CN1512880A - Novel compounds and compositions as cathepsin inhibitors - Google Patents

Novel compounds and compositions as cathepsin inhibitors Download PDF

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Publication number
CN1512880A
CN1512880A CNA02811289XA CN02811289A CN1512880A CN 1512880 A CN1512880 A CN 1512880A CN A02811289X A CNA02811289X A CN A02811289XA CN 02811289 A CN02811289 A CN 02811289A CN 1512880 A CN1512880 A CN 1512880A
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methyl
alkyl
sulfonyl
base
chemical compound
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Լ����W��˹��ɭ
约翰·W·帕特森
�����������շѶ�
希拉·齐普费尔
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Axys Pharmaceuticals Inc
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    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
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    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The present invention relates to novel selective cathepsin S inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

Description

New compound and compositions as cathepsin inhibitors
The application relates to such chemical compound and compositions, and they are used for the treatment of and the cysteine protease activity diseases associated, particularly with the active diseases associated of cathepsin S.
Background of invention
Cysteine proteinase represents that it is the peptidase of feature that there is cysteine residues in a class with the catalytic site of enzyme.Cysteine proteinase is degraded normally with protein and is processed relevant.But the abnormal activity of cysteine proteinase for example activates the abnormal activity that produces owing to increasing to express or strengthen, and may produce the consequence of pathology.In this, some cysteine proteinase is relevant with the numerous disease state, comprises arthritis, amyotrophy, inflammation, tumor infringement, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy or the like.The pathology and/or the symptom of cathepsin S active increase causing numerous disease.Therefore, the molecule of inhibition of histone enzyme S proteinase activity can be used as this treatment of diseases agent of treatment.
Summary of the invention
The application relates to the chemical compound of formula I:
Wherein:
X 1Be-NHC (R 1) (R 2) X 2Perhaps-NHX 3
X 2Be cyano group ,-C (R 7) (R 8) X 3,-C (R 7) (R 8) CF 3,-C (R 7) (R 8) CF 2CF 2R 9,-CH=CHS (O) 2R 5,-C (O) CF 2C (O) NR 5R 5,-C (O) C (O) NR 5R 6,-C (O) C (O) OR 5,-C (O) CH 2OR 5,-C (O) CH 2N (R 6) SO 2R 5Or-C (O) C (O) R 5R wherein 5Be (C 1-4) alkyl, (C 5-10) aryl (C 0-6) alkyl or (C 5-10) heteroaryl (C 0-6) alkyl; R 6Be hydrogen or (C 1-6) alkyl; R 7Be hydrogen or (C 1-4) alkyl, R 8Be hydroxyl or R 7And R 8-work forming oxo; R 9Be hydrogen, halogen, (C 1-4) alkyl, (C 5-10) aryl (C 0-6) alkyl or (C 5-10) heteroaryl (C 0-6) alkyl;
X 3Comprise the assorted monocycle that contains 4-6 annular atoms or contain the assorted dicyclo ring system of condensing of 8-14 annular atoms, with and carbocyclic ring ketone arbitrarily, imino group ketone or 40 thione derivatives;
Wherein at R 5, X 2Or X 3In, alicyclic ring or aromatic ring can further be independently selected from (C by 1-5 arbitrarily 1-6) alkyl, (C 1-6) alkylidene radical, cyano group, the halogen, (C that halogen replaces 1-4) alkyl, nitro ,-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4NR 12C (O) R 13,-X 4S (O) R 13With-X 4S (O) 2R 13Group replace, and/or be selected from-R by 1 14,-X 4OR 14,-X 4SR 14,-X 4S (O) R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) OR 14,-X 4OC (O) R 14,-X 4NR 14R 12,-X 4NR 12C (O) R 14,-X 4NR 12C (O) OR 14,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 14R 12,-X 4NR 12S (O) 2R 14,-X 4NR 12C (O) NR 14R 12With-X 4NR 12C (NR 12) NR 14R 12Group replace X wherein 4Be a key or (C 1-6) alkyl; R 12All be hydrogen in all cases independently, (C 1-6) (the C that replaces of alkyl or halogen 1-6) alkyl; R 13Be (C 1-6) (the C that replaces of alkyl or halogen 1-6) alkyl; R 14Be (C 3-10) cycloalkyl (C 0-6) alkyl, assorted (C 3-10) cycloalkyl (C 0-3) alkyl, (C 6-10) aryl (C 0-6) alkyl, assorted (C 5-10) aryl (C 0-6) alkyl, (C 9-10) bicyclic aryl (C 0-6) alkyl or assorted (C 8-10) bicyclic aryl (C 0-6) alkyl;
R 1Be hydrogen, halogen or (C 1-6) alkyl, R 2Be selected from hydrogen, cyano group, halogen ,-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4NR 12C (O) R 13,-X 4S (O) R 13,-X 4S (O) 2R 13,-R 14,-X 4OR 14,-X 4SR 14,-X 4S (O) R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) OR 14,-X 4OC (O) R 14,-X 4NR 14R 12,-X 4NR 12C (O) R 14,-X 4NR 12C (O) OR 14,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 14R 12,-X 4NR 12S (O) 2R 14,-X 4NR 12C (O) NR 14R 12With-X 4NR 12C (NR 12) NR 14R 12, X wherein 4, R 12, R 13And R 14Definition as above; Perhaps R 1And R 2Be connected to R simultaneously 1And R 2On carbon atom form (C altogether 3-8) cycloalkylidene or (C 3-8) inferior Heterocyclylalkyl; Wherein, at described R 2In, heteroaryl, aryl, cycloalkyl, Heterocyclylalkyl, cycloalkylidene or inferior Heterocyclylalkyl are all optional arbitrarily is independently selected from (C by 1-3 1-6) alkyl, (C 1-6) alkylidene radical, cyano group, the halogen, (C that halogen replaces 1-4) alkyl, nitro ,-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4NR 12C (O) R 13,-X 4S (O) R 13,-X 4S (O) 2R 13With-X 4C (O) R 13Group replace X wherein 4, R 12And R 13Definition as above;
R 3Be-C (R 6) (R 6) X 5, R wherein 6Define as above X 5Be selected from-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4R 12,-X 4OP (O) (OR 12) OR 12,-X 4C (O) R 13,-X 4NR 12C (O) R 13,-X 4S (O) R 13With-X 4S (O) 2R 13,-R 14,-X 4OR 14,-X 4SR 14,-X 4S (O) R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) OR 14,-X 4OC (O) R 14,-X 4NR 14R 12,-X 4NR 12C (O) R 14,-X 4NR 12C (O) OR 14,-X 4C (O) NR 14R 12,-X 4S (O) 2NR 14R 12,-X 4NR 12S (O) 2R 14,-X 4NR 12C (O) NR 14R 12With-X 4NR 12C (NR 12) NR 14R 12, X wherein 4, R 12, R 13And R 14Definition as above;
R 4Be-NR 6R 6,-NR 6R 14,-NR 6R 15Perhaps-NR 6X 5C (O) R 14, R wherein 6, X 5And R 14As mentioned above, and R 15Be hydrogen ,-(C 1-6) alkyl or-X 5OR 6, X wherein 5As mentioned above; Perhaps R 6And R 15Be connected to R simultaneously 6And R 15On nitrogen-atoms form assorted (C together 3-10) cycloalkyl, assorted (C 5-10) aryl or assorted (C 8-10) bicyclic aryl;
Wherein, at R 3And R 4In, alicyclic ring or aromatic ring can further be independently selected from (C by 1-5 arbitrarily 1-6) alkyl, (C 1-6) alkylidene radical, cyano group, the halogen, (C that halogen replaces 1-4) alkyl, nitro ,-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4NR 12C (O) R 13,-X 4S (O) R 13,-X 4C (O) R 13With-X 4S (O) 2R 13Group replace, and/or be selected from-R by 1 14,-X 4OR 14,-X 4SR 14,-X 4S (O) R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) OR 14,-X 4OC (O) R 14,-X 4NR 14R 12,-X 4NR 12C (O) R 14,-X 4NR 12C (O) OR 14,-X 4C (O) NR 14R 12,-X 4S (O) 2NR 14R 12,-X 4NR 12S (O) 2R 14,-X 4NR 12C (O) NR 14R 12With-X 4NR 12C (NR 12) NR 14R 12Group replace; And at R 3And R 4In, the aliphatic segment can further be independently selected from cyano group, halogen, nitro ,-NR by 1-5 arbitrarily 12R 12,-NR 12C (O) R 12,-NR 12C (O) OR 12,-NR 12C (O) NR 12R 12,-NR 12C (NR 12) NR 12R 12,-OR 12,-SR 12,-C (O) OR 12,-C (O) R 12,-OC (O) R 12,-C (O) NR 12R 12,-S (O) 2NR 12R 12,-NR 12S (O) 2R 12,-P (O) (OR 12) OR 12,-OP (O) (OR 12) OR 12,-NR 12C (O) R 13,-S (O) R 13With-S (O) 2R 13Group replace; Wherein, X 4, R 12, R 13And R 14As mentioned above;
Prerequisite is at R 3Or R 4In only have a twin nuclei;
With its N-oxide derivative, prodrug derivant, the derivant of protection, single isomer and mixture of isomers; And the pharmaceutically acceptable salt of this chemical compound and solvate (for example hydrate) and its N-oxide derivative, prodrug derivant, the derivant of protection, single isomer and mixture of isomers.
A second aspect of the present invention is a kind of pharmaceutical composition, and it comprises chemical compound or its N-oxide derivative of formula I, single isomer or mixture of isomers, and perhaps its pharmaceutically acceptable salt, they mix with one or more appropriate excipients.
A third aspect of the present invention is the method for treatment disease in animal, inhibition of histone enzyme S can prevent, suppresses or improve the pathology and/or the symptom of this disease in this animal, described method comprises chemical compound or its N-oxide derivative of the formula I that gives this treatment of animals effective dose, single isomer or mixture of isomers; Perhaps its pharmaceutically acceptable salt.
A fourth aspect of the present invention is formula I chemical compound and its N-oxide derivative, prodrug derivant, the derivant of protection, single isomer and mixture of isomers, with and the preparation method of pharmaceutically acceptable salt.
Detailed Description Of The Invention
Definition:
Except as otherwise noted, the definition of the following term that uses in description and the claim is for the application's purpose and has following meaning.
" alicyclic " means such segment, and it is with the feature that is arranged as of carbon atom in the non-aromatic ring structure of sealing with similar aliphatic character, and can be saturated or have two or more pairs of keys or the undersaturated segment of triple-linked part.
" aliphatic " means such segment, and it is arranged as feature with straight chain or the side chain of forming carbon atom, and can be saturated or have two or more pairs of keys or the undersaturated segment of triple-linked part.
" alkyl " means itself has straight chain or the side chain of indicating carbon number, saturated or undersaturated aliphatic group (for example, (C 1-6) alkyl comprises methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl, isobutyl group, the tert-butyl group, vinyl, pi-allyl, the 1-acrylic, isopropenyl, the 1-butylene base, crotyl, the 3-cyclobutenyl, the 2-methacrylic, acetenyl, the 1-propinyl, 2-propynyl, etc.).The alkyl of representing with another group (for example, as the alkyl in the aralkyl) means straight chain or side chain with the atomic number indicated, saturated or undersaturated aliphatic divalent group, and perhaps ought indicate does not have the atomic time to mean key (for example a, (C 6-10) aryl (C 0-3) alkyl comprises phenyl, benzyl, phenethyl, the 1-phenethyl, the 3-phenylpropyl, etc.).
" alkylidene " unless otherwise specified, means and has straight chain or the side chain of indicating carbon number, saturated or undersaturated aliphatic divalent group (for example, (C 1-6) alkylidene comprises methylene (CH 2-), ethylidene (CH 2CH 2-), trimethylene (CH 2CH 2CH 2-), tetramethylene (CH 2CH 2CH 2CH 2-), 2-butenylidene (CH 2CH=CHCH 2-), 2-methyl tetramethylene (CH 2CH (CH 3) CH 2CH 2-), pentamethylene (CH 2CH 2CH 2CH 2CH 2-) etc.).
" alkylidene radical " means has the straight or branched of indicating carbon number, saturated or undersaturated aliphatic divalent group ((C for example 1-6) alkylidene radical comprises methene base (=CH 2), ethidine (=CHCH 3), isopropylidene (=C (CH 3) 2), propylidene base (=CHCH 2CH 3), allylidene base (=CH-CH=CH 2), etc.).
" amino " means group-NH 2Unless otherwise noted, comprise the derivant that amino pulsating chemical compound of the present invention comprises its protection.Suitable amino segment protecting group comprises acetyl group, tert-butoxycarbonyl, and benzyloxycarbonyl group, etc.
" animal " comprises the people, non-human mammal (for example, Canis familiaris L., cat, rabbit, cattle, horse, sheep, goat, pig, deer, etc.) and nonmammalian (for example, bird, etc.).
" aromatics " means such segment, and wherein composed atom constitutes unsaturated ring system, and atoms all in the ring system are sp 2Hydridization, and the pi-electron sum equals 4n+2.
" aryl " means and contains monocycle or the condensed-bicyclic group of indicating the ring carbon atom sum, and wherein each ring is made up of 6 ring carbon atoms and is armaticity, perhaps forms the aromatic rings group when condensing with second ring.For example, be used for the optional (C that replaces of the application 6-10) aryl includes but are not limited to biphenyl-2-base; the 2-bromophenyl, 2-bromine carbonyl phenyl, 2-bromo-5-fluorophenyl; the 4-tert-butyl-phenyl, 4-carbamoyl phenyl, 4-carboxyl-2-nitrobenzophenone; the 2-chlorphenyl, 4-chlorphenyl, the chloroformyl phenyl of 3-; the chloroformyl phenyl of 4-, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl; 4-chloro-2-nitrobenzophenone, 6-chloro-2-nitrobenzophenone, 2; the 6-dibromo phenyl, 2, the 3-Dichlorobenzene base; 2,5-Dichlorobenzene base, 3; the 4-Dichlorobenzene base, 2-difluoro-methoxy phenyl, 3; the 5-3,5-dimethylphenyl, 2-ethoxy carbonyl phenyl, 2-fluorophenyl; the 2-iodophenyl, 4-isopropyl phenyl, 2-anisyl; the 4-anisyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl; the 4-aminomethyl phenyl, 5-methyl-2-nitrobenzophenone, 4-methyl sulphonyl phenyl; naphthalene-2-base, 2-nitrobenzophenone, 3-nitrobenzophenone; the 4-nitrobenzophenone, 2,3; 4,5, the 6-pentafluorophenyl group; phenyl, 2-Trifluoromethoxyphen-l, 3-Trifluoromethoxyphen-l; the 4-Trifluoromethoxyphen-l, 2-trifluoromethyl, 3-trifluoromethyl; the 4-trifluoromethyl; 2-trifluoromethyl sulfane base phenyl, 4-trifluoromethyl sulfane base phenyl, etc.Be used for the optional (C that replaces of the application 6-10) aryl comprises the 3-acetylphenyl, 3-tertbutyloxycarbonyl aminomethyl phenyl, biphenyl-4-base, the 3-hydroxyphenyl, the 4-hydroxyphenyl, the 3-anisyl, naphthalene-2-base, the 3-Phenoxyphenyl, phenyl, etc.
" bicyclic aryl " means and contains the dicyclo group of indicating the ring carbon atom number, its medium ring connect by singly-bound or condense and at least one to constitute described group ring be armaticity, with and carbocyclic ring ketone arbitrarily, thioketone or imino group ketone derivatives (for example, (C 9-10) bicyclic aryl comprises cyclohexyl phenyl, 1,2-dihydro naphthyl, 2,4-dioxo-1,2,3, the 4-tetralyl, indanyl, indenyl, 1,2,3, the 4-tetralyl, etc.).
" carbamoyl " means group-C (O) NH 2Unless otherwise noted, comprise the derivant that the pulsating chemical compound of the present invention of carbamoyl comprises its protection.Be used for the pulsating suitable protecting group of carbamoyl and comprise acetyl group, tert-butoxycarbonyl, benzyloxycarbonyl group, etc., and derivant unprotected and protection all belongs to scope of the present invention.
" carbocyclic ring ketone derivatives " mean contain segment-C (O)-derivant.
" carboxyl " means group-C (O) OH.Unless otherwise noted, contain the derivant that the pulsating chemical compound of the present invention of carboxyl comprises its protection.Be used for the pulsating suitable protecting group of carboxyl and comprise benzyl, the tert-butyl group etc.
" cycloalkyl " means that to contain the saturated or part of indicating the ring carbon atom number unsaturated, monocycle, condensed-bicyclic or bridge joint polycyclic ring group, with and carbocyclic ring ketone arbitrarily, thioketone or imino group ketone derivatives (for example, (C 3-10) cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexenyl group, 2,5-cyclohexadiene base, dicyclo [2.2.2] octyl group, diamantane (obsolete)-1-base, decahydro naphthyl, the oxa-cyclohexyl, dioxacyclohexyl, the sulfo-cyclohexyl, 2-oxabicyclo [2.2.1] heptan-1-base, etc.).
" cycloalkylidene " means that to contain the bivalence of indicating the ring carbon atom number saturated or part is unsaturated, monocycle or bridge joint polycyclic ring group, with and carbocyclic ring ketone, thioketone or imino group ketone derivatives arbitrarily.
For example, " R wherein 1And R 2Be connected to R simultaneously 1And R 2On carbon atom form (C together 3-8) cycloalkylidene " and situation include but are not limited to following listed:
" disease " specifically comprises any unhealthy condition of animal or its part, comprise treating unhealthy condition that cause or that be easy to be subjected to its influence by the medical science or the veterinary that are applied on the animal, that is, and " side effect " of this treatment.
" halogen " means fluorine, chlorine, bromine or iodine.
When defining this term in this application, " alkyl that halogen replaces " as independently group or the more part of macoradical, means " alkyl " that replaced by one or more " halogen " atom.The alkyl that halogen replaces comprises haloalkyl, dihalo alkyl, tri haloalkyl, the ((C that replaces of halogen for example such as whole haloalkyl 1-3) alkyl comprises chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2, the 2-trifluoroethyl, the perfluor ethyl, 2,2,2-three fluoro-1, the 1-Dichloroethyl, etc.).
" hetero atom segment " comprises-N=,-NR-,-O-,-S-or-S (O) 2-, wherein R is a hydrogen, (C 1-6) alkyl or protecting group.
" inferior Heterocyclylalkyl " means cycloalkylidene, and as defining among the application, condition is that one or more ring carbon atoms of indicating are selected from-N=,-NR-,-O-,-S-or-S (O) 2-the hetero atom segment replace, wherein R is hydrogen or (C 1-6) alkyl.For example, R wherein 1And R 2Be connected to R 1And R 2On carbon atom form assorted (C together 3-8) cycloalkyl " and situation include but are not limited to following listed:
Figure A0281128900192
Wherein R is a hydrogen, (C 1-6) alkyl, perhaps protecting group.
" heteroaryl " means aryl, and as defining among the application, condition is that one or more ring carbon atoms of indicating are selected from-N=,-NR-, and-O-, the hetero atom segment of-S-replaces, and wherein R is hydrogen or (C 1-6) alkyl, protecting group or expression are used as the free valency with ring nitrogen tie-point, and each ring is made up of 5 or 6 annular atomses.For example, the assorted (C that is used for the application's optional replacement 5-10) aryl comprises, but be not restricted to 4-amino-2-hydroxy pyrimidine-5-base; benzothiazole-2-base, 1H-benzimidazolyl-2 radicals-Ji, 2-pyridine bromide-5-base; 5-pyridine bromide-2-base, 4-carbamoyl thiazol-2-yl, 3-carboxyl pyridine-4-base; 5-carboxyl-2,6-lutidines-3-base, 3; 5-dimethyl isoxazole-4-base, 5-ethyoxyl-2,6-lutidines-3-base; 5-fluoro-6-hydroxy pyrimidine-4-base, furan-2-base, furan-3-base; 5-hydroxyl-4,6-lutidines-3-base, 8-hydroxyl-5; 7-dimethyl quinoline-2-base, 5-methylol isoxazole-3-base, 3-hydroxyl-6-picoline-2-base; 3-pyridone-2-base, 1H-imidazoles-2-base, 1H-imidazol-4 yl; the 1H-indol-3-yl; isothiazole-4-base ， isoxazole-4-base, 2-methylfuran-3-base; 5-methylfuran-2-base; 1-methyl isophthalic acid H-imidazoles-2-base, 5-methyl-3H-imidazol-4 yl, 5-methyl-isoxazole-3-base; 5-methyl-2H-pyrazole-3-yl; 3-picoline-2-base, 4-picoline-2-base, 5-picoline-2-base; 6-picoline-2-base; 2-picoline-3-base, 2-methylthiazol-4-base, 5-nitropyridine-2-base; the 2H-pyrazole-3-yl; 3H-pyrazoles-4-base, pyridazine-3-base, pyridine-2-base; pyridin-3-yl; pyridin-4-yl, 5-pyridin-3-yl-2H-[1,2; 4] triazole-3-base; pyrimidine-4-base, pyrimidine-5-base, 1H-pyrroles-3-base; quinoline-2-base; 1H-tetrazolium-5-base, thiazol-2-yl, thiazole-5-base; thianthrene-2-base; thianthrene-3-base, 2H-[1,2; 4] triazole-3-base; 3H-[1,2,3] triazole-4-base; 5-5-flumethiazine-2-base, etc.Suitable protecting group comprises tert-butoxycarbonyl, benzyloxycarbonyl group, and benzyl, the 4-methoxybenzyl, the 2-nitrobenzyl, etc.Be used for the application and define R 4Assorted (the C of optional replacement 5-10) aryl comprises benzofuran-2-base, furan-2-base, furan-3-base, pyridin-3-yl, pyridin-4-yl, chinol-2-base, chinol-3-base, thianthrene-2-base, thianthrene-3-base, etc.
" assorted bicyclic aryl " means bicyclic aryl, and as defining among the application, condition is that one or more ring carbon atoms of indicating are selected from-N=,-NR-, and-O-, the hetero atom segment of-S-replaces, and wherein R is a hydrogen, (C 1-6) alkyl, protecting group or expression as and the free valency of ring nitrogen tie-point, with and carbocyclic ring ketone, thioketone or imino group ketone derivatives arbitrarily.For example, be used for the optional assorted (C that replaces of the application 8-10) bicyclic aryl includes but are not limited to 2-amino-4-oxo-3,4-dihydropteridine-6-base, etc.In general, the assorted bicyclic aryl of term that is used for the application comprises, for example, and benzo [1,3] dioxolanes-5-base, 3,4-dihydro-2H-[1,8] naphthyridinyl, 3,4-dihydro-2H-quinolyl, 2,4-dioxo-3,4-dihydro-2H-quinazolyl, 1,2,3,4,5,6-six hydrogen [2,2 '] bipyridyl, 3-oxo-2,3-dihydrobenzo [1,4] oxazinyl, 5,6,7, the 8-tetrahydric quinoline group, etc.
" Heterocyclylalkyl " means cycloalkyl, and as definition in this application like that, condition is that one or more ring carbon atoms of indicating are selected from-N=,-NR-,-O-or-the hetero atom segment replacement of S-, wherein R is a hydrogen, (C 1-6) alkyl, protecting group or as and the free valency of ring nitrogen tie-point, with and carbocyclic ring ketone arbitrarily, thioketone or imino group ketone derivatives (for example, the assorted (C of term 5-10) cycloalkyl comprises imidazolidinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quininuclidinyl, etc.).Suitable protecting group comprises tert-butoxycarbonyl, benzyloxycarbonyl group, and benzyl, the 4-methoxybenzyl, the 2-nitrobenzyl, etc.Derivant unprotected and protection all belongs to scope of the present invention.
" hydroxyl " means group-OH.Unless otherwise noted, the chemical compound of the present invention that comprises hydroxyl comprises the derivant of its protection.Suitable hydroxyl segment protecting group comprises benzyl etc.
" imino group ketone derivatives " means and contains-C (NR)-pulsating derivant, and wherein R is hydrogen or (C 1-6) alkyl.
But " isomer " means has identical molecular formula its different in kind or its atomic linkage sequence is different or its atom is spatially arranged different formula I chemical compounds.Its atoms in space is arranged different isomers and is called " stereoisomer ".Each other not for the stereoisomer of mirror image is called " diastereomer ", is that the stereoisomer of non-superimposable mirror image then is called " enantiomer " or also claims " optical isomer " sometimes.Be bonded to 4 carbon atoms on the substituent group inequality and be called " chiral centre ".The chemical compound that has a chiral centre has two kinds of enantiomerism forms that chirality is opposite, is called " racemic mixture ".Chemical compound with an above chiral centre has 2 (n-1)Individual enantiomerism is right, and wherein n is the chiral centre number.Chemical compound with an above chiral centre can exist or exist with the form of non-enantiomer mixture with single diastereomer form, is called " diastereo-isomerism mixture ".When having a chiral centre, stereoisomer may be feature with the absolute configuration of chiral centre.Absolute configuration is meant and is connected to substituent spatial arrangements on the chiral centre.Enantiomer is characterised in that the absolute configuration of its chiral centre, and by Cahn, the R-of Ingold and Prelog and S-sequence rule are described.The convention that is used for the spatial chemistry nomenclature is used for determining that the method for spatial chemistry and separation of stereoisomers is well-known (for example, referring to " Advanced Organic Chemistry " the 4th edition,, March Jerry, John Wiley ﹠amp in 1992 in the art; Sons, NewYork).Should be appreciated that being used for the application describes the title of formula I chemical compound and explanation and mean and comprise all possible stereoisomer.Therefore; for example; N-[1-(1-benzylamino formoxyl-formoxyl (methanoyl))-propyl group]-the 4-morpholine-4-base-4-oxo-title of 2-phenylmethane sulfonyl methyl-butyramide means and comprises N-[(S)-[1-(1-benzylamino formoxyl-formoxyl)-propyl group]-4-morpholine-4-base-4-oxo-2-phenylmethane sulfonyl methyl-butyramide and N-[(R)-[1-(1-benzylamino formoxyl-formoxyl)-propyl group]-4-morpholine-4-base-4-oxo-2-phenylmethane sulfonyl methyl-butyramide with and mixture arbitrarily, racemic modification or opposite.
" ketone derivatives " mean contain segment-C (O)-derivant.For example, in this application, X 3It can be 2-acetoxyl group-azetidine-3-base.This X 3" carbocyclic ring ketone derivatives " in the example will be that 2-acetoxyl group-4-oxo-azetidine-3-base is (referring to table 3, C32).
" nitro " means group-NO 2
" optional " or " choose " means incident or the situation described subsequently and may take place or may not take place, and this description comprises incident or the situation of situation generation and the situation that does not take place.For example, phrase is " wherein at R 3And R 4In, alicyclic arbitrarily or aromatic ring can be further by 1-5 ... group replace and " mean in order to belong to scope of the present invention, R 3And R 4May or may not be substituted.
" oxoalkyl group " means alkyl as defined above, wherein indicate in the carbon number one by oxygen groups (O-) replace, for example, oxo (C 2-6) alkyl comprises methoxy, etc.
" N-oxide derivative " means the derivant of formula I chemical compound, and wherein nitrogen is the state of oxidation (that is, O-N) and have a pharmacological activity of hope.
" pathology " of disease means main character, reason or the development of disease and by the variation of the 26S Proteasome Structure and Function that this lysis produced.
" pharmaceutically acceptable " mean its can be used for preparing common safe, nontoxic and neither biologically be not again the not welcome pharmaceutical composition in other aspects, it comprise for animals and human pharmaceutical use acceptable those.
" pharmaceutically acceptable salt " means the salt of formula I chemical compound, and this salt is as above to define pharmaceutically acceptablely, and has the pharmacological activity of hope.This salt comprises and mineral acid, the acid-addition salts that example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. form; The perhaps acid-addition salts that forms with organic acid; described organic acid such as acetic acid; propanoic acid; acid; enanthic acid; the Pentamethylene. propanoic acid; glycolic; acetone acid; lactic acid; malonic acid; succinic acid; malic acid; maleic acid; fumaric acid; tartaric acid; citric acid; benzoic acid; neighbour-(4-hydroxy benzoyl) benzoic acid; cinnamic acid; mandelic acid; Loprazolam; ethane sulfonic acid; 1; the 2-ethane disulfonic acid; the 2-hydroxyethanesulfonic acid; benzenesulfonic acid; right-chlorobenzenesulfonic acid; the 2-LOMAR PWA EINECS 246-676-2; p-methyl benzenesulfonic acid; camphorsulfonic acid; 4-methyl bicycle [2.2.2] oct-2-ene-1-carboxylic acid; glucoheptonic acid; 4,4 '-di-2-ethylhexylphosphine oxide (3-hydroxyl-2-alkene-1-carboxylic acid); the 3-phenylpropionic acid; trimethylacetic acid; NSC 4537; lauryl sulfate; gluconic acid; glutamic acid; carbonaphthoic acid; salicylic acid; stearic acid; muconic acid etc.
Pharmaceutically acceptable salt also comprises base addition salts, and it can form with inorganic or organic base reaction when having acid proton.Acceptable inorganic base comprises sodium hydroxide, sodium carbonate, potassium hydroxide, aluminium hydroxide and calcium hydroxide.Acceptable organic base comprises ethanolamine, diethanolamine, triethanolamine, trometamol (tromethamine), N-methylglucosamine etc.
" prodrug " means can be in vivo by the chemical compound of metabolic way (for example hydrolysis) conversion accepted way of doing sth I chemical compound.For example, the ester that contains the formula I chemical compound of hydroxyl can be hydrolyzed in vivo and convert its parent molecule to.Perhaps, the ester that contains the formula I chemical compound of carboxyl can be hydrolyzed in vivo and convert its parent molecule to.The ester of the formula I chemical compound of suitable hydroxyl for example is acetas, citrate, lactate, tartrate, malonate, ethanedioic acid ester, salicylate, propionic ester, succinate, fumarate, maleate, di-2-ethylhexylphosphine oxide-b-hydroxynaphthoic acid ester, Radix Gentianae acid esters, isethionic acid ester, two pairs-toluyl tartrate, methane sulfonate, ethane sulfonic acid ester, benzene sulfonate, p-toluenesulfonic esters, cyclohexyl sulfamate and quinate.The ester of suitable carboxylic formula I chemical compound, for example be those by F.J.Leinweber at Drug Metab.Res., the ester of describing in 1987,18,379 pages.The ester of the formula I chemical compound of the useful especially hydroxyl of one class can be by being selected from people such as Bundgaard at J.Med.Chem., 1989,32, the sour segment of describing in the 2503-2507 page or leaf forms, and (the aminomethyl)-benzoate that comprises replacement, for example, the dialkyl amino methyl benzoic acid ester, two alkyl nitrogen-atoms that can be connected with each other and/or be interrupted or be optionally substituted by an oxygen atom wherein, for example alkylating nitrogen-atoms interrupts, and (morpholino-methyl) benzoate more especially is as 3-or 4-(morpholino methyl) benzoate, (4-alkyl piperazine-1-yl) benzoate, for example 3-or 4-alkyl piperazine-1-yl)-benzoate.
" derivant of protection " means the derivant of formula I chemical compound, and wherein reactive site protects with protecting group.The derivant of the protection of formula I chemical compound can be used for the chemical compound of preparation formula I or itself can be active cathepsin S inhibitor.The list of details of due care base can be referring to " protecting group in the organic synthesis " of T.W.Greene, the third edition, John Wiley﹠amp; Sons, Inc., 1999 publish.
" treatment effective dose " means such amount, and when giving animal and treat a kind of disease, this amount is enough to realize for this treatment of diseases.
" 40 thione derivatives " mean contain segment-C (S)-derivant.
" treatment " or " processing " mean the behavior that gives The compounds of this invention arbitrarily, comprising:
(1) infect or demonstrate the generation that wards off disease in the animal of the pathology of this disease or symptom characteristic in this disease of easy infection but also be not subjected to,
(2) in the animal of pathology that is subjected to infect or demonstrates this disease or symptom characteristic, suppress this disease (that is, suppressing further developing of pathology and/or symptom), perhaps
(3) in the animal of pathology that is subjected to infect or demonstrates this disease or symptom characteristic, make amelioration of disease (that is, reversing pathology and/or symptom).
Naming rule:
Formula I chemical compound with and preparation in the intermediate that uses and raw material according to the name of IUPAC nomenclature, wherein order of priority reduces characteristic group as described below successively when making main group quoting: acid, ester, amide, or the like.Perhaps, (BeilsteinInformation Systems Inc.) names chemical compound by AutoNom 4.0.For example, X wherein 1Be-NHC (R 1) (R 2) X 2(R 1And R 2The hydrogen of respectively doing for oneself), X 2Be cyano group, R 3Be cyclohexyl methyl, R 4It is the formula I chemical compound of phenylamino; That is the chemical compound that, has following structure:
Figure A0281128900251
Called after N-cyanogen methyl-2-cyclohexyl methyl-N '-phenyl Malondiamide.
The preferred embodiments of the invention:
Though illustrated the wideest definition of the present invention in summary of the invention, some aspect of the present invention is preferred.For example, X 1Be-NHC (R 1) (R 2) X 2Perhaps-NHX 3X 2Be cyano group ,-C (O) X 3,-C (O) CF 3,-C (O) CF 2CF 2R 9,-CH=CHS (O) 2R 5,-C (O) CF 2C (O) NR 5R 5,-C (O) C (O) NR 5R 6,-C (O) C (O) OR 5,-C (O) CH 2OR 5,-C (O) CH 2N (R 6) SO 2R 5Or-C (O) C (O) R 5R wherein 5And R 6As mentioned above; X 3Comprise the assorted monocycle that contains 4-6 annular atoms or contain the assorted dicyclo ring system of condensing of 8-14 annular atoms, with and carbocyclic ring ketone arbitrarily, imino group ketone or 40 thione derivatives; Wherein at R 5, X 2Or X 3In, alicyclic ring or aromatic ring can further be independently selected from (C by 1-5 arbitrarily 1-6) alkyl, or-X 4OC (O) R 12Group replace, and/or be selected from-R by 1 14,-X 4C (O) R 14Perhaps-X 4OC (O) R 14Group replace; X wherein 4, R 12And R 14As mentioned above; R 1Be hydrogen or (C 1-6) alkyl, R 2Be hydrogen ,-X 4OR 12, (C 5-10) heteroaryl (C 0-6) alkyl, (C 5-10) aryl (C 0-6) alkyl, (C 5-10) cycloalkyl (C 0-6) alkyl, (C 5-10) Heterocyclylalkyl (C 0-6) alkyl, perhaps (C 1-6) alkyl; Perhaps R 1And R 2Be connected to R 1And R 2On carbon atom form (C altogether 3-8) cycloalkylidene or (C 3-8) inferior Heterocyclylalkyl, wherein at described R 2In, heteroaryl, aryl, cycloalkyl, Heterocyclylalkyl, cycloalkylidene or inferior Heterocyclylalkyl are optional arbitrarily is independently selected from (C by 1-3 1-6) group of alkyl and hydroxyl replaces; R 3Be-CH 2X 5, X wherein 5Be independently selected from all cases-X 4SR 12,-X 4C (O) NR 12R 12,-X 4S (O) 2R 13,-X 4C (O) R 13,-X 4SR 14,-X 4R 12,-R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) NR 14R 12, X wherein 4, R 12, R 13And R 14Definition as above; R 4Be-NR 6R 6,-NR 6R 14,-NR 6R 15Perhaps-NR 6X 5C (O) R 14, R wherein 6, X 5And R 14As mentioned above, and R 15Be hydrogen ,-(C 1-6) alkyl or-X 5OR 6, X wherein 5As mentioned above; Perhaps R 6And R 15Be connected to R 6And R 15On nitrogen-atoms form assorted (C altogether 3-10) cycloalkyl, assorted (C 5-10) aryl or assorted (C 8-10) bicyclic aryl; Wherein, at R 3And R 4In, alicyclic ring or aromatic ring can further be independently selected from (C by 1-5 arbitrarily 1-6) alkyl, cyano group, halogen, the nitro, (C that halogen replaces 1-4) alkyl ,-X 4OR 12,-X 4C (O) OR 12,-X 4C (O) R 13,-X 4C (O) NR 12R 12,-X 4NR 12S (O) 2R 12Group replace and/or be selected from-R by 1 14,-X 4OR 14With-X 4C (O) NR 14R 12Group replace; At R 3And R 4In, the aliphatic segment can further be replaced by 1-5 group that is independently selected from cyano group arbitrarily; X wherein 4, R 12, R 13And R 14As mentioned above; Prerequisite is at R 3Or R 4In only have a twin nuclei.
Particularly, X 1Be-NHC (R 1) (R 2) X 2Perhaps-NHX 3X 2Be cyano group ,-C (O) X 3,-CF 3,-CF 2CF 3, (E)-and 2-benzenesulfonyl-vinyl, 2-formyl-dimethylamino-2,2-two fluoro-acetyl group, 1-benzylamino formoxyl-formoxyl, 1-benzyloxy (oxalyl group), 2-benzyloxy-acetyl group, 2-benzenesulfonyl amino-acetyl group or 2-oxo-2-phenyl acetyl; X 3Be 1H-benzimidazolyl-2 radicals-Ji, pyrimidine-2-base, benzoxazole-2-base, benzothiazole-2-base, pyridazine-3-base, 3-phenyl-[1,2,4] oxadiazole-5-base, 3-ethyl-[1,2,4] oxadiazole-5-base, 2-methyl-4-oxo-tetrahydrofuran-3-base, 2-ethyl-4-oxo-tetrahydrofuran-3-base, 4-oxo-1-(1-phenyl formoxyl)-pyrrolidine-3-base or (S)-2-acetoxyl group-4-aza-oxo-cyclobutane-3-base; R 1Be hydrogen or methyl, R 2Be hydrogen, methoxy, (C 1-6) alkyl, phenethyl, thiophene-2-base or 5-methylfuran-2-base, perhaps (ii) R 1And R 2Be connected to R 1And R 2On carbon atom form cyclopropylidene altogether, Pentamethylene oxide .-4-subunit or methyl piperidine-4-subunit (methyl-piperidin-4-ylene).
R 3Thiophene-2-sulfonyl methyl more preferably, 3-chloro-2-fluoro-phenylmethane sulfonyl methyl, benzenesulfonyl methyl; phenylmethane sulfonyl methyl, 2-(1,1-two fluoro-methoxyl groups)-phenylmethane sulfonyl methyl; 2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfuryl base)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl; 2-phenylmethane sulfonyl-ethyl, oxygen base-pyridine-2-methylmethane sulfonyl methyl, third-2-alkene-1-sulfonyl methyl; 4-methoxyl group-phenylmethane sulfonyl methyl, p-methylphenyl sulfonyl methane ylmethyl, 4-chloro-phenylmethane sulfonyl methyl; neighbour-tolyl sulfonyl methane ylmethyl, 3,5-dimethyl-phenylmethane sulfonyl methyl; 4-trifluoromethyl-phenylmethane sulfonyl methyl, 4-trifluoromethoxy-phenylmethane sulfonyl methyl, 2-bromo-phenylmethane sulfonyl methyl; pyridine-2-methylmethane sulfonyl methyl, pyridin-3-yl sulfonyl methane ylmethyl, pyridin-4-yl sulfonyl methane ylmethyl; naphthalene-2-methylmethane sulfonyl methyl, 3-methyl-phenylmethane sulfonyl methyl, 3-trifluoromethyl-phenylmethane sulfonyl methyl; 3-trifluoromethoxy-phenylmethane sulfonyl methyl, 4-fluoro-2-trifluoromethoxy-phenylmethane sulfonyl methyl, 2-fluoro-6-trifluoromethyl-phenylmethane sulfonyl methyl; 3-chloro-phenylmethane sulfonyl methyl, 2-fluoro-phenylmethane sulfonyl methyl, 2-three fluoro-phenylmethane sulfonyl methyl; 2-cyano group-phenylmethane sulfonyl methyl, the 4-tert-butyl group-phenylmethane sulfonyl methyl, 2-fluoro-3-methyl-phenylmethane sulfonyl methyl; 3-fluoro-phenylmethane sulfonyl methyl, 4-fluoro-phenylmethane sulfonyl methyl, 2-chloro-phenylmethane sulfonyl methyl; 2,5-two fluoro-phenylmethane sulfonyl methyl, 2; 6-two fluoro-phenylmethane sulfonyl methyl, 2,5-two chloro-phenylmethane sulfonyl methyl; 3,4-two chloro-phenylmethane sulfonyl methyl, 2-(1; 1-two fluoro-methoxyl groups)-and phenylmethane sulfonyl methyl, 2-cyano group-phenylmethane sulfonyl methyl, 3-cyano group-phenylmethane sulfonyl methyl; 2-trifluoromethoxy-phenylmethane sulfonyl methyl, 2,3-two fluoro-phenylmethane sulfonyl methyl; 2,5-two fluoro-phenylmethane sulfonyl methyl, biphenyl-2-methylmethane sulfonyl methyl; cyclohexyl methyl, 3-fluoro-phenylmethane sulfonyl methyl, 3; 4-two fluoro-phenylmethane sulfonyl methyl; 2,4-two fluoro-phenylmethane sulfonyl methyl, 2; 4; 6-three fluoro-phenylmethane sulfonyl methyl, 2,4; 5-three fluoro-phenylmethane sulfonyl methyl; 2,3,4-three fluoro-phenylmethane sulfonyl methyl; 2; 3,5-three fluoro-phenylmethane sulfonyl methyl, 2; 5; 6-three fluoro-phenylmethane sulfonyl methyl, 2-chloro-5-trifluoromethyl sulfonyl methane ylmethyl, 2-methylpropane-1-sulfonyl; 2-fluoro-3-trifluoromethyl sulfonyl methane ylmethyl; 2-fluoro-4-trifluoromethyl sulfonyl methane ylmethyl, 2-fluoro-5-trifluoromethyl sulfonyl methane ylmethyl, 4-fluoro-3-trifluoromethyl sulfonyl methane ylmethyl; 2-methoxyl group-phenylmethane sulfonyl methyl; 3,5-bis trifluoromethyl-phenylmethane sulfonyl methyl, 4-difluoro-methoxy-phenylmethane sulfonyl methyl; 2-difluoro-methoxy-phenylmethane sulfonyl methyl; 3-difluoro-methoxy-phenylmethane sulfonyl methyl, 2,6-Dichlorobenzene base sulfonyl methane ylmethyl; biphenyl-4-methylmethane sulfonyl methyl; 3,5-dimethyl-isoxazole-4-base sulfonyl methane ylmethyl, 5-chlorothiophene-2-methylmethane sulfonyl methyl; 2-[4-(1; 1-two fluoro-methoxyl groups)-benzenesulfonyl]-ethyl, 2-[2-1,1-difluoro-methoxy)-benzenesulfonyl]-ethyl; 2-[3-(1; the 1-difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl; 2-(2-trifluoromethoxy-benzenesulfonyl)-ethyl; (cyanogen methyl-methyl-carbamoyl)-methyl, butyl, biphenyl-3-ylmethyl; 2-oxo-2-pyrrolidine-1-base ethyl; 2-benzenesulfonyl-ethyl, isobutyl group sulfane ylmethyl, 2-phenyl sulfane base-ethyl; cyclohexyl-methane sulfonyl methyl; 2-cyclohexyl-ethane sulfonyl, benzyl, naphthalene-2-base; the dibenzylsulfide. alkyl methyl; 2-trifluoromethyl-dibenzylsulfide. alkyl methyl, 5-bromothiophene-2-ylmethyl, phenyl sulfane base-ethyl and cyclopropyl sulfonyl methane ylmethyl.
R 4Phenylamino more preferably, benzyl amino, 4-phenoxy group phenylamino; phenethyl amino, 3-phenyl-propyl group amino, morpholine-4-base; cyclohexyl amino; naphthalene-1-ylmethyl-amino, pyridin-3-yl amino, 6-methoxyl group-pyridin-3-yl amino; diisobutyl amino; 4-nitro-benzyl amino, 2-thiophene-2-base-ethylamino, 3-phenoxy group phenylamino; the cyanogen methylamino; (pyridin-3-yl methyl)-amino, 5,6; 7; 8-naphthane-1-base is amino, 2-pyridine-2-base-ethylamino, 2; 3-indoline-1-base; 3,4-dihydro-1H-isoquinolin-2-base, cyclohexyl methyl-amino; 2-methoxyl group-benzyl amino; 1-phenyl ethylamino, (pyridin-4-yl methyl)-amino, benzyl methylamino; 3-nitro-benzyl amino; 4-methoxybenzene amino, 3-carbamyl phenylamino, 4-carbamyl phenylamino; (oxolane-2-ylmethyl)-amino; 3,4-dihydro-2H-quinoline-1-base, dimethylamino; butyl methyl amino; diisopropylaminoethyl, propyl group methylamino, 1-(benzoxazole-2-carbonyl)-the amino and isobutyl group methylamino of propyl group.
With reference to more than the preferred embodiment illustrated mean and comprise specific and all combinations preferred group.
The concrete chemical compound of the present invention is selected from the chemical compound that forms by the following method, is about to the acyl group carbon atom (C in the fragment (A1-A37) shown in the table 1 *) be connected to the inferior first carbon atom in the fragment (B1-B88) shown in the table 2 ( *CH *) on, and the inferior first carbon atom in the fragment (B1-B88) shown in the table 2 ( *CH *) be connected to the acyl group carbon atom (C in the described fragment of table 3 (C1-C36) *) on.
Following table is used to provide and instructs so that implement the present invention better.But they do not limit scope of the present invention.Those of ordinary skill can be optionally by being connected to a fragment in the fragment shown in the table 1 on any one fragment shown in the table 2, then the fragment shown in the table 2 is connected on any one fragment in the table 3 and produces concrete chemical compound.
Table 1
Figure A0281128900311
Table 2
Figure A0281128900321
Figure A0281128900331
Figure A0281128900351
Figure A0281128900361
Table 3
Figure A0281128900362
Figure A0281128900381
Therefore; for example; in table 4, the chemical compound that is expressed as A2-B45-C35 is group A2 and the combination of group B 45 in the table 2 and the group C35 in the table 3, i.e. N-[1-(1-benzoxazole-2-base-formoxyl)-3-phenyl propyl in the table 1]-N '-benzyl-2-cyclohexyl methyl-Malondiamide:
Preferably be selected from formula I chemical compound as described below in addition:
2-butyl-N-cyanogen methyl-N '-phenyl-Malondiamide (chemical compound 1; Be expressed as A1-B88-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-phenyl Malondiamide (chemical compound 2; Be expressed as A1-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-PEMA (chemical compound 3; Be expressed as A4-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-4-yl methyl-Malondiamide (chemical compound 4; Be expressed as A24-B45-C1);
N-[1-(benzoxazole-2-carbonyl)-the 3-phenyl propyl]-N '-benzyl-2-cyclohexyl methyl Malondiamide (chemical compound 5; Be expressed as A2-B45-C35);
N-cyanogen methyl-N '-cyclohexyl-2-cyclohexyl methyl-Malondiamide (chemical compound 6; Be expressed as A7-B45-C1);
N-benzyl-N '-cyanogen methyl-2-cyclohexyl methyl-Malondiamide (chemical compound 7; Be expressed as A2-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-Phenoxyphenyl)-Malondiamide (chemical compound 8; Be expressed as A3-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(3-phenyl propyl)-Malondiamide (chemical compound 9; Be expressed as A5-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-3-morpholine-4-base-3-oxo propionic acid amide. (chemical compound 10; Be expressed as A6-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-naphthalene-1-ylmethyl-Malondiamide (chemical compound 11; Be expressed as A8-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-3-yl-Malondiamide (chemical compound 12; Be expressed as A9-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-diisobutyl-Malondiamide (chemical compound 13; Be expressed as A11-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-diisopropyl-Malondiamide (chemical compound 14; Be expressed as A36-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(6-methoxypyridine-3-yl)-Malondiamide (chemical compound 15; Be expressed as A10-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-thiophene-2-base-ethyl)-Malondiamide (chemical compound 16; Be expressed as A13-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N ' (3-Phenoxyphenyl)-Malondiamide (chemical compound 17; Be expressed as A14-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-nitrobenzyl)-Malondiamide (chemical compound 18; Be expressed as A12-B45-C1);
N, N '-two cyanogen methyl-2-cyclohexyl methyl-Malondiamide (chemical compound 19; Be expressed as A15-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(5,6,7,8-naphthane-1-yl) Malondiamide (chemical compound 20; Be expressed as A17-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-pyridine-2-base-ethyl)-Malondiamide (chemical compound 21; Be expressed as A18-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-3-(2,3-indoline-1-yl)-3-oxo propionic acid amide. (chemical compound 22; Be expressed as A19-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxo propionic acid amide. (chemical compound 23; Be expressed as A20-B45-C1);
N-cyanogen methyl-2, N '-dicyclohexyl methyl-Malondiamide (chemical compound 24; Be expressed as A21-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-methoxy-benzyl)-Malondiamide (chemical compound 25; Be expressed as A22-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(1-phenylethyl)-Malondiamide (chemical compound 26; Be expressed as A23-B45-C1);
N-benzyl-N '-cyanogen methyl-2-cyclohexyl methyl-N-methyl-Malondiamide (chemical compound 27; Be expressed as A25-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(3-nitrobenzyl)-Malondiamide (chemical compound 28; Be expressed as A26-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-methoxy-benzyl)-Malondiamide (chemical compound 29; Be expressed as A27-B45-C1);
N-(3-carbamyl phenyl)-N '-cyanogen methyl-2-cyclohexyl methyl-Malondiamide (chemical compound 30; Be expressed as A28-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-3-yl methyl-Malondiamide (chemical compound 31; Be expressed as A16-B45-C1);
N-(4-carbamoyl phenyl)-N '-cyanogen methyl-2-cyclohexyl methyl Malondiamide (chemical compound 32; Be expressed as A29-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-oxolane-2-ylmethyl Malondiamide (chemical compound 33; Be expressed as A30-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-3-(3,4-dihydro-2H-quinoline-1-yl)-3-oxo propionic acid amide. (chemical compound 34; Be expressed as A31-B45-C1);
The N-tert-butyl group-N '-cyanogen methyl-2-cyclohexyl methyl-N-methylmalonyl amine (chemical compound 35; Be expressed as A35-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N '-methyl-N '-propyl group Malondiamide (chemical compound 36; Be expressed as A34-B45-C1);
N-butyl-N '-cyanogen methyl-2-cyclohexyl methyl-N-methylmalonyl amine (chemical compound 37; Be expressed as A33-B45-C1);
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-dimethyl propylene diamides (chemical compound 38; Be expressed as A32-B45-C1);
N-benzyl-N '-cyanogen methyl-2-(2-phenyl sulfane base ethyl) Malondiamide (chemical compound 39; Be expressed as A2-B80-C1);
2-(2-phenyl sulfonyl ethyl)-N-benzyl-N '-cyanogen methylmalonyl amine (chemical compound 40; Be expressed as A2-B6-C1);
2-(2-benzenesulfonyl-ethyl)-N-[(S)-1-(1-benzoxazole-2-base-formoxyl)-amyl group]-N '-benzyl-Malondiamide (chemical compound 41; Be expressed as A2-B6-C12);
N, N '-two [(S)-1-(1-benzoxazole-2-base-formoxyl)-propyl group]-2-cyclohexyl methyl Malondiamide (chemical compound 42; Be expressed as A37-B45-C13);
With its N-oxide derivative, prodrug derivant, the derivant of protection, single stereoisomer and mixture of isomers; And the pharmaceutically acceptable salt of this chemical compound and solvate (for example hydrate) and its N-oxide derivative, prodrug derivant, the derivant of protection, single isomer and mixture of isomers.
Pharmacology and practicality:
Chemical compound of the present invention is a cathepsin S inhibitor optionally, thereby can be used for treating wherein that the cathepsin S activity causes in the disease of described disease pathology and/or symptom.For example, chemical compound of the present invention can be used for treating autoimmune disease, includes but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis and struma lymphomatosa; Allergic disorder includes but not limited to asthma; And the alloimmunization reaction, include but not limited to organ transplantation or tissue transplantation.
The disorder that cathepsin S also relates to excessive elastolysis has relation, as chronic obstructive pulmonary disease (for example, edema due to disorder of QI), bronchiolitis, excessive air flue elastolysis in asthma and the bronchitis, pneumonia and cardiovascular disease are broken and gruel type as speckle.Cathepsin S and fibril are formed with and involve, and therefore, the inhibitor of cathepsin S can be used for the therapy system amyloidosis.
The cysteine proteinase of The compounds of this invention suppresses activity and can measure by well known to a person skilled in the art method.It is known being used to measure the suitable in vitro tests that proteinase activity and tested chemical compound suppress.Usually, the protease of measuring the peptide substrate in the test is induced hydrolysis.The detailed content that is used to measure the test of the protease inhibiting activity embodiment 6-9 that vide infra.
Administration and pharmaceutical composition:
In general, the chemical compound of formula I will anyly common give to treat the effective dose administration with acceptable manner by known in the art, itself or individually dosed or combine administration with one or more therapeutic agents.The treatment effective dose can change according to the order of severity, patient's age and the relative health condition of disease, effectiveness and other factors of the chemical compound that uses widely.For example, the treatment effective dose of formula I chemical compound can for about 1 microgram of every kg body weight every day (μ g/kg) to every kg body weight every day about 1 milligram (mg/kg), be generally about 10 μ g/kg/ days to about 0.1mg/kg/ days.Therefore, when the patient is 80 kilograms a man-hour, the treatment effective dose can be about 100 μ g/ days to about 100mg/ days, normally about 1 μ g/ days to about 10mg/ days.In general, those of ordinary skills are according to self knowledge and the disclosed content of the application treatment effective dose that can be identified for treating a certain given disease up-to-date style I chemical compound.
The chemical compound of formula I can come administration by one of following path with the form of pharmaceutical composition: oral, be administered systemically (as percutaneous, through intranasal or pass through suppository) or parenteral (for example, intramuscular injection, intravenous or subcutaneous).Compositions can be tablet, pill, capsule, semisolid, powder, extended release preparation, solution, suspension, elixir, aerosol or any other suitable composition forms, in general, combine with at least a pharmaceutically acceptable excipient by the chemical compound of formula I and form.Acceptable excipient is nontoxic, helps administration, and can not cause adverse effect to the therapeutic effect of active component.This excipient can be arbitrarily solid, liquid, semisolid or, under the situation of aerosol combination, be the gaseous state excipient that those skilled in the art can get usually.
The solid drugs excipient comprises starch, cellulose, Talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, Chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, defatted milk powder etc.Liquid and semisolid excipient can be selected from water, ethanol, glycerol, propylene glycol and various oil, comprise the oil (for example, Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Semen Sesami wet goods) in oil, animal, plant or artificial source.Preferred liquid-carrier during especially for injectable solution, comprises water, normal saline, D/W and glycol.
The amount of formula I chemical compound in compositions can change according to preparation type, dosage unit size, excipient type and known other factors of pharmaceutical science field those of ordinary skill widely.In general, the formula I compound compositions that is used for the treatment of given disease will comprise 0.01 weight %-10 weight %, the active component of preferred 0.3 weight-1 weight %, and all the other are excipient.Preferred pharmaceutical compositions to be to be used for processed continuously single unit dosage form administration, perhaps in the time specifically need extenuating symptom optionally with single unit dosage form administration.The representational pharmaceutical preparation that contains formula I chemical compound is described in embodiment 10.
Chemistry:
The preparation method of formula I chemical compound:
Chemical compound of the present invention can or suitably be revised known method by utilization and prepare, these methods are mean methods of using up to now or describe in the literature, for example the method for describing in the Comprehensive OrganicTransformations of the R.C.Larock that VCH in 1989 publishes.
In the reaction described below, when needing active function groups in end product, may essentially protect these groups, for example hydroxyl, amino, imino group, sulfenyl or carboxyl undesirably participate in the reaction to avoid them.General protecting group can the secundum legem rule of operation be used, for example referring to " the vitochemical protecting group " of T.W.Greene and P.G.M.Wuts, and John Wiley ﹠amp; Sons, 1991.
X wherein 1Be-NHC (R 1) (R 2) X 2Formula I chemical compound can be by being prepared by following reaction process 1:
Reaction process 1:
Figure A0281128900441
X wherein 2, R 1, R 2, R 3And R 4Such as in the summary of the invention definition.
The chemical compound of formula I can be by acid and the formula NH that makes formula 2 2CR 1R 2X 2Compound condensation prepare.Condensation reaction can be with suitable coupling agent (benzotriazole-1-base oxygen base tripyrrole alkane-phosphorus hexafluorophosphate (PyBOP_) for example, 1-(3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), O-benzotriazole-1-base-N, N, N ', N '-tetramethyl hexafluorophosphate (HBTU), 1,3-dicyclohexyl-carbodiimide (DCC), or the like), optional suitable catalyst (as I-hydroxybenzotriazole (HOBt), 1-hydroxyl-azepine benzotriazole (HOAt) etc.) and non-nucleophilicity alkali (as N-methylmorpholine, triethylamine etc., perhaps its appropriate combination arbitrarily), in appropriate solvent (N-Methyl pyrrolidone or the like), realize at ambient temperature, and need 3-10 to finish reaction in individual hour.The embodiment that comes the detailed description of synthetic compound of formula i vide infra by the method in the reaction process 1.
X wherein 1Be-NHX 3Formula I chemical compound can be by being prepared by following reaction process 2:
Reaction process 2
X wherein 3, R 3And R 4Such as in the summary of the invention definition.
The chemical compound of formula I can be by acid and the formula NH that makes formula 2 2X 3Compound condensation prepare.Condensation reaction can be with suitable coupling agent (benzotriazole-1-base oxygen base tripyrrole alkane-phosphorus hexafluorophosphate (PyBOP_) for example, 1-(3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), O-benzotriazole-1-base-N, N, N ', N '-tetramethyl hexafluorophosphate (HBTU), 1,3-dicyclohexyl-carbodiimide (DCC), or the like), optional suitable catalyst (as I-hydroxybenzotriazole (HOBt), 1-hydroxyl-azepine benzotriazole (HOAt) etc.) and non-nucleophilicity alkali (as N-methylmorpholine, triethylamine or the like, perhaps its appropriate combination arbitrarily), in appropriate solvent (N-Methyl pyrrolidone or the like), realize at ambient temperature, and need 3-10 to finish reaction in individual hour.The embodiment that comes the detailed description of synthetic compound of formula i vide infra by the method in the reaction process 1.
The other method that is used for preparation I compound:
The chemical compound of formula I can be by making free alkali form chemical compound and the pharmaceutically acceptable inorganic or organic acid reaction form of making its pharmaceutically-acceptable acid addition.Perhaps, the pharmaceutically acceptable base addition salts of formula I chemical compound can prepare by free acid form chemical compound and pharmaceutically acceptable inorganic or organic base are reacted.Be suitable for the inorganic and organic acid of pharmaceutically acceptable salt of preparation I compound and inorganic and organic base definitional part referring to the application.Perhaps, the salt form of formula I chemical compound can use the salt of raw material or intermediate to prepare.
The free acid of formula I chemical compound or free alkali form can be prepared by corresponding base addition salts or acid-addition salts form.For example, the formula I chemical compound that is the acid-addition salts form can pass through be converted into corresponding free alkali with suitable alkali (for example, Ammonia, sodium hydroxide etc.) processing.The formula I chemical compound that is the base addition salts form can be by being converted into corresponding free acid with suitable acid (for example, hydrochloric acid etc.) processing.
The N-oxide of formula I chemical compound can prepare by method known to a person of ordinary skill in the art.For example, the N-oxide can be by (as trifluoroperacetic acid, crossing maleic acid, benzylhydroperoxide with oxidant, peracetic acid, metachloroperbenzoic acid, etc.) at suitable inert organic solvents (for example, halogenated hydrocarbons is as dichloromethane) in, handling not under about 0 ℃, the formula I chemical compound of oxidised form prepares.Perhaps, the N-oxide of formula I chemical compound can be by the N-oxide preparation of suitable raw material.
By (for example using Reducing agent, sulfur, sulfur dioxide, triphenyl phasphine, lithium borohydride, sodium borohydride, Phosphorous chloride., tribromide or the like) at suitable inert organic solvents (for example, acetonitrile, ethanol, dioxane aqueous solution etc.) in, under 0-80 ℃, handle and to prepare the not formula I chemical compound of oxidised form from the N-oxide of formula I chemical compound.
The prodrug derivant of formula I chemical compound can be by method preparation known to a person of ordinary skill in the art (for example, relevant details be referring to people's such as Saunier (1994) Bioorganic andMedicinal Chemistry Letters, and the 4th rolls up 1985 pages).For example, suitable prodrug can prepare by making non-deutero-formula I chemical compound and suitable carbamyl agent (as 1,1-acyloxyalkyl group phosgene, carbonic acid p-nitrophenyl ester etc.) reaction.
The derivant of the protection of formula I chemical compound can prepare by mode known to a person of ordinary skill in the art.Be applicable to that the detailed description that generates protecting group and remove the method for protecting group can be referring to " protecting group in the organic synthesis " of T.W.Greene, the 3rd edition, John Wiley ﹠amp; Sons, Inc., 1999.Chemical compound of the present invention can be easily in the process of implementing the inventive method with the form preparation of solvate (for example hydrate) or generate.The hydrate of The compounds of this invention can be easily by with an organic solvent, as dioxin, oxolane or methanol recrystallization and preparing from aqueous solution/ORGANIC SOLVENT MIXTURES.Mix to form a pair of diastereo-isomerism chemical compound by the chemical compound that makes formula I with the optically active resolving agent, separate diastereomer then and reclaim optically pure enantiomer, formula I compound can be become their single stereoisomers.Though the fractionation of enantiomer can use the covalency diastereo-isomerism derivant of formula I chemical compound to carry out, preferred dissociable complex (for example, crystalline diastereomeric salt).Diastereomer has different physical property (for example, fusing point, boiling point, dissolubility, reactivity etc.), can be at an easy rate by utilizing these differences that they are separated.Diastereomer can by chromatography or, preferably separate by separation/method for splitting based on difference in solubility.The mode of any practicality by can not causing racemization reclaims optically pure enantiomer with resolving agent then.For being applicable to that stereoisomer with chemical compound splits the Collet referring to Jean JacquesAndre that is described in more detail of the method that comes from their racemic mixture, the enantiomer of Samuel H.Wilen, racemate and fractionation (Enantiomers, Racemates and Resolutions) book, John Wiley ﹠amp; Sons, Inc. (1981).
In a word, the chemical compound of formula I is prepared by a method comprising the following steps:
(A) make chemical compound as shown in the formula 2:
Figure A0281128900471
With formula NH 2CR 1R 2X 2Chemical compound reaction, wherein, R 1, R 2, R 3, R 4And X 2As in the summary of the invention for the definition of formula I; Perhaps
(B) make the chemical compound and the formula NH of formula 2 2X 3Chemical compound reaction, R wherein 3, R 4And X 3As summary of the invention for described in the formula I; With
(C) optional chemical compound with formula I is converted into pharmaceutically acceptable salt;
(D) salt form of optional chemical compound with formula I is converted into salt-independent shape;
(E) optional not oxidised form with formula I chemical compound is converted into pharmaceutically acceptable N-oxide;
(F) optional N-oxide form with formula I chemical compound is converted into its unoxidized form;
(G) optional individual isomer with formula I chemical compound splits from mixture of isomers;
(H) optional non-derivative compound with formula I is converted into prodrug derivant pharmaceutically; With
(I) prodrug derivant of optional chemical compound with formula I is converted into its non-deutero-form;
Embodiment:
The present invention will further be illustrated, but be not limited to the embodiment of following explanation formula I chemical compound of the present invention (embodiment) and intermediate (reference) preparation.
With reference to 1
2-phenyl amino formoxyl-caproic acid
Dichloromethane (150 milliliters) solution of aniline (5.47 milliliters, 60 mMs) and triethylamine (8.36 milliliters, 60 mMs) is cooled to-20 ℃ of dichloromethane (20 milliliters) solution-treated of also using methyl malonyl chloride (8.36 milliliters, 60 mMs).Allow reactant mixture to be warming up to ambient temperature, and experience 3 hours, be poured into then in the cold 1N hydrochloric acid.Separate organic layer and with sodium bicarbonate aqueous solution, be the salt water washing then, through dried over mgso and evaporate and obtain 2-phenyl amino formoxyl methyl acetate.
With 2-phenyl amino formoxyl methyl acetate (1.159 grams; 6 mMs), Lithium hydrate (0.43 gram; 18 mMs) and the mixture that in N-Methyl pyrrolidone (10 milliliters), forms of 1-iodobutane (0.91 milliliter, 8 mMs) stirred at ambient temperature 1.5 hours.Reactant mixture is poured in the frozen water, with ethyl acetate extraction (twice, each 50 milliliters).The extract salt water washing that merges is through dried over mgso and evaporation.Residue carries out the flash chromatography purification by the ethyl acetate/hexane eluting with 20% on silica gel, obtains 2-phenyl amino formoxyl methyl caproate (0.715 gram, yield 48%).
Use sodium hydroxide (4 milliliters, 4 mMs) to handle at ambient temperature 17 hours methanol (10 milliliters) solution of 2-phenyl amino formoxyl methyl caproate (0.98 gram, 3.9 mMs).Methanol is removed in decompression, and residue is with the acid treatment of 1N salt and use ethyl acetate extraction (twice, each 50 milliliters).Organic layer salt water washing through dried over mgso and evaporation, obtains 2-phenyl amino formoxyl caproic acid (0.68 gram, 2.9 mMs, yield 74%).
With reference to 2
2-cyclohexyl methyl-N-Phenylpropionamide acid
With 2-phenyl amino formoxyl methyl acetate (as preparation in the reference example 1) (4.39 grams; 22.7 Lithium hydrate (1.08 grams mM); 45 mMs) and the mixture that in N-Methyl pyrrolidone (25 milliliters), forms of bromomethyl cyclohexane extraction (3.76 milliliters, 27 mMs) stirred at ambient temperature 17 hours.Reactant mixture is poured in the frozen water and with ether extraction (3 times, each 100 milliliters).The extract water is the salt water washing then, through dried over mgso and evaporation.Residue carries out the flash chromatography purification by ethyl acetate (hexane) eluting with 10% on silica gel, obtains 2-cyclohexyl methyl-N-Phenylpropionamide acid methyl ester (1.89 grams, 6.5 mMs, yield 29%).Above water layer through ice-cooled and with the 1N hcl acidifying to pH=2.Ether aqueous layer extracted (3 times, each 100 milliliters) and with the extract water, be the salt water washing then, through dried over mgso and evaporation, obtain 2-cyclohexyl methyl-N-Phenylpropionamide acid (1.12 grams, yield 18%).
With reference to 3
2-cyclohexyl methyl-N-phenethyl malonamic acid
Sodium (6.9 grams, 0.3 mole) is dissolved in ethanol (300 milliliters), adds diethyl malonate (50.3 milliliters, 0.3 mole) then.Adding bromomethyl cyclohexane extraction (46 milliliters, 0.33 mole) also heats reactant mixture 14 hours down at 70 ℃.Remove ethanol with the reactant mixture cooling and by evaporation.The gained material is dissolved in the frozen water, uses ethyl acetate extraction then.The organic layer water is the salt water washing, through dried over mgso then.Removal of solvent under reduced pressure obtains malonic acid diethyl cyclohexyl ester.
With ethanol (100 milliliters) solution of malonic acid diethyl cyclohexyl ester (12.8 gram, 0.05 mole) water (50 milliliters) solution-treated, stirred at ambient temperature then 15 hours with Lithium hydrate (1.2 grams, 0.05 mole).Decompression is removed ethanol and add entry (50 milliliters) in residue.Reactant mixture extracts with ether, through ice-cooled and with hcl acidifying to pH=1.5.Water is saturated and with ethyl acetate extraction (twice, each 150 milliliters) with sodium chloride.Obtain 2-cyclohexyl malonic ester (8.52 grams, 37 mMs, yield 74%) through dried over mgso and evaporating solvent.
Ethyl acetate (80 milliliters) solution of 2-cyclohexyl malonic ester (8.52 grams, 37 mMs) is cooled to 0 ℃ also with formic acid dimethyl ester (50 microlitre) processing, uses oxalyl chloride (3.93 milliliters, 45 mMs) to handle then.Reaction temperature is elevated to room temperature, and after 2 hours, removal of solvent under reduced pressure obtains 2-ring ethyl malonyl chloride mono ethyl ester.
It is 28 milliliters that above malonyl chloride is diluted to volume with ethyl acetate, and under-20 ℃, 2 milliliters of these solution are joined (0.376 milliliter of phenethylamine, 3 mMs) and in the solution of N-methylmorpholine (0.40 gram, 4 mMs) formation in ethyl acetate (4 milliliters).Making reactant mixture be warming up to ambient temperature after 15 minutes spends the night.Reactant mixture dilutes with ethyl acetate (5 milliliters) and frozen water (5 milliliters).Separate organic layer, and, be NaHCO then with cold 0.05N hydrochloric acid 3Aqueous solution is the salt water washing, through dried over mgso and reduction vaporization afterwards.Residue obtains 2-cyclohexyl methyl-N-phenethyl malonamic acid ethyl ester (0.366 gram, 1.10 mMs, yield 42%) by the radial chromatography purification.
Use sodium hydrate aqueous solution (1N, 1.3 milliliters) to handle at ambient temperature 2.5 hours ethanol (10 milliliters) solution of above ester (0.366 gram, 1.10 mMs).Reactant mixture water (30 milliliters) dilutes and washs (3 times, each 30 milliliters) with ether.With the water layer cooling, 1N hydrochloric acid (2 milliliters) acidify is also used ethyl acetate extraction (3 times, each 30 milliliters).The salt water washing of ethyl acetate extraction liquid through dried over mgso and evaporation, obtains 2-cyclohexyl methyl-N-phenethyl malonamic acid (0.138 gram, 0.46 mM, yield 42%).
With reference to 4
2-cyclohexyl methyl-N-pyridin-4-yl methyl propanamide acid
Use the method in the reference 3, to obtain 2-cyclohexyl methyl-4-pyridin-4-yl methyl propanamide acetoacetic ester (0.237 gram as the 2-cyclohexyl methyl malonyl chloride mono ethyl ester (0.307 gram, 1.25 mMs) and the condensation of 4-aminomethyl-pyridine of preparation in the reference 3,0.74 mM, yield 58%).
Method in the use reference 3 obtains 2-cyclohexyl methyl-N-pyridin-4-yl methyl propanamide acid (0.041 gram, 0.14 mM, yield 19%) with this ester sodium hydroxide hydrolysis.
Can provide following chemical compound according to experimentizing as above-mentioned reference example:
N-benzyl-2-cyclohexyl methyl-malonamic acid;
2-cyclohexyl methyl-N-(4-Phenoxyphenyl)-malonamic acid;
2-cyclohexyl methyl-N-(3-phenyl propyl)-malonamic acid;
2-cyclohexyl methyl-3-morpholine-4-base-3-oxo propanoic acid;
N-cyclohexyl-2-cyclohexyl methyl-malonamic acid;
2-cyclohexyl methyl-N-naphthalene-1-ylmethyl malonamic acid;
2-cyclohexyl methyl-N-pyridin-3-yl malonamic acid;
2-cyclohexyl methyl-N, N-diisobutyl malonamic acid;
2-cyclohexyl methyl-N-(6-methoxypyridine-3-yl) malonamic acid;
2-cyclohexyl methyl-N-(2-thiophene-2-base ethyl) malonamic acid;
2-cyclohexyl methyl-N-(3-Phenoxyphenyl)-malonamic acid;
2-cyclohexyl methyl-N-(4-nitrobenzyl)-malonamic acid;
N-cyanogen methyl-2-cyclohexyl methyl-malonamic acid;
2-cyclohexyl methyl-N-(5,6,7,8-naphthane-1-yl) malonamic acid;
2-cyclohexyl methyl-N-(2-pyridine-2-base ethyl) malonamic acid;
2-cyclohexyl methyl-3-(2,3-indoline-1-yl)-3-oxo propanoic acid;
2-cyclohexyl methyl-3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxo propanoic acid;
2, N-dicyclohexyl methyl-3-oxo butyramide;
2-cyclohexyl methyl-N-(2-methoxy-benzyl)-3-oxo butyramide;
2-cyclohexyl methyl-N-(1-phenylethyl)-malonamic acid;
N-benzyl-2-cyclohexyl methyl-N-methyl-malonamic acid;
2-cyclohexyl methyl-N-(3-nitrobenzyl)-3-oxo butyramide;
2-cyclohexyl methyl-N-(4-methoxy-benzyl)-malonamic acid;
N-(3-carbamyl phenyl)-2-cyclohexyl methyl-malonamic acid;
2-cyclohexyl methyl-N-pyridin-3-yl methyl propanamide acid;
N-(4-carbamyl phenyl)-2-cyclohexyl methyl-malonamic acid;
2-cyclohexyl methyl-N-(oxolane-2-ylmethyl)-malonamic acid;
2-cyclohexyl methyl-3-(3,4-dihydro-2H-quinoline-1-yl)-3-oxo propanoic acid;
The N-tert-butyl group-2-cyclohexyl methyl-N-methyl-malonamic acid;
2-cyclohexyl methyl-N-methyl-N-propyl group-malonamic acid;
N-butyl-2-cyclohexyl methyl-N-methyl-malonamic acid;
2-cyclohexyl methyl-N, N-dimethyl propylene amic acid;
(R)-2-benzylamino formoxyl-4-phenyl sulfane base-butanoic acid; With
4-benzenesulfonyl-2-benzylamino formoxyl-butanoic acid.
Embodiment 1
2-butyl-N-cyanogen methyl-N '-phenyl Malondiamide (chemical compound 1)
Figure A0281128900521
Will by with reference to preparation in 1 by 2-carbanilino acid (188g; 0.8mmol) DMF (5.0mL) solution formed with PyBOP_ (425mg, 0.8mmol), aminoacetonitriles disulfate (140mg; 0.9 mM) and triethylamine (600 μ l 4.3mmol) handle.Mixture stirred 3 hours, distributed between water (20mL) and ethyl acetate (50mL) then.Separate organic layer and use 1M saturated sodium bicarbonate solution, 1M hydrochloric acid solution and water washing, dry (MgSO 4) and concentrate.Purification obtains product, 2-butyl-N-cyanogen methyl-N '-phenyl Malondiamide (125mg, yield 57%) by dodging at silica gel on the formula post with 50% ethyl acetate/hexane eluting and from residue.
1H?NMR：(DMSO)10.01(s，1H)，7.59(d，J＝8Hz，2H)，7.31(t，J＝7Hz，2H)，7.06(t，J＝7Hz，1H)，4.13(d，J＝6Hz，2H)，3.32(t，J＝8Hz，1H)，1.80(m，2H)，1.25(m，4H)，0.86(t，J＝7Hz，3H).MS：m/e?273.9.
Embodiment 2
N-cyanogen methyl-2-cyclohexyl methyl-N '-phenyl Malondiamide (chemical compound 2)
Figure A0281128900531
Will be by following component at N, the solution of forming in the N-dimethyl pyrrolidone (5 milliliters), promptly by with reference to 2 preparations by 2-cyclohexyl methyl-N-Phenylpropionamide acid (350 milligrams, 1.2 mMs), (250 milligrams of EDCI, 1.3 mM), HOBt hydrate (199 milligrams, 1.3 mMs), (200 milligrams of aminoacetonitriles disulfates, 1.3 mM) and N-methylmorpholine (0.30 milliliter, 2.7 mMs), stirred at ambient temperature 15 hours.Be poured into reactant mixture in the cold 1N hydrochloric acid and use ethyl acetate extraction.Organic facies with saturated sodium bicarbonate aqueous solution, be salt water washing (each 50 milliliters) then, through dried over mgso and evaporation.Residue through the radial chromatography purification, obtains N-cyanogen methyl-2-cyclohexyl methyl-N '-phenyl Malondiamide (179 milligrams, yield 48%) as eluent by using 50% ethyl acetate/hexane. 1H
NMR：(DMSO)10.01(s，1H)，8.47(t，J＝5Hz，1H)，7.59(d，J＝7Hz，2H)，7.31(t，J＝8Hz，2H)，7.07(t，J＝7Hz，1H)，4.13(d，J＝5Hz，2H)，3.47(t，J＝7Hz，1H)，1.6(m，7H)，1.1(m，4H)，0.9(m，2H).MS：m/e?313.2.
Embodiment 3
N-cyanogen methyl-2-cyclohexyl methyl-N '-PEMA (chemical compound 3)
Will be by following component at N, the solution of forming in the N-dimethyl pyrrolidone (4 milliliters) is promptly by with reference to (138 milligrams of the 2-cyclohexyl methyls of 3 preparations-N-phenethyl malonic acid, 0.46 mM), EDCI (115 milligrams, 0.60 mM), (92 milligrams of HOBt hydrates, 0.60 mM), N-methylmorpholine (0115 milliliter, 1.38 mMs) stirred 10 minutes at ambient temperature, add aminoacetonitriles disulfate (106 milligrams, 0.69 mM) then.Reactant mixture stirred 2 hours at ambient temperature, was poured into then in the cold 1N hydrochloric acid also with twice of ethyl acetate extraction (each 50 milliliters).Organic facies with saturated sodium bicarbonate aqueous solution, be salt water washing (each 50 milliliters) then, through dried over mgso and evaporation.Residue through the radial chromatography purification, obtains N-cyanogen methyl-2-cyclohexyl methyl-N '-PEMA (56 milligrams, yield 36%) as eluent by using 50% ethyl acetate/hexane.
1H?NMR：(DMSO)8.38(t，J＝5Hz，1H)，7.98(t，J＝6Hz，1H)，7.25(m，5H)，4.10(d，J＝6Hz，2H)，3.2(m，3H)，2.71(t，J＝7Hz，2H)，1.6(m，7H)，1.1(m，4H)，0.85(m，2H).MS：m/e?342.10.
Embodiment 4
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-4-yl methylmalonyl amine (chemical compound 4)
Figure A0281128900541
Will by with reference to preparation in 4 by (41 milligrams of 2-cyclohexyl methyls-N-pyridin-4-yl methyl-malonic acid, 0.14 mM) solution of Zu Chenging is coupled on the aminoacetonitriles as described in embodiment 3, obtain N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-4-yl methylmalonyl amine (13 milligrams, yield 28%). 1H?NMR：(DMSO)8.5(m，4H)，7.20(d，J＝6Hz，2H)，4.3(m，2H)，4.13(d，J＝5Hz，2H)，3.3(m，1H)，1.6(m，7H)，1.1(m，4H)，0.83(m，2H).MS：m/e?329.08.
Embodiment 5
N-[1-(1-benzoxazole-2-base-formoxyl)-3-phenyl propyl]-N '-benzyl-2-cyclohexyl methyl-Malondiamide (chemical compound 5)
Figure A0281128900551
With N-benzyl-2-cyclohexyl methyl-malonamic acid (200mg, 0.69mmol), HOBt (159mg, 1.04mmol), EDC (146mg, 0.76mmol), 2-amino-1-benzoxazole-2-base-4-phenyl butane-1-ketone (195mg, 0.69mmol), (106 μ l, mixture 0.76mmol) stirred 2 hours for dichloromethane (3ml) and triethylamine.Product is extracted in the ethyl acetate (60ml) also with two parts (every part 15ml) 1N hydrochloric acid, the saturated NaHSO of two parts (every part 15ml) 3Washing is through MgSO 4Dry and concentrated.Add ethyl acetate (5ml), form white precipitate, collect and obtain N-[1-(1-benzoxazole-2-base-1-hydroxymethyl)-3-phenyl propyl]-N '-benzyl-2-cyclohexyl methyl-Malondiamide (81mg, 0.12mmol, yield 21%).
With N-[1-(1-benzoxazole-2-base-1-hydroxymethyl)-3-phenyl propyl]-N '-benzyl-2-cyclohexyl methyl-Malondiamide (70mg, 0.126mmol) be dissolved in the 0.6ml dichloromethane also with DessMartin periodinane (107mg, 0.253mmol) processing.Mixture stirred 2 hours, added 8mL then and was in saturated NaHSO 3In 0.26M NaS 2O 3, and the ethyl acetate extraction of mixture with each 15mL of two parts, with the saturated NaHSO of each 4mL 3Washed twice.Organic layer is through MgSO 4Dry and concentrated.With ethyl acetate and hexane product is carried out recrystallization, obtains N-[1-(1-benzoxazole-2-base-formoxyl)-3-phenyl propyl]-N '-benzyl-2-cyclohexyl methyl-Malondiamide (40mg, 0.072mmol, yield 57%). 1H?NMR：(DMSO)7.88(m，1H)，7.68-7.40(m，3H)，7.35-7.10(m，10H)，6.90(m，1H)，5.65(m，1H)，4.43(d，J＝5.7Hz，2H)，3.25(m，1H)，2.74(t，J＝8.0Hz，1H)，2.46(m，1H)，2.17(m，1H)，1.77(t，J＝7.4Hz，1H)，1.64(m，7H)，1.22(m，4H)，0.87(m，2H)；MS：(M ++1)552.8；551.68.
Obtain following formula I chemical compound by continuing to experimentize by the foregoing description:
N-cyanogen methyl-N '-cyclohexyl-2-cyclohexyl methyl Malondiamide (chemical compound 6); 1HNMR (DMSO): 8.31 (t, J=6Hz, 1H), 7.82 (d, J=8Hz, 1H), 4.10 (d, J=8Hz, 2H), 3.52 (m, 1H), 3.20 (t, J=7Hz, 1H), 1.6 (m, 12H), 1.1 (m, 9H), 0.83 (m, 2H); MS (m/e)=320.11;
N-benzyl-N '-cyanogen methyl-2-cyclohexyl methyl Malondiamide (chemical compound 7); 1HNMR (DMSO): 8.45 (m, 2H), 7.3 (m, 5H), 4.33 (dd, J=6,15Hz, 1H), 4.23 (dd, J=6,15Hz, 1H), 4.12 (d, 2H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e)=328.15, M.Wt.=327.43;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-Phenoxyphenyl)-Malondiamide (chemical compound 8); 1H NMR (DMSO): 10.1 (s, 1H), 8.50 (t, J=5Hz, 1H), 7.61 (d, J=7Hz, 2H), 7.37 (t, J=7Hz, 2H), 7.11 (t, J=7Hz, 1H), 7.0 (m, 4H), 4.14 (d, J=5Hz, 2H), 3.47 (t, J=7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.92 (m, 2H); MS (m/e)=406.10, M.Wt.=405.49;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(3-phenyl propyl)-Malondiamide (chemical compound 9);
1H?NMR(DMSO)：8.38(t，J＝6Hz，1H)，8.00(t，J＝6Hz，1H)，7.2(m，5H)，4.10(d，J＝5Hz，2H)，3.23(t，J＝7Hz，1H)?3.1(m，2H)，2.5(m，2H)，1.6(m，9H)，1.1(m，4H)，0.85(m，2H)；MS(m/e)＝356.02；
N-cyanogen methyl-2-cyclohexyl methyl-3-morpholine-4-base-3-oxo propionic acid amide. (chemical compound 10); 1H NMR (DMSO): 8.54 (t, J=4Hz, 1H), 4.12 (d, J=5Hz, 2H), 3.5 (m, 8H), 1.65 (m, 8H), 1.15 (m, 4H), 0.85 (m, 2H); MS (m/e)=308.05;
N-cyanogen methyl-2-cyclohexyl methyl-N '-naphthalene-1-base Malondiamide (chemical compound 11);
1H?NMR(DMSO)：8.53(t，J＝5Hz，1H)，8.43(t，J＝6Hz，1H)，8.04(m，1H)，7.94(m，1H)，7.86(d，J＝8Hz，1H)，7.5(m，4H)，4.85(dd，J＝6，15Hz，1H)，4.65(dd，J＝5，15Hz，1H)，4.12(d，J＝3Hz，2H)，3.3(m，1H)，1.6(m，8H)，1.0(m，5H)；MS(m/e)＝378.18，M.Wt.377.18；
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-3-yl Malondiamide (chemical compound 12);
1H?NMR(DMSO)：10.24(s，1H)，8.75(s，1H)，8.54(t，J＝5Hz，1H)，8.29(d，J＝5Hz，1H)，8.04(d，J＝7Hz，1H)，7.36(m，1H)，4.13(d，J＝5Hz，2H)，3.49(t，J＝7Hz，1H)，1.7(m，7H)，1.1(m，4H)，0.9(m，2H)；MS(m/e)＝314.91；
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-diisobutyl Malondiamide (chemical compound 13);
1H?NMR(DMSO)：8.50(t，J＝4Hz，1H)，4.09(m，2H)，3.63(t，J＝7Hz，1H)，3.2(m，2H)，3.05(m，2H)，1.9(m，2H)，1.6(m，7H)，1.1(m，4H)，0.8(m，14H)；MS(m/e)＝350.08，M.Wt.349.51；
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-diisopropyl-Malondiamide (chemical compound 14);
1H?NMR(DMSO)：8.45(t，J＝5Hz，1H)，4.1(m，3H)，3.55(t，J＝7Hz，1H)，3.46(m，1H)，1.6(m，7H)，1.27(d，J＝7Hz，6H)，1.11(m，10H)，0.85(m，2H)；MS(m/e)＝321.99，M.Wt.321.24；
N-cyanogen methyl-2-cyclohexyl methyl-N '-(6-methoxypyridine-3-yl)-Malondiamide (chemical compound 15); 1H NMR (DMSO): 10.04 (s, 1H), 8.50 (t, J=5Hz, 1H), 8.35 (s, 1H), 7.88 (d, J=9Hz, 1H), 6.80 (d, J=9Hz, 1H), 4.13 (m, 2H), 3.81 (s, 3H), 3.44 (t, J=8Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m/e)=345.01, M.Wt.344.18;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-thiophene-2-base-ethyl)-Malondiamide (chemical compound 16);
1H?NMR(DMSO)：8.40(t，J＝5Hz，1H)，8.07(t，J＝5Hz，1H)，7.33(d，J＝5Hz，1H)，6.95(m，1H)，6.87(m，1H)，4.10(d，J＝5Hz，2H)，3.3(m，3H)，3.21(t，J＝7Hz；2H)，1.6(m，7H)，1.1(m，4H)，0.85(m，2H)；MS(m/e)＝348.09，M.Wt.347.48；
N-cyanogen methyl-2-cyclohexyl methyl-N '-(3-Phenoxyphenyl)-Malondiamide (chemical compound 17); 1H NMR (DMSO): 10.1 (s, 1H), 8.45 (t, J=5Hz, 1H), 7.41 (t, J=8Hz, 2H), 7.33 (m, 3H), 7.16 (t, J=7Hz, 1H), 7.03 (d, J=8Hz, 2H), 6.73 (m, 1H), 4.1 (m, 2H), 3.42 (t, J=7Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e)=406.04, M.Wt.405.49;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-nitrobenzophenone)-Malondiamide (chemical compound 18);
1H?NMR(DMSO)：8.61(t，J＝6Hz，1H)，8.53(t，J＝6Hz，1H)，8.17(d，J＝9Hz，2H)，7.47(d，J＝9Hz，2H)，4.41(d，J＝6Hz，2H)，4.14(d，J＝6Hz，2H)，3.3(m，1H)，1.6(m，7H)，1.1(m，4H)，0.87(m，2H)；MS(m/e)＝373.02，M.Wt.372.42；
N, N '-two cyanogen methyl-2-cyclohexyl methyl Malondiamide (chemical compound 19); 1HNMR (DMSO): 8.59 (t, J=5Hz, 2H), 4.14 (d, J=6Hz, 4H), 3.28 (t, J=8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.86 (m, 2H); MS (m/e)=276.99, M.Wt.276.34;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(5,6,7,8-naphthane-1-yl) Malondiamide (chemical compound 20); 1H NMR (DMSO): 9.28 (s, 1H), 8.57 (t, J=6Hz, 1H), 7.21 (d, J=8Hz, 1H), 7.05 (t, J=8Hz, 1H), 6.90 (d, J=7Hz, 1H), 4.16 (d, J=6Hz, 2H), 3.49 (t, J=7Hz, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 1.7 (m, 11H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m/e)=368.04, M.Wt.367.48;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-pyridine-2-base-ethyl)-Malondiamide (chemical compound 21); 1H NMR (DMSO): 8.49 (m, 1H), 8.40 (t, J=6Hz, 1H), 8.00 (t, J=5Hz, 1H), 7.68 (dt, J=2,8Hz, 1H), 7.2 (m, 2H), 4.09 (d, J=6Hz, 2H), 3.42 (m, 2H), 3.17 (t, J=8Hz, 1H), 2.85 (t, J=7Hz, 2H), 1.6 (m, 7H), 1.07 (m, 4H), 0.83 (m, 2H); MS (m/e)=343.04, M.Wt.342.44;
N-cyanogen methyl-2-cyclohexyl methyl-3-(2,3-indoline-1-yl)-3-oxo propionic acid amide. (chemical compound 22); 1H NMR (DMSO): 8.73 (t, J=5Hz, 1H), 8.06 (d, J=8Hz, 1H), 7.24 (d, J=7Hz, 1H), 7.15 (t, J=7Hz, 1H), 7.00 (t, J=7Hz, 1H), 4.15 (d, J=5Hz, 2H), 4.1 (m, 2H), 3.66 (t, J=7Hz, 1H), 3.14 (m, 2H), 1.6 (m, 7H), 1.1 (m, 4H), 0.91 (m, 2H); MS (m/e)=340.07, M.Wt.339.19;
N-cyanogen methyl-2-cyclohexyl methyl-3-(3,4-dihydro-1H-isoquinolin-2-yl)-oxo
Propionic acid amide. (chemical compound 23); 1H NMR (DMSO): 8.64 (t, J=5Hz, 1H), 7.15 (s, 4H), 4.65 (m, 2H), 4.11 (t, J=6Hz, 2H), 3.77 (m, 2H), 2.8 (m, 2H), 1.7 (m, 7H), 1.1 (m, 4H), 0.89 (m, 2H), 3.54 (m, 1H); MS (m/e)=354.05, M.Wt.353.46;
N-cyanogen methyl-2, N '-dicyclohexyl methylmalonyl amine (chemical compound 24); 1HNMR (DMSO): 8.34 (t, J=5Hz, 1H), 7.93 (t, J=5Hz, 1H), 4.09 (d, J=6Hz, 2H), 3.23 (dd, J=7,9Hz, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 1.6 (m, 12H), 1.4 (m, 1H), 1.1 (m, 7H), 0.86 (m, 4H); MS (m/e)=334.00, M.Wt.333.47;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-methoxybenzyl)-Malondiamide (chemical compound 25); 1H NMR (DMSO): 8.44 (t, J=5Hz, 1H), 8.27 (t, J=6Hz, 1H), 7.24 (dt, J=2,7Hz, 1H), 7.10 (dd, J=2,7Hz, 1H), 6.96 (d, J=7Hz, 1H), 6.88 (dt, J=7,1Hz, 1H), 4.30 (dd, J=6,16Hz, 1H), 4.20 (dd, J=5,16Hz, 1H), 4.12 (d, J=6Hz, 2H), 3.79 (s, 3H), 3.3 (m, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e)=358.03, M.Wt.357.45;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(1-phenethyl)-Malondiamide (chemical compound 26);
1H?NMR(DMSO)：8.25(m，1H)，7.4(m，5H)，4.02(m，2H)，3.18(s，3H)，3.25(m，1H)，1.6(m，7H)，1.1(m，4H)，0.7(m，2H)；MS(m/e)＝328.08，M.Wt.327.42；
N-benzyl-N '-cyanogen methyl-2-cyclohexyl methyl-N-methylmalonyl amine (chemical compound 27);
1H?NMR(DMSO)：8.62(m，1H)，7.3(m，5H)，4.5(m，2H)，4.13(d，J＝6Hz，2H)，3.7(m，1H)，2.93(s，3H)，1.6(m，7H)，1.1(m，?4H)，0.88(m，2H)；MS(m/e)＝342.09，M.Wt.341.45；
N-cyanogen methyl-2-cyclohexyl methyl-N '-(3-nitrobenzyl) Malondiamide (chemical compound 28);
1H?NMR(DMSO)：8.6(t，1H)，8.5(t，1H)，8.1(m，2H)，7.6(m，2H)，4.1(m，2H)，1.6(m，7H)，1.1(m，4H)，0.8(m，2H)；MS(m/e)＝373.07，M.Wt.372.42；
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-methoxybenzyl)-Malondiamide (chemical compound 29); 1H NMR (DMSO): 8.42 (t, J=5Hz, 1H), 8.38 (t, J=6Hz, 1H), 7.14 (d, J=9Hz, 2H), 6.86 (d, J=9Hz, 2H), 4.25 (dd, J=6,15Hz, 1H), 4.15 (dd, J=7,16Hz, 1H), 3.71 (s, 3H), 3.27 (t, J=8Hz, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.84 (m, 2H), 4.11 (d, J=6Hz, 2H); MS (m/e)=356.97, M.Wt.357.45;
N-(3-carbamoyl phenyl)-N '-cyanogen methyl-2-cyclohexyl methyl Malondiamide (chemical compound 30); 1H NMR (DMSO): 10.14 (s, 1H), 8.48 (t, 1H), 8.03 (s, 1H), 7.75 (d, 1H), 7.54 (d, 1H), 7.35 (m, 2H), 4.12 (d, 2H), 3.4 (t, 1H), 1.6 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H), 3.29 (s, 3H); MS (m/e)=357.11, M.Wt.356.42;
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-3-yl methylmalonyl amine (chemical compound 31); 31); 1H NMR (DMSO): 8.4 (m, 4H), 7.55 (d, 1H), 7.25 (dd, 1H), 4.28 (dd, 1H) 4.18 (dd, 1H), 4.05 (d, 2H), 3.2 (m, 1H), 1.6 (m, 7H), 1.01 (m, 4H), 0.78 (m, 2H); MS (m/e)=329.03, M.Wt.328.41;
N-(4-carbamoyl phenyl)-N '-cyanogen methyl-2-cyclohexyl methyl Malondiamide (chemical compound 32); 1H NMR (DMSO): 10.22 (s, 2H), 8.50 (t, J=6Hz, 1H), 7.83 (d, J=9Hz 2H), 7.64 (d, J=9Hz, 2H), 7.52 (s, 1H), 4.13 (d, J=6Hz, 2H), 3.48 (t, J=7Hz, 1H), 1.7 (m, 7H), 1.1 (m, 4H), 0.9 (m, 2H); MS (m/e)=357.04, M.Wt.356.42;
N-cyanogen methyl-2-cyclohexyl methyl-N '-oxolane-2-ylmethyl Malondiamide (chemical compound 33); 1H NMR (DMSO): 8.38 (t, J=5Hz, 1H), 7.98 (t, J=4Hz, 1H), 4.10 (d, J=6Hz 2H), 3.8 (m, 2H), 3.6 (m, 1H), 3.2 (m, 4H), 1.8 (m, 3H), 1.6 (m, 7H), 1.1 (m, 4H), 0.85 (m, 2H); MS (m/e)=322.02, M.Wt.321.41;
N-cyanogen methyl-2-cyclohexyl methyl-3-(3,4-dihydro-2H-quinoline-1-yl)-3-oxo propionic acid amide. (chemical compound 34); 1H NMR (DMSO): 8.5 (m, 1H), 7.35 (m, 1H), 7.2 (m, 4H), 4.1 (m, 2H), 3.82 (dd, 1H), 2.78 (t, 1H), 2.72 (t, 1H), 2.59 (m, 1H), 1.8 (m, 2H), 1.5 (m, 7H), 1.0 (m, 4H), 0.7 (m, 2H); MS (m/e)=354.02, M.Wt.353.46;
The N-tert-butyl group-N '-cyanogen methyl-2-cyclohexyl methyl-N-methylmalonyl amine (chemical compound 35); 1H NMR (DMSO): 8.41 (t, J=5Hz, 1H), 4.09 (d, J=5Hz, 1H), 3.56 (t, J=7Hz, 1H), 2.86 (s, 3H), 1.6 (m, 7H), 1.31 (s, 9H), 1.1 (m, 4H), 0.8 (m, 2H); MS (m/e)=308.04, M.Wt.307.43;
N-cyanogen methyl-2-cyclohexyl methyl-N '-methyl-N '-propyl group-Malondiamide (chemical compound 36);
1H?NMR(DMSO)：8.5(m，1H)，4.10(m，2H)，3.60(t，J＝7Hz，1H)，3.2(m，2H)，2.96(s，3H)，1.65(m，7H)，1.45(m，2H)，1.1(m，4H)，0.8(m，5H)；MS(m/e)＝294.02，M.Wt.293.40；
N-butyl-N '-cyanogen methyl-2-cyclohexyl methyl-N-methylmalonyl amine (chemical compound 37);
1H?NMR(DMSO)：8.5(m，1H)，4.10(d，J＝5Hz，2H)，3.60(t，1H)，3.3(m，2H)，2.95(s，3H)，1.6(m，7H)，1.4(m，2H)，1.1(m，6H)，0.8(m，5H)；MS(m/e)＝308.01，M.Wt.307.43；
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-dimethyl propylene diamides (chemical compound 38);
1H?NMR(DMSO)：8.55(t，J＝5Hz，1H)，4.11(d，J＝7Hz，2H)，3.62(t，J＝8Hz，1H)，2.99(s，3H)，2.81(s，3H)，1.6?(m，7H)1.1(m，4H)，0.85(m，2H)；MS(m/e)＝266.01，M.Wt.265.18；
N-benzyl-N '-cyanogen methyl-2-(2-phenyl sulfane base ethyl) Malondiamide (chemical compound 39);
1H NMR (DMSO): 8.56 (t, J=6Hz, 1H), 8.49 (t, J=6Hz, 1H), 7.3 (m, 10H), 4.29 (d, J=6Hz, 2H), 4.14 (d, J=6Hz, 2H), 3.40 (t, J=7Hz, 1H), 2.86 (t, J=8Hz, 2H), 2.05 (m, 2H); MS (m/e)=368.02, M.Wt.367.14; With
2-(2-benzenesulfonyl ethyl)-N-benzyl-N '-cyanogen methyl-Malondiamide (chemical compound 40);
1H?NMR(DMSO)：8.56(t，J＝6Hz，1H)，8.43(t，J＝6Hz，1H)，7.86(d，J＝7Hz，2H)，7.79(t，J＝5Hz，1H)，7.68(t，J＝8Hz，2H)，7.25(m，5H)，4.26(d，J＝6Hz，2H)，4.13(d，J＝6Hz，2H)，3.36(m，1H)，3.19(m，2H)，2.00(m，2H)；MS(m/e)＝400.04，M.Wt.399.47；
2-(2-benzenesulfonyl-ethyl)-N-[(S)-1-(1-benzoxazole-2-base-formoxyl)-amyl group]-N '-benzyl-Malondiamide (chemical compound 41); With 1H NMR (DMSO): 8.56 (d, J=6Hz, 1H), 8.2 (m, 1H), 8.0-7.5 (m, 9H), 7.3-7.1 (m, 5H), 5.3 (m, 1H), 4.24 (t, J=6Hz, 2H), 3.41 (t, J=7Hz, 1H), 3.18 (m, 2H), 1.96 (m, 3H), 1.67 (m, 1H), 1.30 (m, 4H), 0.82 (m, 3H); MS (m/e)=576.27, M.Wt.575.21; With
N, N '-two [(S)-1-(1-benzoxazole-2-base-formoxyl)-propyl group]-2-cyclohexyl methyl Malondiamide (chemical compound 42) 1H NMR (DMSO): 8.41 (d, J=6Hz, 2H), 8.00 (d, J=8Hz, 2H), 7.89 (d, J=8Hz, 2H), 7.65 (t, J=7Hz, 2H), 7.53 (t, J=8Hz, 2H), 5.19 (m, 2H), 3.42 (t, J=8Hz, 1H), 1.98 (m, 2H), 1.74 (m, and 2H) 1.52 (m, 7H), 0.94 (m, 10H), 0.77 (m, 2H); MS (m/e)=572.26, M.Wt.573.4.
Embodiment 6
The cathepsin S test
The test compounds solution of preparation variable concentrations is diluted to then that (40 microlitres comprise: MES, 50mM (pH=6.5) in the test buffer agent in 10 microlitre dimethyl sulfoxines (DMSO); EDTA, 2.5mM; And NaCl, 100mM).Tissue protease S (0.158pMoles is in the test buffer agent of 25 microlitres) is joined in the diluent.5-10 second is mixed by testing liquid on oscillating plate, covered and cultivate at ambient temperature 30 minutes with lid.Z-Val-Val-Arg-AMC (9nMoles is in the 25 microlitre test buffer agents) is joined in the testing liquid, follow the tracks of (the hydrolysis of λ=460nm) 5 minutes with spectrophotometric.Use standard mathematical model is by enzyme progress curve calculation apparent inhibition constant (K i).
Embodiment 7
Cathepsin B's test
The test compounds solution of preparation variable concentrations in 10 microlitre dimethyl sulfoxines (DMSO) is diluted to then in the test buffer agent that (40 microlitres comprise: N, two (2-the ethoxy)-2-aminoethyl sulfonic acid (BES) of N-, 50mM (pH=6); The polyoxyethylene sorbitan monolaurate, 0.05%; And dithiothreitol, DTT (DTT), 2.5mM).Tissue protease B (0.025pMoles is in the test buffer agent of 25 microlitres) is joined in the diluent.5-10 second is mixed by testing liquid on oscillating plate, covered and cultivate at ambient temperature 30 minutes with lid.Z-FR-AMC (20nMoles is in the 25 microlitre test buffer agents) is joined in the testing liquid, follow the tracks of (the hydrolysis of λ=460nm) 5 minutes with spectrophotometric.Use standard mathematical model is by enzyme progress curve calculation apparent inhibition constant (Ki).
Embodiment 8
The cathepsin K test
The test compounds solution of preparation variable concentrations is diluted to then that (40 microlitres comprise: MES, 50mM (pH=5.5) in the test buffer agent in 10 microlitre dimethyl sulfoxines (DMSO); EDTA, 2.5mM; And DTT, 2.5mM).Tissue E.C. 3.4.21.64 (0.0906pMoles is in the test buffer agent of 25 microlitres) is joined in the diluent.5-10 second is mixed by testing liquid on oscillating plate, covered and cultivate at ambient temperature 30 minutes with lid.Z-Phe-Arg-AMC (4nMoles is in the 25 microlitre test buffer agents) is joined in the testing liquid, follow the tracks of (the hydrolysis of λ=460nm) 5 minutes with spectrophotometric.Use standard mathematical model is by enzyme progress curve calculation apparent inhibition constant (K i).
Embodiment 9
Cathepsin L's test
The test compounds solution of preparation variable concentrations is diluted to then that (40 microlitres comprise: MES, 50mM (pH=5.5) in the test buffer agent in 10 microlitre dimethyl sulfoxines (DMSO); EDTA, 2.5mM; And DTT, 2.5mM).Tissue protease L (0.05pMoles is in the test buffer agent of 25 microlitres) is joined in the diluent.5-10 second is mixed by testing liquid on oscillating plate, covered and cultivate at ambient temperature 30 minutes with lid.Z-Phe-Arg-AMC (1nMoles is in the 25 microlitre test buffer agents) is joined in the testing liquid, carry out spectrophotometric during this period and follow the tracks of (the hydrolysis of λ=460nm) 5 minutes.Use standard mathematical model is by enzyme progress curve calculation apparent inhibition constant (K i).
Test chemical compound of the present invention according to above-mentioned protease inhibition test, observe it and demonstrate optionally cathepsin S inhibition activity.For example, find, under than the concentration that produces low at least 50 times of isoreactivity inhibition of histone enzyme K concentration that proteinase activity requires, but the proteinase activity of chemical compound inhibition of histone enzyme S of the present invention.Apparent inhibition constant (K with cathepsin S The compounds of this invention vis-a-vis i) about 10 -10M-about 10 -7In the scope of M.
Embodiment 10
The representational pharmaceutical preparation that contains formula I chemical compound:
Oral formulations
Formula I chemical compound 10-100 milligram
105 milligrams of citric acid monohydrate compounds
18 milligrams of sodium hydroxide
Correctives
Water adds to 100 milliliters in right amount
Iv formulation
Formula I chemical compound 0.1-10 milligram
Dextrose monohydrate is an amount of so that preparation etc. ooze
1.05 milligrams of citric acid monohydrate compounds
0.18 milligram of sodium hydroxide
Water for injection adds to 1.0 milliliters in right amount
Sheet type preparation
Formula I chemical compound 1%
Microcrystalline Cellulose 73%
Stearic acid 25%
Cabosil 1%

Claims (10)

1. the chemical compound of formula I:
Wherein:
X 1Be-NHC (R 1) (R 2) X 2Perhaps-NHX 3
X 2Be cyano group ,-C (R 7) (R 8) X 3,-C (R 7) (R 8) CF 3,-C (R 7) (R 8) CF 2CF 2R 9,-CH=CHS (O) 2R 5,-C (O) CF 2C (O) NR 5R 5,-C (O) C (O) NR 5R 6,-C (O) C (O) OR 5,-C (O) CH 2OR 5,-C (O) CH 2N (R 6) SO 2R 5Or-C (O) C (O) R 5R wherein 5Be (C 1-4) alkyl, (C 5-10) aryl (C 0-6) alkyl or (C 5-10) heteroaryl (C 0-6) alkyl; R 6Be hydrogen or (C 1-6) alkyl; R 7Be hydrogen or (C 1-4) alkyl, R 8Be hydroxyl or R 7And R 8Form oxo together; R 9Be hydrogen, halogen, (C 1-4) alkyl, (C 5-10) aryl (C 0-6) alkyl or (C 5-10) heteroaryl (C 0-6) alkyl;
X 3Comprise the assorted monocycle that contains 4-6 annular atoms or contain the assorted dicyclo ring system of condensing of 8-14 annular atoms, with and carbocyclic ring ketone arbitrarily, imino group ketone or 40 thione derivatives;
Wherein at R 5, X 2Or X 3In, alicyclic ring or aromatic ring can further be independently selected from (C by 1-5 arbitrarily 1-6) alkyl, (C 1-6) alkylidene radical, cyano group, the halogen, (C that halogen replaces 1-4) alkyl, nitro ,-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4NR 12C (O) R 13,-X 4S (O) R 13With-X 4S (O) 2R 13Group replace, and/or be selected from-R by 1 14,-X 4OR 14,-X 4SR 14,-X 4S (O) R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) OR 14,-X 4OC (O) R 14,-X 4NR 14R 12,-X 4NR 12C (O) R 14,-X 4NR 12C (O) OR 14,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 14R 12,-X 4NR 12S (O) 2R 12,-X 4NR 12C (O) NR 14R 12With-X 4NR 12C (NR 12) NR 14R 12Group replace X wherein 4Be a key or (C 1-6) alkyl; R 12All be hydrogen in all cases independently, (C 1-6) (the C that replaces of alkyl or halogen 1-6) alkyl; R 13Be (C 1-6) (the C that replaces of alkyl or halogen 1-6) alkyl; R 14Be (C 3-10) cycloalkyl (C 0-6) alkyl, assorted (C 3-10) cycloalkyl (C 0-3) alkyl, (C 6-10) aryl (C 0-6) alkyl, assorted (C 5-10) aryl (C 0-6) alkyl, (C 9-10) bicyclic aryl (C 0-6) alkyl or assorted (C 8-10) bicyclic aryl (C 0-6) alkyl;
R 1Be hydrogen, halogen or (C 1-6) alkyl, R 2Be selected from hydrogen, cyano group, halogen ,-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4NR 12C (O) R 13,-X 4S (O) R 13,-X 4S (O) 2R 13,-R 14,-X 4OR 14,-X 4SR 14,-X 4S (O) R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) OR 14,-X 4OC (O) R 14,-X 4NR 14R 12,-X 4NR 12C (O) R 14,-X 4NR 12C (O) OR 14,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 14R 12,-X 4NR 12S (O) 2R 14,-X 4NR 12C (O) NR 14R 12With-X 4NR 12C (NR 12) NR 14R 12, X wherein 4, R 12, R 13And R 14Definition as above; Perhaps R 1And R 2Be connected to R simultaneously 1And R 2On carbon atom form (C altogether 3-8) cycloalkylidene or (C 3-8) inferior Heterocyclylalkyl; Wherein, at described R 2In, heteroaryl, aryl, cycloalkyl, Heterocyclylalkyl, cycloalkylidene or inferior Heterocyclylalkyl are all optional arbitrarily is independently selected from (C by 1-3 1-6) alkyl, (C 1-6) alkylidene radical, cyano group, the halogen, (C that halogen replaces 1-4) alkyl, nitro ,-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4NR 12C (O) R 13,-X 4S (O) R 13,-X 4S (O) 2R 13With-X 4C (O) R 13Group replace X wherein 4, R 12And R 13Definition as above;
R 3Be-C (R 6) (R 6) X 5, R wherein 6Define as above X 5Be selected from-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4C (O) R 13,-X 4NR 12C (O) R 13,-X 4S (O) R 13With-X 4S (O) 2R 13,-R 14,-X 4OR 14,-X 4SR 14,-X 4S (O) R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) OR 14,-X 4OC (O) R 14,-X 4NR 14R 12,-X 4NR 12C (O) R 14,-X 4NR 12C (O) OR 14,-X 4C (O) NR 14R 12,-X 4S (O) 2NR 14R 12,-X 4NR 12S (O) 2R 14,-X 4NR 12C (O) NR 14R 12With-X 4NR 12C (NR 12) NR 14R 12, X wherein 4, R 12, R 13And R 14Definition as above;
R 4Be-NR 6R 6,-NR 6R 14,-NR 6R 15Perhaps-NR 6X 5C (O) R 14, R wherein 6, X 5And R 14As mentioned above, and R 15Be hydrogen ,-(C 1-6) alkyl or-X 5OR 6, X wherein 5As mentioned above; Perhaps R 6And R 15Be connected to R simultaneously 6And R 15On nitrogen-atoms form assorted (C together 3-10) cycloalkyl, assorted (C 5-10) aryl or assorted (C 8-10) bicyclic aryl;
Wherein, at R 3And R 4In, alicyclic ring or aromatic ring can further be independently selected from (C by 1-5 arbitrarily 1-6) alkyl, (C 1-6) alkylidene radical, cyano group, the halogen, (C that halogen replaces 1-4) alkyl, nitro ,-X 4NR 12R 12,-X 4NR 12C (O) R 12,-X 4NR 12C (O) OR 12,-X 4NR 12C (O) NR 12R 12,-X 4NR 12C (NR 12) NR 12R 12,-X 4OR 12,-X 4SR 12,-X 4C (O) OR 12,-X 4C (O) R 12,-X 4OC (O) R 12,-X 4C (O) NR 12R 12,-X 4S (O) 2NR 12R 12,-X 4NR 12S (O) 2R 12,-X 4P (O) (OR 12) OR 12,-X 4OP (O) (OR 12) OR 12,-X 4NR 12C (O) R 13,-X 4S (O) R 13,-X 4C (O) R 13With-X 4S (O) 2R 13Group replace, and/or be selected from-R by 1 14,-X 4OR 14,-X 4SR 14,-X 4S (O) R 14,-X 4S (O) 2R 14,-X 4C (O) R 14,-X 4C (O) OR 14,-X 4OC (O) R 14,-X 4NR 14R 12,-X 4NR 12C (O) R 14,-X 4NR 12C (O) OR 14,-X 4C (O) NR 14R 12,-X 4S (O) 2NR 14R 12,-X 4NR 12S (O) 2R 14,-X 4NR 12C (O) NR 14R 12With-X 4NR 12C (NR 12) NR 14R 12Group replace; And at R 3And R 4In, the aliphatic segment can further be independently selected from cyano group, halogen, nitro ,-NR by 1-5 arbitrarily 12R 12,-NR 12C (O) R 12,-NR 12C (O) OR 12,-NR 12C (O) NR 12R 12,-NR 12C (NR 12) NR 12R 12,-OR 12,-SR 12,-C (O) OR 12,-C (O) R 12,-OC (O) R 12,-C (O) NR 12R 12,-S (O) 2NR 12R 12,-NR 12S (O) 2R 12,-P (O) (OR 12) OR 12,-OP (O) (OR 12) OR 12,-NR 12C (O) R 13,-S (O) R 13With-S (O) 2R 13Group replace; Wherein, X 4, R 12, R 13And R 14As mentioned above;
Prerequisite is at R 3Or R 4In only have a twin nuclei;
With the N-oxide derivative of this chemical compound, prodrug derivant, the derivant of protection, single isomer and mixture of isomers; And the pharmaceutically acceptable salt of this chemical compound and solvate and its N-oxide derivative, prodrug derivant, the derivant of protection, single isomer and mixture of isomers.
2. the chemical compound of claim 1, wherein:
X 1Be-NHC (R 1) (R 2) X 2Perhaps-NHX 3
X 2Be cyano group ,-C (O) X 3,-C (O) CF 3,-C (O) CF 2CF 2R 9,-CH=CHS (O) 2R 5,-C (O) CF 2C (O) NR 5R 5,-C (O) C (O) NR 5R 6,-C (O) C (O) OR 5,-C (O) CH 2OR 5,-C (O) CH 2N (R 6) SO 2R 5Or-C (O) C (O) R 5R wherein 5And R 6As mentioned above;
X 3Comprise the assorted monocycle that contains 4-6 annular atoms or contain the assorted dicyclo ring system of condensing of 8-14 annular atoms, with and carbocyclic ring ketone arbitrarily, imino group ketone or 40 thione derivatives;
Wherein at R 5, X 2Or X 3In, alicyclic ring or aromatic ring can further be independently selected from (C by 1-5 arbitrarily 1-6) alkyl or-X 4OC (O) R 12Group replace, and/or be selected from-R by 1 14,-X 4C (O) R 14Perhaps-X 4OC (O) R 14Group replace;
X wherein 4, R 12And R 14As mentioned above;
R 1Be hydrogen or (C 1-6) alkyl, R 2Be hydrogen ,-X 4OR 12, (C 5-10) heteroaryl (C 0-6) alkyl, (C 5-10) aryl (C 0-6) alkyl, (C 5-10) cycloalkyl (C 0-6) alkyl, (C 5-10) Heterocyclylalkyl (C 0-6) alkyl, perhaps (C 1-6) alkyl; Perhaps R 1And R 2Be connected to R 1And R 2On carbon atom form (C altogether 3-8) cycloalkylidene or (C 3-8) inferior Heterocyclylalkyl, wherein at described R 2In, heteroaryl, aryl, cycloalkyl, Heterocyclylalkyl, cycloalkylidene or inferior Heterocyclylalkyl are optional arbitrarily is independently selected from (C by 1-3 1-6) group of alkyl and hydroxyl replaces;
R 3Be-CH 2X 5, X wherein 5Be independently selected from all cases-X 4SR 12,-X 4C (O) NR 12R 12,-X 4S (O) 2R 13,-X 4C (O) R 13,-X 4SR 14,-R 14,-X 4S (O) 2R 14,-X 4R 12,-X 4C (O) R 14,-X 4C (O) NR 14R 12, X wherein 4, R 12, R 13And R 14Definition as above;
R 4Be-NR 6R 6,-NR 6R 14,-NR 6R 15Perhaps-NR 6X 5C (O) R 14, R wherein 6, X 5And R 14As mentioned above, and R 15Be hydrogen ,-(C 1-6) alkyl or-X 5OR 6, X wherein 5As mentioned above; Perhaps R 6And R 15Be connected to R 6And R 15On nitrogen-atoms form assorted (C altogether 3-10) cycloalkyl, assorted (C 5-10) aryl or assorted (C 8-10) bicyclic aryl;
Wherein, at R 3And R 4In, alicyclic ring or aromatic ring can further be independently selected from (C by 1-5 arbitrarily 1-6) alkyl, cyano group, halogen, the nitro, (C that halogen replaces 1-4) alkyl ,-X 4OR 12,-X 4C (O) OR 12,-X 4C (O) R 13,-X 4C (O) NR 12R 12,-X 4NR 12S (O) 2R 12Group replace and/or be selected from-R by 1 14,-X 4OR 14With-X 4C (O) NR 14R 12Group replace; At R 3And R 4In, the aliphatic segment can further be replaced by 1-5 group that is independently selected from cyano group arbitrarily; X wherein 4, R 12, R 13And R 14As mentioned above; Prerequisite is at R 3Or R 4In only have a twin nuclei;
With the N-oxide derivative of this chemical compound, prodrug derivant, the derivant of protection, single isomer and mixture of isomers; And the pharmaceutically acceptable salt of this chemical compound and solvate and its N-oxide derivative, prodrug derivant, the derivant of protection, single isomer and mixture of isomers.
3. the chemical compound of claim 2, wherein
X 1Be-NHC (R 1) (R 2) X 2Perhaps-NHX 3
X 2Be cyano group ,-C (O) X 3,-CF 3,-CF 2CF 3, (E)-and 2-benzenesulfonyl-vinyl, 2-formyl-dimethylamino-2,2-two fluoro-acetyl group, 1-benzylamino formoxyl-formoxyl, 1-benzyloxy (oxalyl group), 2-benzyloxy-acetyl group, 2-benzenesulfonyl amino-acetyl group or 2-oxo-2-phenyl acetyl;
X 3Be 1H-benzimidazolyl-2 radicals-Ji, pyrimidine-2-base, benzoxazole-2-base, benzothiazole-2-base, pyridazine-3-base, 3-phenyl-[1,2,4] oxadiazole-5-base, 3-ethyl-[1,2,4] oxadiazole-5-base, 2-methyl-4-oxo-tetrahydrofuran-3-base, 2-ethyl-4-oxo-tetrahydrofuran-3-base, 4-oxo-1-(1-phenyl formoxyl)-pyrrolidine-3-base or (S)-2-acetoxyl group-4-aza-oxo-cyclobutane-3-base;
R 1Be hydrogen or methyl, R 2Be hydrogen, methoxy, (C 1-6) alkyl, phenethyl, thiophene-2-base or 5-methylfuran-2-base, perhaps (ii) R 1And R 2Be connected to R 1And R 2On carbon atom form cyclopropylidene altogether, Pentamethylene oxide .-4-subunit or methyl piperidine-4-subunit.
4. the chemical compound of claim 3, wherein R 3Be selected from thiophene-2-sulfonyl methyl, 3-chloro-2-fluoro-phenylmethane sulfonyl methyl, benzenesulfonyl methyl; phenylmethane sulfonyl methyl, 2-(1,1-two fluoro-methoxyl groups)-phenylmethane sulfonyl methyl; 2-benzenesulfonyl-ethyl, 2-(pyridine-2-sulfuryl base)-ethyl, 2-(pyridine-4-sulfonyl)-ethyl; 2-phenylmethane sulfonyl-ethyl, oxygen base-pyridine-2-methylmethane sulfonyl methyl, third-2-alkene-1-sulfonyl methyl; 4-methoxyl group-phenylmethane sulfonyl methyl, p-methylphenyl sulfonyl methane ylmethyl, 4-chloro-phenylmethane sulfonyl methyl; neighbour-tolyl sulfonyl methane ylmethyl, 3,5-dimethyl-phenylmethane sulfonyl methyl; 4-trifluoromethyl-phenylmethane sulfonyl methyl, 4-trifluoromethoxy-phenylmethane sulfonyl methyl, 2-bromo-phenylmethane sulfonyl methyl; pyridine-2-methylmethane sulfonyl methyl, pyridin-3-yl sulfonyl methane ylmethyl, pyridin-4-yl sulfonyl methane ylmethyl; naphthalene-2-methylmethane sulfonyl methyl, 3-methyl-phenylmethane sulfonyl methyl, 3-trifluoromethyl-phenylmethane sulfonyl methyl; 3-trifluoromethoxy-phenylmethane sulfonyl methyl, 4-fluoro-2-trifluoromethoxy-phenylmethane sulfonyl methyl, 2-fluoro-6-trifluoromethyl-phenylmethane sulfonyl methyl; 3-chloro-phenylmethane sulfonyl methyl, 2-fluoro-phenylmethane sulfonyl methyl, 2-three fluoro-phenylmethane sulfonyl methyl; 2-cyano group-phenylmethane sulfonyl methyl, the 4-tert-butyl group-phenylmethane sulfonyl methyl, 2-fluoro-3-methyl-phenylmethane sulfonyl methyl; 3-fluoro-phenylmethane sulfonyl methyl, 4-fluoro-phenylmethane sulfonyl methyl, 2-chloro-phenylmethane sulfonyl methyl; 2,5-two fluoro-phenylmethane sulfonyl methyl, 2; 6-two fluoro-phenylmethane sulfonyl methyl, 2,5-two chloro-phenylmethane sulfonyl methyl; 3,4-two chloro-phenylmethane sulfonyl methyl, 2-(1; 1-two fluoro-methoxyl groups)-and phenylmethane sulfonyl methyl, 2-cyano group-phenylmethane sulfonyl methyl, 3-cyano group-phenylmethane sulfonyl methyl; 2-trifluoromethoxy-phenylmethane sulfonyl methyl, 2,3-two fluoro-phenylmethane sulfonyl methyl; 2,5-two fluoro-phenylmethane sulfonyl methyl, biphenyl-2-methylmethane sulfonyl methyl; cyclohexyl methyl, 3-fluoro-phenylmethane sulfonyl methyl, 3; 4-two fluoro-phenylmethane sulfonyl methyl; 2,4-two fluoro-phenylmethane sulfonyl methyl, 2; 4; 6-three fluoro-phenylmethane sulfonyl methyl, 2,4; 5-three fluoro-phenylmethane sulfonyl methyl; 2,3,4-three fluoro-phenylmethane sulfonyl methyl; 2; 3,5-three fluoro-phenylmethane sulfonyl methyl, 2; 5; 6-three fluoro-phenylmethane sulfonyl methyl, 2-chloro-5-trifluoromethyl sulfonyl methane ylmethyl, 2-methyl-propane-1-sulfonyl; 2-fluoro-3-trifluoromethyl sulfonyl methane ylmethyl; 2-fluoro-4-trifluoromethyl sulfonyl methane ylmethyl, 2-fluoro-5-trifluoromethyl sulfonyl methane ylmethyl, 4-fluoro-3-trifluoromethyl sulfonyl methane ylmethyl; 2-methoxyl group-phenylmethane sulfonyl methyl; 3,5-bis trifluoromethyl-phenylmethane sulfonyl methyl, 4-difluoro-methoxy-phenylmethane sulfonyl methyl; 2-difluoro-methoxy-phenylmethane sulfonyl methyl; 3-difluoro-methoxy-phenylmethane sulfonyl methyl, 2,6-Dichlorobenzene base sulfonyl methane ylmethyl; biphenyl-4-methylmethane sulfonyl methyl; 3,5-dimethyl-isoxazole-4-base sulfonyl methane ylmethyl, 5-chlorothiophene-2-methylmethane sulfonyl methyl; 2-[4-(1; 1-two fluoro-methoxyl groups)-benzenesulfonyl]-ethyl, 2-[2-1,1-difluoro-methoxy)-benzenesulfonyl]-ethyl; 2-[3-(1; the 1-difluoro-methoxy)-benzenesulfonyl]-ethyl, 2-(4-trifluoromethoxy-benzenesulfonyl)-ethyl, 2-(3-trifluoromethoxy-benzenesulfonyl)-ethyl; 2-(2-trifluoromethoxy-benzenesulfonyl)-ethyl; (cyanogen methyl-methyl-carbamoyl)-methyl, butyl, biphenyl-3-ylmethyl; 2-oxo-2-pyrrolidine-1-base ethyl; 2-benzenesulfonyl-ethyl, isobutyl group sulfane ylmethyl, 2-phenyl sulfane base-ethyl; cyclohexyl-methane sulfonyl methyl; 2-cyclohexyl-ethane sulfonyl, benzyl, naphthalene-2-base; the dibenzylsulfide. alkyl methyl; 2-trifluoromethyl-dibenzylsulfide. alkyl methyl, 5-bromothiophene-2-ylmethyl, phenyl sulfane base-ethyl and cyclopropyl sulfonyl methane ylmethyl.
5. the chemical compound of claim 4, wherein R 4Be selected from phenylamino, benzyl amino, 4-phenoxy group phenylamino; phenethyl amino, 3-phenyl-propyl group amino, morpholine-4-base; cyclohexyl amino; naphthalene-1-ylmethyl-amino, pyridin-3-yl amino, 6-methoxyl group-pyridin-3-yl amino; diisobutyl amino; 4-nitro-benzyl amino, 2-thiophene-2-base-ethylamino, 3-phenoxy group phenylamino; the cyanogen methylamino; (pyridin-3-yl methyl)-amino, 5,6; 7; 8-naphthane-1-base is amino, 2-pyridine-2-base-ethylamino, 2; 3-indoline-1-base; 3,4-dihydro-1H-isoquinolin-2-base, cyclohexyl methyl-amino; 2-methoxyl group-benzyl amino; 1-phenyl ethylamino, (pyridin-4-yl methyl)-amino, benzyl methylamino; 3-nitro-benzyl amino; 4-methoxybenzene amino, 3-carbamyl phenylamino, 4-carbamyl phenylamino; (oxolane-2-ylmethyl)-amino; 3,4-dihydro-2H-quinoline-1-base, dimethylamino; butyl methyl amino; diisopropylaminoethyl, propyl group methylamino, 1-(benzoxazole-2-carbonyl)-the amino and isobutyl group methylamino of propyl group.
6. the chemical compound of claim 5, it is selected from:
2-butyl-N-cyanogen methyl-N '-phenyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-phenyl Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-PEMA;
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-4-yl methyl-Malondiamide;
N-[1-(benzoxazole-2-carbonyl)-the 3-phenyl propyl]-N '-benzyl-2-cyclohexyl methyl Malondiamide;
N-cyanogen methyl-N '-cyclohexyl-2-cyclohexyl methyl-Malondiamide;
N-benzyl-N '-cyanogen methyl-2-cyclohexyl methyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-Phenoxyphenyl)-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(3-phenyl propyl)-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-3-morpholine-4-base-3-oxo propionic acid amide.;
N-cyanogen methyl-2-cyclohexyl methyl-N '-naphthalene-1-ylmethyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-3-yl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-diisobutyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-diisopropyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(6-methoxypyridine-3-yl)-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-thiophene-2-base-ethyl)-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(3-Phenoxyphenyl)-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-nitrobenzyl)-Malondiamide;
N, N '-two-cyanogen methyl-2-cyclohexyl methyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(5,6,7,8-naphthane-1-yl) Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-pyridine-2-base-ethyl)-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-3-(2,3-indoline-1-yl)-3-oxo propionic acid amide.;
N-cyanogen methyl-2-cyclohexyl methyl-3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxo propionic acid amide.;
N-cyanogen methyl-2, N '-dicyclohexyl methyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(2-methoxy-benzyl)-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(1-phenylethyl)-Malondiamide;
N-benzyl-N '-cyanogen methyl-2-cyclohexyl methyl-N-methyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(3-nitrobenzyl)-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-(4-methoxy-benzyl)-Malondiamide;
N-(3-carbamyl phenyl)-N '-cyanogen methyl-2-cyclohexyl methyl-Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-pyridin-3-yl methyl-Malondiamide;
N-(4-carbamoyl phenyl)-N '-cyanogen methyl-2-cyclohexyl methyl Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-N '-oxolane-2-ylmethyl Malondiamide;
N-cyanogen methyl-2-cyclohexyl methyl-3-(3,4-dihydro-2H-quinoline-1-yl)-3-oxo propionic acid amide.;
The N-tert-butyl group-N '-cyanogen methyl-2-cyclohexyl methyl-N-methylmalonyl amine;
N-cyanogen methyl-2-cyclohexyl methyl-N '-methyl-N '-propyl group Malondiamide;
N-butyl-N '-cyanogen methyl-2-cyclohexyl methyl-N-methylmalonyl amine;
N-cyanogen methyl-2-cyclohexyl methyl-N ', N '-dimethyl propylene diamides;
N-benzyl-N '-cyanogen methyl-2-(2-phenyl sulfane base ethyl) Malondiamide;
2-(2-phenyl sulfonyl ethyl)-N-benzyl-N '-cyanogen methylmalonyl amine;
2-(2-benzenesulfonyl-ethyl)-N-[(S)-1-(1-benzoxazole-2-base-formoxyl)-amyl group]-N '-benzyl-Malondiamide;
N, N '-two [(S)-1-(1-benzoxazole-2-base-formoxyl)-propyl group]-2-cyclohexyl methyl Malondiamide;
With the N-oxide derivative of this chemical compound, prodrug derivant, the derivant of protection, single stereoisomer and mixture of isomers; And the pharmaceutically acceptable salt of this chemical compound and solvate and its N-oxide derivative, prodrug derivant, the derivant of protection, single isomer and mixture of isomers.
7. pharmaceutical composition, it comprises the combination of the chemical compound and the acceptable excipient of pharmacy of the claim 1 for the treatment of effective dose.
One kind in animal the treatment disease method, inhibition of histone enzyme S can prevent, suppresses or improve the pathology and/or the symptom of this disease in this animal, described method comprises chemical compound or its N-oxide derivative of the claim 1 that gives this treatment of animals effective dose, single isomer or mixture of isomers; Perhaps this chemical compound pharmaceutically acceptable salt or solvate with and the N-oxide derivative, prodrug derivant, the derivant of protection, single isomer and mixture of isomers.
9. the chemical compound of claim 1 is used for purposes in the medicine of animal treatment disease in preparation, and wherein the cathepsin S activity causes the pathology and/or the symptom of described disease in described animal.
10. the method for a preparation I compound:
(A) make chemical compound as shown in the formula 2:
Figure A0281128900111
With formula NH 2CR 1R 2X 2Chemical compound reaction, wherein, R 1, R 2, R 3, R 4And X 2As in the summary of the invention for the definition of formula I; Perhaps
(B) make the chemical compound and the formula NH of formula 2 2X 3Chemical compound reaction, R wherein 3, R 4And X 3As summary of the invention for described in the formula I; With
(C) optional chemical compound with formula I is converted into pharmaceutically acceptable salt;
(D) salt form of optional chemical compound with formula I is converted into salt-independent shape;
(E) optional not oxidised form with formula I chemical compound is converted into pharmaceutically acceptable N-oxide;
(F) optional N-oxide form with formula I chemical compound is converted into its unoxidized form;
(G) optional individual isomer with formula I chemical compound splits from mixture of isomers;
(H) optional non-derivative compound with formula I is converted into prodrug derivant pharmaceutically; With
(I) prodrug derivant of optional chemical compound with formula I is converted into its non-deutero-form.
CNA02811289XA 2001-06-04 2002-06-04 Novel compounds and compositions as cathepsin inhibitors Pending CN1512880A (en)

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