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HK1101871B - Novel keto-oxadiazole derivatives as cathepsin inhibitors - Google Patents

Novel keto-oxadiazole derivatives as cathepsin inhibitors Download PDF

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Publication number
HK1101871B
HK1101871B HK07106732.3A HK07106732A HK1101871B HK 1101871 B HK1101871 B HK 1101871B HK 07106732 A HK07106732 A HK 07106732A HK 1101871 B HK1101871 B HK 1101871B
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HK
Hong Kong
Prior art keywords
acid
difluoro
morpholine
carbonyl
group
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HK07106732.3A
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Chinese (zh)
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HK1101871A1 (en
Inventor
Sukanthini Thurairatnam
David John Aldous
Vincent Leroy
Andreas Paul Timm
Original Assignee
Aventis Pharmaceuticals Inc.
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Priority claimed from PCT/US2004/035282 external-priority patent/WO2005040142A1/en
Publication of HK1101871A1 publication Critical patent/HK1101871A1/en
Publication of HK1101871B publication Critical patent/HK1101871B/en

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Description

Keto oxadiazole derivatives as cathepsin inhibitors
Technical Field
The present invention relates to the use of a novel class of keto-oxadiazole derivatives for the treatment of diseases associated with cysteine proteases, in particular diseases associated with cathepsin S, K and B activity. The invention also relates to methods for preparing such compounds.
Background
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue at the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. However, aberrant activity of cysteine proteases, for example, due to increased expression or enhanced activation, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of diseases, including arthritis, atherosclerosis, emphysema, osteoporosis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, periodontal disease, heterochromatic leukodystrophy and others.
Increased activity of cathepsins, such as cathepsin S, contributes to the pathology and/or symptomology of a number of diseases, such as autoimmune diseases, including but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, graves 'disease, myasthenia gravis, systemic lupus erythematosus, irritable bowel disease, rheumatoid arthritis, and hashimoto' S thyroiditis; allergic diseases including, but not limited to, asthma; and alloimmune responses including, but not limited to, organ transplantation or tissue transplantation. Cathepsin S has also been implicated in diseases involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g. emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonia, and cardiovascular diseases such as plaque rupture and atheroma. Cathepsin S is implicated in fibril formation and therefore inhibitors of cathepsin S are useful in the treatment of systemic amyloid diseases.
For example, cathepsin B activity in synovial fluid is significantly elevated in models of osteoarthritis (F.Mehraban Ann.Rheum.Dis.1997; 56, 108-115). Similarly, cathepsin K is also a key protease in synovial fibroblast-mediated collagen degradation (W. -S.Hou (et al) am.J.Pathol.2001, 159, 2167-2177). Thus, for example, inhibition of cathepsins B and K is a useful method for treating degenerative joint diseases such as osteoarthritis. Inhibition of cathepsin K, for example, results in inhibition of bone resorption (G.B.Stroup (et al) J.bone Mineral Res.2001, 16, 1739-1746). Therefore, cathepsin K inhibitors may be useful in the treatment of osteoporosis.
It is well known in the art that cathepsins play an important role in the degradation process of connective tissue and in the formation of bioactive proteins and antigenic processes. They are involved in osteoporosis, muscular dystrophy, bronchitis, emphysema, viral infections, cancer metastasis and neurodegenerative diseases such as alzheimer's disease and huntington's disease. Recently, there has been increasing interest in cathepsin inhibitors for certain potential therapeutic targets, such as cathepsin K or cathepsin L for osteoporosis, and cathepsin S for immunomodulation (w.kim., k.kang.expert opin.ther. Pat.2002, 12, 419-432). An increase in cathepsin K or B activity contributes to the pathology and/or symptomology of many diseases. Accordingly, molecules that inhibit tissue protease activity are useful as therapeutic agents for the treatment of such diseases.
Summary of The Invention
In one aspect of the present invention, there is provided a class of compounds that inhibit the enzymatic activity of cathepsin S, B and K, having the formula (I):
wherein
A is
Or
X1Is methylene, ethylene or a bond;
X2is CN, CHO, C (O) R6、C(O)C(O)NR7R7、C(O)C(O)NR7R8、C(O)C(O)R13、C(O)C(O)OR13、C(O)CH2X3R13；
X3Selected from O, S (O)n、CO、CONH、NHCO、NHSO2And SO2NH；
X4Is CH (R)12) Or CH (R)12)-CH2；
X5Is methylene, ethylene, propylene or a bond;
X6is a bond or (C)1-2) A hydrocarbylene group;
R1is H, R13C(O)-、R13S(O)2-、R13OC(O)-、R8R7NC(O)-、R8R7NS(O)2-；R13S(O)2NC (O) -or R13C(O)NS(O)2-; or R1Is selected from (C)1-9) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)5-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Hydrocarbyl and hetero (C)5-13) Aryl radical (C)0-6) (ii) hydrocarbyl, each group optionally substituted with 1 to 5 groups independently selected from: (C)1-4) Hydrocarbyl, cyano, halogen, halo (C)1-4) Hydrocarbyl radicals, -X6NR9R9、-X6OR9、-X6SR9、-X6C(O)NR9R9、-X6OC(O)NR9R9、-X6C(O)OR9、-X6NC(O)OR9、-X6S(O)R10、-X6S(O)2R10and-X6C(O)R10；
R2Selected from hydrogen, (C)1-6) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)5-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Alkyl or hetero (C)5-12) Aryl radical (C)0-6) A hydrocarbyl group;
R3selected from H, (C)1-6) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)5-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Alkyl or hetero (C)5-13) Aryl radical (C)0-6) A hydrocarbyl group optionally substituted with 1 to 5 groups independently selected from the group consisting of: (C)1-4) Hydrocarbyl, cyano, halogen, halo (C)1-4) Hydrocarbyl radicals, -X6NR9R9、-X6OR9、-X6SR9、-X6C(O)NR9R9、-X6OC(O)NR9R9、-X6C(O)OR9、-X6NC(O)OR9、-X6S(O)R10、-X6S(O)2R10And-X6C(O)R10；
R4is H or (C)1-6) A hydrocarbyl group; or R3And R4And R3And R4The carbon atoms to which both are attached together form (C)3-8) Cycloalkylene radical or (C)3-8) A heterocycloalkylene group;
R5is H, F, or R5Is (C)1-9) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)3-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Alkyl, hetero (C)5-13) Aryl radical (C)0-6) (ii) hydrocarbyl, each group optionally substituted with 1 to 5 groups independently selected from: (C)1-4) Hydrocarbyl, cyano, halogen, halo (C)1-4) Hydrocarbyl radicals, -X6NR9R9、-X6OR9、-X6SR9、-X6C(O)NR9R9、-X6OC(O)NR9R9、-X6C(O)OR9、-X6NC(O)OR9、-X6S(O)R10、-X6S(O)2R10and-X6C(O)R10；
R6Is (C)6-12) Aryl, hetero (C)5-13) Aryl and halo (C)1-6) A hydrocarbyl group; wherein R is6Optionally substituted with 1 to 5 groups independently selected from: (C)1-9) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)5-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Alkyl, hetero (C)5-13) Aryl radical (C)0-6) Hydrocarbyl, cyano, halogen, halo (C)1-6) Hydrocarbyl radicals, -X6NR9R9、-X6OR9、-X6SR9、-X6C(O)NR9R9、-X6OC(O)NR9R9、-X6C(O)OR9、-X6NC(O)OR9、-X6S(O)R10、-X6S(O)2R10and-X6C(O)R10；
R7Is H, (C)1-6) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)3-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Alkyl, hetero (C)5-13) Aryl radical (C)0-6) Hydrocarbyl and halo (C)1-6) A hydrocarbyl group; wherein R is7Optionally substituted with 1 to 5 groups independently selected from: (C)1-4) Hydrocarbyl, cyano, halogen, halo (C)1-4) Hydrocarbyl radicals, -X6NR9R9、-X6OR9、-X6SR9、-X6C(O)NR9R9、-X6OC(O)NR9R9、-X6C(O)OR9、-X6NC(O)OR9、-X6S(O)R10、-X6S(O)2R10and-X6C(O)R10；
R8Selected from H, (C)1-6) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)3-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Hydrocarbyl and hetero (C)5-13) Aryl radical (C)0-6) A hydrocarbon group, or R7And R8Together with the atom to which they are attached to form (C)3-8) Cycloalkylene radical or (C)3-8) A heterocycloalkylene group;
R9independently at each occurrence, is hydrogen, (C)1-6) Hydrocarbyl or halo (C)1-6) A hydrocarbyl group;
R10is (C)1-6) Hydrocarbyl or halo (C)1-6) A hydrocarbyl group;
R11selected from hydrogen, (C)1-9) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)5-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Alkyl, hetero (C)5-13) Aryl radical (C)0-6) Hydrocarbyl radical, (C)9-12) Two-ringAryl radical (C)0-3) Alkyl, hetero (C)8-12) -bicyclic aryl (C)0-3) Hydrocarbyl, -C (O) R13、-C(S)R13、-S(O)2R13、-C(O)OR13、-C(O)N(R7)R8、-C(S)N(R7)R8and-S (O)2N(R7)R8；
R12Is H or C1-6Hydrocarbyl, optionally amido, (C)6-12) Aryl, hetero (C)5-12) Aryl, hetero (C)5-12) Cycloalkyl or hydroxy;
R13is (C)1-6) Hydrocarbyl radical, (C)3-12) Cycloalkyl (C)0-6) Alkyl, hetero (C)3-12) Cycloalkyl (C)0-6) Hydrocarbyl radical, (C)6-12) Aryl radical (C)0-6) Alkyl, hetero (C)5-13) Aryl radical (C)0-6) Hydrocarbyl and halo (C)1-6) A hydrocarbyl group; wherein R is13Optionally substituted with 1 to 5 groups independently selected from: (C)1-4) Hydrocarbyl, cyano, halogen, halo (C)1-4) Hydrocarbyl radicals, -X6NR9R9、-X6OR9、-X6SR9、-X6C(O)NR9R9、-X6OC(O)NR9R9、-X6C(O)OR9、-X6NC(O)OR9、-X6S(O)R10、-X6S(O)2R10and-X6C(O)R10(ii) a And is
n is zero or an integer 1 or 2;
and their corresponding N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds of formula (Ia) as well as their N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers.
In another aspect of the invention, subject of the invention is a backbone structure of formula II, III, IV or V, wherein sub1-sub8 are general substituents. The specific substituents located at sub1-sub8 are not part of this aspect of the invention, but may be any chemical group or group substituted at those positions (hereinafter "generic substituents"), including those substituents made possible by any conventional means or any new technique developed in the future. Thus, for the purposes of this application, "general substituents" are not intended to be a component of or limit the claims, and they may be novel and non-obvious or unknown per se at the time the invention is made.
In another aspect of the invention, the inventive subject matter includes a backbone structure of formula II, III, IV, or V and a general substituent located at sub1-sub 8. For the purposes of this application, "general substituent" means a chemical group or group that one of ordinary skill in the art would consider suitable for substitution at the sub1-sub8 position by reference to the specific substituents disclosed below in making the invention without undue experimentation in practicing the invention.
In yet another aspect of the invention, the inventive subject matter includes a backbone structure of formula II, III, IV or V and specific substituents disclosed below at sub1-sub 8. Specific substituents disclosed herein are referred to as "particular substituents". For the purposes of this application, a particular substituent is recited in the claims as a limitation on the claim and may be patentable by itself or in combination with the backbone structure and other substituents therein.
Defining:
unless otherwise indicated, the following terms used in the specification and claims sections are defined for the purposes of this application and have the following meanings.
"related chemical entities" of a compound means an N-oxide derivative, prodrug derivative, protected derivative, individual isomer, mixture of isomers, or pharmaceutically acceptable salt or solvate of said compound, which can be prepared by one of ordinary skill in the art without undue experimentation.
"acyl" means a H-CO-or hydrocarbyl-CO-group in which the hydrocarbyl group is as described herein.
"acylamino" is an acyl-NH-group, wherein acyl is as defined herein.
"hydrocarbyloxy" means a hydrocarbyl-O-group wherein the hydrocarbyl group is as described herein. Typical hydrocarbyloxy groups include allyloxy, difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptyloxy.
"hydrocarbyloxycarbonyl" means a hydrocarbyl-O-CO-group wherein the hydrocarbyl group is as described herein. Typical hydrocarbyloxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
"hydrocarbyl" itself means a straight or branched, saturated or unsaturated aliphatic group having the indicated number of carbon atoms (e.g., (C)1-6) The hydrocarbon group includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl and the like). When the alkyl group is taken together with another group (e.g. arylalkyl) means a linear or branched, saturated or unsaturated, aliphatic divalent group having the indicated number of carbon atoms, or a bond (e.g. (C) when the number of atoms is not indicated6-12) Aryl radical (C)0-6) The hydrocarbon group includes phenyl, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, etc.). It will be understood by those skilled in the art that when the hydrocarbon group represents an unsaturated aliphatic groupWhen present, such groups must not be directly attached to an oxygen, nitrogen or sulfur atom through the carbon-carbon multiple bond of the unsaturated aliphatic group.
"alkylene", unless otherwise indicated, means a straight or branched, saturated or unsaturated aliphatic divalent radical having the indicated number of carbon atoms, (C)1-2) The alkylene group includes methylene (-CH)2-) and ethylene (-CH)2CH2-). It will be understood by those skilled in the art that when the alkylene group represents an unsaturated aliphatic divalent radical, such radical must not be directly attached to an oxygen, nitrogen or sulfur atom through the carbon-carbon multiple bond of the unsaturated aliphatic divalent radical.
"Alkylenedioxy" means an-O-alkylene-O-group in which alkylene is as defined above. Typical alkylenedioxy groups include methylenedioxy and ethylenedioxy.
"hydrocarbylsulfinyl" means a hydrocarbyl-SO-group in which the hydrocarbyl group is as described above. The hydrocarbyl group in the preferred hydrocarbylsulfinyl group is C1-4A hydrocarbyl group.
"Hydrocarbylsulphonyl" means a hydrocarbyl group-SO2-a group wherein the hydrocarbon group is as described above. The hydrocarbyl group in the preferred hydrocarbyl sulfonyl group is C1-4A hydrocarbyl group.
"hydrocarbylthio" means a hydrocarbyl-S-group in which the hydrocarbyl group is as described above. Typical hydrocarbylthio groups include methylthio, ethylthio, isopropylthio, and heptylthio.
By "aromatic group" is meant a group whose constituent atoms constitute an unsaturated cyclic system in which all atoms are sp2 hybridized atoms and the total number of pi electrons is equal to 4n + 2.
"aroyl" means an aryl-CO-group in which the aryl group is as described herein. Typical aroyl groups include benzoyl and 1-and 2-naphthoyl.
An "aroylamino" group is an aroyl-NH-group, wherein aroyl is as defined above.
"aryl" as a group or part of a group means: (i) an optionally substituted monocyclic or polycyclic aromatic carbon ring moiety of 6 to 12 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated polycyclic aromatic carbon ring portion wherein the aryl and cycloalkyl or cycloalkenyl groups are fused together to form a cyclic structure, such as a tetrahydronaphthalene ring, indenyl or 2, 3-indane ring. Unless otherwise defined, an aryl group may be substituted with one or more aryl substituents, which may be the same or different, including, for example, acyl, acylamino, hydrocarbyloxy, hydrocarbyloxycarbonyl, hydrocarbylenedioxy, hydrocarbylsulfinyl, hydrocarbylsulfonyl, hydrocarbylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or acid bioisosteres), cyano, cycloalkyl, halogen, heteroarylacyl, heteroaryl, heteroarylalkoxy, heteroarylacylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl, -NY3Y4、-CONY3Y4、-SO2NY3Y4、-NY3-C (═ O) hydrocarbyl, -NY3SO2Hydrocarbyl, or hydrocarbyl, optionally substituted by aryl, heteroaryl, hydroxy or-NY3Y4Substituted (wherein Y is3And Y4Independently is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or-NY3Y4The groups may form cyclic amines). Typically optionally substituted (C)6-12) Aryl groups include, but are not limited to, biphenyl, bromophenyl, chlorophenyl, dichlorophenyl, difluoromethoxyphenyl, dimethylphenyl, ethoxycarbonylphenyl, fluorophenyl, isopropylphenyl, methoxyphenyl, methylphenyl, methylsulfonylphenyl, naphthyl, pentafluorophenyl, phenyl, trifluoromethoxy phenyl, trifluoromethylphenyl, and the like. As used herein for the definition of and R6Group-bound substituent(s), optionally substituted (C)6-12) Aryl groups include trifluoromethoxyphenyl, difluoromethoxyphenyl, 4-fluorophenyl, and the like.
"Aryloxyalkyl" means an arylalkyl-O-group wherein the arylalkyl group is as described above. Typical arylalkoxy groups include benzyloxy and 1-or 2-naphthylmethoxy.
"Aryloxycarbonyl" means an arylalkyl-O-CO-group wherein the arylalkyl group is as described above. A typical arylalkoxycarbonyl group is benzyloxycarbonyl.
"Arylalkylthio" means an arylalkyl-S-group wherein the arylalkyl group is as described above. A typical arylalkylthio group is benzylthio.
"aryloxy" means an aryl-O-group in which the aryl group is as described above. Typical aryloxy groups include phenoxy and naphthoxy, each of which is optionally substituted.
"aryloxycarbonyl" means an aryl-O-C (═ O) -group in which the aryl group is as described above. Typical aryloxycarbonyl groups include phenoxycarbonyl and naphthyloxycarbonyl.
"Arylsulfinyl" means an aryl-SO-group in which the aryl group is as described above.
"arylsulfonyl" means aryl-SO2-a group wherein aryl is as described above.
"Arylthio" means an aryl-S-group wherein the aryl group is as described above. Typical arylthio groups include phenylthio and naphthylthio.
"cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic combination containing the indicated number of ring carbon atoms, and any carbocyclic ketone, thione, or iminoketone derivative thereof (e.g., (C)3-12) The cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2, 5-cyclohexadienyl, bicyclo [2.2.2]Octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo [2.2.1]Hept-1-yl, etc.). Those skilled in the art will appreciate thatWhen the cycloalkyl group represents an unsaturated cyclic combination, such ring must not be directly attached to an oxygen, nitrogen or sulfur atom through a carbon-carbon multiple bond.
"Cyclohydrocarbylene" means a divalent, saturated or partially unsaturated, monocyclic or bridged polycyclic combination containing the indicated number of ring carbon atoms, and any carbocyclic ketone, thione, or iminoketone derivative thereof.
"heteroaroyl" means a heteroaryl-C (═ O) -group in which the heteroaryl group is as described herein. Typical heteroaryl groups include pyridylcarbonyl.
"Heteroaroylamino" means a heteroaroyl-NH-group in which the heteroaryl group is as described above.
"heteroaryl" as a group or part of a group means: (i) an optionally substituted aromatic mono-or polycyclic organic moiety having from about 5 to about 13 ring atoms, wherein one or more of the ring atoms is an element other than carbon, such as nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1, 3, 4-thiadiazolyl, thiazolyl, thienyl and triazolyl, optionally substituted with one or more aryl substituents as defined above, unless otherwise defined); (ii) an optionally substituted partially saturated polycyclic heterocarbocyclic moiety in which the heteroaryl and cycloalkyl or cycloalkenyl groups are fused together to form a cyclic structure (examples of such groups include 4-azaperhydroindenyl, optionally substituted with one or more "aryl substituents" as defined above, unless otherwise defined). Optional substituents include one or more "aryl substituents" as defined above, unless otherwise defined. As used herein to define R6The substituent used, optionally substituted hetero (C)5-13) Aryl radicals including benzoxazol-2-yl, 5-tert-butyl- [1, 2, 4%]Oxadiazol-3-yl, 3-cyclopropyl-1, 2, 4-oxadiazol-5-yl, 5-cyclopropyl-1, 2, 4-oxadiazolOxazol-5-yl, 5-cyclopropyl-1, 3, 4-oxadiazol-2-yl, 5-ethyl- [1, 3, 4] methyl]Oxadiazol-2-yl, 5- (4-fluoro-phenyl) -1, 2, 4-oxadiazol-3-yl, 5-isopropylisoxazol-3-yl, 5- (5-methylisoxazol-3-yl) -oxazol-2-yl, 3-phenyl-1, 2, 4-oxadiazol-5-yl, 5-phenyl-1, 2, 4-oxadiazol-3-yl, 3- (tetrahydro-pyran-4-yl) -1, 2, 4-oxadiazol-5-yl, 5-thiophen-2-yloxazol-2-yl, 5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl, and the like.
"Heteroarylalkoxy" means a heteroarylalkyl-O-group in which the heteroarylalkyl group is as described above. Typical heteroaryloxy groups include optionally substituted pyridylmethoxy.
"heteroaryloxy" means a heteroaryl-O-group in which the heteroaryl group is as described above. Typical heteroaryloxy groups include optionally substituted pyridyloxy.
"Heterocycloalkyl" means cycloalkyl as defined herein, but wherein one or more of the ring carbon atoms shown is partially substituted with a heteroatom selected from-N ═ NR-, -O-, or-S-, wherein R is hydrogen, (C)1-6) A hydrocarbyl group, a protecting group or represents a free valence as a point of attachment to a ring nitrogen atom, and any carbocyclic ketone, thione or iminoketone derivative thereof (e.g. the term hetero (C)5-12) Cycloalkyl groups include imidazolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl and the like. Both unprotected and protected derivatives are within the scope of the invention.
"Heterocycloalkylene" means cycloalkylene as defined herein, but wherein one or more of the ring carbon atoms shown is selected from-N ═ NR-, -O-, -S-or-S (O)2-wherein R is hydrogen, (C) is1-6) A hydrocarbyl group or a protecting group.
"isomers" as used in this disclosure means voids having the same molecular formula but in which the atoms differ in nature and order of incorporation or atomsThe compounds of the invention differ in their meta arrangement. Isomers that differ in the arrangement of atoms in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", while stereoisomers whose mirror images do not overlap are referred to as "enantiomers" or sometimes "optical isomers". The carbon atom to which four substituents different from each other are attached is called a "chiral center". Compounds with one chiral center have two enantiomeric forms of opposite chirality. The "racemic mixture" contains both enantiomers in a ratio of 1: 1. However, for the purposes of this application, when both enantiomers are present simultaneously, a racemic mixture is employed, regardless of the ratio between them. The compounds having more than one chiral center have 2n-1Enantiomeric pair, wherein n is the number of chiral centers. Compounds having more than one chiral center may exist as individual diastereomers, or as mixtures of diastereomers, referred to as "diastereomeric mixtures". When a chiral center is present, stereoisomers may be characterized by the absolute configuration of the chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to a chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and are described according to the R-and S-sequence rules set forth by Cahn, Ingold, and Prelog. Conventions for stereochemical nomenclature, methods for determining stereochemical structures, and methods for separating stereoisomers are well known in the art (see, e.g., advanced organic chemistry, 4 th edition, March, Jerry, John Wiley&Sons, new york, 1992). It is to be understood that the names and illustrations used in this disclosure to describe the compounds of the present invention are intended to include all possible stereoisomers. Thus, for example, morpholine-4-carboxylic acid {1- [1- (3-cyclopropyl- [1, 2, 4]]Oxadiazole-5-carbonyl) -propylcarbamoyl]The name-3, 3-difluorohexyl } -amide is meant to include morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl]-3, 3-difluorohexyl } -amide and morpholine-4-carboxylic acid { (R) -1- [ (R) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl]-3, 3-Difluorohexan(iv) a group } -amide and any mixtures thereof, racemic or otherwise.
By "N-oxide derivative" is meant a derivative of a compound of the invention in which the nitrogen is in the oxidized state (i.e., N-O) and which possesses the desired pharmacological activity.
By "pharmaceutically acceptable" it is meant that it can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, biologically or otherwise non-negative, and acceptable for both veterinary use and human pharmaceutical use.
By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention which is pharmaceutically acceptable as defined above and which has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, or with the following organic acids: acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4' -methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, pivalic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, Salicylic acid, stearic acid, muconic acid, and the like.
Pharmaceutically acceptable salts also include base addition salts formed when an acidic proton present is capable of reacting with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
By "prodrug" is meant a compound that is metabolically convertible in vivo to a compound of the invention. For example, esters of the compounds of the invention containing a hydroxy group may be converted to the parent molecule in vivo by hydrolysis. Likewise, esters of the compounds of the present invention containing a carboxyl group may be converted to the parent molecule in vivo by hydrolysis. Suitable esters of the compounds of the invention containing a hydroxyl group are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-b-hydroxynaphthoate, cholate, isethionate, di-p-toluoyl tartrate, methylsulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinic acid ester. Suitable esters of the compounds of the invention containing a carboxyl group are, for example, those described in f.j.leinweber, Drug metab.res, 1987, 18, page 379. A particularly useful class of esters of the compounds of the invention containing a hydroxyl group may be prepared from an acid selected from those described by Bundgaard et al, j.med.chem., 1989, 32, 2503-2507, which include substituted aminomethyl benzoates, such as dihydrocarbylaminomethyl benzoates, in which the two hydrocarbyl groups may be linked together and/or interrupted by an oxygen atom or an optionally substituted nitrogen atom, such as a hydrocarbylated nitrogen atom, especially a morpholinomethyl benzoate, such as 3-or 4- (morpholinomethyl) -benzoate, and (4-hydrocarbylpiperazin-1-yl) benzoates, such as 3-or 4- (4-hydrocarbylpiperazin-1-yl) benzoate.
By "protected derivative" is meant a derivative of a compound of the invention in which one or more reactive sites are blocked with a protecting group. Protected derivatives of the compounds of the invention may be used in the preparation of the compounds of the invention or may themselves be potent cathepsin S inhibitors. For a more complete list of suitable protecting groups, see protecting groups in organic synthesis (t.w. greene, 3 rd edition, John Wiley & Sons, inc., 1999).
By "therapeutically effective amount" is meant a dose, when administered to an animal to treat a disease, sufficient to cause the treatment to be effective against the disease.
By "treatment" is meant any administration of a compound of the invention, including:
(1) preventing the onset of disease in an animal that may be predisposed to the disease but does not yet experience or exhibit the pathology or symptomatology of the disease,
(2) inhibiting the disease (i.e., arresting the further development of the pathology and/or symptoms) in an animal experiencing or exhibiting the pathology or symptoms of the disease, or
(3) The condition is ameliorated (i.e., the pathology and/or symptoms are reversed) in an animal that is experiencing or developing the pathology or symptoms of the disease.
Naming:
the compounds of the invention, as well as the intermediates and starting materials for their preparation, are named according to the IUPAC rules, wherein the descending order of preference of the characteristic groups as main bases is as follows: acids, esters, amides, and the like. Alternatively, the compounds are named according to AutoNom 4.0 software (Beilstein Information Systems, Inc.). [ e.g., a compound of formula (I) wherein R1Is morpholine-4-carbonyl, X1Is methylene, R5Is methyl, R2Is H and A isWherein R is3Is ethyl, R4Is H and X2Is C (O) R6Wherein R is6Is 3-cyclopropyl-1, 2, 4-oxadiazol-5-yl; i.e. a compound having the structure:
is named morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl ] -3, 3-difluorobutyl } -amide.
However, it is understood that for a particular compound referred to by both structural formula and nomenclature, the structural formula controls if the structural formula and nomenclature are inconsistent with one another.
The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a fuller understanding of the invention, its operating advantages and specific objects attained by its uses, reference should be made to the following description wherein there is illustrated and described a preferred embodiment of the invention.
Detailed description of the preferred embodiments
With respect to the compounds of formula (I) above, the following are specific classes:
X1may particularly represent methylene.
A may particularly representWherein: r3Is H, (C)6-12) Aryl (C2-6) hydrocarbyl or optionally substituted by-X6OR9Is (C)1-6) Hydrocarbyl radical [ wherein X6Is a bond and R9Is (C)1-6) Hydrocarbyl radical]；R4Is H or (C)1-6) A hydrocarbyl group; x2Is CHO, CN or C (O) R6[ wherein R6Is optionally covered with (C)1-9) Hydrocarbyl radical, (C)3-12) Cycloalkyl group, (C)6-12) Aryl or hetero (C)5-13) Hetero (C) of aryl5-13) Aryl radicals]。
A may also particularly representWherein X5Is propylene and R11is-C (O) OR13or-S (O)2R13Wherein R is13Is a hydrocarbon group or (C)6-12) And (4) an aryl group.
R1May especially represent R13C (O) -, wherein R13Is a hetero compound (C)5-12) A cyclic hydrocarbon group.
R1May also particularly represent R13OC (O) -, wherein R13Is (C)6-12) Aryl radical (C)1-6) A hydrocarbyl group.
R1May also particularly represent (C)1-9) A hydrocarbyl group.
R1May also particularly represent hetero (C)5-12) A cyclic hydrocarbon group.
R2May particularly represent H.
R5Can particularly represent (C)1-9) A hydrocarbyl group.
R5May also particularly represent (C)6-12) Aryl radical (C)1-6) A hydrocarbyl group.
The special types are as follows:
one particular group of compounds of the invention are compounds of formula (Ia):
wherein R is1、R3、R4And R5As described above, and their corresponding N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds of formula (Ia) as well as their N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers.
Examples are compounds of formula (Ia) wherein R1Is R13C (O) -and R13Is a hetero compound (C)5-12) A cyclic hydrocarbon group. Particular examples are compounds of formula (Ia), wherein R1Is that
Examples are compounds of formula (Ia) wherein R3Is H, (C)6-12) Aryl radical (C)1-6) Hydrocarbyl or (C)1-6) A hydrocarbyl group. Particular examples are compounds of the formula (Ia), in whichR3Is H,Or CH3-CH2—CH2-
Examples are those in which R4A compound of formula (Ia) which is H or methyl.
Examples are those in which R5Is (C)6-12) Aryl radical (C)1-6) Hydrocarbyl group of the formula (Ia).
Particular examples are those wherein R is5RepresentsA compound of formula (Ia).
A particular group of compounds of the invention are compounds of formula (Ia) wherein: r1Is R13C (O) - (in particular)；R3Is H, (C)6-12) Aryl radical (C)1-6) Hydrocarbyl (especially) Or (C)1-6) Hydrocarbyl (especially CH)3-CH2-CH2-)；R4Is H or methyl and R5Is (C)6-12) Aryl radical (C)1-6) Hydrocarbyl (especially
A particular group of compounds of the invention are compounds of formula (Ib),
wherein: r1Is R13C (O) - (in particular)；R3Is H, (C)6-12) Aryl radical (C)1-6) Hydrocarbyl (especially) Or (C)1-6) Hydrocarbyl (especially CH)3-CH2-)；R4Is H or methyl and R5Is (C)6-12) Aryl radical (C)1-6) Hydrocarbyl (especially
Another particular group of compounds of the invention are compounds of formula (Ic):
wherein R is1、R3、R4、R5And R6Are as described above, and their corresponding N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers;
and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds of formula (Ic) as well as their N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers.
Examples are compounds of formula (Ic), wherein R1Is R13C (O) -and R13Is a hetero compound (C)5-12) A cyclic hydrocarbon group. Particular examples are compounds of formula (Ic) wherein R1Is that
Examples are compounds of formula (Ic), wherein R3Is optionally substituted by-X6OR9[ wherein X6Is a bond and R9Is (C)1-6) Hydrocarbyl radical]Substituted (C)1-6) A hydrocarbyl group. Particular examples are compounds of formula (Ic) wherein R3Is CH3-CH2-、CH3-CH2-CH2-or CH3-O-CH2-。
Examples are those in which R4A compound of formula (Ic) which is H or methyl. Examples are those in which R4A compound of formula (Ic) which is H.
Examples are compounds of formula (Ic), wherein R5Is (C)1-9) Hydrocarbyl or (C)6-12) Aryl radical (C)1-6) A hydrocarbyl group. Particular examples are compounds of formula (Ic) wherein R5Represents CH3CH2CH2Or CH3CH2Or CH3OrParticular examples are those wherein R is5RepresentsA compound of formula (Ic).
Examples are compounds of formula (Ic), wherein R6Is a hetero compound (C)5-13) Aryl, optionally substituted by (C)1-9) Hydrocarbyl radical, (C)3-12) Cycloalkyl group, (C)6-12) Aryl or hetero (C)5-13) Aryl substitution. Typical optionally substituted hetero (C)5-13) Aryl includes optionally substituted benzoxazolyl, oxadiazolyl, isoxazolyl, or oxazolyl. Examples are compounds of formula (Ic), wherein R6Is benzoxazol-2-yl, 5-tert-butyl- [1, 2,4]Oxadiazol-3-yl, 3-cyclopropyl-1, 2, 4-oxadiazol-5-yl, 5-cyclopropyl-1, 2, 4-oxadiazol-2-yl, 5-cyclopropyl-1, 3, 4-oxadiazol-2-yl, 5-ethyl-1, 3, 4-oxadiazol-2-yl, 5- (4-fluoro-phenyl) -1, 2, 4-oxadiazol-3-yl, 5-isopropylisoxazol-3-yl, 5- (5-methylisoxazol-3-yl) -oxazol-2-yl, 5- (5-methylthion-2-yl) -oxazol-2-yl, oxa-l-2-yl, oxa, Oxazol-2-yl, 3-phenyl-1, 2, 4-oxadiazol-5-yl, 5-phenyl-1, 2, 4-oxadiazol-3-yl, 5-thiophen-2-yloxazol-2-yl, 5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl and the like. Wherein R is6Compounds of formula (Ic) which are benzoxazol-2-yl, 3-cyclopropyl-1, 2, 4-oxadiazol-5-yl, oxazol-2-yl are particular examples.
A particular group of compounds of the invention are compounds of formula (Ic), whichThe method comprises the following steps: r1Is R13C (O) - (in particular)；R3Is optionally substituted by X6OR9- (especially CH)3-CH2-、CH3-CH2-CH2-or CH3-O-CH2-) substituted (C1-6) A hydrocarbyl group; r4Is H and R5Is (C)1-9) Hydrocarbyl or (C)6-12) Aryl radical (C)1-6) Hydrocarbyl (especially)；R6Is a hetero compound (C)5-13) Aryl, optionally substituted by (C)1-9) Hydrocarbyl radical, (C)3-12) Cycloalkyl, hetero (C)5-12) Cycloalkyl group, (C)6-12) Aryl or hetero (C)5-13) Aryl (especially benzoxazol-2-yl, 3-cyclopropyl-1, 2, 4-oxadiazol-5-yl, oxazol-2-yl and 5-methylisoxazol-3-yloxazol-2-yl) substituted.
Another particular group of compounds of the invention are compounds of formula (Id):
wherein R is1、R5、R11And X5As described above, and their corresponding N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds of formula (Id) as well as their N-oxides, their prodrugs, their protected derivatives, and their individual isomers and mixtures of isomers.
Examples are compounds of formula (Id) wherein R1Is R13C (O) -and R13Is a hetero compound (C)5-12) A cyclic hydrocarbon group. Particular examples are compounds of formula (Id), wherein R1Is that
Examples are compounds of formula (Id) wherein R5Is (C)6-12) Aryl radical (C)1-6) A hydrocarbyl group. Particular examples are compounds of formula (Id), wherein R5Represents
Examples are compounds of formula (Id) wherein R11is-C (O) OR13or-S (O)2R13Wherein R is13Is a hydrocarbon group or (C)6-12) And (4) an aryl group. Particular examples are compounds of formula (Id), wherein R11represents-C (O) OC (CH)3)3Or
Examples are those in which X1A compound of formula (Id) which is propylene.
A particular group of compounds of the invention are compounds of formula (Id) wherein R1Is R13C (O) - (in particular)；R5Is (C)6-12) Aryl radical (C)1-6) Hydrocarbyl (especially)；R11is-C (O) OR13[ especially-C (O) OC (CH)3)3]or-S (O)2R13(especially inAnd X1Is a propylene group.
Particular compounds of the invention include:
morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl ] -3, 3-difluorohexyl } -amide;
morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (5-cyclopropyl-1, 3, 4-oxadiazole-2-carbonyl) -propylcarbamoyl ] -3, 3-difluorohexyl } -amide;
morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (S) -1- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazole-2-carbonyl ] -propylcarbamoyl } -hexyl) -amide;
morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl ] -3, 3-difluoro-4-phenyl-butyl } -amide;
morpholine-4-carboxylic acid {1- [1- (3-cyclopropyl- [1, 2, 4] oxadiazole-5-carbonyl) -propylcarbamoyl ] -3, 3-difluoro-5-methyl-hexyl } -amide;
morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl ] -3, 3-difluorobutyl } -amide;
morpholine-4-carboxylic acid { (S) -3, 3-difluoro-1- [ (S) -1- (3-phenyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl ] -butyl } -amide;
morpholine-4-carboxylic acid { (S) -3, 3-difluoro-1- [ (S) -1- (5-phenyl-1, 2, 4-oxadiazole-3-carbonyl) -propylcarbamoyl ] -butyl } -amide;
morpholine-4-carboxylic acid {1- [1- (5-cyclopropyl- [1, 3, 4] oxadiazole-2-carbonyl) -propylcarbamoyl ] -3, 3-difluoro-4-phenyl-butyl } -amide;
morpholine-4-carboxylic acid {3, 3-difluoro-1- [1- (5-isopropylisoxazole-3-carbonyl) -propylcarbamoyl ] -hexyl } -amide;
morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- {1- [5- (5-methylisoxazol-3-yl) -oxazole-2-carbonyl ] -propylcarbamoyl } -hexyl) -amide;
morpholine-4-carboxylic acid { (S) -3, 3-difluoro-1- [ (S) -1- (oxazole-2-carbonyl) -propylcarbamoyl ] -4-phenyl-butyl } -amide;
morpholine-4-carboxylic acid { (S) -3, 3-difluoro-4-phenyl-1- [ (S) -1- (5-thiophen-2-yloxazole-2-carbonyl) -propylcarbamoyl ] -butyl } -amide;
morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (benzoxazole-2-carbonyl) -butylcarbamoyl ] -3, 3-difluoro-4-phenyl-butyl } -amide;
morpholine-4-carboxylic acid [1- (2-benzooxazol-2-yl-1-methoxymethyl-2-oxoethylcarbamoyl) -3, 3-difluoro-4-phenyl-butyl ] -amide;
morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (benzoxazole-2-carbonyl) -1-methyl-butylcarbamoyl ] -3, 3-difluoro-4-phenyl-butyl } -amide;
morpholine-4-carboxylic acid [ (S) -1- ((S) -1-cyano-3-phenylpropylcarbamoyl) -3, 3-difluoro-4-phenyl-butyl ] -amide;
morpholine-4-carboxylic acid [ (S) -1- (cyanomethyl-carbamoyl) -3, 3-difluoro-4-phenyl-butyl ] -amide;
morpholine-4-carboxylic acid [ (S) -3, 3-difluoro-1- ((S) -1-formyl-1-methyl-butylcarbamoyl) -4-phenyl-butyl ] -amide;
morpholine-4-carboxylic acid { (S) -1- [1- (5-ethyl- [1, 3, 4] oxadiazole-2-carbonyl) -propylcarbamoyl ] -3, 3-difluoro-4-phenyl-butyl } -amide;
morpholine-4-carboxylic acid { (S) -1- [1- (5-tert-butyl- [1, 2, 4] oxadiazole-3-carbonyl) -propylcarbamoyl ] -3, 3-difluoro-4-phenyl-butyl } -amide;
morpholine-4-carboxylic acid { (S) -3, 3-difluoro-4-phenyl-1- [ (S) -1- (5-phenyl- [1, 2, 4] oxadiazol-3-yl) -propylcarbamoyl ] -butyl } -amide;
[ (S) -1- (cyanomethyl-carbamoyl) -3, 3-difluoro-4-phenyl-butyl ] -carbamic acid benzyl ester;
(S) -4, 4-difluoro-5-phenyl-2- (tetrahydro-pyran-4-ylamino) -pentanoic acid cyanomethylamide;
(S) -4, 4-difluoro-2-isobutylamino-5-phenylpentanoic acid cyanomethylamide;
morpholine-4-carboxylic acid [ (S) -1- ((S) -1-benzenesulfonyl-3-oxo-azepan-4-ylcarbamoyl) -3, 3-difluoro-4-phenyl-butyl ] -amide;
(S) -4- { (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino ] -5-phenylpentanoylamino } -3-oxo-azepan-1-carboxylic acid tert-butyl ester;
morpholine-4-carboxylic acid ((S) -1- { (S) -1- [ (5-ethyl-1, 3, 4-oxadiazol-2-yl) -hydroxymethyl ] -propylcarbamoyl } -3, 3-difluorohexyl) -amide;
morpholine-4-carboxylic acid { (S) -1- [1- (5-cyclopropyl-1, 3, 4-oxadiazole-2-carbonyl) -propylcarbamoyl ] -3, 3-difluorobutyl } -amide;
morpholine-4-carboxylic acid { (S) -1- [1- (5-cyclopropyl-1, 2, 4-oxadiazole-3-carbonyl) -propylcarbamoyl ] -3, 3-difluorohexyl } -amide;
morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (S) -1- [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazole-3-carbonyl ] -propylcarbamoyl } -butyl) -amide;
morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- {1- [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazole-3-carbonyl ] -propylcarbamoyl } -butyl) -amide;
morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (R) -1- [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazole-3-carbonyl ] -propylcarbamoyl } -butyl) -amide;
morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (benzoxazole-2-carbonyl) -propylcarbamoyl ] -3, 3-difluorobutyl } -amide;
morpholine-4-carboxylic acid [ (S) -1- (cyanomethyl-carbamoyl) -3, 3-difluorohexyl ] -amide;
morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (R) -1- [5- (5-methylthiophen-2-yl) -oxazole-2-carbonyl ] -propylcarbamoyl } -hexyl) -amide;
morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (S) -1- [5- (5-methylthiophen-2-yl) -oxazole-2-carbonyl ] -propylcarbamoyl } -hexyl) -amide;
and their corresponding N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds of formula (Ia) as well as their N-oxides, their prodrugs, their protected derivatives, their individual isomers and mixtures of isomers.
Pharmacology and use:
the compounds of the present invention are inhibitors of cathepsin S and are therefore useful in the treatment of diseases in which cathepsin S activity contributes to the pathology and/or symptomology of the disease. For example, the compounds of the invention may be useful in the treatment of autoimmune diseases, including but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, graves 'disease, myasthenia gravis, systemic lupus erythematosus, irritable bowel disease, rheumatoid arthritis, and hashimoto's thyroiditis; allergic diseases including, but not limited to, asthma; and alloimmune responses including, but not limited to, organ transplantation or tissue transplantation.
Cathepsin S is also implicated in diseases involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g. emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonia, and cardiovascular diseases such as plaque rupture and atheroma. Cathepsin S is implicated in fibril formation and therefore inhibitors of cathepsin S are useful in the treatment of systemic amyloidosis.
The cysteine protease inhibitory activity of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring tissue protease activity and inhibition thereof by test compounds are known. Generally, this assay measures protease-induced hydrolysis of peptidyl substrates. The details of the assays for measuring protease inhibitory activity are detailed in examples 31, 32, 33 and 34 below.
The compounds of the present invention are also inhibitors of cathepsin K and B and are therefore useful in the treatment of diseases in which cathepsin K and B activity contributes to the pathology and/or symptomology of the disease. For example, the compounds of the invention may be used to treat pain, osteoarthritis, osteoporosis, or cancer, such as lung cancer, leukemia (B-and T-cell, acute), ovarian cancer, sarcoma, kaposi's sarcoma, intestinal cancer, lymph node cancer, brain tumor, breast cancer, pancreatic cancer, prostate cancer, or skin cancer.
Administration and pharmaceutical compositions:
in general, the compounds of the present invention will be administered in therapeutically effective amounts, alone or in combination with one or more therapeutic agents, by any available and acceptable means known in the art. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the patient, the potency of the compound used, and other factors. For example, a therapeutically effective amount of a compound of the invention may range from about 1 microgram per kilogram of body weight per day (μ g/kg) to about 60 milligrams per kilogram of body weight per day (mg/kg), usually from about 1 μ g/kg/day to about 20 mg/kg/day. Thus, for a patient of 80kg, a therapeutically effective amount may be from about 80 μ g/day to about 4.8 g/day, typically from about 80 μ g/day to about 1.6 g/day. In general, one of ordinary skill in the art, with the knowledge of his or her own and the disclosure of this invention, will be able to determine a therapeutically effective amount of a compound of the present invention for treating a particular disease.
The compounds of the invention may be administered in the form of pharmaceutical compositions by one of the following routes: oral, systemic (e.g. transdermal, intranasal or in the form of suppositories) or parenteral (e.g. intramuscular, intravenous or subcutaneous). The pharmaceutical compositions may be in the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition and generally consist of a compound of the invention in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are nontoxic, easy to administer, and do not adversely affect the therapeutic benefits of the active ingredient. Such excipients may be any solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. The liquid and semi-solid excipients may be selected from water, ethanol, glycerol, propylene glycol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
The amount of the compounds of the present invention in the compositions may vary widely depending on the type of formulation, the size of the unit dose, the type of excipient, and other factors known to those skilled in the art of medical science. In general, a composition of a compound of the invention for the treatment of a particular disease may contain from 0.01% w to 10% w of the active ingredient, preferably from 0.3% w to 1% w, the remainder being one or more excipients. Preferably, the pharmaceutical composition is administered in a single unit dosage form for continuous treatment, or optionally in a single unit dosage form when needed for specific relief of symptoms. A representative pharmaceutical formulation containing a compound of the invention is described in example 35.
Chemistry:
methods of preparing the compounds of the invention:
the compounds of the invention can be prepared by adapting and modifying known methods which have been used hitherto or described in the literature, for example those described by R.C. Larock in the organic switching university (VCH publishers, 1989).
In the various reactions described below, where certain reactive functional groups are desired in the final product, such as hydroxyl, amino, imino, thio or carboxyl groups, it may be necessary to protect them from undesired participation in the reaction. Conventional protecting groups can be utilized according to standard practice, for example, see "protecting groups in organic chemistry" by t.w.greene and p.g.m.wuts (john wiley and Sons, 1991).
The compounds of the invention can be prepared according to reaction scheme 1:
reaction scheme 1
Wherein X1、R1、R3、R4、R5And R6Each as defined in the summary of the invention. Thus, in step 1, an acid may be condensed with an amino compound represented by the general formula to produce a β -hydroxyamide. The condensation reaction may be carried out at ambient temperature using a suitable coupling agent (e.g. benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate)1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 1, 3-Dicyclohexylcarbodiimide (DCC), etc.), optionally with a suitable catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), O- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium Hexafluorophosphate (HATU), etc.) and a non-nucleophilic base (e.g., triethylamine, N-methylmorpholine, etc., or any suitable combination thereof), for 2 to 10 hours. The β -hydroxyamide can then be oxidized in step 2 to yield the compound of formula (Ic). The oxidation reaction is conveniently carried out using DMP (Dess-Martin periodinane) in an inert solvent such as methylene chloride at a temperature of from about 0 deg.C to about room temperature.
Alternatively, the compounds of the invention can also be prepared according to reaction scheme 2:
reaction scheme 2
Wherein X1、R1、R3、R4、R5And R6Each as defined in the summary of the invention, PG is a suitable protecting group. Thus, in step 1, the acid may condense with an amino compound of the formula to produce a β -hydroxyamide. Removal of the protecting group (step 2) and subsequent introduction of R1Radical (step 3) and oxidation (step 4) to yield the compound of formula (Ic).
Example (b):
the following examples illustrate the preparation of compounds of formula (I) (examples) and intermediates (reference examples) according to the invention, which further illustrate the invention but do not limit it.
1H nuclear magnetic resonance spectra (NMR) were recorded on a Varian Mercury-300 or Unity-400 or Unityplus-500 or Inova-500 instrument. Chemical shifts (δ) relative to tetramethylsilane are expressed in ppm in nuclear magnetic resonance spectroscopy (NMR). Abbreviations have the following meanings: s is singlet; d is bimodal; t is a triplet; m is multiplet; q is quartet; dd double peak; ddd is bimodal.
High Pressure Liquid Chromatography (HPLC) was performed on a Kromasil 10 micron, 100A silica gel, 4.6mm ID x250mm column using a heptane/THF/1, 2-dichloroethane mixture as the mobile phase.
Mass spectrometry was performed on an Agilent 1100 series or MICROMASS LCT-TOF MS instrument.
R of Thin Layer Chromatography (TLC)FValues were determined using Merck silica gel plates.
Acronyms
CBZ-benzyloxycarbonyl
DAST- (diethylamino) sulfur trifluoride
DCM-dichloromethane
DMF-dimethylformamide
DMSO-dimethyl sulfoxide
DTT-dithiothreitol
EDCI-N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride
EDTA-EDTA
EtOAc-ethyl acetate
HOBT-1-hydroxybenzotriazole hydrate
MeOH-methanol
MES-2-morpholineethanesulfonic acid
PyBOP- (benzotriazol-1-yloxy) trispyrrolidinylphosphonium hexafluorophosphate
THF-tetrahydrofuran
Reference example 1
(S) -2-benzyloxycarbonylamino-4-oxo-5-phenylpentanoic acid methyl ester:
in N2To a suspension of copper (I) bromide (4.26mmol, 611.1mg) in 3mL dry THF under an atmosphere was added a solution of lithium bromide (8.52mmol, 740mg) in 5mL dry THF. The mixture was stirred at room temperature for 20min and then cooled to-78 ℃. Benzyl magnesium chloride solution (20 wt.% in THF, 4.26mmol, 3.25mL) and methyl (S) -2-benzyloxycarbonylamino-3-chlorocarbonyl propionate were added sequentially [ reference: comm 1993, 23(18), 2511-](3.59mmol) in 7mL dry THF. Mixing the mixture withStirring at-78 deg.C for 30min, and adding saturated NH4The reaction was stopped with Cl (50 mL). The mixture was extracted twice with ethyl acetate (30 mL). The organic layer was dried over magnesium sulfate and then concentrated in vacuo. The residue was purified on 35g silica eluting with EtOAc: heptane (1:1) to afford (S) -2-Benzyloxycarbonyl-amino-4-oxo-5-phenylpentanoic acid methyl ester(1.07g，84％)。
1H NMR(CDCl3)：δ 7.4-7.17(m，10H)，5.73(d，J＝8.2Hz，1H)，5.11(s，2H)，4.57(m，1H)，3.7(2xs，5H)，3.24(dd，J＝18.5，4.4Hz，1H)，3.0(dd，J＝18.2，4.1Hz，1H)；LC/MS：100％ 378(M+Na)。
Reference example 2
(S) -2-Benzyloxycarbonylamino-4-oxoheptanoic acid methyl ester
(S) -Acrosso-benzene was obtained in a similar manner to the above-mentioned reference example 1, but using propylmagnesium chloride instead of benzylmagnesium chloride2-Benzyloxycarbonylamino-4-oxoheptanoic acid methyl ester。
1H NMR(CDCl3)：δ 7.35(m，5H)，5.78(d，J＝8.5Hz，1H)，5.13(s，2H)，4.58(m，1H)，3.75(s，3H)，3.2(dd，J＝18.3，4.2Hz，1H)，2.96(dd，J＝18.3，4.1Hz，1H)，2.4(m，2H)，1.6(m，2H)，0.92(t，J＝7.4Hz，3H)；LC/MS：330(M+Na)。
Reference example 3
(S) -2-benzyloxycarbonylamino-4, 4-difluoro-5-phenylpentanoic acid methyl ester:
a mixture of methyl 2-benzyloxycarbonylamino-4-oxo-5-phenylpentanoate (3.310g, 9.31mmol) and DAST (7mL) was stirred at room temperature for 3 days. The mixture was diluted with dichloromethane (100mL) and 0.5N NaOH solution (150mL) was added carefully. The aqueous layer was extracted with dichloromethane (50 mL). The organic layer was dried over magnesium sulfate and then concentrated in vacuo. The residue was purified on 110g silica eluting with EtOAc: heptane (1:4 then 1:3) to afford(S) -2-benzyloxycarbonylamino-4, 4-difluoro-5-benzene Valproic acid methyl ester(1.797g，51.1％)。
1H NMR(CDCl3)δ 7.3(m，10H)，5.43(d，J＝7.6Hz，1H)，5.14(s，2H)，4.65(m，1H)，3.74(s，3H)，3.2(t，J＝16.5Hz，2H)，2.4(m，2H)；LC/MS：97％ 400(M+Na)。
Reference example 4
(S) -2-amino-4, 4-difluoro-5-phenylpentanoic acid methyl ester hydrochloride:
a solution of (S) -2-benzyloxycarbonylamino-4, 4-difluoro-5-phenylpentanoic acid methyl ester (7.806g, 20.68mmol) in 120mL methanol and 4M HCl in dioxane (41.4mmol, 10.3mL) was hydrogenated over 10% Pd/C (1.0g) at 50psi pressure. After 8 hours, an additional portion of 10% Pd/C (1.0g) was added. After 24 hours, the catalyst was removed by filtration through a celite filter, and the filtrate was concentrated in vacuo. The resulting pale yellow solid was dissolved in a minimum amount of methanol and slowly added to diethyl ether (150 mL). The resulting slurry was allowed to age for 30min and then filtered. Suction drying the white solid to obtain(S) -2-amino-4, 4-difluoro-5-phenylpentanoic acid methyl ester hydrochloride(4.950g，85.5％)。
1H NMR(DMSO-D6)：δ 8.6(b，3H)，7.3(m，5H)，4.26(t，J＝6Hz，1H)，3.73(s，3H)，3.3(t，J＝17.5Hz，2H)，2.55(m，2H)；LC/MS：100％ 244(M+1)。
Reference example 5
(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-methyl 5-phenylpentanoate:
in N2Morpholine carbonyl chloride (13.4mmol, 2.0g) was added dropwise to a mixture of (S) -methyl 2-amino-4, 4-difluoro-5-phenylpentanoate hydrochloride (2.50g, 8.94mmol) and diisopropylamine (22.3mmol, 2.89g) in dry dichloromethane (40mL) under an atmosphere. The mixture was stirred at room temperature for 15 hours, then diluted with water (50 mL). The aqueous layer was extracted with dichloromethane (30 mL). The organic layer was dried over magnesium sulfate and then concentrated in vacuo. Purification on 110g silica eluting with EtOAc in heptane (1:1 then 2:1) afforded(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-Phenylpentanoic acid methyl ester(2.82g，88.5％).。1H NMR(CDCl3)：δ 7.3(m，5H)，5.16(d，J＝7.5Hz，1H)，4.75(dd，J＝13，6Hz，1H)，3.73(s，3H)，3.7(m，4H)，3.4(m，4H)，3.2(t，J＝16.7Hz，2H)，2.4(m，2H).LC/MS：100％ 357(M+1)。
Reference example 6
(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid:
to (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]Methyl (2.81g, 7.88mmol) 5-phenylpentanoate in MeOH H2A solution in O (2:1vol, 40mL) was added LiOH monohydrate (662mg, 15.76 mmol). The mixture was stirred at room temperature for 2.5h and then diluted with waterRelease (30 mL). The methanol was removed in vacuo. The pH was adjusted to pH1 with 6N HCl and the aqueous layer was extracted with dichloromethane (2 × 30 mL). Drying the organic layer with magnesium sulfate and concentrating in vacuo to give(S) -4, 4-difluoro-2- [ (morpholine) Quinoline-4-carbonyl) -amino]-5-phenylpentanoic acid(2.509g，93％)。
1H NMR(CDCl3)：δ 8.2(b，1H)，7.3(m，5H)，5.3(m，1H)，4.6(m，1H)，3.65(m，4H)，3.4(m，4H)，3.2(t，J＝16.5Hz，2H)，2.4(m，2H)；LC/MS：94％ 343(MH+)。
Reference example 7
(S) -5-benzyloxycarbonylamino-2-isopropyl-3-oxo-adipic acid 1-tert-butyl ester 6-methyl ester:
in N2To a solution of diisopropylamine (3.53g, 34.88mmol) in dry THF (20mL) cooled to-78 deg.C under an atmosphere was added dropwise a solution of n-butyllithium (2.5M in hexane, 34.88mmol, 13.95 mL). The mixture was stirred at-78 ℃ for 30min, then a solution of 3-methyl-tert-butyl butyrate (34.88mmol, 5.52g) in THF (40mL) was added. The mixture was stirred at-78 ℃ for 30min, then a solution of (S) -2-benzyloxycarbonylamino-3-chlorocarbonyl-propionic acid methyl (cf.: Synth. Comm 1993, 23(18), 2511-propan-6) (16.6mmol) in 30mL of dry THF was added dropwise. After stirring at-78 ℃ for a further 2 hours, the reaction was quenched with 50mL of 1N HCl and warmed to room temperature. The pH was adjusted to pH3 with 1N NaOH and THF was removed in vacuo. The organic layer was extracted with EtOAc (2 × 60 mL). The organic layer was dried over magnesium sulfate and then concentrated in vacuo. The residue was purified on 90g silica eluting with EtOAc: heptane (1:3 then 1:2) to afford(S) -5-benzyloxycarbonylamino-2- Isopropyl-3-oxoadipic acid 1-tert-butyl 6-methyl ester(2.417g，34.5％)。
1H NMR(CDCl3)：δ 7.4(m，5H)，5.73(d，J＝8.4Hz，1H)，5.12(s，2H)，4.6(m，1H)，3.74(s，3H)，3.39-3.06(m，3H)，2.4(m，1H)，1.45(2s，9H)，0.98(d，J＝6.6Hz，3H)，0.88(d，J＝6.7Hz，3H)；LC/MS：100％ 422(M+1)。
Reference example 8
(S) -2-benzyloxycarbonylamino-4-oxo-adipic acid 6-tert-butyl ester 1-methyl ester:
to a solution of N-CBZ L-aspartic acid 1-methyl ester (1.00g, 3.55mmol) in dry tetrahydrofuran (17mL) was added carbonyldiimidazole (634.1mg, 3.91 mmol). The mixture was stirred at room temperature for 6 hours, then magnesium salt of mono-tert-butyl malonate (1.339g, 3.91mmol) (prepared according to Angew.chem.int.Ed.Engl.1979, 18(1), 72-74) was added. The mixture was stirred at room temperature for an additional 20h, then concentrated in vacuo. The residue was partitioned between ether (60mL) and 0.5N HCl (60 mL). With saturated NaHCO3The organic layer was washed with a solution (50mL), then dried over magnesium sulfate and concentrated in vacuo. The residue was purified on 35g silica eluting with EtOAc: heptane (1:1) to afford(S)-2- Benzyloxycarbonylamino-4-oxo-adipic acid 6-tert-butyl ester 1-methyl ester(1.17g，87％)。
1H NMR(CDCl3)：δ 7.4(m，5H)，5.73(d，J＝8.3Hz，1H)，5.1(s，2H)，4.6(m，1H)，3.75(s，3H)，3.37(s，2H)，3.32(dd，J＝18.7，4.3Hz，1H)，3.13(dd，J＝18.5，4.1Hz，1H)，1.47(s，9H)；LC/MS：93％ 402(M+Na)。
Reference example 9
(S) -2-benzyloxycarbonylamino-6-methyl-4-oxo-heptanoic acid methyl ester:
in N2A solution of 5-benzyloxycarbonylamino-2-isopropyl-3-oxo-adipic acid 1-tert-butyl ester 6-methyl ester (1.06g, 2.51mmol) and p-toluenesulfonic acid monohydrate (35.8mg, 0.19mmol) in toluene (20mL) was heated under reflux for 6.5 hours under an atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified on 35g silica eluting with EtOAc: heptane (1:4) to afford(S)-2- Benzyloxycarbonylamino-6-methyl-4-oxo-heptanoic acid methyl ester(727mg，90％)。1H NMR(CDCl3)：δ 7.4(m，5H)，5.78(d，J＝9.1Hz，1H)，5.13(s，2H)，4.6(m，1H)，3.74(s，3H)，3.2(dd，J＝18.3，4.4Hz，1H)，2.95(dd，J＝18.2，4.0Hz，1H)，2.3(m，2H)，2.1(m，1H)，0.92(d，J＝6.7Hz，6H)；LC/MS：77％ 322(MH+)。
Reference example 10
(S) -2-benzyloxycarbonylamino-4-oxo-pentanoic acid methyl ester:
prepared in a similar manner to reference example 9 above, but using 2-benzyloxycarbonylamino-4-oxoadipic acid 6-tert-butyl ester 1-methyl ester(S) -2-Benzyloxycarbonylamino-4-oxo-pentanoic acid methyl ester。1H NMR(CDCl3)：δ 7.4(m，5H)，5.76(d，J＝8.1Hz，1H)，5.14(s，2H)，4.57(m，1H)，3.75(s，3H)，3.23(dd，J＝18.4，4.3Hz，1H)，3.0(dd，J＝18.4，4.3Hz，1H)，2.18(s，3H)；LC/MS：>85％ 280(MH+)。
Substitution method
In N2Cooling copper iodide (I) to 0 ℃ in an atmosphereA suspension in ether (20mL) was slowly added methyllithium (1.6M in ether, 21.3mmol, 13.3 mL). The mixture was stirred at 0 ℃ for 10min and then cooled to-78 ℃. A solution of 3.55mmol of (S) -2-benzyloxycarbonylamino-3-chlorocarbonyl-propionic acid methyl ester (cf. Synth. Comm 1993, 23(18), 2511-2526) in 12mL of dry THF was added dropwise. The mixture was stirred at-78 ℃ for 30min, and then methanol (2mL) was added to terminate the reaction. The mixture was poured into saturated NH4Cl (80mL) and extracted with diethyl ether (2X 40 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on 35g silica eluting with EtOAc: heptane (1:1) to afford(S) -2-Benzyloxycarbonylamino-4-oxo-pentanoic acid methyl ester(261mg，26％)。
Reference example 11
(S) -2-benzyloxycarbonylamino-4, 4-difluoro-6-methylheptanoic acid methyl ester:
a mixture of (S) -2-benzyloxycarbonylamino-6-methyl-4-oxo-heptanoic acid methyl ester (915mg, 2.85mmol) and DAST (3mL, XS) was stirred at-35 ℃ for 47 h. The mixture was diluted with dichloromethane (50mL) and saturated NaHCO was added carefully3Solution (150 mL). The aqueous layer was extracted with dichloromethane (30 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on 35g silica eluting with EtOAc: heptane (1:4) to afford (S) -2-benzyloxycarbonylamino-4, 4-difluoro-6-methyl Heptanoic acid methyl ester(156mg，16％)。
1H NMR(CDCl3)：δ 7.4(m，5H)，5.48(d，J＝7.9Hz，1H)，5.15(s，2H)，4.61(q，J＝5.9Hz，1H)，3.78(s，3H)，2.4(m，2H)，1.95(m，1H)，1.8(m，2H)，0.98(d，J＝6.6Hz，6H)；LC/MS：98％ 366(M+Na)。
Reference example 12
(S) -2-benzyloxycarbonylamino-4, 4-difluoro-pentanoic acid methyl ester
Prepared in a similar manner to reference example 11 above, but using methyl (S) -2-benzyloxycarbonylamino-4-oxopentanoate(S) -2-benzyloxycarbonylamino-4, 4-difluoro-pentanoic acid methyl ester。
1H NMR(CDCl3)：δ 7.4(m，5H)，5.46(d，J＝7.1Hz，1H)，5.15(s，2H)，4.61(q，J＝7.3Hz，1H)，3.78(s，3H)，2.45(m，2H)，1.67(t，J＝18.8Hz，3H)；LC/MS：94％ 324(M+Na)。
Reference example 13
(S) -2-Benzyloxycarbonylamino-4, 4-difluoroheptanoic acid methyl ester
By carrying out the reaction in a similar manner to the above-mentioned reference example 11 but using methyl (S) -2-benzyloxycarbonylamino-4-oxoheptanoate, there is obtained (S) -propionic acid2-Benzyloxycarbonylamino-4, 4-difluoroheptanoic acid methyl ester。
LC/MS：96％ 330(MH+)，352(M+Na)。
Reference example 14
(S) -2-amino-4, 4-difluoro-6-methylheptanoic acid methyl ester hydrochloride：
A solution of (S) -2-benzyloxycarbonylamino-4, 4-difluoro-6-methylheptanoic acid methyl ester (333mg, 0.97mmol) in methanol (10mL) and 4M HCl in dioxane (4mmol, 1mL) was hydrogenated over 10% Pd/C (150mg) at 55psi pressure. After 7 hours, a further portion of 10% Pd/C (200mg) was added and the hydrogenation was resumed. After 5.5 hours, the reaction did not progress. The catalyst was filtered off and the filtrate was concentrated in vacuo and hydrogenation conditions were applied. After 6.5 hours, the catalyst was removed by filtration through a celite filter and the filtrate was concentrated in vacuo to give(S) -2-amino-4, 4-difluoro-6-methylheptanoic acid methyl ester hydrochlorideSalt as a yellow viscous solid (240mg, quantitative).
1H NMR(CDCl3)：δ 4.8(b，3H)，4.35(b，1H)，3.84(s，3H)，2.6(m，2H)，1.9(m，3H)，0.99(d，J＝6.2Hz，6H)；LC/MS：90％ 210(M+1)。
Reference example 15
(S) -2-oxo-4, 4-difluoro-pentanoic acid methyl ester hydrochloride salt:
prepared in a similar manner to reference example 14 above, but using (S) -2-benzyloxycarbonylamino-4, 4-difluoro-pentanoic acid methyl ester(S) -2-amino-4, 4-difluoro-pentanoic acid methyl ester hydrochloride。
1H NMR(CDCl3)：δ 4.8(s，3H)，4.37(m，1H)，3.86(s，3H)，2.4-2.8(m，2H)，1.73(t，J＝18.9Hz，3H)；LC/MS：100％ 168(M+1)。
Reference example 16
(S) -2-amino-4, 4-difluoroheptanoic acid methyl ester hydrochloride
Prepared in a similar manner to reference example 14 above, but using methyl (S) -2-benzyloxycarbonylamino-4, 4-difluoroheptanoate(S) -2-amino-4, 4-difluoroheptanoic acid methyl ester hydrochloride。
LC/MS：100％ 196(MH+)。
Reference example 17
(S) -4, 4-difluoro-6-methyl-2- [ (morpholine-4-carbonyl) -amino]-methyl heptanoate:
in N2Morpholine carbonyl chloride (1.45mmol, 218mg) was added dropwise to a mixture of (S) -methyl 2-amino-4, 4-difluoro-6-methylheptanoate hydrochloride (238mg, 0.97mmol) and diisopropylamine (2.42mmol, 313mg) in dry dichloromethane (5mL) under an atmosphere. The mixture was stirred at room temperature for 23h, then diluted with dichloromethane (25mL) and diluted HCl (30mL) and saturated NaHCO3(30mL) washed. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification on 12g silica eluting with EtOAc in heptane (1:1 then 2:1) afforded(S) -4, 4-difluoro-6-methyl-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid Methyl ester(206mg，66％)。
1H NMR(CDCl3)：δ 5.2(d，J＝7.4Hz，1H)，4.72(dd，J＝13，6Hz，1H)，3.78(s，3H)，3.7(m，4H)，3.4(m，4H)，2.4(m，2H)，1.95(m，1H)，1.8(m，2H)，0.99(d，J＝6.4Hz，6H)；LC/MS：90％ 345(M+Na)。
Reference example 18
(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-pentanoic acid methyl ester：
(S) -Acutanoate was obtained in a similar manner to the above-mentioned reference example 17 but using (S) -2-amino-4, 4-difluoro-pentanoic acid methyl ester hydrochloride4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-pentanoic acid methyl ester。1H NMR(CDCl3)：δ 5.18(d，J＝7.5Hz，1H)，4.71(q，J＝7Hz，1H)，3.78(s，3H)，3.71(m，4H)，3.4(m，4H)，2.37-2.55(m，2H)，1.67(t，J＝18.7Hz，3H)；LC/MS：100％ 303(M+Na)。
Reference example 19
(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid methyl ester：
In a similar manner to reference example 17 above, but using(S) -2-amino-4, 4-difluoroheptanoic acid Methyl ester hydrochlorideIs ready to prepare(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid methyl ester。LC/MS：100％ 309(MH+)。
Reference example 20
(S) -4, 4-difluoro-6-methyl-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid：
To methyl ester (205mg, 0.63mmol) in MeOH H2A solution in O (2:1vol, 4mL) was added LiOH monohydrate (80mg, 1.9 mmol). The mixture was stirred at room temperature for 21h, then diluted with water (15mL) and extracted with ether (20 mL). The aqueous layer was washed with 1N HClWas adjusted to pH1 and extracted with dichloromethane (2 × 20 mL). Drying the organic layer with magnesium sulfate and concentrating in vacuo to give(S) -4, 4-difluoro-6-methyl-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid(168mg，86％)。
1H NMR(CDCl3)：δ 6.4(b，1H)，5.3(d，J＝6.2Hz，1H)，4.6(m，1H)，3.7(m，4H)，3.4(m，4H)，2.5(m，2H)，2.0(m，1H)，1.8(m，2H)，1.0(d，J＝6.6Hz，6H)；LC/MS：90％ 309(M+1)。
Reference example 21
(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-valeric acid：
Was conducted in a similar manner to the above-mentioned reference example 20 except that (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino group was used]Methyl valerate, i.e. to(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-valeric acid。1H NMR(CDCl3)：δ 5.9(b，1H)，5.29(d，J＝6.3Hz，1H)，4.6(m，1H)，3.71(m，4H)，3.4(m，4H)，2.38-2.65(m，2H)，1.70(t，J＝18.9Hz，3H)；LC/MS：100％267(M+1)。
Reference example 22
(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid
In a similar manner to reference example 20 above, but using(S) -4, 4-difluoro-2- [ (morpholine-4- Carbonyl) -oxy]-heptanoic acid methyl esterIs ready to prepare(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid。
1H NMR(CDCl3)：δ 5.3(b，1H)，5.25(d，J＝5.4Hz，1H)，4.6(m，1H)，3.71(m，4H)，3.4(m，4H)，2.6-2.3(m，2H)，1.9(m，2H)，1.55(m，2H)，1.0(t，J＝7.3Hz，3H)；LC/MS：83％ 295(M+1)。
Reference example 23
5-thiophen-2-yloxazoles
In N2To a solution of p-toluenesulfonylmethylcyanide (3.0g, 15.36mmol) and thiophene-2-carbaldehyde (1.72g, 15.36mmol) in methanol (45mL) was added potassium carbonate (2.12g, 15.36mmol) under atmosphere. The mixture was heated at reflux for 5 hours, then cooled and concentrated in vacuo (cold water bath). The residue was partitioned between ether (100mL) and water (100 mL). The organic layer was washed with water (100mL), dried over magnesium sulfate, and then concentrated in vacuo. The residue was purified on 35g silica gel eluting with ethyl acetate heptane (1:5) to give5-thiophen-2-yloxazoles(0.852g，37％)。
1H NMR(CDCl3)：δ 7.9(s，1H)，7.3(m，2H)，7.2(s，1H)，7.1(dd，J＝5，3.8Hz，1H)；LC/MS：100％ 152(M+1)。
Reference example 24
{ (S) -1- [ hydroxy- (5-thiophen-2-yloxazol-2-yl) -methyl]-propyl } -carbamic acid tert-butyl ester
To a solution of 5-thiophen-2-yloxazole (0.85g, 5.62mmol) in dry THF (4mL) was addedTriethylborane (1.0M in THF, 5.62mmol, 5.62 mL). The mixture was stirred at room temperature for 45min, then cooled to-78 ℃ and n-butyllithium (1.6M in hexane, 5.62mmol, 3.51mL) was added dropwise. The mixture was stirred at-78 ℃ for 45min, then a solution of (1-formylpropyl) -carbamic acid tert-butyl ester (2.81mmol, 0.526g) in dry THF (3mL) was added slowly. The mixture was stirred at-78 ℃ for 4h, then warmed to 0 ℃ and quenched by the addition of 30mL of 10% (vol) HOAc in ethanol. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo. The residue was purified on 90g silica eluting with ethyl acetate heptane (1:2 then 1:1) to give{ (S) -1- [ hydroxy- (5-thiophen-2-yloxazol-2-yl) -methyl]-propyl } -carbamic acid tert-butyl ester(363mg, 38%) as a yellow oil.
1H NMR(CDCl3): δ (isomer mixture) 7.35(m, 2H), 7.1(m, 2H), 4.9(m, 2H), 4.0(b, 1H), 3.6(m, 1H), 1.8-1.55(m, 2H), 1.4 and 1.3(2s, 9H), 1.0 and 0.9(2t, J ═ 7.4Hz, 3H): LC/MS: 100339 (M +1).
Reference example 25
(S) -2-amino-1- (5-thiophen-2-yloxazol-2-yl) -but-1-ol hydrochloride
To { (S) -1- [ hydroxy- (5-thiophen-2-yloxazol-2-yl) -methyl]A solution of-propyl } -carbamic acid tert-butyl ester (361mg, 1.07mmol) in dry dichloromethane (3mL) was added 4N HCl in dioxane (3.0mL, XS). The mixture was stirred at room temperature for 16h and then concentrated in vacuo to give(S) -2-amino-1- (5-thiophen-2-yloxazol-2-yl) -but-1-ol hydrochlorideAs a brown solid (quantitative).1H NMR(CDCl3)：δ 7.5(dd，J＝5.2，1.2Hz，1H)，7.4(dd，J＝3.6，1.1Hz，1H)，7.3(s，1H)，7.1(dd，J＝5，3.6Hz，1H)，4.8(m，3H)，3.6(m，2H)，3.3(b，1H)，1.75(m，2H)，1.0(t，J＝7.5Hz，3H)；LC/MS：100％ 239(M+1)。
Reference example 26
(1-Ethyl-2-hydroxy-3-nitropropyl) -carbamic acid tert-butyl ester
To a solution of (1-formylpropyl) -carbamic acid tert-butyl ester (1.0g, 5.34mmol) in dry THF (10mL) and ethanol was added nitromethane (3.91g, 64.09mmol) followed by triethylamine (2.70g, 26.7 mmol). The mixture was stirred at room temperature for 22h, then concentrated in vacuo. The residue was diluted with ether (50mL) and concentrated NH4Cl (60 mL). The ether layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on 35g silica eluting with ethyl acetate heptane (1:3) to give the desired alcohol (1.09g, 82%) as a pale yellow oily solid.
1H NMR(CDCl3): δ 4.2-4.8(m, 4H), 3.15-3.8(m, 2H), 1.69-1.6(m, 2H), 1.47(2xs, 9H), 1.02 and 1.0(2xt, J ═ 7.1Hz, 3H); LC/MS: 2 isomers, amounting to 100% 149(M-BOC +1).
Reference example 27
(1-Ethyl-3-nitro-2-trimethylsiloxypropyl) -carbamic acid tert-butyl ester
In N2To a mixture of (1-ethyl-2-hydroxy-3-nitropropyl) -carbamic acid tert-butyl ester (1.83g, 7.37mmol) and triethylamine (1.49g, 14.75mmol) in dry dichloromethane (25mL) was added trimethylsilyl chloride (1.20g, 11.05mmol) under atmosphere.The mixture was stirred at room temperature for 24h, then diluted with 40mL of dichloromethane and washed with water (40 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on 110g silica gel eluting with ethyl acetate heptane (1:4) to give(1-Ethyl-3-nitro-2-trimethylsiloxypropyl) -carbamic acid tert-butyl ester(1.505g, 86%) as colorless oil.
1H NMR(CDCl3): δ 4.4-4.65(m, 4H); 3.55(m, 1H), 1.2-1.7(m, 11H), 0.98(2xt, J ═ 7.4Hz, 3H), 0.13(2s, 9H); LC/MS: 2 isomers, totaling 100% 221(M-BOC +1).
Reference example 28
{1- [ (5-isopropylisoxazol-3-yl) -trimethylsiloxymethyl group]-propyl } -carbamic acid tert-butyl ester
In N2To a solution of (1-ethyl-3-nitro-2-trimethylsilyloxypropyl) -carbamic acid tert-butyl ester (918mg, 2.86mmol), 1, 4-phenylene diisocyanate (1.38g, 8.5mmol) and 3-methyl-1-butyne (586mg, 8.5mmol) in dry toluene (15mL) was added triethylamine (10 drops) under atmosphere. The mixture was heated to 50 ℃ in a sealed vial for 28h, then cooled to room temperature, water (1mL) was added and the mixture was stirred for an additional 2h, then filtered. The filtrate was concentrated in vacuo and the residue was purified on 35g silica eluting with ethyl acetate heptane (1:5) to give{1- [ (5-isopropylisoxazole) -3-yl) -trimethylsiloxymethyl group]-propyl } -carbamic acid tert-butyl ester(764mg, 72%) as colorless oil.
1H NMR(CDCl3): δ 6.0(2s1H), 4.4-4.9(m, 2H), 3.7(m, 1H), 3.0(m, 1H), 1.2-1.6(m, 17H), 1.0(m, 3H), 0.11 and 0.1(2xs, 9H); LC/MS: 2 isomer, 67% total 271(M-BOC +1).
Reference example 29
2-amino-1- (5-isopropylisoxazol-3-yl) -but-1-ol hydrochloride
In N2In the atmosphere to {1- [ (5-isopropylisoxazol-3-yl) -trimethylsiloxymethyl group]A solution of-propyl } -carbamic acid tert-butyl ester in dry dichloromethane (5mL) was added 4M HCl in dioxane (5.0mL, XS). The mixture was stirred at room temperature for 22h, then concentrated in vacuo to afford the amine salt (475mg, 99%) as a brown solid.
1H NMR(CDCl3)：δ 6.25(2xs，1H)，5.0(d，J＝3.9Hz，1H)，4.8(d，J＝6.8Hz，1H)，3.4(m，1H)，3.1(m，1H)，1.5-1.7(m，2H)，1.3(d，J＝6.8Hz，6H)；1.0(t，J＝6.7Hz，3H)；LC/MS：100％ 199(M+1)。
Reference example 30
5-methyl-3-oxazol-5-ylisoxazole
Diisobutylaluminum hydride (1.0M DCM solution, 25.5ml, 25.5mmol) was added dropwise with stirring at-78 ℃ to a solution of methyl 5-methylisoxazole-3-carboxylate (3.0gm, 21.3mmol) in 35ml dry dichloromethane over 20min and the reaction mixture was stirred at-78 ℃ for 5.5 h. The reaction was allowed to warm to-40 ℃ and quenched with ice (60 gm). After the biphasic mixture had warmed to room temperature, potassium sodium tartrate tetrahydrate (100ml of saturated aqueous solution) was added. The layers were separated and the aqueous layer was extracted with dichloromethane. Drying the organic extract over sodium sulfate and reducing the pressureConcentrating to obtain5-first The 3-formaldehyde of the base isoxazole is,as a white solid (1.3 gm).
Para-toluenesulfonylmethylcyanamide (1.75gm, 8.97mmol) and potassium carbonate (1.24gm, 8.97mmol) were added to a solution of 5-methylisoxazole-3-carbaldehyde (1.0gm, 8.97mmol) in 35ml dry methanol and the reaction mixture was refluxed (90 ℃ C.) for 5 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ether (100ml) and water (200 ml). The organic layer was separated and the aqueous layer was extracted with ether. The organic extracts were washed with brine and water, dried over sodium sulfate and concentrated under reduced pressure to give the title compound as a yellowish solid (1.25 gm). LC/MS: 87%, 238(M +1).
Reference example 31
((S) -1- { hydroxy- [5- (5-methylisoxazol-3-yl) -oxazol-2-yl]-methyl } -propyl) -carbamic acid tert-butyl ester Esters
Triethylborane (1M in THF, 12ml, 12mmol) was added to a solution of 5-methyl-3-oxazol-5-ylisoxazole (1.8gm, 12mmol) in 40ml dry tetrahydrofuran and the mixture was stirred at room temperature for 15 min. The mixture was cooled to-78 deg.C, n-butyllithium (2.5M in hexane, 4.8ml, 12mmol) was added dropwise, and the mixture was stirred at-78 deg.C for 15 min. A solution of (S) -1-formylpropyl) -carbamic acid tert-butyl ester (898.7mg, 4.8mmol) in 15ml of dry tetrahydrofuran was added dropwise and the reaction mixture was stirred at-78 ℃ for 3h, then allowed to warm to-30 ℃ and quenched with an ethanolic solution of acetic acid (4%, 250ml) and stirred for an additional 2h while warming to room temperature. The reaction was concentrated under reduced pressure; the residue was dissolved in diethyl ether (250ml) and stirred at room temperature for 1.5 hours. Filtering out the precipitate; the filtrate was concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of dichloromethane and ethyl acetate afforded the title compound as a pale yellow solid (830 mg). LC/MS 100%, 338(M +1).
Reference example 32
(S) -2-amino-1- [5- (5-methylisoxazol-3-yl) -oxazol-2-yl]-butan-1-ol; hydrochloride salt
Hydrogen chloride (4M 1, 4-dioxane solution, 3.3ml) was added dropwise to a solution of ((S) -1- { hydroxy- [5- (5-methylisoxazol-3-yl) -oxazol-2-yl ] -methyl } -propyl) -carbamic acid tert-butyl ester (0.75gm, 2.22mmol) in 10ml dichloromethane and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction was diluted with ether (50ml) and stirred at room temperature for a further 1 h. Concentration under reduced pressure afforded the title compound as a yellowish solid (0.75 gm).
1H NMR[(CD)3SO]：δ 8.18(m，3H)，7.84(s，1H)，6.70(s，1H)，4.90(m，1H)，3.58(m，2H)，2.50(s，3H)，1.60(m，2H)，0.90(t，3H)；LC/MS 100％，238(M+1)。
Reference example 33
(S) -2-amino-1- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -butan-1-ol
A solution of (S) -3-tert-butoxycarbonylamino-2-hydroxypentanoic acid (2.00g, 8.57mmol) and N-hydroxycyclopropylformamidine (1.03g, 10.29mmol) in dichloromethane (20mL) was stirred at 0 ℃ and 1.25 equivalents of N-cyclohexylcarbodiimide-N' -methyl polystyrene (1.70mmol/g, 6.30g, 10.72mmol) were added portionwise. The reaction mixture was stirred under nitrogen for 3 hours while warming to 15 ℃. The reaction mixture was filtered, the resin was washed with dichloromethane and the filtrate was evaporated to dryness in vacuo. [ LC/MS M/z ═ 338(M + H + Na) ].
The residue was dissolved in tetrahydrofuran (20mL) and heated in a microwave reactor (Smith Creator) at 160 ℃ for 3min, cooled to room temperature and evaporated to dryness in vacuo. [ LC/MS M/z 320(M + H + Na) ]. The residue was dissolved in dichloromethane (50mL) and stirred at room temperature while 50mL of a 50% trifluoroacetic acid in dichloromethane was added dropwise. After 3 hours, the reaction was evaporated to dryness in vacuo and redissolved in 50mL of dichloromethane. 3 equivalents of triamine-3 from the company Silicacle are added and the mixture is stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. Evaporation in vacuo gave 1.04g (61% total). [ LC/MS M/z 198(M + H) ]
Or, deprotecting the BOC protecting group with HCl in dioxane to obtain (S) -2-amino-1- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -butan-1-ol hydrochloride.
Reference example 34
(S) -2-amino-1- (3-phenyl-1, 2, 4-oxadiazol-5-yl) -butan-1-ol
A solution of (S) -3-tert-butoxycarbonylamino-2-hydroxypentanoic acid (2.00g, 8.57mmol) and N-hydroxybenzamidine (1.3g, 9.5mmol) in dichloromethane (40mL) was stirred at 0 ℃. N-cyclohexylcarbodiimide-N' -methylpolystyrene (1.90mmol/g, 6g, 11.4mmol) was added portionwise. The reaction mixture was stirred under nitrogen atmosphere for 1 hour. The reaction mixture was filtered, the resin was washed with dichloromethane and the filtrate was evaporated to dryness in vacuo. [ LC/MS M/z ═ 352(M + H)+)，296(M+H+-isobutene)]. The residue was dissolved in tetrahydrofuran (20mL) and heated in a microwave reactor (Smith Creator) at 180 ℃ for 3min, cooled to room temperature and evaporated to dryness in vacuo. Will be provided withThe residue was purified by flash chromatography (eluting with a gradient of 5% to 65% ethyl acetate/heptane) to give the product as a white solid [ LC/MS M/z 356(M + Na)+)，234(M+H+-Boc)]。
The product was dissolved in dichloromethane (45mL) and trifluoroacetic acid (5mL) was added. After 2 hours, the reaction was evaporated to dryness in vacuo. The residue was redissolved in 50mL of dichloromethane. Silicone triamine-3 (9.9g, 39mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. Concentrating the filtrate in vacuo to obtain(S) -2-amino-1- (3-phenyl) -1, 2, 4-oxadiazol-5-yl) -butan-1-ol(775mg, 38%) as a white solid.
1H NMR(CDCl3)：δ 8.12-8.06(m，2H)，7.54-7.45(m，3H)，4.93 & 4.75(2xd，J＝5Hz & 3.5Hz，1H)，3.25 & 3.11(2xm，1H)，1.78-1.42(2xm，2H)，1.04 &1.01(2x t，J＝7.5Hz，3H).[LC/MS m/z＝234(M+H)]。
Reference example 35
(S) -2-amino-1- (5-phenyl- [1, 2, 4)]Oxadiazol-3-yl) -butan-1-ols
Synthesized according to the following reaction scheme:
{ (S) -1- [ hydroxy- (N-hydroxycarbamimidoyl)) -methyl]-propyl } -amino Tert-butyl formate (2)
A solution of (2-cyano-1-ethyl-2-hydroxy-ethyl) -carbamic acid tert-butyl ester (9.53g, 44mmol) in methanol (80ml) was cooled to 0 ℃ and successively treated with a solution of hydroxylamine hydrochloride (3.05g, 44mmol) in methanol (80ml) and a solution of 25% sodium methoxide solution in methanol (10.2 ml). After stirring at 0 ℃ for 5min, the reaction mixture was stirred at room temperature for 5h and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate, and then evaporated under reduced pressure. The residual yellow oil was separated by medium pressure chromatography (MPLC) eluting with a mixture of ethyl acetate and heptane to give { (S) -1- [ hydroxy- (N-hydroxycarbamimidoyl) -methyl ] -propyl } -carbamic acid tert-butyl ester (3.5g) as a white solid. MS: MH + 248.
{1- [ hydroxy- (N-benzoyloxymethylimidoyl) -methyl]-propyl } -carbamic acid tert-butyl ester (3)
Reacting {1- [ hydroxy- (N-hydroxycarbamimidoyl) -methyl]A solution of tert-butyl-propyl } -carbamate (2) (2.5g, 10mmol) in dichloromethane (125mL) was treated with benzoic acid (1.36g, 11mmol), EDCI (2.14g, 11mmol), HOBT (1.37g, 10mmol) and triethylamine (1.35mL, 11mmol) successively and stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution and then with water, followed by Na2SO4Dried and evaporated under reduced pressure. The residue was chromatographed at medium pressure using 1% triethylamine in a 2: eluting the solution in the mixture of 3v/v ethyl acetate and heptane to obtain{1- [ hydroxy Radical- (N-benzoyloxy carbamimidoyl) -methyl]-propyl } -carbamic acid tert-butyl ester(850mg) as a yellow solid. MS: MH + 352.
2-amino-1- (5-phenyl- [1, 2, 4)]Oxadiazol-3-yl) -butan-1-ol (5)
A solution of compound (3) (1.5g, 4.3mmol) in diglyme was heated in a microwave reactor (Smith Creator, S00219) at 150 ℃ for 40 min. The solvent was evaporated in a Genevac evaporator at 80 ℃ under vacuum for 3 hours to give a brown solid. It was dissolved in dichloromethane (40ml) and treated with trifluoroacetic acid at room temperature for 2 hours.The solvent was evaporated to dryness under reduced pressure, the crude was dissolved in water, washed with DCM, the aqueous layer was basified with 1M NaOH solution and extracted with dichloromethane. With Na2SO4Drying the organic layer and evaporating under reduced pressure to obtain2-amino-1- (5-phenyl- [1, 2, 4)] Oxadiazol-3-yl) -butan-1-ols(300mg) as a light brown solid.
1H NMR(CDCl3)：δ 8.14-8.10(m，2H)，7.59-7.47(m，3H)，4.83 & 4.65(d，J＝5Hz，1H)，3.18-3.05(2m，1H)，1.71-1.20(m，2H)，1.05-0.97(2xt，J＝7.2Hz，3H)。
Reference example 36
(S) -2-acetoxy-3-tert-butoxycarbonylaminopentanoic acid
Pyridine (5ml), 4- (dimethylamino) pyridine (0.01g) and acetic anhydride (11mmol, 1.12g) were dissolved in dichloromethane (150ml), and the resulting solution was cooled to 0 ℃. (S) -3-tert-Butoxycarbonylamino-2-hydroxypentanoic acid (10mmol, 2.33g, A) was immediately added, and the resulting reaction mixture was stirred for 5 hours.
1M hydrochloric acid (250ml) was added and the mixture was transferred to a separatory funnel. The two phases were separated and the aqueous phase was extracted three times with ethyl acetate (200 ml). The combined organic phases were washed twice with water (200ml) and brine (100ml), respectively. Drying the organic phase with magnesium sulfate and evaporating the solvent under reduced pressure to obtain(S) -2-acetoxy-3-tert-butoxycarbonylaminopentanoic acid(2.535g，92％)。MS：m/z＝298(M+Na+)，276(M+H+)。
Reference example 37
Acetic acid (S) -2-tert-butoxycarbonylamino-1- [ N' - (4-trifluoromethoxybenzoyl) hydrazinocarbonyl]-D Esters
(S) -2-acetoxy-3-tert-butoxycarbonylaminopentanoic acid (1.82mmol, 0.5g, A) was dissolved in 30ml dichloromethane. N-cyclohexylcarbodiimide-N' -methyl polystyrene (3.64mmol, 1.92g, B) was added and the resulting reaction mixture was stirred for 2 min. 4- (trifluoromethoxy) benzoic acid hydrazide (1.65mmol, 0.363g, C) was added and the reaction mixture was stirred overnight. After 16 hours, LC/MS analysis still showed the presence of hydrazide. Polystyrene methyl isocyanate (1.65mmol, 1.15g) was added and stirring was continued for 8 hours. Filtering the reaction mixture under suction and concentrating the filtrate under reduced pressure to obtainSecond step (S) -2-tert-Butoxycarbonylamino-1- [ N' - (4-trifluoromethoxybenzoyl) hydrazinocarbonyl ] acid]-butyl esterAs a yellow foam (0.5g, 64%). LC/MS analysis still showed some hydrazide present. MS: 500(M + Na) ═ M/z+)，478(M+H+)。
Reference example 38
Acetic acid (S) -2-tert-butoxycarbonylamino-1- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl]- Butyl ester
The (S) -2-tert-butoxycarbonylamino-1- [ N' - (4-trifluoromethoxybenzoyl) -hydrazinocarbonyl ] -butyl acetate obtained above was divided into 5 parts, and reacted as follows:
acetic acid (S) -2-tert-butoxycarbonylamino-1- [ N' - (4-trifluoromethoxybenzoyl) -hydrazinocarbonyl ] -butyl ester (0.21mmol, 0.1g) was dissolved in THF (5ml) and the solution was injected into a Smith microwave synthesis reaction vessel. Polystyrene supported 2-tert-butylimino-2-diethylamino-1, 3-dimethyl-perhydro-1, 2, 3-diazaphosphorine (1.05mmol, 0.456g, 2.3mmol/g support) and p-toluenesulfonyl chloride (0.25mmol, 0.048g) were added and the reaction mixture was heated in a microwave synthesizer at 150 ℃ for 10min (fixed hold time).
The combined reaction mixture was filtered with suction and the resin was washed with 300ml of ethyl acetate. The combined filtrates were concentrated under reduced pressure.
The crude product was purified by flash chromatography (Biotage Horizon, 25M column, crude loaded into caplet, flow rate 17ml/min, 12 ml/part, 120ml gradient from 0% ethyl acetate in heptane to 30% ethyl acetate in heptane, 240ml 30% ethyl acetate in heptane, 60ml gradient from 30 → 50% ethyl acetate in heptane, 300ml 50% ethyl acetate in heptane) to affordAcetic acid (S) -2-tert-Butoxycarbonylamino-1- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl]-butyl ester(0.28g，58％)。MS：m/z＝460(M+H+)。
Reference example 39
((S) -1- { hydroxy- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl]-methyl } -propyl) -carbamic acid methyl ester Tert-butyl ester
Reacting (S) -2-tert-butoxycarbonylamino-1- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl acetate]Butyl ester (0.61mmol, 0.28g) was dissolved in a mixture of THF (10ml) and water (10 ml). Lithium hydroxide hydrate (1.22mmol, 0.051g) was added and the reaction mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the residue was transferred to a separatory funnel containing 300ml of ethyl acetate and 50ml of water. The phases were separated and the organic phase was washed with brine (100 ml). The organic phase is then dried over magnesium sulfate. Evaporating the solvent under reduced pressure and drying under high vacuum to obtain (A)(S) -1- { hydroxy- [5- (4-trifluoromethoxybenzene) 1, 3, 4-oxadiazol-2-yl radicals]-methyl } -propyl) -carbamic acid tert-butyl esterAs a yellow oil (0.225g, 89%). MS: 440(M + Na) M/z+)，418(M+H+)。
Reference example 40
(S) -2-amino-1- (5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl) -butan-1-ol
((S) -1- { hydroxy- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazole-2-yl)]-methyl } -propyl) -carbamic acid tert-butyl ester (0.54mmol, 0.225g) was dissolved in dichloromethane (9ml) and treated with trifluoroacetic acid (1 ml). The reaction mixture was stirred for 4 hours. The solvent was evaporated under reduced pressure. The residue was redissolved in dichloromethane (20ml) and silica triamine (5.4mmol, 1.47g) was added. The reaction mixture was stirred for 60h (over the weekend). Filtering the reaction mixture with suction and evaporating the solvent to obtain(S) -2-amino group -1- (5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl) -butan-1-ol(0.164g，96％)。MS：m/z＝318(M+H+)。
Reference example 41
2-cyclopropyl- [1, 3, 4]Oxadiazoles as fungicides
A mixture of methyl cyclopropanecarboxylate (10g, 0.1mol) and hydrazine hydrate (7.3mL, 0.15mol) was refluxed for 28 hours and cooled to room temperature. The mixture was evaporated under reduced pressure and then dried by removing the solvent azeotropically with toluene. The residue was dissolved in dichloromethane and washed with saturated NaCl. Over anhydrous MgSO4Drying the organic phase and evaporating the solvent under reduced pressureTo obtainCyclopropanecarboxylic acid hydrazide(4.36g，44％)。
A mixture of cyclopropanecarboxylic acid hydrazide (31.35g, 0.31mol), trimethyl orthoformate (300mL), and p-toluenesulfonic acid monohydrate (200mg) was heated under reflux overnight. Excess trimethyl orthoformate and methanol were removed by distillation. Vacuum distilling the residue to obtain2-cyclopropyl- [1, 3, 4]Oxadiazoles as fungicides(22g，64％)。1H NMR(CDCl3)：δ 8.24(s，1H)，2.2(m，1H)，1.15(m，4H)；LCMS：100％，111(MH+)。
Reference example 42
{1- [ (5-cyclopropyl- [1, 3, 4]]Oxadiazol-2-yl) -hydroxymethyl]-propyl } -carbamic acid tert-butyl ester
2-cyclopropyl- [1, 3, 4]A solution of oxadiazole (2.16g, 19.6mmol) in dry THF (100mL) was cooled to-78 ℃. N-butyllithium (1.6M in hexane, 12.3mL, 19.6mmol) was added dropwise, and the reaction mixture was stirred at-78 ℃ for 40 min. Adding MgBr2·OEt2(5.0692g, 19.6 mmol). The reaction mixture was allowed to warm to-45 ℃ and stirred at this temperature for 1.5 hours. A solution of (1-formylpropyl) -carbamic acid tert-butyl ester (3.7g, 19.6mmol) in dry THF (40mL) was added. The reaction mixture was allowed to warm to-20 ℃ and stirred at this temperature for 3.5 hours. With saturated NH4The reaction mixture was quenched with Cl solution and extracted with ethyl acetate. The combined organic extracts were washed with saturated NaCl solution and MgSO4And (5) drying. Evaporating the solvent under reduced pressure and purifying the crude product by column chromatography, eluting with a mixture of ethyl acetate and heptane to obtain{1- [ (5-cyclopropyl- [1, 3, 4]] Oxadiazol-2-yl) -hydroxymethyl]-propyl } -carbamic acid tert-butyl ester(2.83g，49％)。LCMS：298(MH+)。
Reference example 43
(S) -2-amino-1- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) -butan-1-ol; compounds with trifluoroacetic acid
Will {1- [ (5-cyclopropyl- [1, 3, 4]]Oxadiazol-2-yl) -hydroxymethyl]A mixture of-propyl } -carbamic acid tert-butyl ester (2.83g, 9.95mmol), trifluoroacetic acid (5mL) in dichloromethane (20mL) was stirred at room temperature for 2 hours and concentrated to dryness under reduced pressure to give(S) -2-amino-1- (5-cyclopropyl-1, 3, 4-oxa-bis Compound of azol-2-yl) -butan-1-ol and trifluoroacetic acid。LCMS：100％ 198(MH+)。
Reference example 44
(S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxa-4-carbonyl) -amino]-pentanoic acid methyl ester。
Triphosgene was dissolved in dichloromethane (10mL) and a mixture of S-2-amino-4, 4-difluoro-pentanoic acid hydrochloride (1.00g, 4.90mmol) (see reference example 15) and diisopropylethylamine (1.88mL, 10.80mmol) dissolved in dichloromethane was added to this solution over a period of 1h by means of a syringe pump. After stirring for a further 15min, a solution of homomorpholine hydrochloride (0.67g, 4.90mmol) and diisopropylethylamine (1.90mL, 10.90mmol) in dichloromethane (10mL) was added to the solution. The resulting solution was stirred at room temperature for 2 h. The solvent was evaporated and the residue was diluted with ethyl acetate (100mL) and then with 1M KHSO3(2X 10mL), saturated NaHCO3And a brine wash. With Na2SO4The organic phase was dried, filtered and concentrated to give a pale yellow oil. The crude material was purified over 20g of silica gel using ethyl acetateEthyl acetate heptane gradient elution was 50-100%. To obtain(S) -4, 4-difluoro-2- [ (perhydro-1, 4-Oxazan-4-carbonyl) -amino]-pentanoic acid methyl esterAs a white solid (0.40g, 28%).
1H NMR(CDCl3)δ 5.12(d，J＝7.5Hz，1H)，4.72(dd，J＝12.0，7.2Hz，1H)，3.75(m，7H)，3.55(m，4H)，2.45(m，2H)，1.98(m，2H)，1.66(t，J＝18.7Hz，3H)；LC/MS：295，100％，(M+H)，317(M+Na)。
Reference example 45
(S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxa-4-carbonyl) -amino]-valeric acid
Reacting (S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxaza)-4-carbonyl) -amino]Methyl valerate (0.38g, 1.29mmol) was dissolved in tetrahydrofuran/methanol (15mL/10mL) and aqueous lithium hydroxide (35mg, 1.40mmol) was added (5 mL). The reaction was stirred at room temperature for 18h, then methanol/tetrahydrofuran was removed in vacuo. The residue was acidified with 6M hydrochloric acid (0.25mL) and extracted with dichloromethane (3X 20mL) and Na2SO4Drying and concentrating to obtain(S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxaza-4-carbonyl) - Amino group]-valeric acidAs a white solid (0.36g, 99%).
1H NMR(DMSO-d6)δ 12.6(bs，1H)，6.60(d，8.3Hz，1H)，4.30(dd，J＝14.5，7.0Hz，1H)，3.57(m，4H)，3.43(m，4H)，2.38(m，2H)，1.77(m，2H)，1.61(t，J＝19.2Hz，3H)；LC/MS：100％ 281(M+H)。
Reference example 46
(S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxa-4-carbonyl) -amino]-heptanoic acid methyl ester
In a nitrogen atmosphere(S) -2-amino-4, 4-difluoroheptanoic acid methyl ester hydrochloride (5.79g, 0.025mol)To a mixture of sodium bicarbonate (5.25g) and p-nitrochloroformate (5.03g, 25mmol) in acetonitrile (130ml) was added and stirred at room temperature for 5 hours. Homomorpholine hydrochloride (3.61g, 26.25mmol) and triethylamine (12.5ml) were added and the reaction stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the crude was partitioned between water (150ml) and ethyl acetate (200 ml). Separating the organic layer, successively using K2CO3The solution (150ml), HCl (150ml) and brine (150ml) were washed. The organic layer was separated over MgSO4Dried and evaporated under reduced pressure. Purifying the crude product by column chromatography eluting with v/v 1:1 to 8:2 ethyl acetate in heptane followed by ethyl acetate to obtain(S) -4, 4-difluoro -2- [ (perhydro-1, 4-oxaza-4-carbonyl) -amino]-heptanoic acid methyl ester(4.8g) as a pale yellow oil. LC/MS: 323(M + H).
Reference example 47
(S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxa-4-carbonyl) -amino]-heptanoic acid
Was conducted in a similar manner to the above-mentioned reference example 45 except that (S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxaza) was used-4-carbonyl) -amino]Methyl-heptanoate, i.e. preparation(S)4, 4-difluoro-2- [ (perhydro-1, 4-oxaza) -4-carbonyl) -amino]-heptanoic acid。LC/MS：309(M+H)。
Reference example 48
(S) -2-amino-1- (3-isopropyl- [1, 2, 4)]Oxadiazol-5-yl) -butan-1-ols
Prepared in a similar manner by following the procedure of reference example 33. LCMS: 200(M + H).
Reference example 49
{ (S) -1- [ (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) -hydroxymethyl]-propyl } -carbamic acid tert-butyl ester
Treatment of a solution containing { (S) -1- [ hydroxy- (N-hydroxycarbamimidoyl) -methyl group with trimethylacetic anhydride (0.212ml, 1.04mmol)]-propyl } -carbamic acid tert-butyl ester (235mg, 0.95mmol) of diglyme (2ml) and the reaction mixture was heated at 170 ℃ for 5min in an EmrysOptizer microwave oven, produced by Personal Chemistry. The solvent was evaporated under high vacuum. Purifying the crude product by flash chromatography, eluting with a mixture of ethyl acetate and heptane (1:4) to obtain{ (S) -1- [ (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) -hydroxymethyl]-propyl } -carbamic acid tert-butyl esterAs a brown oil (100mg) (mixture of diastereomers).
1H NMR(CDCl3)δ：4.92-4.69(m，2H)，4.05-3.85(m，1H)，3.57-3.41 &3.32-3.15(2xbs，1H)，1.73-1.48(m，2H)，1.45 & 1.44(2xs，9H)，1.43&1.39(2xs，9H)，0.99 & 0.96(2xt，J＝7.5Hz，3H)；MS：314(M+H)。
Reference example 50
(S) -2-amino-1- (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) -butan-1-ol
Treatment of { (S) -1- [ (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) -hydroxymethyl with trifluoroacetic acid (5.18ml, 67.25mmol)]-propyl } -carbamic acid tert-butyl ester (2.11g, 6.72mmol) in dichloromethane (20ml) and stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (100ml) and treated with PS-trimethylolmethylamine (trisamine) (5.38g, 20.18mmol, 3.75mmol/g load) from Argonaut Technologies, the reaction was stirred at room temperature for 4 hours, filtered and the filtrate evaporated to give(S) -2-amino-1- (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) -butan-1-olAs an orange oil (975mg) (mixture of diastereomers).
1H NMR(CDCl3)δ：4.73 & 4.58(2xd，J＝5Hz，1H)，3.12-3.00(m，1H)，2.64-2.31(bs，3H)，1.69-1.44(m，2H)，1.43(s，9H)，0.99 & 0.97(2xt，J＝7.5Hz，3H)；MS：214(M+H)。
Reference example 51
(S) -1- { [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazol-3-yl]-hydroxymethyl } -propyl) -carbamic acid tert-butyl ester
With (S) -1- [ hydroxy- (N-hydroxycarbamimidoyl) -methyl]-propyl } -carbamic acid tert-butyl ester (3g, 0.012mol) and triethylamine (1.54ml, 0.011mol) treated 4-fluorobenzoic acid (1.70g, 0.012mol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2).12g, 0.011mol) in dichloromethane (80 ml). The reaction was stirred at rt overnight. Then, it was diluted with 40ml of dichloromethane and washed with saturated aqueous carbonate (30ml), water (30ml), brine (30ml) and then Na2SO4Dried and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with a mixture of ethyl acetate and heptane (2:1), to give an off-white solid (2.20 g).
1H NMR(CDCl3)δ：8.10-7.95(m，2H)，7.16-7.00(m，2H)，5.43-5.24(m，2H)，5.22-5.05(m，1H)，5.01-4.85(m，1H)，4.50-4.39(m，1H)，3.80-3.60(m，1H)，1.90-1.78(m，2H)，1.40(s，9H)，0.98(t，J＝7.5Hz，3H)；MS：370(M+H)。
240mg of the solid compound (0.65mmol) obtained above was dissolved in diglyme (5ml) and heated at 160 ℃ for 18min in a microwave reactor (Smith Creator, S00219). The solvent was evaporated under high vacuum. Purifying the crude product by flash chromatography, eluting with a mixture of ethyl acetate and heptane (1:4) to obtain(S) -1- { [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazol-3-yl]-hydroxymethyl } -propane Yl) -carbamic acid tert-butyl esterAs a white solid (148 mg).
1H NMR(CDCl3)δ：8.16-8.09(m，2H)，7.25-7.12(m，2H)，4.98-4.73(m，2H)，4.13-3.87(m，1H)，3.82-3.35(m，1H)，1.80-1.52(m，2H)，1.46 & 1.34(2xs，9H)，1.02 & 0.99(2xt，J＝7.5Hz，3H)；MS：352(M+H)。
Reference example 52
(S) -2-amino-1- [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazol-3-yl]-butan-1-ol
Prepared in a similar manner following the procedure of reference example 50 above, but using (S) -1- { [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazol-3-yl ] -hydroxymethyl } -propyl) -carbamic acid tert-butyl ester.
1H NMR(CDCl3)δ：8.18-8.05(m，2H)，7.26-7.12(m，2H)，4.92 & 4.73(2xd，J＝5Hz，1H)，3.27-3.05(m，1H)，1.75-1.62(m，1H)，1.59-1.41(m，1H)，1.02 &1.00(2xt，J＝7.5Hz，3H)；MS：252(M+H)。
Reference example 53
{ (S) -1- [ (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -hydroxymethyl]-propyl } -carbamic acid tert-butyl ester
(S) -1- [ hydroxy- (N-hydroxycarbamimidoyl) -methyl ] treatment with triethylamine (3.46ml, 24.82mmol)]-suspension of propyl } -carbamic acid tert-butyl ester (6.12g, 24.78mmol) in dichloromethane (150ml) then cooled to 0 ℃. Cyclopropylcarbonyl chloride (2.25ml, 24.79mmol) was added dropwise. The reaction was stirred at room temperature for 1h 45min and diluted with 150ml dichloromethane. Washed successively with water (40ml), saturated aqueous bicarbonate solution (20ml), water (20ml) and Na2SO4Drying and evaporation of the solvent under reduced pressure gave a white solid (7.16 g). MS: 338(M + Na).
A solution of the compound obtained above (7.45g, 0.024mol) in dioxane (150ml) was heated at reflux for 15 hours. Evaporating the solvent under reduced pressure and purifying the residue by flash chromatography, eluting with a mixture of ethyl acetate and heptane to obtain(S) -1- [ (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -hydroxymethyl]-C Methyl-carbamic acid tert-butyl esterAs a pale yellow solid (5 g).
1H NMR(CDCl3)δ：4.94-4.74(m，2H)，3.97 & 3.85(2xm，1H)，3.62 & 3.48(2xbs，1H)，2.19(m，1H)，1.72-1.42(m，2H)，1.44 & 1.39(2xs，9H)，1.26-1.18(m，4H)，0.98 & 0.95(2xt，J＝7.4Hz，3H)；MS：298(M+H)。
Reference example 54
(S) -2-amino-1- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -butan-1-ol hydrochloride
{ (S) -1- [ (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -hydroxymethyl ] in 4N HCl in dioxane (43ml, 0.172mmol)]A solution of-propyl } -carbamic acid tert-butyl ester (3.41g, 0.011mmol) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Triturating the residue with a mixture of ethyl acetate and diethyl ether and filtering(S) -2-amino-1- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) - Salt of butane-1-ol hydrochlorideAs a brown solid (2.47 g).
1H NMR(CDCl3)δ：8.21(bs，2H)，5.37 & 5.14(2xd，1H)，3.88 & 3.73(2xm，1H)，2.21(m，1H)，1.92-1.50(m，2H)，1.24(m，4H)，1.08 & 1.06(2xt，J＝7.4Hz，3H)；MS：198(M+H)。
Example 1
Morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl Base of]-3, 3-difluorohexyl } -amide
PyBOP (113mg, 0.87mmol) was added to (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]Heptanoic acid (104mg, 0.35mmol), (S) -2-amino-1- (3-cyclopropyl-A mixture of 1, 2, 4-oxadiazol-5-yl) -but-1-ol hydrochloride (86.7mg, 0.37mmol) and diisopropylamine (219mg, 0.42mmol) in dry dichloromethane (5 mL). The mixture was stirred at room temperature for 16h and evaporated in vacuo. The residue was diluted with ethyl acetate (25mL) and successively with saturated NaHCO3(30mL), dilute HCl (30mL) and saturated NaHCO3(30mL) washed. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue is purified on 12g of silica gel, eluting with ethyl acetate, heptane (2:1 then 1:0) to giveMorpholine-4-carboxylic acid (1- {1- [ (3-cyclopropyl- [1, 2, 4)]Oxadiazol-5-yl) -hydroxymethyl]-propylcarbamoyl 3, 3-Difluorohexyl-carboxamides(146mg, 88%) as a white solid. LC/MS showed 2 isomers, totaling 100% M + 1474.
In N2DMP (15% wt in dichloromethane, 1.73g, 0.061mmol) was added to morpholine-4-carboxylic acid (1- {1- [ (3-cyclopropyl- [1, 2, 4] under an atmosphere]Oxadiazol-5-yl) -hydroxymethyl]-propylcarbamoyl } -3, 3-difluorohexyl) -amide (145mg, 0.31mmol) in dry dichloromethane (3 mL). The reaction was stirred at room temperature for 2 hours, then Na was added2S2O3(193mg, 1.22mmol) in saturated NaHCO3The reaction was stopped by a solution in (30 mL). The aqueous layer was extracted with dichloromethane (2 × 30 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on 12g silica eluting with ethyl acetate, heptane (1:1 then 2:1) to give the desired ketone (119mg, 81%) as a brown solid.
1H NMR(CDCl3)：δ 7.4(d，7.0Hz，1H)，5.27(m，1H)，5.13(d，J＝6.9Hz，1H)，4.65(dd，J＝13.1，6.9Hz，1H)，3.7(m，4H)，3.4(m，4H)，2.4(m，2H)，2.2(m，1H)，2.05(m，1H)，1.8(m，3H)，1.55(m，2H)，1.15(m，4H)，0.98(t，J＝7.4Hz，6H)；LC/MS：28％ 512(M+H2O + Na) and 68% 494(M + Na).
Example 2
Morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (5-cyclopropyl-1, 3, 4-oxa-bisAzole-2-carbonyl) -propylcarbamoyl Base of]-3, 3-difluorohexyl } -amide
PyBOP (171.73mg, 0.33mmol), diisopropylethylamine (0.0575ml, 0.33mmol) and a mixture of (S) -2-amino-1- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) -butan-1-ol and trifluoroacetic acid (0.30mmol) were added to (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid (88.29mg, 0.30mmol) in dry dichloromethane (4ml) and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous sodium bicarbonate, extracted twice with dichloromethane, the organic extracts were dried over sodium sulfate and evaporated under reduced pressure. Separating with silica gel column chromatography, eluting with mixture of dichloromethane and ethyl acetate to obtainMorpholine-4-carboxylic acid ((S) -1- { (S) -1- [ (5-cyclopropyl-1, 3, 4-oxadiazole-2-) Radical) -hydroxymethyl]-propylcarbamoyl } -3, 3-difluorohexyl) -amideAs a white solid (87 mg). LC/MS 97%, 474(M +1).
DMP (15 wt% DCM solution, 0.79gm, 0.28mmol) was added to morpholine-4-carboxylic acid ((S) -1- { (S) -1- [ (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) -hydroxymethyl)]-propylcarbamoyl } -3, 3-difluorohexyl) -amide (67mg, 0.14mmol) in dry dichloromethane (10ml) and stirred at room temperature for 2.5 h. With NaHCO3Na in aqueous solution2S2O3(110.68mg, 0.70mmol) solution was used to stop the reaction. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated under reduced pressure. Separating with silica gel column chromatography, eluting with mixture of dichloromethane and ethyl acetate to obtainMorpholine-4-carboxylic acid { (S) -1- [ (S) -1- (5-cyclopropyl-1, 3, 4-oxa-bis Azole-2-carbonyl) -propylcarbamoyl]-3, 3-difluorohexyl } -amideAs a white powder (48 mg).1H NMR(CDCl3)：δ 7.52(d，J＝7.5Hz，1H)，5.34(m，1H)，5.18(d，J＝7.5Hz，1H)，4.65(m，1H)，3.72(m，4H)，3.40(m，4H)，2.50-2.22(m，3H)，2.18-2.08(m，1H)，1.96-1.78(m，3H)，1.60-1.45(m，2H)，1.30(m，4H)，0.98(t+t，6H)；LC/MS 95％，472(M+1)。
Example 3
Morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (S) -1- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazole-2- Carbonyl radical]-propylcarbamoyl } -hexyl) -amide.
PyBOP (68.69mg, 0.13mmol), diisopropylethylamine (0.023ml, 0.13mmol) and (S) -2-amino-1- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl]-butan-1-ol (38.0mg, 0.12mmol) was added (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid (34mg, 0.12mmol) in dry dichloromethane (4ml) and the reaction mixture was stirred at room temperature overnight. With NaHCO3The reaction was quenched with aqueous solution, extracted twice with dichloromethane, and extracted with Na2SO4The organic extracts were dried and evaporated under reduced pressure. Separating with silica gel column chromatography, eluting with mixture of dichloromethane and ethyl acetate to obtainMorpholine-4-carboxylic acid [ (S) -3, 3-difluoro-1- ((S) -1- { hydroxy- [5- (4-trifluoromethoxy) hydroxy Phenyl) -1, 3, 4-oxadiazol-2-yl]-methyl } -propylcarbamoyl) -hexyl radical]-amides ofAs a white solid (61 mg). LC/MS 71%, M +1 ═ 594.
DMP (15 wt% DCM solution, 0.58gm, 0.21mmol) was added to morpholine-4-carboxylic acid [ (S) -3, 3-difluoro-1- ((S) -1- { hydroxy- [5- (4-trifluoromethoxyphenyl) -1, 3, 4-oxadiazol-2-yl)]-methyl } -propylcarbamoyl) -hexyl radical]A solution of the amide (61mg, 0.10mmol) in dry dichloromethane (8ml) and stirred at room temperature for 3 hours. With Na2S2O3(81.43mg, 0.50mmol) of NaHCO3The reaction was terminated with an aqueous solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. With sodium sulfateThe organic extracts were dried and concentrated under reduced pressure. Separating with silica gel column chromatography, eluting with mixture of dichloromethane and ethyl acetate to obtainMorpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (S) -1- [5- (4-trifluoro-l) Methoxyphenyl) -1, 3, 4-oxadiazole-2-carbonyl]-propylcarbamoyl } -hexyl) -amideAs a white powder (39 mg).
1H NMR(CDCl3)：δ 8.25(d，J＝7.5Hz，2H)，7.60(d，J＝7.5Hz，1H)，7.42(d，J＝7.5Hz，2H)，5.36(m，1H)，5.16(d，J＝7.5Hz，1H)，4.70(m，1H)，3.74(m，4H)，3.42(m，4H)，2.54-2.32(m，2H)，2.28-2.14(m，1H)，2.02-1.80(m，3H)，1.60-1.45(m，2H)，1.06(t，J＝7Hz，3H)，0.96(t，J＝7Hz，3H)；LC/MS：96％，592(M+1)。
Example 4
Morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl Base of]-3, 3-difluoro-4-phenyl-butyl } -amide
In analogy to example 1 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-1- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -butan-1-olMorpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylamino Formyl radical]-3, 3-difluoro-4-phenyl-butyl } -amide。
1H NMR(CDCl3)：δ 7.3(m，6H)，5.25(m，1H)，5.08(d，J＝6.9Hz，1H)，4.7(dd，J＝12.8，7.4Hz，1H)，3.7(m，4H)，3.4(m，4H)，3.2(t，16.8Hz，2H)，2.4-2.1(m，3H)，2.05(m，1H)，1.8(m，1H)，1.1(m，4H)，0.95(t，J＝7.5Hz，3H)；LC/MS：35％ 560(M+H2O + Na) and 65％ 542(M+Na)。
Example 5
Morpholine-4-carboxylic acid {1- [1- (3-cyclopropyl- [1, 2, 4]]Oxadiazole-5-carbonyl) -propylcarbamoyl]-3, 3-bis Fluoro-5-methyl-hexyl } -amide
In analogy to example 1 above, but using (S) -4, 4-difluoro-6-methyl-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid and (S) -2-amino-1- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -butan-1-olMorpholine-4-carboxylic acid {1- [1- (3-cyclopropyl- [1, 2, 4]]Oxadiazole-5-carbonyl) -propylaminomethane Acyl radical]-3, 3-difluoro-5-methyl-hexyl } -amide。
1H NMR(CDCl3)：δ 7.6(d，J＝6.8Hz，1H)，5.2(m，2H)，4.66(dd，J＝13，7.2Hz，1H)，3.7(m，4H)，3.4(m，4H)，2.3(m，2H)，2.2(m，1H)，2.05(m，1H)，1.95(m，1H)，1.8(m，3H)，1.1(m，4H)，0.97(d，J＝6.6Hz，6H)，0.96(t，J＝7.4Hz，3H)；LC/MS：26％，526(M+H2O + Na) and 74%, 508(M + Na).
Example 6
Morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl Base of]-3, 3-difluorobutyl } -amide
In analogy to example 1 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-pentanoic acid and (S) -2-amino-1- (3-cyclopropyl-1,2, 4-oxadiazol-5-yl) -butan-1-ol, i.e. obtainingMorpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl Base of]-3, 3-difluorobutyl } -amide。
1H NMR(CDCl3)：δ 7.47(d，J＝6.8Hz，1H)，5.3(m，1H)，5.16(d，J＝6.9Hz，1H)，4.65(dd，J＝13，7.4Hz，1H)，3.7(m，4H)，3.4(m，4H)，2.4(m，2H)，2.2(m，1H)，2.05(m，1H)，1.8(m，1H)，1.67(t，18.7Hz，3H)，1.1(m，4H)，0.97(t，J＝7.5Hz，3H)；LC/MS：37％ 484(M+H2O + Na) and 63% 484(M + CH)3CN)。
Example 7
Morpholine-4-carboxylic acid { (S) -3, 3-difluoro-1- [ (S) -1- (3-phenyl-1, 2, 4-oxadiazole-5-carbonyl) -propylamino Formyl radical]-butyl } -amide
In analogy to example 1 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-pentanoic acid and (S) -2-amino-1- (3-phenyl-1, 2, 4-oxadiazol-5-yl) -butan-1-olMorpholine-4-carboxylic acid { (S) -3-3-difluoro-1- [ (S) -1- (3-phenyl-1, 2, 4-oxadiazole-5-carbonyl) -propylamino Formyl radical]-butyl } -amideIt was a light brown solid.
1H NMR(CDCl3)：δ 8.15(dd，J＝7.7，1.5Hz，2H)，7.61(d，J＝6.4Hz，1H)，7.5(m，3H)，5.35(m，1H)，5.2(d，J＝＝6.9Hz，1H)，4.68(dd，J＝13.2，7.8Hz，1H)，3.7(m，4H)，3.4(m，4H)，2.4(m，2H)，2.2(m，1H)，1.95(m，1H)，1.66(t，18.7Hz，3H)，1.03(t，J＝7.5Hz，3H)；LC/MS：37％ 520(M+H2O + Na) and 63% 502(M + Na).
Example 8
Morpholine-4-carboxylic acid { (S) -3, 3-difluoro-1- [ (S) -1- (5-phenyl-1, 2, 4-oxadiazole-3-carbonyl) -propylamino Formyl radical]-butyl } -amide
In analogy to example 1 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-pentanoic acid and (S) -2-amino-1- (5-phenyl- [1, 2, 4)]Oxadiazol-3-yl) -butan-1-ol, i.e. to obtainMorpholine-4-carboxylic acid { (S) -3, 3-difluoro-1- [ (S) -1- (5-phenyl-1, 2, 4-oxadiazole-3-carbonyl) -propylamino Formyl radical]-butyl } -amide。
1H NMR(CDCl3)：δ 8.2(d，J＝7.1Hz，2H)，7.65(d，J＝7.4Hz，1H)，7.55(m，3H)，5.4(dd，J＝12.2，7Hz，1H)，5.3(d，J＝7.4Hz，1H)，4.7(dd，J＝13，7.3Hz，1H)，3.7(m，4H)，3.4(m，4H)，2.4(m，2H)，2.1(m，1H)，1.9(m，1H)，1.67(t，18.7Hz，3H)，1.0(t，J＝7.4Hz，3H)；LC/MS：6％ 520(M+H2O + Na) and 94% 502(M + Na).
Example 9
Morpholine-4-carboxylic acid {1- [1- (5-cyclopropyl- [1, 3, 4]]Oxadiazole-2-carbonyl) -propylcarbamoyl]-3, 3-bis Fluoro-4-phenyl-butyl } -amide:
in analogy to example 1 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-1- (5-cyclopropyl-1, 3, 4-oxadiazol-2-yl) -butan-1-ol trifluoroacetate, to givemorpholine-4-AAcid {1- [1- (5-cyclopropyl- [1, 3, 4]]Oxadiazole-2-carbonyl) -propanes Radical carbamoyl]-3, 3-difluoro-4-phenyl-butyl } -amide。
1H NMR(CDCl3): δ 7.3(m, 6H), 5.27(m, 1H), 5.0(d, J ═ 7.0Hz, 1H major), 4.95(d, J ═ 7.3Hz, 1H times), 4.7(m, 1H), 3.7(m, 4H), 3.4(m, 4H), 3.2(t, 16.3Hz, 2H), 2.4-2.2(m, 3H), 2.05(m, 1H), 1.8(m, 1H), 1.2(m, 4H), 0.95(t, J ═ 7.5Hz, 3H); LC/MS: 12% 560(M + H)2O + Na) and 83% 542(M + Na).
Example 10
Morpholine-4-carboxylic acid {3, 3-difluoro-1- [1- (5-isopropylisoxazole-3-carbonyl) -propylcarbamoyl]-already Group } -amide:
by proceeding in a similar manner to example 1 above, but using 2-amino-1- (5-isopropylisoxazol-3-yl) -but-1-ol hydrochloride instead of (S) -2-amino-1- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -but-1-ol hydrochloride, we obtainMorpholine-4-carboxylic acid {3, 3-difluoro-1- [1- (5-isopropylisoxazole-3-carbonyl) -propyl ester Carbamoyl radical]-hexyl } -amideAs a white solid.
1H NMR(CDCl3): δ ca 2:1 isomer mixture 7.4(b, 1H), 6.37(s, 1H), 5.4(m, 1H), 5.26(d, J ═ 6.9Hz, 1H predominant), 5.2(d, J ═ 7.2Hz, 1H times), 4.7(m, 1H), 3.7(m, 4H), 3.4(m, 4H), 3.15(m, 1H), 2.4(m, 2H), 2.1(m, 1H), 1.8(m, 4H), 1.5(m, 1H), 1.35(d, J ═ 7.0Hz, 6H), 0.95(m, 6H); LC/MS: 100% 473(M +1).
Example 11
Morpholine-4-carboxylic acid ((S) -3, 3-difluoro)-1- {1- [5- (5-methylisoxazol-3-yl) -oxazole-2-carbonyl]-propylamine Carbamoyl } -hexyl) -amides
In analogy to example 3 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acid and (S) -2-amino-1- [5- (5-methylisoxazol-3-yl) -oxazol-2-yl]-butane-1-ol hydrochloride, i.e. preparationMorpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- {1- [5- (5-methylisoxazol-3-yl) -oxazole-2- Carbonyl radical]-propylcarbamoyl } -hexyl) -amideAs a white solid.
1H NMR(CDCl3)：δ 7.78(s，1H)，7.40(m，1H)，6.44(s，1H)，5.48(m，1H)，5.22-5.10(m，1H)，4.68(m，1H)，3.72(m，4H)，3.40(m，4H)，2.54(s，3H)，2.50-2.30(m，2H)，2.22-2.08(m，1H)，1.94-1.78(m，3H)，1.60-1.46(m，2H)，1.08-0.94(2xt，6H)；LC/MS：99％，512(M+1)。
Example 12
Morpholine-4-carboxylic acid { (S) -3, 3-difluoro-1- [ (S) -1- (oxazole-2-carbonyl) -propylcarbamoyl]-4-phenyl- Butyl } -amide
In analogy to example 2 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-1-oxazol-2-yl-but-1-ol hydrochloride, i.e. preparationMorpholine -4-carboxylic acid { (S) -3, 3-difluoro-1- [ (S) -1- (oxazole-2-carbonyl) -propylcarbamoyl]-4-phenyl-butanes Acyl-amides。
1H NMR(CDCl3)：δ 7.86(s，1H)，7.37(s，1H)，7.30(m，5H)，7.24(m，1H)，5.45(m，1H)，5.08(d，J＝9Hz，1H)，4.70(m，1H)，3.72(m，4H)，3.38(m，4H)，3.22(t，J＝17Hz，2H)，2.35(m，2H)，2.12(m，1H)，1.85(m，1H)，0.95(t，J＝9Hz，3H)；LC/MS：97％，479(M+1)。
Example 13
Morpholine-4-carboxylic acid { (S) -3, 3-difluoro-4-phenyl-1- [ (S) -1- (5-thiophen-2-yloxazole-2-carbonyl) -propylamine Radical formyl radical]-butyl } -amide
In analogy to example 1 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-1- (5-thiophen-2-yloxazol-2-yl) -but-1-ol hydrochloride, i.e. their preparationMorpholine-4-carboxylic acid { (S) -3, 3-difluoro-4-phenyl-1- [ (S) -1- (5-thiophen-2-yloxazole-2- Carbonyl) -propylcarbamoyl]-butyl } -amide。
1H NMR(CDCl3)：δ 7.53(dd，J＝3.6，1Hz，1H)，7.48(dd，J＝5，1Hz，1H)，7.4(s，1H)，7.3(m，6H)，7.15(dd，J＝5，3.6Hz，1H)，5.4(m，1H)，5.15(d，J＝7.1Hz，1H)，4.7(dd，J＝13，7.4Hz，1H)，3.7(m，4H)，3.4(m，4H)，3.2(t，16.7Hz，2H)，2.4(m，2H)，2.1(m，1H)，1.8(m，1H)，0.96(t，J＝7.5Hz，3H)；LC/MS：100％561(M+1)。
Example 14
Morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (benzoxazole-2-carbonyl) -butylcarbamoyl]-3, 3-difluoro-4- Phenyl-butyl } -amides
In analogy to example 1 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-1-benzoxazol-2-yl-pentan-1-ol, i.e.Morpholine -4-carboxylic acid { (S) -1- [ (S) -1- (benzoxazole-2-carbonyl) -butylcarbamoyl]-3, 3-difluoro-4-phenyl- Butyl } -amide。
1H NMR(CDCl3)：δ 7.9(d，J＝8.0Hz，1H)，7.66(d，J＝8Hz，1H)，7.56(t，J＝7.2Hz，1H)，7.47(t，J＝8Hz，1H)，7.2(m，6H)，5.6(m，1H)，5.05(d，J＝7Hz，1H)，4.71(dd，J＝12.8，7.4Hz，1H)，3.7(m，4H)，3.35(m，4H)，3.18(t，J＝16.8Hz，2H)，2.3(m，2H)，2.1(m，1H)，1.8(m，1H)，1.4(m，2H)，0.94(t，J＝7.3Hz，3H)；LC/MS：100％ 543(M+1)。
Example 15
Morpholine-4-carboxylic acid [1- (2-benzoxazol-2-yl-1-methoxymethyl-2-oxo-ethylcarbamoyl -3, 3-difluoro-4-phenyl-butyl]-amides of
In analogy to example 1 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-1-benzoxazol-2-yl-3-methoxy-propan-1-olMorpholine-4-carboxylic acid [1- (2-benzoxazol-2-yl-1-methoxymethyl-2-oxo-ethylcarbamoyl -3, 3-difluoro-4-phenyl-butyl]-amides of。
1H NMR(CDCl3)：δ 7.9(d，J＝7.7Hz，1H)，7.67(d，J＝8Hz，1H)，7.56(t，J＝8Hz，1H)，7.48(t，J＝8Hz，1H)，7.2(m, 6H), 5.7(m, 1H), 5.1(d, J ═ 7Hz, 1H major), 5.05(d, J ═ 7.3Hz, 1H times), 4.8(m, 1H), 4.26(dd, J ═ 9.7, 3.5Hz, 1H), 3.8(m, 1H), 3.7(m, 4H), 3.35(m, 4H), 3.27(s, 3H), 3.22(t, J ═ 16.2Hz, 2H), 2.4(m, 2H); LC/MS: 94% 545(M +1).
Example 16
Morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (benzoxazole-2-carbonyl) -1-methyl-butylcarbamoyl]-3，3- Difluoro-4-phenyl-butyl } -amide
The hydrochloride of (S) -2-amino-1-benzoxazol-2-yl-2-methyl-pentan-1-one (80.6mg, 0.3mmol), (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]A mixture of-5-phenylpentanoic acid (0.102mg, 0.3mmol), EDCI (69mg, 0.36mmol), HOBT (48.6mg, 0.36mmol) and diisopropylethylamine (0.2mL) in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, then with cold 1N HCl followed by saturated NaHCO3And a saturated NaCl solution wash. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the crude product. Purifying with silica gel column chromatography, eluting with a mixture of ethyl acetate and heptane to obtainMorpholine-4-carboxylic acid { (S) -1- [ (S) -1- (benzene) And oxazole-2-carbonyl) -1-methyl-butylcarbamoyl]-3, 3-difluoro-4-phenyl-butyl } -amide(82％)。
1H NMR(CDCl3)：δ 7.8(d，J＝7.8.0Hz，1H)，7.64(d，J＝7.8Hz，1H)，7.53(dt，J＝7.2，1.2Hz，1H)，7.43(dt，J＝8，1.2Hz，1H)，7.2(m，6H)，4.9(d，J＝7.3Hz，1H)，4.65(m，1H)，3.7(m，4H)，3.3(m，4H)，3.1(t，J＝16.8Hz，2H)，2.2(m，3H)，2.1(m，1H)，1.74(s，3H)，1.25(m，2H)，0.9(t，J＝7.3Hz，3H)；LC/MS：100％ 557(M+1)。
Example 17
Morpholine-4-carboxylic acid [ (S) -1- ((S) -1-cyano-3-phenylpropylcarbamoyl) -3, 3-difluoro-4-phenyl-butane Base of]-amides of
The procedure was followed for PyBOP coupling as provided in example 1, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-4-phenylbutyronitrile hydrochloride, i.e. to obtainMorpholine -4-carboxylic acid [ (S) -1- ((S) -1-cyano-3-phenylpropylcarbamoyl) -3, 3-difluoro-4-phenyl-butyl]- Amides of carboxylic acids。
1H NMR(CDCl3)：δ 7.9(d，J＝7.6Hz，1H)，7.2(m，10H)，5.1(d，J＝7.3Hz，1H)，4.6(m，2H)，3.6(m，4H)，3.3(m，4H)，3.2(t，J＝16.5Hz，2H)，2.74(t，J＝7.2H，2H)，2.3(m，2H)，2.1(m，2H)；LC/MS：100％ 485(M+1)。
Example 18
Morpholine-4-carboxylic acid [ (S) -1- (cyanomethyl-carbamoyl) -3, 3-difluoro-4-phenyl-butyl]-amides of
The procedure was followed for PyBOP coupling as provided in example 1, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and aminoacetonitrile hydrochloride, namelyMorpholine-4-carboxylic acid [ (S) -1- (cyanomethyl-carbamoyl) -3, 3-difluoro-4-phenyl-butyl]-amides of。
1H NMR(CDCl3)：δ 7.95(b，1H)，7.3(m，5H)，5.25(d，J＝7.0Hz，1H)，4.7(dd，J＝12.7，7.2Hz，1H)，4.1(m，2H)，3.7(m，4H)，3.35(m，4H)，3.2(t，J＝16.3Hz，2H)，2.4(m，2H)；LC/MS：83％ 403(M+Na)。
Example 19
Morpholine-4-carboxylic acid [ (S) -3, 3-difluoro-1- ((S) -1-formyl-1-methyl-butylcarbamoyl) -4-phenyl- Butyl radical]-amides of
The (S) -2-amino-2-methyl-pentan-1-ol hydrochloride (104.4mg, 0.67mmol), (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]A mixture of-5-phenylpentanoic acid (231mg, 0.67mmol), EDCI (154mg, 0.8mmol), HOBT (108mg, 0.8mmol) and diisopropylethylamine (0.23mL) in DMF (2mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, then with cold 1N HCl followed by saturated NaHCO3And a saturated NaCl solution wash. Over MgSO4The organic phase was dried and the solvent was evaporated under reduced pressure to give the crude product. Purifying with silica gel column chromatography, eluting with a mixture of ethyl acetate and heptane to obtainMorpholine-4-carboxylic acid [ (S) -3, 3-difluoro-1- ((S) -1-hydroxymethyl) -1-methyl-butylcarbamoyl) -4-phenyl-butyl]-amides of(223mg，75％)。
Will be provided withMorpholine-4-carboxylic acid [ (S) -3, 3-difluoro-1- ((S) -1-hydroxymethyl-1-methyl-butylcarbamoyl Yl) -4-phenyl-butyl]-amides ofA mixture of (217mg) and DMP (15% in DCM, 2 eq.) in DCM (5mL) was stirred at room temperature for 3h and saturated NaHCO3The reaction was terminated with sodium thiosulfate solution. The product was extracted with ethyl acetate and washed with saturated NaCl solution. Over anhydrous MgSO4The organic phase was dried and the solvent was evaporated under reduced pressure. Purifying by silica gel chromatography, eluting with ethyl acetate-heptane mixture to obtainMorpholine-4-carboxylic acid [ (S) -3, 3-difluoro-1- ((S) -1-formyl-1-methyl- Butylcarbamoyl) -4-benzeneAlkyl-butyl]Amide (83mg, 38%).
1H NMR(CDCl3)：δ 9.3(s，1H)，7.2(m，5H)，7.0(s，1H)，5.0(d，J＝7Hz，1H)，4.64(dd，J＝13，7.3Hz，1H)，3.7(m，4H)，3.4(m，4H)，3.2(t，J＝16.5Hz，2H)，2.3(m，2H)，1.9(m，1H)，1.65(m，1H)，1.35(s，3H)，1.2(m，2H)，0.9(t，J＝7.3Hz，3H)；LC/MS：100％ 440.(M+1)。
Example 20
Perhydro-1, 4-oxaza-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propane Radical formyl radical]-3, 3-difluorobutyl } -amide
To (S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxaza)-4-carbonyl) -amino]A mixture of pentanoic acid (97mg, 0.35mmol), (S) -2-amino-1- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -butan-1-ol hydrochloride (83mg, 0.36mmol) and diisopropylethylamine (121 μ L, 0.70mmol) in dry dichloromethane (12mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (66mg, 0.35mmol) and 1-hydroxybenzotriazole hydrate (47mg, 0.35 mmol). The mixture was stirred at room temperature for 16h, then diluted with dichloromethane (20mL) and then diluted HCl (30mL), saturated NaHCO3(30mL) washed. Drying the organic layer (Na)2SO4) And concentrated in vacuo. The residue was purified on 12g silica eluting with ethyl acetate heptane (gradient 50-100%) to givePerhydro-1, 4-oxazepine-4-carboxylic acid ((S) -1- { (S) -1- [ (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -hydroxy Methyl radical]-propylcarbamoyl } -3, 3-difluorobutyl) -amide(120mg, 75%) as a colorless glassy solid. LC/MS 100% 460(M + H).
In N2In an atmosphere, DMP (143mg, 0.34mmol) was added to perhydro-1, 4-oxaza-4-carboxylic acid ((S) -1- { (S) -1- [ (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -hydroxymethyl]-propylcarbamoyl } -3, 3-difluorobutyl) -amide (110mg, 0.24mmol) in dry dichloromethane (20 mL). The reaction was stirred at room temperature for 2 hours, then dichloromethane (20mL) was added. With Na2S2O3(0.26M, 2mL) solution was used to stop the reaction and saturated NaHCO was used3(20mL) washed. The aqueous layer was extracted with dichloromethane (2 × 30 mL). With Na2SO4The organic layer was dried and concentrated in vacuo. The residue is purified on 12g of silica gel, eluting with ethyl acetate: heptane (gradient 50-100%) to givePerhydro-1, 4- Oxazan-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamic acid methyl ester Acyl radical]-3, 3-difluorobutyl } -amide(82mg, 75%) as a white solid.
1H NMR(CDCl3)δ 7.52(d，6.2H)，5.28(m，1H)，5.05(d，J＝7Hz，1H)，4.66(m，1H)，3.78(m，4H)，3.59(m，4H)，2.42(m，2H)，2.23(m，1H)，2.07(m，1H)，1.98(m，1H)，1.85(m，1H)，1.69(t，J＝18.8Hz，3H)，1.15(m，4H)，0.98(t，J＝7.5Hz，3H)；LC/MS：97％ 458(M+H)。
Example 21
Perhydro-1, 4-oxaza-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propane Radical carbamoyl]-3, 3-difluorohexyl } -amide
In a similar manner to example 20 above, but using (S) -4, 4-difluoro-2- { (perhydro-1, 4-oxazepine-4-carbonyl) -amino } -heptanoic acid and (S) -2-amino-1- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -butan-1-ol hydrochloride byPerhydro-1, 4-oxaza-4-carboxylic acid { (S) -1- [ (S) -1- (3-cyclopropyl-l-propyl-) -1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl]-3, 3-difluorohexyl } -amide(98mg, 65%) as a white solid.
1H NMR(CDCl3) δ 7.6(d, J ═ 7.5Hz, 1H), 5.25(m, 1H), 5.10(d, J ═ 7.5Hz, 1H), 4.65(dd, J ═ 14, J ═ 7.5Hz, 1H), 3.75(m, 6H), 3.55(m, 4H), 2.4(m, 2H), 2.2(m, 2H), 1.95(m, 1H), 1.8(m, 3H), 1.55(m, 2H), 1.10(m, 4H), 0.95(t, J ═ 7.5Hz, 6H); LC/MS: 70% 486(M +1) and 30% 504(M +1+ H)2O)。
Example 22
Morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-isopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamoyl Base of]-3, 3-difluorohexyl } -amide
In a similar manner to example 20 above, but using(S) -4, 4-difluoro-2- [ (morpholine-4- Carbonyl) -amino]-heptanoic acidAnd (S) -2-amino-1- (3-isopropyl-1, 2, 4-oxadiazol-5-yl) -butan-1-ol, to obtain the final productMorpholine-4-carboxylic acid { (S) -1- [ (S) -1- (3-isopropyl-1, 2, 4-oxadiazole-5-carbonyl) -propylcarbamic acid methyl ester Acyl radical]-3, 3-difluorohexyl } -amide(122mg, 71%) as a white solid.
1H NMR(CDCl3)δ 7.5(d，J＝7.0Hz，1H)，5.3(m，1H)，5.25(d，J＝7.0Hz，1H)，4.65(dd，J＝13，7.0Hz，1H)，3.7(m，4H)，3.4(m，4H)，3.2(m，1H)，2.35(m，2H)，2.1(m，1H)，1.8(m，3H)，1.55(m，2H)，1.40(d，J＝7Hz，6H)，0.9(t，J＝7.0Hz，6H)；LC/MS: 72% 474(M +1) and 28% 492(M +1+ H)2O)。
Example 23
Morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (5-tert-butyl-1, 2, 4-oxadiazole-3-carbonyl) -propylcarbamoyl Base of]-3, 3-difluorohexyl } -amide
(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino ] was treated successively with (S) -2-amino-1- (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) -butan-1-ol (240mg, 1.13mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (226mg, 0.59mmol) and diisopropylethylamine (0.104mL, 0.60mmol)]-a solution of heptanoic acid (175mg, 0.60mmol) in dimethylformamide (6 mL). The reaction was stirred at rt overnight. The solvent was evaporated under high vacuum. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and then with water, over Na2SO4Dried and the solvent evaporated under reduced pressure. Purifying the crude material by flash chromatography over silica gel (10g column) eluting with a mixture of ethyl acetate and heptane (2:1) to obtainMorpholine-4-carboxylic acid ((S) -1- { (S) -1- [ (5-tert-butyl) -1, 2, 4-oxadiazol-3-yl) -hydroxymethyl]-propylcarbamoyl } -3, 3-difluorohexyl) -amideAs a brown oil (60 mg). MS: 490(M + H).
Morpholine-4-carboxylic acid ((S) -1- { (S) -1- [ (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) -hydroxymethyl) -was treated with DMP (59mg, 0.139mmol)]-propylcarbamoyl } -3, 3-difluorohexyl) -amide (57mg, 0.117mmol) in dichloromethane (3mL) and stirred at room temperature for 90 min. Sequentially using Na2S2O3The reaction mixture was washed with aqueous solution (0.26M), saturated aqueous bicarbonate solution and water, and Na2SO4Dried and the solvent evaporated under reduced pressure. Purifying the residue by flash chromatography with ethyl acetateEluting with heptane (1:1) to obtain morpholine-4-carboxylic acid { (S) -1- [ (S) -1- (5-tert-butyl-1, 2, 4-oxadiazole-3-carbonyl) -propylcarbamoyl]-3, 3-difluorohexyl } -amide as an off-white solid (41 mg). MS: 488(M + H).
Example 24
Morpholine-4-carboxylic acid { (S) -1- [1- (5-tert-butyl-1, 2, 4-oxadiazole-3-carbonyl) -propylcarbamoyl]-3，3- Difluoro-4-phenyl-butyl } -amide
In analogy to the procedure described in example 23 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-1- (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) -butan-1-olMorpholine-4-carboxylic acid { (S) -1- [1- (5-tert-butyl-1, 2, 4-oxadiazole-3-carbonyl) -propylamino Formyl radical]-3, 3-difluoro-4-phenyl-butyl } -amideAnd is a 7:3 diastereomer mixture.
1H NMR(CDCl3)δ：7.36-7.19(m，5H)，7.15(d，J＝7.1Hz，1H)，5.31(m，1H)，5.03 & 4.96(2xd，J＝7Hz，1H)，4.68(m，1H)，3.76-3.59(m，4H)，3.45-3.26(m，4H)，3.18(t，J＝16.8Hz，2H)，2.52-2.18(m，2H)，2.17-1.94(m，1H)，1.88-1.70(m，1H)，1.47(s，9H)，0.93(t，J＝7.4Hz，3H)。MS：536(M+H)。
Example 25
Morpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (S) -1- [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazole-3-carbonyl]-C Carbamoyl } -butyl) -amides
In analogy to the procedure described in example 23 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-pentanoic acid and (S) -2-amino-1- [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazol-3-yl]-butan-1-ol, i.e. preparationMorpholine-4-carboxylic acid ((S) -3, 3-difluoro-1- { (S) -1- [5- (4-fluoro-phenyl) -1, 2, 4-oxadiazole-3-carbonyl Base of]-propylcarbamoyl } -butyl) -amide.
1H NMR(CDCl3)δ：8.21(m，2H)，7.31(d，J＝6.8Hz，1H)，7.30-7.20(m，2H)，5.38(m，1H)，5.07(d，J＝6.8Hz，1H)，4.63(m，1H)，3.75-3.64(m，4H)，3.44-3.33(m，4H)，2.58-2.28(m，2H)，2.22-2.04(m，1H)，1.96-1.79(m，1H)，1.66(t，J＝18.8Hz，3H)，0.97(t，J＝7.4Hz，3H)。MS：498(M+H)。
Example 26
Morpholine-4-carboxylic acid { (S) -1- [1- (5-cyclopropyl-1, 2, 4-oxadiazole-3-carbonyl) -propylcarbamoyl]-3，3- Difluoro-4-phenyl-butyl } -amide
In analogy to the procedure described in example 23 above, but using (S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-5-phenylpentanoic acid and (S) -2-amino-1- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -butan-1-ol to give morpholine-4-carboxylic acid { (S) -1- [1- (5-cyclopropyl-1, 2, 4-oxadiazol-3-carbonyl) -propylcarbamoyl]3, 3-difluoro-4-phenyl-butyl } -amide as a 3:1 diastereomeric mixture.1H NMR(CDCl3)δ：7.36-7.20(m，5H)，7.14(d，J＝7.1Hz，1H)，5.26(m，1H)，5.02 & 4.96(2xd，J＝7Hz，1H)，4.70(m，1H)，3.73-3.61(m，4H)，3.43-3.28(m，4H)，3.18(t，J＝16.5Hz，2H)，2.48-2.21(m，3H)，2.14-1.98(m，1H)，1.85-1.70(m，1H)，1.38-1.21(m，4H)，0.91(t，J＝7.5Hz，3H)。MS：520(M+H)。
Example 27
Perhydro-1, 4-oxaza-4-carboxylic acid { (S) -1- [1- (5-cyclopropyl-1, 2, 4-oxadiazole-3-carbonyl) -propylamine Radical formyl radical]-3, 3-difluorohexyl } -amide
Was carried out in a similar manner to example 23 above, but using (S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxaza)-4-carbonyl) -amino]-heptanoic acid and (S) -2-amino-1- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) -butan-1-olPerhydro-1, 4-oxaza-4-carboxylic acid { (S) -1- [1- (5-cyclopropyl-1, 2, 4-oxadiazole -3-carbonyl) -propylcarbamoyl]-3, 3-difluorohexyl } -amideAnd is a 5:1 diastereoisomer mixture.
1H NMR(CDCl3)：7.44 & 7.39(2xd，J＝7.3Hz，1H)，5.30(m，1H)，5.05 &4.98(2xd，J＝6.5Hz，1H)，4.63(m，1H)，3.79-3.73(m，4H)，3.59-3.53(m，4H)，2.47-2.23(m，3H)，2.15-1.76(m，6H)，1.57-1.43(m，2H)，1.38-1.26(m，4H)，0.95(t，J＝7.3Hz，3H)，0.93(t，J＝7.2Hz，3H)。MS：486(M+H)。
Example 28
Perhydro-1, 4-oxaza-4-carboxylic acid [ (S) -1- (cyanomethyl-carbamoyl) -3, 3-difluorohexyl]-acyl Amines as pesticides
Polystyrene-bound carbodiimide (570mg, 0.73mmol) and (S) -4, 4-difluoro-2- [ (perhydro-1, 4-oxaza-4-carbonyl) -amino]A suspension of-heptanoic acid (135mg) in DCM (10mL) was stirred for 10 min. HOBT (60mg) was added thereto, and the mixture was stirred for another 10 min. A suspension of aminoacetonitrile hydrochloride (34mg) and triethylamine (52. mu.L) in DCM (5ml) was added and stirred at room temperature overnight. PS-trimethylolmethylamine (493mg) was added and stirred at room temperature for 2h 30 min. After filtration, the filtrate was diluted with DCM, washed with water, evaporated under reduced pressure and purified by column chromatography eluting with a mixture of ethyl acetate and heptane to givePerhydro-1, 4-oxazepine-4-carboxylic acid [ (S) -1- (cyanomethyl-carbamoyl) 3, 3-Difluorohexyl radical]-amides ofAs a white solid. LCMS: 347(M + H) 100%.
Example 29
Perhydro-1, 4-oxaza-4-carboxylic acid [ (S) -1- ((S) -1-cyanopropylcarbamoyl) -3, 3-difluorohexyl]-amides of
In a similar manner to the above example 28, but using 4, 4-difluoro-2- [ ([1, 4]]Oxazacycloheptane-4-carbonyl) -amino]-heptanoic acid and (S) -2-aminobutyronitrile hydrochloride, i.e. preparationPerhydro-1, 4-oxa-nitrogen Hetero-4-carboxylic acid [ (S) -1- ((S) -1-cyanopropylcarbamoyl) -3, 3-difluorohexyl]-amides of。LCMS：100％ 375(M+H)。
Example 30
Morpholine-4-carboxylic acid [ (S) -1- (1-cyano-cyclopropylcarbamoyl) -3, 3-difluorohexyl ] -amide
By passing(S) -4, 4-difluoro-2- [ (morpholine-4-carbonyl) -amino]-heptanoic acidAnd 1-aminocyclopropanenitrile hydrochloride using TOTU as the coupling agent and diisopropylethylamine as the base. LCMS: 359(M + H).
Example 31
Cathepsin S assay
Solutions of test compounds at various concentrations were prepared in 10. mu.L of dimethyl sulfoxide (DMSO) and diluted to assay buffer (40. mu.L, containing MES, 50mM (pH6.5), EDTA, 2.5 mM; and NaCl, 100mM, 0.5mM DTT, 0.01% triton X-100).
Human cathepsin S (final concentration in culture wells is 1.74nM) was added to the dilution. The test solution was mixed on a shaking culture plate for 5-10 seconds, covered and then incubated at ambient temperature for 30 min. Z-Val-Val-Arg-AMC (final concentration in the culture well is 0.08mM) was added to the test solution, and the hydrolysis was followed spectrophotometrically (at. lamda.460 nm) for 5 min. Calculation of apparent inhibition constants (K) from enzyme course curves using standard mathematical modelsi)。
Example 32
Cathepsin B assay
Test compound solutions were prepared in 10. mu.L of dimethyl sulfoxide (DMSO) at various concentrations and diluted to assay buffer (containing MES 50mM (pH 6); 2.5mM EDTA, 2% DMSO and Dithiothreitol (DTT), 2.5 mM).
Human cathepsin B (final concentration 0.3 ng/. mu.l) was added to the dilution. The test solution was mixed on a shaking culture plate for 5-10 seconds, covered and then incubated at ambient temperature for 30 min. Z-FR-pNa (final concentration 100. mu.M) was added to the assayThe solution was then hydrolyzed spectrophotometrically (at. lambda.405 nm) for 60 min. Calculation of apparent inhibition constants (K) from enzyme course curves using standard mathematical modelsi)。
Example 33
Cathepsin K assay
Solutions of test compounds at various concentrations were prepared in 10. mu.L of dimethyl sulfoxide (DMSO) and diluted to assay buffer (40. mu.L, containing MES, 50mM (pH 5.5); EDTA, 2.5 mM; and DDT, 2.5 mM). Human cathepsin K (0.0906 pMoles, 25 μ L assay buffer) was added to this dilution. The test solution was mixed on a shaking culture plate for 5-10 seconds, covered and then incubated at ambient temperature for 30 min. Z-Phe-Arg-AMC (4 nMoles, 25. mu.L assay buffer) was added to the assay solution, followed by spectrophotometric (. lamda.460 nm) for 5 min. Calculation of apparent inhibition constants (K) from enzyme course curves using standard mathematical modelsi)。
Example 34
Cathepsin L assay
Solutions of test compounds at various concentrations were prepared in 10. mu.L of dimethyl sulfoxide (DMSO) and diluted to assay buffer (40. mu.L, containing MES, 50mM (pH 6); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (10. mu.L, 0.2 ng/. mu.L, final concentration 0.02 ng/. mu.l) was added to the dilution. The test solution was mixed on a shaking culture plate for 5-10 seconds, covered and then incubated at ambient temperature for 30 min. Z-Phe-Arg-AMC (0.1mM, 10. mu.L, final concentration 10. mu.M) was added to the test solution, and the hydrolysis was followed spectrophotometrically (lambda 460nm) for 30 min. Calculation of apparent inhibition constants (K) from enzyme course curves using standard mathematical modelsi)。
The compounds of the present invention were tested according to the protease inhibition assay described above and were observed to exhibit selective cathepsin S inhibitory activity. Of the Compounds of the invention with respect to cathepsin SApparent inhibition constant (Ki) of about 10-10M to about 10-7M is in the range of.
Example 35
Typical pharmaceutical formulations containing a compound of formula (I):
oral preparation
10-100mg of a compound of formula I
Citric acid monohydrate 105mg
Sodium hydroxide 18mg
Flavoring agent
Proper amount of water to 100mL
Intravenous formulations
0.1-10mg of a compound of formula I
Glucose monohydrate is aliquoted after constant volume
Citric acid monohydrate 1.05mg
0.18mg of sodium hydroxide
Proper amount of water for injection is 1.0mL
Tablet formulation
A compound of formula I1%
Microcrystalline cellulose 73%
Stearic acid 25%
Colloidal silicon dioxide 1%
While there have been described and pointed out fundamental novel features of the invention as applied to preferred embodiments thereof, it will be understood that various omissions and substitutions and changes in the form and details of the illustrated pharmaceutical compositions and methods may be made by those skilled in the art without departing from the spirit of the invention. For example, it is expressly intended that all chemical group substitutions and/or method steps which perform substantially the same function in substantially the same way to achieve the same results are within the scope of the invention.
The invention is not limited to the embodiments described above, which are presented as examples only, but these embodiments can be modified in various ways within the scope of protection defined by the appended claims.

Claims (7)

1. A compound having the structure of formula (Ib):
wherein
R1Is thatOr
R3Selected from H, C6-12Aryl radical C1-6Alkyl or C1-6An alkyl group;
R4is H or C1-6An alkyl group; or
R3And R4And R3And R4The carbon atoms to which both are attached together form C3-8A cycloalkylene group;
R5is C6-12Aryl radical C1-6An alkyl group;
wherein aryl is phenyl or naphthyl;
or a pharmaceutically acceptable salt of such a compound of formula (Ib).
2. A compound according to claim 1, wherein R3Is H,Or CH3CH2CH2-。
3. A compound according to claim 1, wherein R4Is H or methyl.
4. A compound according to claim 1, wherein R5Is that
5. A compound according to claim 1 selected from the group consisting of:
morpholine-4-carboxylic acid [ (S) -1- ((S) -1-cyano-3-phenylpropylcarbamoyl) -3, 3-difluoro-4-phenyl-butyl ] -amide; and
morpholine-4-carboxylic acid [ (S) -1- (cyanomethyl-carbamoyl) -3, 3-difluoro-4-phenyl-butyl ] -amide.
6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
7. The use of a compound according to claim 1 in the manufacture of a medicament for the treatment of a patient suffering from: juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, graves 'disease, myasthenia gravis, systemic lupus erythematosus, irritable bowel disease, rheumatoid arthritis, hashimoto's thyroiditis, asthma, obstructive pulmonary disease, emphysema, or bronchiolitis.
HK07106732.3A 2003-10-24 2004-10-22 Novel keto-oxadiazole derivatives as cathepsin inhibitors HK1101871B (en)

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