.55- 3.59 (m, 2H), 4.24 (m, 1H), 4.30 (s, 2H), 6.76-6.94 (m, 3H), 7.04 (d, J = 8.7 Hz, 2H), 7.07 (d, 1 =8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.50 (d, J] = 8.7 Hz, 2H), 7.59 (dd, J = 7.8, 1.5
Hz, 1H).
Example 29(113):
N-{2-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperidin-4- yl]Jamino }carbonyl)amino]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.50(chloroform:methanol=10:1);
NMR (CD;OD): 8 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 2.00- 2.10 (m, 2H), 2.10-2.20 (m, 2H), 2.95 (s, 3H), 2.97 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.60-3.80 (m, 2H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 7.15 (m, 1H), 7.26-7.31 (m, 4H), 7.50 (d, J = 9.0 Hz, 2H), 7.75 (d, ] = 8.1 Hz, 1H).
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Example 29(114):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(4-methylbenzyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride TLC:Rf 0.71(chloroform:methanol=5:1),
NMR (CD;0D): § 7.47 (brd, J = 8.7 Hz, 2H), 7.36-7.14 (m, 8H), 7.10-6.92 (m, 6H), 4.60 (brs, 2H), 4.37 (m, 1H), 4.25 (s, 2H), 3.50 (m, 2H), 3.09 (m, 2H), 2.95 (s, 3H), 2.30 (s, 3H), 2.26-1.84 (m, 4H).
Example 29(115):
N-[4-(4-{[4-(butyl{[(3,4-dihydroxyphenyl)amino]carbonyl }amino)piperidin-1- yllmethyl}phenoxy)phenyljmethanesulfonamide hydrochloride
TLC:Rf 0.40(chloroform:methanol=10:1),
NMR (CDs;0D): 8 0.96 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 6.58 (dd, ] = 8.4, 2.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.50 (d,] = 8.9
Hz, 2H).
Example 29(116):
N-[4-(4-{[4-((cyanomethyl){[(4-fluorophenyl)amino]carbony}}amino)piperidin-1- yl]methyl }phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.55(chloroform:methanol=5:1);
NMR (CD;0D): 6 2.00-2.28 (m, 4H), 2.95 (s, 3H), 3.00-3.10 (m, 2H), 3.50-3.65 (m, 2H), 4.04-4.30 (m, SH), 7.00-7.20 (m, 4H), 7.25-7.52 (m, 8H).
Example 29(117):
N-{4-[4-({4-[butyl({[3-(2H-tetrazol-5-yl)phenyl]amino } carbonyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf0.09(chloroform:methanol=5:1),
NMR (CD3;0D): § 0.97 (t, J = 7.2 Hz, 3H), 1.40 (m, 3H), 1.62 (m, 3H), 1.88 (m, 2H), 2.60 (m, 4H), 2.94 (s, 3H), 3.24 (m, 2H), 3.92 (s,2H), 4.18 (m, 1H), 7.00 (m, 4H), 7.20-7.50 (m, 5H), 7.71 (brd, J = 7.8 Hz, 1H), 7.86 (m,H).
Example 29(118):
N-[4-(4-{[4-(but-3-en-1-yl{[(6-methylpyridin-3-yl)amino]carbonyl } amino)piperidin-1- yl]methyl} phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.51(methylene chloride: methanol=9:1);
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NMR (CD;0D): 6 1.98-2.09 (m, 2H), 2.22-2 45 (m, 4H), 2.70 (s, 3H), 2.95 (s, 3H), 3.12- 3.25 (m, 2H), 3.42 (t, J = 7.8 Hz, 2H), 3.54-3.66 (m, 2H), 4.26 (m, 1H), 4.31 (s, 2H), 5.08 (d, J=102Hz, 1H), 5.15 (d, J = 17.1 Hz, 1H), 5.85 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.07 (d, J =8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 9.0 Hz, 1H), 8.47 (dd, J =9.0,.2.4 Hz, 1H), 9.02 (d, J = 2.4 Hz, 1H).
Example 29(119):
N-(4-{4-[(4-{but-3-en-1-yl[(cyclobutylamino)carbonyl]Jamino} piperidin-1- yl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride TLC:Rf0.61(methylene chloride:methanol=9:1);
NMR (CD;0D): 6 1.62-1.74 (m, 2H), 1.88-2.35 (m, 10H), 2.95 (s, 3H), 3.02-3.15 (m, 2H), 3.20 (t, J = 7.8 Hz, 2H), 3.50-3.59 (m, 2H), 4.06 (m, 1H), 4.20 (m, 1H), 4.28 (s, 2H), 5.05 (d, J=10.2 Hz, 1H), 5.11 (dd, J = 17.1, 2.1 Hz, 1H), 5.81 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J =8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(120):
N-{4-[4-({4-[[(cyclobutylamino)carbonyl](3-methylbut-2-en-1-yl)amino]piperidin-1- yl }methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.60(methylene chloride: methanol=9:1),
NMR (CD;OD): 1.60-2.18 (m, 14H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.02-3.15 (m, 2H), 3.49-3.59 (m, 2H), 3.77-3.82 (m, 2H), 4.15-4.25 (m, 2H), 4.27 (s, 2H), 5.06 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H).
Example 29(121):
N-{4-[4-({4-[{[(cis-4-hydroxycyclohexyl)amino]carbonyl}(3-methylbut-2-en-1- yl)amino]piperidin-1-yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.45(methylene chloride: methanol=9:1);
NMR (CD;0D): § 1.54-1.70 (m, 8H), 1.74 (s, 6H), 1.80-2.10 (m, 4H), 2.95 (s, 3H), 3.05- 3.15 (m, 2H), 3.49-3.66 (m, 3H), 3.74-3.84 (m, 3H), 4.27 (s, 2H), 4.31 (m, 1H), 5.08 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 29(122): N-{4-[4-({4-[{[(cis-4-hydroxycyclohexyl)amino]carbonyl }(2- : methylbenzyl)amino]piperidin-1-yl}methyl)phenoxy]phenyl } methanesulfonamide hydrochloride
TLC:Rf 0.51 (methylene chloride: methanol=9:1);
® Oo
NMR (CD;0D): 8 1.50-1.60 (m, 8H), 1.90-2.03 (m, 4H), 2.33 (s, 3H), 2.95 (s, 3H), 3.02- 3.14 (m, 2H), 3.45-3.53 (m, 2H), 3.63 (m, 1H), 3.79 (m, 1H), 4.24 (s, 2H), 4.40 (s, 2H), 4.45 (m, 1H), 7.01 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.07-7.21 (m, 4H), 7.28 (d,
J = 8.7 Hz, 2H), 7.46 (d, J] = 8.7 Hz, 2H).
Example 29(123):
N-[4-(4-{[4-((2-methylbenzyl){[(]1-methyl- 1H-pyrazol-4- yl)amino]carbonyl }amino)piperidin-1-yl]Jmethyl } phenoxy)phenyl]methanesulfonamide dihydrochloride TLC:Rf0.53(methylene chloride:methanol=9:1);
NMR (CD;OD): 5 1.91-2.19 (m, 4H), 2.35 (s, 3H), 2.95 (s, 3H), 3.06-3.17 (m, 2H), 3.44- 3.52 (m, 2H), 3.94 (s, 3H), 4.29 (s, 2H), 4.49 (m, 1H), 4.52 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06-7.20 (m, 4H), 7.28 (d, J = 8.7 Hz, 2H), 7.48 (d, ] = 8.7
Hz, 2H), 7.77 (s, 1H), 7.94 (s, 1H).
Example 29(124):
N-(4-{4-[(4-{{[(1-methyl-1H-pyrazol-4-yl)amino]carbonyl } [(3-methylpyridin-2- yl)methyl]amino}piperidin-1-yl)methylJphenoxy } phenyl)methanesulfonamide trihydrochloride TLC:Rf 0.49(methylene chioride:methanol=9:1);
NMR (CD;OD): & 2.00-2.10 (m, 2H), 2.18-2.35 (m, 2H), 2.63 (s, 3H), 2.95 (s, 3H), 3.18- 3.34 (m, 2H), 3.50-3.60 (m, 2H), 3.96 (s, 3H), 4.32 (s, 2H), 4.54 (m, 1H), 4.91 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.57 (d, ] = 8.7
Hz, 2H), 7.89 (dd, J = 7.8, 6.0 Hz, 1H), 7.94 (s, 1H), 8.06 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 854(d,J=6.0Hz 1H).
Example 29(125):
N-[4-(4-{[4-((3-methylbut-2-en-1-yl){[(1-methyl- 1H-pyrazol-4- yl)amino]carbonyl }amino)piperidin-1-ylJmethyl } phenoxy)phenylJmethanesulfonamide dihydrochloride
TLC:Rf 0.52(methylene chloride:methanol=9:1);
NMR (CD;0D): 6 1.72 (s, 3H), 1.73 (s, 3H), 1.90-2.22 (m, 4H), 2.95 (s, 3H), 3.08-3.20 (m, 2H), 3.50-3.60 (m, 2H), 3.90-3.97 (m, 2H), 3.97 (s, 3H), 4.23-4.32 (m, 3H), 5.12 (m, 1H), 7.03 (d, ] = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, ] = 8.7 Hz, 2H), 7.51 (d, ] = 8.7
Hz 2H), 7.85(s, 1H), 7.98 (s, 1H).
® Oo
Example 29(126):
N-{3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino }carbonyl)amino]-2,4-difluorophenyl acetamide hydrochloride
TLC:Rf 0.44(chloroform:methanol=5:1);
NMR (CDs;OD): § 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.14 (s, 3H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 6.97-7.08 (m, 5H), 7.29 (d,] = 9.0
Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H), 7.65 (m, 1H).
Example 29(127):
N-{5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino } carbonyl)amino]-2,4-difluorophenyl}acetamide hydrochloride
TLC:Rf 0.56(chloroform:methanol=5:1);
NMR (CDs;OD): § 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.14 (s, 3H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.15 (m, 1H), 4.28 (s, 2H), 7.02-7.10 (m, SH), 7.29 (d, J = 8.9
Hz, 2H), 7.49 (d, J = 8.9 Hz, 2H), 7.95 (t, = 7.5 Hz, 1H).
Example 29(128): N-{3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperidin-4- yl]amino }carbonyl)amino]-4-fluorophenyl } acetamide hydrochloride
TLC Rf 0.48(chloroform:methanol=5:1);
NMR (CDsO0D): § 0.98 (t, J = 7.5 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.10 (s, 3H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.15 (m, 1H), 4.29 (s, 2H), 7.02-7.09 (m, 5H), 7.25 (m, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.77 (dd, = 6.9, 2.4 Hz, 1H).
Example 29(129):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(tetrahydro-2H-pyran-4- yl)amino]piperidin-1-yl}methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.50(methylene chloride: methanol=9:1);
NMR (CD;0D): § 1.65-1.78 (m, 2H), 1.80-1.90 (m, 2H), 1.95-2.08 (m, 2H), 2.78-2.92 (m, 2H), 2.95 (s, 3H), 3.03-3.18 (m, 2H), 3.47-3.60 (m, SH), 3.88-4.05 (m, 3H), 4.27 (s, 2H), 6.97-7.09 (m, 6H), 7.23-7.31 (m, 4H), 7.48 (d, J = 8.7 Hz, 2H).
Example 29(130):
N-[4-(4-{[4-(butyl{[(1,3-dimethy]-1H-pyrazol-4-yl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide dihydrochloride
® ©O
TLC:Rf 0.66(chloroform:methanol=4:1),
NMR (CD;0D): § 0.97 (t, J = 7.5 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.28 (s, 3H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 3.99 (s, 3H), 4.20 (m, 1H), 4.29 (s, 2H), 7.02-7.08 (m, 4H), 729(d,J=9.0Hz 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.95 (m, 1H).
Example 29(131):
N-[4-(4-{[4-({[(4-fluorophenyl)amino]carbonyl } {[3-(trifluoromethyl)pyridin-2- yl]methyl } amino)piperidin-1-yl]Jmethyl }phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.56(methylene chloride:methanol=9:1);
NMR (CD;0D): 6 1.95-2.12 (m, 4H), 2.95 (s, 3H), 3.08-3.21 (m, 2H), 3.47-3.58 (m, 2H), 4.27 (s, 2H), 4.38 (m, 1H), 4.90 (s, 2H), 6.95-7.06 (m, 6H), 7.25-7.35 (m, 4H), 7.48 (d, J] = 8.7 Hz, 2H), 7.62 (dd, J = 8.0, 5.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.81 (d, J = 5.0 Hz, 1H).
Example 30(1)-Example 30(12)
By the same procedure as described in Example 25, using a corresponding amine derivative instead of (3-{[t-butyl(dimethyl)silyloxy}butyl)amine, the following compounds of the present invention were obtained.
Example 30(1):
N-[4-(4-{[4-(butyl{[(3S)-piperidin-3-ylamino]carbonyl } amino)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide dihydrochloride
H H
SUNSRONSE
PY 0 0
N° 'N (0)
H
I + 2HCI
H;C
TLC:Rf 0.15(n-butanol:acetic acid:water=4:2:1);
NMR (DMSO-dg): 8 0.91 (t, J = 7.1 Hz, 3H), 1.20-1.40 (m, 2H), 1.40-1.60 (m, 2H), 1.60- 2.00 (m, 6H), 2.20-2.40 (m, 2H), 2.80-3.60 (m, 10H), 2.96 (s, 3H), 3.99 (m, 1H), 4.15 (m, 1H), 4.18 (s, 2H), 6.23 (m, 1H), 7.03 (d, J = 7.2 Hz, 4H), 7.28 (d, J = 8.7 Hz, 2H), 7.61 (d,
J=8.7 Hz 2H), 8.83 (m, 1H), 9.35 (m, 1H), 9.47 (m, 1H).
® ©
Example 30(2):
N-[4-(4-{[4-(butyl{[(3R)-piperidin-3-ylamino]carbonyl }amino)piperidin-1- yl]lmethyl}phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.15(n-butanol acetic acid:water=4:2:1);
NMR (DMSO-de): 6 0.91 (t, J = 7.4 Hz, 3H), 1.20-1.40 (m, 2H), 1.40-1.60 (m, 2H), 1.60- 2.00 (m, 6H), 2.20-2.40 (m, 2H), 2.80-3.60 (m, 10H), 2.96 (s, 3H), 3.98 (m, 1H), 4.15 (m, 1H), 4.20 (s, 2H), 6.22 (m, 1H), 7.03 (d, J = 8.7 Hz, 4H), 7.28 (d, J = 7.7 Hz, 2H), 7.61 (d,
J =7.7 Hz, 2H), 8.83 (m, 1H), 9.36 (m, 1H), 9.47 (m, 1H).
Example 30(3):
N-[4-(4-{[4-(butyl {[(3-methylisothiazol-5-yl)amino]carbonyl }amino)piperidin-1- yllmethyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.35(chloroform:methanol=10:1),
NMR (CD;0D): § 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.00- 2.10 (m, 2H), 2.30-2.40 (m, 2H), 2.56 (s, 3H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.31 (s, 2H), 7.02-7.08 (m, 5H), 7.29 (d, J = 8.9
Hz, 2H), 7.53 (d, ] = 8.9 Hz, 2H).
Example 30(4): N-[4-(4-{[4-(butyl{[(3-methyl-1,2-benzisothiazol-5-yl)amino]carbonyl}amino)piperidin-1- yl]methyl} phenoxy)phenylJmethanesulfonamide hydrochloride
TLC:Rf 0.46(chloroform:methanol=10:1);
NMR (CDsOD): 6 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 2.00- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.70 (s, 3H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.20 (m, 1H), 4.30 (s, 2H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.9
Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.60 (dd, J = 9.0, 1.7 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 8.08 (d,J =1.7 Hz, 1H).
Example 30(5): N-[4-(4-{[4-(butyl{[(1-methyl-1H-pyrazol-5-yl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenylJmethanesulfonamide dihydrochloride
TLC:Rf 0.30(chloroform:methanol=10:1),
NMR (CD;OD): 8 0.98 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 2.00- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 3.78 (s, 3H), 4.20 (m, 1H), 4.29 (s, 2H), 6.34 (d, J = 2.4 Hz, 1H), 7.02-7.08 (m, 4H), 7.29 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 8.9 Hz, 2H), 7.79 (d, J = 2.4 Hz, 1H).
® ©
Example 30(6):
N-[4-(4-{[4-(butyl {[(3-hydroxycyclohexyl)amino]carbonyl }amino)piperidin-1- yl]methyl}phenoxy)phenyl]methanesulfonamide hydrochloride
TLC:Rf 0.24(methylene chloride: methanol=9:1);
NMR (CD;OD): § 0.95 (t, J = 7.2 Hz, 3H), 1.23-2.20 (m, 16H), 2.95 (s, 3H), 3.02-3.16 (m, 4H), 3.50-3.59 (m, 2H), 3.66 (m, 1H), 3.95-4.22 (m, 2H), 4.28 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H).
Example 30(7):
N-[4-(4-{[4-(butyl{[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]carbonyl}amino)piperidin-1- yllmethyl}phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.60(chloroform:methanol=5:1);
NMR (CDs;OD): 4 0.98 (t, J = 7.2 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.27 (s, 6H), 2.95 (s, 3H), 3.10-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50-3.60 (m, 2H), 3.93 (s, 3H), 4.24 (m, 1H), 4.30 (s, 2H), 7.02-7.07 (m, 4H), 7.29 (d, J =8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H).
Example 30(8): 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- ylJamino}carbonyl)amino}-2,4-difluorobenzoic acid hydrochloride
TLC:Rf 0.17(chloroform:methanol=5:1);
NMR (CD;OD): § 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.30 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.10 (m, 1H), 4.25 (s, 2H), 7.01-7.06 (m, SH), 7.29 (d, J = 8.7 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 7.89 (m, 1H).
Example 30(9): 5-[({butyl][ 1-(4- {4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- ylJamino }carbonyl)amino]-2-fluorobenzoic acid hydrochloride
TLC:RfO0.21(ethyl acetate: methanol=7:1);
NMR (CD;OD): 6 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.30 (s, 2H), 7.02-7.08 (m, 4H), 7.12 (d, ] = 9.0 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.53 (d, ] = 8.7 Hz, 2H), 7.58 (m, 1H), 7.92 (m, 1H). ;
Example 30(10): 3-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino } carbonyl)amino]-2,6-difluorobenzoic acid hydrochloride
® Oo
TLC:Rf 0.21(ethyl acetate:methanol=7:1);
NMR (CD;0D): 6 0.97 (t, J = 7.4 Hz, 3H), 1.30-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.20-3.40 (m, 2H), 3.50- 3.60 (m, 2H), 4.20 (m, 1H), 4.28 (s, 2H), 6.90 (m, 1H), 7.02-7.07 (m, 4H), 7.29 (d, J = 8.9
Hz 2H), 7.40 (m, 1H), 7.50 (d, J= 8.9 Hz, 2H).
Example 30(11): 2,4-difluoro-5-[({[(3-methylpyridin-2-yl)methyl][ 1-(4-{4- [(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- ylJamino}carbonyl)amino]benzamide dihydrochloride
TLC:Rf 0.70(chloroform:methanol=4:1);
NMR (CD;0D): 6 2.10-2.20 (m, 2H), 2.20-2.40 (m, 2H), 2.62 (s, 3H), 2.95 (s, 3H), 3.00- 3.20 (m, 2H), 3.50-3.60 (m, 2H), 4.31 (s, 2H), 4.50 (m, 1H), 7.00-7.06 (m, 4H), 7.17 (t, J = 10.2 Hz, 1H), 7.28 (d, J =9.0 Hz, 2H), 7.56 (d, ] = 9.0 Hz, 2H), 7.90-7.98 (m, 2H), 8.44 (d,
J=72Hz 1H), 857 (d, J=8.7 Hz, 1H).
Example 30(12): 5-[({but-3-en-1-yl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]Jamino}carbonyl)amino]-2,4-difluorobenzamide hydrochloride TILC:Rf0.63(chloroform:methanol=4:1),
NMR (CD3;OD): § 2.10-2.20 (m, 2H), 2.20-2.30 (m, 2H), 2.40-2.50 (m, 2H), 2.95 (s, 3H), 3.00-3.20 (m, 2H), 3.30-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.10 (m, 1H), 4.29 (s, 2H), 5.08- 5.19 (m, 2H), 5.85 (m, 1H), 7.02-7.08 (m, 4H), 7.14 (t, J = 10.4 Hz, 1H), 7.29 (d, J =8.9
Hz, 2H), 7.49 (d, J = 8.9 Hz, 2H), 7.86 (m, 1H).
Example 31(1) and Example 31(2)
By the same procedure as described in Example 27, using O- benzylhydroxyamine or a corresponding amine derivative, and using the compound prepared in Example 3 instead of N-(4-{4-[(4-aminopiperidin-1- yl)methyl]phenoxy }phenyl)methanesulfonamide, the following compounds of the present invention were obtained.
Example 31(1):
N-{4-[4-({4-[{[(benzyloxy)amino]carbonyl}(butyl)amino]piperidin-1- 35S yl}methyl)phenoxy]jphenyl}methanesulfonamide hydrochloride =
H
N...CH
USSSA r:Y
O.
N° 'N (0)
H
I « HCI
H;C
TLC:Rf 0.53(methylene chloride: methanol=9:1);
NMR (CDsOD): § 0.90 (t, ] = 7.2 Hz, 3H), 1.21-1.32 (m, 2H), 1.40-1.52 (m, 2H), 1.87- 1.97 (m, 2H), 2.11-2.30 (m, 2H), 2.95 (s, 3H), 2.98-3.13 (m, 4H), 3.47-3.58 (m, 2H), 3.97 (m, 1H), 4.27 (s, 2H), 4.79 (s, 2H), 7.03 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.27- 7.44 (m, 7H), 7.49 (d, J = 8.7 Hz, 2H).
Example 31(2):
N-[4-(4-{[4-(butyl{[(2-methyl-1,3-benzothiazol-6-yl)amino]carbonyl }amino)piperidin-1- yl]lmethyl}phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf 0.74(chloroform:methanol=5:1);
NMR (CD;0D): 6 0.96 (t, J = 7.1 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 1.90- 2.10 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 2.99 (s, 3H), 3.10-3.30 (m, 2H), 3.30-3.40 (m, 2H), 3.50-3.60 (m, 2H), 4.30 (m, 1H), 4.31 (s, 2H), 7.01-7.05 (m, 4H), 7.29 (d,] = 8.9
Hz, 2H), 7.56 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 8.23 (s, 1H).
Example 32:
N-[4-(4-{[4-([(3,5-dimethylisoxazol-4-yl)methyl]{ [(4- fluorophenyl)amino]carbonyl} amino)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide hydrochloride - HCI H
F N...CH 0 N Gl 7
J oo
H;C ©
By the same procedure as described in Example 1, using N-(4-{4-[(4- aminopiperidin-1-yl)methyl]phenoxy}phenyl)methanesulfonamide used in Example 27 and 3,5-dimethylisoxazole-4-carboaldehyde instead of 4-hydroxypiperidine and 4-(4-
® Oo methylsulfonylaminophenoxy)benzaldehyde respectively, a compound was obtained. By the same procedure as described in Example 23, using the obtained compound and 4- fluorobenzoic acid instead of the compound prepared in Example 3 and I- methylcyclohexane respectively, the title compound (100.2 mg) having the following physical data was obtained.
TLC:Rf 0.56(methylene chloride: methanol=9:1);
NMR (CD30D): 6 1.91-2.00 (m, 2H), 2.12-2.32 (m, 2H), 2.25 (s, 3H), 2.39 (s, 3H), 2.95 (s, 3H), 3.02-3.16 (m, 2H), 3.48-3.57 (m, 2H), 4.05 (m, 1H), 4.26 (s, 2H), 4.42 (s, 2H), 6.97- 7.08 (m, 6H), 7.25-7.37 (m, 4H), 7.49 (d, J = 8.7 Hz, 2H).
Example 32(1)-Example 32(4)
By the same procedure as described in Example 32, using a corresponding aldehyde derivative instead of 3,5-dimethylisoxazole-4-carboaldehyde, the following compounds of the present invention were obtained.
Example 32(1):
N-[4-(4-{[4-([(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]{[(4- fluorophenyl)amino]carbonyl } amino)piperidin-1- yl]Jmethyl} phenoxy)phenyl]methanesulfonamide dihydrochloride
TLC:Rf0.55(methylene chloride:methanol=9:1);
NMR (CD;0D): § 1.92-2.01 (m, 2H), 2.15-2.31 (m, 2H), 2.23 (s, 3H), 2.95 (s, 3H), 3.00- 3.15 (m, 2H), 3.43-3.55 (m, 2H), 3.76 (s, 3H), 4.01 (m, 1H), 4.25 (s, 2H), 4.48 (s, 2H), 6.97-7.08 (m, 6H), 7.25-7.37 (m, 4H), 7.49 (d, J = 8.7 Hz, 2H).
Example 32(2):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(1,3-thiazol-4-ylmethyl)amino]piperidin- 1-yl} methyl)phenoxy]phenyl} methanesulfonamide hydrochloride
TLC:Rf 0.42(chloroform:methanol=5:1);
NMR (CD;0D): 6 1.92-2.04 (m, 2H), 2.16-2.33 (m, 2H), 2.95 (s, 3H), 3.11 (m, 2H), 3.54 (m, 2H), 4.29 (s, 2H), 431 (m, 1H), 4.69 (s, 2H), 6.98-7.08 (m, 6H), 7.22-7.40 (m, 4H), 7.44-7.58 (m, 2H), 7.64 (m, 1H), 9.2 2 (m, 1H).
Example 32(3):
N-(4-{4-[(4-{ {[(4-fluorophenyl)amino]carbonyl }[(6-0xo-1,6-dihydropyridin-2- yl)methyl]amino}piperidin-1-yl)methyl]phenoxy } phenyl)methanesulfonamide hydrochloride
TLC:Rf 0.17(methylene chloride: methanol=9:1),
® Oo
NMR (CD;0D): § 2.00-2.30 (m, 4H), 2.95 (s, 3H), 3.10-3.22 (m, 2H), 3.50-3.62 (m, 2H), 4.30 (s, 2H), 4.38 (m, 1H), 4.57 (s, 2H), 6.78 (d, J = 9.0 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 7.01 (t, J =9.0 Hz, 2H), 7.02 (d, J = 8.7 Hz 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.29(d, J = 8.7
Hz, 2H), 7.37 (dd, J = 9.0, 5.0 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.90 (dd, J = 9.0, 7.5 Hz, 1H).
Example 32(4):
N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl}(1H-imidazol-4- ylmethyl)amino]piperidin-1-yl} methyl)phenoxy]phenyl} methanesulfonamide dihydrochloride
TLC:Rf 0.13(methylene chloride: methanol=9:1),
NMR (CD;OD): § 1.97-2.08 (m, 2H), 2.20-2.40 (m, 2H), 2.95 (s, 3H), 3.08-3.21 (m, 2H), 3.52-2.60 (m, 2H), 4.25-4.40 (m, 3H), 4.62 (s, 2H), 6.98-7.08 (m, 6H), 7.29 (d, J = 8.7 Hz, 2H), 7.40 (dd, J =9.0, 5.0 Hz, 2H), 7.51 (s, 1H), 7.56 (d, J = 8.7 Hz, 2H), 8.80 (s, 1H).
Example 33: 4-[4-({4-[(allyloxy)imino]piperidin-1-yl } methyl)phenoxy]-N-methylbenzamide hydrochloride o
N n-CHa
HC” >" °N . HCI 0
By the same procedure as described in Example 16, using N-methyl-4-{4-[(4- oxopiperidin-1-yl)methyl]phenoxy }benzamide and O-allylhydroxyamine instead of the compound prepared in Example 15 and n-butylamine respectively, the compound of the present invention having the following physical data was obtained.
TLC:Rf 0.60(chloroform:methanol=10:1);
NMR (CD;OD): 6 7.84 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.15 (d, ] = 8.4 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 5.97 (m, 1H), 5.30-5.15 (m, 2H), 4.54 (dt, J = 5.7, 1.5 Hz, 2H), 4.38 (s, 2H), 3.68-3.59 (m, 2H), 3.44 (m, 1H), 3.23-3.07 (m, 2H), 2.91 (s, 3H), 2.68- 2.63 (m, 2H), 2.40 (m, 1H).
Reference Example 11: 2-[4-(4-nitrophenoxy)phenyl]ethanol
To a solution of 4-(2-hydroxyethyl)phenol (2.94 g) and 1-fluoro-4- nitrobenzene (3.0 g) in dimethylformamide (21 mL) was added potassium carbonate (4.41 g) and the solution was stirred at 120°C for 4 hours. After cooling to room temperature,
® 0 water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=1:1) to give the title compound having the following physical data. TLC:Rf 0.80(chloroform:methanol=5:1).
Reference Example 12: 2-[4-(4-aminophenoxy)phenyl]ethanol
Under an atmosphere of hydrogen, to a solution of the compound prepared in
Reference Example 11 (803 mg) in ethanol (15 mL) was added palladium-carbon (wet, 10%, 100 mg) at room temperature for 1.5 hours. The reaction solution was filtrated through CELITE (brand name) and concentrated. The obtained residue was washed with t-butoxymethyl to give the title compound (641.5 mg) having the following physical data.
TLC:Rf 0.55(chloroform:methanol=5:1);
NMR (CDCls): 6 1.37 (t, J = 6.6 Hz, 1H), 2.83 (t, J = 6.6 Hz, 2H), 3.57 (m, 2H), 3.84 (q, J = 6.6 Hz, 2H), 6.62-6.70 (m, 2H), 6.80-6.92 (m, 4H), 7.12-7.20 (m, 2H).
Reference Example 13: 2-(4-{4-[bis(methylsulfonyl)amino]phenoxy } phenyl)ethyl methanesulfonate
To a solution of the compound prepared in Reference Example 12 (196.5 mg) in methylene chloride (8.6 mL) were added triethylamine (0.239 mL) and mesyl chloride (0.133 mL) at 0°C for 30 minutes. The reaction solution was stirred at room temperature for 12 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, which was extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (292.4 mg) having the following physical data.
TLC:Rf 0.89(chloroform:methanol=5:1);
NMR (CDsOD): 4 2.97 (s, 3H), 3.05 (t, J = 6.6 Hz, 2H), 3.41 (s, 6H), 4.43 (t, J = 6.6 Hz, 2H), 6.98-7.08 (m, 4H), 7.30-7.42 (m, 4H).
Example 34:
N-(4-{4-[2-(4-{butyl[(cyclohexylamino)carbonyl]amino} piperidin-1- yl)ethyl]phenoxy } phenyl)-N-(methylsulfonyl)methanesulfonamide
To a solution of the compound prepared in Reference Example 13 (68.6 mg) and N-butyl-N'-cyclohexyl-N-piperidin-4-ylurea (100 mg) in dimethylformamide (2 mL) were added triethylamine (60.2 pL) and sodium iodide (64.6 mg) at room temperature for 12 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate
® Oo and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=2:1) to give the compound of the present invention (32.2 mg) having the following physical data.
TLC:Rf 0.74(chloroform:methanol=5:1).
Example 35:
N-(4-{4-[2-(4-{butyl[(cyclohexylamino)carbonyl]amino } piperidin-1- yDethyl]phenoxy } phenyl)methanesulfonamide hydrochloride oO
JJ TL 4
Se
CL 0 I N"" CH,
NAN + HCI
H
“~eh,
To a solution of the compound prepared in Example 34 (32.2 mg) in ethanol (5 mL) and water (1 mL) was added potassium carbonate (13.7 mg) and the solution was stirred at 60°C for 3 hours. The reaction solution was concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate), and converted to hydrochloride salt by a conventional method to give the compound of the present invention (30.3 mg) having the following physical data.
TLC:Rf 0.69(chloroform:methanol=5:1),
NMR (CDsOD): 6 0.97 (t, J = 7.2 Hz, 3H), 2.00-1.10 (m, 16H), 2.25-2.08 (m, 2H), 2.93 (s, 3H), 3.16-3.00 (m, 6H), 3.38-3.24 (m, 2H), 3.38-3.24 (m, 2H), 3.55 (m, 1H), 3.71 (m, 2H), 4.13 (m, 1H), 7.00-6.90 (m, 4H), 7.32-7.20 (m, 4H).
Reference Example 14: t-butyl[ 1-(4-hydroxyphenyl)ethyl]carbamate
To a solution of 4-(1-aminoethyl)phenol (1.0 g) in ethanol (24 mL) were added di-t-butyl dicarbonate (4.77 g) and sodium hydroxyde (146 mg) at 0°C and the solution was stirred at room temperature for 4.5 hours. The reaction solution was concentrated and water was added thereto. The solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=7:1) to give the title compound (2.18 g) having the following physical data.
TLC:Rf 0.88 (chloroform:methanol=5:1),
NMR (CDCl): § 1.36-1.50 (m, 13H), 4.79 (m, 1H), 7.10-7.18 (m, 2H), 7.26-7.32 (m, 2H),
® ©
Reference Example 15: { 1-[4-(4-nitrophenoxy)phenyl]ethyl }amine hydrochloride
To a solution of the compound prepared in Reference Example 14 (2.18 g) and 1-fluoro-4-nitrobenzene (1.028 g) in dimethylformamide (30 mL) was added potassium carbonate (1.21 g) and the solution was stirred at 150°C for 3 hours. After cooling to room temperature, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography onsilica gel (hexane : ethyl acetate=6:1). To a solution of the compound (2.05 g) in ethyl acetate (30 mL) was added 4N hydrochloric acid/ethyl acetate solution (7.15 mL). the solution was stirred at 40°C for 4 hours and moreover at room temperature for 3 days.
The precipitate was corrected to give the title compound (1.37 g) having the following physical data.
NMR (DMSO-dg): & 1.52 (d, J = 6.6 Hz, 3H), 445 (m, 1H), 7.12 (brd, J = 9.3 Hz, 2H), 7.26 (brd, J = 8.7 Hz, 2H), 7.62 (brd, J = 8.7 Hz, 2H), 8.28 (brd, J = 9.3 Hz, 2H), 8 44 (m, 2H).
Example 36: 1-{1-[4-(4-nitrophenoxy)phenyl]ethyl }piperidin-4-one hydrochloride
To a solution of the compound prepared in Reference Example 15 (550 mg) in ethanol (9.33 mL) and water (4.67 mL) were added N-benzyl-N-methyl-4-piperidone iodide (927 mg) and potassium carbonate (670 mg) and the solution was refluxed for 5 hours. After cooling to room temperature, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=3:1), and converted to hydrochloride salt by a conventional method to give the compound of the present invention (515 mg) having the following physical data.
TLC:Rf0.79(chloroform:methanol=9:1);
NMR (DMSO-dg): 6 1.75 (d, J = 6.9 Hz, 3H), 3H), 2.38-3.20 (m, 6H), 3.52 (m, 1H), 3.82 (m, 1H), 4.78 (m, 1H), 7.19 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.73 (d, 1 = 9.0
Hz, 2H), 8.27 (d, J = 9.0 Hz, 2H).
Example 37:
N-(4-{4-[1-(4-{butyl[(cyclohexylamino)carbonyl]amino} piperidin-1- ylethyl}phenoxy }phenyl)methanesulfonamide hydrochloride
® ©
CH; H sulspeler
NN (0) °°
H - HCI
Neh,
By the same procedure as described in Example 3, using the compound prepared in Example 36 instead of the compound prepared in Example 2, a compound was obtained. By the same procedure as described in Example 23—Reference Example 12—Reference Example 13, using the obtained compound and cyclohexylcarboxylic acid, the compound of the present invention (107 mg) having the following physical data was obtained.
TLC:Rf 0.39(chloroform:methanol=9:1);
NMR (CD;0D): 6 0.94 (t, J = 7.2 Hz, 3H), 1.14-2.28 (m, 18H), 1.76 (d, J = 6.9 Hz, 3H), 2.80-3.05 (m, 2H), 2.95 (s, 3H), 3.12 (m, 2H), 3.41 (m, 1H), 3.52 (m, 1H), 3.74 (m, 1H), 4.02 (m, 1H), 4.46 (m, 1H), 7.00-7.19 (m, 4H), 7.29 (brd, J = 9.3 Hz, 2H), 7.50 (brd, J = 8.7 Hz, 2H).
Example 38: ethyl N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)piperidin-4-yljglycinate hydrochloride
To a solution of the compound prepared in Example 2 (510 mg) and ethyl glycinate (190 mg) in dimethylformamide (10 mL) and acetic acid (1 mL) was added sodium triacetoxyborohydride (345 mg) and was stirred at room temperature for 12 hours.
The reaction solution was concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate), and converted to hydrochloride salt by a conventional method to give the compound of the present invention (583 mg) having the following physical data.
TLC:Rf 0.53(chloroform:methanol=5:1).
Example 39:
N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4-yl]glycine
To a solution of the hydrochloride salt of the compound prepared in Example 38 (303 mg) in dimethylformamide (6 mL) and acetic acid (0.6 mL) were added butanal (56.2 pL) and sodium triacetoxyborohydride (144 mg) sequentially. The solution was stirred at room temperature for 12 hours. The reaction solution was concentrated. Water was added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The
® 0 obtained residue was purified by column chromatography on silica gel (ethyl acetate). To a solution of the obtained compound (179.2 mg) in ethanol (15 mL) was added 2N aqueous solution of sodium hydroxide (0.91 mL) and the solution was stirred at 40°C for 12 hours.
The reaction solution was concentrated and purified by column chromatography on silica gel (ethylacetate : methanol=2:1) to give the compound of the present invention having the following physical data.
TLC:Rf 0.19(chloroform:methanol=5:1).
Example 40:
N2-butyl-N1-cyclohexyl-N2-[ 1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin- 4-yl]glycinamide dihydrochloride
N CH
PUGRONSEY of YON 0 0 en, 2HCI
To a solution of the compound prepared in Example 39 in dimethylformamide (5 mL) were added cyclohexylamine (41.7 pL), 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (87.2 mg) and 1-hydroxy-7-azabenzotriazole (61.9 mg) and the solution was stirred at room temperature for 12 hours. The reaction solution was concentrated and purified by column chromatography on silica gel (ethyl acetate), and converted to hydrochloride salt by a conventional method to give the compound of the present invention (41.4 mg) having the following physical data.
TLC:Rf0.71(chloroform:methanol=5:1);
NMR (CD;OD): 6 0.98 (t, J = 7.2 Hz, 3H), 1.16-1.48 (m, 7H), 1.58-1.94 (m, 7H), 2.08- 2.38 (m, 4H), 2.95 (s, 3H), 3.08-3.35 (m, 4H), 3.56-4.15 (m, 6H), 4.31 (s, 2H), 7.00-7.08 (m, 4H), 7.24-7.34 (m, 2H), 7.55 (brd, J = 8.7 Hz, 2H).
Reference Example 16: 1-(2-chloropyrimidin-4-yl)azepane
To a solution of 2,4-dichloropyrimidine (25 g) in triethylamine (47 mL) and tetrahydrofuran (300 mL) was added azepane (17 g) at 0°C. After returning to room temperature, the solution was stirred for 1 hour. Water was added to thereto and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate : hexane=1:5—1:2) to give the title compound (7.25 g) having the following physical data.
® ©
TLC:Rf 0.43(hexane: ethyl acetate=3:1);
NMR (CDCl): 6 1.57 (m, 4H), 1.79 (m, 4H), 3.45 (m, 2H), 3.79 (m, 2H), 6.29 (d, J = 6.3
Hz, 1H), 7.98 (d, J = 6.3 Hz, 1H).
S Reference Example 17: 4-azepan-1-yl-N-piperidin-4-ylpyrimidin-2-amine trihydrochloride
A mixture of the compound prepared in Reference Example 16 (500 mg) and 1-t-butoxycarbonyl-4-aminopiperidine was stirred at 125°C for 6 hours. After cooling, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=3:1—-0:1). To a solution of the obtained residue in ethyl acetate (1 ml) was added 4N hydrochloric acid/ethyl acetate solution (4 mL) and the solution was stirred for 1.5 hours at room temperature. The reaction solution was concentrated to give the title compound (290 mg) having the following physical data.
TLC:Rf 0.23(dichloromethane:methanol:acetic acid=5:1:0.1);
NMR (CD;0D): 8 1.59-1.61 (m, 4H), 1.83-1.92 (m, 6H), 2.22-2.27 (m, 2H), 3.14-3.22 (m, 2H), 3.44-3.49 (m, 2H), 3.69 (t, J = 6.1 Hz, 2H), 3.91 (t, J = 6.1 Hz, 2H), 4.17 (m, 1H), 6.41(d,J=75Hz, 1H), 7.68 (d, = 7.5 Hz, 1H).
Example 41:
N-{4-[4-({4-[(4-azepan-1-ylpyrimidin-2-yl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide trihydrochloride
H
ISNSAPUeLrS
H - 3HCI
By the same procedure as described in Example 1, using the compound prepared in Reference Example 17 instead of 4-hydroxypiperidine, the compound of the present invention (159 mg) having the following physical data was obtained.
TLC:Rf 0.38(methylene chloride:methanol=10:1),
NMR (CD;0D): 8 1.61-1.62 (m, 4H), 1.83-1.98 (m, 6H), 2.20-2.33 (m, 2H), 2.95 (5, 3H), 3.16-3.24 (m, 2H), 3.55-3.61 (m, 2H), 3.69 (t, J = 6.0 Hz, 2H), 3.91 (t, J] = 6.0 Hz, 2H), 4.15 (m, 1H), 4.31 (s, 2H), 6.40 (d, J = 7.5 Hz, 1H), 7.03 (d, J =8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.54 (d, ] = 8.7 Hz, 2H), 7.66 (d, J = 7.5 Hz, 1H).
® O
Example 41(1):
N-{4-[4-({3-[(4-azepan-1-ylpyrimidin-2-yl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide trihydrochloride
By the same procedure as described in Reference Example 17—Example 37, using I-t-butoxycarbonyl-3-aminopiperidine instead of 1-t- butoxycarbonyl-4- aminopiperidine, the compound of the present invention (51 mg) having the following physical data was obtained.
TLC:Rf 0.53(methylene chloride:methanol=10:1);
NMR (CD;0OD): § 1.55-1.80 (m, 9H), 2.00-2.17 (m, 3H), 2.79 (m, 1H), 2.95 (s, 3H), 3.04 (m, 1H), 3.53-3.86 (m, 7H), 4.25 (d, J = 13.5 Hz, 1H), 4.33 (m, 1H), 4.44 (d, J = 13.5 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 7.29 (d, J =8.7Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 7.5 Hz, 1H).
Biological Example
The fact that the compound of the present invention has CCRS antagonism was demonstrated, for example, by the following experiment. The total operation was based on the basic genetic engineering to prepare gene-highly expressing cells, and the ordinary methods were utilized. Also, in the assaying method of the present invention, in order to evaluate the compound of the present invention, assaying accuracy and/or assaying sensitivity was improved as described below. The detailed experimental methods are shown below.
Biological Example 1
Inhibition test on the binding of RANTES to CCRS: (1) Isolation of human CCRS gene
Human placental cDNA was prepared using Marathon cDNA amplification kit (Clontech). PCR primers hCCR5Xbal-F1: 5'-AGCTAGTCTAGATCCGTTCCCCTACAAGAAACTCTCC-3' (SEQ ID NO:1) and hCCRSXbal-R1: 5'-AGCTAGTCTAGAGTGCACAACTCTGACTGGGTCACCA-3' (SEQ ID NO:2) were designed based on the sequence of GenBank U54994.
Using the human placental cDNA as the template and using Ex Taq (Takara),
PCR reaction (2 minutes at 95°C — (30 seconds at 95°C, 45 seconds at 60°C, 1 minute at 72°C) x 35 times) was carried out. The thus amplified PCR product was subjected to a 1% agarose gel electrophoresis, purified using QIAquick Gel Extraction Kit (QUIAGEN) and then digested with a restriction enzyme Xbal. The digested fragments were ligated to an expression vector pEF-BOS-bsr using DNA Ligation Kit Ver. 2 (Takara) and
® Oo transformed into Escherichia coli DH5a. By preparing the resulting plasmid pEF-BOS- bsr/hCCRS, its DNA sequence was verified. (2) Culturing of CHO cell
CHO-dhfr(-) was cultured using Ham's F-12 (containing fetal bovine serum (10%), penicillin (50 U/mL) and streptomycin (50 mg/mL)). Also, the transduced cell was cultured by adding blasticidin (5 mg/mL) to the above medium. (3) Transduction into CHO cell
The plasmid pEF-BOS-bsr/hCCRS was transduced into the CHO-dhfr(-) cell using DMRIE-C reagent (Gibco BRL). After 48 hours, the medium was replaced with a medium containing 5 mg/ml of blasticidin to carry out the selection, thereby establishing a stably over-expressing cell. (4) Inhibition test on the binding of RANTES to CCRS (activity of RANTES to induce transient increase of Ca ion).
The thus established human CCRS stably over-expressing CHO cell (CCRS/CHO cell) was suspended in Ham's F-12 medium containing FBS (10%) and seeded at a density of 3.0x10° cells/well into a 96 well plate. One day after culturing at 37°C, the culture supernatant was discarded, and Ham's F-12 medium (containing Fura- 2AM (5 uM), Probenecid (2.5 mM) and HEPES (20 mM; pH 7.4)) was dispensed in 80 ul/well portions to carry out 1 hour of incubation at 37°C under shaded condition. After washing twice with 1x Hanks/HEPES (20 mM; pH 7.4) solution, the same solution was dispensed in 100 pl/well portions. Each of the test compounds was added to the thus Fura-2AM-incorporated CCRS5/CHO cell, and 3 minutes thereafter, a recombinant human
RANTES (PeproTach) diluted with 1x Hanks/HEPES (20 mM; pH 7.4) solution was added thereto to a final concentration of 10 nM. Transient increase in the intracellular Ca®* concentration induced by the human RANTES was measured using a Ca" detector for 96 well use (Hamamatsu Photonics), and inhibition ratio (%) of the test compound was calculated by the following calculation formula.
Inhibition ratio = (Ec — Ea)/Ec x 100
Ec: measured value of Ca®* transient increase by RANTES
Ea: measured value of Ca’" transient increase by RANTES when a test compound was added.
® ©
As a result, the compounds of the present invention showed an inhibition ratio of 50% or more at 10 uM. For example, the compound of Example 5(2) showed an ICsg value of 0.077uM.
Biological Example 2
Migration test of human CCRS5 expressing cell (hCCRS-Ba/F3 cell): (1) Establishment of human CCRS5 expressing cell (1-A) Isolation of human CCRS gene
The isolation was carried out according to the method of the isolation of human CCRS gene as described in the above Example 1. (1-B) Culturing of Ba/F3 cell
Ba/F3 cells were statically cultured by using RMMI-1640 medium (Gibco
BRL) containing antibiotics (Antibiotic-Antimycotic) (final concentration: penicillin G sodium (100 U/mL), streptomycin sulfate (100 pg/mL), amphotericin B (0.25 pug/mL)) (Gibco BRL), fetal bovine serum (FBS) (10%), 2-mercaptoethanol (55 uM) and mouse interlekin-3 (IL-3) (5 ng/mL) (Pepro Tech, Inc) in a carbon dioxide incubator (temperature: 37°C, CO; concentration: 5%, humidity: 95%). Exogenous gene stable hyperexpression cells were cultured in the above medium to which blasticidin (Kaken Pharmaceutical) was added to give a final concentration of 10 pg/ml. (1-C) Transformation to Ba/F3 cell
A plasmid for human CCRS expression (pEF-BOS-bsr/hCCRS5) was digested with Aafll for linearization. The linearized plasmid was purified by QIA quick PCR
Purification Kit (QIAGEN), and introduced into Ba/F3 cells by electroporation (Gene
Pulser (BIO RAD), 960 uF/250V). The cells were seeded into a 96-well culture plate at a density of 1,000, 100, 10 cells/100 pl/well, and cultured for 48 hours. Then, blasticidin was added thereto to give a final concentration of 10 pg/ml, followed by cloning of a blasticidin-resistant cell line to thereby establish a stable hyperexpression clone expressing the introduced exogenous gene (hCCRS-Ba/F3 cell). (1-D) Analysis of CCRS expression
The human CCRS expression level in the clone obtained by the method described in the above (1-C) was detected with FAC Sort (trade name, Becton, Dickinson) by detecting the cells with a fluorescence isothiocyanate (FITC)-labeled anti-human CCRS antibody (BD Pharmingen) and analyzed. In this connection, FITC-labeled mouse
IgG2ax (BD Pharmingen) was used as an isotype control antibody.
® © (2) Cell migration test
Influence of a test compound on the migration ability of the human CCR5 expressing Ba/F3 cell against RANTES, MIP-1a or MIP-1f3 was examined. First, 0.3 ml of 0 or 3 nM chemokine (RANTES, MIP-loo or MIP-1B)-containing medium was respectively added to the low room of Chemo T x 96 well plate (Neuro Probe). Next, a filter (pore size: 5S um) was set and a mixture solution (1x10° cells/well) of the test compound and the CCR5-Ba/F3 cell prepared in advance was added at 65 pl. The test compound to be added was prepared by diluting it with 0.1% DMSO-containing medium to give a final concentration on the filter of 0, 0.01, 0.03, 0.1 or 0.3 uM. These cells were cultured in a CO; incubator (37°C, 5% CO», relative humidity: 95%) for 3 hours, and then the medium and unmigrated cells on the filter were eliminated. Furthermore, the filter was removed, the microplate was centrifuged (1,500 rpm, 10 min, RT) and the supernatant was removed by decantation. The cells on the microplate were suspended in 100 ul of a phosphate buffer (PBS), and 1/10 portion thereof was further diluted with 90 pul of PBS, 1S moved on a white plate for fluorescence assay, and used as an assay sample for migrated cell numbers (final: 100 pl/well).
Next, Cell Titer-Glo Reagent (trade name, Promega) which was previously prepared at room temperature was added to the above assay sample for migrated cell numbers (100 pl/well), followed by gently mixing (300 rpm, 2 min with KA-
SCHUTTLER MTS4) for lysating the cells, the mixture was incubated at room temperature for 10 minutes, and the fluorescence was measured with wallac ARVO SX 1420 MULTILABEL COUNTER (trade name, Perkin Elmer) (detection by count/second).
The migrated cell numbers (naturally falling cell numbers) at a chemokine concentration of 0 nmol/l was used as the background, and the inhibition ratio of the test compound against the 0.1% DMSO control group was calculated.
The inhibition migration ratio (%) of the test compound was calculated by the following equation:
Inhibition ratio ~ (EcEa) X100
Ec
Ec: (fluorescence measured value at the addition of 0.1% DMSO) - (fluorescence measured value of the naturally falling cells)
Ea: (fluorescence measured value at the addition of the test compound) - (fluorescence measured value of the naturally falling cells)
Results:
The compound produced in Example 23(126) showed cell migration inhibition ratios of 42% and 77% at concentrations of 10 and 30 uM, respectively, against RANTES.
® ©
Formulation Example 1:
The following components were admixed in a conventional manner, punched out to give 100 tablets each containing 50 mg of active ingredient.
N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)piperidin 5.0g -4-yl]cyclohexanecarboxamide hydrochloride calcium carboxymethyl cellulose (disintegrant) 02g magnesium stearate (lubricant) O0lg microcrystalline cellulose 47g
Formulation Example 2:
The following components were admixed in a conventional technique. The solution was sterilized in a conventional technique, filled in ampoules 5 ml each and freeze-dried over in a conventional technique to give 100 ampoules each containing 20 mg of active ingredient.
N-butyl-N-[1-(4- {4-[(methylsulfonyl)amino]phenoxy} benzy!)piperidin 2.0g -4-yl]cyclohexanecarboxamide hydrochloride mannitol 20g distilled water 500 ml
Formulation Example 3:
The following components were admixed in a conventional manner, punched out to give 10,000 tablets each containing 10 mg of active ingredient.
N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy }benzyl)piperidin 100 g -4-yllcyclohexanecarboxamide hydrochloride calcium carboxymethyl cellulose (disintegrant) 200g magnesium stearate (lubricant) 100g microcrystalline cellulose 870 g
Formulation Example 4:
Each of the following components was mixed by a standard method and filtered through a dustproofing filter, and then 5 ml aliquots were charged into ampoules, which were autoclaved to thereby obtain 10,000 ampoules each containing 20 mg of the active ingredient. N-butyl-N-[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)piperidin 200 g -4-yl]cyclohexanecarboxamide hydrochloride mannitol 2kg distilled water SOL
® ©
INDUSTRIAL APPLICABILITY
The compounds of the present invention represented by formula (I) regulate the effect of CCRS5 receptor, so they are useful in preventing and/or treating various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, ulcerative colitis, efc.), immunological diseases (autoimmune diseases, rejection in organ transplantation, immunosuppression, psoriasis, multiple sclerosis, efc.), infection with human immunodeficiency virus (acquired immunodeficiency syndrome, efc.), allergic diseases (atopic dermatitis, urticaria, allergic bronchoplumonary aspergillosis, allergic eosinophilic gastroenteritis, erc.), ischemic reperfusion injury, acute respiratory distress syndrome, shock accompanying bacterial infection, diabetes, cancer metastasis and so on. Therefore, CCRS5 antagonist is useful as medicament.

Claims (49)

PCT/JP2004/003333 CLAIMS
1. A compound represented by formula (I): Yo X wherein R! represents a hydrogen atom or an acidic group which may be protected, X and Y each independently represents a bond or a spacer containing 1 to 3 atoms as a main chain; ring A and ring B, which are the same or different, each represents a 3- to 15- membered homocyclic group or heterocyclic group which may have a substituent(s); ring D represents a 3- to 15-membered nitrogen-containing heterocyclic group which may have a substituent(s); R? represents (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent(s), (3) a cyano group, (4) a hydroxy group which may be protected, (5) an amino group which may have a substituent(s), (6) an oxo group, (7) a 3- to 15-membered heterocyclic group which may have a substituent(s) or (8) =N-OR®, wherein R® represents a hydrogen atom or C1-4 alkyl, a salt thereof or a solvate thereof, or a prodrug thereof.
2. The compound according to claim 1, wherein R' is an acidic group which may be protected.
3. The compound according to claim 2, wherein the acidic group is carboxy.or sulfonamide.
4. The compound according to claim 1, wherein X and Y are each independently a bond or a divalent group selected from (1)-CR’R®-, (2)-NR’-, (3)-CO-, (4)-0-, (5)-S-, (6)-SO-, (7)-SO- and (8)-C(=N-OR')-, wherein R’ and R® each independently represents a hydrogen atom, C1-4 alkyl, -OR" or phenyl; R® represents a hydrogen atom Cl-4 alkyl, or phenyl, R'® and R' each independently represents a hydrogen atom or C1-4 alkyl.
5. The compound according to claim 4, wherein X is a bond, -O- or -CH;-.
6. The compound according to claim 1, wherein Y is C1-3 alkylene. -194 - AMENDED SHEET
PCT/JP2004/003333
7. The compound according to claim 1, wherein ring D is a 5- to 10-membered nitrogen-containing heterocyclic group which may have a substituent(s).
8. The compound according to claim 1, wherein ring A and ring B, which are the same or different, are each a 5- to 10-membered homocyclic group or heterocyclic group which may have a substituent(s).
9. The compound according to claim 1, wherein ring A and ring B, which are the same or different, are each a 5- or 6-membered aromatic ring which may have a substituent(s).
10. The compound according to claim 1, wherein R? is 0) PR R53 ™~N Nn” R51 R52 wherein the arrow represents a binding position to ring D; R’', R’? and R” each independently represents (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent(s), (3) a 3- to 15-membered heterocyclic group which may have a substituent(s), (4) a C1-4 alkoxy group which may have a substituent(s), (5) a phenoxy group which may have a substituent(s) or (6) a benzyloxy group which may have a substituent(s).
11. The compound according to claim 1, which is represented by formula (Ia): H,
Cc. R! N D'*+-R? (la) X wherein ring D'* is piperidine or piperazine which may have a substituent(s) and other symbols have the same meanings as those described in claim 1.
12. The compound according to claim 1, which is selected from the group consisting of (1) N-[4-(4-{[4-(butyl {[(2,4-difluorophenyl)amino]carbonyl }amino)-1- piperidinyl] methyl } phenoxy)phenyl]methanesulfonamide, 2) N-[4-(4-{[4-(butyl{[(6-methyl-3-pyridinyl)amino]carbonyl}amino)-1- piperidinyl]methyl} phenoxy)phenyl]methanesulfonamide, - 195 - AMENDED SHEET
® 0 3) N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)piperidin-1- yl]methyl}-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]methanesulfonamide, (4) N-[4-(4-{[4-(butyl {[(1-methyl-1H-pyrazol-4- yl)amino]carbonyl}amino)piperidin-1-yl]methyl} phenoxy)phenyl]methanesulfonamide, 5) 3-[({butyl[1-(4- {4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino}carbonyl)amino]benzamide, (6) N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(phenyl)amino]piperidin-1- yl} methyl)phenoxy]phenyl} methanesulfonamide, aN 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino} carbonyl)amino]-2-fluorobenzamide, (8) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy } benzyl)piperidin-4- yl]amino} carbonyl)amino]-2,4-difluorobenzamide, %) N-[4-(4-{[4-(butyl{[(3-cyano-4- fluorophenyl)amino]carbonyl } amino)piperidin-1- yl]methyl }phenoxy)phenyl}methanesulfonamide, and (10) N-[4-(4-{[4-(butyl{[(3-hydroxycyclohexyl)amino]carbonyl }amino)piperidin-1- yl]methyl } phenoxy)phenyl]methanesulfonamide, and N-{4-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(1,3-thiazol-4- ylmethyl)amino]piperidin-1-yl} methyl)phenoxy]phenyl} methanesulfonamide. :
13. A CCRS regulator comprising the compound according to claim 1, a salt thereof or a solvate thereof, or a prodrug thereof.
14. The CCRS regulator according to claim 13, which is a CCRS antagonist.
15. The CCRS regulator according to claim 13, which is an agent for treatment and/or prevention for a disease through the intervention of CCRS.
16 The CCRS regulator according to claim 15, wherein the disease through the intervention of CCRS5 is infection with human immunodeficiency virus.
17. The CCRS regulator according to claim 16, wherein the infection with human immunodeficiency virus is acquired immune deficiency syndrome.
18. The CCRS regulator according to claim 15, wherein the disease through the intervention of CCRS is immunological diseases.
) PCT/JP2004/003333
19. The CCRS5 regulator according to claim 18, wherein the immunological disease is rejection in organ transplantation.
20. The CCRS regulator according to claim 15, wherein the disease through S the intervention of CCRS3 is inflammatory diseases.
21. The CCRS regulator according to claim 20, wherein the inflammatory disease is asthma.
22. An agent for prevention and/or treatment for infection with human immunodeficiency virus. immunological diseases or inflammatory diseases, which comprises the compound represented by formula (I) according to claim 1, a salt thercof or a solvate thereof, or a prodrug thereof.
23. A pharmaceutical composition, which comprises the compound represented by formula (I) according to claim 1, a salt thereof or a solvate thereof, or a prodrug thereof.
24. A medicament which comprises the compound represented by formula (I) according to claim 1, a salt thereof or a solvate thereof, or a prodrug thereof. in combination with one or at least two of a reverse transferase inhibitor, a protease inhibitor, a CCR? antagonist, a CCR3 antagonist, a CCR4 antagonist, a CCRS antagonist, a CXCR4 antagonist. a fusion inhibitor, an antibody against a surface antigen of HIV-1, and a vaccine of HIV-1.
25. Use of a compound represented by formula (I): Y R? N D—+R2 (I) X wherein R' represents a hydrogen atom or an acidic group which may be protected: 50 X and Y each independently represents a bond or a spacer containing 1 to 3 atoms as a main chain: ring A and ring B, which are the same or different, cach independently represents a 3- to 15-membered homocyclic group or heterocyclic group which may have a substituent(s); ring D represents a 3- 10 15-membered nitrogen-containing heterocyclic group which may have a substituent(s); -197 - AMENDED SHEET
) PCT/JP2004/003333 R? represents (1) a hydrogen atom, (2) a hydrocarbon group which have a substituent(s), (3) a cyano group, (4) a hydroxy group which may be protected, (5) an amino group which have a substituent(s), (6) an oxo group, (7) a 3- to 15-membered heterocyclic group which have a substituent(s) or (8) =N-OR®, wherein R® represents a hydrogen atom or C1-4 alkyl, a salt thereof or a solvate thereof, or a prodrug thereof for the manufacture of an agent for prevention and/or treatment for a disease through the intervention of CCRS.
26. Use of the compound according to claim 1, a salt thereof or a solvate thereof, or a prodrug thereof, in the manufacture of a medicament for use as a CCR5S regulator in a method of treatment or prevention.
27. Use according to claim 26. which is a CCRS antagonist for the treatment and/or prevention of a disease through the intervention of CCRS.
28. Use according to claim 27, wherein the discase through the intervention of CCRS5 is infection with human immunodeficiency virus.
29. Use according to claim 28, wherein the infection with human immunodeficiency virus is acquired immune deficiency syndrome.
30. Use according to claim 27, wherein the disease through the intervention of CCRS 1s immunological diseases.
31. Use according to claim 30, wherein the immunological disease is rejection in organ transplantation.
32. Use according to claim 27, wherein the disease through the intervention of CCRS is inflammatory diseases.
33. Use according to claim 32, wherein the inflammatory disease is asthma.
34. A substance or composition for use as a CCRS5 regulator in a method of treatment or prevention, said substance or composition comprising the compound according to claim 1, a salt thereof or a solvale thereof, or a prodrug thereof, and said method comprising administering said substance or composition.
35. A substance or composition for use in a method of treatment or prevention 40 according to claim 34, which is a CCRS antagonist. - 198 - AMENDED SHEET
) PCT/JP2004/003333
36. A substance or composition for use in a method of treatment or prevention according to claim 34, for treatment and/or prevention of a disease through the intervention of CCRS.
37. A substance or composition for use in a method of treatment or prevention according to claim 36, wherein the disease through the intervention of CCRS is infection with human immunodeficiency virus.
38. A substance or composition for use in a method of treatment or prevention according to claim 37, wherein the infection with human immunodeficiency virus is acquired immune deficiency syndrome.
39. A substance or composition for use in a method of treatment or prevention according to claim 36, wherein the disease through the intervention of CCRS is immunological diseases.
40. A substance or composition for use in a method of treatment or prevention according to claim 39, wherein the immunological discase is rejection In organ transplantation.
41. A substance or composition for use in a method of treatment or prevention according to claim 36, wherein the discase through the intervention of CCRS is inflammatory diseases.
42. A substance or composition for use in a method of treatment or prevention according to claim 41, wherein the inflammatory discase is asthma.
43. A compound according to any one of claims 1 to 12, substantially as herein described with reference to and as illustrated in any of the examples. 50
44. A regulator according to any one of claims 13 to 21, substantially as herein described with reference to and as illustrated in any of the examples.
45. An agent according to claim 22. substantially as herein described with reference to and as illustrated in any of the examples.
46. A composition according to claim 23. substantially as herein described with reference to and as illustrated in any of the examples. 40 - 199 -- AMENDED SHEET
® PCT/JP2004/003333
47. A medicament according to claim 24, substantially as herein described with reference to and as illustrated in any of the examples.
48. Use according to any one of claims 25 to 33, substantially as herein described with reference to and as illustrated in any of the examples.
49. A substance or composition for use in a method of treatment or prevention according to any one of claims 34 to 42, substantially as herein described with reference to and as illustrated in any of the examples. - 200 - AMENDED SHEET
ZA200507365A 2003-03-14 2005-09-13 Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient ZA200507365B (en)

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US5169855A (en) * 1990-03-28 1992-12-08 Du Pont Merck Pharmaceutical Company Piperidine ether derivatives as psychotropic drugs or plant fungicides
AR013669A1 (en) * 1997-10-07 2001-01-10 Smithkline Beecham Corp COMPOUNDS AND METHODS
US6172061B1 (en) * 1997-12-19 2001-01-09 Takeda Chemical Industries, Ltd. Pharmaceutical composition for antagonizing CCR5 comprising anilide derivative

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