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HK1110860B - Sulfonyl amino cyclic derivatives and use thereof - Google Patents

Sulfonyl amino cyclic derivatives and use thereof Download PDF

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Publication number
HK1110860B
HK1110860B HK08105290.8A HK08105290A HK1110860B HK 1110860 B HK1110860 B HK 1110860B HK 08105290 A HK08105290 A HK 08105290A HK 1110860 B HK1110860 B HK 1110860B
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HK
Hong Kong
Prior art keywords
sulfonyl
piperazine
hydroxyamino
fluorophenyl
alkyl
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HK08105290.8A
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Chinese (zh)
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HK1110860A1 (en
Inventor
D‧斯维能
A‧邦布伦
P‧戈布
C‧乔兰德-勒布伦
Original Assignee
Merck Serono Sa
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Priority claimed from PCT/EP2005/056910 external-priority patent/WO2006067114A1/en
Publication of HK1110860A1 publication Critical patent/HK1110860A1/en
Publication of HK1110860B publication Critical patent/HK1110860B/en

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Description

Sulfonylamino cyclic derivatives and uses thereof
Technical Field
The present invention relates to sulfonyl amino cyclic derivatives of formula (I) and pharmaceutical compositions thereof, their use in the treatment and/or prevention of autoimmune and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, cancer, respiratory diseases and fibrosis, and methods for their preparation. The invention particularly relates to sulfonyl amino cyclic derivatives useful for modulating, particularly inhibiting, the activity or function of matrix metalloproteinases, such as gelatinases and metalloelastases.
Technical Field
Metalloproteinases belong to the general family of proteases (enzymes) and are so named because they depend on the metal ion (zinc) of the active site.
Matrix Metalloproteinases (MMPs) form a subfamily of metalloproteinases, whose primary biological function is to catalyze the breakdown of connective tissue and extracellular matrix by hydrolyzing various tissue or matrix components such as collagen, gelatin, proteoglycans, fibronectin, and elastin.
The family of matrix metalloproteinases is further divided according to their function and substrates (Visse et al, 2003, Circ. Res., 92, 827-839) which include collagenases (MMP-1, MMP-8, MMP-13 and MMP-18), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10 and MMP-11), cell membrane-type MMPs (MT-MMP-1 to MT-MMP-6 and MMP-14, MMP-15, MMP-16, MMP-17, MMP-24 and MMP-25), matrilysins (MMP-7 and MMP-26) and other unclassified MMPs, such as metalloelastase (MMP-12), amelysin (MMP-20), Epilysin (MMP-28), MMP-19, MMP-22, and MMP-23.
In addition to their connective tissue degradation function, MMPs are involved in TNF- α biosynthesis and post-translational proteolytic processes, or in the release of biologically important membrane proteins (Hooper et al, 1997, Biochem J., 321, 265-279). For example, MMPs contribute to the local growth and spread of malignant lesions and are therefore targets for the development of anti-tumor drugs (Fingleton et al, 2003, Expert opin. Ther. targets, 7 (3): 385-. Inflammatory diseases such as arthritis (Clark et al, 2003, expert. opin. Therr Targets, 7 (1): 19-34), respiratory diseases such as emphysema, atherosclerosis (Galis et al, 2002, circ. Res., 90: 251-.
A variety of matrix metalloproteinase inhibitors (MMPI) have been developed (Skiles et al, 2001, Current medicinal Chemistry, 8, 425-474; Peterson, 2004, Heart Failure Reviews, 9, 63-79; Henrotin et al, 2002, Expert Opin. the. patents, 12 (1): 29-43). However, many MMPIs show dose-limiting side effects of musculoskeletal syndrome (tendonitis, fibroplasia, mylasia, arthrasia). It has been proposed that MMP-1 or MMP-14 inhibition may lead to these side effects.
Therefore, there is an increasing need to develop matrix metalloproteinase inhibitors with well-defined specificity characteristics.
Specific inhibitors, particularly inhibitors directed against MMP-1, including MMP-13 (Stotnicki et al, 2003, Current Opinion in Drug Discovery and Development, 6 (5): 742-759), MMP-12 inhibitors (WO 01/83461; WO03/070711), MMP-2, and MMP-9 inhibitors (Wada et al, 2002, J.Med.chem.45, 219-232) have been reported.
The high relevance of the metalloprotease pathway in some of the widely spread diseases underscores the importance of developing inhibitors, including selective inhibitors of MMPs, such as gelatinases of MMP-2 and/or MMP-9 and/or MMP-12.
Disclosure of Invention
It is an object of the present invention to provide substances suitable for the treatment and/or prevention of autoimmune and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer, respiratory diseases, preterm labor and fibrosis-related diseases.
It is a further object of the present invention to provide substances which are suitable for the treatment and/or prophylaxis of multiple sclerosis, rheumatoid arthritis, emphysema, chronic obstructive pulmonary disease and fibrosis-related diseases.
It is apparent that it is an object of the present invention to provide chemical compounds, such as gelatinases and/or elastase enzymes, which modulate, in particular inhibit, the activity or function of matrix metalloproteinases, such as mammalian, in particular human.
It is a further object of the present invention to provide novel pharmaceutical formulations for the treatment and/or prevention of diseases selected from the group consisting of: autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer, respiratory diseases, premature birth and fibrosis.
It is a further object of the present invention to provide a method for producing the chemical compound according to the present invention.
It is a further object of the present invention to provide novel compounds for use in the process for the manufacture of chemical compounds according to the present invention.
It is a final object of the invention to provide a method for the treatment and/or prevention of a disease selected from the group consisting of: autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer, respiratory diseases, premature birth and fibrosis.
In one aspect, the present invention provides sulfonyl amino cyclic derivatives according to the general formula (I):
wherein, A, B, R1，R2，R3X, Y, m, n and p are defined in the detailed description.
In a second aspect, the present invention provides a sulfonyl amino cyclic derivative according to formula (I) as general formula (I) for use as a medicament.
In a third aspect, the present invention provides the use of a sulfonyl amino cyclic derivative according to formula (I) in the preparation of a pharmaceutical composition for the treatment of a disease selected from: autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer, respiratory diseases, premature birth and fibrosis.
In a fourth aspect, the present invention provides a pharmaceutical composition comprising at least one sulfonamido cyclic derivative of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient therefor.
In a fifth aspect, the present invention provides a method of treatment comprising administering to a patient in need thereof a sulfonyl amino cyclic derivative according to formula (I).
In a sixth aspect, the present invention provides a method of synthesizing sulfonyl amino cyclic derivatives of formula (I).
In a seventh aspect, the present invention provides a compound according to formula (II):
wherein, A, B, R1，R2，R3X, Y, m, n and p are defined in the detailed description.
In an eighth aspect, the invention provides a compound according to formula (III):
wherein, A, B, R1，R2，R3X, Y, m, n and p are defined in the detailed description.
In a ninth aspect, the invention provides a compound according to formula (VIII):
wherein, A, B, R1，R2，R3X, Y, m, n and p are defined in the detailed description.
In a tenth aspect, the invention provides a compound according to formula (VII):
wherein, A, B, R1，R2，R3X, Y, m, n and p are defined in the detailed description.
Detailed Description
In the following, definitions of the various chemical components forming the compounds according to the present invention will be provided for uniform application throughout the specification and claims, unless a definition specifically provided otherwise provides a broader definition.
The term "MMP" refers to "matrix metalloproteases". For a recent MMP review, see Visse et al, 2003, supra; fingleton et al, 2003, supra; clark et al, 2003, supra and Doherty et al, 2002, Exterposition Therapeutic Patents12 (5): 665-707.
Illustrative, non-limiting examples of these MMPs are:
collagenase: are often associated with diseases in which the attachment is based on collagen tissue cleavage, such as rheumatoid arthritis and osteoarthritis:
MMP-1 (also known as collagenase 1 or fibroblast collagenase), substrate: collagen I, collagen II, collagen III, gelatin and proteoglycan. Overexpression of this enzyme is believed to be associated with emphysema, with hyperkeratosis and atherosclerosis, and is overexpressed alone in papillary tumors.
MMP-8 (also known as collagenase 2, or neutrophil collagenase), substrate: over-expression of collagen I, collagen II, collagen III, collagen V, collagen VII, collagen IX, gelatin, can lead to non-healing chronic ulcers.
MMP-13 (also known as collagen 3), substrate: collagen I, collagen II, collagen III, collagen IV, collagen IX, collagen X, collagen XIV, fibronectin, gelatin, which were recently identified as being overexpressed alone in breast cancer and involved in rheumatoid arthritis.
And (3) the stromelysin:
MMP-3 (also known as stromelysin 1), substrate: collagen III, collagen IV, collagen V, collagen IX, collagen X, larninin, nestin, the overexpression of which is believed to be involved in atherosclerosis, aneurysm and restenosis.
Gelatinase-the beneficial effect that is believed to exert inhibition on cancer, specifically invasion and metastasis.
MMP-2 (also known as gelatinase a, 72kDa gelatinase, basement membrane collagenase or proteoglycanase), substrate: collagen I, collagen II, collagen IV, collagen V, collagen VII, collagen X, collagen XI, collagen XIV, elastin, fibronectin, gelatin, nestin, are believed to be associated with tumor progression specific for collagen type IV (high expression observed in solid tumors, believed to be associated with their growth, infiltration, promotion of new blood vessels and metastasis) and also to acute lung infection and respiratory distress syndrome (Krishna et al, 2004, Expert opin. invest. drugs, 13 (3): 255-.
MMP-9 (also known as gelatinase B, or 92kDa gelatinase), substrate: collagen I, collagen III, collagen IV, collagen V, collagen VII, collagen X, collagen XIV, elastin, fibronectin, gelatin, entactin. It is believed that The above enzymes are involved in tumor progression specific for collagen type IV, released by eosinophils in response to extrinsic factors such as air pollution, allergens and viruses, and involved in inflammatory responses in multiple sclerosis (Opdenakker et al 2003, The Lancet neurology, 2, 747-. MMP-9 is also thought to be involved in Stroke (Horstmann et al, 2003, Stroke34(9), 2165-70).
Unclassified MMP:
MMP-12 (also known as metalloelastase, human macrophage elastase or HME), substrate: fibronectin, leninin. MMP-12 is believed to play an important role in tumor growth inhibition and regulation of inflammation such as multiple sclerosis (Vos et al, 2003, Journal of neuroimaging, 138, 106-. MMP-12 is also believed to play a pathological role in emphysema, COPD (Bellvisi et al, 2003, Inflamm. Res.52; 95-100), atherosclerosis, aneurysms, and restenosis.
By expression of "MMP-related diseases" is meant the treatable diseases according to the invention, which includes all diseases in which the expression and/or activity of at least one MMP needs to be reduced, whatever the cause of the disease. These disorders include, for example, those caused by inappropriate degradation of the extracellular matrix (ECM).
Illustrative, but non-limiting examples of these MMP-related diseases are:
cancers, such as breast cancer and solid tumors; inflammatory diseases, such as inflammatory bowel disease and neuroinflammation, such as multiple sclerosis; pulmonary diseases such as Chronic Obstructive Pulmonary Disease (COPD), emphysema, asthma, acute lung injury, and acute respiratory distress syndrome; premature delivery; dental diseases such as periodontal disease and gingivitis; osteoarticular diseases such as osteoarthritis and rheumatoid arthritis; liver diseases such as liver fibrosis, cirrhosis and chronic liver disease; fibrotic diseases, such as pulmonary fibrosis, pancreatitis, lupus, glomerulosclerosis, systemic sclerosis skin fibrosis, post-radiation fibrosis and cystic fibrosis; vascular pathologies such as aortic aneurysm, atherosclerosis, hypertension, cardiomyopathy and myocardial infarction; restenosis; ocular diseases such as diabetic retinopathy, dry eye, macular degeneration and corneal ulceration, and degenerative diseases of the central nervous system such as amyotrophic lateral sclerosis.
“C1-C6-alkyl "refers to a monovalent alkyl group having 1 to 6 carbon atoms. Examples of radicals of this term are as follows: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, n-hexyl and the like. Analogize, "C1-C12-alkyl "refers to a monovalent alkyl group having 1 to 12 carbon atoms, including" C1-C6Alkyl radicals and heptyl, octyl, nonyl, decanoyl, undecanoyl and dodecanoyl radicals, and "C1-C10-alkyl "means a monovalent alkyl group having 1 to 10 carbon atoms," C1-C8-alkyl "means a monovalent alkyl group having 1 to 8 carbon atoms," C1-C5-alkyl "refers to a monovalent alkyl group having 1 to 5 carbon atoms.
"heteroalkyl" means C1-C12-alkyl, preferably C1-C6-alkyl, wherein at least one carbon atom is substituted by a heteroatom selected from O, N or S, including 2-methoxyethyl.
"aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Aryl groups include phenyl, naphthyl, phenanthrenyl (phenantrenyl), and the like.
“C1-C6-alkylaryl "means having a radical-C1-C6Alkyl-substituted aryl groups including methylphenyl, ethylphenyl and the like.
"aryl group C1-C6-alkyl "means C substituted by an aryl group1-C6Alkyl groups including 3-phenylpropyl, benzyl, and the like.
"heteroaryl" refers to a monocyclic heteroaromatic group, or a bicyclic or tricyclic fused cyclic heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-triazinyl, 1, 2, 3-triazinyl, benzofuranyl, [2, 3-dihydro ] benzofuranyl, isobenzofuranyl, 1, 3 benzodioxol-5-yl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1, 2-a ] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, 2, 3-naphthyridinyl (pthalazinyl), quinoxalinyl, cinnolinyl (cinnolinyl), 1, 5-naphthyridinyl (napthylidinyl), pyrido [3, 4-b ] pyridyl, pyrido [3, 2-b ] pyridyl, pyrido [4, 3-b ] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5, 6, 7, 8-tetrahydroquinolyl, 5, 6, 7, 8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthyl or benzoquinolyl.
“C1-C6By "alkylheteroaryl" is meant having a C1-C6Alkyl-substituted heteroaryl groups including methylfuran and the like.
"heteroaryl C1-C6-alkyl" means C substituted with one heteroaryl1-C6Alkyl groups including furylmethyl and the like.
“C2-C6Alkenyl "means an alkenyl group preferably having 2 to 6 carbon atoms and at least 1 or 2 sites for unsaturated alkenyl. The alkenyl group preferably includes a vinyl group (-CH ═ CH)2) N-2-propenyl (allyl, -CH)2CH＝CH2) And the like.
“C2-C6-alkenylaryl "means having one C2-C6Alkenyl-substituted aryl groups including vinylphenyl and the like.
"aryl group C2-C6-alkenyl "means C substituted with one aryl group2-C6Alkenyl groups including phenylvinyl and the like.
“C2-C6-alkenylheteroaryl "means having one C2-C6Alkenyl-substituted heteroaryl groups including vinylpyridinyl and the like.
"heteroaryl group C2-C6-alkenyl "means C substituted with one heteroaryl2-C6Alkenyl groups including pyridylvinyl and the like.
“C2-C6-alkynyl "means an alkynyl group preferably having from 2 to 6 carbon atoms and having at least 1 to 2 sites for unsaturated alkynyl, and alkynyl groups preferably include ethynyl (-C ≡ CH), propynyl (-CH)2C.ident.CH) and the like.
“C3-C8-cycloalkyl "refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Cycloalkyl groups preferably include cyclopentyl, cyclohexyl, norbornyl, and the like.
"Heterocycloalkyl" means a radical C according to the above definition3-C8-cycloalkyl groups, wherein up to 3 carbon atoms are substituted by heteroatoms selected from the group consisting of O, S, NR, wherein R is defined as hydrogen or methyl. Heterocycloalkyl groups include pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, and the like.
“C1-C6-alkylcycloalkyl "means having one C1-C6-alkyl substituted C3-C8Cycloalkyl groups, including methylcyclopentyl and the like.
"cycloalkyl group C1-C6By alkyl is meant having a C3-C8-cycloalkyl-substituted C1-C6Alkyl groups including 3-cyclopentylpropyl and the like.
“C1-C6-Alkylheterocycloalkyl "means having a C1-C6Alkyl-substituted heterocycloalkyl groups, including 1-methylpiperazine and the like.
"Heterocycloalkyl radical C1-C6-alkyl "means C substituted with a heterocycloalkyl group1-C6Alkyl groups including 4-methylpiperidinyl and the like.
"carboxy" refers to the group-C (O) OH.
"carboxy group C1-C6-alkyl "means C substituted by one carboxyl group1-C6Alkyl groups including 2-carboxyethyl and the like.
"acyl" refers to the group-C (O) R, wherein R includes "C1-C12-alkyl ", preferably" C1-C6-alkyl "," aryl "," heteroaryl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl C1-C6-alkyl "," heteroaryl C1-C6-alkyl "," C3-C8-cycloalkyl group C1-C6-alkyl "or" heterocycloalkyl C1-C6-an alkyl group ".
"acyl group C1-C6-alkyl "means C substituted by an acyl group1-C6Alkyl groups including acetyl, 2-acetoacetyl and the like.
"acylaryl" refers to an aryl group substituted with an acyl group, including 2-acetylphenyl and the like.
"acyloxy" refers to the group-OC (O) R, where R includes H and "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl radical"," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ".
"acyloxy group C1-C6-alkyl "means C substituted with one acyloxy group1-C6Alkyl groups including ethyl propionate and the like.
"alkoxy" refers to the group-O-R, where R includes "C1-C6-alkyl "or" aryl "or" heteroaryl "or" aryl C1-C6-alkyl "or" heteroaryl C1-C6-an alkyl group ". The alkoxy group preferably includes, for example, methoxy, ethoxy, phenoxy and the like.
"alkoxy group C1-C6By alkyl is meant having a C1-C6Alkyl-substituted alkoxy groups including methoxy, methoxyethyl, and the like.
"alkoxycarbonyl" refers to the group-C (O) OR, where R includes H, and "C1-C6-alkyl "or" aryl "or" heteroaryl "or" aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "or" heteroalkyl ".
"alkoxycarbonyl group C1-C6-alkyl "means C substituted by one alkoxycarbonyl group1-C5Alkyl groups including 2- (benzyloxycarbonyl) ethyl and the like.
"aminocarbonyl" refers to the group-C (O) NRR 'where each R, R' independently includes hydrogen or C1-C6-alkyl or aryl or heteroaryl or "aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "including N-phenylcarboxamide.
"aminocarbonyl group C1-C6-alkyl "means substituted by one aminocarbonyl groupC1-C6Alkyl groups including 2- (dimethylaminocarbonyl) ethyl, N-ethylacetamide, N, N-diethylacetamide, and the like.
"amido" refers to the group-NRC (O) R ', wherein each R, R' is independently hydrogen, and "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ".
"amido C1-C6-alkyl "means C substituted with one amido group1-C6Alkyl groups including 2- (propylamino) ethyl and the like.
"ureido" means a radical-NRC (O) NR ' R ' wherein each R, R ' is independently hydrogen, or "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-alkyl ", and wherein R' and R", and the nitrogen atom to which they are attached, optionally form a 3-8 membered heterocycloalkyl ring.
"ureido group C1-C6-alkyl "denotes C substituted by a ureido group1-C6Alkyl groups including 2- (N' -methylureido) ethyl and the like.
"carbamoyl ester" refers to the group-NRC (O) OR ', wherein each R, R' is independently hydrogen, and "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ".
"amino" refers to the group-NRR ', where each R, R' is independently hydrogen or "C1-C6-alkyl "or" aryl "or" heteroaryl "or" C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl ", or" cycloalkyl ", or" heterocycloalkyl ", and wherein R and R', and the nitrogen atom to which they are attached, may optionally form a 3-8 membered heterocycloalkyl ring.
"amino group C1-C6-alkyl "means C substituted by one amino group1-C5Alkyl groups including 2- (1-pyrrolidinyl) ethyl, diethylaminomethyl and the like.
"ammonium" means a positively charged group-N+RR ' R ' where each R, R ' is independently "C1-C6-alkyl "or" C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl ", or" cycloalkyl ", or" heterocycloalkyl ", and wherein R and R', and the nitrogen atom to which they are attached, are optionally substitutedForming a 3-8 membered heterocycloalkyl ring.
“C1-C6By alkylammonium is meant C substituted by one ammonium1-C6Alkyl groups including 1-ethylpyrrolidinium (1-ethylpyrrolidinium) and the like.
"halogen" refers to fluorine, chlorine, bromine and iodine atoms.
"Sulfonyloxy" refers to the group-OSO2-R, wherein R is selected from H, "C1-C6-alkyl ", halogen-substituted" C1-C6Alkyl radicals, e.g. -OSO2-CF3Group "C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ".
"Sulfonyloxy group C1-C6-alkyl "means C substituted by one sulfonyloxy group1-C6Alkyl groups including 2- (methylsulfonyloxy) ethyl and the like.
"Sulfonyl" refers to the group "-SO2-R "wherein R is selected from H," aryl "," heteroaryl "," C1-C6-alkyl ", halogen-substituted" C1-C6-alkyl ", such as-SO2-CF3Group "C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "And an aryl group C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ".
"Sulfonyl group C1-C6-alkyl "means C substituted by one sulfonyl group1-C5Alkyl groups including 2- (methylsulfonyl) ethyl and the like.
"sulfinyl" refers to the group "-S (O) -R", wherein R is selected from H and "C1-C6-alkyl ", halogen-substituted" C1-C6Alkyl radicals, e.g. -SO-CF3Group "C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ".
"sulfinyl group C1-C6-alkyl "means C substituted with one sulfinyl group1-C6Alkyl groups including 2- (methylsulfinyl) ethyl and the like.
"Thioalkyl" refers to the group-S-R, where R includes H and "C1-C6-alkyl ", halogen-substituted" C1-C6Alkyl radicals, e.g. -SO-CF3Group "C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylRadical C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ". The sulfanyl group preferably includes methylsulfanyl group, ethylsulfanyl group and the like.
"Thioalkyl radical C1-C6-alkyl "means C substituted by one sulfanyl group1-C5Alkyl groups including 2- (ethylsulfanyl) ethyl and the like.
"sulfonamido" refers to the group-NRSO2-R ', wherein each R, R' independently comprises hydrogen and "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ".
"Sulfonylamino C1-C6-alkyl "means C substituted by one sulfonamido group1-C6Alkyl groups including 2- (ethylsulfonylamino) ethyl and the like.
"aminosulfonyl" refers to the group-SO2-NRR ', wherein each R, R' independently comprises hydrogen and "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heteroCycloalkyl "," aryl "," heteroaryl "," aryl C1-C6-alkyl "or" heteroaryl C1-C6-alkyl "," aryl C2-C6-alkenyl "," heteroaryl C2-C6-alkenyl "," aryl C2-C6-alkynyl "," heteroaryl C2-C6-alkynyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-an alkyl group ".
"Aminosulfonyl group C1-C6-alkyl "means C substituted with one aminosulfonyl group1-C6Alkyl groups including 2- (cyclohexylaminosulfonyl) ethyl and the like.
"substituted or unsubstituted": unless defined by individual substituents, the above-indicated groups, such as "alkenyl", "alkynyl", "aryl", "heteroaryl", "cycloalkyl" and "heterocycloalkyl", and the like, are optionally substituted with 1 to 5 substituents selected from the group consisting of: "C1-C6-alkyl "," C2-C6-alkenyl "," C2-C6-alkynyl "," cycloalkyl "," heterocycloalkyl "," aryl C1-C6-alkyl "," heteroaryl C1-C6-alkyl "," cycloalkyl C1-C6-alkyl "," heterocycloalkyl C1-C6-alkyl "," amino "," ammonium "," acyl "," acyloxy "," acylamino "," aminocarbonyl "," alkoxycarbonyl "," ureido "," aryl "," carbamate "," heteroaryl "," sulfinyl "," sulfonyl "," alkoxy "," sulfanyl "," halogen "," carboxyl ", trihalomethyl, cyano, hydroxyl, mercapto, nitro and the like.
"pharmaceutically acceptable salt or complex" refers to a salt or complex of a compound as identified below, such as of formula (I). Examples of such salts include, but are not limited to, base addition salts formed by reacting a compound of formula (I) with an organic or inorganic base, such as a hydroxide, a carbonate or bicarbonate of a metal cation, such as those selected from the group consisting of alkali metals (sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), or with a primary, secondary or tertiary alkyl amine. Amine salts are derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-Me-glucamine, N' -bis (benzyl) -1, 2-ethylenediamine, tromethamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine and the like within the scope of the present invention.
Also included are salts of acid addition with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts of acid addition with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
"pharmaceutically active derivative" refers to any compound that is capable of providing, directly or indirectly, an activity as disclosed herein to a recipient. The term "indirect" also includes prodrugs that can be converted to a pharmaceutically active form by endogenous enzymes or metabolism. The prodrug consists of the active drug compound itself and a chemical masking group.
"enantiomeric excess" (ee) refers to a product which is obtained by asymmetric synthesis and can be isolated, i.e., synthesis involving non-racemic starting materials and/or reagents or synthesis involving at least one enantioselective step, whereby an enantiomer is obtained in excess of at least about 52% ee.
"interferon" or "IFN" as used herein is meant to include any molecule so defined in the literature, including, for example, any type of IFN as described in the "technical background" section above. Specifically, IFN- α, IFN- β and IFN- γ are included as defined above. According to the invention, IFN- β is a preferred IFN. Suitable IFN- β s, e.g. Liben, according to the invention are on the marketOr Beitailong(Schering)。
The term "interferon-beta (IFN-beta or IFN-beta)" as used herein is intended to include fibroblast interferons, particularly humanized fibroblast interferons isolated from biological fluids or obtained from recombinant DNA techniques of prokaryotic or eukaryotic host cells, and salts, functional derivatives, variants, analogs and active fragments thereof. Preferably IFN- β means recombinant interferon β -1 a.
Suitable IFN- β s, e.g. Liben, according to the invention are on the marketOr BeitailongAccording to the present invention, humanized interferon is preferably used. The term interferon, as used herein, is intended to include salts, functional derivatives, variants, analogs and active fragments thereof.
Libi (R) ratio(recombinant interferon-beta) is the most recently developed interferon for the treatment of Multiple Sclerosis (MS), indicating a significant advance in the therapeutic approach. Libi (R) ratioIs Interferon (IFN) -beta-1 a, produced by a mammalian cell line. Subcutaneous administration of interferon-beta-1 a three times per week has been found to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS). Interferon-beta-1 a by MRI assayHas good effects of reducing the frequency and degree of relapse, and relieving the burden of diseases and disease activities on the long-term course of MS.
According to the present invention, the dosage of IFN- β in the treatment of relapsing-remitting MS depends on the type of IFN- β used.
According to the invention, when IFN is IFN-beta-1 b, recombinantly produced by E.coli, it is commercially available under the trademark IFNPreferably, a dose of about 250 to 300 μ g or 8MIU to 9.6MIU per person is administered subcutaneously every two days.
According to the present invention, when IFN is IFN-. beta.1 a recombinantly produced from Chinese hamster ovary cells (CHO cells), it is commercially available under the trademark "IFN-. beta.1Preferably, a dosage of about 30 to 33 μ g or 6MIU to 6.6MIU per person is administered intramuscularly once a week.
According to the invention, when IFN is IFN-beta-1 a recombinantly produced from Chinese hamster ovary cells (CHO cells), it is commercially available under the trademark LibixPreferably, a dose of about 22 to 44 μ g or 6MIU to 12MIU per person is administered subcutaneously three times per week (TIW).
The compounds according to the invention also include pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts of formula (I) are preferably acid addition salts with pharmaceutically acceptable acids, such as the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate and p-toluenesulfonate salts.
It has been found that the compounds of the invention are modulators of matrix metalloproteinases, such as gelatinases and elastase, including MMP-2 and/or MMP-9, preferably MMP-12. When matrix metalloproteases are inhibited by the compounds of the invention, the inhibited MMPs are unable to elicit their enzymatic, biological and/or pharmaceutical effects. The compounds of the invention are therefore useful for the treatment and prevention of autoimmune and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer, premature birth, respiratory diseases and fibrosis.
In one embodiment, the present invention provides derivatives of formula (I) and optically active forms thereof as enantiomers, diastereomers and racemates thereof, and pharmaceutically acceptable salts thereof:
in the formula:
a is-CR4R5Including gem-dimethyl;
b is-CR4’R5', including methylene (methylene);
R1selected from optionally substituted aryl groups including optionally substituted phenyl groups such as phenyl, halophenyl groups (e.g., 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl), alkoxyphenyl groups (e.g., 4- ((phenylmethyl) oxy) phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- (phenoxy) phenyl, 4- (ethoxy) phenyl, 3, 4-dimethoxyphenyl, optionally substituted C1-C6Alkylphenyl (e.g., 4-trifluoromethylphenyl, 4-methylphenyl) and optionally substituted biphenyl (e.g., 4-biphenyl-4-yl); optionally substituted heteroaryl, including optionally substituted pyridyl, such as pyridyl (e.g. pyridin-2-yl), optionally substituted C1-C6Alkylpyridyl (e.g. 5-trifluoromethylpyridin-2-yl) and halopyridyl (e.g. 5-chloropyridin-2-yl, 5-bromopyridin-2-yl), optionally substituted pyrimidinyl (e.g. pyrimidin-2-yl), optionally substituted benzeneAnd dioxoles (e.g., 1, 3-benzodioxol-5-yl); optionally substituted C3-C8-cycloalkyl and optionally substituted heterocycloalkyl;
R2is selected from H; optionally substituted C1-C6-alkyl, including methyl; optionally substituted C2-C6Alkenyl and optionally substituted C2-C6-an alkynyl group;
R3is selected from H; -Si (C)1-C6-alkyl groups)3(ii) a Optionally substituted amino C1-C6-alkyl, including 4-diethylaminomethyl; optionally substituted C1-C6-alkyl groups including ethyl, propyl, butyl and pentyl; optionally substituted aryl groups including substituted phenyl groups such as phenyl, halophenyl (4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl), alkoxyphenyl (such as 3-methoxyphenyl), optionally substituted heteroarylphenyl groups such as oxadiazolphenyl (such as 1, 2, 4-oxadiazol-3-ylphenyl); optionally substituted heteroaryl, including optionally substituted pyridyl, such as pyridyl (e.g., pyridin-3-yl), optionally substituted benzodioxole (e.g., 1, 3-benzodioxol-5-yl), optionally substituted quinolyl (e.g., 3-quinolin-3-yl); optionally substituted aryl C1-C6-alkyl including arylmethyl, such as phenylmethyl; optionally substituted heteroaryl C1-C6-an alkyl group; optionally substituted C3-C8-cycloalkyl group C1-C6-an alkyl group; optionally substituted heterocycloalkyl C1-C6Alkyl including morpholinomethyl (such as morpholino-4-ylmethyl) and pyrrolidinylmethyl (such as pyrrolidin-1-ylmethyl); optionally substituted C3-C8-cycloalkyl and optionally substituted heterocycloalkyl;
R4，R5，R4' and R5' are each selected from H; halogen; optionally substituted C1-C6-alkyl, including methyl; optionally substituted C2-C6Alkenyl and optionally substituted C2-C6-an alkynyl group;
x is selected from C, CH and N;
y is selected from CH and CH2(ii) a And the radical-X.. Y-is selected from-C ═ CH-, -CH2-and-N-CH2-；
m is selected from 0, 1 and 2; n is selected from 0 and 1;
p is selected from 1 and 2.
In a preferred embodiment, the invention provides derivatives of formula (I) wherein R1Is optionally substituted aryl, including optionally substituted phenyl, such as 4-fluorophenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4- ((phenylmethyl) oxy) phenyl, 4-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- (phenoxy) phenyl, 4- (ethoxy) phenyl, 3, 4-dimethoxyphenyl, 4-trifluoromethylphenyl, 4-methylphenyl and 4-biphenyl-4-yl.
In a preferred embodiment, the invention provides derivatives of formula (I) wherein R1Is optionally substituted heteroaryl, including optionally substituted pyridyl, such as pyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 5-chloropyridin-2-yl, 5-bromopyridin-2-yl; including optionally substituted pyrimidinyl, such as pyrimidin-2-yl, and optionally substituted benzodioxoles, such as 1, 3-benzodioxol-5-yl.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein R2Is H.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein R3Selected from optionally substituted aryl groups including optionally substituted phenyl groups such as phenyl, 3-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 1, 2, 4-oxadiazol-3-ylphenyl and optionally substituted heteroaryl groups including optionally substituted pyridyl groups such as pyridin-3-yl; including optionally substituted benzodioxoles, such as 1, 3-benzodioxol-5-yl; including optionally substituted quinolyl, e.g. 3-quinolin-3-yl and including optionally substituted quinolylBenzodioxolyl groups such as 1, 3-benzodioxol-5-yl.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein R3Selected from optionally substituted C1-C6-alkyl groups including ethyl, propyl, butyl and pentyl; optionally substituted aryl C1-C6Alkyl, including 4-phenylmethyl, optionally substituted heteroaryl C1-C6Alkyl, optionally substituted heteroaryl C1-C6-an alkyl group; optionally substituted C3-C8-cycloalkyl group C1-C6-an alkyl group; and optionally substituted heterocycloalkyl C1-C6Alkyl, including morpholinomethyl, such as morpholino-4-ylmethyl) and pyrrolidinylmethyl, such as pyrrolidin-1-ylmethyl.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein R3Is H.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein R3Is an optionally substituted amino group C1-C6-alkyl including diethylaminomethyl.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein R3is-Si (CH)3)3。
In another preferred embodiment, the invention provides derivatives of formula (I) wherein Y is CH2。
In another preferred embodiment, the invention provides derivatives of formula (I) wherein X is CH and Y is CH2。
In another preferred embodiment, the invention provides derivatives of formula (I) wherein X is N and Y is CH2。
In another preferred embodiment, the invention provides derivatives of formula (I) wherein A is gem-dimethyl.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein B is methyl.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein n is 0.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein m is 0.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein n is 1.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein m is 1.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein n and m are 1.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein p is 1.
In another preferred embodiment, the invention provides derivatives of formula (I) wherein p is 2.
In a preferred embodiment, the present invention provides sulfonyl amino cyclic derivatives of formula (I), wherein R1Selected from optionally substituted aryl and optionally substituted heteroaryl; r2Is H or methyl; y is CH2(ii) a X, A, B, n, m, p and R3As defined above.
In another preferred embodiment, the present invention provides sulfonyl amino cyclic derivatives of formula (I), wherein R1Selected from optionally substituted aryl and optionally substituted heteroaryl; r2Is H or methyl; y is CH2(ii) a p is 1; x, A, B, n, m and R3As defined above.
In another preferred embodiment, the present invention provides sulfonyl amino cyclic derivatives of formula (I), wherein R1Selected from optionally substituted aryl and optionally substituted heteroaryl; r2Is H or methyl; x isN; y is CH2(ii) a p is 2; a, B, n, m and R3As defined above.
In another preferred embodiment, the present invention provides sulfonyl amino cyclic derivatives of formula (I), wherein R1Selected from optionally substituted aryl and optionally substituted heteroaryl; r2Is H or methyl; a is C (CH)3)2(ii) a B is CH2(ii) a n and m are 1; x, Y, B, p and R3As defined above.
In another preferred embodiment, the present invention provides sulfonyl amino cyclic derivatives of formula (I), wherein R1Selected from optionally substituted aryl and optionally substituted heteroaryl; r2Is H; x is N; y is CH2(ii) a n and m are 0; p is 1; r3As defined above.
In yet another preferred embodiment, the present invention provides sulfonyl amino cyclic derivatives of formula (I), wherein R1Selected from optionally substituted aryl and optionally substituted heteroaryl; r2Is H; x is N; y is CH2(ii) a n and m are 0; p is 1; and R3Selected from optionally substituted C1-C6-an alkyl group; optionally substituted aryl C1-C6Alkyl and optionally substituted heteroaryl C1-C6-an alkyl group.
In yet another preferred embodiment, the present invention provides sulfonyl amino cyclic derivatives of formula (I), wherein R1Selected from optionally substituted aryl and optionally substituted heteroaryl; r2Is H; x is N; y is CH2(ii) a n and m are 0; p is 1; and R3Selected from optionally substituted aryl and optionally substituted heteroaryl.
According to the present invention, the sulfonyl amino cyclic derivatives of general formula (I) specifically include compounds selected from the group consisting of:
3- (1, 3-benzodioxol-5-yl) -1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -2-propynyl (hydroxy) carboxamide;
1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -3- (trimethylsilyl) -2-propynyl (hydroxy) carboxamide;
hydroxy [1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } -3- (trimethylsilyl) prop-2-yn-1-yl ] carboxamide;
1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -3-phenyl-2-propynyl (hydroxy) carboxamide;
1- [ ({4- [4- (benzyloxy) phenyl ] -1-piperazinyl } sulfonyl) methyl ] -2-octynyl (hydroxy) carboxamide;
1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -4-phenyl-2-butynyl (hydroxy) carboxamide;
1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -2-octynyl (hydroxy) carboxamide;
1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -3- (3-pyridyl) -2-propynyl (hydroxy) carboxamide;
hydroxy [1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -3- (3-pyridinyl) -2-propynyl ] carboxamide;
hydroxy [3- (3-methoxyphenyl) -1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -2-propynyl ] carboxamide;
4- (diethylamino) -1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -2-butynyl (hydroxy) carboxamide;
hydroxy (1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } prop-2-yn-1-yl) carboxamide;
hydroxy {1- [ ({4- [4- (methoxy) phenyl ] piperidin-1-yl } sulfonyl) methyl ] -3-phenylprop-2-yn-1-yl } carboxamide;
hydroxy (1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } hex-2-yn-1-yl) carboxamide;
[1- ({ [4- (2-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
hydroxy (1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } oct-2-yn-1-yl) carboxamide;
hydroxy {1- [ ({4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide;
[1- ({ [4- (4-fluorophenyl) piperidin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
hydroxy {1- [ ({4- [4- (methoxy) phenyl ] piperidin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide;
{1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3- [3- (methoxy) phenyl ] prop-2-yn-1-yl } hydroxyformamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) hex-2-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3-quinolin-3-ylprop-2-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (4-fluorophenyl) piperidin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] hydroxyformamide;
hydroxy (3-phenyl-1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } prop-2-yn-1-yl) carboxamide;
hydroxy { 3-phenyl-1- [ ({4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl } sulfonyl) methyl ] prop-2-yn-1-yl } carboxamide;
hydroxy {1- [ ({4- [4- (methoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] -3-phenylprop-2-yn-1-yl } carboxamide;
{1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3- [4- (1, 2, 4-oxadiazol-3-yl) phenyl ] prop-2-yn-1-yl } hydroxyformamide;
hydroxy {1- [ ({4- [4- (methoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide;
(1- { [ (4-biphenyl-4-ylpiperazin-1-yl) sulfonyl ] methyl } -3-phenylpropan-2-yn-1-yl) hydroxyformamide;
[1- ({ [4- (5-chloropyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
hydroxy (1- { [ (4-pyrimidin-2-ylpiperazin-1-yl) sulfonyl ] methyl } oct-2-yn-1-yl) carboxamide;
hydroxy (1- { [ (4-phenylpiperazin-1-yl) sulfonyl ] methyl } oct-2-yn-1-yl) carboxamide;
[1- ({ [4- (4-chlorophenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
hydroxy {1- [ ({4- [2- (methoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide;
hydroxy {1- [ ({4- [3- (methoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-5-phenylpent-4-yn-1-yl ] hydroxyformamide;
{4- (diethylamino) -1- [ ({4- [4- (methoxy) phenyl ] piperidin-1-yl } sulfonyl) methyl ] but-2-yn-1-yl } hydroxyformamide;
hydroxy {1- [ ({4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide;
hydroxy {1- [ ({4- [4- (phenoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) hept-2-yn-1-yl ] hydroxyformamide;
{3- (2-fluorophenyl) -1- [ ({4- [4- (methoxy) phenyl ] piperidin-1-yl } sulfonyl) methyl ] prop-2-yn-1-yl } hydroxycarboxamide;
{3- (4-fluorophenyl) -1- [ ({4- [4- (methoxy) phenyl ] piperidin-1-yl } sulfonyl) methyl ] prop-2-yn-1-yl } hydroxycarboxamide;
[1- ({ [4- (4-chlorophenyl) piperidin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
hydroxy [1- ({ [4- (4-methylphenyl) piperidin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] carboxamide;
{3- (3-fluorophenyl) -1- [ ({4- [4- (methoxy) phenyl ] piperidin-1-yl } sulfonyl) methyl ] prop-2-yn-1-yl } hydroxycarboxamide;
hydroxy {1- [ ({4- [5- (trifluoromethyl) pyridin-2-yl ] -1, 4-diazepan-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide;
{1- [ ({4- [4- (ethoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } hydroxyformamide;
[1- ({ [4- (5-bromopyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -4-morpholin-4-ylbut-2-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (3-chlorophenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (1, 3-benzodioxol-5-yl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
hydroxy {1- [ ({4- [3- (methoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] -3-phenylprop-2-yn-1-yl } carboxamide;
hydroxy [1- ({ [4- (4-methylphenyl) piperidin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] carboxamide;
[1- ({ [4- (4-chlorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] hydroxyformamide;
{1- [ ({4- [4- (ethoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] -3-phenylprop-2-yn-1-yl } hydroxycarboxamide;
[1- ({ [4- (5-bromopyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-5-phenylpent-4-yn-1-yl ] hydroxyformamide;
{2, 2-dimethyl-5-phenyl-1- [ ({4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl } sulfonyl) methyl ] pent-4-yn-1-yl } hydroxyformamide;
[1- ({ [4- (5-chloropyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) hex-2-yn-1-yl ] hydroxyformamide;
{1- [ ({4- [4- (ethoxy) phenyl ] piperazin-1-yl } sulfonyl) methyl ] -2, 2-dimethyl-5-phenylpent-4-yn-1-yl } hydroxyformamide;
[1- ({ [4- (3, 4-dimethoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (4-ethoxyphenyl) -1, 4-diazepan-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
[1- ({ [ (2R) -4- (4-fluorophenyl) -2-methylpiperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethylpent-4-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -4-pyrrolidin-1-ylbut-2-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-6-morpholin-4-ylhex-4-yn-1-yl ] hydroxyformamide;
[1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethylhept-4-yn-1-yl ] hydroxyformamide.
In another embodiment of the present invention, there are provided sulfonyl amino cyclic derivatives of formula (I) for use as a medicament.
In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a sulfonyl amino cyclic derivative according to the present invention and a pharmaceutically acceptable carrier, diluent or excipient thereof.
In another embodiment of the present invention, there is provided the use of formula (I) in the manufacture of a medicament for the prevention and/or treatment of a disease selected from: autoimmune and inflammatory diseases, including multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis; stroke, cardiovascular disease, neurodegenerative disease, cancer, premature labor, respiratory disease including emphysema, Chronic Obstructive Pulmonary Disease (COPD); and fibrosis, including liver and lung, pancreatic fibrosis, and liver fibrosis.
In another embodiment of the invention, there is provided the use of a derivative of formula (I) in the modulation, in particular inhibition, of matrix metalloproteinase activity. In particular, there is provided use according to the invention wherein said matrix metalloprotease is selected from the group consisting of MMP-2, MMP-9 and MMP-12. The compounds according to the invention are preferably selective inhibitors of MMP-1 of the metalloprotease MMP-12.
In another embodiment, the invention provides a method of treatment and/or prevention of a disease comprising administering to a patient in need thereof a compound of formula (I) and wherein said disease is selected from the group consisting of autoimmune diseases and inflammatory diseases, including multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis; stroke, cardiovascular disease, neurodegenerative disease, cancer, premature labor, respiratory disease including emphysema, Chronic Obstructive Pulmonary Disease (COPD); and fibrosis, including liver and lung, pancreatic fibrosis, and liver fibrosis.
In another embodiment, the present invention provides a process for the preparation of a derivative of formula (I) according to the present invention comprising the step of reacting a compound of formula (II) with a formylating agent of Formula (FA):
in the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined above; LG (Ligno-lead-acid)1Is a radical OH, -OAc, -O-Piv, -OCH selected from2CN，-OCH2-CF3-O-phenyl and OPfp.
In another embodiment, the invention provides a compound of formula (II):
in the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined above.
In another embodiment, the present invention provides that the compound of formula (II) is selected from the group consisting of:
n- [3- (1, 3-benzodioxol-5-yl) -1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -2-propynyl ] hydroxylamine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (trimethylsilyl) -3-butynyl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) -4- (trimethylsilyl) -3-butynyl ] sulfonyl } -4- (2-pyridyl) piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4-phenyl-3-butynyl ] sulfonyl } piperazine;
1- [4- (benzyloxy) phenyl ] -4- { [2- (hydroxyamino) -3-nonynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -5-phenyl-3-pentynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3-nonynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (3-pyridyl) -3-butynyl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) -4- (3-pyridinyl) -3-butynyl ] sulfonyl } -4- (4-methoxyphenyl) piperazine;
1- { [2- (hydroxyamino) -4- (3-methoxyphenyl) -3-butynyl ] sulfonyl } -4- (4-methoxyphenyl) piperazine;
n, N-diethyl-4- (hydroxyamino) -5- { [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } -2-pentyn-1-amine;
1- { [2- (hydroxyamino) but-3-yn-1-yl ] sulfonyl } -4-pyridin-2-ylpiperazine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- { [2- (hydroxyamino) hept-3-yn-1-yl ] sulfonyl } -4-pyridin-2-ylpiperazine;
1- (2-fluorophenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4-pyridin-2-ylpiperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- [4- (trifluoromethyl) phenyl ] piperazine;
4- (4-fluorophenyl) -1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperidine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (3-methoxyphenyl) but-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) hept-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- [4- (trifluoromethyl) phenyl ] piperazine;
3- [4- { [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } -3- (hydroxyamino) but-1-yn-1-yl ] quinoline;
4- (4-fluorophenyl) -1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } piperidine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4-pyridin-2-ylpiperazine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperazine;
1- (4-fluorophenyl) -4- ({2- (hydroxyamino) -4- [4- (1, 2, 4-oxadiazol-3-yl) phenyl ] but-3-yn-1-yl } sulfonyl) piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperazine;
1-biphenyl-4-yl-4- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } piperazine;
1- (5-chloropyridin-2-yl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
2- (4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazin-1-yl) pyrimidine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4-phenylpiperazine;
1- (4-chlorophenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (2-methoxyphenyl) piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (3-methoxyphenyl) piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyl-6-phenylhex-5-yn-1-yl ] sulfonyl } piperazine;
n, N-diethyl-4- (hydroxyamino) -5- { [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } pent-2-yn-1-amine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- [5- (trifluoromethyl) pyridin-2-yl ] piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (4-phenoxyphenyl) piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) oct-3-yn-1-yl ] sulfonyl } piperazine;
1- { [4- (2-fluorophenyl) -2- (hydroxyamino) but-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- { [4- (4-fluorophenyl) -2- (hydroxyamino) but-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
4- (4-chlorophenyl) -1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperidine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (4-methylphenyl) piperidine;
1- { [4- (3-fluorophenyl) -2- (hydroxyamino) but-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- [5- (trifluoromethyl) pyridin-2-yl ] -1, 4-diazepan;
1- (4-ethoxyphenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- (5-bromopyridin-2-yl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
4- [5- { [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } -4- (hydroxyamino) pent-2-yn-1-yl ] morpholine;
1- (3-chlorophenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- (1, 3-benzodioxol-5-yl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- (3-methoxyphenyl) piperazine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- (4-methylphenyl) piperidine;
1- (4-chlorophenyl) -4- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-ethoxyphenyl) -4- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } piperazine;
1- (5-bromopyridin-2-yl) -4- { [2- (hydroxyamino) -3, 3-dimethyl-6-phenylhex-5-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) -3, 3-dimethyl-6-phenylhex-5-yn-1-yl ] sulfonyl } -4- [4- (trifluoromethyl) phenyl ] piperazine;
1- (5-chloropyridin-2-yl) -4- { [2- (hydroxyamino) hept-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-ethoxyphenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyl-6-phenylhex-5-yn-1-yl ] sulfonyl } piperazine;
1- (3, 4-dimethoxyphenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-ethoxyphenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -1, 4-diazepane;
(2R) -4- (4-fluorophenyl) -1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -2-methylpiperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3, 3-dimethylhex-5-yn-1-yl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -5-pyrrolidin-1-yl-pent-3-yn-1-yl ] sulfonyl } piperazine;
4- [7- { [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } -6- (hydroxyamino) -5, 5-dimethylhept-2-yn-1-yl ] morpholine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyloct-5-yn-1-yl ] sulfonyl } piperazine.
In another embodiment, the present invention provides a process for the preparation of a derivative of formula (I) or (II) according to the present invention comprising the step of reacting a compound of formula (III) with a hydroxylamine or a hydroxylamine derivative of formula (HA):
in the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined above; w is selected from H, benzyl, TMS, TBDMS and THP.
In another embodiment, the invention provides a compound of formula (III):
in the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined above.
In another embodiment, the invention provides a compound of formula (III) selected from the group consisting of:
1- { [ (1E) -4- (1, 3-benzodioxol-5-yl) -1-buten-3-ynyl ] sulfonyl } -4- (4-fluorophenyl) piperazine;
1- { [ (1Z) -4- (1, 3-benzodioxol-5-yl) -1-buten-3-ynyl ] sulfonyl } -4- (4-fluorophenyl) piperazine;
1- (4-fluorophenyl) -4- { [ (1E) -4- (trimethylsilyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [ (1Z) -4- (trimethylsilyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (2-pyridyl) -4- { [ (1E) -4- (trimethylsilyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (2-pyridyl) -4- { [ (1Z) -4- (trimethylsilyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [ (1E) -4-phenyl-1-buten-3-ynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [ (1Z) -4-phenyl-1-buten-3-ynyl ] sulfonyl } piperazine;
4- {4- [ (1E) -1-nonen-3-ynylsulfonyl ] -1-piperazinyl } benzyl phenyl ether;
4- {4- [ (1Z) -1-nonen-3-ynylsulfonyl ] -1-piperazinyl } benzyl phenyl ether;
1- (4-fluorophenyl) -4- { [ (1E) -5-phenyl-1-penten-3-ynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [ (1Z) -5-phenyl-1-penten-3-ynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- [ (1E) -1-nonen-3-alkynylsulfonyl ] piperazine;
1- (4-fluorophenyl) -4- [ (1Z) -1-nonen-3-alkynylsulfonyl ] piperazine;
1- (4-fluorophenyl) -4- { [ (1E) -4- (3-pyridyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [ (1Z) -4- (3-pyridyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (4-methoxyphenyl) -4- { [ (1E) -4- (3-pyridyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (4-methoxyphenyl) -4- { [ (1Z) -4- (3-pyridyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (4-methoxyphenyl) -4- { [ (1E) -4- (3-methoxyphenyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
1- (4-methoxyphenyl) -4- { [ (1Z) -4- (3-methoxyphenyl) -1-buten-3-ynyl ] sulfonyl } piperazine;
n, N-diethyl-N- ((4E) -5- { [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } -4-penten-2-ynyl) amine;
n, N-diethyl-N- ((4Z) -5- { [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } -4-penten-2-ynyl) amine;
1- [ (1E) -but-1-en-3-yn-1-ylsulfonyl ] -4-pyridin-2-ylpiperazine;
1- [ (1Z) -but-1-en-3-yn-1-ylsulfonyl ] -4-pyridin-2-ylpiperazine;
4- (4-methoxyphenyl) -1- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } piperidine;
1- [ -hept-1-en-3-yn-1-ylsulfonyl ] -4-pyridin-2-ylpiperazine;
1- (2-fluorophenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- [ -non-1-en-3-yn-1-ylsulfonyl ] -4-pyridin-2-ylpiperazine;
1- [ -non-1-en-3-yn-1-ylsulfonyl ] -4- [4- (trifluoromethyl) phenyl ] piperazine;
4- (4-fluorophenyl) -1- [ -non-1-en-3-yn-1-ylsulfonyl ] piperidine;
4- (4-methoxyphenyl) -1- [ -non-1-en-3-yn-1-ylsulfonyl ] piperidine;
1- (4-fluorophenyl) -4- { [ -4- (3-methoxyphenyl) but-1-en-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- [ -hept-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } -4- [4- (trifluoromethyl) phenyl ] piperazine;
3- ((3E) -4- { [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } but-3-en-1-yn-1-yl) quinoline;
4- (4-fluorophenyl) -1- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } piperidine;
1- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } -4-pyridin-2-ylpiperazine;
1- (4-methoxyphenyl) -4- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- ({ -4- [4- (1, 2, 4-oxadiazol-3-yl) phenyl ] but-1-en-3-yn-1-yl } sulfonyl) piperazine;
1- (4-methoxyphenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1-biphenyl-4-yl-4- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } piperazine;
1- (5-chloropyridin-2-yl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
2- {4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazin-1-yl } pyrimidine;
1- [ -non-1-en-3-yn-1-ylsulfonyl ] -4-phenylpiperazine;
1- (4-chlorophenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- (2-methoxyphenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- (3-methoxyphenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- { [ -3, 3-dimethyl-6-phenylhex-1-en-5-yn-1-yl ] sulfonyl } -4- (4-fluorophenyl) piperazine;
n, N-diethyl-5- { [4- (4-methoxyphenyl) pyridin-1-yl ] sulfonyl } pent-4-en-2-yn-1-amine;
1- [ -non-1-en-3-yn-1-ylsulfonyl ] -4- [5- (trifluoromethyl) pyridin-2-yl ] piperazine;
1- [ -non-1-en-3-yn-1-ylsulfonyl ] -4- (4-phenoxyphenyl) piperazine;
1- (4-fluorophenyl) -4- [ -oct-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- { [ -4- (2-fluorophenyl) but-1-en-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- { [ -4- (4-fluorophenyl) but-1-en-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
4- (4-chlorophenyl) -1- [ -non-1-en-3-yn-1-ylsulfonyl ] piperidine;
4- (4-methylphenyl) -1- [ -non-1-en-3-yn-1-ylsulfonyl ] piperidine;
1- { [ -4- (3-fluorophenyl) but-1-en-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- [ -non-1-en-3-yn-1-ylsulfonyl ] -4- [5- (trifluoromethyl) pyridin-2-yl ] -1, 4-diazepan;
1- (4-ethoxyphenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- (5-bromopyridin-2-yl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
4- (-5- { [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } pent-4-en-2-yn-1-yl) morpholine;
1- (3-chlorophenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- (1, 3-benzodioxol-5-yl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- (3-methoxyphenyl) -4- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } piperazine;
4- (4-methylphenyl) -1- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } piperidine;
1- (4-chlorophenyl) -4- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-ethoxyphenyl) -4- { [ -4-phenylbut-1-en-3-yn-1-yl ] sulfonyl } piperazine;
1- (5-bromopyridin-2-yl) -4- { [ -3, 3-dimethyl-6-phenylhex-1-en-5-yn-1-yl ] sulfonyl } piperazine;
1- { [ -3, 3-dimethyl-6-phenylhex-1-en-5-yn-1-yl ] sulfonyl } -4- [4- (trifluoromethyl) phenyl ] piperazine;
1- (5-chloropyridin-2-yl) -4- [ -hept-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- { [ -3, 3-dimethyl-6-phenylhex-1-en-5-yn-1-yl ] sulfonyl } -4- (4-ethoxyphenyl) piperazine;
1- (3, 4-dimethoxyphenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- (4-ethoxyphenyl) -4- [ -non-1-en-3-yn-1-ylsulfonyl ] -1, 4-diazepane;
(2R) -4- (4-fluorophenyl) -2-methyl-1- [ -non-1-en-3-yn-1-ylsulfonyl ] piperazine;
1- { [ -3, 3-dimethylhex-1-en-5-yn-1-yl ] sulfonyl } -4- (4-fluorophenyl) piperazine;
1- (4-fluorophenyl) -4- { [ -5-pyrrolidin-1-ylpent-1-en-3-yn-1-yl ] sulfonyl } piperazine;
4- (7- { [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } -5, 5-dimethylhept-6-en-2-yn-1-yl) morpholine;
1- { [ -3, 3-dimethyloct-1-en-5-yn-1-yl ] sulfonyl } -4- (4-fluorophenyl) piperazine.
In another embodiment, the invention provides a process for the preparation of derivatives of formula (I), (II) or (III) according to the invention, comprising the step of reacting a compound of formula (VIII) with a reagent such as MsCl, TMSCl, DBU, HCl.
In the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined above.
In another embodiment, the invention provides a compound according to the invention of formula (VIII):
in the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined above.
In another embodiment, the invention provides a process for the preparation of a derivative of formula (I), (II), (III) or (VIII) according to the invention, which comprises NaBH in a reducing agent, such as MeOH or EtOH in an alcoholic solvent4In the presence of a ketone group reduction step of general formula (VII).
In the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined above.
In another embodiment, the invention provides a compound of formula (VII):
in the formula, A, B and R1，R2，R3，X，Y，mN and p are as defined above.
The compounds of the invention are named according to the standard used in the program "ACD/name" of Advanced Chemistry Development inc, ACD/Labs (version 7.06).
Compounds of formula (I) are useful in the treatment and/or prevention of autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer, preterm labor, respiratory diseases and fibrosis, including multiple sclerosis, arthritis, emphysema, chronic obstructive pulmonary disease, liver and pulmonary fibrosis.
The compounds according to the invention also include their tautomers, geometrical isomers, optically active forms and racemates as enantiomers, diastereomers, and the pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts of the compounds of formula (I) are those formed with pharmaceutically acceptable acids such as the hydrochloride, hydrobromide, sulphate or hydrogen sulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
Examples of derivatives of the invention can be prepared in-situ from the starting materials by the usual methods and procedures. Typical and preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvents, etc.) are preferably used, and other experimental conditions may be used unless otherwise indicated. Optimum reaction conditions vary with the particular reactants or solvents used, but those skilled in the art can determine such conditions by routine optimization methods.
When the compound of the present invention is used as a medicament, it can be typically administered in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient are also included within the scope of the invention. Those skilled in the art will recognize variations of these carriers, diluents or excipients that are suitable for formulating pharmaceutical compositions.
In another embodiment, the compounds of the invention are useful in the treatment of autoimmune diseases, in particular demyelinating diseases, such as multiple sclerosis, either by themselves or in combination with adjuvants for the treatment of autoimmune diseases, such as, for example, compounds selected from the group consisting of:
(a) an interferon, such as a pegylated or non-pegylated interferon, e.g. administered subcutaneously, intramuscularly or orally, preferably interferon beta;
(b) glatiramer, e.g., as acetate;
(c) immunosuppressive agents with optional antiproliferative/antitumor activity, such as mitoxantrone, methotrexate, azathioprine, cyclophosphamide, or steroids, such as methyldichlorocortinol, prednisone or dexamethasone, or steroid secreting agents, such as ACTH;
(d) adenosine deaminase inhibitors, such as cladribine;
(e) antagonist inhibitors of VCAM-1 expression or its ligands, e.g., an antagonist of the α 4/β 1 integrin VLA-4 and/or an α -4- β -7 integrin, e.g., natalizumab (ANTEGREN).
Other adjuvants such as anti-inflammatory agents (in particular demyelinating diseases such as multiple sclerosis) are described below:
other anti-inflammatory agents teriflunomide are described in WO 02/080897
Another anti-inflammatory agent, Fingolimod, is described in EP-727406, WO 2004/028251 and WO 2004/028251.
Another anti-inflammatory agent, Laquinimod, is described in WO 99/55678.
Yet another anti-inflammatory agent, Tensirolimus, is described in WO 02/28866.
Yet another anti-inflammatory agent, zalilodene (Xaliprodene), is described in WO 98/48802.
Yet another anti-inflammatory agent, Deskar Pirfenidone, is described in WO 03/068230.
The following further anti-inflammatory benzothiazole derivatives are described in WO 01/47920.
WO03/070711 describes one of the other anti-inflammatory hydroxamic acid derivatives.
Yet another anti-inflammatory agent, MLN3897, is described in WO 2004/043965.
Yet another anti-inflammatory agent, CDP323, is described in WO 99/67230.
A further anti-inflammatory agent Simvastatin (Simvastatin) is described in WO 01/45698.
Yet another anti-inflammatory agent, Fampridine, is described in US 5,540,938.
The compounds of the present invention are placed together with conventionally used adjuvants, carriers, diluents or excipients to form pharmaceutical compositions and unit dosage forms thereof, and in such forms are formed into solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs or capsules filled with such liquids, all for oral administration, or in the form of sterile injectable preparations for parenteral (including subcutaneous) administration. These pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients, with or without added active compounds or ingredients, and these unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range desired.
Pharmaceutical compositions comprising a compound of the invention may be prepared by methods known in the art of pharmacy and include at least one active compound. Generally, the compounds of the present invention are administered in a pharmaceutically effective amount. The actual administration of the compound will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms.
The pharmaceutical compositions of the present invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The orally administered compositions may be in the form of bulk solutions or suspensions, or bulk powders. More commonly, however, the compositions will be presented in unit dosage form for convenient dosing. The term "unit dosage form" refers to discrete units of a single dose suitable for administration to the human or other mammal, each unit containing a calculated, predicted amount of active agent, and being capable of delivering a desired therapeutic effect in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules of liquid compositions or pills, tablets, capsules of injectables or solid compositions and the like. In these compositions, the derivatives of the invention, together with the remainder of the various excipients or carriers and processing aids used to form the desired dosage form, generally constitute a minor component (about 0.1 to 50% by weight or preferably about 1 to 40% by weight).
Liquid forms suitable for oral administration include suitable aqueous or non-aqueous vehicles for buffers, suspending or dispersing agents, coloring agents, flavoring agents, and the like. Solid forms include, for example, any of the following ingredients or compounds of similar nature: a binder, gum tragacanth or gum of microcrystalline cellulose; excipients such as starch or lactose, disintegrants such as alginic acid, sodium starch glycolate (Primogel) or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are essentially based on injectable sterile saline or phosphate buffered saline or other injectable carriers well known in the art. As mentioned above, the sulfonamide cyclic derivatives of formula (I) are present in minor proportions in such compositions, typically in the range of 0.05% to 10% by weight, with the remainder being injectable carriers and the like.
For orally administered or injectable compositions, the above-described ratios are merely representative. The compounds of the present invention may also be administered in a sustained release manner or from a sustained release drug delivery system. Further materials and processing techniques are set forth in Remington's Pharmaceutical Sciences (twentieth edition, 2000, Marck publishing company, Easton, Pennsylvania (as in section 5)), and are included within the scope of reference of the present invention.
Detailed Description
Synthesis of Compounds of the invention
The novel derivatives of formula (I) can be prepared by several synthetic methods from the prepared starting materials by liquid or solid phase chemistry or by a mixture of liquid and solid phase methods. Examples of synthetic pathways are described below.
The following abbreviations refer to the following definitions, respectively:
aq (aqueous), h (hr), g (g), L (L), mg (mg), MHz (megahertz), min (min), mM (mM), mmol (mmol), mM (mmol concentration), m.p. (melting point), eq. (eq), mL (mL), μ L (μ L), ACN (acetonitrile), BINAP (2, 2 '-bis (diphenylphosphino) -1, 1' -dinaphthalene), Boc (tert-butoxycarbonyl), BuLi (butyllithium), CDCl (megahertz), Boc (tert-butoxycarbonyl), Boc (butyllithium), n (acetonitrile), n (n-butyl-n), n (n-butyl3(deuterated chloroform), CD3OD (deuterated methanol), c-Hex (cyclohexane), DBU (1, 5-diazabicyclo (5, 4, 0) -5-undecene), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), DEA (diethylamine), DEAD (diethyl azodicarboxylate), DIC (diisopropyl ether)Carbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d6(deuterated dimethyl sulfoxide), EDC (1- (3-dimethyl-amino-propyl) -3-ethylcarbodiimide), EtOAc (ethyl acetate), ESI (electrospray ionization), Et2O (diethyl ether), EtOH (ethanol), FA (formic acid), Fmoc (9-fluorenylmethoxycarbonyl), HATU (dimethylamino- ([1, 2, 3 ] hexafluorophosphate)]Triazolo [4, 5-b]Pyridin-3-yloxy) -methylene]-dimethylammonium esters), HPLC (high performance liquid chromatography), i-PrOH (2-propanol), LC (liquid chromatography), LDA (lithium diisopropylamine), LiHMDS (lithium hexamethyl) MeOH (methanol), MS (mass spectrometry), MsCl (methanesulfonyl chloride), MTBE (methyl tert-butyl ether), MW (microwave irradiation), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), OMs (O-methanesulfonyl), O-Piv (O-pivaloyl), OPfp (O-pentafluorophenol), OTs (O-toluenesulfonyl), rt (room temperature), SPE (solid phase extraction), TBDMS (tert-butyldimethylsilyl), TBTU (2- (1-H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), THP (tetrahydropyranyl), TLC (thin layer chromatography), TMAD (N, N' -tetramethyldiazenedicarboxamide), TMS (trimethylsilyl), TMSCl (T trimethylsilyl chloride), TsCl (tosyl chloride), UV (ultraviolet), Z (benzyloxycarbonyl).
The synthesis method comprises the following steps:
in general, the compounds of the general formula (I) are obtainable by formylation of compounds of the general formula (II) in which R is1，R2，R3X, Y, A, B, n and m are as defined above (scheme 1 below).
The general method of such formylation is given in the examples below and uses formylation reagents well known to those skilled in the art, such as formylation reagents of the general Formula (FA), wherein LG1Is selected from the group consisting of: OH, -OAc, -O-Piv, -OCH2CN，-OCH2-CF3-O-phenyl and OPfp.
For example, the formylating agent may be obtained by reacting formic acid with acetic anhydride.
Scheme 1
A preferred method for preparing compounds of the general formula (II) comprises reacting hydroxylamine with a compound of the general formula (III) wherein R is1，R2，R3X, Y, A, B, n, m and p are as defined above, and the reaction is carried out in a suitable solvent such as THF at a temperature ranging from 0 ℃ to 100 ℃ (scheme 2 below).
Scheme 2
The compounds of the general formula (III) can be obtained by reacting a sulfonamide of the general formula (IV) wherein R is R with an aldehyde of the general formula (V)1，R2X and Y are as defined above, (V) wherein R is3A, B, n, m and p are as defined above. Preferred conditions include metal substitution of the sulfonamide of formula (IV) with a base such as but not limited to LiHMDS, LDA or BuLi, followed by contacting the resulting metal substituted sulfonamide with a compound such as ClPO (OEt)2The chlorophosphate and the aldehyde of formula (V) are reacted in a suitable solvent such as THF. Other conditions may include metal substitution of the sulfonamide of formula (IV) with a base and direct reaction of the metal substituted sulfonamide with an aldehyde of formula (V) with or without an additive such as TMSCl, MsCl or TsCl.
Another preparation of the compounds of the general formula (II) can be the initial reaction of the sulfonamides of the general formula (IV), i.e.the first metal substitution as described above with esters of the general formula (IV) in which R is C1-C6Alkyl or C3-C8Cycloalkyl or benzyl, and R3A, B, n and m are asAs defined above, to give a ketone of the general formula (VII) in which R1，R2，R3X, Y, A, B, n, m and p are as defined above (scheme 3 below).
Scheme 3
The compounds of formula (II) are obtainable by reaction of a ketone of formula (VII) with hydroxylamine in a suitable solvent such as DCM, followed by chemoselective reduction of the oxime of formula (IX) formed, wherein R is1，R2，R3X, Y, A, B, n, m and p are as defined above. A preferred reducing agent for such conversion may be, for example, NaBH3CN。
Alternatively, ketones of general formula (VII) are chemically selectively reduced to alcohols of general formula (VIII) in which R is present in the presence of a reducing agent, such as NaBH4 in MeOH or EtOH alcoholic solvents1，R2，R3X, Y, A, B, n, m and p are as defined above (scheme 3 above).
The alcoholic group of the alcohol of the general formula (VIII) can be eliminated by reaction with a base such as NaOH, DBU, DIEA or by giving the alkene of the general formula (III) in the presence of MsCl, TMSCl or TsCl. The compounds of the general formula (II) can be obtained by reacting hydroxylamine with olefins of the general formula (III) in which R is1，R2，R3X, Y, A, B, n, m and p are as defined above, at a temperature ranging from 0 ℃ to 100 ℃, the reaction being carried out in a suitable solvent such as THF (scheme 3 above).
A complementary preparative route to compounds of general formula (II) can be obtained by converting the hydroxyl group of an alcohol of general formula (VIII) into the leaving group OMs, OTs, Cl, Br or I, followed by substitution with hydroxylamine, by reaction conditions well known to those skilled in the art. Similarly, the alcohol of formula (VIII) may be present in a bisazo dicarboxylic acid derivative such as DEAD, TMAD and hydroxylamine or hydroxylamine derivative (e.g. BocO-NHBoc, ZO-NHZ, wherein Z is benzyloxycarbonyl) with a phosphine (e.g. PPh)3，P(nBu)3) And (4) reacting.
Intermediates of general formula (IV) can be prepared by reacting a compound of general formula (X) wherein X, Y, R are X, with methanesulfonyl chloride under conditions well known to those skilled in the art1，R2And p is as defined above (scheme 4 below).
Scheme 4
Intermediates of general formula (X) are either commercially available or can be prepared by conditions well known to those skilled in the art. For example, of the general formula (X) wherein X is a carbon atom, intermediates thereof can be prepared by the methods described in Wustrow et al, Synthesis, 1991, 993. In general formula (X) wherein X is a nitrogen atom, intermediates thereof can be prepared by the methods described in Brenner et al, Tetrahedron, 2002, 58(34), 6913-6924 or Tetrahedron Letters, 1996, 37(26), 4463-4466.
Intermediates of general formula (V) are commercially available or can be prepared by conditions well known to those skilled in the art. A preferred method of obtaining an intermediate of formula (V) comprises using oxidation conditions well known to those skilled in the art (e.g., Dess-Martin reagent or MnO when m and n are 0)2) Oxidation of an alcohol of the general formula (XI) in which A, B, m, n and R are3As defined above (scheme 5 below).
Scheme 5
Intermediate of formula (VI)The bodies may be commercially available or prepared by conditions well known to those skilled in the art. A preferred process for the preparation of intermediates of formula (VI) comprises reacting a compound of formula (XII) with R3-LG2Reaction of (VI) in which at least m or n is not 0 and R3Is optionally substituted aryl or optionally substituted heteroaryl, (XII) wherein A, B, n and m are as defined above and R is C1-C6Alkyl or cycloalkyl or benzyl, R3-LG2In the formula R3Is optionally substituted aryl or optionally substituted heteroaryl, LG2Is halogen or-OSO in the presence of a Pd (0) catalyst2CF3(scheme 6 below).
Scheme 6
Another preferred process for the preparation of intermediates of the general formula (VI) in which n and m are 1 comprises reacting a compound of the general formula (XIII) in which A and R are as defined above and n is 1, with a compound of the general formula (XIV) in which LG3 is a leaving group, e.g. OMs, OTs, Cl, Br or I, m is 1, R is 13And B is as defined above. Preferred conditions include metal substitution of intermediate (XIII) with a base such as, but not limited to, LiHMDS, LDA or BuLi in a suitable solvent such as THF (scheme 7 below).
Scheme 7
According to further general methods, a compound of general formula (I) may be converted to another compound of general formula (I) using suitable interchange techniques well known to those skilled in the art.
The compounds of formula (I) and their precursors of formulae (II) and (VIII) in general comprise at least one chiral center, optically active forms of all monomers and combinations and racemates thereof are disclosed as separate and specific embodiments of the present invention. The processes shown in the above schemes, especially scheme 1 and scheme 2, result in compounds of general formula (I) and their precursors of formula (II) and (VIII) as racemates or as mixtures of diastereomers, if additional chiral centers are present. Pure stereoisomers can be obtained from mixtures by methods well known to those skilled in the art, including separation of isomers, e.g., chiral HPLC, or formation of diastereomeric derivatives with convenient optically active auxiliary species after separation, followed by splicing of the auxiliary species (see, e.g., Basha et al, 1994, J.org.chem., 59, 6103-.
The present invention will be described in detail with reference to the following examples, which, however, are not intended to limit the scope of the present invention.
The following commercial reagents/resins were used: propargyl alcohol (Fluka), manganese dioxide (IV) or MnO2(Aldrich), 4-diethylamino-2-butyn-1-ol (Aldrich), 3- (3-methoxyphenyl) prop-2-yn-1-ol (GFS), 2-bromopyrimidine (Aldrich), copper (I) iodide or CuI (Aldrich), benzyl 2, 2-dimethylbut-3-ynoate (Betapharma), 1- (4-fluorophenyl) piperazine dihydrochloride (Aldrich), methanesulfonyl chloride (Fluka), 1- (2-pyridyl) piperazine (Aldrich), 1- [4- (benzyloxy) phenyl ] piperazine (Aldrich)]Piperazine hydrochloride (EmkaChem), 1- (4-methoxyphenyl) piperazine (Chess), lithium bis (trimethylsilyl) amine (Aldrich), diethyl chlorophosphate (diethyhlorophosphonate) (Aldrich), hydroxylamine (Aldrich), acetic anhydride (Fluka), formic acid (Fluka), 3-trimethylsilylpropynaldehyde (ABCR), phenylpropylaldehyde (Fluka), 2-octenal (Aldrich), ethyl isobutyrate (Aldrich), 4- (4-methoxyphenyl) piperidine (Astatech), 1- (4-trifluoromethylphenyl) piperazine (Emkachem), 4- (4-fluorophenyl) piperidine (HCl), (Astatech), 1- (diphenyl-4-yl) piperazine (Apollo), 1- (2-pyrimidinyl) piperazine (Emkachem), 1- (4-chlorophenyl) piperazine (Acros), 1- (3-methoxyphenyl) -piperazine (Chess), 1- [5- (trifluoromethyl) pyridin-2-yl]Piperazine (Maybridge), 1- [ 4-trifluoromethyl ] pyrimidin-2-yl]-1, 4-diazepanes(Acros), 4- (4-chlorophenyl) piperidine (Astatech), 4- (4-methylphenyl) piperidine (Astatech), 1- [5- (trifluoromethyl) pyridin-2-yl]-1, 4-diazepane (Fluorochem), 1- (4-ethoxyphenyl) piperazine (Emkachem), 1- (5-bromopyridin-2-yl) piperazine (J)&W Pharmlab), 1- (1, 3-benzodioxol-5-yl) piperazine (Fluorochem), 1- (3, 4-dimethoxyphenyl) -piperazine hydrochloride (Fluorochem), 1-bromoethoxybenzene (Aldrich), 1, 4-diazepane (Aldrich), 1-bromo-4-fluorobenzene (Aldrich), (R) -2-methylpiperazine (Astatech), butyraldehyde (Aldrich), 2-hexyn-1-ol (Aldrich), 3-quinolin-3-yl-2-propyn-1-ol (Chembridge), 3-hydroxy-1-propynyl) benzonitrile (Maybrid), 1- (methylsulfonyl) -4-phenylpiperazine (Ambinter), 1- (2-fluorophenyl) -4- (methylsulfonyl) piperazine (Ambinter), 1- (4-chlorophenyl) -4- (methylsulfonyl) piperazine (Ambinter), 1- (2-methoxyphenyl) -4- (methylsulfonyl) piperazine (Ambinter), 4-diethylamino-2-butyl-1-ol (Aldrich), 2-heptyn-1-ol (Aldrich), 3- (3-fluorophenyl) prop-2-yn-1-ol (Apol lo), 1- (3-chlorophenyl) -4- (methylsulfonyl) piperazine (Ambinter).
The HPLC data provided in the examples described below were obtained as follows. HPLC column: watersMS C8 column 50mm × 4.6mm, flow rate 2mL/min, 8min gradient, from 0.1% TFA in water to 0.07% TFA in CH3CN。
Preparative HPLC is available from WatersPrep MS C810 μm column 300mm × 30 mm; UV measurements (254nM and 220 nM); flow rate: 30 mL/min. MS data provided in the examples described below were obtained as follows: mass spectrum: LC/MS Waters ZMD (ESI). GC/MS can be obtained by Agilent 6890 gas chromatography; column: DB-1HS, 10m 0.1mm I.D. times 0.1 μm; carrier gas: helium, 45cm/sec, 50 ℃ (0.6 mL/min); a constant flow rate mode; oven: 1min at 50 ℃; 50 ℃/min to 330 ℃ for 5 min. An injector: 0.2. mu.L at 250 ℃. Detector: agilent 5973 MSD; the transfer line was at 325 ℃ EI SIM. Provided in the examples described below1H-NMR data were obtained with a Bruker DPX-300MHz NMR instrument. The microwave irradiation experiment was carried out with an Emrys Optimizer (Biotage, formerly Personal Chemistry) at an intensity of 300W.
Intermediate a 1: 3- (1, 3-benzodioxol-5-yl) -2-propynal aldehyde
Intermediate A1
To a solution of 3- (1, 3-benzodioxol-5-yl) -2-propyn-1-ol (242mg, 1.37mmol, obtained as described in Nugent et al, 1987, J.Am.chem.Soc., 109, 2788) in anhydrous DCM (12mL) was added MnO portionwise over 2h2(2.70g, 31.1 mmol). The resulting mixture was stirred at room temperature for 1 hour, then filtered over a celite bed and the filtrate was evaporated under reduced pressure to yield 123mg of the title compound as a brown solid (51%). HPLC, Rt: 2.76min (purity: 98.9%).1H NMR(CDCl3)δ：9.37(s，1H)，7.18(m，1H)，7.00(m，1H)，6.82(d，J＝8.3Hz，1H)，6.03(s，2H)。
Intermediate a 2: phenyl-2-butynal aldehyde
Intermediate A2
4-phenyl-2-butyn-1-ol (550 mg; 3.76mmol, obtained as described in Bull. Soc. Chim. Fr, 1954, 816) was dissolved in DCM (10mL) and MnO was added2(1.64 g; 18.8 mmol). The mixture was stirred at room temperature and the reaction was monitored by TLC (EtOAc/c-Hex 10/90, iodine staining). MnO is uniformly added2(1.64 g; 18.8 mmol; three times). Removal of MnO by filtration on a celite bed2. After washing celite with DCM, the filtrate was concentrated under reduced pressure. The crude was purified by flash chromatography on silica (gradient EtOAc/c-Hex 5: 95 to 30: 70) to give the title compound as an orange oil (60mg, 11% yield).1H NMR(CDCl3)δ：9.22(s，1H)，7.26(m，5H)，3.80(s，2H)。
Intermediate a 3: 3- (3-pyridinyl) -2-propynal aldehyde
Intermediate A3
To a solution of 3- (3-pyridyl) -2-propyn-1-ol (250mg, 1.88mmol, obtained as described in J.org.chem.1998, 63, 1109-1118) in anhydrous DCM (10ml) was added MnO portionwise over 1.5h under argon2(3.66g, 42 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured onto the top of a silica gel column and eluted with cHex/EtOAc (2: 1, then 1: 1) to give 43mg (17%) of the title compound as a yellow powder.1H NMR(CDCl3)δ：9.46(s，1H)，8.85(dd，J＝2.1，0.8Hz，1H)，8.71(dd，J＝5.0，1.7Hz，1H)，7.91(ddd，J＝8.0，2.1，1.7Hz，1H)，7.38(ddd，J＝8.0，5.0，0.8Hz，1H)。
Intermediate a 4: 4- (diethylamino) -2-butynal aldehyde
Intermediate A4
MnO was added portionwise over 1 hour to a solution of 4-diethylamino-2-butyn-1-ol (1.00g, 7.08mmol) in anhydrous DCM (60mL)2(20g, 230 mmol). In the roomThe resulting mixture was stirred at room temperature for 2 hours and then filtered over a celite bed. The filtrate was evaporated under reduced pressure to give 352mg (36%) of the title compound as an orange oil (352mg, 36% yield).1H NMR(CDCl3)δ：9.22(s，1H)，3.65(s，2H)，2.58(q，J＝7.2Hz，4H)，1.08(t，J＝7.2Hz，6H)。
Intermediate a 5: 3- (3-methoxyphenyl) -2-propynal aldehyde
Intermediate A5
MnO was added portionwise to a solution of 3- (3-methoxyphenyl) -2-propyn-1-ol (500mg, 3.08mmol) in anhydrous DCM (20ml) over 2 hours2(7.8g, 90 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then filtered and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (cHex: EtOAc, gradient 9: 1 to 4: 1) gave 122mg of the title compound as a yellow oil (25%). HPLC, Rt: 2.9min (purity: 99.9%).1H NMR(CDCl3)δ：9.43(s，1H)，7.32(dd，J＝8.3，7.7Hz，1H)，7.22(ddd，J＝7.7，1.4，1.1Hz，1H)，7.12(dd，J＝2.6，1.4Hz，1H)，7.05(ddd，J＝8.3，2.6，1.1Hz，1H)，3.83(s，3H)。
Intermediate a 6: 2, 2-dimethyl-6-morpholin-4-ylhex-4-ynal
Step a) formation of ethyl 2, 2-dimethyl-6-morpholin-4-ylhex-4-ynoate
Ethyl isobutyrate (530. mu.l; 4.08mmol) in THF (5mL) was added lithium bis (trimethylsilyl) amine (7.30 mL; dissolved at-78 deg.C1.00M solution in THF; 7.30 mmol). The mixture was removed in a cold bath and stirred for 30 min. A catheter was then inserted into the suspension of 4- (4-chloro-2-butyn-1-yl) morpholine hydrochloride (prepared as described in Gomez et al, 1997Tetrahedron, 53(50), 17201-17210; 714 mg; 3.40mmol) in THF (5mL) and the temperature was maintained at-78 ℃. The reaction mixture was left in the cold bath and the temperature was allowed to rise to room temperature. After 3 hours, the reaction was quenched with water and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (gradient DCM: MeOH 100: 0 to 90: 10) to give the title compound as a colorless oil (600mg, 70% yield).1H NMR(DMSO-d6)δ：4.11(qd，J＝7.1Hz，2H)，4.14(m，4H)，3.31(t，J＝2.1Hz，0.6H)，3.25(m，1.4H)，2.52(m，4H)，2.43(t，J＝2.3Hz，2H)，1.25(s，6H)，1.23(t，J＝7.0Hz，3H)。
Step b) formation of 2, 2-dimethyl-6-morpholin-4-ylhex-4-yn-1-ol
LiAlH was added to a solution of ethyl 2, 2-dimethyl-6-morpholin-4-yl-4-hexynoate (380 mg; 1.50mmol) in THF (5mL) at 0 deg.C4(2.25 mL; 1.00M solution in THF; 2.25 mmol). The mixture was stirred at 0 ℃ for 1h and quenched with water (80. mu.L), 80. mu.L NaOH 15% (80. mu.L) and water (3X 80. mu.L). The suspension thus obtained was filtered over a pad of celite and washed several times with EtOAc. The filtrate was concentrated under reduced pressure to give 302mg of the title compound as an orange oil (307mg, 97% yield). GC/MS, m/z: 211, Rt: 4.13 min.
Step c) formation of 2, 2-dimethyl-6-morpholin-4-ylhex-4-ynal (A6)
Intermediate A6
To a solution of oxalyl chloride (152. mu.l; 1.74mmol) in DCM (4mL) at-78 deg.C was added a solution of DMSO (237. mu.l; 3.34mmol) in DCM (2 mL). The mixture was stirred for 5min before adding a solution of 2, 2-dimethyl-6-morpholin-4-ylhex-4-yn-1-ol (307 mg; 1.45mmol) in DCM (2 mL). The mixture was stirred at-78 ℃ for 15min and TEA (1.05mL) was added. Then returned to room temperature and stirred for 2 h. Water was added. With saturated NaHCO3And the salt solution washes the organic phase. Drying over magnesium sulfate, filtration and concentration gave the title compound as a colorless oil (303mg, fixed amount).1H NMR(CDCl3)δ：9.51(s，1H)，3.73(m，4H)，3.27(m，2H)，2.56(m，4H)，2.36(m，2H)，1.14(s，6H)。
Intermediate B1: 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine
Intermediate B1
To a suspension of 1- (4-fluorophenyl) piperazine dihydrochloride (2.53 g; 10.0 mmol; 1.0eq.) in anhydrous DCM (50mL) was added TEA (3.33 g; 33.0 mmol; 3.3eq.) and the resulting mixture was cooled at 0 deg.C. A solution of 1N methanesulfonyl chloride (1.26 g; 11.0 mmol; 1.1eq.) in DCM (11mL) was added dropwise. After 20min at 0 ℃, the reaction mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with DCM. With NaHCO3Washing the combined organic phases with water, saturated aqueous brine solution and then over MgSO4Drying, filtering and evaporating to obtain white powder. Crystallization from EtOAc afforded a white solid (1.98g, 76% yield). HPLC, Rt: 2.3min (purity: 100%).1H NMR(CDCl3)δ：7.08-6.83(m，4H)，3.41(m，4H)，3.22(m，4H)，2.85(s，3H)。
Intermediate B2: 1- (methylsulfonyl) -4- (2-pyridyl) piperazine
Intermediate B2
The compound was prepared as the title white powder (3.14g, 65% yield) by the method described in intermediate B1, but starting from 1- (2-pyridyl) piperazine (3.59g, 22mmol, 1.0 eq.). 1H NMR (CDCl)3)δ：8.22(d，4.3Hz，1H)，7.54(m，1H)，6.71(m，2H)，3.71(m，4H)，3.35(m，4H)，2.82(s，3H)。
Intermediate B3: 1- [4- (benzyloxy) phenyl ] -4- (methylsulfonyl) piperazine
Intermediate B3
By the process described in intermediate B1, but from 1- [4- (benzyloxy) phenyl]Starting with piperazine hydrochloride (2.0g, 6.56mmol, 1eq.) the title compound was prepared as a white powder (1.85g, 82% yield). HPLC, Rt: 1.2min (purity: 99.8%). LC/MS, M+(ESI)：347.1，M-(ESI)：345.0。
Intermediate B41- (4-methoxyphenyl) -4- (methylsulfonyl) piperazine
Intermediate B4
Prepared by the method described in intermediate B1, but starting from 1- (4-methoxyphenyl) piperazine (1920mg, 10.0mmol)Off-white powder compound (2180mg, 81% yield). HPLC, Rt: 1.2min (purity: 99.8%). LC/MS, M+(ESI)：271.1。1H NMR(CDCl3)δ：6.91(m，2H)，6.83(m，2H)，3.77(s，3H)，3.37(m，4H)，3.15(m，4H)，2.82(s，3H)。
Intermediate B5: 4- (4-methoxyphenyl) -1- (methylsulfonyl) piperidine
Intermediate B5
The title compound was prepared by the method described in intermediate B1, but starting from 4- (4-methoxyphenyl) piperidine (2.0g) as a white powder (2.2g, 78.11%). HPLC, Rt: 3.04min (purity: 100%). LC/MS, M+(ESI)：270.1。
Intermediate B6: 1- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl ] piperazine
Intermediate B6
The compound was prepared as the title yellow powder by the method described in intermediate B1, but starting from 1- (4-trifluoromethylphenyl) piperazine (2.3g) (2.34g, 76% yield). HPLC, Rt: 3.56min (purity: 99.9%). LC/MS, M+(ESI)：309.1。
Intermediate B7: 4- (4-fluorophenyl) -1- (methylsulfonyl) piperidine
Intermediate B7
The title compound was prepared as a light brown powder (1.79g, 70% yield) by the method described for intermediate B1, but starting from 4- (4-fluorophenyl) piperidine-HCl (2.15 g). HPLC, Rt: 3.18min (purity: 100%). LC/MS, M+(ESI)：258.1。
Intermediate B8: 1- [1, 1' -diphenyl ] -4-yl-4- (methylsulfonyl) piperazine
Intermediate B8
The title compound was prepared as a white powder by the method described in intermediate B1, but starting from 1- (diphenyl-4-yl) piperazine (1.79g) (2.12g, 89% yield). HPLC, Rt: 3.60min (purity: 99.8%). LC/MS, M+(ESI)：317.2。
Intermediate B9: 1- (5-chloropyridin-2-yl) -4- (methylsulfonyl) piperazine
Intermediate B9
The title compound was prepared as a light brown powder (379mg, 69% yield) by the method described in intermediate B1 but starting from 1- (5-chloro-2-pyridyl) piperazine (prepared as described in Swanson et al, 2005, Journal of Medicinal Chemistry, 48(6), 1857-Amplified 1872, 395mg, 2 mmol). HPLC, Rt: 1.60min (purity: 100%). LC/MS, M+(ESI)：276.2。
Intermediate B10: 2- [4- (methylsulfonyl) piperazin-1-yl ] pyrimidine
Intermediate B10
The title compound was prepared as a white powder by the method described in intermediate B1, but starting from 1- (2-pyrimidinyl) piperazine (2.10g) (2.49g, 80% yield). HPLC, Rt: 1.14min (purity: 100%). LC/MS, M+(ESI)：243.3。
Intermediate B11: 1- (4-chlorophenyl) -4- (methylsulfonyl) piperazine
Intermediate B11
The compound was prepared as the title white powder by the method described in intermediate B1, but starting from 1- (4-chlorophenyl) piperazine (1.97g, 10mmol) (2.08g, 75% yield). HPLC, Rt: 3.02min (purity: 100%). LC/MS, M+(ESI)：275.2。
Intermediate B12: 1- (3-methoxyphenyl) -4- (methylsulfonyl) piperazine
Intermediate B12
The title compound was prepared as a white powder by the method described in intermediate B1, but starting from 1- (3-methoxyphenyl) -piperazine (2.27g) (2.58g, 81% yield). HPLC, Rt: 2.13min (purity: 100%). LC/MS, M+(ESI)：271.3。
Intermediate B13: 1- (methylsulfonyl) -4- [5- (trifluoromethyl) pyridin-2-yl ] piperazine
Intermediate B13
To 400mL of dry dichloromethane maintained at 0 ℃ under nitrogen) of 1- [5- (trifluoromethyl) pyridin-2-yl]To a solution of piperazine (23g, 0.099mol) and TEA (42mL, 0.298mol) was added methanesulfonyl chloride (12.6g, 0.109mol) over 20 min. The reaction mixture was stirred at room temperature for 6h and diluted with water. Separated with evidence, washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was recrystallized from petrol ether EtOAc (9: 1) to yield the title compound as a solid (27g, 87% yield). TLC: Rf-0.75 (chloroform: MeOH; 9: 1).1H NMR(CDCl3，300MHz)δ：2.82(3H，s)，3.32(4H，m)，3.79(4H，m)，6.68(1H，d，J＝9Hz)，7.68(1H，d，J＝9Hz)，8.42(1H，s)。
Intermediate B14: 1- (methylsulfonyl) -4- (4-phenoxyphenyl) piperazine
Intermediate B14
The title compound was prepared as a light brown powder (1.16g, 89% yield) by the method described in intermediate B1 but starting from 1- (4-phenoxyphenyl) piperazine (prepared as described in Kiritsy et al, 1978, Journal of Medicinal Chemistry, 21(12), 1301-1307; 1.0 g; 3.93 mmol). HPLC, Rt: 2.38min (purity: 99.7%). LC/MS, M+(ESI)：333.1，M-(ESI)：331.2。
Intermediate B15: 4- (4-chlorophenyl) -1- (methylsulfonyl) pyridine
Intermediate B15
The compound was prepared as the title yellow powder (473mg, 57% yield) by the method described for intermediate B1, but starting from 4- (4-chlorophenyl) pyridine (700 mg; 3.02 mmol). HPLC, Rt: 3.80min (purity: 97.5%). LC/MS, M+(ESI)：274.1。
Intermediate B16: 4- (4-methylphenyl) -1- (methylsulfonyl) pyridine
Intermediate B16
The compound was prepared as the title white solid by the method described in intermediate B1, but starting from 4- (4-methylphenyl) pyridine (700 mg; 3.02mmol) (769mg, 53% yield). HPLC, Rt: 3.69min (purity: 97.7%). LC/MS, M+(ESI)：254.1。
Intermediate B17: 1- (methylsulfonyl) -4- [5- (trifluoromethyl) pyridin-2-yl ] -1, 4-diazepane
Intermediate B17
By the process described in intermediate B1, but from 1- [5- (trifluoromethyl) pyridin-2-yl]Starting from 1, 4-diazepane (500 mg; 2.04mmol), the compound was prepared as the title off-white powder (472mg, 72%). HPLC, Rt: 2.09min (purity: 99.9%).1H NMR(CDCl3，300MHz)δ：8.39(brs，1H)，7.64(dd，J＝9.0，2.2Hz，1H)，6.56(d，J＝9.0Hz，1H)，3.96(t，J＝5.2Hz，2H)，3.83(t，J＝6.4Hz，2H)，3.51(t，J＝5.2Hz，2H)，3.28(t，J＝6.3Hz，2H)，2.80(s，3H)，2.08(m，2H)。
Intermediate B18: 1- (4-ethoxyphenyl) -4- (methylsulfonyl) piperazine
Intermediate B18
The title compound was prepared by the method described in intermediate B1, but starting from 1- (4-ethoxyphenyl) piperazine (2.0g, 9.7mmol) as a light brown powder (2.55g, 92%). HPLC, Rt: 1.74min (purity: 99.5%). LC/MS, M+(ESI)：285.1。
Intermediate B19: 1- (5-bromopyridin-2-yl) -4- (methylsulfonyl) piperazine
Intermediate B19
The title compound was prepared as a beige solid (29g, 78%) by the method described in intermediate B1, but starting from 1- (5-bromopyridin-2-yl) piperazine (28g, 0.116 mol).1H NMR(CDCl3)δ：2.82(3H，s)，3.33(4H，t)，3.67(4H，t)，6.59(1H，d，J＝9Hz)，7.58-7.59(1H，m)，8.22(1H，d，J＝2.4Hz)。
Intermediate B20: 1- (1, 3-benzodioxol-5-yl) -4- (methylsulfonyl) piperazine
Intermediate B20
The title compound was prepared by the method described in intermediate B1, but starting from 1- (1, 3-benzodioxol-5-yl) piperazine (638 mg; 3.09mmol) as a light brown powder (527mg, 60% yield). HPLC, Rt: 1.63min (purity: 100%). LC/MS, M+(ESI)：285.1。
Intermediate B21: 1- (34-dimethoxyphenyl) -4- (methylsulfonyl) piperazine
Intermediate B21
The compound was prepared as the title white powder by the method described in intermediate B1, but starting from 1- (3, 4-dimethoxyphenyl) -piperazine hydrochloride (2.0 g; 7.73mmol) (1.89g, 81% yield). HPLC, Rt: 1.58min (purity: 99.6%). LC/MS, M+(ESI)：301.1。
Intermediate B22: 1- (4-ethoxyphenyl) -4- (methylsulfonyl) -1, 4-diazepane
Step a) formation of 1- (4-ethoxyphenyl) -1, 4-diazepane dihydrochloride
A solution of homopiperazine (2.74g), 4-bromobenzene ethyl ether (5.0g) and sodium tert-butoxide (3.6g) was prepared in anhydrous toluene (50 ml). Argon was bubbled through the solution for 5min, then Pd (OAc) was added2(280mg) and (+/-) -BINAP (620 mg). The reaction mixture was heated at reflux for 15 hr. The reaction mixture was evaporated under reduced pressure to give a dark brown solid, taken up in DCM and on silicaAnd (4) adsorbing. Purification by flash chromatography on silica (DCM/MeOH) afforded the parent compound as a yellow oil. In Et2Adding the dihydrochloride of O dissolved in Et2O was precipitated in an excess of 1M HCl to give 1.06g (15%) of the title compound as a pale brown powder. LC/MS, M+(ESI)：221.2。
Step b) formation of 1- (4-ethoxyphenyl) -4- (methylsulfonyl) -1, 4-diazepane
Intermediate B22
The title compound was prepared by the method described in intermediate B1, but starting from 1- (4-ethoxyphenyl) -1, 4-diazepane dihydrochloride (250 mg; 0.85mmol) as an orange solid (141mg, 55% yield). HPLC, Rt: 1.59min (purity: 94.7%). LC/MS, M+(ESI): 299.2. intermediate B23: (2R) -4- (4-fluorophenyl) -2-methyl-1- (methylsulfonyl) piperazine
Step a) formation of (3R) -1- (4-fluorophenyl) -3-methylpiperazine
To a mixture of 1-bromo-4-fluorobenzene (5.0g, 0.0285mol), (R) -2-methylpiperazine (3.15g, 0.0313mol) and sodium tert-butoxide (4g, 0.042mol) in dry toluene (100mL) under nitrogen was added Pd (OAc)2(0.25g, 0.0011mol) followed by BINAP (0.75g, 0.0012 mol). The reaction mixture was refluxed for 18h and cooled to room temperature. The reaction mixture was washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica (chloroform: MeOH, 8: 2) to give the title compound as a liquid (2.5g, 46% yield). TLC: Rf-0.25 (chloroform/MeOH: 9/1).
Step b) formation of (2R) -4- (4-fluorophenyl) -2-methyl-1- (methylsulfonyl) piperazine
Intermediate B23
The compound was prepared as the title yellow solid by the method described in intermediate B1, but starting from 1- (4-fluorophenyl) - (3R) -methylpiperazine (500 mg; 2.57 mmol). HPLC, Rt: 2.85min (purity: 96.9%). LC/MS, M+(ESI)：273.1。
Example 1: 3- (1, 3-benzodioxol-5-yl) -1- ({ [4- (4-fluorophenyl) -1-piperazinyl]Sulfonyl } methyl) -2-propynyl (hydroxy) carboxamides(1)
Step a) formation of a mixture of 1- { [ (1E) -4- (1, 3-benzodioxol-5-yl) but-1-en-3-ynyl ] sulfonyl } -4- (4-fluorophenyl) piperazine and 1- { [ (1Z) -4- (1, 3-benzodioxol-5-yl) but-1-en-3-ynyl ] sulfonyl } -4- (4-fluorophenyl) piperazine
Lithium bis (trimethylsilyl) amide (1.49 mL; 1.00M solution in toluene; 1.49mmol) was slowly added to a solution of 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1, 175 mg; 0.68mmol) in THF (5mL) at-78 deg.C under an inert gas atmosphere. The reaction mixture was stirred at-78 ℃ for 1 h. Diethyl chlorophosphate (98. mu.l; 0.68mmol) was then added and the reaction mixture was stirred at-78 ℃ for a further 1 h. A catheter was inserted into a solution of 3- (1, 3-benzodioxol-5-yl) -2-propynal (intermediate A1, 124 mg; 0.71mmol) in THF (1mL), the mixture was warmed to room temperature, and 1 was stirredAnd 8 h. Saturated aqueous ammonium chloride was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (EtOAc: c-Hex, 10: 90 to 30: 70) gave the compound as the title (171mg of the E isomer, 23mg of the Z isomer, 69% total yield). E isomer: HPLC, Rt: 4.56min (purity: 93.0%). LC/MS, M+(ESI)：415.2。1H NMR(CDCl3) δ: 6.79-7.00(m, 6H), 6.78(dd, J ═ 11.5, 3.6Hz, 2H), 6.53(d, J ═ 15.1Hz, 1H), 5.99(s, 2H), 3.45(m, 4H), 3.19(m, 4H); z-isomer: HPLC, Rt: 4.33min (purity: 96.6%).1H NMR(CDCl3)δ：7.08(dd，J＝8.1，1.5Hz，1H)，6.83-6.93(m，5H)，6.77(d，J＝8.1Hz，1H)，6.42(AB，＝41Hz，J＝11Hz，2H)，5.98(s，2H)，3.43(m，4H)，3.16(m，4H)。
Step b) formation of N- [3- (1, 3-benzodioxol-5-yl) -1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -2-propynyl ] hydroxylamine
1- { [ (1E) -4- (1, 3-benzodioxol-5-yl) -1-buten-3-ynyl]Sulfonyl } -4- (4-fluorophenyl) piperazine (171 mg; 0.41mmol) was dissolved in THF (6mL) and 50% aqueous hydroxylamine (0.70 mL; 11.87mmol) was added. The reaction mixture was stirred at 60 ℃ for 5 h. THF was removed under reduced pressure and the residue was dissolved in DCM and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 148mg of white foam. Purification by flash chromatography on silica gel (EtOAc: c-Hex, 50: 50) gave the title compound as a white foam (150mg, 81% yield). HPLC, Rt: 3.39min (purity: 83.7%). LC/MS, M + (ESI): 448.1.1H NMR(CDCl3)δ：6.85-6.94(m，6H)，6.41(d，J＝8.3Hz，1H)，5.95(s，2H)，4.49(dd，J＝7.8，4.6 Hz，1H)，3.63(dd，J＝14.1，7.9Hz，1H)，3.66(m，4H)，3.30(dd，J＝14.1，4.5Hz，1H)，3.16(m，4H)。
step c) formation of 3- (1, 3-benzodioxol-5-yl) -1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -2-propynyl (hydroxy) carboxamide
Acetic anhydride (1.00 mL; 10.59mmol) was added dropwise to formic acid (5mL) at 0 deg.C, and the mixture was stirred for 30 min. 1mL of this solution was then added to N- [3- (1, 3-benzodioxol-5-yl) -1- ({ [4- (4-fluorophenyl) -1-piperazinyl) dissolved in THF (3mL) and formic acid (0.7mL)]Sulfonyl } methyl) -2-propynyl]A solution of hydroxylamine (150.0 mg; 0.34mmol) was stirred overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in MeOH and heated at 60 ℃ for 3 h. The solution was cooled to room temperature and the resulting precipitate was filtered. Redissolved in EtOAc and reprecipitated in pentane, filtered and dried under reduced pressure to give compound (1) as the title white solid (80mg, 50% yield). HPLC, Rt: 3.58min (purity: 96.9%). LC/MS, M+(ESI)：476.3，M-(ESI)：474.3.1H NMR(CDCl3)δ：9.55(s，0.5H)，9.12(s，0.5H)，8.1(m，1H)，6.90-7.09(m，7H)，6.05(s，2H)，4.81(s，0.5H)，4.61(s，0.5H)，3.62(m，2H)，3.31(m，4H)，3.14(m，4H)。
Example 2: 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -3- (trimethylsilyl) -2-propynyl (hydroxy) carboxamide (2)
Step a) formation of a mixture of 1- (4-fluorophenyl) -4- { [ (1E) -4- (trimethylsilyl) -1-buten-3-ynyl ] sulfonyl } piperazine and 1- (4-fluorophenyl) -4- { [ (1Z) -4- (trimethylsilyl) -1-buten-3-ynyl ] sulfonyl } piperazine
The compound was prepared as the title white powder (240mg, 65% yield) by the method described in example 1, step a), starting from 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1, 258mg, 1.0mmol, 1.0eq.) and 3-trimethylsilylpropylaldehyde (132mg, 1.05mmol, 1.05 eq.). HPLC, Rt: 5.03min (purity: 99.7%). LC/MS, M+(ESI)：367.1。1H NMR(CDCl3)δ：7.07-6.86(m，4H)，6.60(m，2H)，3.36(m，4H)，3.21(m，4H)，0.26(s，9H)。
Step b) formation of 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (trimethylsilyl) -3-butynyl ] sulfonyl } piperazine
By the method described in example 1, step b), starting from 1- (4-fluorophenyl) -4- { [ (1E) -4- (trimethylsilyl) -1-buten-3-ynyl]Starting with sulfonyl } piperazine (240mg, 0.65mmol, 1.0eq.) compound (2) was prepared as the title white powder (161mg, 62% yield). HPLC, Rt: 3.89min (purity: 96.0%). LC/MS, M+(ESI)：400.1。1H NMR(CDCl3)δ：7.13-6.84(m，4H)，5.35(brs，2H)，4.35dd(J：4.35Hz，J＝8.23Hz，1H)，3.61(m，1H)，3.52(m，4H)，3.26(m，1H)，3.21(m，4H)，0.22(s，9H)。
Step c) formation of 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -3- (trimethylsilyl) -2-propynyl (hydroxy) carboxamide
Compound (2) was prepared as the title colorless oil by the method described in example 1, step c), starting from 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (trimethylsilyl) -3-butynyl ] sulfonyl } piperazine (40mg, 0.1mmol, 1.0 eq.). HPLC, Rt: 3.80min (purity: 61.3%). LC/MS, M + (ESI): 428.0.
example 3: hydroxy [1- ({ [4- (2-pyridyl) -1-piperazinyl ] sulfonyl } methyl) -3- (trimethylsilyl) -2-propynyl ] carboxamide (3)
Step a) formation of a mixture of 1- (2-pyridyl) -4- { [ (1E) -4- (trimethylsilyl) -1-buten-3-ynyl ] sulfonyl } piperazine and 1- (2-pyridyl) -4- { [ (1Z) -4- (trimethylsilyl) -1-buten-3-ynyl ] sulfonyl } piperazine
The compound was prepared as the title as a brown-like powder by the method described in example 1, step a), starting from 1- (methanesulfonyl) -4- (2-pyridinyl) piperazine (intermediate B2, 1291mg, 5.0mmol, 1.0eq.) and 3-trimethylsilylpropylaldehyde (1325mg, 10.5mmol, 1.05 eq.). (1901mg, 54% yield). HPLC, Rt: 3.11min (purity: 97.6%). LC/MS, M+(ESI)：350.2。1H NMR(CDCl3)δ：8.23(m，1H)，7.54(m，1H)，6.76-6.62(m，2H)，6.61-6.55(m，2H)，3.75-3.65(m，4H)，3.35-3.36(m，4H)，0.25(s，9H)。
Step b) formation of 1- { [2- (hydroxyamino) -4- (trimethylsilyl) -3-butynyl ] sulfonyl } -4- (2-pyridyl) piperazine
By the method described in example 1, step b), starting from 1- (2-pyridyl) -4- { [ (1E) -4- (trimethylsilyl) -1-buten-3-ynyl]Sulfonyl radicalYl } piperazine (349mg, 1.0mmol, 1.0eq.) the title compound was prepared as a colorless oil. (306mg, 80% yield). HPLC, Rt: 2.08min (purity: 94.8%). LC/MS, M+(ESI)：383.3。1H NMR(CDCl 3)δ：8.22(m，1H)，7.52(m，1H)，6.76(brs，1H)，6.66(m，2H)，5.62(brs，1H)，4.35-4.22(m，1H)，3.73-3.52(m，5H)，3.49-3.34(m，4H)，3.29-3.15(m，1H)，0.16(s，9H)。
Step c) formation of hydroxy [1- ({ [4- (2-pyridinyl) -1-piperazinyl ] sulfonyl } methyl) -3- (trimethylsilyl) -2-propynyl ] carboxamide
By the method described in example 1, step c), but from 1- { [2- (hydroxyamino) -4- (trimethylsilyl) -3-butynyl]Starting from sulfonyl } -4- (2-pyridyl) piperazine (650mg, 1.61mmol, 1.0eq.) the title compound (3) was prepared as a white powder. (192mg, 57% yield). HPLC, Rt: 2.33min (purity: 98.2%). LC/MS, M+(ESI)：411.2。
Example 4: 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -3-phenyl-2-propynyl (hydroxy) carboxamide (4)
Step a) formation of a mixture of 1- (4-fluorophenyl) -4- { [ (1E) -4-phenyl-1-buten-3-ynyl ] sulfonyl } piperazine and 1- (4-fluorophenyl) -4- { [ (1Z) -4-phenyl-1-buten-3-ynyl ] sulfonyl } piperazine
By the method described in example 1, step a), but starting from 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1, 1291mg, 5.0mmol, 1.0eq.) and phenylpropanal (683mg, 5.25mmol,1.05eq.) the title compound was prepared as a white powder. (820mg, 44% yield). HPLC, Rt: 4.71min (purity: 98.9%). LC/MS, M+(ESI)：371.1。1H NMR(CDCl3)δ：7.35-7.08(m，5H)，6.83-6.53(m，5H)，6.38(d，J＝15.1Hz，1H)，3.15(m，4H)，2.97(m，4H)。
Step b) formation of 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4-phenyl-3-butynyl ] sulfonyl } piperazine
By the method described in example 1, step b), but starting from 1- (4-fluorophenyl) -4- { [ (1E) -4-phenyl-1-buten-3-ynyl]Starting with sulfonyl } piperazine (800mg, 2.16mmol, 1.0eq.) the compound was prepared as the title white powder. (665mg, 76% yield). HPLC, Rt: 3.51min (purity: 98.8%). LC/MS, M+(ESI)： 404.1。1H NMR(CDCl3)δ：7.62-7.51(m，2H)，7.50-7.31(m，3H)，7.16-6.90(m，4H)，5.81(brs，1H)，5.06(brs，1H)，4.65(dd，J＝4.5Hz，J＝7.9Hz，1H)，3.77(dd，J＝17.7Hz，J＝13.9Hz，1H)，3.62(m，4H)，3.45(dd，J＝4.5Hz，J＝14.2Hz，1H)，3.30(m，4H)。
Step c) formation of 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -3-phenyl-2-propynyl (hydroxy) carboxamide
By the method described in example 1, step c), but starting from 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4-phenyl-3-butynyl]Starting with sulfonyl } piperazine (650mg, 1.61mmol, 1.0eq.) the title compound (4) was prepared as a white powder. (512mg, 74% yield). HPLC, Rt: 3.71min (purity: 98).9％)。LC/MS，M+(ESI)：432.2，M-(ESI)：430.0.1H NMR(CDCl3)δ：8.27(brs，0.35H)，7.97(brs，0.65H)，7.29-7.20(m，2H)，7.19-7.06(m，3H)，6.87-6.61(m，4H)，5.60(brs，0.45H)，5.08(brs，0.55H)，3.75-3.41(m，1H)，3.27(m，4H)，2.96(m，4H)。
Examples 4a, 4 b: [ (1S) -1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3-phenylprop-2-yn-1-yl ] hydroxyformamide (4a) and [ (1R) -1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3-phenylprop-2-yn-1-yl ] hydroxyformamide (4b)
1- ({ [4- (4-fluorophenyl) -1-piperazinyl) was separated by chiral HPLC using a semipreparative CHIRALPACK AD column (MeOH: i-PrOH: FA, 50: 0.1; flow rate ═ 10mL/min)]Sulfonyl } methyl) -3-phenyl-2-propynyl (hydroxy) carboxamide (prepared as described in example 4). First compound (presumed to be the R enantiomer): HPLC, Rt: 3.67min (purity: 98.9%). LC/MS, M+(ESI)：432.2，M-(ESI): 430.0; chiral HPLC (CHIRALPACK AD-H), Rt 9.17min (Hexane: EtOH: DEA, 50: 0.1, flow rate 1 mL/min). Second compound (presumably the S enantiomer): HPLC, Rt: 3.61min (purity: 95.5%). LC/MS, M+(ESI)：432.2，M-(ESI): 430.2; chiral HPLC (CHIRALPACK AD-H), Rt ═ 12.8min (hexane: EtOH: DEA, 50: 0.1, flow rate ═ 1 mL/min).
Example 5: 1- [ ({4- [4- (benzyloxy) phenyl ] -1-piperazinyl } sulfonyl) methyl ] -2-octynyl (hydroxy) carboxamide (5)
Step a) formation of a mixture of 4- {4- [ (1E) -1-nonen-3-ynylsulfonyl ] -1-piperazinyl } benzyl phenyl ether and 4- {4- [ (1Z) -1-nonen-3-ynylsulfonyl ] -1-piperazinyl } benzyl phenyl ether
By the method described in example 1, step a), but from 1- [4- (benzyloxy) phenyl]Starting with-4- (methylsulfonyl) piperazine (intermediate B3, 346mg, 1.0mmol, 1.0eq.) and 2-octynal (130mg, 1.05mmol, 1.05eq.) the compound was prepared as the title white solid (238mg, 55% yield). HPLC, Rt: 5.27min (purity: 84.9%). LC/MS, M+(ESI)：453.4。1H NMR(CDCl 3)δ：7.48-7.28(m，5H)，6.95-6.83(m，4H)，6.61(m，0.35H)，6.56(m，0.65H)，6.45(s，0.65H)，6.41(s，0.35H)，5.01(s，2H)，3.30(m，4H)，3.13(m，4H)，2.37(m，2H)，1.56(m，2H)，1.45-1.15(m，6H)，0.90(m，3H)。
Step b) formation of 1- [4- (benzyloxy) phenyl ] -4- { [2- (hydroxyamino) -3-nonynyl ] sulfonyl } piperazine
By the method described in example 1, step b), but from benzyl 4- {4- [ (1E) -1-nonen-3-ynylsulfonyl]Starting with-1-piperazinyl } phenyl ether (238mg, 0.53mmol, 1eq.) the title compound was prepared as a white solid (211mg, 83% yield). HPLC, Rt: 3.89min (purity: 60.6%). LC/MS, M+(ESI)：486.3。 1H NMR(CDCl3)δ：7.44-7.27(m，5H)，6.95-6.83(m，4H)，5.36(brs，1H)，5.02(s，2H)，4.28(m，1H)，3.60-3.43(m，5H)，3.16(m，5H)，2.20(m，2H)，1.50(m，2H)，1.45-1.24(m，4H)，0.89(m，3H)。
Step c) formation of 1- [ ({4- [4- (benzyloxy) phenyl ] -1-piperazinyl } sulfonyl) methyl ] -2-octynyl (hydroxy) carboxamide
By the method described in example 1, step c), but from 1- [4- (benzyloxy) phenyl]-4- { [2- (hydroxyamino) -3-nonanynyl]Starting with sulfonyl } piperazine (160mg, 0.33mmol, 1.0eq.) the title compound (5) was prepared as a pink solid. (70mg, 41% yield). HPLC, Rt: 4.15min (purity: 93.8%). LC/MS, M+(ESI)：514.4，M-(ESI)：512.2。1H NMR(CDCl3)δ：8.41(brs，0.37H)，8.11(brs，0.63H)，7.45-7.27(m，5H)，6.96-6.83(m，4H)，5.55(brs，0.5H)，5.00(brs，2.5H)，3.80-3.56(m，1H)，3.41(m，3H)，3.23-3.18(m，1H)，3.11(m，4H)，2.19(m，2H)，165-1.43(m，4H)，1.40-1.24(m，4H)，0.88(m，3H)。
Example 6: 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -4-phenyl-2-butynyl (hydroxy) carboxamide (6)
Step a) formation of a mixture of 1- (4-fluorophenyl) -4- { [ (1E) -5-phenyl-1-penten-3-ynyl ] sulfonyl } piperazine and 1- (4-fluorophenyl) -4- { [ (1Z) -5-phenyl-1-penten-3-ynyl ] sulfonyl } piperazine
To a solution of 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1, 107.5 mg; 0.42mmol) in THF (10mL) was added lithium bis (trimethylsilyl) amide (0.92 mL; 1M solution in toluene; 0.92mmol) under nitrogen at-78 deg.C. The mixture was stirred at-78 ℃ for 30 min. Diethyl chlorophosphate (60. mu.l; 0.42mmol) was added and the mixture was stirred at-78 ℃ for a further 30 min. A solution of 4-phenyl-2-butylal (intermediate A2, 60 mg; 0.42mmol) in THF (3mL) was inserted in a catheter and the mixture was stirred at-78 deg.C for 1.5 h. With saturated NH4The mixture was quenched with Cl solution and extracted with EtOAc. Saline water washingThe organic layer was washed, dried over magnesium sulfate, filtered and concentrated. The crude product (190mg) was purified by flash chromatography on silica (EtOAc/c-Hex 10-90 then 20: 80) to give the compound as the title (133mg of the E isomer and 28mg of the Z isomer, 98% overall yield). E-isomer: HPLC, Rt: 4.68min (purity: 94.6%). LC/MS, M+(ESI)：385.2，M-(ESI)：383.2.1H NMR (CDCl3) δ: 7.30(m, 5H), 6.81-6.89(m, 4H), 6.63(dt, J ═ 15.3, 2.2Hz, 1H), 6.48(d, J ═ 15.3Hz, 1H), 3.78(d, J ═ 2.1Hz, 2H), 3.31(m, 4H), 3.15(m, 4H); z-isomer: HPLC, Rt: 4.41min (purity: 76%). LC/MS, M+(ESI)：385.2，M-(ESI)：383.2。1H NMR(CDCl3)δ：7.35(m，5H)，6.99(m，4H)，6.36(d，J＝3.0Hz，2H)，3.84(s，2H)，3.42(m，4H)，3.13(m，4H)。
Step b) formation of 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -5-phenyl-3-pentynyl ] sulfonyl } piperazine
In 1- (4-fluorophenyl) -4- { [ (1E) -5-phenyl-1-penten-3-ynyl dissolved in THF (8mL)]To a solution of sulfonyl } piperazine (155 mg; 0.40mmol) was added hydroxylamine (0.71 mL; 12.1 mmol). The reaction mixture was heated at 60 ℃ for 1 h. It was then diluted with EtOAc, washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product (135mg) was purified by flash chromatography on silica to give the compound as the title (50mg, 30% yield). HPLC, Rt: 3.84min (purity: 94.5%). LC/MS, M+(ESI)：418.3，M-(ESI)：416.2。1H NMR(CDCl3)δ：7.22-7.31(m，5H)，7.01(m，4H)，4.33(m，1H)，3.62(d，J＝1.9Hz，2H)，3.53-3.60(m，5H)，3.20-3.27(m，5H)。1H NMR(CDCl3)δ：7.30(m，5H)，6.95(m，4H)，6.32(d，J＝15.6Hz，1H)，6.07(dt，J＝16.1，7.4Hz，1H)，3.90(s，2H)，3.78(d，J＝6.6Hz，2H)，3.22(m，4H)，2.91(m，4H)。
Step d) formation of 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -4-phenyl-2-butynyl (hydroxy) carboxamide
By the method described in example 1, step d), but starting from 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -5-phenyl-3-pentynyl]Starting with sulfonyl } piperazine (50mg, 0.12mmol), the title compound (6) was prepared as a yellow oil (40mg, 75% yield). HPLC, Rt: 3.72min (purity: 85.2%). LC/MS, M+(ESI)：446.3，M-(ESI)：444.2。1H NMR(CDCl3)δ：8.44(brs，0.4H)，8.10(brs，0.6H)，7.36-7.20(m，5H)，7.05-6.85(m，4H)，5.62(brs，0.5H)，5.10(brs，0.5H)，3.62(s，2H)，3.55-3.25(m，5H)，3.15(brs，5H)。
Example 7: 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -2-octynyl (hydroxy) carboxamide (7)
Step a) formation of a mixture of 1- (4-fluorophenyl) -4- [ (1E) -1-nonen-3-alkynylsulfonyl ] piperazine and 1- (4-fluorophenyl) -4- [ (1Z) -1-nonen-3-alkynylsulfonyl ] piperazine
The compound was prepared by the method described in example 1, step a), but starting from 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1, 258mg, 1.0mmol) and 2-octynal (130mg, 1.05mmol) as an orange solid. (261mg, 72% yield). HPLC, Rt: 5.17min (purity: 99.9%). LC/MS, M+(ESI)：365.3，M-(ESI)：363.2。1H NMR(CDCl3)δ：7.04-6.86(m，4H)，6.63(m，0.35H)，6.56(m，0.65H)，6.45(s，0.65H)，6.40(s，0.35H)，3.35(m，4H)，3.18(m，4H)，2.37(m，2H)，1.53(m，4H)，1.45-1.15(m，4H)，0.90(m，3H)。
Step b) formation of 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3-nonynyl ] sulfonyl } piperazine
By the method described in example 1, step b), but from benzyl 1- (4-fluorophenyl) -4- [ (1E) -1-nonen-3-ynylsulfonyl]Piperazine (264mg, 0.72 mmo)]1.0eq.) the title compound was prepared as a white solid. (169mg, 69% yield). HPLC, Rt: 3.54min (purity: 73.7%). LC/MS, M+(ESI)：398.2，M-(ESI)：396.2。1H NMR(CDCl3)δ：6.97(m，2H)，6.87(m，2H)，4.29(m，1H)，3.52-3.43(m，1H)，3.40(m，4H)，3.16(m，1H)，3.11(m，4H)，2.19(m，2H)，1.50(m，2H)，1.40-1.22(m，4H)，0.88(m，3H)。
Step c) formation of 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -2-octynyl (hydroxy) carboxamide
By the method described in example 1, step c), but from 1- ({ [4- (4-fluorophenyl) -1-piperazinyl]Sulfonyl } methyl) -2-octynyl (hydroxy) carboxamide (162mg, 0.41mmol, 1.0eq.) the title compound (7) was prepared as an orange solid. (110mg, 63% yield). HPLC, Rt: 3.87min (purity: 99.2%). LC/MS, M+(ESI)：426.3，M-(ESI)：424.2。1H NMR(CDCl3)δ：8.41(brs，0.4H)，8.08(brs，0.6H)，6.97(m，2H)，6.88(m，2H)，5.55(brs，0.36H)，5.01(brs，0.64H)，3.82-3.55(m，1H)，3.42(m，4H)，3.27-3.20(m，1H)，3.14(m，4H)，2.18(m，2H)，1.50(m，2H)，1.40-1.20(m，4H)，0.89(m，3H)。
Example 8: 1- ({ [4- (4-fluorophenyl) -1-piperazinyl ] sulfonyl } methyl) -3- (3-pyridyl) -2-propynyl (hydroxy) carboxamide (8)
Step a) formation of a mixture of 1- (4-fluorophenyl) -4- { [ (1E) -4- (3-pyridyl) -1-buten-3-ynyl ] sulfonyl } piperazine and 1- (4-fluorophenyl) -4- { [ (1Z) -4- (3-pyridyl) -1-buten-3-ynyl ] sulfonyl } piperazine
By the method described in example 1, step a), but starting from 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1, 75mg, 0.29mmol) and 3- (3-pyridyl) -2-propynal aldehyde (intermediate A3, 40mg, 0.30mmol), the compound was prepared as the title as a light yellow powder (40mg, 37% yield). HPLC, Rt: 3.1min (purity: 94.7%). LC/MS, M+(ESI)：372.2，M-(ESI)：370.0。1H NMR(CDCl3)δ：8.72(m，1H)，8.61(m，1H)，7.78(m，1H)，7.31(dd，J＝7.9，4.9Hz，1H)，7.04-6.94(m，2H)，6.93-6.83(m，2H)，6.84(d，J＝15.5Hz，1H)，6.68(d，J＝15.5Hz，1H)，3.37(m，4H)，3.18(m，4H)。
Step b) formation of 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (3-pyridyl) -3-butynyl ] sulfonyl } piperazine
By the method described in example 1, step b), but starting from 1- (4-fluorophenyl) -4- { [ (1E) -4- (3-pyridyl) -1-buten-3-ynyl]Starting with sulfonyl } piperazine (36mg, 0.1mmol), prepare the title compoundYellow powder compound (15mg, 38% yield). HPLC, Rt: 1.9min (purity: 94.7%). LC/MS, M+(ESI): 405.2. step c)1- ({ [ [4- (4-fluorophenyl) -1-piperazinyl]Formation of sulfonyl } methyl) -3- (3-pyridyl) -2-propynyl (hydroxy) carboxamides
By the method described in example 1, step c), but starting from 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (3-pyridyl) -3-butynyl]Sulfonyl } piperazine (15mg, 0.04mmol) the compound (8) was prepared starting as the title as a pale yellow powder (6.4mg, 40% yield). HPLC, Rt: 2.1min (purity: 99.0%). LC/MS, M+(ESI)：433.3，M-(ESI)：431.1。1H NMR(CDCl 3)δ：8.66-8.44(m，2.6H)，8.15(brs，0.4H)，7.78(d，J＝7.5Hz，1H)，7.32(m，1H)，7.05-6.86(m，4H)，5.91(brs，0.6H)，5.31(brs，0.4H)，3.95-3.65(m，1H)，3.60-3.37(m，6H)，3.20(m，4H)。
Example 9: hydroxy [1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -3- (3-pyridinyl) -2-propynyl ] carboxamide (9)
Step a) formation of a mixture of 1- (4-methoxyphenyl) -4- { [ (1E) -4- (3-pyridyl) -1-buten-3-ynyl ] sulfonyl } piperazine and 1- (4-methoxyphenyl) -4- { [ (1Z) -4- (3-pyridyl) -1-buten-3-ynyl ] sulfonyl } piperazine
By the method described in example 1, step a), but starting from 1- (4-methoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B4, 338mg, 1.25mmol) and 3- (3-pyridinyl) -2-propynal aldehyde (intermediate A3, 246mg, 1.88mmol), the title was prepared as a yellow powderCompound (31mg, 6.5% yield). HPLC, Rt: 2.4min (purity: 88.1%). LC/MS, M+(ESI)：384.2。1H NMR(CDCl3)δ：8.72(m，1H)，8.61(m，1H)，7.77(m，1H)，7.31(m，1H)，7.04-6.85(m，4H)，6.81(d，J＝15.4Hz，1H)，6.67(d，J＝15.4Hz，1H)，3.77(s，3H)，3.39(m，4H)，3.17(m，4H)。
Step b) formation of 1- { [2- (hydroxyamino) -4- (3-pyridinyl) -3-butynyl ] sulfonyl } -4- (4-methoxyphenyl) piperazine
By the method described in example 1, step b), but starting from 1- (4-methoxyphenyl) -4- { [ (1E) -4- (3-pyridyl) -1-buten-3-ynyl]Starting with sulfonyl } piperazine (27mg, 0.07mmol), the title compound was prepared as a white powder (15mg, 51% yield). HPLC, Rt: 1.5min (purity: 97.1%). LC/MS, M+(ESI)：417.3. 1H NMR(CDCl3)δ：8.71(brs，1H)，8.55(brd，J＝4.7Hz，1H)，7.75(brd，J＝7.9Hz，1H)，7.26(dd，J＝7.9，4.7Hz，1H)，6.93(m，2H)，6.85(m，2H)，4.58(dd，J＝8.2，4.4Hz，1H)，3.78(s，3H)，3.70(dd，J＝14.2，8.2Hz，1H)，3.52(m，4H)，3.34(dd，J＝14.2，4.4Hz，1H)，3.17(m，4H)。
Step c) formation of hydroxy [1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -3- (3-pyridyl) -2-propynyl ] carboxamide
By the method described in example 1, step c), but from 1- { [2- (hydroxyamino) -4- (3-pyridinyl) -3-butynyl]Starting from sulfonyl } -4- (4-methoxyphenyl) piperazine (15mg, 0.04mmol), the preparationCompound (9) was prepared as the title pale yellow powder (11mg, 70% yield). HPLC, Rt: 1.6min (purity: 99.2%). LC/MS, M+(ESI)：445.3，M-(ESI)：443.2。1H NMR(CDCl3)δ：8.64(brs，1H)，8.60-8.44(m，1.6H)，8.15(brs，0.4H)，7.76(d，J＝7.9Hz，1H)，7.30(m，1H)，6.93(m，2H)，6.83(m，2H)，5.93(brs，0.6H)，5.13(brs，0.4H)，4.00-3.65(m，1H)，3.76(s，3H)，3.49(m，6H)，3.16(m，4H)。
Example 10: hydroxy [3- (3-methoxyphenyl) -1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -2-propynyl ] carboxamide (10)
Step a) formation of diethyl { [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methylphosphonate
To a solution of 1- (4-methoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B4, 338 mg; 1.25mmol) in anhydrous THF (10mL) at-20 ℃ under an inert gas was added a solution of 1M lithium bis (trimethylsilyl) amine dissolved in toluene (2.75mL, 2.75 mmol). The resulting mixture was stirred at-20 ℃ for 30 min. Diethyl chlorophosphate (180. mu.l; 1.25mmol) was then added and the mixture was stirred at-20 ℃ for a further 4 hours. Adding saturated NH4Aqueous Cl and reaction mixture extracted with EtOAc (2 ×). With saturated NaHCO3The organic layer was washed with an aqueous solution. The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. Purification by flash chromatography on silica (cHex: EtOAc, gradient 80: 20 to 0: 100) gave 255mg (50%) of the title compound as a yellow powder. HPLC, Rt: 2.22min (purity: 99.8%). LC/MS, M+(ESI)：407.3，M-(ESI)：405.2。1H NMR(CDCl3)δ：6.87(m，4H)，4.26(m，4H)，3.78(s，3H)，3.59(s，1H)，3.53(s，1H)，3.50(m，4H)，3.16(m，4H)，1.39(t，J＝7.0Hz，6H)。
Step b) formation of a mixture of 1- (4-methoxyphenyl) -4- { [ (1E) -4- (3-methoxyphenyl) -1-buten-3-ynyl ] sulfonyl } piperazine and 1- (4-methoxyphenyl) -4- { [ (1Z) -4- (3-methoxyphenyl) -1-buten-3-ynyl ] sulfonyl } piperazine
To { [4- (4-methoxyphenyl) -1-piperazinyl in anhydrous THF (5mL) at-10 ℃ under an inert gas atmosphere]Sulfonyl } methyl phosphate (250mg, 0.62mmol) in toluene (0.74mL, 0.74mmol) was added to a solution of 1M lithium bis (trimethylsilyl) amine. After 15min, 3- (3-methoxyphenyl) -2-propynal (117mg, 0.74mmol, intermediate A5) dissolved in anhydrous THF (0.7mL) was added. The resulting mixture was stirred at-10 ℃ for 12 hours. Saturated aqueous NH4Cl was added and the reaction mixture was extracted with EtOAc (2 ×). With saturated NaHCO3The organic layer was washed with an aqueous solution. The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. Purification by flash chromatography on silica (cHex: EtOAc, gradient 80: 20 to 50: 50) gave 172mg (67%) of the title compound as a white powder. HPLC, Rt: 4.1min (purity: 99.8%). LC/MS, M+(ESI)：413.3。1H NMR(CDCl3)δ：7.29(m，1H)，7.10(m，1H)，7.02-6.85(m，6H)，6.83(d，J＝15.1Hz，1H)，6.63(d，J＝15.1Hz，1H)，3.83(s，3H)，3.79(s，3H)，3.38(m，4H)，3.18(m，4H)。
Step c) formation of 1- { [2- (hydroxyamino) -4- (3-methoxyphenyl) -3-butynyl ] sulfonyl } -4- (4-methoxyphenyl) piperazine
By the method described in example 1, step b), but from 1- (4-methoxy-1Phenyl) -4- { [ (1E) -4- (3-methoxyphenyl) -1-buten-3-ynyl]Starting with sulfonyl } piperazine (91mg, 0.22mmol), the title white foam compound was prepared (126mg, 71% yield). HPLC, Rt: 2.9min (purity: 99.1%). LC/MS, M+(ESI)：446.4.1H NMR(CDCl3)δ：7.21(m，1H)，7.05(m，1H)，6.99-6.85(m，6H)，5.91(brs，1H)，5.08(brs，1H)，4.54(dd，J＝8.3，4.2Hz，1H)，3.78(s，3H)，3.77(s，3H)， 3.66(dd，J＝14.3，8.3Hz，1H)，3.52(m，4H)，3.35(dd，J＝14.3，4.2Hz，1H)，3.16(m，4H)。
Step d) formation of hydroxy [3- (3-methoxyphenyl) -1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -2-propynyl ] carboxamide
By the method described in example 1, step c), but from 1- { [2- (hydroxyamino) -4- (3-methoxyphenyl) -3-butynyl]Starting with sulfonyl } -4- (4-methoxyphenyl) piperazine (123mg, 0.8mmol, 1eq.) the title compound (10) was prepared as a pink foam (131mg, 95% yield). HPLC, Rt: 3.0min (purity: 99.7%). LC/MS, M+(ESI)：474.3，M-(ESI)：472.1。1H NMR(CDCl3)δ：8.47(brs，0.4H)，8.17(brs，0.6H)，7.22(t，1H，J＝8.1Hz)，7.03(m，1H)，6.98-6.81(m，6H)，5.81(brs，0.5H)，5.28(brs，0.5H)，3.78(s，3H)，3.76(s，3H)，3.47(m，4H)，3.14(m，4H)。
Example 11: 4- (diethylamino) -1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -2-butynyl (hydroxy) carboxamide (11)
Step a) formation of a mixture of N, N-diethyl-N- ((4E) -5- { [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } -4-penten-2-ynyl) amine and N, N-diethyl-N- ((4Z) -5- { [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } -4-penten-2-ynyl) amine
The compound was prepared as the title yellow powder (391mg, 60% yield) by the method described in example 1, step a), but starting from 1- (4-methoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B4, 450mg, 1.66mmol) and 4- (diethylamino) -2-butynal (intermediate a4, 347mg, 2.5 mmol). HPLC, Rt: 2.0min (purity: 93.3%). LC/MS, M+(ESI)：392.3。1H NMR(CDCl3)δ：6.94-6.84(m，4H)，6.63(dt，J＝15.0，1.7Hz，1H)，6.52(d，J＝15.0Hz，1H)，3.78(s，3H)，3.63(d，J＝1.7Hz，2H)，3.34(m，4H)，3.15(m，4H)，2.58(q，J＝7.1Hz，4H)，1.10(t，J＝7.1Hz，6H)。
Step b) formation of N, N-diethyl-4- (hydroxyamino) -5- { [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } -2-pentyn-1-amine
By the method described in example 1, step b), but starting from N, N-diethyl-N- ((4E) -5- { [4- (4-methoxyphenyl) -1-piperazinyl]Sulfonyl } -4-penten-2-ynyl) amine (391mg, 1mmol, 1eq.) the compound was prepared as the title yellow oil (165mg, 39% yield). HPLC, Rt: 1.50min (purity: 53.8%). LC/MS, M+(ESI)：425.3。1H NMR(CDCl 3)δ：6.95-6.81(m，4H)，4.33(m，1H)，3.76(brs，3H)，3.60-3.50(m，1H)，3.50-3.38(m，5H)，3.18-3.05(m，4H)，2.53(q，4H，J＝7.1Hz)，1.05(t，6H，J＝7.1Hz)。
Step c) formation of 4- (diethylamino) -1- ({ [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } methyl) -2-butynyl (hydroxy) carboxamide
By the method described in example 1, step c), but starting from N, N-diethyl-4- (hydroxyamino) -5- { [4- (4-methoxyphenyl) -1-piperazinyl]Sulfonyl } -2-penten-1-amine (163mg, 0.38mmol) was prepared as the title compound (11) as a pale yellow foam (70mg, 40% yield). HPLC, Rt: 1.5min (purity: 99.8%). LC/MS, M+(ESI)：453.3，M-(ESI)：451.2.1H NMR(CD3OD)δ：8.34(brs，0.5H)，8.19(brs，0.5H)，7.01(m，2H)，6.89(m，2H)，5.70(brs，0.5H)，5.38(brs，0.5H)，3.80(s，2H)，3.78(s，3H)，3.55(m，2H)，3.16(m，4H)，2.96(m，4H)，1.23(t，J＝7.2Hz， 6H)。
Example 12: hydroxy (1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } prop-2-yn-1-yl) carboxamide (12)
Step a) formation of a mixture of 1- [ (1E) -but-1-en-3-yn-1-ylsulfonyl ] -4-pyridin-2-ylpiperazine and 1- [ (1Z) -but-1-en-3-yn-1-ylsulfonyl ] -4-pyridin-2-ylpiperazine
1- (2-pyridyl) -4- { [ (1E) -4- (trimethylsilyl) -1-buten-3-ynyl in THF (4mL) at-20 deg.C]To a solution of sulfonyl } piperazine (prepared in example 3, step a; 174.8 mg; 0.50 mmol; 1.0eq.) was added a solution of 1N tetrabutylammonium fluoride (0.75 mL; 0.75 mmol; 1.50 eq). After 1h, saturated NH was added4Aqueous Cl solution. The mixture was extracted with EtOAc and the combined organic layers were washed with water and brine over MgSO4Dry, filter and evaporate to give a brown oil. Purification on silica gel (EtOAc/c-Hex 40/60) gave the title colorless oilProduct (30mg, 21%).1H NMR(CDCl3)δ：8.01(m，1H)，7.25(m，1H)，6.50-6.21(m，4H)，3.42(m，4H)，3.20(s，1H)，3.05(m，4H)。
Step b) formation of 1- { [2- (hydroxyamino) but-3-yn-1-yl ] sulfonyl } -4-pyridin-2-ylpiperazine
1- [ (1E) -1-buten-3-ynylsulfonyl in THF (3mL)]To a solution of-4- (2-pyridyl) piperazine (30 mg; 0.11 mmol; 1.00eq.) was added an aqueous solution of hydroxylamine (50%, 0.10 mL; 1.62 mmol; 15.0eq.) and the resulting reaction mixture was stirred at 60 ℃ for 4 h. The solvent was evaporated (rotavap gave an oil). Purification on silica gel (50/50 to 70/30AcOEt-c-Hex) gave a colorless oil (15mg, 44% yield). LC/MS, M+(ESI)：311.1，M-(ESI)：309.0。
Step c) formation of hydroxy (1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } prop-2-yn-1-yl) carboxamide
Acetic anhydride (25 mg; 0.24 mmol; 5.0eq.) is added to cold (0 ℃ C.) formic acid (111 mg; 2.42 mmol; 50.0 eq.). The mixture was stirred for 1 h. Then 1M 1- { [2- (hydroxyamino) -3-butynyl in THF was added]Sulfonyl } -4- (2-pyridyl) piperazine (15 mg; 0.05 mmol; 1.0eq.) solution. After 4h, the solvent was evaporated and the crude product was purified on silica gel (80/20EtOAc/c-Hex) to give compound (12) as the title colorless oil (2.3mg, 14% yield). LC/MS, M+(ESI)：339.2，M-(ESI)：337.1。
Example 13: hydroxy [1- ({ [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] carboxamide (13)
A solution of 4- (4-methoxyphenyl) -1- (methylsulfonyl) piperidine (intermediate B5; 100mg, 0.37mmol) was prepared in dry THF (3mL) and cooled at 0 deg.C. A solution of LiHMDS (1M in THF, 0.8mL, 0.82mmol) was added dropwise. After 5min, diethyl chlorophosphate (54. mu.l, 0.37mmol) was added. After 5min, 3-phenylpropionaldehyde (55 μ l, 0.45mmol) was added and the reaction mixture was stirred at room temperature for 40 min. Then 50% NH was added2An aqueous solution of OH (0.33mL) and the resulting biphasic mixture was heated at 60 ℃ for 2.5 h. Brine (5mL) was added and the two layers were separated. The aqueous layer was extracted with EtOAc (2X 10 mL). The organic layers were combined and dried (MgSO)4) And the solvent was removed under reduced pressure to give a yellow oil. A mixture of formic acid (1.05mL) and acetic anhydride (260mL) was stirred at 0 deg.C for 30min, then an oily solution previously dissolved in anhydrous THF (2mL) was added and the resulting mixture stirred at 0 deg.C for 30 min. The mixture was evaporated under reduced pressure. The residue was taken up in MeOH (4mL) and heated at 60 deg.C for 30 min. The mixture was evaporated under reduced pressure to give a yellow oil, taken up in EtOAc (5mL) and saturated NaHCO3(5mL) aqueous wash. The aqueous layer was extracted with EtOAc (2X 5 mL). The organic layers were combined and dried (MgSO)4) The solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (gradient cHex: EtOAc 2: 1 to 1: 2) gave the title compound as an orange foam (53mg, 32% yield). HPLC, Rt: 4.0min (purity: 96.3%). LC/MS, M+(ESI)：443.3， M-(ESI)：441.1。
Example 14: hydroxy (1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } hex-2-yn-1-yl) carboxamide (14)
Step a) formation of 1- [ (1E) -hept-1-en-3-yn-1-ylsulfonyl ] -4-pyridin-2-ylpiperazine
By the method described in example 1, step a), but starting from 1- (methylsulfonyl) -4- (2-pyridinyl) piperazine (intermediate B2, 502 mg; 2.08mmol) and butyraldehyde (200 mg; 2.08mmol) the title compound was prepared as a white powder (246mg, 37% yield). HPLC, Rt: 2.48min (purity: 98.9%). LC/MS, M+(ESI)：320.3，M-(ESI)：318.3.1H NMR(DMSO-d6)δ：8.16(m，1H)，7.46(m，1H)，6.67(m，2H)，6.56(dt，J＝15.3，2.3Hz，1H)，6.38(d，J＝15.3Hz，1H)，4.09(t，J＝5.2Hz，4H)，3.23(t，J＝5.0Hz，4H)，2.32(td，J＝7.0，2.1Hz，2H)，1.55(sx，J＝7.2Hz，2H)，0.96(t，J＝7.3Hz，3H)。
Step b) formation of 1- { [2- (hydroxyamino) hept-3-en-1-yl ] sulfonyl } -4-pyridin-2-ylpiperazine
By the method described in example 1, step b) but from 1- [ (1E) -hept-1-en-3-yn-1-ylsulfonyl]Starting from (246 mg; 0.77mmol) of 4-pyridin-2-ylpiperazine the title compound was prepared as a colorless oil (158mg, 58% yield). HPLC, Rt: 1.21min (purity: 100%). LC/MS, M+(ESI)：353.3。1H NMR(DMSO-d6)δ：8.16(m，1H)，7.49(m，1H)，6.65(m，2H)，5.5(brs，2H)，4.25(m，1H)，3.63(m，4H)，3.51(dd，J＝14.1，7.7Hz，1H)，3.52(m，4H)，3.15(dd，J＝14.0，4.8Hz，1H)，2.12(td，J＝7.1，2.1Hz，2H)，1.47(sx，J＝7.3Hz，2H)，0.92(t，J＝7.3Hz，3H)。
Step c) formation of hydroxy (1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } hex-2-yn-1-yl) carboxamide
1- { [2- (hydroxyamino) hept-3-yn-1-yl ] in THF (5mL)]Sulfonyl } -4-pyridin-2-ylpiperazine (157 mg; 0.45mmol) was added to a solution of the acetyl formate in THF (2mL) (200mg, prepared as described in Kolle et al, 1983, Helvetica Chimica Acta, 66(8), 2760-8). The reaction mixture was stirred at room temperature for 5h and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (EtOAc: c-Hex, gradient from 50: 50 to 100: 0) to give the title compound as a white foam (90mg, 53% yield). HPLC, Rt: 3.04min (purity: 97.9%). LC/MS, M+(ESI)：381.3，M-(ESI)：379.2。1H NMR(DMSO-d6)δ：8.39(brs，0.4H)，8.18(m，1H)，8.08(brs，0.6H)，7.48(m，1H)，6.66(m，2H)，5.53(brs，0.4H)，5.01(brs，0.6H)，3.63(m，5H)，3.36(m，6H)，2.14(m，2H)，1.49(sx，J＝7.2Hz，2H)，0.93(t，J＝7.3Hz，3H)。
Example 15: [1- ({ [4- (2-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (15)
The title compound was prepared by the method described in example 13, but starting from 1- (2-fluorophenyl) -4- (methylsulfonyl) piperazine (300 mg; 1.16mmol) and 1-octynal (0.17mL, 1.22mmol) as an orange oil (102mg, 20% yield). HPLC, Rt: 4.12min (purity: 99.9%). LC/MS, M+(ESI)：426.3，M-(ESI)：424.2。
Example 16: hydroxy (1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl ] methyl } oct-2-yn-1-yl) carboxamide _ (16)
The title compound was prepared by the method described in example 13 but starting from 1- (methylsulfonyl) -4- (2-pyridyl) piperazine (intermediate B2; 300 mg; 1.24mmol) and 2-octynal (0.19 ml; 1.31mmol) as an orange oil (104mg, 20% yield). HPLC, Rt: 2.35min (purity: 95.2%). LC/MS, M+(ESI)：409.3，M-(ESI)：407.1。
Example 17: hydroxy-N- {1- [ ({4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide (17)
By the method described in example 13, but from 1- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl]Piperazine (intermediate B6; 300 mg; 0.97mmol) and 2-octynal (0.15 mL; 1.02mmol) were prepared starting as the title compound as an orange solid (124mg, 26% yield). HPLC, Rt: 4.50min (purity: 99.9%). LC/MS, M+(ESI)：476.2。
Example 18: [1- ({ [4- (4-fluorophenyl) piperidin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] -N-hydroxyformamide (18)
The compound was prepared by the method described in example 13, but starting from 4- (4-fluorophenyl) -1- (methylsulfonyl) piperidine (intermediate B7; 300 mg; 1.17mmol) and 2-octynal (0.17 mL; 1.22mmol) as the title white solid (35mg, 7% yield). HPLC, Rt: 4.31min (purity: 98.2%). LC/MS, M+(ESI)：425.3，M-(ESI)：423.1。
Example 19: hydroxy [1- ({ [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] carboxamide (19)
The compound was prepared by the method described in example 13, but starting from 4- (4-methoxyphenyl) -1- (methylsulfonyl) piperidine (intermediate B5; 300 mg; 1.11mmol) and 2-octynal (0.17 mL; 1.17mmol), as the title orange solid (54mg, 11% yield). HPLC, Rt: 4.24min (purity: 100%). LC/MS, M+(ESI)：437.3；M-(ESI)：435.2。
Example 20: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3- (3-methoxyphenyl) prop-2-yn-1-yl ] hydroxyformamide (20)
Step a) formation of diethyl ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) phosphonate
The compound was prepared by the method described in example 10, but starting from 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (10.3 g; 40.0mmol) as the title white solid (11.0g, 70% yield). HPLC, Rt: 2.88min (purity: 98.9%).
Step b) formation of a mixture of 1- (4-fluorophenyl) -4- { [ (1E) -4- (3-methoxyphenyl) but-1-en-3-yn-1-yl ] sulfonyl } piperazine and- (4-fluorophenyl) -4- { [ (1Z) -4- (3-methoxyphenyl) but-1-en-3-yn-1-yl ] sulfonyl } piperazine
({ [4- (4-fluorophenyl) piperazin-1-yl) in THF (5mL)]Sulfonyl } methyl) phosphonic acid diethyl ester (404 mg; 1.02mmol), 3-methoxyphenylpropargyl alcohol (intermediate a 5; 249 mg; 1.54mmol), MnO2(890 mg; 10.2mmol), lithium hydroxide (74 mg; 3.1mmol) and molecular sieves (4A, 150mg) suspension were heated at MW, 150 ℃ for 2500 s. The mixture was filtered through a pad of celite, rinsing with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica (EtOAc: c-Hex, 5: 95) to give the title compound as a brown-orange solid (335mg, 82% yield). HPLC, Rt: 4.60min (purity: 93.8%). LC/MS, M+(ESI)：401.2。1H NMR(DMSO-d6)δ：7.23(m，1H)，7.06(m，1H)，6.83-6.95(m，6H)，6.80(d，J＝15.3Hz，0.95H)，6.60(d，J＝15.3Hz，0.95H)，6.46(AB，J＝11.1，33.5Hz，0.1H)，3.80(s，2.85H)，3.78(s，0.15H)，3.35(m，4H)，3.17(m，4H)。
Step c) formation of 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (3-methoxyphenyl) but-3-yn-1-yl ] sulfonyl } piperazine
By the method described in example 1, step b), but from 1- (4-fluorophenyl) -4- { [4- (3-methoxyphenyl) but-1-en-3-yn-1-yl]Starting with sulfonyl } piperazine (335 mg; 0.84mmol), the title compound was prepared as a yellow oil (349mg, 96% yield). HPLC, Rt: 3.47min (purity: 75%). LC/MS, M+(ESI)：434.2。
Step d) formation of [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3- (3-methoxyphenyl) prop-2-yn-1-yl ] hydroxyformamide
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (3-methoxyphenyl) but-3-yn-1-yl]A solution of sulfonyl } piperazine (349 mg; 0.81mmol) and an ester of acetyl carboxylic acid (prepared as described by Koller et al, 1983, supra at 8; 0.58mL of a 1.39M solution in THF; 0.81mmol) was stirred at room temperature for 1 h. THF was removed under reduced pressure and replaced with MeOH. The solution was heated at 60 ℃ for 1h and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (EtOAc: c-Hex 60: 40 to 100: 0) to give the title compound as an orange oil (90mg, 24% yield). HPLC, Rt: 3.69min (purity: 99.3%). LC/MS, M+(ESI)：462.3。1H NMR(DMSO-d6)δ：8.45(brs，0.4H)，8.13(brs，0.6H)，7.19(m，1H)，6.97-7.04(m，7H)，5.80(brs，0.4H)，5.25(brs，0.6H)，3.77(s，3H)，3.68(brs，1H)，3.44(m，6H)，3.14(m，4H)。
Example 21: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) hex-2-yn-1-yl ] hydroxyformamide (21)
({ [4- (4-fluorophenyl) piperazin-1-yl) in THF (5mL)]Sulfonyl } methyl) phosphonic acid diethyl ester (prepared in example 20, step a); 428 mg; 1.09mmol), 2-hexyn-1-ol (179 μ l; 1.63mmol), MnO2(943 mg; 10.9mmol), lithium hydroxide (78 mg; 3.3mmol) and molecular sieves (4A, 150mg) suspension were heated at 150 ℃ for 2500s at MW. The mixture was filtered through a pad of celite, rinsing with EtOAc. The filtrate was concentrated under reduced pressure and redissolved in THF (4 mL). Hydroxylamine (1.8mL) was added and the mixture was heated at 60 ℃ for 2 h. THF was removed under reduced pressure and the residue was dissolved in EtOAc and taken up with saturated NH4Aqueous Cl and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to yield 396mg of a colorless oil. The method as described in example 20, step b)Formylation is carried out. The compound was obtained as the title white solid (125mg, 29% yield). HPLC, Rt: 3.25min (purity: 98.4%). LC/MS, M+(ESI)：398.2，1H NMR(DMSO-d6)δ：8.40(brs，0.4H)，8.07(brs，0.6H)，6.87-6.99(m，4H)，5.52(brs，0.4H)，5.02(brs，0.6H)，3.13-3.80(m，11H)，2.17(m，2H)，1.52(sx，J＝7.2Hz，2H)，0.95(t，J＝7.3Hz，3H)。
Example 22: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3-quinolin-3-ylprop-2-yn-1-yl ] hydroxyformamide (22)
By the method described in example 21, but from ({ [4- (4-fluorophenyl) piperazin-1-yl]Sulfonyl } methyl) phosphonic acid diethyl ester (399 mg; 1.01mmol) and 3-quinolin-3-yl-prop-2-yn-1-ol (278 mg; 1.52mmol) the title compound was prepared as a yellow powder (110mg, 32% yield). HPLC, Rt: 3.08min (purity: 98.6%). LC/MS, M+(ESI)：483.3。1H NMR(DMSO-d6)δ：8.89(s，1H)，8.55(s，0.6H)， 8.12(s，0.4H)，7.77(m，2H)，7.77(m，1H)，7.66(brs，1H)，7.60(m，1H)，6.90-7.00(m，4H)，5.95(brs，0.6H)，5.35(brs，0.4H)，3.75(m，1H)，3.52(m，6H)，3.19(m，4H)。
Example 23: [1- ({ [4- (4-fluorophenyl) piperidin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] hydroxyformamide (23)
The title compound was prepared by the method described in example 13, but starting from 4- (4-fluorophenyl) -1- (methylsulfonyl) piperidine (intermediate B7; 386 mg; 1.5mmol) and phenylpropanal (235mg, 1.8mmol)Compound as yellow oil (228mg, 35% yield). HPLC, Rt: 4.06min (purity: 99.8%). LC/MS, M+(ESI)：431.3，M-(ESI)：429.1。
Example 24: hydroxy (3-phenyl-1- { [ (4-pyridin-2-ylpiperazin-1-yl) sulfonyl]Methyl } prop-2-yn-1-yl) carboxamide (24)
The title compound was prepared by the method described in example 13, but starting from 4- (2-pyridyl) -1- (methylsulfonyl) piperazine (intermediate B2; 362 mg; 1.5mmol) and phenylpropanal (235mg, 1.8mmol) as a yellow powder (66mg, 11% yield). HPLC, Rt: 1.93min (purity: 97.5%). LC/MS, M+(ESI)：415.2，M-(ESI)：413.1。
Example 25: hydroxy { 3-phenyl-1- [ ({4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl } sulfonyl) methyl ] prop-2-yn-1-yl } carboxamide (25)
The title compound was prepared by the method described in example 13 but starting from 4- (2-pyridyl) -1- (methylsulfonyl) piperazine (intermediate B6; 462 mg; 1.5mmol) and phenylpropanal (235mg, 1.8mmol) as a brown powder (209mg, 29% yield). HPLC, Rt: 4.27min (purity: 100%). LC/MS, M+(ESI)：482.2。
Example 26: hydroxy [1- ({ [4- (4-methoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] carboxamide (26)
The compound was prepared by the method described in example 13, but starting from 1- (4-methoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B4; 405 mg; 1.5mmol) and phenylpropanal (235mg, 1.8mmol) as the title yellow powder (75mg, 11% yield). HPLC, Rt: 2.88min (purity: 99.26%). LC/MS, M+(ESI)：444.3，M-(ESI)：442.1。
Example 27: {1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3- [4- (1, 2, 4-oxadiazol-3-yl) phenyl ] prop-2-yn-1-yl } hydroxyformamide (27)
By the method described in example 21, but from ({ [4- (4-fluorophenyl) piperazin-1-yl]Sulfonyl } methyl) phosphonic acid diethyl ester (prepared as in example 20, step a); 468 mg; 1.19mmol) and 3-hydroxyprop-1-ynyl) benzonitrile (279 mg; 1.78mmol) the title compound was prepared as a yellow foam (84mg, 14% yield). HPLC, Rt: 3.57min (purity: 94.7%). LC/MS, M+(ESI)：500.2，M-(ESI)：498.1。1H NMR(DMSO-d6)δ：8.76(s，1H)，8.47(brs，0.4H)，8.16(brs，0.6H)，8.07(d，J＝8.3Hz，2H)，7.56(d，J＝8.3Hz，2H)，6.85-6.99(m，4H)，5.85(brs，0.4H)，5.28(brs，0.6H)，3.4-3.9(m，7H)，3.20(m，4H)。
Example 28: hydroxy [1- ({ [4- (4-methoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] carboxamide (28)
By the method described in example 13, but starting from 1- (4-methoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B4; 300 mg; 1.11mmol) and 2-octyneStarting from aldehyde (0.17 ml; 1.17mmol), the title compound was prepared as a white solid (77mg, 16% yield). HPLC, Rt: 3.25min (purity: 100%). LC/MS, M+(ESI)：438.3，M-(ESI)：436.1。
Example 29: (1- { [ (4-Diphenyl-4-ylpiperazin-1-yl) sulfonyl ] methyl } -3-phenylpropan-2-yn-1-yl) hydroxyformamide (29)
By the process described in example 13, but starting from 1- [1, 1' -biphenyl]Starting with-4-yl-4- (methylsulfonyl) piperazine (intermediate B8; 475 mg; 1.5mmol) and phenylpropanal (235mg, 1.8mmol), the compound was prepared as the title brown powder (39mg, 11% yield). HPLC, Rt: 4.32min (purity: 87.4%). LC/MS, M+(ESI)：490.2，M-(ESI)：488.0。
Example 30: [1- ({ [4- (5-Chloropyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (30)
The title compound was prepared by the method described in example 13 but starting from 1- (5-chloropyridin-2-yl) -4- (methylsulfonyl) piperazine (intermediate B9; 379 mg; 1.37mmol) and 2-octynal (0.17 mL; 1.20mmol) as a white powder (248mg, 41% yield). HPLC, Rt: 3.61min (purity: 100%). LC/MS, M+(ESI)：443.2，M-(ESI)：441.0。
Example 31: hydroxy (1- { [ (4-pyrimidin-2-ylpiperazin-1-yl) sulfonyl ] methyl } oct-2-yn-1-yl) carboxamide (31)
By the method described in example 13, but from 2- [4- (methylsulfonyl) piperazin-1-yl]Starting with pyrimidine (intermediate B10; 400 mg; 1.65mmol) and 2-octynal (0.28 mL; 1.98mmol), the title compound was prepared as a pink powder (155mg, 23% yield). HPLC, Rt: 3.11min (purity: 100%). LC/MS, M+(ESI)：410.3，M-(ESI)：408.1。
Example 32: hydroxy (1- { [ (4-phenylpiperazin-1-yl) sulfonyl ] methyl } oct-2-yn-1-yl) carboxamide (32)
The off-white powder compound as title (258mg, 38% yield) was prepared by the method described in example 13, but starting from 1- (methylsulfonyl) -4-phenylpiperazine (400 mg; 1.66mmol) and 2-octynal (0.29 mL; 2.0 mmol). HPLC, Rt: 3.72min (purity: 100%). LC/MS, M+(ESI)：408.3，M-(ESI)：406.2。
Example 33: [1- ({ [4- (4-chlorophenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (33)
The compound was prepared by the method described in example 13, but starting from 1- (4-chlorophenyl) -4- (methylsulfonyl) piperazine (intermediate B11, 400 mg; 1.46mmol) and 2-octynal (0.25 mL; 1.75mmol) as the title orange powder (192mg, 30% yield). HPLC, Rt: 4.26min (purity: 99.5%). LC/MS, M+(ESI)：442.2，M-(ESI)：440.1。
Example 34: hydroxy [1- ({ [4- (2-methoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] carboxamide (34)
The title compound was prepared by the method described in example 13, but starting from 1- (2-methoxyphenyl) -4- (methylsulfonyl) piperazine (400 mg; 1.48mmol) and 2-octynal (0.25 mL; 1.75mmol) as a light brown powder (159mg, 25% yield). HPLC, Rt: 3.30min (purity: 98.25%). LC/MS, M+(ESI)：438.2，M-(ESI)：435.9。
Example 35: hydroxy [1- ({ [4- (3-methoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] carboxamide (35)
The title compound was prepared by the method described in example 13, but starting from 1- (3-methoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B12; 500 mg; 1.85mmol) and 2-octynal (0.32 mL; 2.22mmol) as a light brown powder (451mg, 56% yield). HPLC, Rt: 3.85min (purity: 99.0%). LC/MS, M+(ESI)：438.3，M-(ESI)：436.2。
Example 36: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-5-phenylpent-4-yn-1-yl ] hydroxyformamide (36)
Step a) formation of 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyl-6-phenylhex-5-yn-1-yl ] sulfonyl } piperazine
At-78 ℃ and N2Next, to a solution of 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1; 600 mg; 2.32mmol) in THF (10mL) was added lithium bis (trimethylsilyl) amine (1.00M solution in THF 4.65 mL; 4.65 mmol). After 30min diethyl chlorophosphate (0.38 mL; 2.56mmol) was added and the mixture was stirred at-78 deg.C for 1 h. A conduit was inserted into a solution of 2, 2-dimethyl-5-phenyl-4-pentynal (prepared as described in Cossy et al, 1997, Journal of Organic chemistry, 62(23), 7900-7901, 432 mg; 2.32mmol) in THF (5mL) and the reaction mixture was allowed to warm to room temperature and stirred for 12 h. Hydroxylamine (4.1 mL; 70mmol) was added and the mixture was heated at 60 ℃ for 3 h. Finally concentrated under reduced pressure, redissolved in EtOAc and treated with saturated NH4Aqueous Cl and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica (EtOAc: c-Hex; gradient from 20: 80 to 50: 50) to give the title compound as a yellow oil (710mg, 66% yield). HPLC, Rt: 4.15min (purity: 95.9%). LC/MS, M+(ESI)：460.2.1H NMR(DMSO-d6)δ：7.37(m，2H)，7.23(m，3H)，6.96(m，2H)，6.86(m，2H)，3.60(dd，J＝14.2，10.1Hz，1H)，3.61(m，4H)，3.34(dd，J＝10.1，1.8Hz，1H)，3.12(m，5H)，2.37(AB，J＝15.9，＝49.3Hz，2H)，1.12(s，3H)，1.14(s，3H)。
Step b) formation of [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-5-phenylpent-4-yn-1-yl ] hydroxyformamide
(36)
By the method described in example 1, step c), but from 1- (4-fluorophenyl) -4- { [2- (hydroxyamine)3, 3-dimethyl-6-phenylhex-5-yn-1-yl]Starting from sulfonyl } piperazine (710 mg; 1.54mmol), the title compound (36) was prepared as a white powder (268mg, 36% yield). HPLC, Rt: 4.08min (purity: 98.8%). LC/MS, M+(ESI)：488.1，M-(ESI)：486.0。1H NMR(DMSO-d6)δ：9.99(s，0.3H)，9.78(s，0.7H)，8.28(s，0.3H)，7.93(s，0.7H)，7.28-7.37(m，5H)，6.88-7.07(m，4H)，4.72(d，J＝8.3Hz，0.3H)，7.03(d，J＝8.3Hz，0.7H)，3.48(m，2H)，3.41(m，4H)，3.10(m，4H)，2.41-2.47(m，2H)，1.05(m，6H)。
Example 37: [4- (diethylamino) -1- ({ [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } methyl) but-2-yn-1-yl ] hydroxyformamide (37)
Step a) ({ [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } methyl) phosphonic acid diethyl ester
By the method described in example 10, step a) but starting from 4- (4-methoxyphenyl) -1- (methylsulfonyl) piperidine (intermediate B4; 2.92 g; 10.9mmol) and the title compound was prepared as a white powder (3.86g, 88% yield). HPLC, Rt: 3.65min (purity: 100%). LC/MS, M+(ESI)：406.3，M-(ESI)：404.2。 1H NMR(DMSO-d6)δ：7.12(d，J＝8.6Hz，2H)，6.86(d，J＝8.6Hz，2H)，4.31-4.21(m，4H)，3.97(m，2H)，3.8(s，3H)，3.56(d，J＝17.3Hz，2H)，2.97(m，2H)，2.59(m，1H)，1.94-1.78(m，4H)，1.40(t，J＝7.0Hz，6H)。
Step b) formation of N, N-diethyl-4- (hydroxyamino) -5- { [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } pent-2-yn-1-amine
({ [4- (4-methoxyphenyl) piperidin-1-yl) in THF (5mL)]Sulfonyl } methyl) phosphonic acid diethyl ester (558 mg; 1.38mmol), MnO2A suspension of (1.2g, 13.8mmol), lithium hydroxide (99 mg; 4.13mmol), molecular sieves (4A, 300mg) and 4-diethylamino-2-butyl-1-ol (306.21. mu.l; 2.06mmol) was heated at 150 ℃ with MW for 2500 s. The mixture was filtered through a pad of celite, rinsing with EtOAc. The filtrate was concentrated under reduced pressure, redissolved in THF (15mL), hydroxylamine (2.44mL) was added and the reaction mixture was heated at 60 ℃ for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and taken up with saturated NH4Aqueous Cl and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product (524mg) was purified by flash chromatography over silica (DCM: MeOH: NH4OH 90: 10: 0.1) to give the title compound as a brown oil (97mg, 17% yield). HPLC, Rt: 2.50min (purity: 80%). LC/MS, M+(ESI)：424.0。1H NMR(DMSO-d6)δ7.10(d，J＝8.7Hz，2H)，6.84(d，J＝8.7Hz，2H)，4.31(m，1H)，3.91(m，2H)，3.77(s，3H)，3.52(dd，J＝13.9，8.3Hz，1H)，3.44(d，J＝1.9Hz，2H)，3.16(dd，J＝13.9，4.3Hz，1H)，2.91(m，2H)，2.56(qd，J＝7.2Hz，4H)，2.53(m，1H)，1.95(m，2H)，1.74-1.88(m，2H)，1.07(t，J＝7.2Hz，6H)。
Step c) formation of [4- (diethylamino) -1- ({ [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } methyl) but-2-yn-1-yl ] hydroxyformamide
By the method described in example 1, step c) but from N, N-diethyl-4- (hydroxyamino) -5- { [4- (4-methoxyphenyl) piperidin-1-yl]Starting with sulfonyl } pent-2-yn-1-amine (97 mg; 0.23mmol), the title compound (37) was prepared as an orange oil (64mg, 49% yield). HPLC, Rt: 2.58min (purity: 100%). LC/MS, M+(ESI)：452.2，M-(ESI)：450.1。1H NMR(DMSO-d6)δ11.80(brs，1H)，8.6(brs，1H)，8.35(s，1H)，7.09(d，J＝8.7Hz，2H)，6.83(d，J＝8.5Hz，2H)，5.67(m，0.6H)，5.10(brs，0.2H)，4.50(brs，0.2H)，3.87-4.00(m，4H)，3.77(s，3H)，3.20-4.42(m，6H)，2.86(t，J＝11.9Hz，2H)，2.56(m，1H)，1.72-1.87(m，4H)，1.34(m，6H)。
Example 38: hydroxy {1- [ ({4- [5- (trifluoromethyl) pyridin-2-yl ] piperazin-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide (38)
The title compound was prepared by the method described in example 13, but starting from 1-methanesulfonyl-4- (5-trifluoromethylpyridin-2-yl) piperazine (intermediate B13; 500 mg; 1.62mmol) and 2-octynal (0.28 mL; 1.94mmol) as a light brown powder (124mg, 16% yield). HPLC, Rt: 4.29min (purity: 96.7%). LC/MS, M+(ESI)：477.4，M-(ESI)：475.2。
Example 39: hydroxy [1- ({ [4- (4-phenoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] carboxamide (39)
The compound was prepared by the method described in example 13, but starting from 1- (methanesulfonyl) -4- (4-phenoxyphenyl) piperazine (intermediate B14; 500 mg; 1.50mmol) and 2-octynal (0.26 mL; 1.80mmol) as the title white powder (273mg, 36% yield). HPLC, Rt: 4.58min (purity: 99.7%). LC/MS, M+(ESI)：500.3，M-(ESI)：498.2。
Example 40: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) hept-2-yn-1-yl ] hydroxyformamide (41)
By the method described in example 20, but starting from ({ [4- (4-fluorophenyl) piperazin-1-yl)]Sulfonyl } methyl) phosphonic acid diethyl ester (prepared as in example 21, step a); 534mg of the total weight of the powder; 1.35mmol) and 2-heptyn-1-ol (228 mg; 2.03mmol) was prepared as the title compound as a light brown solid (372mg, 67% yield). HPLC, Rt: 3.60min (purity: 97.4%). LC/MS, M+(ESI)：412.2，M-(ESI)：410.2。1H NMR(DMSO-d6)δ：10.22(brs，0.5H)，9.84(brs，0.5H)，8.12(brs，1H)，7.06(t，J＝8.7Hz，2H)，6.97(dd，J＝9.2，4.7Hz，2H)，5.40(brs，0.5H)，5.18(brs，0.5H)，3.38-3.54(m，2H)，3.29(m，4H)，3.13(m，4H)，2.18(m，2H)，1.30-1.45(m，4H)，0.84(t，J＝7.0Hz，3H)。
Example 41: [3- (2-fluorophenyl) -1- ({ [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } methyl) prop-2-yn-1-yl ] hydroxyformamide (41)
By the method described in example 1, but starting from ({ [4- (4-methoxyphenyl) piperidin-1-yl)]Sulfonyl } methyl) phosphonic acid diethyl ester (prepared as in example 37, step a); 345 mg; 0.85mmol), 3- (2-fluorophenyl) prop-2-yn-1-ol (192 mg; 1.28mmol) was prepared as the title compound as a light brown solid (169mg, 43% yield). HPLC, Rt: 3.99min (purity: 99.9%). LC/MS, M+(ESI)：461.3，M-(ESI)：459.1。 1H NMR(DMSO-d6)δ：10.42(brs，0.5H)，10.0(brs，0.5H)，8.30(m，1H)，7.57(m，1H)，7.47(m，1H)，7.31(t，J＝8.7Hz，1H)，7.25(t，J＝7.5Hz，1H)，7.13(d，J＝8.7Hz，2H)，6.83(d，J＝8.7Hz，2H)，5.56(m，1H)，3.61-3.94(m，7H)，2.97(m，2H)，2.60(m，1H)，1.79(brd，J＝11.3Hz，2H)，1.61(m，2H)。
Example 42: [3- (4-fluorophenyl) -1- ({ [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } methyl) prop-2-yn-1-yl ] hydroxyformamide (42)
By the method described in example 21, T is selected from ({ [4- (4-methoxyphenyl) piperidin-1-yl)]Sulfonyl } methyl) phosphonic acid diethyl ester (prepared as in example 37, step a); 359 mg; 0.89mmol), 3- (4-fluorophenyl) prop-2-yn-1-ol (199 mg; 1.33mmol) was prepared as the title compound (42) as a beige solid (153mg, 37% yield). HPLC, Rt: 4.03min (purity: 100%). LC/MS, M+(ESI)：461.4，M-(ESI)459.2。1H NMR(DMSO-d6)δ：10.44(brs，0.5H)，9.99(brs，0.5H)，8.18(m，1H)，7.53(dd，J＝8.7，5.7Hz，2H)，7.25(t，J＝9.0Hz，2H)，7.13(d，J＝8.7Hz，2H)，6.84(d，J＝8.7Hz，2H)，5.66(brs，0.5H)，5.48(brs，0.5H)，3.59-3.94(m，7H)，2.92(m，2H)，2.60(m，1H)，1.79(brd，J＝11.3Hz，2H)，1.61(m，2H)。
Example 43: [1- ({ [4- (4-chlorophenyl) piperidin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (43)
Prepared by the method described in example 13, but starting from 4- (4-chlorophenyl) -1- (methylsulfonyl) piperidine (intermediate B15; 458 mg; 1.67mmol) and 2-octynal (0.29 mL; 2.01mmol)The title compound (162mg, 22%) as a white powder. HPLC, Rt: 4.68min (purity: 94.0%). LC/MS, M+(ESI)：441.3，M-(ESI)：439.2。
Example 44: hydroxy [1- ({ [4- (4-methylphenyl) piperidin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] carboxamide (44)
The compound was prepared by the method described in example 13, but starting from 4- (4-methylphenyl) -1- (methylsulfonyl) piperidine (intermediate B16; 423 mg; 1.67mmol) and 2-octynal (0.29 mL; 2.01mmol) as the title white powder (246mg, 35%). HPLC, Rt: 4.64min (purity: 97.6%). LC/MS, M+(ESI)：421.4，M-(ESI)：419.2。
Example 45: [3- (3-fluorophenyl) -1- ({ [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } methyl) prop-2-yn-1-yl ] hydroxyformamide (45)
By the method described in example 21, but starting from ({ [4- (4-methoxyphenyl) piperidin-1-yl)]Sulfonyl } methyl) phosphonic acid diethyl ester (prepared in example 37, step a); 330 mg; 0.81mmol), 3- (3-fluorophenyl) -2-propyn-1-ol (183 mg; 1.22mmol) and the title compound was prepared as a light brown powder (25mg, 7% yield). HPLC, Rt: 4.04min (purity: 99.6%). LC/MS, M+(ESI)：461.3，M-(ESI)459.2。 1H NMR(DMSO-d6)δ：10.46(brs，0.5H)，9.96(brs，0.5H)，8.18-8.31(m，1H)，7.45(m，1H)，7.26-7.33(m，3H)，7.14(d，J＝8.7Hz，2H)，6.84(d，J＝8.7Hz，2H)，5.68(brs，0.5H)，5.50(brs，0.5H)，3.61-4.03(m，7H)，2.92(m，2H)，2.56(m，1H)，1.80(m，2H)，1.16(m，2H)。
Example 46: hydroxy-1- [ ({4- [5- (trifluoromethyl) pyridin-2-yl ] -1, 4-diazepan-1-yl } sulfonyl) methyl ] oct-2-yn-1-yl } carboxamide (46)
By the method described in example 13, but from 1- (methylsulfonyl) -4- [5- (trifluoromethyl) pyridin-2-yl]Starting from 1.4-diazepane (intermediate B17; 441 mg; 1.36mmol) and 2-octynal (203 mg; 1.64mmol), the compound was prepared as the title white powder (216mg, 33%). HPLC, Rt: 3.86min (purity: 100%). LC/MS, M+(ESI)：491.4，M-(ESI)：489.1。
Example 47: [1- ({ [4- (4-ethoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (47)
The compound was prepared by the method described in example 13, but starting from 1- (4-ethoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B18; 426 mg; 1.5mmol) and 2-octynal (225 mg; 1.8mmol) as the title white powder (135mg, 20%). HPLC, Rt: 3.58min (purity: 98.4%). LC/MS, M+(ESI)：452.3，M-(ESI)：450.3。
Example 48: [1- ({ [4- (5-bromopyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (48)
The compound was prepared by the method described in example 13, but starting from 1- (5-bromo-pyridin-2-yl) -4- (methylsulfonyl) piperazine (intermediate B19; 400 mg; 1.25mmol) and 2-octynal (186 mg; 1.5mmol) as the title white powder (258mg, 41%). HPLC, Rt: 3.85min (purity: 99.3%). LC/MS, M+(ESI)：488.9，M-(ESI)：487.9。
Example 49: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -4-morpholin-4-ylbut-2-yn-1-yl ] hydroxyformamide (49)
By the method described in example 20, but starting from ({ [4- (4-fluorophenyl) piperazin-1-yl)]Sulfonyl } methyl) phosphonic acid diethyl ester (prepared in example 21, step a); 558 mg; 1.41mmol) and 329mg of 4-morpholin-4-ylbut-2-yn-1-ol; 2.12mmol) was prepared as the title compound as a white powder (67mg, 58% yield). HPLC, Rt: 1.91min (purity: 100%). LC/MS, M+(ESI)：455.3。1H NMR(DMSO-d6)δ：10.35(brs，5H)，9.95(brs，5H)，8.15(m，1H)，6.95-7.09(m，4H)，5.45(brs，5H)，5.30(brs，5H)，3.40-3.60(m，6H)，3.27(m，6H)，3.14(m，4H)，2.43(m，4H)。
Example 50: [1- ({ [4- (3-chlorophenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (50)
Prepared as described for example 13, but starting from 1- (3-chlorophenyl) -4- (methylsulfonyl) piperazine (500 mg; 1.8mmol) and 2-octynal (270 mg; 2.2mmol)The title compound (346mg, 51%) as a white powder. HPLC, Rt: 4.48min (purity: 99.9%). LC/MS, M+(ESI)：442.1，M-(ESI)：439.8。
Example 51: [1- ({ [4- (1, 3-benzodioxol-5-yl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (51)
The compound was prepared by the method described in example 13, but starting from 1- (1, 3-benzodioxol-5-yl) -4- (methylsulfonyl) piperazine (intermediate B20, 500 mg; 1.76mmol) and 2-octenal (0.30 mL; 2.11mmol) as the title white powder (184mg, 23%). HPLC, Rt: 3.78min (purity: 99.9%). LC/MS, M+(ESI)：452.3，M-(ESI)：450.1。
Example 52: hydroxy [1- ({ [4- (3-methoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] carboxamide (52)
The title compound was prepared by the method described in example 13, but starting from 1- (3-methoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B12; 500 mg; 1.85mmol) and phenylpropanal (0.27 mL; 2.22mmol) as a light brown solid (379mg, 46%). HPLC, Rt: 3.72min (purity: 97.9%). LC/MS, M+(ESI)：444.4，M-(ESI)：442.2。
Example 53: hydroxy [1- ({ [4- (4-methylphenyl) piperidin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] carboxamide (53)
The title compound was prepared by the method described in example 13 but starting from 4- (4-methylphenyl) -1- (methylsulfonyl) piperidine e (intermediate B16; 340 mg; 1.34mmol) and phenylpropanal (0.20 mL; 1.61mmol) as a pale brown solid (252mg, 44%). HPLC, Rt: 4.20min (purity: 100%). LC/MS, M+(ESI)：427.4，M-(ESI)：425.3。
Example 54: [1- ({ [4- (4-chlorophenyl) piperazin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] hydroxyformamide (54)
The compound was prepared by the method described in example 13, but starting from 1- (4-chlorophenyl) -4- (methylsulfonyl) piperazine (intermediate B11; 500 mg; 1.82mmol) and phenylpropanal (0.27 mL; 2.18mmol) as the title orange solid (445mg, 55%). HPLC, Rt: 4.20min (purity: 99.4%). LC/MS, M+(ESI)：448.3，M-(ESI)：446.2。
Example 55: [1- ({ [4- (4-ethoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) -3-phenylpropan-2-yn-1-yl ] hydroxyformamide (55)
The compound was prepared by the method described in example 13, but starting from 1- (4-ethoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B18; 500 mg; 1.76mmol) and phenylpropanal (0.26 mL; 2.11mmol) as the title orange solid (265mg, 32%). HPLC, Rt: 3.22min (purity: 99.7%). LC/MS, M+(ESI)：458.4，M-(ESI)：456.3。
Example 56: [1- ({ [4- (5-bromopyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-5-phenylpent-4-yn-1-yl ] hydroxyformamide (56)
The title compound was prepared by the method described in example 13, but starting from 1- (5-bromopyridin-2-yl) -4-methanesulfonylpiperazine (intermediate B19, 512 mg; 1.60mmol) and 2, 2-dimethyl-5-phenylpent-4-ynal (prepared as described in Cossy et al, 1997, supra, 298 mg; 1.60mmol) as a pale brown powder (149mg, 17% yield). HPLC, Rt: 3.94min (purity: 96.9%). LC/MS, M+(ESI)：551.2.1HNMR(DMSO-d6)δ：9.98(s，0.4H)，9.78(s，0.6H)，8.29(s，0.4H)，8.19(m，1H)，7.95(s，0.6H)，7.71(m，1H)，7.26-7.36(m，5H)，6.85(m，1H)，4.73(d，J＝7.9 Hz，0.4H)，4.04(d，J＝8.7Hz，0.6H)，3.57(m，4H)，3.39-3.53(m，2H)，3.26(m，4H)，2.42-2.52(m，2H)，1.05(m，6H)。
Example 57: {2, 2-dimethyl-5-phenyl-1- [ ({4- [4- (trifluoromethyl) phenyl ] piperazin-1-yl } sulfonyl) methyl ] pent-4-yn-1-yl } hydroxyformamide (57)
By the method described in example 13, but from 1- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl]Piperazine (intermediate B6, 511 mg; 1.66mmol) and 2, 2-dimethyl-5-phenylpent-4-ynal aldehyde (prepared as described in Cossy et al, 1997, supra, 309 mg; 1.66mmol) were prepared as the title compound as a light brown powder (220mg, 25% yield). HPLC, Rt: 4.58min(purity: 92.7%). LC/MS, M+(ESI)：538.5，M-(ESI)：536.4。1H NMR(DMSO-d6)δ：9.99(s，0.3H)，9.79(s，0.7H)，8.30(s，0.3H)，7.95(s，0.7H)，7.50(m，2H)，7.25-7.38(m，5H)，7.00-7.08(m，2H)，4.76(d，J＝8.7Hz，0.3H)，4.06(d，J＝8.7Hz，0.7H)，3.26-3.55(m，10H)，2.37-2.52(m，2H)，1.06(m，6H)。
Example 58: [1- ({ [4- (5-Chloropyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) hex-2-yn-1-yl ] hydroxyformamide (58)
Step a) formation of diethyl ({ [4- (5-chloropyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) phosphonate
By the method described in example 10, step a), but starting from 1- (5-chloropyridin-2-yl) -4-methanesulfonylpiperazine (intermediate B9; 2.63 g; 9.54mmol) was prepared as the title compound (2.4g, 61% yield) as a yellow powder. HPLC, Rt: 2.58min (purity: 91.9%). LC/MS, M+(ESI)：412.1，M-(ESI)：410.1。 1H NMR(DMSO-d6)δ：8.09(d，J＝2.3Hz，1H)，7.43(dd，J＝9.0，2.6Hz，1H)，6.57(d，J＝9.0Hz，1H)，4.23(m，4H)，3.62(m，4H)，3.51(d，J＝17.3Hz，2H)，3.42(m，4H)，1.34(t，J＝7.0Hz，6H)。
Step b) formation of [1- ({ [4- (5-chloropyridin-2-yl) piperazin-1-yl ] sulfonyl } methyl) hex-2-yn-1-yl ] hydroxyformamide
By the method described in example 21, but from ({ [4- (5-chloropyridin-2-yl) piperazin-1-yl)]Sulfonyl } methyl) phosphonic acidDiethyl ester (485 mg; 1.18mmol) and 2-hexyn-1-ol (195. mu.l; 1.77mmol) were started to prepare compound (58) as the title. Et2O/HCl was added to a solution of the compound as title in EtOAc to give the hydrochloride salt. The precipitate was filtered to give a brown powder compound (228mg, 43% yield). HPLC, Rt: 2.78min (purity: 93.0%). LC/MS, M+(ESI)：415.3，M-(ESI)：413.1。1H NMR (DMSO-d6) delta: 10.3(brs, 1H), 8.15(brs, 1H), 8.12(d, J ═ 2.2Hz, 1H), 7.63(dd, J ═ 9.0, 2.6Hz, 1H), 6.93(d, J ═ 9.0Hz, 1H), 5.12-5.60(brm, 2H), 3.59(m, 4H), 3.16-3.41(m, 6H), 2.13(m, 2H), 1.43(m, 2H), 0.89(t, J ═ 7.2Hz, 3H). CHN analysis: [ C ]17H23N4O4ClS-HCl]Calculated: 45.24% of C, 5.36% of H and 12.41% of N; the following are found: 45.04% of C, 5.59% of H and 12.40% of N.
Example 59: [1- ({ [4- (4-ethoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-5-phenylpent-4-yn-1-yl ] hydroxyformamide (59)
The title compound was prepared by the method described in example 13, but starting from 1- (4-ethoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B18, 457 mg; 1.61mmol) and 2, 2-dimethyl-5-phenylpent-4-ynal (prepared as described in Cossy et al, 1997, supra, 299 mg; 1.61mmol) as a white powder (40mg, 4% yield). HPLC, Rt: 3.63min (purity: 100%). LC/MS, M+(ESI)：514.5，M-(ESI)：512.3。1H NMR(DMSO-d6)δ：9.96(brs，1H)，8.30(s，0.3H)，7.95(s，0.7H)，7.31-7.40(m，5H)，6.80-6.90(m，4H)，4.30(brs，2H)，3.94(d，J＝6.9Hz，0.3H)，4.05(d，J＝7.9Hz，0.7H)，4.73(qd，J＝9.0Hz，2H)，3.43(m，2H)，3.32(m，4H)，3.06(m，4H)，2.48-2.51(m，2H)，1.28(t，J＝6.9Hz，3H)，1.07(m，6H)。
Example 60: [1- ({ [4- (3, 4-Dimethoxyphenyl) piperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (60)
The compound was prepared by the method described in example 13, but starting from 1- (3, 4-dimethoxyphenyl) -4- (methylsulfonyl) piperazine (intermediate B21; 450 mg; 1.50mmol) and 2-octynal (0.26 mL; 1.81mmol), as the title pink powder compound (110mg, 13%). HPLC, Rt: 3.14min (purity: 99.6%). LC/MS, M+(ESI)：468.4，M-(ESI)：466.3。
Example 61: [1- ({ [4- (4-ethoxyphenyl) -1, 4-diazepan-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (61)
The compound was prepared by the method described in example 13, but starting from 1- (4-ethoxyphenyl) -4- (methylsulfonyl) -1, 4-diazepane (intermediate B22; 141 mg; 0.47mmol) and 2-octynal (0.08 mL; 0.57mmol) as the title orange powder (24mg, 11%). HPLC, Rt: 3.36min (purity: 76.4%). LC/MS, M+(ESI)：466.5，M-(ESI)：464.4。
Example 62: [1- ({ [ (2R) -4- (4-fluorophenyl) -2-methylpiperazin-1-yl ] sulfonyl } methyl) oct-2-yn-1-yl ] hydroxyformamide (62)
The compound was prepared by the method described in example 13, but starting from (2R) -4- (4-fluorophenyl) -2-methyl-1- (methylsulfonyl) piperazine (intermediate B23; 460 mg; 1.69mmol) and 2-octynal (0.29 mL; 2.03mmol), as the title orange powder (282mg, 38%). HPLC, Rt: 4.45min (purity: 99.4%). LC/MS, M+(ESI)：440.4，M-(ESI)：438.3。
Example 63: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethylpent-4-yn-1-yl ] hydroxyformamide (63)
The title compound was prepared as a yellow powder (24mg, 4% yield) by the method described in example 1 but starting from 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1; 411 mg; 1.59mmol) and 2, 2-dimethylpent-4-ynal (prepared as described in Rigby et al, 2004, J.Org.Chem., 69(20), 6751-S.6760, 175 mg; 1.59 mmol). HPLC, Rt: 3.00min (purity: 100%). LC/MS, M+(ESI)：412.3，M-(ESI)：410.3。1H NMR(DMSO-d6)δ：8.33(s，0.2H)，7.89(s，0.8H)，6.76-7.12(m，4H)，4.65(brd，0.2H)，4.20(d，J＝8.7Hz，0.8H)，3.56(m，1H)，3.26(m，4H)，3.02(m，4H)，2.92(m，1H)，2.12(m，2H)，1.97(m，1H)，0.95(m，6H)。
Example 64: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -4-pyrrolidin-1-ylbut-2-yn-1-yl ] hydroxyformamide (64)
By the method described in example 21, but from ({ [4- (4-fluorophenyl) piperazin-1-yl]Sulfonyl } methyl group) Diethyl phosphonate (prepared in example 21, step a), 351 mg; 0.89mmol), 4-pyrrolidin-1-ylbut-2-yn-1-ol (e.g. Bieber et al, 2004, Tetrahedron Letters, 45 (45); 8281-8283 the method described in, 186 mg; 1.34mmol) was prepared as the title compound as an orange oil (9mg, 2% yield). HPLC, Rt: 1.87min (purity: 91.8%). LC/MS, M+(ESI)：439.5。
Example 65: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-6-morpholin-4-ylhex-4-yn-1-yl ] hydroxyformamide (65)
Step a) formation of 4- [7- { [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } -6- (hydroxyamino) -5, 5-dimethylhept-2-yn-1-yl ] morpholine
By the method described in example 36, step a), but starting from 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1, 380 mg; 1.45mmol) and 2, 2-dimethyl-6-morpholin-4-ylhex-4-ynal-al (intermediate A6, 303mg) the compound was prepared as the title white powder (250mg, 36% yield). HPLC, Rt: 2.20min (purity: 98.2%). LC/MS, M+(ESI)：483.6。
Step b) formation of [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethyl-6-morpholin-4-ylhex-4-yn-1-yl ] hydroxyformamide
By the method described in example 1, step c), but from 4- [7- { [4- (4-fluorophenyl) piperazin-1-yl]Sulfonyl } -6- (hydroxyamino) -5, 5-dimethylhept-2-yn-1-yl]Starting with morpholine (250mg, 0.52mmol), a white color was prepared as the titleCompound (65) as a powder (100mg, 38% yield).1H NMR (DMSO-d6) delta: HPLC, Rt: 2.34min (purity: 93.8%). LC/MS, M+(ESI)：511.4，M-(ESI)：509.3。
Example 66: [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethylhept-4-yn-1-yl ] hydroxyformamide (66)
Step a) formation of 1- { [ (1E) -3, 3-dimethyloct-1-en-5-yn-1-yl ] sulfonyl } -4- (4-fluorophenyl) piperazine
By the method described in example 1, step a), but starting from 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine (intermediate B1, 855 mg; 3.31mmol) and 2, 2-dimethyl-hept-4-ynal, 457 mg; 3.31mmol) was prepared as the title compound as a white powder (764mg, 61% yield). HPLC, Rt: 4.75min (purity: 97.7%). LC/MS, M+(ESI)：379.4，1H NMR(DMSO-d6)δ：6.97-6.82(m，4H)，6.74(d，J＝15.4Hz，1H)，6.07(d，J＝14.9Hz，1H)，3.26(m，4H)，3.15(m，4H)，2.21(m，2H)，2.01-2.16(m，2H)，1.15(s，6H)，1.06(t，J＝7.4Hz，3H)。
Step b) formation of 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyloct-5-yn-1-yl ] sulfonyl } piperazine
By the method described in example 1, step b), but starting from 1- { [ (1E) -3, 3-dimethyloct-1-en-5-yn-1-yl]Starting from sulfonyl } -4- (4-fluorophenyl) piperazine (760 mg; 2.01mmol), the compound was prepared as the title compound (836mg, quantitative) as a light brown oil. HPLC, Rt: 3.49min (purity: 95.0)％)。LC/MS，M+(ESI)：412.4。
Step c) formation of [1- ({ [4- (4-fluorophenyl) piperazin-1-yl ] sulfonyl } methyl) -2, 2-dimethylhept-4-yn-1-yl ] hydroxyformamide
By the method described in example 1, step c), but starting from 1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyloct-5-yn-1-yl]Starting with sulfonyl } piperazine (836 mg; 2.03mmol), the title compound was prepared as a white solid (241mg, 27% yield). HPLC, Rt: 3.82min (purity: 93.6%). LC/MS, M+(ESI)： 440.6，M-(ESI)：438.5。1H NMR(DMSO-d6)δ：9.93(s，0.3H)，9.71(s，0.7H)，8.26(s，0.3H)，8.26(s，0.7H)，6.95-7.90(m，4H)，4.60(d，J＝9.0Hz，0.3H)，3.96(d，J＝8.7Hz，0.7H)，3.35-3.98(m，6H)，3.15(m，4H)，2.15(m，4H)，1.04(t，J＝7.2Hz，3H)，0.98(m，6H)。
According to further general methods, the compound of general formula (I) and its precursors of general formulae (II) to (XII) can be converted into another compound of general formula (I), respectively, using suitable interchange techniques well known to those skilled in the art.
If the general synthetic methods described above are not suitable for obtaining compounds of general formula (I) and/or for obtaining the necessary intermediates of compounds of general formula (I), suitable preparation methods well known to the person skilled in the art should be used. In general, the synthetic route for any single compound of formula (I) depends on the substituents per molecule and the possibility of using the necessary intermediates; those skilled in the art will also recognize these elements. For all Protecting and deprotecting Groups see PhilipJ.Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and "Protective Groups in Organic Synthesis" by Theodora W.Greene and Peter G.M.Wuts, Wiley Interscience, third edition 1999. Those skilled in the art will appreciate that some reactions are best performed when the molecular functionalization of the potential reaction is masked or protected, thus avoiding side reactions and/or increasing the yield of the reaction. Examples of protecting group moieties can be found in: philip J.Kocienski, 1994 supra and Greene et al, 1999, supra. The need and choice of protecting groups for a particular reaction is well known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxyl, amino, carboxyl, etc.), the structure and stability of the molecule of the substituent also being part of the reaction conditions.
The compounds of the invention can be isolated in combination with solvent molecules by evaporative crystallization of a suitable solvent. Pharmaceutically acceptable acid addition salts of compounds of formula (I) which contain a basic center may be prepared by conventional methods. For example, the free base solution may be treated with a suitable acid alone or in a suitable solution, and the resulting salt isolated by filtration or evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of the compound of formula (I) with a suitable base. The two types of salts may be formed or interchanged using ion exchange resin techniques.
The present invention will be described below with reference to some examples, which, however, are not intended to limit the scope of the present invention.
And (3) biological determination:
the compounds of the invention can be subjected to the following assays:
example 67: enzyme inhibition assay
The compounds of the invention were tested to evaluate their activity as inhibitors of MMP-1, MMP-2, MMP-9 and MMP-12.
MMP-9 assay procedure
The inhibitory activity of the compounds of the invention on 92kDa gelatinase (MMP-9) was determined by using a coumarin-labeled peptide substrate, (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [2, 4-dinitrophenyl ] -L-2, 3-diaminopropionyl) -Ala-Arg-NH2(McAPLGLDpaAR) (Knight et al, 1992, FEBSLett., 263-266) in the assay.
The total solution was prepared as follows: determination of buffer: 100mM Tris-HCI pH 7.6 containing 100mM NaCl, 10mM CaCl2, and 0.05% Brij 35.
Substrate: 0.4mM total solution of McAPLGLDpaAR (Bachem) (0.437mg/ml) dissolved in 100% DMSO (-20 ℃ storage). Diluted to 8 μ M in assay buffer.
Enzyme: recombinant human 92kDa gelatinase (MMP-9) diluted appropriately in assay buffer; APMA (4-aminophenylmercuric acetate) -activated, if desired).
Test compounds were initially formulated as 10mM compounds dissolved in 100% DMSO, diluted to 1mM in 100% DMSO, and serially diluted 3-fold in 100% DMSO in columns 1-10 in 96-well microtiter plates to assay concentration ranges, 100 μ M (column 1) to 5.1nM (column 10).
The assay was performed in a total volume of 100 μ L per well of a 96-well microtiter plate. Activated enzyme (20. mu.L) and 20. mu.L of assay buffer were added to each well. Then the appropriate concentration of test compound dissolved in 10. mu.L of LDMSO and 50. mu.L of McaPLGLDpaAR (8. mu.M, prepared by diluting the total DMSO solution in assay buffer) were added. For each assay, ten concentrations of test compound were determined in duplicate. Control wells lack the enzyme and test compound. The reaction was incubated at 37 ℃ for 2 hours. Immediately, a SLT Fluostar fluorometer (SL T Labinstruments GmbH,austria) measured the fluorescence at 405nm, excited at 320nm, without stopping the reaction.
The effect of the test compound can be determined from a dose-response curve generated from 10 replicate concentrations of the inhibitor. The data was substituted into equation Y ═ a + ((b-a)/(1+ (c/X) d)) to give IC50 (the desired compound concentration with 50% reduction in enzyme activity). (Y-inhibition obtained for a particular dose; X-nM for a dose; a-min Y or 0% inhibition; b-max Y or 100% inhibition; c-IC 50; d-tilt). The result is a significant number.
MMP-12 assay procedure
The compounds of the invention were tested for their inhibitory activity against metalloelastase (MMP-12) using a coumarin-labeled peptide substrate, (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [2, 4 dinitrophenyl ] -L-2, 3-diaminopropionyl) -Ala-Arg-NH2(McAPLGLDpaAR) (Knight et al, 1992, supra) in an assay. The procedure for this assay is as described above for the MMP-9 assay.
MMP-1 assay procedure
The compounds of the invention were tested for collagenase (MMP-1) inhibitory activity using a coumarin-labeled peptide substrate, (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [2, 4 dinitrophenyl ] -L-2, 3-diaminopropionyl) -Ala-Arg-NH2(McAPLGLDpaAR) (Knight et al, 1992, supra) in an assay. The procedure for this assay is as described above for the MMP-9 assay.
MMP-2 assay procedure
The compounds of the invention were tested for their inhibitory activity against gelatinase B (MMP-2) using a coumarin-labeled peptide substrate, (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [2, 4 dinitrophenyl ] -L-2, 3-diaminopropionyl) -Ala-Arg-NH2(McAPLGLDpaAR) (Knight et al, 1992, supra) in an assay. The procedure for this assay is as described above for the MMP-9 assay.
The results are expressed in terms of IC50 (the concentration of the desired compound with 50% reduction in enzymatic activity) as shown in the following table:
table 1: IC of different MMPs50
Examples MMP-1 IC50(nM) MMP-12 IC50(nM)
Example 1 ＞5000 46
Example 4 ＞5000 58
Example 6 ＞5000 21
Example 7 ＞5000 20
Example 9 ＞5000 48
Example 10 ＞5000 33
Example 19 ＞5000 18
Example 27 ＞5000 95
Example 36 ＞5000 20
Example 37 ＞5000 6
Example 61 ＞5000 24
Example 64 ＞5000 40
Example 68: IL-2-induced peritoneal recruitment of lymphocytes
Intraperitoneal administration of IL-2 results in migration of lymphocytes into the peritoneal cavity. This is a model of cell migration in the development of inflammation.
Step (ii) of
C3H/HEN mice (Elevige Janvier, France) were injected intraperitoneally with IL-2(Serono pharmaceutical research Institute, 20. mu.g/kg, saline).
The compounds of the invention were suspended in 0.5% carboxymethylcellulose (CMC)/0.25% tween-20 and administered to mice 15min before IL-2 administration, either by s.c. or p.o. (10 ml/kg).
Twenty-four hours after IL-2 administration, peritoneal leukocytes were collected by 3 successive peritoneal lavages with 5ml Phosphate Buffered Saline (PBS) -1mM EDTA (+4 ℃). The suspension was centrifuged (1700g × 10min at +4 ℃). The resulting pellet was suspended in 1ml PBS-1mM EDTA.
Lymphocytes were identified and counted using a Beckman/Coulter counter.
Design of experiments
Animals were divided into 6 groups (6 mice per group):
group 1: (baseline) received 0.5% CMC/0.25% tween-20 (excipient for the compound of the invention) and saline (excipient for IL-2);
group 2: (control IL-2) received 0.5% CMC/0.25% Tween-20 and IL-2 injections;
group 3: experimental group (dose 1 of compound of the invention) received an injection of compound of the invention and IL-2;
group 4: experimental group (compound of the invention dose 2) received the compound of the invention and IL-2 injection;
group 5: experimental group (compound of the invention dose 3) received the compound of the invention and IL-2 injection;
group 6: the reference group received dexamethasone and IL-2 injections as reference compounds.
Computing
Lymphocyte recruitment inhibition was calculated as follows:
where Ly 1 equals the number of lymphocytes in group 1 (E3/. mu.l), Ly 2 equals the number of lymphocytes in group 2 (E3/. mu.l), and Ly X equals the number of lymphocytes in group X (3-5) (E3/. mu.l).
ED50 (the concentration of compound required to obtain 50% inhibitory activity) was calculated as shown in table 2 below.
Table 2: ED in IL-2-induced lymphocyte peritoneal recruitment model50：
Examples ED50(mg/kg) Route of the way
Example 1 0.8 po
Example 7 2 po
Example 68: model of Chronic Obstructive Pulmonary Disease (COPD)
The effect of the compounds of the invention on smoking-induced COPD can be assessed.
Each group of 5 female AJ mice (Harlan, 17-25g) were exposed daily to smoking smoke (CS) in separate, transparent chambers for 11 consecutive days. Animals were weighed on day 6 and day 12 prior to treatment. CS was produced from a 1R1 cigarette purchased from the tobacco institute, University of Kentucky, USA and was introduced into the chamber at a flow rate of 100 ml/min.
To minimize any potential problems caused by repeated daily exposure to high levels of CS, exposure of mice to TS gradually increased to a maximum of 6 cigarettes over a period of time between day 5 and day 11 (approximately 48min exposure).
The mouse mock group was also exposed to air daily for the same time period as a control (no CS exposure).
Treatment of
The compounds of the invention were formulated in 0.5% carboxymethylcellulose Na salt (CMC, Sigma reference C-4888) as an excipient.
Animals were gavaged orally at a dose volume of 5ml/kg twice daily, 1h prior to air or CS exposure, and 6h after cessation of exposure.
Mock groups of animals (n ═ 10) received vehicle and were exposed to air for up to 50 minutes daily. The control group (n-10) received vehicle and was exposed to CS (up to 6 cigarettes per day). The other groups were contacted with CS (up to 6 cigarettes per day) and treated with either the test compound or the reference compound.
Bronchoalveolar lavage and cytometric analysis
Bronchoalveolar lavage was performed 24 hours after the final CS exposure as follows:
the trachea was dissected under deep anesthesia (phenobarbital sodium) and cannulated with a short to about 8mm Portex nylon intravenous tube. Phosphate buffered saline (PBS, Gibco) containing 10 units/ml heparin (0.4ml) was slowly poured in and 3 withdrawals were made. Lavage fluid was placed in Eppendorf vials and kept on ice prior to the assay. Centrifugation separates the perfusate from the cells. The supernatant was removed and frozen for subsequent analysis. The cell pellet was resuspended in PBS and the total cell number was calculated by stained specimens (Turks staining) under microscope with a hemocytometer.
Differential cell counts were performed as follows: the remaining cell pellets were diluted to approximately 105 cells/ml. The volume was 500. mu.l placed in the funnel of a cytospin slide and centrifuged at 800rpm for 8 min. Slides were air dried and stained with a ' Kwik-Diff ' solution (Shandon) according to the purchaser's instructions. After the slides were dried, the coverslips were covered and differential cell counts were performed using an optical microscope. Up to 400 cells were counted on each slide. Cells were differentiated using standard morphological techniques. Statistical analysis
Mean +/-s.d. was calculated for each experimental group.
Results were subjected to multiple sets of comparisons using one-way analysis of variance (ANOVA) followed by Bonferroni correction. p < 0.05 indicates statistical significance.
Example 69: experimental encephalomyelitis (EAE) model
The compounds of the invention can be evaluated for their activity in a mouse model of multiple sclerosis.
Animal(s) production
C57BL/6NCrlBR female mice were used. Mice were housed in metal cages (cm 32X 14X 13h) with stainless steel feeders and were fed ad libitum with standard defined chow (4RF21, Charles River, Italy) and water. From day 7, moist food was also placed daily on the bottom of the cage. Plastic bottles are also used in addition to automated tax systems.
Experimental procedure
Mice were injected s.c. in the left flank with 0.2ml of 200. mu.g MOG in complete Freund's adjuvant (CFA, Difco, Detroit, U.S.A.) containing 0.5mg Mycobacterium tuberculosis35-55Emulsions of peptides (Neosystem, Strasbourg, France) were immunized (day 0). Immediately thereafter, mice received an intraperitoneal injection of pertussis toxin (List Biological lab, Campbell, CA, u.s.a.) dissolved in 400 μ L of buffer (0.5M NaCl, 0.017% Triton X-100, 0.015M Tris, pH 7.5). On day 2, the animals were given a second injection of 500ng of pertussis toxin.
Day 7, mice were injected s.c. in the right flank with a second dose of 200 μ g of MOG in CFA35-55A peptide. Starting from about day 8-10, this approach can lead to paralysis from the tail to the forelimbs.
Animals were weighed individually, appearance of paralysis determined and scored according to the following scoring system (1):
0 ═ absence of signs of disease
0.5 partial paralysis of the tail
Paralysis of 1 ═ tail
1.5 tail paralysis + unilateral hind limb partial paralysis
2-tail paralysis + bilateral hind limb weakness or partial paralysis
2.5 Tail paralysis + hind limb paralysis (pelvic lowering)
3-tail paralysis + complete paralysis of hind limbs
3.5 tail paralysis + hind limb paralysis + incontinence
4 ═ tail paralysis, hind limb paralysis, weakness or partial paralysis of forelimbs
Dying or dying
A technician unaware of treatment was allowed to monitor mortality and clinical signs daily for each group of treatments.
In all animal groups, daily treatment with compounds, their excipients or with reference compound started on day 7 and continued for 15 or 21 days.
Histopathological examination
At the end of the treatment period, each mouse was anesthetized with phenobarbital sodium and perfused-fixed with 4% paraformaldehyde through the left ventricle via the heart. The fixed spine is carefully distracted.
The spinal slides were embedded in paraffin blocks. Sections and hematoxylin and eosin staining and CD45 staining for inflammation were performed, as well as Kluver-PAS (rockwell blue plus periodic acid schiff's stain) and Bielchowski staining to detect demyelination and axonal loss.
In the spinal cord, the total area of all slides was measured for each animal at the intersection of a 10 × 10 grid and each grid was enlarged to 0.4 × 0.4 mm. The inflammatory permeabilities around the vessels were counted on each slide, giving the total number per animal in mm2Is evaluated. Areas of demyelination and axonal loss were measured at the intersections of a 10 × 10 grid, 0.1 × 0.1mm per grid, for each animal and expressed as the percentage of total demyelinated area divided by total slide area.
Data evaluation and statistical significance
Clinical and histopathological observations for each treatment group are presented as mean (± SEM) scores. The values obtained from drug treatment of the test group were compared to the values of the positive control group. Groups associated with clinical scores were analyzed for differential significance from group to group using one-way ANOVA, and Fisher test analysis was continued if significant (p < 0.05).
Perivascular inflammatory infiltration and demyelination and axonal loss in spinal cord were analyzed by one-way ANOVA for differences between groups of body weight data, and if significant (p < 0.05), Fisher test analysis was continued.
Example 70: preparation of pharmaceutical formulations
The following examples of formulations are representative of, but not limiting of, the pharmaceutical compositions of the present invention.
Formulation 1-tablet
The compounds of the invention are mixed in dry powder form with a dry gelatin binder in a weight ratio of about 1: 2. A small amount of magnesium stearate was added as a lubricant. The mixture was formed into 240-270mg tablets (each containing 80-90mg of the active sulfonylamino cyclic derivative) in a tablet press.
Preparation 2-capsule
The compounds of the present invention are mixed in dry powder form with a starch diluent in a weight ratio of about 1: 1. The mixture was filled into 250mg capsules (125mg of active sulfonamido cyclic derivative per capsule).
Formulation 3-liquid
The compound of the invention (1250mg), sucrose (1.75g) and xanthan gum (4mg) were mixed and passed through a mesh No. 10 u.s. sieve and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose (11: 89, 50mg) dissolved in water. Sodium benzoate (10mg), flavoring agent and coloring agent are diluted with water and added under stirring. Sufficient water was then added to achieve a total volume of 5 mL.
Formulation 4-tablet
The compounds of the invention are mixed in dry powder form with a dry gelatin binder in a weight ratio of about 1: 2. A small amount of magnesium stearate was added as a lubricant. The mixture was formed into 450-900mg tablets (each containing 150-300mg of the active sulfonylamino cyclic derivative) in a tablet press.
Preparation 5-injection
The compounds of the invention were dissolved in a buffered sterile saline injectable water base to a concentration of about 5 mg/ml.

Claims (22)

1. A sulfonyl amino cyclic derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof,
in the formula:
a is-CR4R5；
B is-CR4’R5’；
R1Selected from the group consisting of optionally selected from halogen, -O-R, trihalomethyl, phenyl and C1-C6Phenyl substituted with a substituent of alkyl, wherein R is selected from C1-C6Alkyl, phenyl and phenyl C1-C6-an alkyl group;
R2is selected from H;
R3selected from benzodioxolyl, optionally selected from halogen, -O-C1-C6Phenyl substituted by alkyl and oxadiazole substituents, RR' -N-C1-C6-alkyl radical, C1-C6Alkyl, phenyl-C1-C6-alkyl, pyrrolidinylmethyl, pyrrolidinyl and pyridyl wherein R and R' are independently selected from H and C1-C6-an alkyl group;
R4，R5，R4' and R5' are independently selected from H and C1-C6-an alkyl group;
x is selected from CH or N;
y is selected from CH2(ii) a And the group-X … Y-is selected from-CH-CH2-and-N-CH2-；
m is selected from 0 and 1;
n is selected from 0 and 1; and
p is selected from 1.
2. A sulfonyl amino cyclic derivative according to claim 1 wherein R1Is optionally selected from halogen, -O-R, trihalomethyl and C1-C6Phenyl substituted with a substituent of alkyl, wherein R is selected from C1-C6Alkyl, phenyl and phenyl C1-C6-an alkyl group.
3. A sulfonyl amino cyclic derivative according to claim 1 wherein R1Is phenyl optionally substituted with a substituent selected from halogen and trihalomethyl.
4. A sulfonyl amino cyclic derivative according to claim 1 wherein R1Is phenyl.
5. A sulfonyl amino cyclic derivative according to any one of claims 1 to 4 wherein R3Selected from the group optionally selected from halogen, -O-C1-C6-alkyl and phenyl substituted by a substituent of oxadiazole.
6. A sulfonyl amino cyclic derivative according to any one of claims 1 to 4 wherein R3Selected from RR' -N-C1-C6-alkyl and C1-C6-alkyl, R and R' are independently selected from H and C1-C6-an alkyl group.
7. A sulfonyl amino cyclic derivative according to any one of claims 1 to 4 wherein n is 0.
8. A sulfonyl amino cyclic derivative according to any one of claims 1 to 4 wherein m is 0.
9. A sulfonyl amino cyclic derivative according to any of claims 1 to 4 wherein m and n are 1.
10. A sulfonyl amino cyclic derivative according to any one of claims 1 to 4 wherein R3Selected from RR' -N-C1-C6-alkyl, R and R' are independently selected from H and C1-C6-an alkyl group.
11. A sulfonyl amino cyclic derivative according to any one of claims 1 to 4 wherein R3Selected from pyrrolidinylmethyl, pyrrolidinyl and pyridyl.
12. A sulfonyl amino cyclic derivative according to any one of claims 1 to 4 wherein R3Is selected from C1-C6-an alkyl group.
13. A sulfonyl amino cyclic derivative according to any one of claims 1 to 4 wherein X is N.
14. A sulfonyl amino cyclic derivative according to claim 1 selected from the group consisting of:
15. use of a sulfonyl amino cyclic derivative according to any one of claims 1 to 14 for the preparation of a pharmaceutical formulation for the treatment of a matrix metalloproteinase related disease selected from: autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer, premature birth, respiratory diseases and fibrosis.
16. The use according to claim 15, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis and multiple sclerosis.
17. A pharmaceutical composition comprising a sulfonyl amino cyclic derivative according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a sulfonyl amino cyclic derivative according to any one of claims 1 to 14 and a pharmaceutically acceptable diluent.
19. A pharmaceutical composition comprising a sulfonyl amino cyclic derivative according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.
20. A process for the preparation of a sulfonyl amino cyclic derivative according to any one of claims 1 to 14 comprising the step of reacting a compound of formula (II):
in the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined in any one of the preceding claims 1 to 14; LG (Ligno-lead-acid)1Is one group selected from the following groups: OH, -OAc, -O-Piv，-OCH2CN，-OCH2-CF3-O-phenyl and OPfp.
21. A compound represented by the general formula (II):
in the formula, A, B and R1，R2，R3X, Y, m, n and p are as defined in claim 1.
22. A compound of formula (II) according to claim 21 selected from:
n, N-diethyl-4- (hydroxyamino) -5- { [4- (4-methoxyphenyl) -1-piperazinyl ] sulfonyl } -2-pentyn-1-amine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- (2-fluorophenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- [4- (trifluoromethyl) phenyl ] piperazine;
4- (4-fluorophenyl) -1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperidine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -4- (3-methoxyphenyl) but-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) hept-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- [4- (trifluoromethyl) phenyl ] piperazine;
4- (4-fluorophenyl) -1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } piperidine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperazine;
1- (4-fluorophenyl) -4- ({2- (hydroxyamino) -4- [4- (1, 2, 4-oxadiazol-3-yl) phenyl ] but-3-yn-1-yl } sulfonyl) piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperazine;
1-biphenyl-4-yl-4- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4-phenylpiperazine;
1- (4-chlorophenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (2-methoxyphenyl) piperazine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (3-methoxyphenyl) piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyl-6-phenylhex-5-yn-1-yl ] sulfonyl } piperazine;
n, N-diethyl-4- (hydroxyamino) -5- { [4- (4-methoxyphenyl) piperidin-1-yl ] sulfonyl } pent-2-yn-1-amine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (4-phenoxyphenyl) piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) oct-3-yn-1-yl ] sulfonyl } piperazine;
1- { [4- (2-fluorophenyl) -2- (hydroxyamino) but-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- { [4- (4-fluorophenyl) -2- (hydroxyamino) but-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
4- (4-chlorophenyl) -1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperidine;
1- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } -4- (4-methylphenyl) piperidine;
1- { [4- (3-fluorophenyl) -2- (hydroxyamino) but-3-yn-1-yl ] sulfonyl } -4- (4-methoxyphenyl) piperidine;
1- (4-ethoxyphenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- (3-chlorophenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- (3-methoxyphenyl) piperazine;
1- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } -4- (4-methylphenyl) piperidine;
1- (4-chlorophenyl) -4- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-ethoxyphenyl) -4- { [2- (hydroxyamino) -4-phenylbut-3-yn-1-yl ] sulfonyl } piperazine;
1- { [2- (hydroxyamino) -3, 3-dimethyl-6-phenylhex-5-yn-1-yl ] sulfonyl } -4- [4- (trifluoromethyl) phenyl ] piperazine;
1- (4-ethoxyphenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyl-6-phenylhex-5-yn-1-yl ] sulfonyl } piperazine;
1- (3, 4-dimethoxyphenyl) -4- { [2- (hydroxyamino) non-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -5-pyrrolidin-1-yl-pent-3-yn-1-yl ] sulfonyl } piperazine;
1- (4-fluorophenyl) -4- { [2- (hydroxyamino) -3, 3-dimethyloct-5-yn-1-yl ] sulfonyl } piperazine.
HK08105290.8A 2004-12-21 2005-12-19 Sulfonyl amino cyclic derivatives and use thereof HK1110860B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP04106814 2004-12-21
EP04106814.9 2004-12-21
US63825704P 2004-12-22 2004-12-22
US60/638,257 2004-12-22
PCT/EP2005/056910 WO2006067114A1 (en) 2004-12-21 2005-12-19 Sulfonyl amino cyclic derivatives and use thereof

Publications (2)

Publication Number Publication Date
HK1110860A1 HK1110860A1 (en) 2008-07-25
HK1110860B true HK1110860B (en) 2012-08-10

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