CZ2001687A3 - Aryl piperazines and their use as agents inhibiting metalloproteinase (MMP) - Google Patents

Abstract

The arylpiperazines of formula I are useful as metalloproteinase inhibitors, in particular MMP inhibitors 13.

Description

Technical field

The present invention relates to compounds that are useful for inhibition. metalloproteinases, especially pharmaceutical compositions containing them and their use.

BACKGROUND OF THE INVENTION

The compounds of the invention are inhibitors of one or more metalloproteinase enzymes. Metalloproteinases are a superfamily of proteinases (enzymes), the number of which has been increasing recently. Depending on their structure and functional factors, these enzymes are classified into families and subfamilies as described by N.M. Hooper (1994) FEBS Letters 354: 1-6. Examples of metalloproteinases include matrix metalloproteinases (MMPs) such as collagenases (MMP1, MMP8, MMP13), gelatinases (MMP2, MMP9), stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP), enamelysin (MMP), MT-MMP (MMP14)

MMP16, MMP17); reprolysin or adamalysin or the MDC family that includes secretases and sheddases, such as TNF converting enzymes (ADAM10 and TACE); an astacin family that includes enzymes such as procollagen-processing proteinase (PCP); and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family, and the angiotensin converting enzyme family.

Metalloproteinases are believed to be important in a number of physiological processes that involve tissue transformation, such as embryonic development, bone formation, and uterine transformation during menstruation. This is based on the ability of metalloproteinases to cleave a wide range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing or secretion of biologically important cell mediators, such as tumor necrosis factor (TNF); and post translational proteolytic processing or release of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a complete list, see M. Hooper et al., (1997) Biochem J. 321: 265-279).

• * 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Metalloproteinases are associated with a number of disease states. Inhibition of the activity of one or more metalloproteinases may be very beneficial in these disease states, for example: various inflammatory and allergic diseases such as joint inflammation (earth rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (particularly inflammatory bowel disease, ulcerative colitis and gastritis) skin inflammation (especially psoriasis, eczema, dermatitis); tumor invasion or metastasis; a disease associated with unregulated degradation of the extracellular matrix such as osteoarthritis; bone resorption disease (such as osteoporosis and Paget's disease)); aberrant angiogenesis-associated disease; increased collagen metabolism associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, skin ulceration, postoperative conditions (such as intestinal anastomosis), and healing of skin injuries; demyelinating diseases of the central and peripheral nervous system (such as multiple sclerosis); Alzheimer's disease; and extracellular matrix rearrangements observed in cardiovascular diseases such as restenosis and atherosclerosis.

A number of metalloproteinase inhibitors are known; different classes of compounds have varying degrees of potency and selectivity to inhibit different metalloproteinases. We have discovered a new class of compounds which are metalloproteinase inhibitors and of particular interest in inhibiting MMP-13 as well as MMP-9. The compounds of the invention have useful potency and / or pharmacokinetic properties.

MMP13 or collagenase 3 was originally cloned from a breast cancer cDNA library [J. Μ. P. Freije et al. (1994) Journal of Biological Chemistry 269 (24): 16766-16773], PCR-RNA analysis of RNA from a wide range of tissues indicated that MMP13 expression is restricted to breast cancer tumors as it was not found in fibroadenomas of breast, normal or resting mammary glands , placenta, liver, ovary, uterus, prostate or parotic glands, or in breast cancer cell lines (T47-D, MCF-7, and 2R75-1). Subsequently, MMP13 was found in transformed epidermal keratinocytes [N. Johansson et al (1997) Cell Growth Differ. 8 (2): 243-250], flat cell tumors [N. Johansson et al., (1997) Am. J. Pathol. 151 (2): 499-508] and skin tumors [K. Airola et al., (1997) J. Invest. Dermatol. 109 (2): 225-231]. These results suggest that MMP13 is secreted by transformed epithelial cells and may be involved in extracellular matrix degradation and cell-matrix interaction associated with metastasis, particularly as observed in invasive lesions of breast cancer and malignant epithelial cells. growth in carcinogenesis of the skin.

Recent publications suggest that MMP13 plays a role in the transformation of other connective tissues. For example, consistent with the specificity of substrate MMP13 and preference for degradation of type II collagen [P. G. Mitchell et al., (1996) J. Clin. Invest. 97 (3): 761-768; V. Knauper et al., (1996) The Biochemical Journal 271: 15441550] is thought to play a role during primary ossification and skeletal remodeling [M. Stahle-Backdahl et al., (1997) Lab. Invest. 76 (5): 717-728. N. Johansson et al .; (1997) Dev. Dyn. 208 (3): 387-397], in joint destruction diseases such as rheumatoid osteoarthritis [D. Wernicke et al., (1996) J. Rheumatol. 23: 590-595; P.

G. Mitchell et al., (1996) J. Clin. Invest. 97 (3): 761-768; O. Lindy, et al., (1997) Artritis Rheum 40 (8): 1391-1399]; and during aseptic loosening of hip replacements [S. Imai et al., (1998) J. Bone Joint Surg. Br. 80 (4): 701-710], MMP13 is also associated with chronic periodontitis in adults, as it has been located in the epithelium of chronically inflamed mucosal human gingival tissue [V. J. Uitto et al., (1998) Am. J. Pathol. 152 (6): 1489-1499] and in the rebuilding of the collagen matrix in chronic wounds [M. Vaalamo et al., (1997) J. Invest. Dermatol. 109 (1): 96-101]

MMP9 (gelatinase B; 92kDa collagenase type IV; 92kDa gelatinase) is a secreted protein that was first purified and then cloned and sequenced, in 1989 (SM Wilhelm et al. (1989) J. Biol Chem. 264 (29): 17213-) Published patch in J. Biol. Chem. (1990) 265 (36): 22570.). A recent review of MMP6 provides an excellent source for detailed information and references on this protease: T.H. Vu & Z. Werb (in: Matrix Metalloproteinases. 1998. Publisher W.C. Parks & R. P. Mecham. P. 115148. Academic Press. ISBN 0-12-545090-7). From this review, T.H. In & Werb (1998), the following points are important.

MMP9 expression is usually restricted to several cell types, including trophoblasts, osteoclasts, neutrophils, and macrophages. However, its expression can be induced in the same cells and in other cell types by several mediators, including exposure of the cells to growth factors or cytokines. These are the same mediators that are often implicated in the inflammatory response. As with other secreted MMPs, MMP9 is released as an inactive Pro-enzyme, which is then cleaved to form an enzymatically active enzyme. Proteases required for this in vivo activation

0000 0000 * 00

0 000 0 * 0 0 '0000000 0 0 0000 00 000 are not known. The alignment of active MMP9 to the inactive enzyme is further regulated by in vivo interaction with TIMP-1 (a tissue inhibitor of metalioproteinase-1), a naturally occurring protein. TIMP-1 binds to the C-terminal region of MMP9, resulting in inhibition of the catalytic domain of MMP9. The combination of balancing induced ProMMP9 expression, Pro-cleavage of active MMP9 and the presence of TIMP-1 determines the amount of catalytically active MMP9 that is present at a particular site. Proteolytically active MMP9 attacks substrates that include gelatin, elastin and natural type IV and type V collagens; it has no activity against natural type I collagen, proteoglycans or laminins. There is a data set implying the role of MMP9 in various physiological and pathological processes. Physiological roles include the invasion of embryonic trophobiastes through the uterine epithelium at an early stage of fertilization of the fertilized egg; a role in bone growth and development; and the migration of inflammatory cells from the vasculature to the tissues. Overexpression of MMP9 has also been observed in certain pathological conditions, and thus the involvement of MMP9 in the process of diseases such as arthritis, tumor metastasis, Alzheimer's disease, multiple sclerosis and plaque disruption in atherocclerosis leading to acute coronary conditions such as myocardial infarction.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides compounds of Formula I

wherein B is a monocyclic or bicyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring containing up to 12 ring atoms and containing one or more heteroatoms independently selected from the group consisting of N, O and S; alternatively B may be biphenyl; ring B may optionally be attached to ring A by a C 1 -C 4 alkyl chain or a C 1 -C 4 alkoxy chain linking the 2-position of ring B to the carbon atom at the alpha position to X 2;

* 0 0 · 0 0 0 · • 00 0 0 00 0 0

0 0 0 0 0 0

Each R 3 is independently selected from the group consisting of hydrogen, halogen, NO 2, COOR wherein R is hydrogen or alkyl of 1 to 6 carbon atoms, CN, CF 3, -S-alkyl of 1 to 6 carbon atoms, -SO-alkyl of 1 to 6 carbon atoms, -SO2-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and aryloxy of up to 10 carbon atoms, n is 1, 2 or 3;

P is - (CFU 1 -) wherein n is 0, 1, 2 or P is an alkene or alkyne chain of up to 6 carbon atoms; when X 2 is C, P can be -Het-, - (CH [R 6]) _n -Het- , -Het- (CH [R 6]) _n - or -Het- (CH [R 6]) _n -Het, wherein Het is selected from -CO-, -S-, -SO-, -SO 2 -, -NR 6 - or -O-, wherein n is 1 or 2, or P is selected from -CO-N (R 6) -, -N (R 6) -CO-, -SO 2 -N (R 6) - and N (R 6) -SO 2 and R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 10 aralkyl, and C 9 -C 9 heteroalkyl;

ring A is a 5-7 membered aliphatic ring and can optionally be mono- or disubstituted with an optionally substituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy group, each substituent independently selected from the group consisting of halogen, alkyl C 1 -C 6 or oxo;

X 1 and X 2 are independently selected from N and C, wherein the ring substituent on ring A is oxo and is preferably adjacent to a ring nitrogen atom;

Y is -SO 2 - and -CO-;

Z is -CONHOH, Y is -CO- and Q is selected from -C (R 6) (R 7) -, -C (R 6) (R 7) -CH 2 - N (R 6) - and -N (R 6) -CH 2 - wherein R 6 is as defined above and only in relation to Q as defined herein, R 6 may also represent aryl of up to 10 carbon atoms, heteroaryl of up to 9 carbon atoms, and R 7 is H, an alkyl group of 1 to 6 carbon atoms or together with R 6 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, the heterocyclic ring comprising at least one heteroatom selected from N,

O or S;

Z is -CONHOH, Y is -SO 2 - and Q is selected from -C (R 6) (R 7) -, and -C (R 6) (R 7) -CH 2 -; or Z is -N (OH) CHO and Q is selected from -CH (R 6) -, -CH (R 6) -CH 2 -, and -N (R 6) CH 2 -;

R 1 is H, (C 1 -C 6) alkyl, (C 5 -C 6) cycloalkyl, (C 10 -C 10) aryl, (C 10 -C 10) heteroaryl, (C 12 -C aralkyl) or (C 12 -C 12) heteroaralkyl carbon atoms, all of which are optionally substituted up to

three groups independently selected from NO 2, CF 3, halogen, C 1 -C 4 alkyl, C 1 -C 4 carboxyalkyl, C 1 -C 6 cycloalkyl, -OR 4, -SR 4 C1-C4alkyl substituted with -OR4, -SR4 (and its oxidized analogues), -NR4, -NY-R4, or C1-C4alkyl-Y-NR4, provided that when R 1 is -OH, -OR 4, -SR 4 or -NR 4 or -NY-R 4, then Z is not -N (OH) CHO, or R 1 is 2,3,4,5,6-pentafluorophenyl;

* R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 10 aryl, C 1 -C 10 heteroaryl, C 9 -C 8 aralkyl, each optionally substituted with a substituent selected from from the group consisting of halogen, NO2, CN, CF3, (C1-C6) -alkyl, (C1-C6) -alkyl, (SO-C1-C6) -SO2-alkyl, C 1 -C 6 or C 1 -C 6 alkoxy;

R 2 is H, an alkyl group having 1 to 6 carbon atoms, or together with R 1 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, wherein the heterocyclic ring comprises at least one heteroatom selected from N, O and S;

Q may also be bonded to R 1 or R 2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring containing one or more O,

S and N.

_K Any of the above alkyl groups may be straight chain or branched.

^s Conventional values for the above groups include the following:

ring A is a 5-6 membered aliphatic ring, such as a piperazine ring, and may optionally be mono- or disubstituted with optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, each substituent independently selected from the group consisting of: includes halogen, (C1-C6) -alkyl or oxo;

R 3 is hydrogen, halogen, NO 2, CF 3, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, n is 1 or 2, such as 4-fluoro, CF 3, 4-chloro and 3,4-dichloro;

ring B is a monocyclic or bicyclic aryl group, an aralkyl or heteroaryl group of up to 10 carbon atoms, in particular a monocyclic aryl group, 4 4 9 4

4 4 9 4 4 9 4 9 4 9

4 9 9 9

4499 4999 4 4 9 49 9 4 44 4 an aralkyl or heteroaryl group containing up to 7 carbon atoms, more preferably a monocyclic aryl or heteroaryl group containing up to 6 carbon atoms, such as a phenyl or pyridyl ring;

P is - (CH 2) _n -, wherein n is 0 or 1 or -O- or -CO-NR 6) -; one or both of X 2 and X 1 are N or X 1 is N or X 2 is C;

Y is -SO 2 -, or -CO-;

Q is -CH (R 6) -, -CH (R 6) -CH 2 - and -N (R 6) -CH 2 -, wherein R 6 is hydrogen or C 1 -C 6 alkyl; also when Q binds to R 1 or R 2 to form an alkyl or heteroalkyl ring of 5 to 7 carbon atoms, such as a cycolhexyl ring;

R 1 is hydrogen, C 1 -C 6 alkyl, C 5 -C 7 cycloalkyl, C 1 -C 12 aralkyl, C 1 -C 11 heteroarylalkyl, C 1 -C 10 aryl or heteroaryl such as aryl a group of up to 6 carbon atoms, all of which are optionally substituted with up to three halogen atoms or CF 3;

R 2 is hydrogen or together with R 1 represents a carbocyclic or heterocyclic spiro 5- or 6-membered ring, such as a tetrahydropyran ring;

R 4 is aryl of up to 10 carbon atoms, optionally substituted with halogen, NO 2, CN, CF 3, alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, -SO-alkyl of 1 to 6 carbon atoms carbon atoms, -SO 2 -alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms;

Z is -CONHOH-, Z is -N (OH) CHO.

Preferred values for the above groups include:

R 3 is hydrogen, halogen, such as chlorine, bromine or fluorine, NO 2, CF 3, methyl, ethyl, methoxy, ethoxy, especially methoxy or fluoro;

ring B is a monocyclic aryl, aralkyl or heteroaryl group containing up to 7 carbon atoms such as phenyl, biphenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, especially phenyl, pyridyl and pyrimidinyl, especially phenyl, 2-pyridyl or 2,4- pyrimidyl;

P is a direct bond; X2 and X1 are both N;

Y is -SO 2 -;

Q is -CH28

R 1 is phenyl, 4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl, cyclopentyl, benzyloxymethyl, 3,4-dichlorophenyl, pyridyl, pyridylethyl, thiophenylpropyl, bromothiophenyl, pyrimidinylethyl, pyrimidinylpropyl, pyridylethyl, pyridylpropyl or together with R 2 is spiroclohexyl pyran; R 2 is hydrogen;

Z is -N (OH) CHO

More preferred values for R 3 include halogen, wherein the substituent is preferably in the meta or para position to attach the ring and wherein ring B is an aryl or heteroaryl ring, when ring B is phenyl, is especially 4-fluoro, and when ring B is pyridyl - or 4-chlorine (as appropriate);

Q = -CH ₂ Preferred combinations of rings B and A include phenyl and piperazinyl; pyridyl and piperazinyl and pyrimidine and piperazinyl, respectively. .

Alicyclic, fused, and heterocyclic rings for ring B include, in particular, any of the following rings:

• * • *

and their corresponding seven-member analogs.

It will be appreciated that the particular substituents and number of substituents on rings A and B are selected so as to avoid undesirable steric combinations. This approach also applies to the rings if they can be formed by R1 and Q, R2 and Q as well as R6 and R7.

When active centers exist in a compound of formula I, all individual optically active forms and combinations of these individual specific embodiments of the invention and their corresponding racemates are included in the present invention.

Specific compounds include W W V 9 9 · · · · · · · · · · · · · · · · · · · · · · ·

M / Z M + 1 (ESP +) 438

M / ZM + I (ESP +) 455

O

M / Z M + 1 (ESP +) 487

M / Z M + 1 (ESP +) 454

M / Z M + 1 (ESP +) 420. · · · · · · · · · · · · · · · · ·

M / Z M + 1 (ESP +) 451

M / Z M + 1 (ESP +) 457

M / Z M + 1 (ESP +) 438

M / Z M + 1 (ESP +) 496

M / Z M + 1 (ESP +) 471. · I · 1 i · i i 11 11 11 11

M / Z M + 1 (ESP +) 528

M / ZM + 1 (ESP +) 511

M / Z M + 1 (ESP +) 470

M / ZM + 1 (ESP +) 495

M / ZM + l (ESP +) 495 · 0 ·· 00 00 ♦ 00 0 '0 0 · 0 0 000 • 0 00 0 000 • 0 0 0 0 0 00 0 0 • 0 000 000 0000 0000. · 0 0000 00 000

M / Z M + 1 (ESP +) 455

M / Z M + 1 (ESP +) 468

M / Z M + 1 (ESP +) 455

M / Z M + 1 (ESP +) 427

M / Z M + 1 (ESP +) 456

·· · φ ·· · » 99 9 • · · · '9 • · · 9 9 9 9 • · 9 • · 9 9 9 . * ·. 9 • · • · 9999 9 9 99 9 999

• ·

• ·

• ·

wherein R = isobutyl or spiro-4-pyran ring.

As mentioned above, the compounds of the invention are metalloproteinase inhibitors, in particular they are MMP 13 inhibitors. Each of the above indications for compounds of Formula I represents an independent and individual embodiment of the present invention. Without wishing to be bound by theory, it is believed that the compounds of the invention exhibit selective inhibition for any of the above indications related to any MMP1 inhibitory activity, by way of non-limiting example, may exhibit 100-1000 fold selectivity to the inhibitory activity of any MMP1.

We have further found that compounds of formula 1 wherein B is a phenyl, pyridyl (such as 2-pyridyl or 3-pyridyl, especially 2-pyridyl) ring, optionally mono or disubstituted, preferably monosubstituted with a halogen atom (e.g. chlorine), P is direct custody; ring A is a piperazinyl or piperidinyl ring; Y is -SO 2 - and Q is C 1 -C 4 alkylene (for example -CH 2 -), especially -CH 2 -; R1 is as defined for compound I and is especially 2-phenylpropyl, 2- (2-pyridyl) propyl, 2- (3-pyridyl) propyl, 2- (4-pyridyl) propyl, phenyl, benzyloxymethyl, 4-phenylbutyl, 2-phenylbutyl or 2- (2-thienyl) propyl; and Z is 17 · 4 44 ·· 44 4 • 4 4 · 4 · · 4 4 4 4 4

445 4 * 4 ·

4 4 4 4 4 4

4444 4444 44 4444 44 444

N (OH) CHO; are particularly useful as aggrecanase inhibitors, i.e., aggrecan degradation inhibitors. Of particular interest are compounds of formula I wherein ring B is phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl or 5-chloro-2-pyridyl; P is a direct bond; ring A is piperidinyl or piperazinyl, especially piperazinyl, Y is SO 2, Q is -CH 2 -, Z is -N (OH) CHO and R 1 is phenyl, phenylbutylene, phenylisopropylene, 2-pyridylethylene, 2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylsopropylene or 4-chlorophenyloxydimethylmethylene. Also disclosed are compounds of formula I wherein ring B is phenyl monosubstituted with chloro or fluoro, especially 4-chlorophenyl and 4-fluorophenyl; P is a direct bond; A is piperidinyl, Y is SO2, Q is -CH2-, Z is -CONHOH and R1 is hydrogen, isobutyl or spiro-tetrahydropyranyl.

Special compounds include

(B) AND Y Q R1 OF 4-F-Ph PIP SO2 CH2 CH 2 CH (CH 3) Ph RH 4-F-Ph PIP SO2 CH2 PhCH2CH2CH'2CH2 RH 3-Cl-Ph PIP SO2 CH2 PhCH2OCH2 RH 4-F-Ph PIP SO2 CH2 4-PyridylCH (CH 3) CH 2 RH 4-F-Ph Piperidinyl SO2 CH2 PhCH (CH 3) CH 2 RH 4-F-Ph PIP SO2 CH2 (R) -2-PhCH (CH 3) CH 2 RH 3-Cl-Ph PIP SO2 CH2 3-PyridylCH (CH 3) CH 2 RH 3-CH 3 -Ph PIP SO2 CH2 Ph RH 4-F-Ph PIP SO2 CH2 CH2CH (CH2CH3) Ph RH 5-C 1-2-Pyridyl PIP SO2 CH2 3-PyridylCH (CH 3) CH 2 RH 4-F-Ph PIP SO2 CH2 2-ThiophenylCH (CH3) CH2 RH 4-F-Ph BEEP SO2 CH2 2-CH 3 PhCH 2 CH 2 RH 4-F-Ph Piperidinyl SO2 CH2 3-PyridylCH (CH 3) CH 2 RH 4-Br-Ph PIP SO2 CK2 PhCH (CH 3) CH 2 RH 4-F-Ph PIP SO2 CH2 4-F-PhCH (CH 3) CH 2 RH 4-F-Ph PIP SO2 CH2 2-PyrazinylCH (CH 3) CH 2 RH

wherein PIP is piperazinyl

RH is a reverse hydroxamate group R 2 is hydrogen 4 4 4 Φ 4 »4 Φ!

·. ·

The compounds of the invention may be provided as pharmaceutically acceptable salts. These salts include acid addition salts such as hydrochlorides, hydrobromides, citrate and maleate salts, and salts formed with phosphoric acid and sulfuric acid. In another aspect, suitable salts are basic salts such as alkali metal salts such as sodium or potassium, rare earth metal salts such as calcium or magnesium, or amine salts such as triethylamine.

The compounds may also be provided as in vivo hydrolysable esters. They are pharmaceutically acceptable ersters that hydrolyze in the human body to form the parent compound. Such esters can be identified by administering, for example, an intravenously tested animal, a compound to be tested and subsequently examining the body fluid of the test animal. Suitable in vivo hydrolysable. esters for the carboxyl group include methoxymethyl and for the hydroxy group include formyl and acetyl, especially acetyl.

Typically, a compound of Formula I, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use in the therapeutic treatment (including prophylactic treatment) of mammals, including humans, is formulated according to standard pharmaceutical practice as a pharmaceutical composition.

Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may be administered in a standard manner for a disease state that is desired to be treated, for example, orally, topically, parenterally, buccally, nasally, vaginally or rectally, or by inhalation. For this purpose, the compounds of the present invention can be formulated by methods known in the art into, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation and for parenteral administration (including intravenous, intramuscular or infusion) of sterile aqueous or oily solutions or suspensions or sterile emulsions.

Further, the compounds of the present invention and the pharmaceutical composition of the present invention may also contain or be co-administered (simultaneously or sequentially) with one or more pharmaceutical agents that are valuable for the treatment of one or more of the disease states listed above.

·· ·· · 0 ·· ·· 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0000 0000 0

0 000 000 0

0000 0000 00 0000 00 000

The pharmaceutical compositions of the present invention will normally be administered to humans so that, for example, the daily dose is 0.5 to 75 mg / kg body weight, preferably 0.5 to 30 mg / kg body weight. This daily dose may be divided into several doses, if necessary, the exact amount of compound administered and the route of administration being dependent on the weight, age and sex of the patient to be treated and the particular nature and severity of the disease being treated according to the principles of known in the art.

Typical unit dosage forms will contain about 1 mg to 500 mg of a compound of the present invention.

Another aspect of the present invention is to provide a compound of Formula I, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof, for use in a method of therapeutic treatment of the human or animal body.

In yet another aspect, the present invention provides a method of treating a metalloproteinase-mediated condition comprising administering to a warm-blooded animal a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof.

In yet another aspect, the present invention provides a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof, wherein the process comprises:

a) reacting a compound of formula II or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof with a compound of formula III

Y '

OF'

R1 R2

III • φ • φ · where X? X is X or a precursor derived from X (whether by modification or displacement) or an activated form X suitable for reaction with Yt;

Y 1 represents Y, a Y-derived precursor or an activated form of Y suitable for reaction with X 2; as a non-limiting example, when X is C, then X may be derivatized to include a Y-derived precursor for reaction with a compound of Formula III wherein Y ¹ is a Y-derived precursor; Z ¹ represents a protected form Z, a precursor derived from Z (whether by modification or displacement of Z ¹ ) or an activated form Z;

and when Q is - (CH 2) (R 6) - then reacting a compound of formula IX with a suitable compound of formula R 1 -CO-R 2 to give an alkene of formula X, which is then converted to a compound of formula XI wherein Z * is hydroxylamine precursor of group Z and then conversion of group Z * as shown below:

i 9 9

..9 9,999 · · ·························

b) reacting a compound of formula IV or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof with a compound of formula V

From ¹

IV

R1 R2

wherein B ¹ represents a suitable ring function or substituent for reaction with P ¹ ; Z ¹ is as defined above; and

P ¹ represents a suitable activated form of linker P for reaction with B ¹ or when X 2 is N, then P 1 may be present on ring A rather than ring

B or as desired, the linker P may be formed by a suitable reaction of the precursor groups P and P 'found on rings B ¹ or A, or vice versa.

The compound of formula II is conventionally prepared by reacting a compound of formula VI with a compound of formula VII

AND

VII wherein B ¹ represents a suitable ring function or substituent, X ²¹ represents X or a precursor derived from X (whether by modification or displacement) or an activated form X suitable for reaction B ¹ and wherein B ¹ and X ²¹ co-react with each other «• ·

between ring A and B in the compound of formula II. As a non-limiting example, when X ₂ is N, then ring B is suitably derivatized to introduce linker P via B ¹ and when X 2 is C, both rings A and B are suitably derivatized to provide linker P by reactions B ¹ and X 2 '.

It will be appreciated that many of the relevant starting materials are commercially available. Further, the following table shows the details of the aldehyde intermediates and their corresponding Chemical Abstracts registration numbers.

RCHO Registration number Chemical Abstracts 2-methyl-2- (4-chlorophenoxy) propionaldehyde 6390-87-0 2-methyl-2- (4-chlorophenylthio) propionaldehyde 56421-90-0 4-Phenoxybutyraldehyde 19790-62-6 cyclohexylacetaldehyde 5664-21-1 3-Cyclohexylpropionaldehyde 4361-28-8 4-Cyclohexylbutyraldehyde 1860-41-9 3- (3-pyridyl) butyraldehyde 79240-21-4 3- (2-pyridyl) propionaldehyde 2057-32-1 5-phenylvaleraldehyde 36884-28-3 6-phenylhexanal 16387-61-4 3-phenylvaleraldehyde 34097-95-5 3- (2-thienyl) butyraldehyde 63362-02-7 3- (2-methylphenyl) propionaldehyde 19564-40-0 3-Phenyl-4-methylvaleraldehyde 54784-84-8 3- (2-pyrazinyl) butyraldehyde 177615-94-0 furan-2-carboxaldehyde 221525-60-6 3- (4-chlorophenyl) propionaldehyde 75677-02-0 3- (4-fluorophenyl) propionaldehyde 63416-70-6 3- (4-pyridyl) propionaldehyde 120690-80-4 4-phenylbutyraldehyde 170650-98-3 2-Pyridyicarboxaldehyde 1121-60-40 3- (3-pyridyl) propionaldehyde 1802-16-0 3- (2-Furyl) propionaldehyde 4543-51-5

• · · ·:: *::::::

4- (2-pyridyl) butyraldehyde 90943-32-1 4-bromothiophene-2-carboxaldehyde 18971-75-8 cyclopentanecarboxaldehyde 872-53-7 Benzoxazole, 2- (1-piperazinyl) - (9CI) 111628-39-8 Benzothiazole, 2- (1-piperazinyl) - (9CI) 55745-83-0 Benzoxazole, 5-chloro-2- (1-piperazinyl) - (9CI) 140233-44-9 Benzothiazole, 6-chloro-2- (1-piperazinyl) - (9CI) 153025-29-7 3-pyridyl-5-bromo-carboxaldehyde 113118-81-3

Aldehydes without registration numbers Chemical Abstracts

3- (2-pyrimidyl) propionaldehyde. To a solution of 2-bromopyrimidine (7.95 g, 0.05 M) in acetonitrile (150 mL) was added propargyl alcohol (4.2 g, 0.075 M), bis (triphenylphosphine) palladium (II) chloride (750 mg, 1 mM). ), cuprous iodide (100 mg, 0.5 mM) and triethylamine (25 mL, 0.25 M) and the mixture was stirred and heated to 70 ° C for 2 hours. Then add an additional amount of propargyl alcohol (2.1 g, 0.038 M), bis (triphenylphosphine) palladium (II) chloride (375 mg, 0.5 mM), and copper (I) iodide (50 mg, 0.25 mM) and the reaction mixture. was stirred and heated at 70 ° C for an additional 1 hour.

The reaction mixture is evaporated to dryness and the residue is pre-absorbed on silica gel and chromatographed. Elution with ethyl acetate gave 3- (2-pyrimidyl) prop-2-in-3-ol as a yellow solid in a yield of 4.45 g (66%). NMR (CDCl ₃ ) 2.9 (1H, t), 4.5 (2H, d), 7.3 (1H, d), 8.8 (2H, t), MS found MH ⁺ 135

3- (2-Pyrimidyl) prop-2-yn-1-ol (4.45 g, 0.033 M) was dissolved in ethyl acetate (140 mL), 10% Pd / C (890 mg) was added and the mixture was stirred under atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through celite and the filtrate was evaporated to give 3- (2-pyrimidyl) propan-1-ol as a yellow oil, yield 4.15 g (91%). NMR (CDCl ₃ ) 2.1 (2H, m), 3.2 (2H, t),

3.8 (2H, t), 7.2 (1H, t), 8.7 (2H, d) MS found MH ⁺ 139.

3- (2-pyrimidyl) propan-1-ol is oxidized to give 3- (2-pyrimidyl) propionaldehyde as a yellow oil NMR (CDCl 3) 3.0 (2H, t), 3.4 (2H, t), 7, (1H, t), 8.7 (2H, d), 9.9 (1H, sj), using the Sewern oxidation described in this patent.

Using the procedure described above, the following aldehydes were prepared: 4- (2-pyrimidyl) butyraldehyde using 3-butin-1-ol instead of propargyl alcohol NMR CDCl 3

9.8 (1H, s), 8.6 (2H, m), 7.15 (1H, m), 3.0 (2H, m), 2.5 (2H, m), 2.2 (2H, m) ).

π Λ ······· ·. ··· - · ··· · »·« «· · · · · · · · ·

4- (5-pyrimidyl) butyraldehyde using 3-butin-1-ol instead of propargyl alcohol and

5-bromopyrinidine instead of 2-bromopyrimidine NMR CDCl 3 9.8 (1H, s), 9.1 (1H, s), 8.6 (2H, s), 2.7 (2H, t), 2.55 (2H t, 2.0 (2H, m).

4- (2-pyridyl) butyraldehyde using 3-butin-1-ol instead of propargyl alcohol and 2-bromopyridine instead of 2-bromopyrimidine NMR CDCl 3 9.8 (1H, s), 8.6 (1H, s), 7.6 (1H m), 7.1 (2H, m), 2.8 (2H, t), 2.55 (2H, t), 2.0 (2H, m).

The compounds of the invention can be evaluated, for example, in the following tests:

Isolated enzyme tests

The matrix metalloproteinase family including, for example, MMP13

Recombinant human proMMP13 can be expressed and purified as described by Knauper et al. [IN. Knauper et al., (1996) The Biochemical Journal 271: 1544-1550 (1996)]. To monitor the activity of the inhibitors, the purified enzyme may be used as follows: purified proMMP 13 is activated using 1 mM aminophenyl mercuric acid (ΑΡΜΑ) for 20 hours at 21 ° C; activated MMP13 (11.25 ng per assay) is incubated for 4-5 hours at 35 ° C in assay buffer (0.1M Tris-HCl, pH 7.5 containing 0.1M NaCl, 20 mM CaCl 2, 0.02 mM ZnCl 2). and 0.05% (w / v) Brij 35) using a synthetic substrate 7-methoxycoumarin-4-yl) acetyl.Pro.Leu.Gly.Leu.N-3- (2,4-dinitrophenyl) -L- 2,3-diaminopropionyl.Ala.Arg.NH2 in the presence or absence of inhibitors. Activity is determined by measuring fluorescence at λex 328 nm and λem 393 nm. Percent inhibition was calculated as follows:% inhibition = _[p i _us fluorescence inhibitor fluorescence _Pos ranks] divided by the [Fluorescence _m in _U.S. inhibitor - Fluorescence _pos ranks] ·

A similar procedure can be used for other expressed and purified for MMPs. the use of substrates and buffers optimal for a particular MMP, for example as described in C. Graham Knight et al., (1992) FEBS Lett. 296 (3): 263-266.

The Adamalysin family, including, for example, TNF convertase

The ability of compounds to inhibit TNFα convertase enzyme can be investigated using a partially purified, isolated enzyme assay, wherein the enzyme is obtained from THP-1 membranes as described by KM Mohler et al., (1994) Nature 370: 218-220. enzyme is determined by incubating the partially purified enzyme in the presence or absence of test compounds using a substrate of 4 ', 5'-dimethoxyfluoresceinyl Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser. Ser.Ser.Arg.Cys (4 (3-succinimid-1-yl) fluorescein) -NH2 in assay buffer (50 mM Tris HCl, pH 7.4 containing 0.1% (w / v) Triton X-100m and 2 mM CaCl 2) at 26 ° C for 18 hours. The amount of inhibition is determined as for MMP 13 using λex 490 nm and λem 530 nm. The substrate is prepared as follows. The peptide portion of the substrate is collected on Fmoc-NH-Rink-MBHA-polystyrene resin either manually or on an automated peptide synthesizer by standard methods including the use of Fmoc-amino acid and O-benzotriazol-1-yl-N, N, N ', N'Tetramethyluronium hexafluorophosphate ( HBTU) as a coupling agent with at least a 4 or 5-fold excess of Fmoc-amino acid and HBTU. Ser ¹ and Pro ² were coupled in duplicate. The following branch chain protection strategies were used; Ser ¹ (Bu ¹ ), Gln ⁵ (Trityl), Arg ^8.12 (Pmc or Pbf), Ser ^9,10.11 (Trityl), Cys ¹³ (Trytyl). After assembly, the N-terminal Fmoc-protecting group is removed by treatment with Fmoc-peptidyl resin in DMF. The aminopeptidyl resin so obtained is acylated by treatment for 1.5 to 2 hours at 70 ° C with 1.5 to 2 equivalents of 4 ', 5'-dimethoxyfluorescein-4 (5) carboxylic acid [Khanna & Ullmann, (1980) Anal Biochem. 108: 156-161) which was previously activated with diisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF]. The protecting group is then simultaneously deprotected from the dimethoxyfluoresceinyl peptide and cleaved from the resin by treatment with trifluoroacetic acid containing 5% water and 5% triethylsilane. The dimethoxyfluoresceinyl peptide is isolated by evaporation, triturated with diethyl ether and filtered. The isolated peptide is reacted with 4- (N-maleimido) fluorescein in DMF containing diisopropylethylamine, the product is purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid. The product is characterized by MALDI-TOF MS and amino acid analysis.

Natural substrates

The activity of the compounds of the invention as inhibitors of aggrecan degradation can be investigated using a method based, for example, on the discoveries of E. C. Arner et al., (1998) Osteoarthritis and Cartilage 6: 214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601 and the antibodies described herein. The potency of the compounds to act as inhibitors against collagenesis can be determined as described by T. Cawston and A. Barrett (1979) Anal. Biochem. 99: 340-345. , *

• 9

Inhibition of metalloproteinase activity in cell / tissue activity

Assay of the ability of an agent to inhibit membrane sheddases such as TNF convertase The ability of the compounds of the invention to inhibit cellular production processes

TNFα can be assayed in THP-1 cells using ELISA to determine released TNF, essentially as described by KM Mohler et al., (1994) Nature 370: 218220. In a similar manner, the processing or shedding of other membrane molecules such as those can be tested. that he described Ν. M. Hooper et al., (1997) Biochem. J. 321: 265-279 using suitable cell lines and appropriate antibodies to detect the released protein.

Assay of the ability of an agent to inhibit cell invasion

The ability of the compounds of the invention to inhibit cell migration in an invasion assay can be determined as described by A. Albíni et al., (1987) Cancer Research 47: 32393245.

Assay for the ability of an agent to inhibit TNF sheddase activity in whole blood

The ability of the compounds of the invention to inhibit TNFα production is evaluated in a whole human blood assay using LPS to stimulate TNFα release. Heparinized (10 U units / ml) human blood obtained from volunteers is diluted 1: 5 with medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160 μΙ) with 20 μΙ of the test compound (in triplicate) in DMSO or appropriate vehicle for 30 minutes at 37 ° C in a humidified (5% 002/95% air) incubator before adding 20 μΙ LPS (E. coli. 0111: B4; final concentration 10 μg / ml). Each assay includes diluted blood controls incubated with medium alone (6 wells / plate) or a known TNFα inhibitor as standard. The plates are then incubated for 6 hours at 37 ° C (humidified incubator), centrifuged (2000 rpm for 10 min; 4 ° C), the plasma is collected (50-100 μΙ) and stored at 96 ° C. well plates at -70 ° C prior to subsequent analysis for TNFα concentration by ELISA.

Test for the ability of an agent to inhibit cartilage degradation in vitro

9 9 9 9

9

9

9 9. 9 9 • 9999 99 9

The ability of the compounds of the invention to inhibit the degradation of aggrecan or collagen cartilage components is investigated essentially as described Κ. M. Bottomley et al., (1987) Biochem J 323: 483-488.

Pharmacodynamic test

To assess the clearance and bioavailability of the compounds of the invention, an ex vivo pharmacodynamic assay is employed which utilizes synthetic substrate assays as described above, or alternatively, HPLC or mass spectroscopy analysis. This is a generic assay that can be used to determine the rate of clearance of compounds in different species. Animals (e.g., rats, marmosets) are dosed i.v. or p.o. a soluble formulation of the compound (such as 20% w / v DMSO, 60% w / v PEG400) and subsequently at time points (e.g., 5, 15, 30, 60, 120, 240, 480, 720, 1220 min) are blood samples from a suitable vein are taken up to 10 U heparin. Plasma fractions are obtained by centrifugation and plasma proteins are precipitated with acetonitrile (80% w / v final concentration). After 30 minutes at -20 ° C, the plasma proteins are sedimented by centrifugation and the supernatant is evaporated to dryness using vacuum ("Svant speed va"). The precipitate is diluted in assay buffer and then analyzed for compound content using a synthetic substrate assay. Briefly, the compound concentration-response curve is plotted for the compound being evaluated.

Gradual dilutions of plasma extracts are assayed for activity and the amount of compound present in the original plasma sample is calculated using a concentration-response curve, taking into account the total plasma dilution factor.

In vivo test

Anti-TNF reagent assay

The ability of the compounds of the invention as ex vivo inhibitors of TNFα is investigated in rats. Briefly, a group of male Wistar Alderley Park (AP) rats (180-210 g) are dosed with compound (6 rats) or drug vehicle (10 rats) by an appropriate route, for example orally (p.o.), intraperitoneally (i.p.), subcutaneously (s.c.). After ninety minutes, the rats are sacrificed using increasing concentrations of CO 2 and bled through the posterior hollow vein into 5 units of sodium heparin per ml of blood. Blood samples are immediately placed on ice and centrifuged at 2000 rpm for 10 minutes at 4 ° C and the plasma obtained is frozen at -20 ° C for subsequent testing for their effect on TNFα production by LPS-stimulated human blood. . Rat plasma samples and 175 μΙ of each sample are added to a set of formatted samples in a 96-well plate.

Then 50 μΙ of heparized human blood is added to each well, mixed and the plate is incubated for 30 minutes at 37 ° C (humidified incubator). LPS (25 μΙ; final concentration 10 µg / ml) was added to each well and incubation continued for an additional 5.5 hours. Control wells are incubated with 25 μΙ of medium alone. The plates are then centrifuged for 10 minutes at 2000 rpm and 200 μΙ of the supernatant is transferred to a 96 well plate and frozen at -20 ° C for subsequent analysis for TNF concentration by ELISA.

From the data obtained in the analysis, the dedicated software is calculated for each compound and dose using:

Percentage of TNFα inhibition = Mean TNFα (controls) -Mean TNFα (treated) x 100 Mean TNFα (controls)

Test of the ability of the anti-arthritis agent

Compound activity as an anti-arthritic agent is assayed in collagen-induced arthritis (CIA) as defined by D. E. Trentham et al., (1977) J. Exp. Copper. 146: 857. In this model, acid-soluble natural type II collagen causes polyarthritis in rats when administered in Freund's incomplete adjuvant. Similar conditions can be used to induce arthritis in mice and primates.

Anti-Cancer Agency Assay The activity of the compound as an anti-cancer agent can be performed essentially as described in IJ Fidler (1978) Methods in Cancer Research 15: 399-439, using, for example, the B16 cell line (described by B. Hibner et al. , Abstract 283, page 75 10. NCIt,

EORTC Symposium, Amsterdam, 16-19. June 1998).

The invention will be further illustrated by the following non-limiting examples.

· · · · · · · · · · · · · · · · · · · · · · · ·

9 9 9 999

9 99 9.9 99

DETAILED DESCRIPTION OF THE INVENTION

Example 1

1- [2- (N-Formyl-N-hydroxyamino) -2-phenylethanesulfonyl] -4- (4-fluorophenyl) piperazine

To a solution of 1- [2- (hydroxyamino) -2-phenylethanesulfonyl] -4- (4-fluorophenyl) piperazine (338 mg, 0.89 mmol) in THF (5 mL) and formic acid (2 mL) was added pre-treated a mixture of formic acid (2 mL) and acetic anhydride (0.5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was evaporated in vacuo, toluene (2x5 ml) was added and the mixture was evaporated in vacuo. The residue was taken up in CH 2 Cl 2 -MeOH (6 mL, 9: 1) and silica gel (1 g) was added. The mixture was stirred for 18 hours. The silica gel was filtered off and washed with CH 2 Cl 2 -methanol (9: 1). The residue was purified on silica gel (eluent: CH 2 Cl 2 - MeOH 4%) to give the title compound as a light orange solid (220 mg, 61%).

¹ H NMR (CDCl ₃ ): 8.45 and 8.15 (s, 1H), 7.39 (m, 5H), 6.97 (m, 2H), 6.88 (m, 2H), 5, 89 and 5.35 (m, 1H), 4.05 and 3.85 (m, 1H), 3.30-3.53 (m, 5H), 3.20-3.10 (m, 4H);

MS (ESI): 408 (MH < ⁺ &^gt;), 430 (MNa < ⁺ & gt ^; ); EA: calculated for C19H22FN3Q4S: C, 56.01, H, 5.44, N, 10.31, S, 7.87. Found: C, 56.01, H, 5.52, N, 10.04, S, 7.39.

The starting material is prepared as follows:

i) To a solution of 1- (4-fluorophenyl) piperazine (35 g, 194 mmol) and pyridine (17.5 mL) in dry dichloromethane (200 mL) at 0 ° C was added dropwise methanesulfonyl chloride (20 mL, 258 mmol). ). The mixture was stirred at room temperature for 3 hours. The mixture was washed with water and extracted with dichloromethane (2 x 100 mL). The organic layers were dried over MgSO 4 and evaporated in vacuo. The residue was triturated and washed with methanol to give 1- (4-fluorophenyl) -4- (methanesulfonyl) piperazine (39.35 g) as white crystals.

¹ H NMR (CDCl 3): 7.00 (m, 2H), 6.90 (m, 2H), 3.40 (m, 4H), 3.20 (m, 4H), 2.83 (s,

3H).

ii) To a LDA solution [8.5 mmol; prepared by slowly adding n-butyl lithium (3.5 mL, 8.5 mmol, 2.5 M in hexane) to a solution of diisopropylamine (860 mg, 8.5 mmol) in dry THF (5 mL) at -78 ° A solution of 1- (4-fluorophenyl) -4- (methanesulfonyl) piperazine (1 g, 3.87 mmol) in THF (25 mL) was added dropwise at -78 ° C. The mixture was stirred at -78 ° C for 1 hour and a solution of diethyl chlorophosphate (670 mg, 3.87 mmol) in THF (3 mL) was added. The mixture was stirred at -78 ° C for 1 hour and benzaldehyde (450 mg, 4.24 mmol) in THF (3 mL) was added. The mixture was carefully heated at room temperature for 18 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over MgSO ₄ . Purification of the residue on silica gel (eluent: dichloromethane) afforded 1- (4-fluorophenyl) -4 (trans-R-styrenesulfonyl) piperazine as a white powder (621 mg, 46%).

¹ H NMR (CDCl 3): 7.50 (m, 3H), 7.43 (m, 3H), 6.97 (m, 2H), 6.89 (m, 2H), 6.71 (d, 1H) J = 15.4 Hz), 3.37 (m, 4H), 3.19 (m, 4H).

iii) To a solution of 1- (4-fluorophenyl) -4- (trans-S-styrenesulfonyl) piperazine (620 mg, 1.79 mmol) in THF (20 mL) was added hydroxylamine (3 mL, 50% aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over MgSO ₄ to give 1- [2- (hydroxyamino) 2-phenylethanesulfonyl] -4- (4-fluorophenyl) piperazine (730 mg).

¹ H NMR (CDCl 3): 7.4-7.1 (m, 5H), 6.97 (m, 2H), 6.87 (m, 2H), 5.95 (broad s, 1H), 4, 74 (s, 1H), 4.60 (dd, 1H, J = 4Hz, J = 8.8Hz), 3.56 (dd, 1H, J = 8.8Hz, J '= 14.3Hz) 3.40 (m, 4H), 3.19 (dd, 1H, J = 4Hz, J '= 14.3Hz), 3.12 (m, 4H).

Example 2

Similarly, the following compounds are obtained:

• 4 4 4 4 4 44 44 • 4 4 4 4 4 '4 4 4 44 4 4 4 4 4 4 4 4 44 4444 4 4 4 4 4

Compound

Data

MS (ESI): 436 (MH +), 458 (MH +)

MS (ESI): 400 (MH < + >), 422 (MNa < + >)

MS (ESI): 476 (MH +, ³³ Cl); 498 (MNa +, ³³ C1)

O

MS (ESI): 422 (MH +)

Example 3

N-Hydroxy-3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] propionamide

To a solution of N- (2,4-dimethoxybenzyloxy) -N- (2,4,6-triemethoxybenzyl) -3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] propionamide (125 mg, 0.19 mmol) in dichloromethane (2 mL) was added triethylsilane (66 µL, 0.42 mmol) and trifluoroacetic acid (150 µL). The mixture was stirred at room temperature for 4 hours. The solvents were evaporated in vacuo. The residue was purified by silica gel chromatography (eluent: dichloromethane, then ethyl acetate, then dichloromethane - 10% MeOH) to give 35 mg of the title compound.

¹ H NMR (DMSO-d-6 + CF ₃ COOD): 7.16 (m, 4H) 3.36 (m, 6H), 3.25 (m, 4H), 2.45 (t,

2H, J = 7.4Hz); MS (ESI); 332 (MN ⁺ ), 354 (MN ⁺ ) ·

The starting material is prepared as follows;

i) A solution of 3-mercaptopropionic acid (20 g, 185 mmol) in acetic acid (150 mL) and water (30 mL) is treated with chlorine gas (preferably condensed at -78 ° C, 20 mL) at 0 ° C. Then the chlorine was distilled off and the solvents were evaporated in vacuo; toluene was added and evaporated to give 1,2-oxathiolan-5-one-2-dioxide (36.12 g). ¹ H NMR (DMSO d-6): 2.70 (t, 2H, J = 7.2 Hz), 2.50 (t, 2H, J = 7.2 Hz).

ii) A solution of 1,2-oxathiolan-5-one-2-dioxide (3.8 g, 28 mmol) in thionyl chloride (20 mL) and DMF (5 drops) was stirred at room temperature for 18 hours. The mixture was heated at 40 ° C for 1 hour. The solvents were evaporated; toluene was added and evaporated to give crude 3-chlorosulfonylpropionyl chloride (NMR purity; 70%, 3.58 g).

¹ H NMR (CDCl 3): 4.02 (t, 2H, J = 7.2 Hz), 3.63 (t, 2H, J = 7.2 Hz).

iii) To a solution of 3-chlorosulfonylpropionyl chloride (500 mg, 1.83 mmol, 70% purity) and diisopropylethylamine (75 μ 75) in dichloromethane (5 mL) at -78 ° C was added a solution of O-dimethoxybenzyl- N-trimethoxybenzylhydroxylamine ^[Ref1] (664 mg, 1.83 mmol) and diisopropylethylamine (320 μΙ, 1.83 mL) in dichloromethane (5 mL). After 30 minutes, a solution of 1- (4-fluorophenyl) piperazine (330 mg, 1.83 mmol) and diisopropylethylamine (320 μΙ, 1.83 mmol) in dichloromethane (5 mL) was added to the reaction mixture. The solution was warmed to room temperature and stirred for 2 hours. The solution was partitioned between dichloromethane and 1N hydrochloric acid. The organic layers were washed with brine and dried over MgSO ₄ . Chromatography of the residue on silica gel (eluent: ethyl acetate-petroleum ether: gradient from 50/50 to 80/20) affords N- (2,4-dimethoxybenzyloxy) -N- (2,4,6-trimethoxybenzyl) -3 [4- ( 4-Fluorophenyl) piperazine-1-sulfonyl] propionamide (260 mg).

MS (EI): 661 (M ^& lt ^{; +} & gt ^; ).

Example 4

N-Hydroxy-3- [4-benzylpiperazine-1-sulfonyl] propionamide - »φφφ.............. φ φ φ φ φ φ · · »» φ

ΙΦΦΦΦΦΦ φφ φφφφ φφ Φ · «& Η ^{in N} v_ / ^N ~ ^ 5 ^ in ⁿ ° ^H

Following a procedure analogous to that described in Example 3, the title compound is obtained from 4-benzylpiperazine and 3-chlorosulfonylpropionyl chloride.

¹ H NMR (DMSO d-6 + CF ₃ COOD): 7.50 (m, 5H), 4.41 (s, 2H), 3.78 (m, 2H), 3.41 (m, 4H), 3.18 (m, 2H); 2.43 (t, 2H, J = 7.1 Hz); MS (ESI): 328 (MH ^< ^{+ >} ).

Example 5

N-Hydroxy-3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropionamide

To a solution of N- (2,4-dimethoxybenzyloxy) -3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropionamide (220 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (200 μΙ) and triethylsilane. (145 μΙ). The mixture was stirred at room temperature for 15 minutes, evaporated in vacuo and the residue purified on silica gel (eluent: dichloromethane-ethermethanol (80: 20: 0.5) then dichloromethane-methanol (80:20)) to give the title compound. of title (88 mg, 56%).

¹ H NMR (DMSO d-6): 10.72 (s, 1H), 7.08 (m, 2H), 6.99 (m, 2H), 3.37 (dd, 1H, J = 8.4) Hz, J '= 14.3 Hz), 3.27 (m, 4H), 3.15 (m, 4H), 3.00 (dd, 1H, J = 4 Hz, J' = 14.3 Hz) 2.62 (m, 1H), 1.6-1.2 (m, 3H), 0.89 (d, 3H, J = 6.6 Hz), 0.85 (d, 3H, J = 6) , 6 Hz); MS (ESI): 388 (MH < ⁺ >), 410 (MNa < ⁺ & gt ^; ).

The starting material is prepared as follows:

·· ··

i) A solution of 3-acetylthio-2-isobutylpropinic acid [obtained by Michael addition of thiol acetic acid to 2-isobutylacrylic acid] (7 g, 34.3 mmol), benzyl bromide (4.29 mL, 36 mmol) and DBU (5.2 mL) , 35 mmol) in toluene (55 mL) was stirred at ambient temperature for 18 hours. The solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic layer was washed with brine and dried over MgSO 4. Purification of the residue by silica gel chromatography (eluent: dichloromethane-ether (9: 1)) gave benzyl 3-acetylthio-2-isobutylpropionate (8.4 g). MS (ESI: 317 (MNa < ⁺ & gt ^; )).

ii) A solution of benzyl 3-acetylthio-2-isobutylpropionate (588 mg, 2 mmol) in acetic acid (12 mL) and water (1.6 mL) is treated with chlorine gas at 0 ° C (preferably condensed at -78 ° C). C, 1.9 mL). After distilling off the chlorine, the solvents were evaporated in vacuo to give crude benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg).

MS (EI): 318 (M ^& lt ^{; +} & gt ^; ).

iii) A solution of benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg, 2 mmol), 1- (4-fluorobenzyl) piperazine (378 mg, 2.1 mmol) and triethylamine (340 µL, 2.4 mmol) in dichloromethane (15 ml) was stirred at 0 ° C for 18 hours. After evaporation of the solvents, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgSO 4. After evaporation of the solvent in vacuo, the residue was purified by silica gel chromatography (eluent: dichloromethane-ether (9: 1)) to give benzyl 3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropionate (640 mg) .

MS (EI): 462 (M ⁺ ) iv) A solution of benzyl 3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropionate (630 mg) in methanol (10 mL) was hydrogenated at 0, 28 MPa in the presence of palladium on charcoal (63 mg, 10%) for 18 hours. The catalyst was removed by filtration and the solvents were removed in vacuo to give 3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropinic acid (460 mg).

MS (ESI): 373 (MH < ⁺ >), 395 (MNa < ⁺ & gt ^; ).

v) To a solution of 3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropinic acid (230 mg, 0.62 mmol), 2,4-dimethoxybenzylhydroxylamine ^[Ref1i (124 mg, 0.68 mmol) )

DMAP (75 mg, 0.62 mmol) in DMF (1 mL) was added N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride (152 mg, 0.8 mmol). The mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, brine and dried over MgSO ₄ . Purification of the residue on silica gel (eluent: dichloromethane-ether: gradient from 9/1 to 8/2) gave N- (2,4-dimethoxybenzyloxy) -3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] - 2-Isobutylpropionamide (158 mg).

¹ H NMR (CDCl 3): 8.21 (s, 1H), 7.30 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H), 6.46 (m,

2H), 4.95 (m, 2H), 3.82 (s, 6H), 3.50 (dd, 1H, J = 9 Hz, J '= 14.2 Hz), 3.37 (m, 4H) ), 3.14 (m, 4H), 2.84 (dd, 1H, J = 14.2Hz, J = 2Hz), 2.60 (m, 1H), 1.7-1.2 (m 3H), 0.90 (m, 6H).

Example 6

4- [4- (4-Fluorophenyl) piperazine-1-sulfonylmethyl] tetrahydropyran-4- (N-hydroxycarboxamide)

To a solution of 4- [4- (4-fluorophenyl) piperazine-1-sulfonylmethyl] tetrahydropyran-4-carboxylic acid (470 mg, 1.21 mmol) in dichloromethane (8 mL) was added oxalyl chloride (700 mg, 5.6 mmol). ) and DMF (18 µl). The mixture was heated at 35 ° C for 1 hour. After evaporation of the solvents, the crude acid chloride was dissolved in dichloromethane (4 mL) and added to an ice-cooled solution of hydroxylamine (440 µL, 50% aqueous solution) in THF (8 mL). The mixture was stirred at room temperature for 90 minutes. After evaporation of the solvents, the residue was triturated in dichloromethane-ether-methanol (80: 20: 5). The resulting solid was washed with water and ethyl acetate and dried to give the title compound as white crystals (230 mg, 47%).

9. @ ¹ H NMR (DMSO d6): 10.56 (broad.). s, 1H), 8.74 (broad s, 1H), 7.07 (m, 2H), 6.99 (m,

2H), 3.66 (m, 2H), 3.47 (m, 2H), 3.40 (s, 2H), 3.25 (m, 4H), 3.16 (m, 4H), 1, 99 (m,

2H), 1.72 (m, 2H);

MS (ESI): 402 (MH < ⁺ >), 424 (MNa < ⁺ & gt ^; ).

The starting material is prepared as follows:

(i) Thiol acetic acid (760 µL, 10 mmol), and tributylphosphine (2.5, 10 mmol) in DMF (5 mL) were added dropwise to an ice-cooled suspension of sodium hydride (530 mg, 60% in oil, 13 mmol) ) in DMF (1.5 mL) under argon. The mixture was stirred at 0 ° C for 30 minutes. To the above solution was added 2,7-dioxaspiro [3,5] nonan-1-one ( ^Ref2) (1.4 g, 10 mmol) in DMF (40 mL). The reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 18 hours. The mixture was diluted with diethyl ether.

The precipitate was filtered off and dried to give 4- (acetylthiomethyl) tetrahydropyran-4-carboxylic acid sodium salt.

¹ H NMR (DMSO d-6): 3.65-3.40 (m, 4H), 2.99. (s, 2H), 2.27 (s, 3H), 1.86 (m, 2H),

1.23 (m, 2 H).

(ii) Using the same procedure as in Example 5 (i), (ii), (iii), (iv), (v), except that the DBU does not apply in step 1, the 4- (acetylphthiomethyl) tetrahydropyran-4-carboxylic acid (fluorophenyl) piperazine-1sulfonylmethyl] tetrahydropyran-4-carboxylic acid (490 mg).

4- (Acetylthiomethyl) tetrahydropyran-4-carboxylic acid benzyl ester: MS (ESI):

331 (MNa < ⁺ & gt ^; ); 4- (chlorosulfonylmethyl) tetrahydropyran-4-carboxylic acid benzyl ester: MS (ESI): 354 (MNa ⁺ ); 4- [4- (4-Fluorophenyl) piperazine-1sulfonylmethyl] tetrahydropyran-4-carboxylic acid benzyl ester: MS (ESI): 477 (MH ⁺ ), 499 (MNa ⁺ ); 4- [4- (4-fluorophenyl) piperazine-1-sulfonylmethyl] tetrahydropyran-4-carboxylic acid

acid: MS (ESI): 387 (MH < ⁺ >), 409 (MNa < ⁺ & gt ^; ).

Ref. 1: B. Barlaam, A. Hamon, M. Maudet; Tetrahedron Lett, 1998, 39, 7865.

Ref. 2: F. Hoffmann-La Roche, Agouron Pharm; Eur. Appl. EP 780386.

Example 7 É 9 · 4 f

B · · · · 4 4

1- [2- (N-Formyl-N-hydroxyamino) -2-phenylethanesulfonyl] -4-phenylpiperazine

To a solution of 1- [2- (hydroxyamino) -2-phenylethanesulfonyl] -phenylpiperazine (140 mg) in THF (0.75 mL) and formic acid (0.25 mL) was added a pre-treated mixture of formic acid (0.58 mL). and acetic anhydride (0.29 mL). The solution was stirred at ambient temperature for 18 hours. The mixture was evaporated in vacuo, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, dried (Na ₂ SO 4) and evaporated. The residue was purified by chromatography using 1% methanol in dichloromethane as eluent to give 1-phenyl- (4-trans-b-styrenesulfonyl) piperazine (420 mg) as a foam (105 mg).

¹ H NMR (d 6 -DMSO at 100 ° C): 9.60 (s, 1H), 8.25 (s, 1H), 7.40 (m, 2H), 7.30 (m,

3H), 7.20 (m, 2H), 6.90 (d, 2H), 6.75 (m, 1H), 5.60 (m, 1H), 3.85 (dd, 1H), 3, 60 (dd,

1H), 3.30 (m, 4H), 3.15 (m, 4H) m / z: 390 (M + 1).

The starting material is prepared as follows:

A solution of phenylpiperazine (487 mg) in dichloromethane (6 mL) containing triethylamine (0.63 mL) was added dropwise over 5 minutes to trans-b-styrene sulfonyl chloride (638 mg) in dichloromethane (4 mL). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by chromatography using 1% methanol in dichloromethane as eluent to give 1-phenyl- (4-trans-b-styrenesulfonyl) piperazine (420 mg) as a solid.

¹ H NMR (d 6 -DMSO): 7.75 (m, 2H), 7.40 (m, 4H), 7.30 (d, 1H), 7.20 (dd, 2H), 6.90 (d H, 6.80 (dd, 1H), 3.20 (s, 8H) m / z: 329 (M + 1).

v r

• · I · · · 4 · 4 · 4 ··· · 4 · «

Κ A solution of 1-phenyl-4- (trans-b-styrenesulfonyl) piperazine (108 mg) in THF (3 mL) was treated with hydroxylamine (0.45 mL, 50% aqueous solution). The mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane, washed with water, dried (Na ₂ SO ₄ ) and evaporated to give 1- [2- (hydroxyamino) -2-phenylethanesulfonyl] -4-phenylpiperazine as a foam (120 mg).

¹ H NMR (d 6 -DMSO): 7.50 (m, 1H), 7.40 (m, 2H), 7.30 (m, 5H), 6.90 (d, 2H), 6.80 (dd) 1H, 5.90 (m, 1H), 4.20 (m, 1H), 3.60 (dd, 1H), 3.40 (dd, 1H), 3.20 (m, 4H), 3 10 (m, 4H) m / z 362 (M + 1).

Example 8

1- [2- (N-Formyl-N-hydroxyamino) -2- (quinolin-4-yl) ethane-1-sulfonyl] -4- (4-fluorophenyl) piperazine

To a suspension of 1- [2- (N-hydroxyamino) -2- (quinolin-4-yl) ethane-1-sulfonyl] -4- (4-fluorophenyl) piperazine (148 mg, 0.34 mmol) in THF (2 mL) - CH 2 Cl 2 (2 mL) was added 5-methyl-3-formyl-1,3,4-thiadiazol-2 (3H) -thione ⁽¹⁾ (140 mg, 0.87 mmol) and stirred for 3 h. ml) and silica gel (1 g), the reaction mixture was stirred for 18 hours, the solids were filtered, the filtrate was washed with saturated NaHCO 3 and brine, followed by evaporation of the solvents followed by trituration with acetonitrile - CH 2 Cl 2 to give the starting material (60 ml). acetonitrile - CH 2 Cl 2 (1: 1) gave the title compound (20 mg, 13%).

¹ H NMR (CDCl 3): 8.97 (m, 1H), 8.21 (m, 2H), 8.01 (s, 1H), 7.8-7.65 (m, 3H), 6.97 (m, 2H), 6.86 (m, 2H), 5.66 (m, 1H), 3.55-3.1 (m, 10H);

MS (ESI) 459 (MH ^< ^{+ >} ).

The starting material was prepared from quinoline-4-carboxaldehyde and 1- (fluorophenyl) -4 (methanesulfonyl) piperazine in a similar manner to Example 1 ii-iii): 188 mg; MS (ESI): 431 (MH ^< ⁺ >); HPLC ir (TSKgel super ODS column 2 mm 4.6 mm x 5 cm, methanol / water gradient 20 to 100% in 5 minutes, flow rate: 1.4 mL / min): 3.43 min (1) Yazawa, H ; Goto, S. Tetrahedron Lett., 1985, 26, 3703.

Example 9. ’

- [1- (N-formyl-N-hydroxyamino) -1- (3,4-dichlorophenyl) pentane-2-sulfonyl] -4- (4-fluorophenyl) piperazine

Similar to Example 1, the syn and anti diastereoisomers of 1- [1- (N-hydroxyamino) -1 (3,4-dichlorophenyl) pentane-2-sulfonyl] -4- (4-fluorophenyl) piperazine are converted to the title compound (as 2 diastereoisomers):

diastereoisomer 1 of less polar hydroxylamine: 36 mg, 70%; ¹ H NMR (CDCl 3): 8.45 and 8.10 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.8 (m, 2Ή), 5.96 and 5.18 (m, 1H), 3.8 3.4 (m, 5H), 2.9-3.15 (m, 4H), 2.0-1.0 (m, 4H), 0.88 α 0.76 (t, 3H, J = 7Hz); MS (ESI): 540 (M { ³⁵ Cl, ³⁵ Cl} Na ⁺ ), 542 (M { ³⁷ Cl, ³⁵ Cl} Na ⁺ ).

diastereoisomer 2 of more polar hydroxylamine: 49 mg, 63%; ¹ H NMR (CDCl 3): 8.28 and 8.13 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.85 (m, 2H), 5.54 and 5.02 (m, 1H), 3.453.9 (m, 5H), 3.15 (m, 4H), 1.7-1.2 (m, 4H), 0.76 (t, 3H, J = 7 Hz); MS (ESI): 540 (M { ³⁵ Cl, ³⁵ Cl} Na ⁺ ), 542 (M { ³⁷ Cl, ³⁵ Cl} Na ⁺ ).

The starting material is prepared as follows:

· 9

9 9 • ·

9 λ 99 9 • · 9

9 4

9 9 <9 · 9 9 9

Similar to Example 1 i), 1- (4-fluorophenyl) -4- (butane-1-sulfonyl) piperazine (1.84 g) was obtained from 1- (4-fluorophenyl) piperazine and 1-butanesulfonyl chloride. similar to Example ii), reacted with 3,4-dichlorobenzaldehyde to give 4- (4-fluorophenyl) -1- [1- (3,4-dichlorophenyl) pent-1-ene-2-sulfonyl] piperazine as a mixture E isomers (330 mg, 22%): MS (ESI): 457 (M { ³⁵ Cl, ³⁵ Cl} H ⁺ ), 459 (M { ³⁷ Cl, ³⁵ Cl} H ⁺ ); similar to Example 1 (iii) except that the mixture was heated to reflux for 3 days and converted to 1- [1- (N-hydroxyamino) -1- (3,4-dichlorophenyl) pentane-2-sulfonyl] -4 - (4-fluorophenyl) piperazine as son and anti diastereoisomers.

Less polar isomer (50 mg, 15%) (TLC: EtOAc - CH 2 Cl 2 - petroleum ether (1545-50) eluent); ¹ H NMR (CDCl 3): 7.53 (d, 1H, J = 2.2 Hz), 7.46 (d, 1H, J = 7.4 Hz), 7.27 (m,

1H), 6.97 (m, 2H), 6.88 (m, 2H), 4.63 (m, 1H), 3.55 (m, 4H), 3.16 (m, 5H), 1, 75 (m, 2H), 1.4 (m, 1H), 1.2 (m, 1H), 0.77 (t, 3H, J = 7.4 Hz).

More polar isomers (76 mg, 23%); ¹ H NMR (CDCl ₃ ): 7.52 (d, 1H, J = 2Hz), 7.45 (d, 1H, J = 8Hz), 7.27 (m, 1H), 6.99 (m 2H, 6.89 (m, 2H), 4.42 (m, 1H), 3.55 (m, 4H), 3.41 (rh, 1H), 3.14 (m, 4H), 1 Δ (m, 2H), 1.25 (m, 4H), 0.76 (t, 3H, J = 7.3 Hz).

Example 10

Trans 1- [2- (N-formyl-N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) piperazine

F

Similar to Example 1, the title compound (68 mg, 23%) was obtained from trans 1- [2- (N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) piperazine.

¹ H NMR (CDCl 3): 8.39 and 8.02 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.40 and 3.92 (m,

1H), 3.35-3.55 (m, 5H), 3.15 (m, 4H), 2.35 (m, 1H), 2.0-1.8 (m, 3H), 1.2 1.6 (m, 4H); MS (ESI): 408 (MNa @ ⁺ ) ·

The starting material is obtained as follows:

· · 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

i) To a solution of LDA (51 mmol, prepared by slow addition of n-butyllithium (20.4 mL, 2.5M in hexane, 51 mmol) to a solution of diisopropylamine (5.16 g, 51 mmol) in THF (30 mL) at A solution of 1- (4-fluorophenyl) -4- (methanesulfonyl) piperazine (6 g, 23.2 mmol) in THF (150 mL) was added at -78 ° C. The mixture was stirred at -78 ° C for 1 hour. A solution of 5-chlorvaleryl chloride (4 g, 25.8 mmol) in THF (20 mL) was added dropwise. The mixture was stirred at -78 ° C for 1 hour and at room temperature for 18 hours. The solution was diluted with EtOAc and washed with saturated NH ₄ Cl and brine and dried over MgSO ₄ . Chromatography of the residue on silica gel (eluant: EtOAc - CH ₂ Cl ₂ - petroleum ether (3:35:50 p.m.)) to obtain 1- (6-chloro-2-hexanone-1-sulfonyl) -4- (4-fluorophenyl) piperazine (5.22 g, 60%) as white crystals: MS (ESI): 399 (MNa ⁺ ).

ii) A mixture of this compound (5.22 g, 13.9 mmol) and NaI (42 g) in acetone (90 mL) was refluxed for 5 hours. After cooling and partitioning between EtOAc and water, the organic layer was washed with 10% NaHSO ₃ and brine and dried over MgSO ₄ to give 1- (6-iodo-2-hexanone-1-sulfonyl) -4- (4-fluorophenyl) piperazine ( 6.13 g, quantitative) as yellowish crystals:

1 H NMR (CDCl 3): 6.98 (m, 2H), 6.88 (m, 2H), 4.00 (s, 2H), 3.46 (t, 4H, J = 4.8 Hz), 3.19 (t, 2H, J = 6.6 Hz), 3.16 (t, 4H, J = 4.8 Hz), 2.79 (t, 2H, J = 6.6 Hz), 1, 85 (m, 2H), 1.74 (m, 2H) iii) A mixture of this compound (1.27 g, 4.85 mmol) and cesium carbonate (8 g, 24.5 mmol) in CH ₂ Cl ₂ (90 ml) was stirred at room temperature for 4 hours. Water and 2N HCl were added slowly to pH about 7. The mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ . Chromatography on silica gel (eluent: EtOAc - petroleum ether (4: 6)) afforded 1- (cyclohexanone-2-sulfonyl) -4- (4-fluorophenyl) piperazine (880 mg, 53%).

¹ H NMR (CDCl 3): 6.97 (m, 2H), 6.88 (m, 2H), 3.83 (m, 1H), 3.48 (m, 4H), 3.12 (m,

4H), 2.81 (m, 1H), 2.54 (m, 1H), 2.46 (m, 1H), 2.2-2.0 (m, 3H), 1.75 (m, 2H) ); MS (ESI): 363 (MNa &lt; ⁺ & gt ^; ); IR: 1716.

Further elution (EtOAc-petroleum ether (6: 4)) gave 1 - [(tetrahydropyran-2-yl) methylidenesulfonyl] -4- (4-fluorophenyl) piperazine (630 mg, 38%):

• Λ ·

¹ H NMR (CDCl 3): 6.98 (m, 2Η), 6.87 (m, 2Η), 5.21 (s, 1H), 4.14 (t, 2H, J = 5.2Hz)

3.32 (m, 4H), 3.15 (m, 4H), 2.35 (t, 2H, J = 6.6 Hz), 1.82 (m, 4H); MS (ESI): 363 (M Na ⁺ ).

iv) To a solution of 1- (cyclohexanone-2-sulfonyl) -4- (4-fluorophenyl) piperazine (284 mg, 0.83 mmol) in methanol / THF (16 mL, 3: 1) at 0 ° C add sodium borohydride (3.7 mg, 1 mmol). The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour and 30 minutes. The solvents were evaporated. Saturated NH 4 Cl and water were added. The precipitate was filtered, washed with water and dried to give 1- (2-cyclohexanol-1-sulfonyl) -4- (4-fluorophenyl) piperazine (250 mg, 88%): MS (ESI): 343 (MH ⁺ ).

v) To a solution of 1- (2-cyclohexanol-1-sulfonyl) -4- (4-fluorophenyl) piperazine (310 mg, 0.9 mmol) in THF (15 mL) was added dropwise triphenylphosphine (1.18 g, 4.5 mmol) and DEAD (712 µL, 4.5 mmol). The mixture was stirred at room temperature for 18 hours. Evaporation of the solvents and purification on silica gel (eluent: EtOAc-petroleum ether, gradient from 2: 8 to 3: 7) gave 1- [1-cyclohexene-1-sulfonyl] -4- (4-fluorophenyl) piperazine (285 mg, 98 %):

MS (ESI): 325 (MH ^&lt; ^{+ &gt;} ).

vi) Similar to Example 1 iii) except that the reaction mixture was heated at 65 ° C for 30 hours, starting from (1- (1-cyclohexene-1-sulfonyl) -4- (4-fluorophenyl) piperazine (280). mg, 0.86 mmol) gave trans 1- [2- (N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) piperazine (270 mg, 88%):

¹ H NMR (CDCl 3): 6.98 (m, 2H), 6.88 (m, 2H), 3.54 (m, 4H), 3.34 (m, 2H), 3.14 (m,

4H), 2.30 (m, 1H), 2.17 (m, 1H), 2.05 (m, 1H), 1.9-1.2 (m, 5H); MS (ESI) 358 (MH ^&lt; ^{+ &gt;} ).

Example 11

Cis 1- [2- (N-Formyl-N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) -piperazine

♦ «• · ··· 4 ·«

4 Λ 4 4 4 4

4 4 ·· 4 • ♦ <«·

44444444 444499

Similar to Example 1, cis 1 - [- 2- (N-hydroxyamino) cyclohexane-1-sulfonyl] -4 (4-fluorophenyl) piperazine yielded the title compound (18 mg, 18%):

¹ H NMR (CDCl 3): 8.39 and 8.07 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.77 and 4.25 (m,

1H), 3.48 (m, 5H), 3.13 (m, 4H), 2.25 - 1.3 (m, 8H); MS (ESI): 408 (MNa &lt; ⁺ & gt ^; ).

The starting material is prepared as follows:

i) A mixture of 1- (cyclohexanone-2-sulfonyl) -4- (4-fluorophenyl) piperazine (50 mg, 0.14 mmol), hydroxylamine hydrochloride (51 mg, 0.73 mmol) and potassium acetate (72 mg, 0, 73 mmol) in methanol (5 ml) was heated at 70 ° C for 4 hours. The solvents were evaporated. After partitioning between EtOAc and water, the organic layer was washed with brine and dried over MgSO ₄ to give 1- [2- (N-hydroxyimino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) piperazine as a white solid (48 mg, 94%): MS (ESI): 356 (MH ^&lt; ^{+ &gt;} ).

ii) To this compound (210 mg, 0.6 mmol) in a mixture of THF and acetic acid (7 mL, 1: 1) was added sodium cyanoborohydride (276 mg, 4.4 mmol). The mixture was stirred at room temperature for 18 hours. Water was added and the pH was adjusted to 9. The mixture was extracted with EtOAc. The organic layer was washed with brine and dried over MgSO ₄ . Chromatography on silica gel (eluent: EtOAc - petroleum ether, gradient from 1: 1 to 8: 2) afforded cis 1- [2- (N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) piperazine (97 mg, 45%):

¹ H NMR (CDCl 3): 6.98 (m, 2H), 6.89 (m, 2H), 3.63 (m, 1H), 3.52 (m, 4H), 3.24 (dt,

1H, J _d = 10.6 Hz, J _t = 3.5 Hz), 3.15 (m, 4H), 2.2-1.2 (m, 8H); MS (ESI) 358 (MH ^&lt; ^{+ &gt;} ).

• 4

The following compounds were prepared using the procedure of Example 1:

·· 4 »

Example 12

* = M-H

R 2 = hydrogen

PIP = piperazinyl

RH = reverse hydroxamate

A = carboxylic acid

m.p. low. m.p. up. M + H (B) AND Y O Rl OF 117 117 492-494 4-F-Ph BEEP SO2 CH2 : 2- (5-Br-thiophene) RH 128 128 409 4-F-Ph PIP SO2 CH2 3-Pvridvl RH 125 125 414 4-F-Ph PIP SO2 CH2 2-thiophenvl RH 135 135 414 4-F-Ph PIP SO2 CH2 3-thiophenyl RH 409 4-F-Ph PIP SO2 CH2 2-Pyridvl RH 372 4-F-Ph PIP WHAT N (S) -PhCH 2 AND 426 4-F-Ph PIP SO2 CH2 4-F-Ph RH 358 * 4-F-Ph PIP SO2 CH2 Gem-di-Me RH 450 4-F-Ph 2-Me-PIP SO2 CH2 PhCH2CH2 RH 498 * 4-F-Ph PIP SO2 CH2 4-Cl-PhOC (Me) 2 RH 129 130 389 4-Ph Piperidinyl SO2 CH2 Ph RH 500-502 3.4-di-Cl-Ph PIP SO2 CH2 CH 2 CH (CH 3) Ph RH 466 4-F-Ph PIP SO2 CH2 PhOCH2CH2CH2 RH 110 110 514 * 4-Cl-Ph BEEP SO2 CH2 4-Cl-PhOC (Me) 2 RH 138 140 550-552 3,4-di-Cl-Ph PIP SO2 CH2 4-Cl-PhOC (Me) 2 RH

9 9. 9 9 9

9 9 9 • 9 9 9

9999999 99 9 9 99

999

m.p. n Í2 • m.p. .. 'vys. M + H (B) AND Y Q Rl of 69 70 389 Ph 4- Piperidinyl SO2 CH2 Ph RH 456 4-F-Ph PEP SO2 CH2 c-HexyICH2CH2CH2 RH 442 4-F-Ph PEP SO2 CH2 CyclohexylCH2CH2 RH 139 140 407 4-F-Ph Piperidinv SO2 CH2 Ph RH 172 172 516 4-F-Ph PEP SO2 CH2 4-Cl-PhSC (Me) 2 RH 517-519 5-C1-2- Pyridyl PEP SO2 CH2 4-Cl-PhOC (Me) 2 RH 516-518 3-Cl-Ph PEP SO2 CH2 4-Cl-PhOC (Me) 2 RH 505 4-F-Ph PIP SO2 CH2 N-PhCH2-4- Piperidinvl RH 104 104 548 4-F-Ph PEP SO2 CH2 4-Cl-PhSO 2 C (Me) 2 RH 135 135 451 4-F-Ph PEP SO2 CH2 3- Acid CH (CH3) CH2 RH 100 ALIGN! 100 ALIGN! 451 4-F-Ph PEP SO2 CH2 4- PyridylCH (CH 3) CH 2 RH 65 65 451 4-F-Ph PIP SO2 CH2 2-PyridylCH (CH 3) CH 2 RH 69 70 449 4-F-Ph Piperidinyl SO2 CH2 PhCH (CH 3) CH 2 RH 54 55 436 4-F-Ph PiperidinvI SO2 CH2 2-PyridylCH 2 CH 2 RH 66 67 449-501 4-F-Ph Piperidinvl SO2 CH2 4-Cl-PhOC (Me) 2 RH 480 3-Cl-Ph PIP SO2 CH2 PhCH2CH2CH2CH2 RH 50 55 480-482 4-Cl-Ph PIP SO2 CH2 PhCH2CH2CH2CH2 RH 450 4-F-Ph BEEP SO2 CH2 (S) -2- PhCH (CH 3) CH 2 RH 450 4-F-Ph PIP SO2 CH2 (R) -2- PhCH (CH 3) CH 2 RH 467 3-Cl-Ph PEP SO2 CH2 3- PyridylCH (CH 3) CH 2 RH 464 4-F-Ph BEEP SO2 CH2 CH 2 CH (CH 2 CH 3) Ph RH 160 163 428 4-F-Ph PIP SO2 CH2 CH2c-hexvl RH 468 5-C1-2- Pyridvl PIP SO2 CH2 3- PyridviCH (CH 3) CH 2 RH 456 4-F-Ph PIP SO2 CH2 2- ThiophenylCH (CH3) C ' H2 RH 45 ^: 46 478 4-F-Ph PIP SO2 CH2 PhCH2CH2CH2CH2 CH2 RH 67 68 450 4-F-Ph PEP SO2 CH2 2-CH 3 PhCH 2 CH 2. RH 75 76 450 4-F-Ph Piperidinyl SO2 CH2 3- Pyrid 1 CH (CH 3) CH 2 RH 69 70 510-512 4-Br-Ph PEP SO2 CH2 PhCH (CH 3) CH 2 RH 133 135 346 4-F-Ph PEP SO2 CH2 CH3 RH 465 4-F-Ph PIP SO2 CH2 CH2CH2CH (CH3) 3- Pyr RH 60 63 450 4-F-Ph PEP SO2 CH2 CH (CH 3) CH 2 Ph RH 478 4-F-Ph PIP SO2 CH2 CH 2 CH (Pri) Ph RH 452 4-F-Ph PEP SO2 CH2 CH2CH (CH3) Pyrazine yi RH

· -4 ♦ -4 -4 -4 -4 »-4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 4 4 4 4 4 «·« (», _{4 <} • 44

m.p. low. m.p. up. M + H (B) AND Y 0 Rl OF 420 2- Pyrimidinyl PIP S02 CH2 PhCH2CH2 RH 155 157 454 6-0-4- Pyrimidinyl PIP S02 CH2 PhCH2CH2 RH 452 4-Art PIP S02 CH2 PhCH2CH2 RH 452 3-Cl-Ph PIP S02 CH2 PhCH2CH2 RH 486 3,4-di-Cl-Ph PIP S02 CH2 PhCH2CH2 RH 453 • 5-0-2- Pyridyl PIP · · S02 CH2 PhCH2CH2 RH 453 3-0-2- Pyridyl PIP S02 CH2 PhCH2CH2 RH 466 4-Cl-Ph Homopipe razin S02 CH2 PhCH2CH2 RH 419 2-Pyridyl PIP S02 CH2 PhCH2CH2 RH 494 6-0-4- Pvrimidinvl PIP S02 CH2 3,4-di-Cl-Ph RH 450 6-MeO-4- Pyrimidine PIP S02 CH2 PhCH2CH2 RH 118 120 470 6-0-4- Pyrimidinyl PIP S02 CH2 PhCH2OCH2 RH 493 6-0-2- Pyridvl PIP S02 CH2 3,4-di-Cl-Ph RH 527 5-CF3-2- Pyridvl PIP S02 CH2 3,4-di-Cl-Ph RH 562 3-C1-5-CF3- 2-Pyridyl PIP SQ2 CH2 3,4-di-Cl-Ph RH 469 5-0-2- Pyridyl PIP S02 CH2 PhCH2OCH2 RH 493 5-0-2- Pyridvl PIP S02 CH2 3,4-di-Cl-Ph RH 494 6-0-4- Pvrimidinvl PIP S02 CH2 4-CF 3 -Ph RH 523 4-Me-2 quinolyl PIP S02 CH2 3,4-di-Cl-Ph RH 468 3-Cl-Ph PIP S02 CH2 PhCH2OCH2 RH 454 2-0-4- Pyrimidinvl PIP S02 CH2. PhCH2CH2 RH 459 2- Benzoxazole yi PIP S02 CH2 PhCH2CH2 RH 475 2- Benzthiazole pr.n. PIP S02 CH2 PhCH2CH2 RH 454 6-0-3- Pvridazinyl PIH- S02 CH2 PhCH2CH2 RH

φ · »*« φφφ

· 3 Φ

Φ Φ 'Φ φ φ Φφφφ

m.p. ηίζ. m.p. up. Μ + Η Β AND Y 9 Rl OF 460 2-Pyridyl PIP SO2 CH2 3,4-di-Cl-Ph RH 459 2-Pyridyl PIP SO2 CH2 4-CF 3 -Ph RH 435 2-Pyridyl PIP SO2 CH2 PhCH2OCH2 RH 420 2-Pyridvl PIP SO2 CH2 2-PyridylCH 2 CH 2 RH 509 7-CI-2- Benzthiazoles 1 PIP SO2 CH2 PhCH2CH2 RH 461 2-Pyrazines PIP - · SO2 CH2 3,4-di-Cl-Ph RH 460 2-Pyrazinyl PIP SO2 CH2 4-CF 3 -Ph RH 436 2-Pvrazinyl PIP SO2 CH2 PhCH2OCH2 RH 421 2-Pyrazinvl PIP SO2 CH2 3-PyridylCH 2 CH 2 RH 420 2-Pyrazinyl PIP SO2 CH2 PhČH2CH2 RH 470 6-C1-3- PyridazinvI PIP SO2 CH2 PhCH2OCH2 RH 136 138 420 4- Pyrimidine! BEEP SO2 CH2 PhCH2CH2 RH 421 2-Pyrazinvl PIP SO2 CH2 2-PyridylCH 2 CH 2 RH 417 5-0-2- Pyridvi. PIP SO2 CH2 c-Pentyl RH 484 5 <N-2- Pyridvl PIP SO2 CH2 3,4-di-Cl-Ph RH 494 6-C1-2- Benzoxazoles 1 PIP SO2 CH2 2-PyridylCH 2 CH 2 RH 4-F-Ph PIP SO2 CH2 2-Furvl RH 437 4-F-Ph PIP SO2 CH2 3-PvridyICH2CH2 RH 437 4-F-Ph PIP SO2 CH2 4-PyridyICH2CH2 RH 492 4-F-Ph PIP SO2 CH2 ' PhČH2CH2CH2C (Me) 2 RH, 470.472 4-F-Ph PIP SO2 CH2 4-Cl-PhCH 2 CH 2 RH 450 4-F-Ph PIP SO2 CH2 PhCH2CH2CH2 RH 426 4-F-Ph PIP SO2 CH2 2-FurylCH2CH2 RH 456 4-F-Ph PIP SO2 CH2 2-Thiophenyl · CH2CH2CH2 RH 468 4-F-Ph PIP SO2 CH2 4-F- PhCH2CH2CH2 RH 454 4-F-Ph PIP SO2 CH2 4-F-PhCH 2 CH 2 RH 437 4-F-Ph PIP SO2 CH2 2-PyridylCH 2 CH 2 RH 509,511 5-0-2- Pyridyl PIP SO2 CH2 4-Br-2-Thiophenyl RH 420 2-Pyridvl. PIP SO2 CH2 3-PyridylCH 2 CH 2 RH 453,455 3-Cl-Ph PIP SO2 CH2 3-PyridylCH 2 CH 2 RH 487,489 3,4-di-Cl-Ph PIP SO2 CH2 3-pyridylCH 2 CH 2 RH 464 4-F-Ph PIP ' SO2 CH2 PhCH2CH2CH2C H2 RH. 454,456 5-0-2- Pyridyl PIP SO2 CH2 3-PyridyICH2CH2 RH

»·

m.p. low. m.p. up. M + H (B) AND Y 0 RI OF 466,468 3-Cl-Ph PIP SO2 CH2 PhCH2CH2CH2 RH 467,469 5-CI-2- Pyridyl PIP SO2 CH2 PhCH2CH2CH2 RH 468,470 6-CI-4- Pyrimidinyl PIP SO2 CH2 PhCH2CH2CH2 RH 455,457 2-C1-4- Pyrimidinvl PIP SO2 CH2 3-PyridylCH 2 CH 2 RH 455,457 6-C1-4- Pyrimidine PIP SO2 CH2 3-PyridylCH 2 CH 2 RH 454,456 3-0-2- Pyridvl PIP SO2 CH2 3-PyridylCH 2 CH 2 RH 433 2-Pyridvl PIP SO2 CH2 PhCH2CH2CH2 RH 503 5-CF3-2- Pyridyl PIP SO2 CH2 PhCH2OCH2 RH 468,470 P2-C1-4- Pyrimidinvl PIP SO2 CH2 PhCH2CH2CH2 RH 453,455 3-Cl-Ph PIP SO2 CH2 2-pyridylCH 2 CH 2 RH 487.489 3,4-di-Cl-Ph PIP SO2 CH2 2-PyridylCH 2 CH 2 RH 135 137 455,457 6-0-4- Pyrimidinyl PIP SO2 CH2 2-PyridylCH 2 CH 2 RH 107 109 488 5-CF3-2- Pyridvl PIP SO2 CH2 2-PyridylCH 2 CH 2 RH 451 4-F-Ph PIP SO2 CH2. 2- PvridvICH2CH2CH2 RH 120 123 452 4-F-Ph PIP SO2 CH2 2- PyrimidinylCH 2 CH 2 CH2 RH 452 4-F-Ph PIP SO2 CH2 5- Pyrimidine 1CH 2 CH 2 CH 2 RH 119 121 468 5-0-2- Pyridvl PIP SO2 CH2 2- PvridvICH2CH2CH2 RH 469,471 5-0-2- Pyridyl PIP SO2 CH2 5- PyrimidinylCH 2 CH 2 CH2 RH 131 134 469,471 5-0-2- _; Pyridyl PIP SO2 CH2 2- PyrimidinylCH 2 CH 2 CH2 RH 426,428 5-0-2- Pvridvl PIP SO2 CH2 2-Pyridyl RH

MS calcd for C 17 H 24 FN 3 O 5 S (Μ + H) 402, found 402.

O

The aryl / heteroarylpiperazines and piperidines used as starting materials are commercially available or are described in the literature, for example 4- (4-fluorophenyl) piperidine, CAS number 37656-48-7 1- [1,1'-Biphenyl] -4-yl -piperazine (180698-19-5)

1- [1,1'-Biphenyl] -3-yl-piperazine (115761-61-0)

- (2-Naphthalenyl) piperazine (57536-91 -1)

1-Phenylpiperazinone (90917-86-5)

- (4-Chlorophenyl) hexahydro-1H-1,4-diazepine (41885-98-7)

4-Methyl-2- (1-piperazinyl) quinoline (50693-78-2)

- (4-Phenoxyphenyl) piperazine (62755-61-7)

1- (3-Chlorophenyl) piperazine

The 2-methyl-4- (4-fluorophenyl) -piperazine used as starting material is prepared as follows:

Sodium tert-butoxide (4.1 g) was added to a solution of tri-tolylphosphine (0.638 g) and palladium acetate (0.319 g) in toluene (250 mL) under argon, and the mixture was stirred for 20 minutes. 4-Fluorobromobenzene (5 g) and 2-methylpiperazine (2.85 g) were added and the mixture was heated at 110 ° C for 7 hours, then allowed to cool to ambient temperature and maintained at this temperature for 20 hours. The reaction mixture was filtered through Celite®, the filter cake was washed twice with dichloromethane (2 x 25 mL) and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel using dichloromethane first and then dichloromethane: methanol: ammonium hydroxide (100: 5: 1) as eluent to give 2-methyl-4- (4-fluorophenyl) piperazine, 2.5 g.

Using the same procedure and 2,6-dimethylpiperazine as starting material, 2,6-dimethyl-4- (4-fluorophenyl) -piperazine was obtained. 1- [1,1'-Biphenyl-4'-fluoro] -4-yl-hydrochloride piperazine

1- [1,1'-Biphenyl-4'-fluoro] -4-yl-tert-butoxycarbonylpiperazine (0.712 g) was stirred in a mixture of dichloromethane (10 mL) trifluoroacetic acid (1.0 mL) at ambient temperature for 18 hours, Evaporate in vacuo to a gray solid and use without further purification. The 1- [1,1'-biphenyl-4'-fluoro] -4-yl-tert-butoxycarbonylpiperazine used as starting material is prepared as follows:

Sodium tert-butoxide (1.35 g) was added to a solution of S - (-) - 2,2'-bis (diphenylphosphino) -1-1 binaphthyl (0.046 g) and bis (dibenzylideneacetone) palladium (0.023 g) in toluene (25 mL) under argon, then 4-bromo-4'-fluorobiphenyl (2.51 g) and tert-butoxycarbonylpiperazine (2.2 g) were added and the mixture was heated at 80 ° C for 5 hours. The reaction mixture was filtered, the filtrate was evaporated in vacuo to a yellow solid, which was triturated and then filtered from diethyl ether (20 mL) to give 1- (1,1'-biphenyl-4'-fluoro] -4-yl ether. butoxycarbonylpiperazine, (2.67 g), mp = 165-166 ° C.

NMR (d 6 -DMSO) 1.42 (s, 9H), 3.15 (m, 4H), 3.48 (m, 4H), 7.02 (d, 2H), 7.22 (m, 2H) 7.51 (d, 2H); 7.63 (m, 2H); m / z 357 (M + 1).

Example 13

Acetic anhydride (0.23 mL) was added directly to formic acid (0.9 mL). The solution was stirred at room temperature for 30 minutes and then a solution of N - [- {[4- (6-chloropyrimidin-4-yl) tetrahydropirazin-1-yl] sulfonyl} -1- (3,4-dichlorophenyl) ethyl] hydroxylamine was added ( 0.227 g) in tetrahydrofuran (5 mL). The solution was stirred at room temperature for 18 hours. The solution was evaporated (water bath at 30 ° C) and the resulting gum was purified by chromatography using a 10g silica gel isolate eluting with CH ₂ Cl ₂ and 3% methanol / CH ₂ Cl ₂ to give N- [2 - {[4- (6-chloropyrimidin-4-yl) piperazino] sulfonyl} -1- (3,4-dichlorophenyl) ethyl-N-hydroxyformamide (0.178 g), 98-101 ° C.

NMR (d 6 -DMSO 100 ° C): 3.31 (m, 4H), 3.70 (dd, 1H), 3.75 (m, 4H), 3.95 (dd, 1H), 5.61 ( vbs, 1H), 6.89 (s, 1H), 7.43 (dd, 1H), 7.60 (d, 1H), 7.70 (d, 1H), 8.29 (s, 1H), 8.36 (s, 1 H); m / z 494 (M + 1).

Cl

* 9 9 · ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦

·. ^ ^ ^ ^ * ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^

Acetic anhydride (0.63 mL) was added directly to formic acid (2.48 mL). The solution was stirred at room temperature for 30 minutes and then a solution of N- [2 - {[4- (5-chloropyridin-2-yl) piperazino] sulfonyl} -1- (3,4-dichlorophenyl) ethyl] hydroxylamine (0.61) was added. g) in tetrahydrofuran (10 mL). The solution was stirred at room temperature for 3 hours and then diluted with ethyl acetate, adjusted to pH neutral with saturated aqueous sodium carbonate. The ethyl acetate layer was separated, dried (N 2 SO 4) and evaporated to dryness. The residue is purified by chromatography using a 10 g silica gel isolate eluting with 10% ethyl acetate / hexane and 80% ethyl acetate / hexane, and then

Evaporate to dryness. The resulting white solid was filtered from diethyl ether to give N- [2 {[4- (5-chloropyridin-2-yl) piperazino] sulfonyl} -1- (3,4-dichlorophenyl) ethyl] -N-hydroxyformamide (0.431 gj, Mp 211-212 ° C.

NMR (d 6 -DMSO 100 ° C): 3.30 (m, 4H), 3.80 (m, 4H), 3.85 (dd, 1H), 3.95 (dd, 1H),

5.58 (vbs, 1H), 6.85 (d, 1H), 7.43 (m, 1H), 7.58 (m, 2H), 7.85 (d, 1H), 8.10 (d) (1H),

8.13 (s, 1 H); m / z 493 (M + 1).

O

Acetic anhydride (0.48 mL) was added directly to formic acid (1.9 mL). The solution was stirred at room temperature for 30 minutes and then a solution of N- (2- (benzyloxy) -1 - {[(4-pyridin-2-ylpiperazino) sulfonyl] methyl} ethyl) hydroxylamine (0.42 g) in tetrahydrofuran (5) was added. ml). The solution was stirred at room temperature for 3 hours and then diluted with ethyl acetate, adjusted to pH neutral with saturated aqueous sodium carbonate. The ethyl acetate layer was separated, dried (Na ₂ SO 4) and evaporated to dryness. The residue was purified by chromatography using 10 g of silica gel isolate eluting with CH 2 Cl 2 and 25% methanol / CH ₂ Cl ₂ to give N- (2- (benzyloxy) -1 - {[(4-pyridin-2-ylpiperazino) sulfonyl] methylethyl) - N-hydroxyformamide (0.233 g), 70-75 ° C.

NMR (d 6 -DMSO 100 ° C): 3.25 (dd, 1H), 3.31 (m, 4H), 3.48 (dd, 1H), 3.65 (m, 4H), 3.66 ( dd, 1H), 3.70 (dd, 1H), 4.55 (vbs, 1H), 4.55 (s, 2H), 6.70 (m, 1H), 6.85 (d, 1H) 7.28 (m, H), 7.32 (m, 4H), 7.58 (m, 1H), 8.17 (m, 2H), 7.45 (bs, 1H); m / z 435 (M + 1).

4 • 4 4 4 4 4

- 4,444 4> 94 4

4 4 4 4 4 5

Acetic anhydride (0.48 mL) was added directly to formic acid (1.9 mL). The solution was stirred at room temperature for 30 minutes and then a solution of N- (3-pyridin-2-yl-1 - {[(4-pyridin-2-ylpiperazine) sulfonyl] methylpropyl) hydroxylamine (0.152 g) in tetrahydrofuran (5 mL) was added. . The solution was stirred at room temperature for 3 hours and then diluted with ethyl acetate, adjusted to pH neutral with saturated aqueous sodium carbonate. The ethyl acetate layer was separated, dried (Na 2 SO ₄ ) and evaporated to dryness! The residue was purified by chromatography using 10 g of silica gel isolation, eluting with CH 2 Cl 2 and 25% methanol / CFbCl 2 to give N-hydroxy-N- (3-pyridin-2-yl-1 - {[(4-pyridin-2-ylpiperazine) sulfonyl] methyl} propyl) formamide (0.039 g), 80-84 ° C.

NMR (d 6 -DMSO 100 ° C): 2.10 (m, 2H), 2.80 (m, 2H), 3.25 (dd, 1H), 3.30 (m, 4H),

3.50 (dd, 1 H), 3.60 (m, 4 H), 4.42 (vbs, 1 H), 6.70 (m, 1 H), 6.85 (d, 1 H), 7.19 (m, 1 H) 7.22 (d, 1H), 7.54 (m, 1H), 7.65 (m, 1H), 8.10 (vbs, 1H), 8.15 (m, 1H), 8.45 (m, 1 H),

9.50 (vbs, 1 H); m / z 420 (M + 1).

Example 14

N- {1 - [({4 - [(5-Chloropyridin-2-yl) oxy] piperidino} sulfonyl) methyl] -3-pyridin-3-ylpropyl} -N-hydroxyformamide

To a solution of 1-N- [2- (hydroxyamino) -2- (3-pyridinyl) butanesulfonyl] -4-O- (5-chloro-2-pyridinyl) piperidine (2.1 g, 4.18 mmol) in THF (36 ml) was added a preformed mixture of formic acid (9.0 ml) and acetic anhydride (2.25 ml). The mixture was stirred at room temperature for 18 hours. Before extraction of the solution with EtOAc (2x), the reaction is neutralized by * 9 9 9 9 99 9 9 99 999

9,999,999

9999 9999 99 9999 9 «999 using a saturated aqueous NaHCO ₃ solution. The combined organics were dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was dried in MeOH at room temperature for 20 hours to remove the bis-formyl. The residue was crystallized from EtOH to give a white solid (0.898 g), mp = 130-140 ° C.

¹ H NMR (DMSO-100 ° C): 9.50 (broad s, 1H), 8.43 (d, 1H), 8.39 (dd, 1H), 8.15 (d,

1H), 8.13 (broad s, 1H), 7.74 (dd, 1H), 7.60 (m, 1H), 7.27 (m, 1H), 6.83 (d, 1H), 5 12 (m, 1H), 4.32 (broad s, 1H), 3.42 (m, 3H), 3.16 (m, 3H), 2.68-2.54 (m, 2H), 2 0.06 1.93 (m, 4H), 1.76 (m, 2H); MS (ES +): 469.2 (MH ⁺ ), 491.1 (MNa ⁺ ); EA: calculated for C ₂₀ H ₂₅ ClN ₄ O ₅ S: C 51.22, H 5.37, Cl 7.56, N 11.95, S, 6.84, found C 50.92, H 5.30 Cl 7.55, N 11.90, S 6.75.

The starting material is prepared as follows:

i) NaH (2.88 g, 66 mmol, 55% dispersion in mineral oil) was stirred in dry DME (200 mL), under argon. A mixture of 2,5-dichloropyridine (8.87 g, 60 mmol) and 4-hydroxypiperidine (6.67 g, 66 mmol) dissolved in dry DME (200 mL) was added dropwise to the NaH suspension over 30 minutes. After the addition was complete, the reaction mixture was heated under argon at 82 ° C for 48 hours. The reaction is slowly stopped before most of the THF is removed. The aqueous layers were extracted with DCM (3x). The organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo to give 2- (4-piperidinyloxy) -5-chloropyridine as a yellow oil (12.7 g, quantitative).

¹ H NMR (DMSO): 8.17 (d, 1H), 7.76 (dd, 1H), 6.81 (d, 1H), 4.96 (m, 1H), 2.93 (m,

2H), 2.53 (m, 2H), 1.91 (m, 2H), 1.46 (m, 2H); MS (ES +): 213.3 (MH ⁺ ), 225.3 (MNa ⁺ ).

ii) To a solution of 2- (4-piperidinyloxy) -5-chloropyridine (12.9 g, 0.06 mol) and Et ₃ N (25.4 mL,

0.182 mol) in dry dichloromethane (400 ml) at 0 ° C under argon was added dropwise methasulfonyl chloride (5.3 ml, 0.067 mol) in dry dichloromethane (100 ml). The mixture was stirred at room temperature for 20 hours. The mixture was diluted with dichloromethane (250 mL), then washed with water (3x) and then brine. The organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was triturated and washed with diethyl ether to give 2 (N-methanesulfonyl-4-piperidinyloxy) -5-chloropyridine (15.1 g) as a pale yellow solid.

¹ H NMR (DMSO): 8.20 (d, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.32 (m ,

2H), 3.11 (m, 2H), 2.90 (s, 3H), 2.02 (m, 2H), 1.75 (m, 2H); MS (ES +): 291.2 (MH ^&lt; ^{+ &gt;} ),

313.2 (MNa ⁺ ),

9 • 0 • 0 0 0 ♦ (iii) 2- (N-Methanesulfonyl-4-piperidinyloxy) -5-chloropyridine (2.0 g, 6.89 mmol) was placed in anhydrous THF (100 mL) under argon and before Add Li (TMSA) (13.8 mL of a 1.0 M solution in THF, 13.8 mmol) to cool to -78 ° C. The mixture was stirred at 78 ° C for 20 minutes and a solution of diethyl chlorophosphate (1.05 mL, 7.23 mmol) was added. The mixture was stirred at -78 ° C for 1 hour and then 3-pyridinylpropanal (1.12 g, 8.27 mmol) was added and the mixture was stirred at -78 ° C for an additional hour. The mixture was allowed to warm to room temperature and then washed with saturated ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over Na ₂ SO ₄ . Purification of the residue on silica gel (eluent: gradient, DCM -2% MeOH / DCM) afforded 2 {N- [E / Z-4- (3-pyridyl) -but-1-phenyl] sulfonyl} -4-piperidinyloxy) - 5-chloropyridine as a yellow oil (2.09 g).

¹ H NMR (DMSO): 8.45 (m, 1H), 8.37 (m, 1H), 8.19 (m, 1H), 7.82 (m, 1H), 7.64 (m,

1H), 7.30 (m, 1H), 6.85 (m, 1H), 6.88-6.27 (m, 2H, E / Z isomers), 5.00 (m, 1H), 3, 15 (m, 2H), 2.83 (m, 5H), 2.61 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H); MS (ES +): 408.1 (MH ⁺ ), 430.2 (MNa ⁺ ).

iv) To a solution of 2- {N- [E / Z-4- (3-pyridyl) -but-1-enyl] sulfonyl} -4-piperidinyloxy) -5-chloropyridine (2.09 g, 5.1 mmol) in THF (20 mL) was added hydroxylamine (3.4 mL, 50% aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in EtOAc and washed with water (4x). The organic layer was dried over Na ₂ SO ₄ and evaporated in vacuo to give 2- (4-piperidinyloxy) -5-chloropyridine 1 -N- [2- (hydroxyamino) -2- (3-pyridinyl) butanesulfonyl] -4-O- (5-chloro-2-pyridinyl) piperidine (730mg).

¹ H NMR (DMSO): 8.43 (d, 1H), 8.37 (dd, 1H), 8.18 (d, 1H), 7.78 (dd, 1H), 7.61 (m, 1H) ), 7.36 (s, 1H), 7.29 (m, 1H), 7.85 (d, 1H), 5.70 (s, 1H), 5.08 (m, 1H), 3.35 (m, 3H), 3.16-3.00 (broad m, 4H), 2.80-2.60 (broad, 2H), 1.98 (m, 2H), 1.84 (m, 2H) 1.69 (m, 2H); MS (ES +): 441.2 (MH ⁺ ), 463.2 (MNa ⁺ ).

Using a procedure analogous to that described in Example X, aryl-4-opiperidine is reacted with a suitable aldehyde to give the compounds listed below.

• 9 9 9 99

9 9 9 9 9 9

999 9 9 99 9 9 · · 9 9 «« 9 9

R1 R2 R3 Mol.hm. MS (ES ⁺ ) Ph H 4-chlorophenyl 438 439 PhCH ₂ CH ₂ H 3-chlorophenyl 466.99 468 PhCH ₂ CH ₂ H 3,4-dichlorophenyl 501.43 501 PhCH ₂ CH ₂ H 4-chlorophenyl 466.99 468. PhCH ₂ CH ₂ H 5-chloro-2-pyridyl 467.98 468 PhCH ₂ CH ₂ H 6-chloro-4-pyrimidinyl 468.96 469 Methyl Methyl 5-chloro-2-pyridyl 391.88 392 PhCH ₂ CH ₂ H 2-pyridyl 433.53 434 3-pyridyl H 5-chloro-2-pyridyl 440.91 441 3-pyridylCH ₂ CH ₂ H 5-chloro-2-pyridyl 468.96 469 2-pyridylCH ₂ CH ₂ H 5-chloro-2-pyridyl 468.96 469 PhCH ₂ OCH ₂ H 5-chloro-2-pyridyl 483.97 484

The following aryl-4-O-piperidines have been previously described:

4- (3-Chlorophenoxy) - (9CI) -piperidine, CAS (97840-40-9)

4- (4-Chlorophenoxy) - (9CI) -piperidine, CAS (97839-99-1)

2- (4-Piperidinyloxy) - (9CI) -pyridine, CAS (127806-46-6)

4- (3,4-Dichlorophenoxy) - (9Cl) -piperidine was prepared in the following alternative route:

1) To a stirred solution of 4-hydroxypiperidine (3.5 g, 0.35 mol) in dry methanol (50 mL) at 0 ° C was added dropwise di-tert. butyldicarbonate (9.2 mL, 0.042 mol) in dry methanol (50 mL). The mixture was stirred at room temperature for 20 hours. The methanol was removed and the resulting solution was taken up in Et ₂ O, then washed with 1M citric acid (3x) and water (3x). The combined aqueous extracts were extracted with Et ₂ O, which was dried over Na ₂ SO ₄ and evaporated in vacuo. Purification of the residue on silica gel (eluent: gradient, DCM - 30% MeOH / DCM) gave N-BOC-4-hydroxypiperidine as a yellow oil (6.4 g).

• 4 · 44 · 4 44

44 4 '4 44 4 4 4 4 rc 4444444

OO »······ · 4

4 4

4444 4444 44 ¹ 444 44 4 ¹ H NMR (DMSO): 4.05 (m, 2H), 3.70-3.52 (wide m, 3H), 2.92 (m, 2H), 1.66 ( m,

2H), 1.40 (s, 9H), 1.33-1.18 (broad m, 2H); MS (ES +): 201.3 (MH ⁺ ), 219.4 (MNH +).

2) To a stirred solution of N-BOC-4-hydroxypiperidine (2.0 g, 0.01 mol), triphenylphosphine (3.68 g, 0.014 mol) and 3,4-dichlorophenol (1.96 g, 0.012 mol) in dry toluene (75 mL) [with molecular sieves, at 0 ° C under argon] was added dropwise diethyl azodicarboxylate (2.52 mL, 0.016 mol). The mixture was stirred at 0 ° C for 1.5 hours. The solution was filtered and the toluene was removed before vigorous stirring in isohexane (100 mL) and the resulting suspension was filtered. The filtrate was washed with 2M aqueous NaOH (8x), dried over Na ₂ SO 4 and evaporated in vacuo. Purification of the residue on silica gel (eluent: 20% EtOAc / isohexane) gave 4- (3,4-dichlorophenoxy) - (9Cl) N-Boc-Piperidine as a yellow solid (1.96 g). ¹ H NMR (DMSO): 7.52 (d, 1H), 7.31 (d, 1H), 7.01 (dd, 1H), 4.62 (m, 1H), 3.65 (m, 2H) 1.11 (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H), 1.40 (s, 9H); MS (ES +): 346.3 (MH ⁺ ), 368.4 (MNa ⁺ ).

3) 50% aqueous trifluoroacetic acid (18 mL) was added to a stirred solution of 4- (3,4-dichlorophenoxy) - (9Cl) N-Boc-piperidine (1.96 g, 5.66 mmol). After 3.5 hours toluene was added and evaporated in vacuo, this was repeated twice. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO ₃ (3x), dried over Na ₂ SO 4 and evaporated in vacuo to give 4- (3,4-dichlorophenoxy) - (9Cl) piperidine as a white solid (1.3 g). ). ¹ H NMR (DMSO): 7.54 (d, 1H), 7.35 (d, 1H), 7.04 (dd, 1H), 4.70 (m, 1H), 3.31 (m, 2H) 1.09 (m, 2H), 2.08 (m, 2H), 1.80 (m, 2H); MS (ES +): 226.3 (MH ^&lt; ^{+ &gt;} ).

4- (3,4-dichlorophenoxy) - (9Cl) piperidine is then transferred to steps ii-iv as described above.

Example 15

1-Mesyl-4- (5-methoxycarbonyl-2-pyridyl) piperazine

1-Mesylpiperazine hydrochloride (4.24 g) was added to a solution of methyl 6-chloronicotinate (1.7 g) and N, N-diisopropylethylamine (6.3 ml) in dimethylacetamide (20 ml) and the mixture was heated at 120 ° C 2 hours. The mixture was allowed to cool to ambient temperature and poured into a mixture of crushed ice and water (50 mL) to precipitate a brownish solid. Fixed

99 99 99

9 9 9 9 9 9 9 was collected by filtration and dried at 80 ° C for 18 hours in a vacuum oven to give 1-mesyl-4- (5-methoxycarbonyl-2-pyridyl) piperazine (2.05 g), m.p. Mp = 205-207 ° C.

NMR (d 6 -DMSO): 2.90 (s, 3H), 3.20 (m, 4H), 3.78 (m, 3H), 3.80 (s, 3H), 6.92 (d, 1H) ), 8.00 (dd, 1H), 8.67 (d, 1H); m / z 300 (M + 1).

Using an analogous procedure, 1-mesylpiperazine hydrochloride, CAS (161357-89-7), is reacted with the appropriate chloropyridine to give the following compounds.

R-N \

NO

II

-S — CH. II o

R Mol. hm. m / z (M + 1). 6-Cl-2-pyridyl 275 276 5-Cl-2-pyridy I 275 276 5-CF ₃ -2-pyridyl 309 310 3-Cl-5-CF ₃ -2-pyridyl 343 344 5-CN-2-pyridyl 266 267 3-Cl-2-pyridyl 275 276 5-Br-2-pyridy I 320/322

1- (6-Chloro-pyrimidin-4-yl) -4-mesyl-piperazine

A mixture of 4,6-dichloropyrimidine (39.4 g), 1-mesylpiperazine hydrochloride (55.7 g) and triethylamine (116 mL) in ethanol (500 mL) was stirred at reflux for 4 hours. The mixture was then stirred at room temperature for 12 hours. The solid that was collected was collected by filtration, the slurry washed with ethanol (2 x 80 mL, 160 mL) followed by diethyl ether (150 mL) and dried to give 1- (6-chloropyrimidin-4-yl) -4-mesylpiperazine as cream solid (71.9 g), m.p. M.p. = 200-202 ° C.

NMR (d 6 -DMSO): 2.88 (s, 3H), 3.18 (m, 4H), 3.80 (m, 4H), 7.04 (s, 1H), 8.38 (m,

1H); m / z 277.3 (M + 1).

44 444

4 4 4 4

4 4 4 4 4

4444 44 444

Using an analogous procedure, 1-mesyipiperazine hydrochloride, CAS (161357-89-7) is reacted with the appropriate chlorpyrimidine or chloropyridazine to give the following compounds.

ΛΛ

R-N NV_7 o

II

-S — CH, II ² o

R Mol.hm. m / z (M + 1) 2-Cl-pyrimidin-4-yl 276 277 6-Cl-pyridazin-3-yl 276 277 pyrimidin-4-yl 242 243 6-methoxy-pyrimidin-4-yl 273.1

Example 16

Acetic anhydride (19 mL) was added directly to formic acid (76 mL). The solution was stirred at room temperature for 30 minutes. A solution of 1- (6-chloropyrimidin-4-yl) -4 - {[(2-hydroxyamino) -4-phenylbutyl] sulfonyl} piperazine (17.2 g) was added portionwise to the above solution at 27 ° C over 25 minutes. in tetrahydrofuran (85 mL). The solution was stirred at room temperature for 1 hour. The solution was evaporated (water bath at 30 ° C) and the resulting gum was dissolved in ethyl acetate (500 mL). This solution was treated with a saturated aqueous solution of sodium bicarbonate (200 mL) and the mixture (pH 8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated

9

9 9 9 9 9

Wash with saturated brine (100 mL), dry (Na 2 SO 4) and evaporate to dryness. The resulting foam was dissolved in ethanol, the solid was collected, and the mixture was stirred for 2 days. The solid was collected by filtration, the slurry washed with diethyl ether (100 mL) and dried to give N [1 - ({[4- (6-chloropyrimidin-4-yl) piperazino] sulfonyl} methyl) -3-phenylpropyl] -N-hydroxyformamide as a colorless solid (12.8 g), m.p. Mp 155-157 ° C.

Found C, 50.29, H, 5.29, Cl, 7.82, N, 15.31, and S, 6.82%. C19H24ClN5O4S requires C, 50.27, H, 5.33, Cl, 7.81, N, 15.43, and S, 7.06%.

NMR (d 6 -DMSO, 100 ° C): 1.93 (m, 1H), 2.03 (m, 1H), 2.57 (m, 1H), 2.65 (m, 1H),

3.20 (dd, 1H), 3.26 (t, 4H), 3.48 (dd, 1H), 3.74 (t, 4H), 4.3 (broad, 1H), 6.90 ( s, 1H), 7.19 (m, 3H), 7.27 (m, 2H), 8.1 (broad, 1H), 8.38 (s, 1H), 9.5 (s, 1H); m / z 454.2 (M + 1). · · '

Acytic anhydride (31.5 mL) was added directly to formic acid (126 mL). The solution was stirred at room temperature for 30 minutes.

A solution of 1 - {[3-benzyloxy-2- (hydroxyamino) propyl] sulfonyl} -4- (6-chloropyrimidin-4-yl) piperazine (25.9 g) in tetrahydrofuran (150 mL) and formic acid (25 mL) was added. portionwise to the above solution at 25 ° C over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water bath at 30 ° C) and the resulting gum was dissolved in ethyl acetate (500 mL). This solution was treated with a saturated aqueous solution of sodium bicarbonate (2x250 mL) and the mixture (pH 8) was stirred at room temperature for 16 hours. The ethyl acetate was evaporated, washed with saturated brine (100 mL), dried (Na ₂ SO 4) and evaporated to dryness. The resulting foam was dissolved in methanol (70 mL) and the solution was stirred for 16 hours. Evaporate the solution to dryness (water bath at 30 ° C). The resulting foam was stirred in ethanol (250 mL), the solid was collected and stirred for 18 hours. The solid was collected by filtration, the slurry washed with diethyl ether (100 mL), and dried to give N- [2- (benzyloxy) -1 - ({[4- (660 ·· ·· ·· ·· 44)

4 4 9 4 * 4 4 4 4 4 4. ., 4 4 4 • 444 4 4 44 4 • 4 4 4 4 4

4444 4444 44 4444 44 4 Chloropyrimidin-4-yl) piperazino] sulfonyl} methyl) ethyl N-hydroxyformamide (25.5 g), m.p.

M.p. = 118-120 ° C.

Found C, 48.35, H, 5.09, Cl, 7.26, N, 14.73, and S, 6.78%. C19H24ClN5O5S requires C, 48.56, H, 5.15, Cl, 7.54, N, 14.90, and S, 6.82%.

NMR (d 6 -DMSO, 100 ° C): 3.23 (dd, 1H), 3.30 (t, 4H), 3.46 (dd, 1H), 3.57 (dd, 1H),

3.67 (dd, 1H), 3.72 (t, 4H), 4.50 (s, 2H), 4.50 (m, 1H), 7.35 (m, 5H), 8.15 (broad) (1H),

8.38 (s, 1H); 9.48 (broad, 1H); m / z 470.2 (M + 1).

Acetic anhydride (0.8 mL) was added directly to formic acid (3.2 mL). The solution was stirred at room temperature for 30 minutes. A solution of 1- (5-chloro-2-pyridyl) -4 - {[2- (hydroxyamino) -4-phenylbutyl] sulfonyl} piperazine (0.72 g) in tetrahydrofuran (5 mL) was added to the above solution at room temperature. The solution was stirred at room temperature for 2 days. The solution was evaporated (water bath at 40 ° C).

The residue was dissolved in 5% methanol in dichloromethane. Silica gel (5g Merck 9385) was added to the solution, the mixture was stirred for 21 hours, and evaporated to dryness. The material (pre-adsorbed onto silica gel) was purified by silica gel chromatography (Bond Elut 10 g), using 0-3% methanol in dichloromethane as eluent, to give N- [1 - ({[4- (5-chloro-2-pyridyl)] piperazino] sulfonyl} methyl) -3-phenylpropyl] -N-hydroxyformamide as an orange foam (0.17 g).

NMR (d 6 -DMSO 100 ° C): 1.92 (m, 1H), 2.04 (m, 1H), 2.55 (m, 1H), 2.64 (m, 1H),

3.20 (dd, 1H), 3.27 (m, 4H), 3.47 (dd, 1H), 3.58 (m, 4H), 4.35 (in broad, 1H), 6.88 ( dd, 1H), 7.17 (m, 3H), 7.27 (m, 2H), 7.57 (dd, 1H), 8.10 (s, 1H), 8.10 (broad, 1H), 9.5 (s, 1 H); m / z = 453.3 (M + 1).

Example 17 • and • ♦

• »« 9 • 98 9

9 9

9 9

9 9 ♦ 9 9999

J

Η

To formic acid (31.5 mL) was added acetic anhydride (7.9 mL) at 0 ° C. After 20 minutes, the mixture was added to hydroxylamine (6.10 g) dissolved in THF (80 mL) and formic acid (40 mL), and the resulting solution was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in DCM (500 mL), washed with saturated sodium bicarbonate solution (2 x 500 mL), dried and evaporated to dryness. To the residue dissolved in DCM (10 mL) was added diethyl ether (100 mL) to give the product as a white solid (5.60 g), which was collected by filtration, mp = 168-170 ° C. NMR _DMSOd6 d 10.2 (br s, 1H) *; 9.8 (broad s, 1H) *; 8.7 (broad s, 1H) *; 8.6 (broads, 1H); 8.5 (d, 1H); 8.3 (m, 1H); 8.1 (d, IH); 7.9 - 7.8 (m, 1H); 7.6 (dd,

1H); 7.4 (dd, IH); 6.9 (d, IH); 5.8 (m, 1 H) +; 5.5 (m, 1H); 4.1-3.6 (m, 2H); 3.6 (m, 4H); 3.2 (m, 4H) Analysis calculated for C 17 H 20 ClN 5 O 4 S: C, 48 H, 4.7; Cl, 8.3; N, 16.5; S, 7.5 Found: C, 47.9; H, 4.7; Cl, 8.4; S, 7.5 MS calcd for C17H20ClN5O4S (M + H) 426, found 426.

* Rotameric signals

Step A

• · · · · · · · · · · · · · · · · · · · · · · · J i · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The oxime (31.05 g) [Tetrahedron Letters 1994, 35, 1011] was dissolved in DCM (500 mL) and 3-pyridinecarboxaldehyde (12.09 g) was added followed by anhydrous magnesium sulfate (13.6 g).

After stirring at room temperature for 2 days, magnesium sulfate (13.6 g) was added and stirring was continued for a further 3 days. The mixture was then filtered, the solvent was evaporated and the residue was triturated with diethyl ether to give the product (36.34 g) as a white solid. m.p. =

Mp 174-175 ° C. NMR CDCl 3 d 9.0 (s, 1H); 8.9 (d, IH); 8.7 (d, 1 H); 7.7 (s, 1 H); 7.4 (dd, IH); 5.6 (s, 1H); 5.3 (d, 1H); 4.9 (dd, 1H); 4.6 (dd, IH); 4.6 (dd, IH); 4.4 (ddd, IH);

4.2 (dd, IH); 3.7 (dd, IH); 1.5 (s. 3H); 1.4 (s, 3 H); 1.4 (s, 3 H); 1.3 (s, 3H).

Step B

0) (2)

Methylsulfonamide (14.30 g) was dissolved in THF (500 mL) and cooled to -10 ° C and lithium hexamethyidisylazide (78 mL, 1.0 M in THF) was added. After 30 minutes, the solution was cooled to -78 ° C and nitrone (18.00 g) dissolved in THF (350 mL) was added while keeping the temperature below -65 ° C. The resulting solution was stirred at -78 ° C for 3 hours and quenched by the addition of brine (500 mL) and the aqueous layer was extracted with ethyl acetate (3x500 mL). The combined organic layers were dried and evaporated to give a yellow solid, which was triturated with ethyl acetate: isohexane (4: 1) and then purified by flash chromatography eluting with dichloromethane / methanol (97: 3) to give 1 (16, 40 g) as a white solid. m.p. Melting point = 209 DEG -211 DEG C. (decomposition). NMR CDCl 3 d 8.6 (s, 1H) 8.4 (d, 1H); 8.1 (d, IH); 7.8 (d, 1H); 7.5 (broad s, 1H); 7.4 (dd, IH); 7.3 (dd, IH); 6.6 (d, 1 H); 4.9 (d, 1 H); 4.8 (s, 1 H); 4.7 - 4.6 (m, 2H); 4.2 - 4.1 (m, 3H); 3.8 (dd, IH); 3.6 (dd, IH); 3.5-3.4 (m, 5H); 3.3-3.2 (m, 4H); 1.4 (s. 3H); 1.3 (s. 3H);

1.3 (s. 3H); 1.3 (s, 3H).

StepC

(2)

9 9 9 '99 9 9 99 9

(3)

To a solution of hydroxylamine 2 (14.90 g) in ethanol (300 mL) was added water (220 mL), followed by O-benzylhydroxylamine hydrochloride (13.91 g) and sodium bicarbonate (6.95 g). Heating gave a solution which was stirred overnight at 80 ° C. The ethanol was removed under reduced pressure and the residue was partitioned between water (500 mL) and ethyl acetate (500 mL). The aqueous layer was washed with ethyl acetate (2 x 500 mL) and the combined organic layers were dried and evaporated to give a residue which was triturated with dichloromethane (100 mL) to give 3 (6.10 g) as a white solid. The mother liquor was purified by flash column chromatography using ethyl acetate followed by dichloromethane / methanol (96: 4) as eluent to give an additional 3 (0.85 g). m.p. M.p. = 170-173 ° C. NMR DMSO d6 8.6 (s, 1H), 8.5 (d, 1H), 8.1 (d, 1H), 7.8 (d, 1H); 7.6 (dd, 1 H) 7.6 (s, 1 H);

7.3 (dd, IH); 6.9 (d, IH); 6.1 (broad s, 1H); 4.3 (broad s, 1H); 3.7-3.4 (m, 6H); 3.2 3.1 (m, 4H).

Example 18

The following compounds were obtained using the methods described in Example 7.

m.p. low. m.p. up. M + H (B) AND Y Q Rl OF 403 4-PhCH2 Piperidinvl SO2 CH2 Ph RH 357 4-HCOO Piperidinvl SO2 CH2 Ph RH PhNCO Piperidinvl SO2 CH2 Ph RH 128 131 412 t-butyl NCO Piperidinvl SO2 CH2 Ph RH

9

9

9

9

9999 9999

9 9

9999

m.p. low. m.p. up. M + H (B) AND Y Q ri OF 122 124 446 PhCH2NCO Piperidinvl SO2 CH2 Ph RH 129 131 423 c-PentvNCO Piperidinyl SO2 CH2 Ph RH 390 Ph PIP SO2 CH2 Ph RH 420 4-MeO-Ph PIP SO2 CH2 Ph RH 435 4-NO2-Ph PIP SO2 CH2 Ph RH 404 4-CH 3 -Ph PIP SO2 CH2 Ph RH 424 2-Cl-Ph PIP SO2 CH2 Ph RH 420 2-OMe-Ph PIP SO2 CH2 Ph RH 424 3-Cl-Ph PIP SO2 CH2 Ph RH 458 3-CF 3 -Ph PIP SO2 CH2 Ph IRH 424 4-Cl-Ph PIP SO2 CH2 Ph RH 420 3-OMe-Ph PIP SO2 CH2 Ph RH 458 3,4-di-Cl-Ph PIP SO2 CH2 Ph RH 438 4-Cl-PhCH 2 PIP SO2 CH2 Ph RH 452 4-Cl-PhCO PIP SO2 CH2 Ph RH 472 4-F-PhSO 2 PIP SO2 CH2 Ph RH 436 5-NO2-2-Pyridvl PIP SO2 CH2 Ph (RH 432 PhCH2CO PIP SO2 CH2 Ph RH 504 2-NaphtylSO2 BEEP SO2 CH2 Ph RH 467 4-Ph-Ph PIP SO2 CH2 Ph RH 392 2-PvTazinvl PIP SO2 CH2 Ph RH 391 2-Pvdydyl PIP SO2 CH2 Ph RH 396 Cyclohexyl PIP SO2 CH2 Ph RH 466 3-Ph-Ph PIP SO2 CH2 Ph RH 458 4-CF 3 -Ph PIP SO2 CH2 Ph RH 467 4-Cl-PhNCO PIP SO2 CH2 Ph RH 440 2-Naphthyl PIP SO2 CH2 Ph RH 356 n-Propvl PIP SO2 CH2 Ph RH 448 4-Piperone-CH2- PIP SO2 CH2 Ph | RH 460 4-t-Butyl-PhCH2- PIP SO2 CH2 Ph fŘH ~ 55 60 439 4-Cl-PhO Piperidinyl SO2 CH2 Ph RH 391 4-Pyridyl PIP SO2 CH2 Ph RH 484 4'-F-4-Ph-Ph PIP SO2 CH2 Ph | RH 482 4-Ph-O-Ph PIP SO2 CH2 Ph RH 404 4-Ph ’ 3-OxoPIP SO2 CH2 Ph | RH 449 5-CO2Me-Pvridvl PIP SO2 CH2 Ph (RH 501 2-Pyridyl NCCO Piperidinvl SO2 CH2 3,4-di-Cl-Ph RH 535 5-Cl-2-pyridyl-NCO Piperidinvl SO2 CH2 3,4-di-Cl-Ph RH 534 4-Cl-PhNCO Piperidinvl SO2 CH2 3,4-di-Cl-Ph RH 500 PhNCO Piperidinyl SO2 | CH2 3,4-di-Cl-Ph 1 RH

= M-H

R 2 = hydrogen

PIP = piperazinyl RH = reverse hydroxamate • f 0 * 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

The starting material is prepared as follows:

Addition of hydroxylamine to 1-trans-β-styrenesulfonylpiperidine-4- (N-phenylcarboxamide) and subsequent formulations of the material were performed as described in Example 7. Dimethylformamide (2 drops) was added to a suspension of 1-trans-β-styrenesulfonylpiperidine-4-carboxylic acid. (0.75 g) and oxalyl chloride (0.23 mL) in dichloromethane (10 mL) and stirred for 2 hours. The reaction mixture was evaporated to dryness, redissolved in dichloromethane (10 mL) and evaporated again to dryness. The obtained residue was dissolved in dichloromethane (4 ml) and a mixture of aniline (0.23 ml) and triethylamine (0.35 ml) was added dropwise. The mixture was stirred for 20 hours and washed with dilute 2M hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water and dried. Removal of the solvent gave 1-trans-β-styrenesulfonylpiperidine-4- (N-phenylcarboxamide), 0.89 g.

Using the method described above, the following 1-trans-β-styrenesulfonylpiperidine-4-carboxamides were prepared.

Clx CT ϋ ο 438 437 (Μ-1) Cl _x cU θγ 0 Ό 439 440 (Μ + 1) Cl π Ν η Cl II 473 472 Μ-1 Ο ί-λ Cl- Ύ ί 7 1 Cl ' ο η. 472 471

A solution of ethyl piperidine-4-carboxylate (3.99 g) in a mixture of THF (30 ml) and methanol (6 ml) was treated with aqueous sodium hydroxide solution (20 ml of 2M NaOH) and the mixture was stirred for 3 hours. acidify to pH 6 with dilute 2M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2 x 25 mL), the ethyl acetate extracts were washed with water, dried and evaporated to dryness to give t-trans-β-styrenesulfonylpiperidine-4-carboxylic acid, 2.64 g.

A solution of ethylpiperidine-4-carboxylate (3.0 mL) and triethylamine (2.7 mL) in dichloromethane (10 mL) was added dropwise to a cooled (ice bath) solution of trans-β-styrene sulfonyl chloride (3.95 g) in dichloromethane (10 mL). ml). The reaction mixture was allowed to warm to room temperature and stirring was continued for 20 hours. The reaction mixture was evaporated to dryness, the residue was diluted with water and extracted with ethyl acetate (2 x 25 mL). The combined ethyl acetate extracts were washed with brine and dried (MgSO ₄ ) to give ethyl (1-transB-styrenesulfonyl) -piperidine-4-carboxylate, 5.76 g, M + H = 324.

An alternative procedure may also be used to prepare 1-trans-β-3,4-dichlorostyrenesulfonyl-piperidine-4-carboxylic acid:

To a solution of 1-trans-β-3,4-dichlorostyrenesulfonyl chloride (2.7 g) and hexahydropyridine-3-carboxylic acid (1.41 g) in acetonitrile (15 mL) was added 2M sodium hydroxide (11 mL) and the solution was stirred at ambient temperature for 1 hour. The reaction mixture was acidified to pH 3 with 2M hydrochloric acid and extracted with ethyl acetate (2 x 15 mL), the ethyl acetate extracts were dried (Na ₂ SO ₄ ), filtered and evaporated to give 1-trans-β-3,4-dichlorostyrenesulfonyl-piperidine-4. carboxylate (2.67 g), m / z 364 (M + 1).

Example 19

The following compounds were prepared

PIP = piperazinyl

Z = reverse hydroxamate group

R2 = inh

♦ 9

M + H Β AND Y Q Rl OF 4-F-Ph PIP SO2 CH2 i-Propyl RH 360 4-F-Ph PIP SO2 CH2 Ethyl RH 386 4-F-Ph PIP SO2 CH2 spiro-c-pentyl RH 450.8 4-F-Ph PIP SO2 CH2 4-NMe 2 -Ph RH 442 4-F-Ph PIP SO2 CH2 4-Cl-Ph RH 388 4-F-Ph PIP SO2 CH2 tert-Butyl RH 442 4-F-Ph PIP SO2 CH2 2-Cl-Ph RH 484 4-F-Ph PIP SO2 CH2 4-Ph-Ph RH 468 4-F-Ph PIP SO2 CH2 2,4-di-OMe-Ph RH 452.9 4-F-Ph PIP SO2 CH2 3-NO2-Ph RH 475.9 4-F-Ph PIP SO2 CH2 4-CF 3 -Ph RH 475.9 4-F-Ph PIP SO2 CH2 2-CF 3 -Ph RH 374 4-F-Ph PIP SO2 CH2 Propyl RH 458 4-F-Ph PIP SO2 CH2 1-Naphthyl RH 387.9 4-F-Ph PIP SO2 CH2 3-Furyl RH 450.9 4-F-Ph PIP SO2 CH2 CH2CH2SCH3 RH 388 4-F-Ph PIP SO2 CH2 iso-Butyl RH 491.8 4-F-Ph PIP SO2 CH2 4-Br-2-thiophenyl RH 485.8. 4-F-Ph PIP SO2 CH2 3-Br-Ph RH 458 4-F-Ph PIP SO2 CH2 1-Naphthyl RH 496 4-F-Ph PIP SO2 CH2 2-Fluorenyl RH 466 4-F-Ph PIP SO2 CH2 4-CO 2 Me-Ph RH 414 4-F-Ph PIP SO2 CH2 Cyclohexyl RH 402 4-F-Ph PEP SO2 CH2 2-neopentyl RH 533.9 4-F-Ph PIP ^- SO2 CH2 3- (4-Cl-PhO) -Ph RH 452 4-F-Ph PIP SO2 CH2 PhCH2OCH2 RH 507.9 4-F-Ph PIP SO2 CH2 2- (5-4'-Cl-Ph) Furyl. RH 450 4-F-Ph PIP SO2 CH2 CH 2 CH (CH 3) Ph RH 451.9 4-F-Ph ' PIP SO2 CH2 4-Piperone RH 4-F-Ph PIP SO2 CH2 3- (OCH 2 Ph) Ph RH 4-F-Ph PIP SO2 CH2 4- (OCH 2 Ph) Ph RH 4-F-Ph PIP SO2 CH2 3-CF 3 -Ph RH 497.9 4-F-Ph PIP SO2 CH2 C6F5 RH

4 4

4

4444

Example 20

We provide NMR data for the following compounds:

o (DMSO) 9.6 (1H, s), 8.5 (1H, m), 8.4 and 7.9 (1H, s), 7.7 (1H, m), 7.2 (2H, m, m), 7.1 (2H, m), 7.0 (2H, m), 4.7 and 4.2 (1H, broad m), 3.4 (1H, m), 3.3 (5H, m), 3.1 (4H, m), 2.7

(DMSO) 9.8 and 9.5 (1H, broad s), 8.3 and 8.0 (1H, s), 8.1 (1H, d), 7.6 (1H, dd), 7, 2 (5H, m), 6.9 (1H, d), 4.7 and 4.1 (1H, broad m), 3.6 (4H, m), 3.4 (1H, m), 3, 3 (1H, m), 3.2 (4H, m), 2.6 (2H, m), 1.6 (4H, m).

(DMSO) 9.6 (1.H, broad s), 8.4 (1H, m), 8.3 and 7.9 (1H, s), 8.1 (1H, d), 7.6 ( 2H, m), 7.2 (1H, d), 7.1 (1H, m), 6.9 (1H, d), 4.7 and 4.1 (1H, broad m), 3.6 ( 4H, m), 3.4 (1 H, m),

3.3 (1H, m), 3.2 (4H, m), 2.7 (2H, m), 2.0 (2H, m).

Cl

// Λ

N

O \ II N — S

O

^V 19 9 11-919 (DMSO) 9.7 (1H, broad m), 8.5 (1H, s), 8.4 (1H, m) ), 8.1 and 7.9 (1H, s), 7.6 (1H, m),

7.2 (2H, m), 7.0 (1H, m), 4.6 and 4.1 (1H, broad m), 3.7 (4H, m), 3.4 (1H, m), 3.3 (5H,

m), 2.7 (2H, m), 2.0 (2H, m).

(DMSO) 9.9 (1H, s), 8.4 (2H, m), 8.2 (1H, d), 7.65 (2H, m), 7.3 (1H, m), 7, 0 (1H, m), 4.0-4.2 (2H, m), 3.6 (4H, wide m), 3.4-3.2 (6H, wide m), 2.0 (2H, wide m).

(DMSO) 10.0 (1H, s), 8.5 (2H, d), 8.2 (1H, broad s), 7.8 (1H, broad), 7.6 (1H, m), 7 4 (1H, m), 6.9 (1H, m), 3.6 (4H, broad m), 3.2 (6H, broad m).

10.0 (1H, s), 8.5 (2H, m), 8.4 and 8.0 (1H, s), 7.9 (1H, m), 7.7 (1H, m), 7.3 (1H, m), 7.1 (1H, m), 3.7 (4H, broad m), 3.45 (2H, m), 3.3 (4H, broad m), 2.75 (3H, m), 2.1 (2 H, m).

(DMSO) 10.0 (1H, broad s), 8.6 (2H, m), 8.2 (1H, d), 7.2 (1H, m), 6.9 (4H, m), 4 , 9 a

4.2 (1H, broad), 3.4 (6H, m), 3.0 (6H, m), 1.9 (4H, m).

(DMSO) 9.8 (1H, broad), 8.7 (2H, m), 8.3 and 7.9 (1H, s), 8.1 (2H, s), 7.6 (1H, m) 7.3 (1H, m), 6.9 (1H, m), 4.1 (1H, broad m), 3.6 (4H, m), 3.2 (6H, m), 2, Δ (2H, m), 1.8 (4H, m).

(CDCl ₃ ) 8.5 (1H, m), 8.1 (2H, s), 8.5 and 8.0 (1H, s), 7.8 (1H, m), 7.4 (1H, m, m), 7.3 (2H, m), 6.6 (1H, m), 4.8 and 4.2 (1H, broad m), 3.6 (4H, m), 3.2 (6H, m, m), 2.8, (2H, rh), 1.8 (4H, m).

(DMSO) 8.5 (1H, d), 8.4 and 8.2 (1H, s), 7.7 (1H, m), 7.2 (6H, m), 4.8 and 4.2 (1H, broad m), 3.6 (4H, m), 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m).

Example 21 • to ·. · To to to to to to to to to to to to to to to to to to to to to to to to to to to to to to ·············

The following compounds were prepared

R1

PIP = piperazinyl

Z = reverse hydroxamate group, <

R 2 = hydrogen

m.p. low. m.p. up. M + H (B) AND Y Q Rl of 467 4-Cl-Ph PIP SO2 CH2 3-PyridylCH (CH 3) CH 2 RH 55 60 456 4-F-Ph PIP SO2 CH2 c hexvC (Me) CH2 RH 125 128 440 4-F-Ph PIP SO2 CH2 PhCH2SCH2 RH 130 131 460 4-F-Ph Piperidinyl SO2 CH2 2-IndanCH2 RH 64 65 448 4-F-Ph Piperidinyl SO2 CH2 (R) -2-PhCH (CH 3) CH 2 RH 63 64 448 4-F-Ph Piperidinyl SO2 CH2 (S) -2-PhCH (CH 3) CH 2 RH 132 137 484 4-F-Ph PIP SO2 CH2 2-Cl-PhCH (CH 3) CH 2 RH 484 4-F-Ph PIP SO2 CH2 4-Cl-PhCH (CH 3) CH 2 RH 484 4-F-Ph PEP SO2 CH2 3-Cl-PhCH (CH 3) CH 2 RH 469 5-Cl-2-pyridyl PIP SO2 CH2 2-Pyiazine (CH 2 CH 3) CH 2 RH 516 4-F-Ph PIP SO2 CH2 4-Cl-Ph-S-CH (CH 3) CH 2 RH 466 3-Cl-Ph PEP SO2 CH2 (S) -2-PhCH (CH3) .CH2 RH 467 5-C 1-2 -Pyridyl PIP SO2 CH2 (S) -2-PhCH (CH 3) CH 2 RH 50 51 450 4-F-Ph Piperidinyl SO2 CH2 2-Pyrazine CH (CH 3) CH 2 RH 60 61 454 4-F-Ph Piperidinyl. SO2 CH2 2-ThiophenylCH (CH3) CH2 ^v RH 82 83 449 4-F-Ph Piperidinyl SO2 CH2 4-PyridyICH (CH 3) CH 2 RH 65 66, 407 4-F-Ph PEP SO2 CH-Ph RH 91 100 ALIGN! 484 4-F-Ph PIP SO2 CH2 PhCH2SOCH2 RH 142 145. 484 4-F-Ph PIP SO2 CH2 PhCH2SOCH2 RH 455 5-Cl-2-pyridyl PIP SO2 CH2 2-PyrimidinylCH 2 CH 2 RH 460 5-Cyano-2-pyridyl PIP SO2 CH2 2-PyrimidinylCH 2 CH 2 CH 2 RH 444 5-cyano-2-pyridyl PIP SO2 CH2 PhCH2CH2 RH 464 5-cyano-2-pyridyl PIP SO2 CH2 2-ThiophenylCH 2 CH 2 CH 2 RH 445 5-Cyano-2-pyridyl BEEP SO2 CH2 3-PyridylCH 2 CH 2 RH 459 5-cyano-2H-pyridyl PEP SO2 CH2 2-PyridylCHHH2CH2CH2 RH 460 5-cyano-2-pyridyl PIP SO2 CH2 PhČH2OCH2 RH 445 5-Cyano-2-pyridyl BEEP SO2 CH2 2-PyridylCH 2 CH 2 RH 417 5-cyano-2-pyridyl PIP SO2 CH2 3-Pyridyl RH 498 / 500 5-Br-2-pyridyl PIP SO2 CH2 2-PyridylCH 2 CH 2 RH 498 / 500 5-Br-2-pyridyl PIP SO2 CH2 3-PyridylCH 2 CH 2 RH 497 / 499 5-Br-2-pyridyl PIP SO2 CH2 PhCH2CH2 RH 513 / 515 5-Br-2-pyridyl PEP, SO2 CH2 PhCH2OCH2 RH 470 / 472 5-Br-2-pyridyl PIP SO2 CH2 3-Pyridyl RH

• 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9. »

9 »

ťt ntz. AT up. M + H (B) AND Y Q Rl OF 517 / 519 5-Br-2-pyridyl BEEP SO2 CH2 2-ThiophenylCH 2 CH 2 CH 2 RH 513 / 515 5-Br-2-Pyridyl PIP SO2 CH2 2-Pyrimidinyl CH 2 CH 2 CH 2 RH 512 / 514 5-Br-2-pyridyl BEEP SO2 CH2 2-PyridylCH 2 CH 2 CH 2 RH 436 2-Pyrazinyl PIP SO2 CH2 2-Pyrimidine-1CH 2 CH 2 CH 2 RH 439 2-Pyridyl PIP SO2 CH2 2-ThiophenylCH 2 CH 2 CH 2 RH RH RH 440 2-Pyrazinyl PIP SO2 CH2 2-ThiophenylCH 2 CH 2 CH 2 488.1 5-C 1-2-Pyridyl 4-0-Piperid- inyl SO2 CH2 2-ThiophenylCH 2 CH 2 CH 2 103 104 484.1 5-0-2-Pyridyl 4-0-Piperid- inyl SO2 CH2 2-ThiophenylCH 2 CH 2 CH 2 RH 483.3 5-C 1-2-Pyridyl 4-0-Piperid- inyl SO2 CH2 2-Pyridyl CH 2 CH 2 CH 2. RH 508.1 5-Cl-2-pyridyl 4-0-Piperid- inyl SO2 CH2 3,4-di-Cl-Ph RH 504 / 506 5-Cl-2-pyridyl PIP SO2 CH2 3-Pyridyl-5-bromo RH 123 125 466.3 6-MeO-4-Pyrimidinyl PIP SO2 CH2 PhCH2OCH2 RH 99 101 451.3 6-MeO-4-pyrimidinyl PIP SO2 CH2 2-PyridyICH2CH2 RH 95 99 451.4 6-MeO-4-Pyrimidinyl PIP SO2 CH2 3-PyridvICH2CH2 RH 156 158 470.3 6-MeO-4-Pyrimidinyl PIP SO2 CH2 2-ThiophenylCH 2 CH 2 CH 2 RH 122 124 466.3 6-MeO-4-pyrimidinyl PIP SO2 CH2 2-Pyrimidinyl-CH2CH2CH2 RH 465.3 6-MeO-4-Pyrimidinyl PIP SO2 CH2 2-PyridylCH 2 CH 2 CH 2 RH

All compounds were prepared as in Example 1, except those wherein Ring A is 4O-piperidinyl; it is prepared as in Example 14.

Example 22

We provide NMR data for the following compounds listed in Example 21:

M452587 - new compound

9 «··

9999 99 · 9 9

9 9 9 9 * 9 • 9 999 «· φ

99999999 '. <9 · 9 · 9 99 99

NMR (DMSO) 9.9, 9.6 (1H, broad s); 8.6 (2 H, m); 8.3 and 7.9 (1H, s); 8.1 (1 H, dd); 7.3 (1 H, m); 6.9 (1 H, d); 4.7 and 4.2 (1H, broad m); 3.6 (4 H, m); 3.4-3.2 (6H, m); 2.8 (2H, m); 2.1 (2H, m).

(DMSO) 9.9 and 9.6 (1H, broad s), 8.7 (2H, d), 8.3 and 8.0 (1H, s), 8.2 (1H, d), 7, Δ (1H, d), 7.3 (1H, m), 6.9 (1H, d), 5.1 (1H, broad m), 4.7 and 4.1 (1H, broad m), 3 4 (3H, m), 3.1 (3H, m), 2.9 (3H, m), 2.0 (2H, m), 1.7 (6H, m).

Example 23

Preparation:

To formic acid (4.8 mL) was added acetic anhydride (1.2 mL) at 0 ° C. After 20 minutes, this mixture was added to hydroxylamine 2 (0.68 g) dissolved in THF (11 mL) and formic acid (5 mL) and the resulting solution was stirred overnight at room temperature.

9 · · 9 99 β · * 9 9 .9 ♦ ♦ 9 9 9 09 <<90 · 999 0 0 · 0 · 9 0 0 • 00 · 0000 00 0000 «

The solvent was removed under reduced pressure and the residue was dissolved in DCM (100 mL), washed with saturated sodium bicarbonate solution (2 x 100 mL), dried (MgSO ₄ ) and evaporated to dryness. The residue was purified by flash column chromatography using a 96: 4 mixture of dichloromethane and methanol as eluent to give the product (0.41 g) as a gum. NMR CDCl 3 δ 9.7 (broad s, 1H) *; 9.2 (broad s, 1H) *; 8.4 (s, 1H) &lt; + &gt;; 8.0 (s,

1H) *; 7.5-7.2 (m, 5H); 7.0 - 6.8 (m, 5H); 5.7 (m, 1 H) +; 5.4 (m, 1 H) +; 3.9-3.4 (m,.

5H); 3.3 (m, 1 H) +; 3.2 to 2.9 (m, 4H), 2.8 (m, 1H); MS for C ₂₀ H ₂ 2 FN ₃ O 3 (M + H) calcd 372, found 372nd

* Rotameric signals

Step A

O

To 1- (4-fluorophenyl) piperazine (1.00 g) dissolved in DCM (10 mL) was added cinnamoyl chloride (0.85 g) in DCM (10 mL) followed by triethylamine (1.55 mL). The solution was stirred at room temperature overnight. It was then partitioned between DCM (150 mL) and water (100 mL), then the organic layer was washed with water (100 mL), dried (MgSO ₄ ) and evaporated to dryness to give a cream solid which was triturated with diethyl ether (10 mL). mi) to give 1 (1.20 g) as a white solid. NMR CDCl 3 δ 7.7 (d, 1H); 7.5 (m. 2H); 7.4 (m, 3 H); 7.0-6.9 (m, 5H); 4.0-3.8 (m, 4H); 3.1 (m, 4 H). MS for C ₉ H ₁₉ FN ₂ O (M + H) calcd 311, found 311th

Step B

(7

4 »·

Φ '

Idu amide (2.00 g) dissolved in THF (40 mL) was added hydroxylamine (1 mL, 50% aqueous solution). The solution was stirred at room temperature for 48 hours. The solvent was then evaporated under reduced pressure, toluene (50 ml) was added, which was then evaporated under reduced pressure. The residue was triturated with dichloromethane / methanol (98: 2) and the mother liquor was purified by flash column chromatography using dichloromethane / methanol (98: 2) as eluent to give 2 (0.70 g) as a gum. NMR CDCl 3 δ 7.5 7.2 (m, 5H); 7.0 - 6.9 (m, 2H); 6.9 - 6.8 (m, 2H); 4.5 (dd, IH); 3.8-3.7 (m, 2H); 3.6 3.5 (m, 2H); 3.1-2.8 (m, 5H); 2.7 (dd, 1 H). MS calcd for C19H22FN3O2 (M + H) 344, found 344.

0

0 0 0 0 0 0 0 0 0 0 '0 0 0 0 0 0 0 0 0 0 0 0 0 0

000 0000 00 0000

Claims (14)

PATENT CLAIMS Compound of Formula I R 1 R 2 wherein B is a monocyclic or bicyclic alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl ring containing up to 12 ring atoms and containing one or more heteroatoms independently selected from the group consisting of N, O and S; alternatively B may be biphenyl; ring B may optionally be attached to ring A by a C 1 -C 4 alkyl chain or a C 1 -C 4 alkoxy chain linking the 2-position of ring B to the carbon atom at the alpha position to X 2; each R 3 is independently selected from the group consisting of hydrogen, halogen, NO 2, COOR wherein R is hydrogen or alkyl of 1 to 6 carbon atoms, CN, CF 3, -S-alkyl of 1 to 6 carbon atoms, -SO-a (C 1 -C 6) -alkyl, -SO 2 -C 1 -C 6 -alkyl, (C 1 -C 6) -alkoxy, and (C 1 -C 10) aryloxy, n is 1, 2 or 3; P is - (CH ₂ ) n - wherein n is 0, 1, 2; or P is an alkene or alkyne chain of up to 6 carbon atoms; when X 2 is C, P can be -Het-, - (CH [R 6]) _n -Het-, -Het- (CH [R 6]) _n or -Het- (CH [R 6]) _n -Het, where Het is selected from -CO-, -S-, -SO-, -SO 2 -, -NR 6 - or -O where n is 1 or 2 or P is selected from -CO-N (R 6) -, -N (R 6) -CO-, -SO 2 -N (R 6) - and N (R 6) -SO 2 -, and R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 10 aralkyl, and C 9 heteroalkyl carbon; ring A is a 5-7 membered aliphatic ring and can optionally be mono- or disubstituted with an optionally substituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy group, each substituent independently selected from the group consisting of halogen, alkyl C 1 -C 6 or oxo; X 1 and X 2 are independently selected from N and C, wherein the ring substituent on ring A is oxo and is preferably adjacent to a ring nitrogen atom; Y is -SO 2 -α-CO-; 49 99 44 4.94 4 4 4 4 4 4 4 49 4 9 4 4 · · · · Z is -CONHOH, Y is -CO- and Q is selected from -C (R 6) (R 7) -, -C (R 6) (R 7) -CH 2 -, N (R 6) - and -N (R 6) -CH 2 - wherein R 6 is as defined above and only in relation to Q as defined herein, R 6 may also represent aryl of up to 10 carbon atoms, heteroaryl of up to 9 carbon atoms, and R 7 is H, an alkyl group of 1 to 6 atoms carbon or together with R 6 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, wherein the heterocyclic ring contains at least one heteroatom selected from N, O or S; Z is -CONHOH, Y is -SO 2 - and Q is selected from -C (R 6) (R 7) -, and -C (R 6) (R 7) -CH 2 -; or Z is -N (OH) CHO and Q is selected from -CH (R 6) -, -CH (R 6) -CH 2 - and -N (R 6) CH 2 -; R 1 is H, (C 1 -C 6) alkyl, (C 5 -C 7) cycloalkyl, (C 10 -C 10) aryl, (C 10 -C 10) heteroaryl, (C 12 -C aralkyl), or (C 1 -C 5) heteroaralkyl All of which are optionally substituted with up to three groups independently selected from NO 2, CF 3, halogen, C 1 -C 4 alkyl, C 1 -C 4 carboxyalkyl, cycloalkyl up to 6 carbon atoms, -OR4, -SR4, C1-C4 alkyl substituted with -OR4, -SR4 (and its oxidized analogs), -NR4, -NY-R4, or C1-C4 alkyl -Y-NR 4, provided that when R 1 is -OH, -OR 4, -SR 4 or -NR 4 or -NY-R 4, then Z is not -N (OH) CHO or R 1 is 2,3,4,5, 6-pentafluorophenyl; R 4 is hydrogen, (C 1 -C 6) alkyl, (C 1 -C 10) aryl, (C 1 -C 10) heteroaryl, (C 1 -C 9) aralkyl, each optionally substituted with a substituent selected from the group consisting of: which includes halogen, NO 2, CN, CF 3, C 1 -C 6 alkyl, S-C 1 -C 6 alkyl, -SO-C 1 -C 6 alkyl, -SO 2 -C 1 -C 6 alkyl carbon atoms or alkoxy of 1 to 6 carbon atoms; R 2 is H, an alkyl group having 1 to 6 carbon atoms, or together with R 1 forms a carbocyclic or heterocyclic spiro 5, 6 or 7 membered ring, the heterocyclic ring containing at least one heteroatom selected from N, O and S; group Q may also be bonded to R 1 or R 2 to form a 5, 6 or 7 membered alkyl or heteroalkyl ring containing one or more O, S and N; ·· ·· r · * *... And wherein any of the above alkyl groups may be straight chain or branched, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable precursor. A compound according to claim 1, wherein ring A is a 5-6 membered aliphatic ring and may optionally be mono- or disubstituted with optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, each substituent independently selected from among the following: halogen, C1-C6alkyl or oxo; R 3 is hydrogen, halogen, NO 2, CF 3, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, n is 1 or 2; ring B is a monocyclic or bicyclic aryl group, an aralkyl or heteroaryl group of up to 10 carbon atoms; P is - (CH 2) _n - wherein n is 0 or 1 or -O- or -CO-NR 6) -; one or both of X 2 and X 1 are N or X 1 is N or X 2 is C; R 1 is hydrogen, C 1 -C 6 alkyl, C 5 -C 7 cycloalkyl, C 1 -C 12 aralkyl, C 1 -C 11 heteroarylalkyl, C 1 -C 10 aryl or heteroaryl, all the groups are optionally substituted with up to three halogen atoms or CF 3; R 2 is hydrogen or together with R 1 represents a carbocyclic or heterocyclic spiro 5- or 6-membered ring, such as a tetrahydropyran ring; R 4 is aryl of up to 10 carbon atoms, optionally substituted with halogen, NO 2, CN, CF 3, alkyl of 1 to 6 carbon atoms, -S-alkyl of 1 to 6 carbon atoms, -SO-alkyl of 1 to 6 carbon atoms carbon atoms, -SO 2 -alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable prodrug thereof. A compound as claimed in claim 1 wherein R 3 is hydrogen, halogen, NO 2, CF 3, methyl, ethyl, methoxy or ethoxy; • 44 44 ·· 4 4 4 4 4 4 4444 44 4444 44 444 ring Β is a monocyclic aryl, aralkyl or heteroaryl group containing up to 7 carbon atoms; P is a direct bond; X2 and X1 are both N; Y is -SO 2 -; Q is -CH 2 R 1 is phenyl, 4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl, cyclopentyl, benzyloxymethyl, 3,4-dichlorophenyl, 2-pyridyl, 3-pyridyl, 2-pyridylethyl, 3-pyridylethyl, thiophenylpropyl, bromothiophenyl, 2 -pyrimidinylethyl, 2-pyrimidinylpropyl, pyridylpropyl or together with R 2 is spirocyclohexane or spirp-4-pyran; R 2 is hydrogen; Z is -N (OH) CHO; or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable prodrug thereof. A compound according to any one of claims 1 to 3, wherein ring A is piperazinyl and ring B is selected from an optionally substituted phenyl, pyridyl or pyrimidine ring; or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable prodrug thereof. A compound of formula I as claimed in claim 1, wherein ring B substituted with R 3 (n) is phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl, or is 5-chloro-2-pyridyl; P is a direct bond; ring A is piperidinyl or piperazinyl; Y is SO 2, Q is -CH 2 -, and Z is N (OH) CHO; or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable prodrug thereof. A compound of formula I according to claim 1, wherein ring B is phenyl, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl or 5-chloro-2-pyridyl; P is a direct bond; ring A is piperidinyl or piperazinyl, Y is SO 2, Q is CH 2 -, Z is -N (OH) CHO and R 1 is phenyl, phenylbutylene, phenylisopropylene, 2-pyridyl-ethylene, 2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene or 4-chlorophenyloxydimethylmethylene; or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable prodrug thereof. 99 99 99 99 99 9900 9900 99 99 9 9 9 9 9 9,999,999 9999 9999 99 99 · 9 .9 9,999 A compound of formula I, according to claim 1, wherein ring B is phenyl monosubstituted with chlorine or fluorine, P is a direct bond; ring A is piperidinyl, Y is SO 2, Q is -CH 2 -, Z is -CONHOH and R 1 is hydrogen, isobutyl or spirotetrahydropyranyl, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable precursor thereof. * A pharmaceutical composition comprising a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof, and a pharmaceutically acceptable carrier. A compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof for use in a method of therapeutic treatment of the human or animal body. 10. A method of treating a disease state mediated by a metaloproteinase, comprising administering to a warm-blooded animal a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof. 11. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof, comprising: a) reacting a compound of formula II, or a pharmaceutically acceptable salt thereof, or in. an in vivo hydrolysable ester with a compound of formula III Yk Q III R1 R2 'φ · Φ φφφφ · φ φ · · · · ·, · φφφ φφφφ Where Χ _} 'denotes X or a precursor derived from X (whether by modification or displacement) or an activated form X suitable for reaction with Υμ. Y 1 is Y, a Y-derived precursor or an activated form Y suitable for reaction with X 2; Z ¹ represents a protected form Z; a Z-derived precursor (whether by modification or displacement of Z ¹ ) or an activated form, Z; and when Q is - (CH 2) (R 6) - then reacting a compound of formula IX with a suitable compound of formula R 1 -CO-R 2 to give an alkene of formula X, which is then converted to a compound of formula XI wherein Z * is hydroxylamine precursor of group Z and then conversion of group Z * as shown below: XI · »nebo nebo nebo nebo nebo nebo nebo b) reacting a compound of formula IV or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof with a compound of formula V IV wherein B ¹ represents a suitable ring function or substituent for reaction with P ¹ ; Z ¹ is as defined above; and P ¹ represents a suitable activated form of the linker P for reaction with B ^1, or when X2 is N then P1 may be present on ring A rather than ring B, or as desired, the linker P may be formed by a suitable reaction of the precursor groups P and P 'found on the rings B ^! or A, or vice versa. Use of a compound of formula I or a pharmaceutically acceptable salt or in vivo hydrolysable prodrug thereof for the preparation of a medicament for use in a disease state mediated by one or more metalloproteinase enzymes. Use of a compound of formula I or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable prodrug thereof for the preparation of a medicament for use in the treatment of arthritis. Use of a compound of formula I or a pharmaceutically acceptable salt or in vivo hydrolysable prodrug thereof for the preparation of a medicament for use in the treatment of atherosclerosis.