JP2002544257A - Hydroxamic acid derivatives as matrix metalloprotease inhibitors - Google Patents

Abstract

SUMMARY OF THE INVENTION A sulfonyl aromatic or heteroaromatic hydroxamic acid compound is disclosed which inter alia inhibits matrix metalloprotease activity and is contemplated for a host having a condition associated with pathological matrix metalloprotease activity. Also disclosed is a method of treatment comprising administering a sulfonyl aromatic or heteroaromatic hydroxamic acid compound in an MMP enzyme-inhibiting effective amount. Contemplated compounds have the formula (a) Wherein the groups W and R are as defined separately.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] FIELD The present invention belongs technology, proteinase (protease) inhibitors, and more particularly, among others, sulfonyl aryl or heteroaryl hydroxamic acid compound that inhibits the activity of matrix metalloproteinases, compositions of those inhibitors , Intermediates for the synthesis of those compounds, methods for preparing the compounds, and methods for treating pathological conditions associated with pathological matrix metalloproteinase activity.

BACKGROUND connective tissue invention, extracellular matrix components and basement membrane is a component that is required of all mammals. These components are biological materials that provide rigidity, differentiation, adhesion, and possibly elasticity to biological systems, including humans and other mammals. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals consist or are components of structures such as skin, bone, teeth, tendons, cartilage, basement membrane, blood vessels, cornea and vitreous humor.

[0003] Under normal conditions, the connective tissue turnover and / or repair processes are regulated and balanced. Loss of this balance for any reason causes a number of disease states. Inhibition of enzymes that contribute to loss of equilibrium provides a regulatory mechanism for this tissue decomposition,
And, as a result, provide treatment for these diseases.

[0004] Degradation of connective tissue or connective tissue components results from the action of proteinase enzymes released from residual tissue cells and / or invading inflammatory or tumor cells. The major class of enzymes involved in this function is zinc metalloproteinases (metalloproteases, or MMPs).

[0005] Metalloprotease enzymes are divided into classes with several members having several different names that are commonly used. Examples include: Collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3)
); Collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17)
), Stromlysine 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24) , Gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysine 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14)
. MMP is an abbreviation or acronym for matrix metalloprotease, a term with an accompanying number that provides for differentiation between particular members of the MMP group.

[0006] Uncontrolled breakdown of connective tissue by metalloproteases is characteristic of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulcers; tumor metastasis, invasive (inva
periodontal disease; proteinuria; Alzheimer's disease; coronary thrombosis and bone disease. Defective damage repair processes can also occur. This allows
Improper wound healing can cause weak repair, adhesions and scarring. These latter defects can result in permanent disability, such as those with disfigurement and / or post-surgical adhesions.

[0007] Matrix metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF), and inhibiting the production or action of TNF and related compounds is an important clinical disease treatment mechanism. For example, TNF-α is currently
It is a cytokine initially thought to be favored as a 28 kD cell binding molecule. This molecule is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF
Has and / or inflammatory effects, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrogenic disease, cancer, infectious disease, malaria, mycobacterium infection, meningitis, fever, psoriasis Cardiovascular / pulmonary effects (such as post-ischemic reperfusion injury, congestive heart failure, bleeding, coagulation, hyperoxic alveolar injury, radiation damage) and shocks such as septic shock and hemodynamic shock. Infections and septic acute phase reactions such as those that can be caused and / or involved.
Chronic release of active TNF can cause cachexia and anorexia. TNF is potentially lethal.

[0008] TNF-α converting enzymes are metalloproteinases that are involved in the formation of active TNF-α. Inhibition of the TNF-α converting enzyme inhibits the production of active TNF-α. Compounds that both inhibit MMP activity are described in WIPO WO 94/24140, WO 94/02466 and WO 97 /
20824. There remains a need for effective MMP and TNF-α converting enzyme inhibitory agents. Compounds that inhibit MMPs, such as collagenase, stromal lysine and gelatinase, have been shown to inhibit the release of TNF (Gearing et al.
al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1
994)).

[0009] MMPs are also involved in other biochemical processes in mammals. Regulation of ovulation, post-partum uterine regression, possibly egg implantation, A
PP cut to amyloid plaques (beta-amyloid precursor protein) and alpha ₁ - include inactivation of protease inhibitor (α ₁ -PI). Inhibition of these metalloproteases allows for regulation of fertilization and treatment or prevention of Alzheimer's disease. In addition, endogenous or administered serine protease inhibitor drugs or α _1-
Increasing and maintaining levels of biochemicals such as PI can treat and treat diseases such as emphysema, lung disease, inflammatory diseases and aging diseases such as loss of skin or organ elasticity and resilience. Support prevention.

[0010] Inhibition of selected MMPs may be desirable in other cases. Treatment of cancer and / or inhibition of metastasis and / or inhibition of angiogenesis can be achieved by selecting stromal lysine (MMP-3), gelatinase (MMP-2), gelatinase B (MMP-9) or collagenase III (MMP-13). Is an example of an approach to the treatment of disease, where dynamic inhibition may be relatively more important than inhibition of collagenase I (MMP-1). Drugs that do not inhibit collagenase I may have a good therapeutic profile.
Bone joint, another prevalent disease, in which cartilage degradation in inflamed joints is thought to be caused by MMP-13 released from cells such as at least partially stimulated chondrocytes The disease can best be treated by administering one of the drugs whose mode of action is inhibition of MMP-13. For example, Mitchell et al., J. Clin. Invest., 97: 761-768 (1996) and Reboul
See et al., J. Clin. Invest., 97: 2011-2019 (1996).

[0011] Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitors of metalloproteinases (TIMP), α ₂ -macroglobulin and analogs or derivatives thereof. These are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of small peptidomimetic compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives showed ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) is a potent hyperactive substance in mammals, and inhibition of this enzyme aids in the production of angiotensin II, which causes a decrease in blood pressure.

[0012] Thiol group-containing amide or peptidyl amide-based metalloproteases (MMP) inhibitors are known, as indicated, for example, in W095 / 12389, W096 / 11209 and US 4,595,700. Hydroxamate group-containing MMP inhibitors are described, for example, in WO 95/29892, WO 97/24117, WO 97/49, which disclose carbon backbone compounds.
WO 90/05719, WO 93/20047, which disclose hydroxamates having a 679 and EP 0 780 386, and a peptidyl or peptidomimetic backbone,
In a number of published patent applications such as WO 95/09841 and WO 96/06074, Schwartz
(Progr. Med. Chem., 29: 271-334 (1992)) and those of R
(Pharmacol. Ther., 75 (1): 69-75 (1997)) and Denis et al. (Invest
New Drugs, 15 (3): 175-185 (1997)).

One of the problems that may be associated with known MMP inhibitors is that such compounds often show the same or similar inhibition success for each MMP enzyme. For example, a peptidomimetic hydroxamate known as batimastat has about 1 to about 20 nanomolar (MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9, respectively) It has been reported to exhibit an IC ₅₀ value of nM). Another peptidomimetic hydroxamate a is marimastat (marimastat), except that marimastat exhibits an IC ₅₀ value of 230 nM with respect to MMP-3, the enzyme inhibitory spectrum very similar to Batima stat Having another broad-spectrum M
It was reported to be an MP inhibitor (Rasmussen et al., Pharmacol. Ther., 75 (1
): 69-75 (1997)).

[0014] Late, rapidly aggressive, refractory solid tumor cancers (colorectal, pancreatic, ovarian,
In patients with prostate), a meta-analysis of the data obtained from phase I / II studies using Marimastat indicates that the increase in cancer-specific antigens used as surrogate markers for biological activity -Showed to decrease by relevance. Marimastat showed some measure of efficiency through these markers, but the toxic side effects were significant. In those clinical trials, the most common drug-related toxicities of Marimastat were musculoskeletal pain and stiffness, often starting from the small joints of both hands and extending to the arms and shoulders. After a short dose-free period of 1-3 weeks, the dose can be reduced and treatment can continue (Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75).
(1997)). It is believed that the lack of specificity of the inhibitory effect among MMPs may cause such effects.

The importance of hydroxamate MMP inhibitor compounds in the treatment of several diseases,
In the light of the lack of enzyme specificity exhibited by the more potent drugs in two clinical trials, it would be of great advantage if a hydroxamate with higher enzyme specificity was found. This is associated with some pathological conditions of the hydroxamate inhibitor, while at the same time the restricted nature of MMP-1 which is relatively widespread but has nothing to do with pathological conditions Only show inhibition
This is the case if it shows strong inhibitory activity against one or more of MP-2, MMP-9 or MMP-13. The following description describes one family of hydroxamate MMP inhibitors that exhibit the desired activity.

SUMMARY OF THE INVENTION The present invention, among other features, inhibits matrix metalloprotease (MMP) activity, and in particular, the activity of one or more MMP-2, MMP-9, or MMP-13 A family of molecules that inhibits, while generally displaying little activity against MMP-1. The present invention also relates to intermediates that are useful in the synthesis of inhibitors, processes for preparing the contemplated compounds, and processes for treating mammals having conditions associated with pathological matrix metalloprotease activity.

Briefly, one aspect of the present invention is directed to sulfonylaryl or heteroaryl hydroxamic acid compounds, or pharmaceutically acceptable salts of those compounds that can act as matrix metalloprotease enzyme inhibitors, A precursor to such a compound, or a prodrug form of such a compound. The contemplated compounds are structurally represented by Formula C:

[0018]

Embedded image

Corresponds to Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;¹Is (i) the indicated SO_Two-A 5- or 6-membered cyclohydride directly attached to the group
Containing a locarbyl, heterocyclo, aryl or heteroaryl group, and
Longer than approximately the length of a hexyl group and shorter than approximately the length of an eicosyl group
A substituent having a long length, wherein R¹Defines a three-dimensional volume,
SO of member ring group_TwoAn axis drawn through the 1- and 4-positions to which-is bonded, or the SO _Two -Rotation around the axis drawn through the 1-position and the center of the 3,4-bond
, Its widest length in the horizontal direction relative to the axis of rotation is
About the number of phenyl rings. Or R¹Is -NR⁷R⁸Group,
Where R⁷And R⁸Is a hydride, hydrocarbyl, aryl, substituted aryl, a
Independent from the group consisting of reel hydrocarbyl and substituted aryl hydrocarbyl
Selected. More preferably, R⁷And R⁸Is hydride, alkyl, alke
Nil, alkynyl, alkoxyalkyl, haloalkyl, R^aOxyalkyl,
Chloroalkyl, cycloalkylalkyl, aryl, arylalkyl, hetero
From the group consisting of aryl, heteroarylalkyl, and heterocyclo substituents
Independently selected, each of which substituents is optionally replaced by a -A-R-E-Y substituent
In such -A-R-E-Y substituents, A is (1) -O-; (2) -S-; (3) -NR^k-; (4) -CO-N (R^k) Or -N (R^k(5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH- (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R^k)-Or -N (R^k) -CS-; (13) -CH_Two-; (14) -O-CH_Two-Or-CH_Two-O-; (15) -S-CH_Two-Or-CH_Two-S-; (16) -SO-; and (17) -SO_Two-; Or (18) A is absent and R is R⁷Or R⁸Or R⁷And R⁸For both
A direct bond; moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cyclo
Loalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocy
Chloroalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocy
Chloroalkoxyalkyl, aryloxyalkyl, heteroaryloxyal
Kill, arylthioalkyl, heteroarylthioalkyl, cycloalkylthio
Selected from the group consisting of oalkyl, and heterocycloalkylthioalkyl groups
Where aryl, heteroaryl, cycloalkyl or heterocycloal
The kill substituent may be (i) unsubstituted or (ii) halo, alkyl,
Fluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trif
Fluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy,
C₁-C_Two-Alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbo
Nylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoyl
By amino or 1 or 2 groups selected from the group consisting of alkoxycarbonyl groups
Substituted; group E is (1) -COR^g-Or-R^gCO-; (2) -CON (R^k)-Or-(R^k) NCO-; (3) -CO-; (4) -SO_TwoR^g-Or-R^gSO_Two-; (5) -SO_Two-; (6) -N (R^k) -SO_Two-Or-SO_Two-N (R^kOr (7) E is absent and R is directly attached to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl
, Aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitro
Ryl, nitro, aryloxy, alkoxy, heteroaryloxy, hete
Lower aralkyl, R^aOxyalkyl, perfluoroalkoxy, perfluoroal
Kirthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl,
Cycloalkyl, trifluoromethyl, alkoxycarbonyl, and amino
Selected from the group consisting of alkyl groups, wherein aryl, heteroaryl, aralkyl
Or heterocycloalkyl groups are (i) unsubstituted or (ii)
Lucanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl,
Aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and
Substituted by one or two groups independently selected from the group consisting of amino groups
Wherein the amino nitrogen is (i) unsubstituted or (ii) one or two groups
From the group consisting of the more substituted hydride, alkyl, and aralkyl groups.
Selected vertically; or R⁷And R⁸Forms the group -G-A-R-E-Y with the nitrogen atom to which they are attached,
Wherein G is an N-heterocyclo group; Substituent A is (1) -O-; (2) -S-; (3) -NR^k-; (4) -CO-N (R^k) Or -N (R^k(5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH- (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R^k)-Or -N (R^k) -CS-; (13) -CH_Two-; (14) -O-CH_Two-Or-CH_Two-O-; (15) -S-CH_Two-Or-CH_Two-S-; (16) -SO-; and (17) -SO_TwoOr; (18) A is absent and R is directly attached to the N-heterocyclo group, G; the moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl;
Loalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocy
Chloroalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocy
Chloroalkoxyalkyl, aryloxyalkyl, heteroaryloxyal
Kill, arylthioalkyl, heteroarylthioalkyl, cycloalkylthio
Independently from the group consisting of oalkyl, and heterocycloalkylthioalkyl groups
Where aryl or heteroaryl or cycloalkyl or
The heterocycloalkyl substituent can be (i) unsubstituted or (ii) halo,
Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroal
Kirthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl
, Alkoxy, C₁-C_Two-Alkylenedioxy, hydroxycarbonylalkyl,
Hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl
Alkanoylamino, and alkoxycarbonyl groups.
Moiety E is substituted by (1) -COR^g-Or-R^gCO-; (2) -CON (R^k)-Or-(R^k) NCO-; (3) -CO-; (4) -SO_Two-R^g-Or-R^g-SO_Two-; (5) -SO_Two-; (6) -N (R^k) -SO_Two-Or-SO_Two-N (R^k)-; Selected from the group consisting of
Is (7) E is absent and R is directly attached to Y; and the moiety Y is absent or is a hydride, alkyl, alkoxy, haloalkyl,
Aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile
, Nitro, aryloxy, aralkoxy, heteroaryloxy, hetero
Aralkyl, R^aOxyalkyl, perfluoroalkoxy, perfluoroalkyl
Ruthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl,
Chloroalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl
Selected from the group consisting of a kill group, wherein aryl, heteroaryl, aralkyl
Or the heterocycloalkyl group is (i) unsubstituted, or (ii)
Canoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, a
Reel, alkoxy, perfluoroalkyl, perfluoroalkoxy and
Substituted by one or two groups independently selected from the group consisting of a mino group,
Here, the amino nitrogen is (i) unsubstituted or (ii) one or two groups
Independently selected from more substituted hydride, alkyl, and aralkyl groups
Is done.

Alternatively and more preferably, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached; ie, at the —NR ⁷ R ⁸ group, form the group —GAREY, where G is N-heterocyclo A substituent A is (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k )- (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; ( 9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R k) - or -N (R ^k) -CS-; ( _{13) -CH 2 -; (14} ) -O-CH 2 - or _{-CH 2 -O-; (15) -S} -CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and ( 17) —SO ₂ —; or (18) A is absent and R is directly attached to the N-heterocyclo group, G; the moiety R is alkyl, alkoxyalkyl , Aryl, heteroaryl, cycloalkyl, heterocycloalkyl , Aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl Wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxy, fluoroalkyl thio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ - alkylenedioxy, hydroxycarbonated Ruarukiru, hydroxycarbonyl alkylamino, nitro, hydroxy, hydroxyalkyl, substituted by 1 or 2 groups selected from the group consisting alkanoylamino, and alkoxycarbonyl groups; moiety E is, (1) -COR ^g - Or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO-; (4) -SO ₂ -R ^g -or -R ^g -SO ₂ -; (5) -SO _2- ; (6) selected from the group consisting of -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k )-; or (7) E is Absent, and R is directly attached to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl,
Aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heteroalkyl Selected from the group consisting of cycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted, or (ii) ) From the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and amino groups Standing and is optionally substituted with 1 or 2 groups selected,
Here, the amino nitrogen is substituted by one or two groups independently selected from (i) unsubstituted or (ii) hydride, alkyl, or preliminary aralkyl groups.

The substituents R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, thiol (-SH
), Alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and R ^b R ^c aminoalkyloxy substituents; or R ⁵ and R ⁶ together with the atoms to which they are attached form an additional aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members.

The R ²⁰ group is (a) —OR ²¹ , where R ²¹ is a hydride, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl group and pharmaceutically acceptable (B) -NR ¹³ -OR ²² , wherein R ²² is 2-tetrahydropyranyl, benzyl, p-methoxybenzyl, C ₁ -C ₆ -alkoxycarbonyl, trisubstituted silyl selected from the group consisting of cations Or an o-nitrophenyl group, a selectively removable protecting group such as a peptide synthetic resin, wherein the trisubstituted silyl group is C ₁ -C ₆ -alkyl, aryl, or alk-C ₁ -C ₆ -alkyl or a mixture thereof, and R ¹³ is a hydride,
(C) -NR ¹³ -OR ¹⁴ , which is a C ₁ -C ₆ -alkyl or benzyl group, wherein R ¹³ is as described above and R ¹⁴ is a hydride, a pharmaceutically acceptable cation Or C (V) R ¹⁵ , where V is O (oxo) or S (thioxo), and
R ¹⁵ is C ₁ -C ₆ - alkyl, aryl, C ₁ -C ₆ - alkoxy, heteroaryl -C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl -C ₁ -C ₆ - alkyl, aryl Oxy, al-C ₁ -C _6-
Selected from the group consisting of alkoxy, ar-C ₁ -C ₆ -alkyl, heteroaryl and amino C ₁ -C ₆ -alkyl groups, wherein the amino C ₁ -C ₆ -alkyl nitrogen is (i) substituted No or (ii) C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, ar-C ₁ -C ₆ -Alkoxycarbonyl,
Substituted by one or two substituents independently selected from the group consisting of C ₁ -C ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkanoyl groups, or (iii) wherein the amino C _1- The C ₆ -alkyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) -NR ²³ R ²⁴ , wherein R ²³ and R ²⁴ are Hydride, C ₁ -C ₆ -alkyl, amino C ₁ -C ₆ -alkyl, hydroxy C _1-
Is independently selected from the group consisting of C ₆ -alkyl, aryl, and ar-C ₁ -C ₆ -alkyl groups, or R ²³ and R ²⁴ together with the indicated nitrogen atom are oxygen, nitrogen or Forming a 5- to 8-membered ring containing 0 or 1 additional heteroatom that is sulfur.

In the above formula, R ^a is hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c aminoalkyl, R ^b and R ^c are selected from the group consisting of alkoxyalkyl, haloalkyl and arylalkyloxy groups; R ^b and R ^c are hydride, alkanoyl, arylalkyl, aroyl, bis
Alkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl,
Aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, alalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, Aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, Alkoxycarbonyl, ally Independently selected from the group consisting of oxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted, or (ii) 1 or 2 R ^d is optionally substituted independently by a group, or a substituent on the amino group together with the amino nitrogen, optionally, optionally, two or three groups independently selected from R ^f substituents R ^d and R ^e form a saturated or partially unsaturated heterocyclo group substituted by one, two or three groups independently selected from a R ^d substituent or a heteroaryl group substituted by , Hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxy It is independently selected from the group consisting of carbonyl or arylalkyloxy group; R ^f is, nitro, hydroxy, alkyl, halogen (halo; F, Cl, Br, I ), aryl, alkoxy, cyano, and R ^d R ^{e is} selected from the group consisting of ^e- amino groups; R ^g is hydride, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F, Cl, Br, I), cyano, aldehyde (CHO, formyl), , amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyalkyl heteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy , Aryloxy Cycloalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ^i- Aminocarbonyloxy, R ^h R ⁱ -aminocarbonyl, R ^h R ⁱ -aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ -aminosulfonyl,
R ^h R ⁱ -aminocarbonyl (R ^h ) amino, trifluoromethylsulfonyl (R ^h ) amino, heteroarylsulfonyl- (R ^h ) amino, arylsulfonyl (R ^h ) amino, arylsulfonyl (R ^h ) -aminocarbonyl , Alkylsulfonyl (R ^h
R) is selected from the group consisting of amino, arylcarbonyl- (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) -aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, From the group consisting of alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups And each of those groups is optionally one or two groups independently selected from R ^j substituents such as substituted aminoalkyl and substituted aminoalkanoyl groups. R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxy Alkyl, haloalkyl, alkanoyl,
Aroyl, substituted or unsubstituted aminoalkanoyl, is selected from the group consisting of halo alkanoyl and a hydroxyalkyl group, each of those groups optionally 1 or substituted by 2 R ^j substituents; R ^j is, Arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted Selected from the group consisting of substituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups; wherein the substituted aminoalkyl and substituted aminoalkanoyl substituents are alkyl, alkenyl, Alkenyl, aryl, arylalkyl, heteroaryl,
R ^k is selected from the group consisting of heteroarylalkyl, aryloxycarbonyl and alkyloxycarbonyl groups; and R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxy Carbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl,
It is selected from the group consisting of R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkyl (alky) sulfonyl.

In some preferred embodiments, R ⁵ and R ⁶ are hydride, hydrocarbyl, preferably C ₁ -C ₄ hydrocarbyl, hydroxyl hydrocarbyl, hydroxyl, amino, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy , And heterocyclothio.

In a preferred embodiment, the 5- or 6-membered aromatic or heteroaromatic ring W is 1,2-
A phenylene, a 2,3-pyridinylene, a 3,4-pyridinylene, a 4,5-pyridinylene, a 2,3-pyrazinylene, a 4,5-pyrimidinylene, or a 5,6-pyrimidinylene group.

In some preferred embodiments, R ²⁰ is -NR ¹³ -OR ¹⁴ , while in other preferred embodiments, R ²⁰ is -NR ¹³ -OR ²² . In a particularly preferred embodiment, R ²⁰ is -NHOH, whereby the compound of formula C has the structure

[0027]

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Wherein W, R ¹ , R ⁵ , R ⁶ , R ¹³ and R ¹⁴ are as previously defined. In one preferred embodiment, contemplated compounds have the structure of Formula C2

[0029]

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Wherein W, R ⁵ , R ⁶ and R ¹⁴ are as defined above, and Ph is a phenyl group substituted in its 4-position by a substituent R ⁴ . R ⁴ substituents are monocyclic cyclohydrocarbyl, heterocyclo, 3, such as aryl, such as phenyl or heteroaryl group or a hydrocarbyl or hydrocarbyloxy group, [e.g., C ₃ -C ₁₄ hydrocarbyl, or OC ₂ -C ₁₄ hydrocarbyl] about 14 another substituent having a chain length of carbon atoms, a phenoxy group [-OC ₆ H _5], a thiophenoxy group [phenylsulfanyl; -SC ₆ H _5], an anilino group [-NHC ₆ H _5], phenylazo group [-N ₂ C ₆ H _5], a phenyl ureido group [aniline carbonylamino; -NHC (O) NH-C 6 H 5 ]
, A benzamide group [-NHC (O) C ₆ H ₅ ], a nicotinamide group [3-NHC (O) C ₅ H ₄ N],
Isonicotinamide group [4-NHC (O) C ₅ H ₄ N] or picolinamide group [2-NHC
(O) C ₅ H ₄ N]. The R ⁴ substituent is further defined below.

In another aspect of the present invention, contemplated compounds have the structure of formula VI-1
Corresponding to

[0032]

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Wherein each of R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ²⁰ is as defined above,
And each of A, B, C and D is carbon, nitrogen, sulfur or oxygen and is present or absent such that the indicated ring has a 5- or 6-member. If R ^{2 0} is NH-OH, the compounds with one of the above-mentioned formula, such as Formula C or C1 is, MMP
Hydroxamate, a selective inhibitor of MMP-2, which takes precedence over -1 and usually also over MMP-13. That is, a hydroxamate compound having one of the formulas such as Formula C or C1 exhibits greater activity in inhibiting MMP-2 as compared to inhibiting MMP-1 and usually also MMP-13. . When R ²⁰ is other than NH-OH, the formula V
The compound of I-1 may be a precursor, prodrug or active carboxylate, such as the compound of Example 13.

A particularly preferred embodiment of this aspect is that in its structure the formula VIA or VIA-1

[0035]

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Wherein R ²⁰ , R ⁴ , R ⁵ and R ⁶ are as defined above, and the indicated nitrogen-containing ring structure W ² is 5- or 6- a heterocyclic ring containing membered, and R ⁴ is
When W ² is a 6-membered ring, at the 4-position relative to the indicated nitrogen atom, and when W ² is a 5-membered ring, relative to the indicated nitrogen. At the 3- or 4-position.

Another particularly preferred embodiment of this aspect is a compound of the formula VIB, VIB-1, VIB-2
Or VIB-3

[0038]

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Wherein R ²⁰ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as previously defined. A particularly preferred group of this class of compounds is that whose structure is of the formula D

[0040]

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Wherein the substituents or moieties A, R, E, Y, R ²⁰ , R ⁵ and R ⁶ are as described above. Methods for treating a host mammal having a condition associated with pathological matrix metalloprotease activity are also contemplated. The method comprises administering to a mammalian host having such a condition, for example, a compound corresponding to Formula C in the structure, such as a compound corresponding to Formula C1 below or a salt of such a compound, in the structure: To include, such a compound in one or more MMPs
Selectively, while exhibiting at least lower activity against MMP-1 in an MMP enzyme-inhibiting effective amount. The contemplated compounds also do not substantially inhibit TNF production.

[0042]

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Where W, R ¹ , R ⁵ , R ⁶ , R ¹³ and R ¹⁴ are as previously defined. Among the benefits and advantages of the present invention, providing compounds and compositions that are effective in inhibiting metalloproteinases is associated with diseases and conditions that involve dysregulated degradation of connective tissue.

More specifically, the benefits of the present invention include, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal ulcer, epidermal or gastric ulcer, tumor metastasis, invasive or angiogenesis, periodontal disease, protein Compounds and compositions effective for inhibiting metalloproteinases, especially MMP-13 and / or MMP-2, associated with pathological conditions such as urine, Alzheimer's disease, coronary thrombosis, plaque formation and bone disease It is to provide things.

An advantage of the present invention is to provide a method of preparing such compounds and compositions. Another benefit of the present invention is to provide a method of treating a pathological condition associated with abnormal matrix metalloproteinase activity.

Another advantage of the present invention is that while its activity is necessary or desired for normal body function, its side effects resulting from inhibition of other proteinases such as MMP-1 are minimized, It is to provide compounds, compositions and methods useful for treating such pathological conditions by selective inhibition of metalloproteinases such as MMP-13 and MMP-2 associated with such conditions .

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In accordance with the present invention, a matrix metalloproteinase ("MMP") which is specifically unregulated or otherwise believed to be associated with pathological destruction of connective tissue. For inhibition, certain sulfonylaryl or heteroarylhydroxamic acids (hydroxamates) have been found to be effective. It is particularly destructive to tissues and may exhibit pathological activity, especially when present or produced in abnormal amounts or concentrations.
These specific sulfonylaryl or heteroarylhydroxamic acid compounds are effective at inhibiting collagenase III (MMP-13) and also gelatinase A (MMP-2).

In addition, many of these aromatic sulfonyl α-cycloaminohydroxamic acids do not unduly inhibit other collagenases that are essential for normal body functions such as tissue turnover and repair. Have been found to be selective in inhibiting MMPs associated with disease states. More specifically, particularly preferred sulfonylaryl or heteroaryl hydroxamic acid compounds or salts of those compounds are particularly active in inhibiting MMP-13 and / or MMP-2 while restricted to MMP-1 It was found that some compounds, such as the compound of Example 8, also had minimal or minimal effect and also showed minimal inhibition of MMP-7 inhibition. This is discussed in detail below and is shown in the inhibition table below.

One aspect of the invention is a sulfonylaryl or heteroaryl hydroxamic acid compound, a pharmaceutically acceptable salt of such a compound that can function as a matrix metalloprotease enzyme inhibitor, a precursor of such a compound. To the body or prodrug forms of such compounds. Contemplated compounds have the structure of Formula C:

[0050]

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Wherein ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; R ¹ is (i) a substituent 5- or 6-membered cyclohydrocarbyl, heterocyclo , aryl or indicated sO ₂ - containing heteroaryl group directly attached to the base, and longer than the length of a hexyl group, and shorter than the approximate length of eicosyl group, R ¹ groups are 3 defines the volume of the dimensions, the 6-membered ring group SO ₂ - bonded 1-position and the axis or 5-membered cyclic group, taken through the 4-position SO ₂ - bonded 1-position and 3,4-bond When rotated about an axis drawn through the center of the ring, its widest length in the transverse direction of the axis of rotation is between the approximate length of one furanyl ring and the approximate length of two phenyl rings. It is. Alternatively, the R ¹ group is (ii) a —NR ⁷ R ⁸ group wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydride, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl. . More preferably, R ¹ groups are hydrido R ⁷ and R ⁸ are alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl Independently selected from the group consisting of alkyl, and heterocyclo substituents
-NR ⁷ R ⁸ groups, each of which substituents is optionally substituted with an -AREY substituent; in such -AREY substituents, A is (1) -O-; (2) (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; ( (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C-; (10) -N = N-; (11) ) -NH-NH-; (12) -CS-N (R k) - or ^{-N (R k) -CS-; (} 13) -CH 2 -; (14) -O-CH 2 - or -CH _{2 -O-; (15) -S-} CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and (17) -SO ₂ -; or is selected from the group consisting of, or (18 A) is absent and R is directly attached to R ⁷ or R ⁸ , or to both R ⁷ and R ⁸ ; the moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, aralkyl, heteroaralkyl, heterocy Selected from the group consisting of a loalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups; Wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, Amino, alkoxycarbonylalkyl, alkoxy,
C ₁ -C ₂ -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamine, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and substituted by one or two groups selected from the group consisting of alkoxycarbonyl groups The group E is (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO-; (4) -SO _From (R ^g )-or-(R ^g ) SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k )-; Or (7) E is absent and R is directly attached to Y; and the moiety Y is absent or is a hydride, alkyl, alkoxy, haloalkyl,
Aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heteroalkyl Selected from the group consisting of cycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted, or (ii) ) From the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and amino groups Optionally substituted by 1 or 2 groups standing to be selected,
Wherein the amino nitrogen is independently selected from hydride, alkyl, and aralkyl groups that are (i) unsubstituted or (ii) substituted by one or two groups; or R ⁷ and R ⁸ are Together with the nitrogen atom to which they are attached (-NR ⁷ R ⁸ ), the group -GAREY
Wherein G is an N-heterocyclo group, and the substituent A is (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N ( R ^k) or ^{-N (R k) -CO-; (} 5) -CO-0- or -O-CO-; (6) -O -CO-O-; (7) -HC = CH-; ( (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k )-or -N (R ^k ) -CS-; (13) -CH _2- ; (14) -O-CH ₂ -or -CH ₂ -O-; (15) -S-CH ₂ -or -CH ₂ -S -; (16) -SO-; and (17) -SO _2- ; or (18) A is absent and R is an N-heterocyclo group, direct to G Join.

The moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, Selected from the group consisting of heteroaryl-oxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is i) unsubstituted or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoro B methyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ - alkylene - dioxy, hydroxycarbonylalkyl, hydroxycarbonyl alkylamino, nitro, hydroxy, hydroxyalkyl,
Selected from the group consisting of alkanoylamino, and alkoxycarbonyl groups
It is substituted by one or two groups.

Part E comprises: (1) —COR ^g — or —R ^g CO—; (2) —CON (R ^k ) — or — (R ^k ) NCO—; (3) —CO—; (4) -SO ₂ (R ^g )-or-(R ^g ) SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k )- Or (7) E is absent and R is directly attached to Y; and the moiety Y is absent or is a hydride, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl ,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted, or (ii) alkanoyl, Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl,
Substituted by one or two groups independently selected from the group consisting of aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and amino groups, wherein the amino nitrogen is (i) unsubstituted, or (Ii) independently selected from hydride, alkyl, and aralkyl groups substituted by one or two groups; R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, R ⁵ and R ⁶ are independently selected from the group consisting of cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, and R ^b R ^c aminoalkyl substituents; or R ⁵ and R ⁶ , together with the atoms to which they are attached, Forms a heterocyclic ring having an aromatic or aromatic carbocyclic or 5- to 7-member.

In the above formula, ^Ra is hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, R ^b R ^c aminoalkanoyl, haloalkanoyl, R ^b R ^c aminoalkyl, alkoxy R ^b and R ^c are selected from the group consisting of alkyl, haloalkyl and arylalkyloxy groups; R ^b and R ^c are hydride, alkanoyl, arylalkyl, aroyl, bis
Alkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl,
Aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, alalkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, Aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, Alkoxycarbonyl, ally Independently selected from the group consisting of oxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted, or (ii) one or Two R ^d groups, or a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from the R ^d substituents together with the amino nitrogen A substituent on the amino group forming
R ^d and R ^e are independently hydride, alkyl, heteroaryl groups optionally substituted with one, two or three groups independently selected from R ^f substituents; , Alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl or arylalkyloxycarbonyl group; R ^f is nitro, hydroxy, alkyl, halogen (halo; R, Cl, Br, I), aryl, alkoxy, cyano, and R ^{d Re} amino; R ^g is hydride, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen (F , Cl, Br, I), cyano, aldehyde (CHO, formyl), hydroxy, amide Bruno, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyalkyl heteroaryl, R ^h R ⁱ - amino, alkoxyalkyl, alkylenedioxy, Aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -aminocarbonyloxy, R ^h R ⁱ -aminocarbonyl, R ^h R ⁱ -aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ -aminosulfonyl,
R ^h R ⁱ -aminocarbonyl (R ^h ) amino, trifluoromethylsulfonyl (R ^h ) amino, heteroarylsulfonyl- (R ^h ) amino, arylsulfonyl (R ^h ) amino, arylsulfonyl (R ^h ) -aminocarbonyl , Alkylsulfonyl (R ^h
R) is selected from the group consisting of amino, arylcarbonyl- (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) -aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, From the group consisting of alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups One or two groups, each of which is optionally selected independently from R ^j substituents, as well as substituents on substituted aminoalkyl and substituted aminoalkanoyl groups. R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, Haloalkyl, alkanoyl,
R ^j is selected from the group consisting of aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups, each of which groups is optionally substituted by one or two R ^j substituents; , Arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or Unsubstituted aminoalkanoyl, haloalkanoyl and hydroxyalkyl groups are selected from the group consisting of substituted aminoalkyl and substituted aminoalkanoyl groups, , Alkenyl, aryl, arylalkyl, heteroaryl, selected from the group consisting of heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group; and R ^k is hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl , Heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl,
It is selected from R ^c R ^d aminoalkanoyl and R ^c R ^d aminoalkylsulfonyl.

R ²⁰ is (a) R ²¹ is selected from the group consisting of hydride, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl and pharmaceutically acceptable cations. -OR ²¹ , (b
) A protecting group from which R ²² can be selectively removed, such as 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), C ₁ -C ₆ -alkoxycarbonyl, trisubstituted silyl group or o-nitrophenyl group , A peptide synthetic resin or the like -NR ¹³ -OR ²² wherein the tri-substituted silyl group is C ₁ -C ₆ -alkyl, aryl, or al-C _1-
R ¹³ is a hydride, C ₁ -C ₆ -alkyl or benzyl group, (c) R ¹³ is the same as described above, and R ¹⁴ is substituted with C ₆ -alkyl or a mixture thereof. Is hydride, a pharmaceutically acceptable cation or C (V) R ¹⁵ -NR ¹³ -O-
R ¹⁴ , where V is O (oxo) or S (thioxo) and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl-C ₁ -C ₆ -Alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, aryloxy, ar-C ₁ -C ₆ -alkoxy, ar-C ₁ -C ₆ -alkyl, heteroaryl and amino C _1- Selected from the group consisting of C ₆ -alkyl groups, wherein the amino C ₁ -C ₆ -alkyl nitrogen is (i) unsubstituted or (ii) C ₁ -C ₆ -alkyl, aryl, al-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₆ -alkyl, ar-C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, and C ₁ -C _6- Substituted with one or two substituents independently selected from the group consisting of alkanoyl groups, or (iii) attached to an amino C ₁ -C ₆ -alkyl nitrogen and bonded thereto Two substituents form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) R ²³ and R ²⁴ are hydride, C ₁ -C ₆ -alkyl, amino C ₁ -C ₆ -alkyl Independently selected from the group consisting of: hydroxy C ₁ -C ₆ -alkyl, aryl, and ar-C ₁ -C ₆ -alkyl groups, or R ²³ and R ²⁴ , together with the indicated nitrogen atom, —NR ²³ R ²⁴ that forms a 5- to 8-membered ring containing 0 or 1 additional heteroatoms that are oxygen, nitrogen or sulfur.

Compounds of formula C are useful precursor compounds, prodrug forms of hydroxamate and
And hydroxamates themselves, and also as intermediates and MMP inhibitor compounds
Includes amide compounds that can be used. So, for example, R²⁰Is R ^{twenty one} Is hydride, C₁-C₆-Alkyl, aryl, al-C₁-C₆-Alkyl groups and drugs
-O-R selected from the group consisting of chemically acceptable cations^{twenty one}If
As shown in some examples, the precursor carboxylic acid or ester is
It is defined so that it can be easily transformed into loxamic acid. Hi
Such carboxyl compounds, which are precursors of droxamate, have been
As can be seen from the example inhibition table, it also has activity as an inhibitor of MMP enzyme.
it can.

[0057] Another useful precursor compounds, R ²⁰ is R ²² is selectively removable protecting group, R ^{1 3} is hydrido or benzyl group, -NR ¹³ -OR preferably hydride group Specified when it is ²² . Selectively removable protecting groups include 2-tetrahydropyranyl, benzyl, p-methoxybenzyloxycarbonyl (MOZ), benzyloxycarbonyl (BOC), C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -Alkoxy-CH _2- , C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkoxy-CH _2- , trisubstituted silyl group, o-nitrophenyl group, peptide synthetic resin and the like. Tri-substituted silyl groups may be C ₁ -C ₆ -alkyl, aryl, or ar-C ₁ -C ₆ -alkyl substituents or trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, triphenylsilyl, t-butyldiphenylsilyl, diphenylmethyl A silyl group substituted by a mixture of silyl, tribenzylsilyl group, and the like. Exemplary tri-substituted silyl protecting groups and their uses are described in Greene et al. ( Protective Groups In Organic Synthesis , 2nd ed., J
ohn Wiley & Sons, Inc., New York (1991)).

Contemplated peptide synthetic resins are commercially available from Sigma Chemical Co. (St. Louis, MO), a so-called Merrifield peptide adapted for synthesis and selective release of hydroxamic acid derivatives A solid support known as a resin. Exemplary peptide synthetic resins so adapted and their use in the synthesis of hydroxamic acid derivatives are described in Floyd et al. (Tetrahedron Let., 37 (44): 8048-
8048 (1996)).

The 2-tetrahydropyranyl (THP) protecting group is a particularly preferred selectively removable protecting group, and is often used when R ¹³ is a hydride group. Contemplated THP-protected hydroxamate compounds of Formula A include N-methylmorpholine, N-hydroxybenzotriazole hydrate and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in water. the presence of a water-soluble carbodiimide, a carboxylic acid precursor compound of formula a [wherein R ²⁰ is -OR ^21, and R ^{2 1} is hydrido group] a, O- (tetrahydro -2H- pyran -2 -Yl) hydroxylamine. The resulting THP-protected hydroxamate corresponds in structure to the following formula C3, wherein W, R ¹ , R ⁵ and R ⁶ are as previously defined, and Define. THP
Protecting groups are readily removable in aqueous acid solutions, such as aqueous mixtures of p-toluenesulfonic acid or HCl and acetonitrile or methanol.

[0060]

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Another aspect of the present invention is a compound of formula VI-1

[0062]

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Wherein each of R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ²⁰ is as previously defined and as defined in more detail below, And each A, B, C and D is carbon, nitrogen, sulfur or oxygen, and is present or absent such that the indicated ring has a 5- or 6-member. The hydroxamate compounds of formula VI-1 are selective inhibitors of MMP-2 over both MMP-1 and MMP-13. That is, the hydroxamate compound of Formula VI exhibits more potent activity in inhibiting MMP-2 in inhibiting MMP-1 and usually also in inhibiting MMP-13.

A particularly preferred embodiment of this aspect of the invention is that, in its structure, formula VIA or VIA-1

[0065]

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Wherein R ²⁰ , R ⁵ , R ⁶ and R ⁴ are as defined below, and the indicated nitrogen-containing ring structure W ² is a 5- or 6-membered And R ⁴ is a heterocyclic ring containing
When W ² is a 6-membered ring, it is attached at the 4-position in relation to its indicated nitrogen atom, and when W ² is a 5-membered ring, its relation to the indicated nitrogen To the 3- or 4-position. Ring W ² is preferably preferably are themselves substituted as discussed below N- piperazinyl group.

Another particularly preferred embodiment of this aspect is a compound of formula VIB

[0068]

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Wherein R ²⁰ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined below. A further aspect of the present invention is to a sulfonylaryl or heteroaryl hydroxamic acid compound that can function as a matrix metalloprotease enzyme inhibitor. The compound has the structure of formula C4

[0070]

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Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; R ¹ is a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or as indicated SO ₂ - containing directly bonded to a heteroaryl group group and an approximate short substituents than the length of the approximate long and eicosyl than the length of a hexyl group, wherein R ¹ is defined a 3-dimensional volume And the axis drawn through the 1-position and the 4-position bonded to the SO ₂ -of the 6-membered ring group, or drawn through the center of the 1-position and the 3,4-bond bonded to the 5-membered ring group SO _2- When rotated about an axis, its widest length transverse to the axis of rotation is from about the length of one furanyl ring to about the length of two phenyl rings; and R ⁵ and R ⁶ is hydride, alkyl, cycloalkyl, acylalkyl, halo, nitro B, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and R ^{b and} R ^c are independently selected from the group consisting of aminoalkyloxy substituents; or R ⁵ and R ⁶ , together with the atoms to which they are attached, are further aliphatic or aromatic carbocyclic or 5- Forming a heterocyclic ring having 77-members.

[0072] Again, in some preferred embodiments, (ii), R ¹ is selected R ⁷ and R ⁸ are hydrido, hydrocarbyl, aryl, substituted aryl, aryl hydrocarbyl, and independently from the group consisting of substituted aryl hydrocarbyl -NR ⁷ R ⁸ group. More preferably, R ⁷ and R ⁸ are hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo Independently selected from the group consisting of substituents, each of which substituents is optionally substituted with an -AREY substituent; in such -AREY substituents, A represents (1) -O-; (2) -S- (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO- (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; ( 12) -CS-N (R k) - or ^{-N (R k) -CS-; (} 13) -CH 2 -; (14) -O-CH 2 - or _{-CH 2 -0-; (15) -S} -CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and (17) -SO ₂ -; or is selected from the group consisting of, or (18) A is absent and R is bonded directly to both the R ⁷ or R ⁸ or R ⁷ and R ^8, Part R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryl Selected from the group consisting of oxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituent is (i) substituted Not been Or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy,
C ₁ -C ₂ -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and substituted by one or two groups selected from the group consisting of alkoxycarbonyl groups The group E is (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO-; (4) -SO _From (R ^g )-or-(R ^g ) SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k )-; Or (7) E is absent and R is directly attached to Y; and the moiety Y is absent or is a hydride, alkyl, alkoxy, haloalkyl,
Aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heteroalkyl Selected from the group consisting of cycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted, or (ii) ) From the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and amino groups Substituted by 1 or 2 groups standing to be selected,
Wherein the amino nitrogen is substituted with one or two groups independently selected from (i) unsubstituted or (ii) hydride, alkyl, and aralkyl groups.

Even more preferably, R ⁷ and R ⁸ together with the nitrogen atom to which they are attached (
-NR ⁷ R ⁸ ), forming a group -GAREY, wherein G is an N-heterocyclo group; the substituent A is (1) -O-; (2) -S-; (3) -NR ^k -; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (8) -NH-CO-NH-; (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k )-or -N (R ^k ) -CS-; (13) -CH _2- ; (14) -O-CH ₂ -or -CH ₂ -O-; (15) -S -CH ₂ - or _{-CH 2 -S-; (16) -SO-} ; and (17) -SO ₂ -; or is selected from the group consisting of, or (18) A is absent and R is An N-heterocyclo group, directly attached to G; the moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl Selected from the group consisting of heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroaryl-thioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, wherein aryl or heteroaryl or cycloalkyl or Heterocycloalkyl substituents are (i) unsubstituted or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl,
Selected from the group consisting of alkanoylamino, and alkoxycarbonyl groups
Moiety E is (1) -COR ^g -or -R ^g CO-; (2) -CONR ^k -or -R ^k NCO-; (3) -CO-; (4) -SO ₂ (R ^g )-or-(R ^g ) SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k )-; or (7) E is absent and R is directly attached to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl ,
Aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heteroalkyl Selected from the group consisting of cycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted, or (ii) ) From the group consisting of alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy and amino groups Standing and is optionally substituted with 1 or 2 groups selected,
Wherein the amino nitrogen is substituted with one or two groups independently selected from (i) unsubstituted or (ii) hydride, alkyl, and aralkyl groups.

The superscript “R” groups mentioned above and shown herein, R ^a , R ^b, etc. are as previously defined. In one preferred embodiment, R ⁵ and R ⁶ are hydride, hydrocarbyl, preferably C ₁ -C ₄ hydrocarbyl, hydroxyl hydrocarbyl, hydroxyl, amino, R ^b R ^c aminohydrocarbyl, halo, nitro, cyano, hydrocarbyloxy, halohydrocarbyl , Halohydrocarbyloxy, hydroxyhydrocarbyl, dihydrocarbylamino, heterocyclo, heterocyclohydrocarbyl, heterocyclooxy, and heterocyclothio groups. More preferably, R ⁵ and R ⁶ consist of hydride, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, and R ^b R ^c aminoalkyl substituents Selected independently from the group.

The aromatic or heteroaromatic rings contemplated include 1,2-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5-pyridinylene, 2,3-pyridinylene, 4,5- Includes pyrimidinylene and 5,6-pyrimidinylene groups. 1,2-phenylene (1,2-disubstituted phenyl ring) is a particularly preferred aromatic or heteroaromatic ring, and is used herein by way of example as W.

As noted above, the R ¹ substituent contains a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group directly attached to the indicated SO ₂ — group. The R ¹ substituent also has length, width, and substitution requirements, as discussed in detail below. Here, however, the monocyclic or fused cyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group is such that it satisfies the length requirement for preferred compounds, especially when R ¹ is NR ⁷ R ^8. Note that it is not long enough. As such, the cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group itself should be substituted.

An exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl group that can form part of the R ¹ substituent and that is itself substituted as discussed herein. Heteroaryl groups include phenyl, 2-, 3-, or 4-pyridyl, 2-naphthyl, 2-pyrazinyl, 2- or 5-pyrimidinyl, 2- or 3-benzo (b) thienyl, 8-purinyl, 2 -Or 3-furyl, 2- or 3-pyrrolyl, 2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or 3-morpholinyl, 2- or 3-tetrahydropyranyl, 2-imidazolidinyl,
2- or 3-pyrazolidinyl and the like. Phenyl groups are particularly preferred and are used exemplarily herein.

When examined with its longest chain of atoms, the R ¹ substituent, including its own substituent, if present (including NR ⁷ R ⁸ as the R ¹ substituent) is fully extended Saturated 6
It has an overall length that is equal to or greater than the length of the chain of carbon atoms (hexyl group); that is, a heptyl chain of staggered conformation or greater, and a total of about 20 carbons The length is shorter than the length of the saturated chain (eicosyl group) extended to the target. More atoms may be present in the ring structure or substituents, but preferably, the length is from about 8 to about 18 carbon atoms. This length requirement is discussed further below.

When viewed more generally, and apart from the specific moiety being constructed, the R ¹ substituent (radical, group, or moiety) may be as long as or longer than the heptyl group. Having. Such R ¹ substituents also have a shorter length than the length of the eicosyl group. That is, R ¹ has a length greater than the length of a fully extended saturated 6 carbon chain, and has a length less than the length of a fully extended saturated 20 carbon chain, and more preferably, A substituent having a length longer than the length of the octyl group and shorter than the length of the palmityl group. The chain length of the group is measured along the longest straight chain of atoms in the group and then optionally along the ring backbone atoms.
Each atom in the chain, eg, carbon, oxygen or nitrogen, is assumed to be carbon for ease of calculation.

Such a length can be determined by drawing and measuring a chain, using the disclosed bond angles, bond lengths, and atomic radii, as needed, or by combining the bond angles, bond lengths, It can be easily determined by constructing a model using commercially available kits where the radius of the atoms is acceptable and the values disclosed. Although the above-described measurement mode is preferred, the length of the group (substituent) is assumed to be assuming that all atoms have a bond length of a saturated carbon, and that the unsaturated bond and the aromatic bond are saturated bonds. It can also be determined to some extent less accurate by assuming that it has the same length as and that the bond angle for unsaturated bonds is the same as the bond angle for saturated bonds. For example, 4-phenyl or 4-
The pyridyl group, as in the case of the propoxy group, has a length of 4 carbon chains, while the biphenyl group has a length of about 8 carbon chains, using the intended mode of measurement.

[0081] Further, R ¹ substituent is a 6-membered ring group SO ₂ - axes taken through bonded 1-position and 4-position or the 5-membered cyclic group SO _2, - bound 1-position and When rotated around an axis drawn through a 3,4 bond, a three-dimensional volume is defined, and in the horizontal axis direction with respect to the rotation axis,
Its widest width is from that of about one furanyl ring to that of about two phenyl rings.

When using this width or volume criterion, naphthyl or purinyl
Fused ring systems such as groups are considered to be 6- or 5-membered rings. SO ₂ is regarded as in the 1-position as described above - in a position suitable from the binding, it is substituted. Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an R ¹ group appropriately sized for width as measured manually using the rotation width criteria described above. On the other hand, 1-naphthyl groups or 7- or 9-purinyl groups are too large for rotation and are excluded.

As a result of these length and width requirements, 4- (phenyl) phenyl [biphenyl]
4- (4'-methoxyphenyl) -phenyl, 4- (phenoxy) phenyl, 4- (thiophenyl) phenyl [4- (phenylthio) phenyl], 4- (phenylazo) phenyl 4- (phenylureido) phenyl, 4 -(Anilino) phenyl, 4- (nicotinamide) phenyl, 4- (isonicotinamide) phenyl, 4- (picolinamide)
R ¹ substituents such as phenyl and 4- (benzamido) phenyl are among the particularly preferred R ¹ substituents, with 4- (phenoxy) phenyl and 4- (thiophenyl) phenyl being most preferred.

The SO ₂ -linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group is itself a 5- or 6-membered monocyclic ring, which is substituted by one other substituent, R ⁴ . The SO ₂ -linked monocyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group is R ⁴ -substituted in its own 4-position when it is a 6-membered ring and when it is a 5-membered ring. Is substituted by its own 3- or 4-position.
In some embodiments, the cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group to which R ⁴ is attached is preferably a phenyl group, whereby R ¹ is preferably PhR ⁴ where R ⁴ is SO ₂ - optionally attached to the 4-position of the bound phenyl (Ph) radical and R ⁴ is as discussed below, may itself be substituted. In another aspect, preferably than heterocyclo or heteroaryl group is a phenyl group, which has the R ⁴ substituents attached at the 4-position relative to the bond between the ring and the SO ₂ group.

[0085] R contemplated^FourSubstituents include monocyclic cyclohydrocarbyl, heterocyclo, aryl
Or another substituent having a chain length of 3 to about 14 carbon atoms
Groups, such as hydrocarbyl or hydrocarbyloxy groups [eg, C_Three-C ₁₄ Hydrocarbyl or O-C_Two-C₁₄Hydrocarbyl], phenyl group, phenoxy group
[-OC₆H_FiveThiophenoxy group [phenylsulfanyl; -SC₆H_Five], Anilino group
[-NHC₆H_Five], A phenylazo group [-N_TwoC₆H_Five], Phenylureido group [anilinecal
Bonylamino; -NHC (O) NH-C₆H_Five], Benzamide group [-NHC (O) C₆H_Five], Nico
Tinamide group [3-NHC (O) C_FiveH_FourN], isonicotinamide group [4-NHC (O) C_FiveH_FourN]
Or a picolinamide group [2-NHC (O) C_FiveH_FourN]. Additional intent
R^FourSubstituents include heterocyclo, heterocyclohydrocarbyl, arylhydrido
Locarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarb
Bil, heteroarylheterocyclo-hydrocarbyl, arylhydrocarbyl
Oxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarbonyl (ca
rboyl) hydrocarbyl, aryl hydrocarbonyl (carboyl) hydrocarbyl
, Arylcarbonylhydrocarbyl, arylazoaryl, arylhydra
Dinoaryl, hydrocarbyl-thiohydrocarbyl, hydrocarbylthioali
, Arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydr
Locarbylthioarylhydrocarbyl, arylhydrocarbyl-thiohydro
Carbyl, aryl hydrocarbyl thioaryl, aryl hydrocarbyl ami
A heteroarylhydrocarbylamino or heteroarylthio group
It is.

The contemplated R ⁴ substituents are themselves substituted at the meta- or para-position with one or more substituents, or a single atom or up to 10 atoms longest except oxygen. May be substituted with both of the 6-membered rings having a substituent containing Exemplary substituents include halo, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethyl-hydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, hetero Aryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, Heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl- Hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocycle, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbiroyl, arylcarbonyl, arylhydrocarbyloxy, hydrocarbonyl (carboyloxy), aryl Hydrocarbyloxy, hydroxyhydrocarbyl, hydroxy-hydrocarbyloxy, hydrocarbylthio, hydrocarbyloxy-hydrocarbylthio,
Hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxy-carbonylhydrocarbyl, hydrocarbylhydroxycarbonyl-hydrocarbylthio, hydrocarbyloxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonyl-hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino A heterocyclohydrocarbylcarbonylamino, an arylhydrocarbylcarbonylamino, a heteroaryl-carbonylamino,
Heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl-sulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-mono Replace or
Includes N, N-disubstituted aminohydrocarbyl groups wherein the substituent (s) at the nitrogen are hydrocarbyl, aryl, arylhydrocarbyl,
Selected from the group consisting of cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and carboyl, or wherein nitrogen and the two attached thereto are a 5- to 8-membered heterocyclic group or heteroaryl ring Form a group.

Thus, according to initial work, as far as the length, substitution and width (volume upon rotation) requirements for the SO ₂ -bonded R ¹ substituent discussed herein are concerned, Demonstrating compatibility, the R ¹ substituent may be significantly altered.

Particularly preferred R ⁴ substituents on the SO ₂ -linked Ph group are monocyclic aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, phenylureido, nicotinamide, isonicotinamide, picolinamide, anilino or substituted Unsubstituted or substituted (optionally substituted) at the para-position if it is itself a 6-membered ring or substituted at the 3- or 4-position (optionally substituted) if it is a 5-membered ring )
Benzamide group. Where one other than the halogen moiety or oxygen
Substituents containing a chain of about 10 atoms can be used, for example a single atom such as a C ₁ -C ₁₀ hydrocarbyl, C ₁ -C ₉ hydrocarbyloxy or carboxyethyl group.

Exemplary particularly preferred PhR ⁴ (particularly preferred R ¹ ) substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-phenylureido, 4-anilinophenyl, Includes 4-nicotinamide, 4-isonicotinamide, and 4-picolinamide. Exemplary particularly preferred R ⁴ groups contain a 6-membered aromatic ring, and a phenyl group, a phenoxy group, thiophenoxy group, a phenylazo group, a phenyl ureido group, an anilino group, nicotinamide group, isonicotinamide group, Includes picolinamide and benzamide groups.

More specifically, particularly preferred sulfonylbutane hydroxamate compounds are
Phenyl group, phenoxy group, thiophenoxy group, phenylazo group, phenylure
Id group, anilino group, nicotinamide group, isonicotinamide group, picolinamido
Group or itself is optionally substituted at its own meta or para position
Or halogen, halohydrocarbyl group, halo C₁-C₉Hydrocarbyloxy group
, Perfluoro C₁-C₉Hydrocarbyl group, C₁-C₉Hydrocarbyloxy (-O-C₁-C₉ Hydrocarbyl) group, C₁-C_TenHydrocarbyl group, di-C₁-C₉Hydrocarbylamino
[-N (C₁-C₉Hydrocarbyl) (C₁-C₉Hydrocarbyl)] group, carboxyl C₁-C ₈ Hydrocarbyl (C₁-C₈Hydrocarbyl-CO_TwoH) group, C₁-C_FourHydrocarbyloxy
Carbonyl C₁-C_FourHydrocarbyl (C₁-C_FourHydrocarbyl-O- (CO) -C₁-C_FourHydro
Carbyl) group, C₁-C_FourHydrocarbyloxycarbonyl C₁-C_FourHydrocarbyl (C₁ -C_FourHydrocarbyl (CO) -O-C₁-C_FourHydrocarbyl] group and C₁-C₈Hydrocarb
Lucarboxamide [-NH (CO) -C₁-C₈Hydrocarbyl] groups.
Substituted by both groups, or by two methyl groups or
C such as a tylenedioxy group₁-C_TwoWith the alkylenedioxy group, meta- and para-
R is a benzamide group substituted at the^FourIt has a substituent.

Since the contemplated SO ₂ -linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group is preferably itself substituted by a 6-membered aromatic ring, it is easy to understand the position of the substituents. To do so, two types of nomenclature systems are used together herein. The first system, SO ₂ - is intended to use a number of positions relative to the ring directly bonded to the base, while the second system, SO ₂ - bound cyclohydrocarbyl, heterocyclo, aryl or heteroaryl Relative to the position of one or more substituents on the 6-membered ring attached to the aryl group,
Use ortho, meta or para. When the R ⁴ substituent is other than a 6-membered ring, the position of the substituent is numbered from the position of the bond to the aromatic or heteroaromatic ring.
Formal chemical nomenclature is used when naming specific compounds.

[0092] Thus, SO ₂ described above - bound cyclohydrocarbyl, heterocyclo, 1-position of the aryl or heteroaryl group, SO ₂ - is a position where the base is bonded to the ring. The 4- and 3-positions of the ring considered here are from the site of the substituent linking the contrasted SO ₂ -bond to the ring represented in the numbered formula as used in heteroaryl nomenclature. , Number.

[0093]

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In some preferred embodiments, contemplated compounds have, in their structure, the formula
Corresponds to C2, wherein W, R ⁵ , R ⁶ and R ¹⁴ are as defined above, and Ph is phenyl substituted at the ^4-position by the substituent R ⁴ defined above.

The length of the R ¹ substituent attached to the SO ₂ group is believed to play a role in the overall activity of the contemplated inhibitor compound, generally on MMP enzymes.
Thus, R ¹ substituent is a short length than a heptyl group, a compound having e.g. a 4-methoxyphenyl group, a against all of MMP enzymes, shows typically a moderate or weak inhibitory activity but while its R ¹ substituent has a length of about 9 carbon chain, approximately heptyl chain or longer chain, the compound having for example 4-phenoxyphenyl group, a, MMP-13 or MMP -2 typically shows good or great potential, and also has selectivity for MMP-1. Exemplary data is provided in the following Inhibition Table, which can compare assays for the two compounds described above.

In light of the options discussed above, compounds that correspond in structure to specific formulas constitute specific embodiments. In one such embodiment, a contemplated compound has the structure of Formula C4:

[0097]

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Wherein W, R ¹ , R ⁵ , and R ⁶ are as defined above, and R ¹ is preferably PhR ⁴ , also as defined above. Furthermore, in view of the above selection that W is a 1,2-phenylene group and R ¹ is PhR ⁴ , particularly preferred compounds have the following formulas VIB, VIB-1, VIB-2, VIB in structure: -3, VII, VII-B, VI
Corresponds to IC, VIID, VIIE, VIII and VIIIB, where -AREY, -GAREY, W ²
The above definitions for R ¹ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ²⁰ also apply, wherein the substituent -AREY is attached to the ring structure W ² or the indicated ring structure .

[0099]

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[0100]

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Compounds corresponding in their structure to the formulas D, D1, D2, D3 and D4 below, wherein the above definitions for -AREY, R ⁴ , R ⁵ , R ⁶ and R ²⁰ also apply here And wherein each of A, B, C and D in the ring structure is carbon, nitrogen, sulfur or oxygen, which is present or absent such that the indicated ring is 5- or 6-membered. Included among the particularly preferred contemplated compounds herein, and can be viewed as a subset of the Formula VIB compounds.

[0102]

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[0103]

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The compound of Example 24 has a structure corresponding to the structure of Formula D2. In that compound, R ⁵ and R ⁶ are both methoxy, the A moiety is a sulfur atom, -S-, and R is 1
, 4-phenylene; E is absent, and the moiety Y is hydride. The compound of Example 25 also corresponds in structure to formula D2. Here, R ⁵ and R ⁶ are again methoxy, the A portion is an oxygen atom, -O-, and R is 1,4-
Phenylene, E is absent, and moiety Y is a dialkoxy-substituted phenyl (
Aryl) group.

Particularly preferred compounds contemplated herein are shown below, along with the numbers of the specific examples for preparing each.

[0106]

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[0107]

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[0108]

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[0109]

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[0110]

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[0111]

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[0112]

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[0113]

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[0114]

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[0115]

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[0116]

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[0117]

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The term “hydrocarbyl” is used herein as a shorthand term including linear and branched aliphatic and cycloaliphatic groups or groups containing only carbon and oxygen. Thus, alkyl, alkenyl and alkynyl groups are contemplated, while aromatic hydrocarbons such as phenyl and, more precisely, naphthyl groups, which are also strictly hydrocarbyl groups, are substituted with aryl groups as discussed herein below. Referred to as a group. Where specific aliphatic hydrocarbyl substituents are intended,
The groups are listed; ie, C ₁ -C ₄ alkyl, methyl or dodecenyl.
Exemplary hydrocarbyl groups contain 1 to about 12 carbon atom chains, and preferably contain 1 to about 10 carbon atom chains.

Particularly preferred hydrocarbyl groups are alkyl groups. In conclusion, generalized but more preferred substituents can be listed by substituting the descriptor "hydrocarbyl" with "alkyl" in any of the substituents enumerated herein. . Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like. Examples of suitable alkenyl groups include ethynyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. It is. Examples of alkynyl groups include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

If the usual way of removing the trailing “yl” and adding an appropriate suffix is not always appropriate because the resulting name may resemble one or more substituents Except for when using the term “hydrocarbyl”, the usual chemical suffix nomenclature is followed. Thus, hydrocarbyl ethers are referred to as "hydrocarbyloxy" groups rather than "hydrocarbonyl (carboyy)" groups, as they may probably be more appropriate when following the usual rules of chemical nomenclature. On the other hand, when using the suffix, it is not unclear whatsoever,
) Hydrocarbyl groups containing an O-functionality are referred to as hydrocarbyl groups. As the skilled artisan will appreciate, substituents that may not be present, such as in a C ₁ alkenyl group, are not intended to be encompassed by the term “hydrocarbyl”.

The term “carbonyl”, alone or in combination, signifies a —C (= O) — group,
Here, the remaining two bonds (valency) are independently substituted. The terms "thiol" or "sulfhydryl", alone or in combination, refer to an -SH group. The term "thio" or "thia", alone or in combination, means a thiaether group; that is substituted ether oxygen by sulfur atom, such as in thiophenoxy group (C ₆ H ₅ -S-) , An ether group.

The term “amino”, alone or in combination, means an amine or —NH ₂ group, while the term mono-substituted amino, alone or in combination, refers to a substituted amine —N (H
) (Substituent) group, wherein one oxygen atom is substituted by a substituent, and disubstituted amine means -N (substituent) ₂ , where two oxygen atoms of an amino group Is substituted by independently selected substituents. Amines, amino groups and amides are labeled as primary (I °), secondary (II °) or tertiary (III °) or unsubstituted classes, depending on the degree of amino nitrogen substitution Can be mono-substituted or di-substituted. A quaternary amine (IV °) means a nitrogen having _four substituents [-N + (substituent) ₄ ] to which a positively charged counter ion is bound, or N-
Oxide one substituent is oxygen and the group is [-N + (substituent) ₃ -O ^-] meant to be shown as; that is, charge is consumed internally.

The term “cyano”, alone or in combination, signifies a —C-triple bond —N (—CN) group. The term "azido", alone or in combination, means -N-double bond-N-double bond-N-(-N = N = N-).

The term “hydroxyl”, alone or in combination, signifies an —OH group. The term "nitro", alone or in combination, means a -NO ₂ group. The term "azo", alone or in combination, signifies the -N = N- group, wherein the bond at the terminal position is independently substituted. The term "hydrazino", alone or in combination, signifies the group -NH-NH-, wherein the remaining two bonds (valency) are independently substituted. The oxygen atom of the hydrazino group may be independently substituted with a substituent, and the nitrogen atom may form an acid addition salt or may be quaternized.

The term “sulfonyl”, alone or in combination, signifies the group —S (O) ₂ —
The remaining two bonds (valency) may be independently substituted. The term “sulfoxide”, alone or in combination, signifies the group —S (= O) —, where the remaining 2
Two bonds (valency) may be independently substituted. The term “sulfonylamide”, alone or in combination, signifies the group —S (= O) ₂ —N 基, where the remaining 3
The two bonds (valency) are independently substituted. The term "sulfinamide", alone or in combination, means a -S (= O) ₁ N = group wherein the remaining three bonds (valences) are independently substituted. The term "sulfenamide", alone or in combination, signifies the -SN = group, wherein the remaining three bonds (valency) are
Independently substituted.

The term “hydrocarbyloxy”, alone or in combination, signifies a hydrocarbyl ether group, wherein the term hydrocarbyl is as described above.
Examples of suitable hydrocarbyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term "cyclohydrocarbyl", alone or in combination, signifies a hydrocarbyl group containing 3 to about 8 carbon atoms, preferably about 3 to about 6 carbon atoms, and is cyclic. The term "cyclohydrocarbyl hydrocarbyl" means a hydrocarbyl group as defined above, which is substituted by cyclohydrocarbyl, also as defined above. Examples of such cyclohydrocarbyl hydrocarbyl groups include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctynyl and the like.

The term “aryl”, alone or in combination, optionally, refers to one or more substituents selected from hydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, nitro, and the like, for example, phenyl, p-tolyl ( tolyl), 4-
A phenyl or naphthyl group is meant having methoxyphenyl, 4- (tert-butoxy) phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and the like. The term “arylhydrocarbyl”, alone or in combination, signifies a hydrocarbyl group as defined above wherein one oxygen atom is replaced by an aryl group as defined above, eg, benzyl, 2-phenylethyl, and the like. The term "arylhydrocarbyloxycarbonyl", alone or in combination, is intended to mean the term "arylhydrocarbyl" having the meaning given above.
A group of the formula -C (O) -O-arylhydrocarbyl is meant. An example of an arylhydrocarbyloxycarbonyl group is benzyloxycarbonyl. The term "aryloxy" has the meaning indicated above on the term aryl, of the formula aryl
It means a group of -O-. The term “aromatic ring” refers to substituted-aromatic ring sulfonamides, substituted
An aryl or heteroaryl as defined above in combination with an aromatic ring sulfinamide or a substituted aromatic ring sulfenamide and the like.

The term “hydrocarbyloyl” or “hydrocarbylcarbonyl”, alone or in combination, signifies an acyl group derived from a hydrocarbyl carboxylic acid,
Examples include acetyl, propionyl, acryloyl, butyryl, valeryl, 4-methylvaleryl, and the like. The term "cyclohydrocarbylcarbonyl"
Acyl groups derived from monocyclic or bridged cyclohydrocarbylcarboxylic acids such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, etc., optionally, for example, 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido- Hydrocarbiroylamino groups such as 1,2,3,4-tetrahydro-2-naphthoyl,
Derived from a benz-fused monocyclic cyclohydrocarbyl carboxylic acid, substituted by The terms “arylhydrocarbyloyl” or “arylhydrocarbylcarbonyl” are phenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl, (2-naphthyl) acetyl, 4-chlorohydrocinnamoyl, 4-aminocinna An acyl group derived from an aryl-substituted hydrocarbyl carboxylic acid, such as moyl, 4-methoxycinnamoyl, is meant.

The term “aroyl” or “arylcarbonyl” refers to an acyl group derived from an aromatic carboxylic acid. Examples of such groups include benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl) benzoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6- (benzyloxycarbonyl)- Aromatic carboxylic acids, optionally substituted benzoic or naphthoic acids, such as 2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxyformamido) -2-naphthoyl Is included.

A heterocyclyl (heterocyclo) or heterocyclohydrocarbyl moiety of a heterocyclylcarbonyl, a heterocyclyloxycarbonyl, a heterocyclylhydrocarbyloxycarbonyl, or a heterocyclohydrocarbyl group may be
One or more carbon atoms by halogen, alkyl, alkoxy, oxo groups, etc., and / or 2 by hydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbylyl, aryl or arylhydrocarbyl.
A nitrogen atom (i.e., -NH-) or a tertiary nitrogen atom (i.e., = N-) substituted by an oxide and attached via a carbon atom, one to one selected from nitrogen, oxygen and sulfur. A saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle containing 4 heteroatoms.

A tertiary nitrogen atom having three substituents can also form an N-oxide [= N ⁺ (O) ⁻ ] group. Examples of such heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, and the like.

The heteroaryl portion of the heteroaroyl, heteroaryloxycarbonyl, or heteroarylhydrocarbiroyl (heteroarylhydrocarbylcarbonyl) group, for example, contains a heteroatom and is optionally substituted as defined above for heterocyclyl. An aromatic monocyclic, bicyclic, or tricyclic heterocycle. A “heteroaryl” group is a group of one or two other than carbon
Or an aromatic heterocyclic ring substituent, preferably containing up to 4 atoms. Those heteroatoms may be nitrogen, sulfur or oxygen. Heteroaryl groups can contain fused ring systems having one 5- or 6-membered ring or two 6-membered rings or 5- and 6-membered rings. Exemplary heteroaryl groups include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl;
3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-,
5-membered ring substituents such as 1,2,5- or 1,3,4-oxadiazolyl and isothiazolyl groups; benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl,
6- / 5-membered fused ring substituents such as benzoxazolyl, purinyl and anthranilyl groups; and 1,2-, 1,4-, 2,3- and 2,1-benzopyronyyl, quinolinyl, isoquinolinyl, cinnolinyl, Includes 6- / 6-membered fused rings such as quinazolinyl, and 1,4-benzoxazonyl groups.

The term “cyclohydrocarbylhydrocarbyloxy-carbonyl” refers to an acyl group derived from the cyclohydrocarbylhydrocarbyloxycarboxylic acid of the formula cyclohydrocarbylhydrocarbyl-O—COOH, where cyclohydrocarbylhydrocarbyl has the meaning indicated above. Have. The term "aryloxyhydrocarbiroyl" refers to an acyl group of the formula aryl-O-hydrocarbiroyl, where aryl and hydrocarbylyl have the meanings indicated above. The term "heterocyclyloxycarbonyl" refers to an acyl group derived from heterocyclyl-O-COOH, where heterocyclyl is as defined above. The term "heterocyclylhydrocarbyloyl" is an acyl group derived from a heterocyclyl-substituted hydrocarbylcarboxylic acid, wherein heterocyclyl has the meaning indicated above. the term"
“Heterocyclylhydrocarbyloxycarbonyl” refers to an acyl group derived from heterocyclyl-substituted hydrocarbyl-O—COOH, where heterocyclyl has the meaning indicated above. The term “heteroaryloxycarbonyl” refers to heteroaryl
Means an acyl group derived from a carboxylic acid represented by -O-COOH, where heteroaryl has the meaning indicated above.

The term “aminocarbonyl,” alone or in combination, refers to an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid, where the amino group is oxygen, hydrocarbyl, aryl, aralkyl, cycloalkyl, It may be a primary, secondary or tertiary amino group containing a substituent selected from hydrocarbyl, cyclohydrocarbyl hydrocarbyl group and the like. The term "aminohydrocarbilloyl" refers to an acyl group derived from an amino-substituted hydrocarbyl-carboxylic acid,
Here, the amino group may be a primary, secondary or tertiary amino group independently containing a substituent selected from oxygen, alkyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbyl hydrocarbyl groups and the like.

The term “halogen” means fluorine, chlorine, bromine or iodine. The term "halohydrocarbyl" means a hydrocarbyl group having the meanings indicated above, wherein one or more oxygens has been replaced by a halogen. Examples of such halohydrocarbyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. The term perfluorohydrocarbyl refers to a hydrocarbyl group,
Here, each oxygen is substituted by a fluorine atom. Examples of such perfluorohydrocarbyl groups are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl, in addition to trifluoromethyl described above.

Tables 1 to 88 below show some contemplated sulfonylaryl or heteroaryl hydroxamic acid compounds as structural formulas showing the substituents. Ta
The groups of each of the compounds from ble 1 to 70 are represented by the general formula followed by a series of preferred moieties or constituents of various substituents, which can be attached at the positions explicitly indicated in the general structure or Represents a group. Substituent symbols, for example, R ¹ , R ² , X
, Are as shown in the respective Tables, and are often different from those shown in the structural formulas having uppercase Roman numeral numbers elsewhere herein. One or two bonds (straight lines) are shown with their substituents to indicate the position of each of the bonds in the exemplified compound. This system is
It is well known in the field of chemical communication and is widely used in scientific papers and presentations. Tables 71-88 show specific compounds of the preceding Table and other contemplated compounds using the complete molecular formula. (In these Tables, Example indicates the number of the embodiment shown below.)

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Treatment Methods Processes for treating a host mammal having a condition associated with pathological matrix metalloprotease activity are also contemplated. Such methods include administering to a mammalian host having such a condition an effective amount of a compound described herein for inhibiting MMP enzyme. In particular, the use of multiple repeated administrations is contemplated.

A contemplated compound is for treating a host mammal, such as a primate, such as a mouse, rat, rabbit, dog, horse, monkey chimpanzee or human, having a condition associated with pathological matrix metalloprotease activity. Used for

It is also contemplated that contemplated compounds are similarly used for the treatment of disease states that may be affected by the activity of metalloproteases such as TNF-α convertase.
Representative of such disease states include acute phase reactions of shock and sepsis, coagulation reactions, bleeding and cardiovascular effects, fever and inflammation, anorexia and cachexia.

In the treatment of disease states associated with pathological matrix metalloprotease activity, the contemplated MMP inhibitory compounds can be used, where appropriate, in the form of an inorganic or organic acid derived amine salt. Representative acid salts include the following,
Not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate Salt, cyclopentane propionate,
Dodecyl sulfate, ethane sulfonate, glucoheptanate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy -Ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectate, persulfate, 3-phenylpropionate, picrine Acid salts, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.

Also, the basic nitrogen-containing groups may be substituted with lower alkyl (C ₁ -C ₆ ) halides such as methyl, ethyl, propyl and butyl chloride, bromide, and iodide to enhance water solubility; dimethyl, diethyl Long chain (C ₈ -C ₂₀ ) halides, such as dialkyl sulfates, such as, dibutyl, and diamyl sulfate, decyl, lauryl, myristyl and dodecyl chloride, bromide, iodide, aralkyl halides, such as benzyl and phenethyl bromide And the like. Thereby, a water or fat-soluble or dispersible product is obtained as desired. A salt is formed by combining the basic compound with the desired acid.

Other compounds useful in the present invention that are acids can also form salts. Examples include salts with alkali or alkaline earth metals or organic bases, such as sodium, potassium, calcium or magnesium, or basic quaternary ammonium salts.

In some cases, salts may be used as an aid in isolating, purifying, or dissolving the compound of the present invention. A single or aliquot of the effective amount of the MMP enzyme inhibitor is administered to the host mammal, for example, at about 0
. 001 to about 100 mg / kg body weight, preferably about 0.001 to about 30 mg / kg body weight per day and more usually about 0.01 to about 10 mg can be administered. Dosage unit compositions may be in amounts or submultiples thereof to make up the daily dose. Appropriate dosages can be administered in divided daily doses for the daily dose. Multiple doses per day can also increase the total daily dose, if desired by the person prescribing the drug.

The mode of administration for treating a disease state with a compound and / or composition of the invention is selected according to a variety of factors, including the type, age, weight,
Pharmacological studies such as gender, diet and medical condition, disease severity, route of administration, activity, efficacy, pharmacokinetic and toxicological aspects of the specific compound used, presence or absence of drug delivery system and compound Is administered as part of a drug combination. Thus, the dosage regimen actually used will vary widely and can depart from the preferred dosage regimens described above.

[0233] Useful compounds of the present invention can be formulated as pharmaceutical compositions. Therefore,
Such compositions may be administered orally, parenterally, by inhalation spray, rectally or topically, and the dosage unit formulation may be any conventional pharmaceutically acceptable non-toxic carrier, as desired. Includes adjuvant, and vehicle. Topical administration may also include the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. For drug formulations, for example, Hoov
er, John E. , Remington's Pharmaceutical Sciences , Merck Publishing Co.
Easton, Pennsylvania; 1975 and Liberman, H .; A. and Lachman, L. , Ed
s. , Pharmaceutical Dosage Forms , Marcel Decker, New York, N.W. Y. , 1980
It is explained in.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. further,
Fatty acids such as oleic acid find use in the preparation of injectables. Dimethylacetamide, surfactants, including ionic and non-ionic surfactants, polyethylene glycol can be used. Mixtures of solvents and wetting agents as described above are also useful.

Suppositories for rectal administration of the drug may be prepared by mixing the drug with a suitable nonirritating excipient, such as cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and polyethylene glycol. Such excipients are solid at normal temperatures, but liquid at rectal temperatures, and will therefore melt in the rectum to release the drug.

[0236] Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound of the invention is usually combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally,
The compounds are lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid,
It can be mixed with gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol and then made into tablets or capsules for convenient administration. Such tablets or capsules may include sustained release formulations, which may be provided during the dispersion of the active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage form may contain buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.

For therapeutic purposes, preparations for parenteral administration may be in the form of sterile injectable aqueous or non-aqueous solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules, which contain one or more carriers or diluents, for use in formulations for oral administration. The compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the formulation arts.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and inert diluents commonly used in the art, such as water. Elixir. Such compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host mammal treated and the particular mode of administration. Preparation of Useful Compounds Preparation methods are provided in the detailed description and schemes according to representative chemical transformations that are useful for preparing the compounds of the present invention. These syntheses, like all reactions described herein, can be performed in a dry, inert atmosphere such as nitrogen or argon, if desired. The selected reactions known to those skilled in the art may be performed under a dry atmosphere, such as dry air, but other synthetic steps, such as aqueous acid or base ester or amide hydrolysis, should be performed under laboratory air. Can be.

The aryl and heteroaryl compounds of the invention as defined above by W can be prepared by methods analogous to those known to those skilled in the art. The following detailed description is
It is to be understood that any reference to one refers to both aromatic systems, ie, heteroaromatic and carbon aromatic.

In general, the choice of starting materials and reaction conditions may vary as is known to those skilled in the art. Usually, the conditions are not limited to one type, as they can be varied according to the requirements and choices of a person skilled in the art. Conditions will be selected as desired for a particular purpose, such as small scale production or large scale production. In each case, the use of unsafe or environmentally unfriendly materials and reagents will usually be minimized. Examples of less desirable materials include diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, some halogenated solvents, benzene, and the like. In addition, many starting materials are available commercially from catalogs and other arrangements.

The aromatic compounds of the present invention wherein y is 1 can be prepared by converting a carbonyl group bonded to an aromatic ring ortho-substituted by a sulfide (eg, benzene) as described. The sulfide can be produced by a nucleophilic substitution reaction of orthofluoride.

The nucleophile may be a thiol or thiolate prepared from an aryl thiol as described below. A preferred thiol is 4-phenoxybenzene thiol, which is prepared in situ using potassium carbonate in isopropyl alcohol at reflux temperature.
Converted to its anion (thiolate) with u.

The carbonyl group may be an aldehyde, ketone or carboxylic acid derivative, ie, a protected carboxylic acid or hydroxamate. The preferred carbonyl group is an aldehyde, and the preferred aldehyde is 2-fluorobenzene aldehyde (ortho-fluorobenzaldehyde). Ketones can be prepared using reagents such as those described below for the oxidation of sulfides, or other methods known in the art.
It can be converted to an acid and / or an acid derivative by oxidation. Note that this oxidation may be the oxidation of the sulfide intermediate to the corresponding sulfone in the same reaction system, ie, in the same pot, if desired.

Further, the carbonyl group can be homologated, if desired, by reaction with an anion to form an addition compound. Examples of homologation reagents include trisubstituted methane compounds such as tetraethyldimethyl ammonium ethylene diphosphonate or trimethyl orthoformate. Tetraethyldimethylammonium ethylene diphosphonate is preferred. Hydrolysis of the reaction product can provide a phenylacetic acid-substituted aromatic ring having a sulfide of the present invention. Acid hydrolysis is preferred. The acids and bases are described below, with hydrochloric acid being preferred.

In addition, the sulfide can be oxidized to form a sulfone in one or two steps as described below. A preferred oxidizing reagent is hydrogen peroxide in acetic acid.
The carboxylic acid intermediates of the present invention can be converted to protected derivatives, such as esters, or activated carboxyls for reaction with hydroxylamine and / or protected hydroxylamine, ie, a hydroxamate. It is possible to convert to a group. The conversion of the acid to the hydroxamate is described below, along with the coupling method and removal of protecting groups, if necessary.

A preferred protected hydroxamic acid derivative is an O-tetrahydropyranyl compound and the preferred coupling method is diimide (EDC), hydroxybenzo for coupling reactions to form intermediate hydroxybenzotriazole activated esters. Use triazole and DMF solvents. A preferred reagent for removal of the THP protecting group is hydrochloric acid.

The alkylation of the acid at the carbon alpha with a carbonyl group to form the compounds of the present invention can be accomplished by first forming an anion using a base. Bases are discussed below. Preferred bases are strong bases that are constrained and / or non-nucleophilic, such as lithium amide, metal hydride or lithium alkyl.

Following or during anion formation, an alkylating agent (electrophile) that undergoes a nucleophilic substitution reaction is added. Non-limiting examples of such alkylating agents include:
Examples include haloalkanes, dihaloalkanes, haloalkanes that are also substituted with activated ester groups or activated esters, and alkanes that are substituted with sulfate esters.

Activated ester groups are known in the art and include, for example, activated esters of alcohols or halo compounds, esters of halo alcohols such as bromo, iodo, or chloro derivatives of tosylate, triflate or mesylate. Can be. Compounds with R ² and R ³ as defined above together, 2-substituted alkylating agent, i.e., using an alkylating agent with two leaving groups in the same molecule, can be produced it can. For example, a 1,5-dihalo-diethyl ester or similar reagent containing one or more sulfate leaving groups substituted for one or more halogens can be used to form a pyran ring. Similar sulfur, nitrogen or protected nitrogen alkylating agents can be used to form the thiapiran or piperidine ring. Thiapiran can be oxidized to form a sulfoxide or sulfone using the methods described herein. The leaving group in the electrophile may be a halogen, such as chlorine, bromine or iodine, or a sulfonic ester as described above, for example, toluenesulfonic acid (tosylate), triflate, as is known in the art. , Mesylate or the like.

A cyclic amino acid, heterocyclic or alpha amino acid is defined by R ² and R ³ , which may include an amino acid (nitrogen heterocyclic) and may be protected or unprotected. However, their conversion into compounds of the invention can be effected by alkylation or acylation. The carboxylic acid group may be protected with a group such as an alkyl ester such as methyl, ethyl, tert-butyl, or an arylalkyl ester such as benzyl, or may remain as a carboxylic acid. Protected amino acids such as ethyl esters are preferred. The substituents on the heterocyclic group are as defined above, but may also include hydrogen, tert-butoxycarbonyl (BOC or tBOC), benzyloxycarbonyl (Z) and iso-butyloxycarbonyl groups. Further, when the N-substituent is not hydrogen, the amine can be considered not only a product of the invention, but also a protected intermediate.

The nitrogen substituents on the amino acid portion of the compounds of the invention can be varied. In addition, such changes can be made based on the needs and objectives of those skilled in the art of preparing compounds of the present invention. Changes in the nitrogen side chain include replacing the hydrogen substituent with an alkyl, arylalkyl, alkene or alkyne.

This can be done by methods known in the art, such as alkylation of the amine with an electrophile such as a desired side chain halo or sulfate (activated ester) derivative. . The alkylation reaction is generally performed in the presence of a base as described above, and in a pure or mixed solvent as described above. The preferred base is potassium carbonate and the preferred solvent is DMF.

The alkenes, arylalkenes, arylalkynes and alkynes so formed can be reduced to the alkyl or arylalkyl compounds of the present invention by, for example, hydrogenation with a metal catalyst and hydrogen; Aryl alkynes can be reduced to alkenes, aryl alkenes, aryl alkanes or alkanes by the catalytic hydrogenation conditions described herein or by non-activated metal catalysts. Catalysts include, for example, Pd, Pd-carbon, Pt, PtO ₂
And the like. Less active catalysts (deactivated) include Pd-BaCO ₃ or Pd-quinoline and / or sulfur.

An alternative to amine nitrogen alkylation is reductive alkylation. In this method known in the art, a secondary amine is treated with an aldehyde or ketone in the presence of a reducing agent such as borane, borane: THF, borane: pyridine, lithium aluminum hydride. Alternatively, the reductive alkylation is performed under hydrogenation conditions in the presence of a metal catalyst. Catalysts, hydrogen pressures and temperatures are described herein and are known in the art. A preferred reductive alkylation catalyst is a borane: pyridine complex.

When the intermediate is a carboxylic acid, standard coupling reactions known in the art can be used to form the compounds of the present invention including the protected intermediate.
For example, an acid can be converted to an acid chloride, mixed anhydride or activated ester,
It is possible to react with an alcohol, amine, hydroxylamine or protected hydroxylamine in the presence of a base to form an amide, ester, hydroxamic acid, protected hydroxamic acid. This is the same product as described above. The base is described above and includes N-methyl-morpholine, triethylamine and the like.

Coupling reactions of this nature are known in the art, especially in the art relating to peptide and amino acid chemistry. Removal of protecting groups, if desired, can be accomplished using standard hydrolysis conditions, such as base hydrolysis or exchange, or acid exchange or hydrolysis, as described.

The schemes and / or specifications also describe the conversion of a carboxylic acid protected as an ester or amide to a hydroxamic acid derivative such as an O-arylalkyl ether or O-cycloalkoxyalkyl ether group such as a THP group. I do. Methods for treating an acid or acid derivative with hydroxylamine or a hydroxylamine derivative to form a hydroxamic acid or hydroxamate derivative have been described above. Hydroxylamine can be used in an exchange reaction by treatment of the precursor compound directly to provide the hydroxamic acid, where the carboxyl is at room temperature or higher and the ester or the hydroxylamine is hydrolyzed by hydroxylamine hydrochloride or one or more equivalents of hydroxylamine. Protected as amide. The solvent or solvents are usually the protic or protic solvent mixtures described herein.

The exchange process can be further catalyzed by adding an acid. Alternatively, a base such as a salt of an alcohol used as a solvent, for example sodium methoxide in methanol, can be used in situ to form hydroxylamine from hydroxylamine hydrochloride, which is exchanged for an ester or amide. May be. As mentioned earlier, tetrahydropyranyl - hydroxamic (THPONH _2), benzylhydroxylamine (BnONH _2), such as the protected hydroxylamine such as O- (trimethylsilyl) hydroxylamine makes it possible to exchange. In this case, the compound formed is a tetrahydropyranyl (THP), benzyl (Bn) or TMS hydroxamic acid derivative. Removal of protecting groups, if desired, can be accomplished by standard methods known in the art, for example, after conversion of other portions of the molecule or after storage, acid hydrolysis of the THP group described above or hydrogen and palladium, It can be carried out by reducing and removing the benzyl group with a metal catalyst such as platinum or palladium-carbon.

The alpha-amino acids or alpha-hydroxycarboxylic acids or protected carboxylic acids, hydroxamates or hydroxamic acid derivatives or intermediates (precursors) of the present invention can be prepared, for example, from the alpha carbon or derivative of the acid described.
It can be prepared by substituting a halogen, sulfate or other electrophile. Halogenations of acids, esters, acid chlorides, etc. are known in the art and include, for example, HVZ reaction, CuCl ₂ treatment, N-bromo or N-chloro-succinimide, I ₂ , carbon tetraiodide or tetrabromide. Examples of the treatment include carbon. Halogen can be replaced with a nucleophilic reagent in a SN ₂ reaction. Nucleophiles can include hydroxides, ammonia or amines.

The aryl or heteroaryl carboxylic acids of the present invention wherein y is 0 and z is 1 can be prepared from a heteroaryl or aryl fused lactone. An example of a fused lactone is phthalide. The preferred starting material is phthalide. It can be in order to perform to provide the intermediate sulfide or thiol compound, or a compound of the present invention of the present invention, the SN ₂ substitution with methylene carbon, treating the compound thiol, with thiolate or metal -SH . A preferred thiol is 4-phenoxy-benzenethiol, which is used in the presence of potassium carbonate as the preferred base.
Before or after the conversion of the acid to the hydroxamate or hydroxamic acid, the sulfide may be oxidized to the sulfone of the invention. A preferred oxidizing agent is meta-chloroperbenzoic acid.

Preferred acid activating groups are chlorides prepared by reacting oxalyl chloride as a preferred reagent with an acid. Phthalide or a heteroaryl analog of phthalide is an ortho- (haloalkyl) -aryl acid or ortho- (haloalkyl)-
To form a heteroaryl acid derivative, it can be treated with a Lewis acid such as zinc chloride or zinc bromide together with a halogenating reagent such as phosphorus trichloride or thionyl bromide. Examples include bromomethyl acid bromide and chloromethyl acid chloride. These carboxylic acids can be derivatized to a hydroxamic acid or hydroxamic acid precursor (hydroxamate) by a protecting group, or hydrolyzed to the acid, as desired. A preferred hydroxamate forming reagent is O- (trimethylsilyl) hydroxylamine (TMS-hydroxylamine), and removal of the TMS protecting group is preferably performed by acid hydrolysis using hydrochloric acid.

In this example, replacement of a halogen by a thiol in the presence of a base or a preformed thiolate (SN ₂ ) is as described and / or as indicated, and as is known in the art. Can be performed. Further oxidation of the sulfide can be performed before or after derivatization of the carboxylic acid, as described for making the hydroxamic acids of the present invention. Removal of the protecting group can be performed using acid hydrolysis or reduction, as described herein.

The alcohols of the present invention can be protected or deprotected as needed or desired. Protecting groups include THP ethers, acylated compounds and various silyl derivatives. Those groups, including their protection and elimination, are known in the art.

Examples of bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium or magnesium, oxides such as sodium, potassium, lithium, calcium or magnesium, sodium, potassium, lithium Primary (I) such as metal carbonates such as calcium or magnesium, metal bicarbonates such as sodium or potassium bicarbonate, alkylamines, arylalkylamines, alkylarylalkylamines, heterocyclic amines or heteroarylamines °), 2nd grade (II °) or 3rd grade (III °
) Organic amines, ammonium hydroxide or quaternary ammonium hydroxide. Non-limiting examples of such amines include triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclonan, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N, N'-dimethyl. Examples thereof include piperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, and tetramethylethylenediamine.

Non-limiting examples of ammonium hydroxide, usually made from amines and water, include:
Ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiisopropyl ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholium hydroxide, N-
Methylmorpholium hydroxide, N, N'-dimethylpiperazium hydroxide, N
-Ethylpiperidium hydroxide and the like. Non-limiting examples of quaternary ammonium hydroxides include tetraethylammonium hydroxide,
Tetramethylammonium hydroxide, dimethyldiisopropylammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, methyltribenzylammonium hydroxide, N, N-dimethylmorpholium hydroxide, N, N, N ', N'-tetramethylpiperazenium hydroxide, N-ethyl-N'-hexylpiperidinium hydroxide and the like can be mentioned. Suitable reagents include metal hydrides, amides or alcoholates, for example, calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium ethoxide Amides, potassium diisopropylamide and the like can also be mentioned. Alkyl or aryl lithium reagents such as methyl, phenyl, butyl, iso-butyl, sec-butyl or tert-butyl lithium, nodium or potassium salts of dimethyl sulfoxide, Grignard reagents such as methyl magnesium bromide or methyl magnesium chloride, dimethyl cadmium and the like Organometallic deprotonating agents, such as organic cadmium reagents, can also be used as bases that form salts or catalyze the reaction. Also quaternary ammonium hydroxide or mixed salts,
Useful for assisting phase transfer coupling or as a phase transfer reagent. A preferred base for use in the alkylation reaction is lithium diisopropylamide as described above.

In general, the reaction medium may contain a single solvent, a mixed solvent of the same or a different class, and may be used as a reagent in a single or mixed solvent system. The solvent may be protic, aprotic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or 95% pure or absolute ethanol, isopropanol, and the like. Representative aprotic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butyl methyl ether (TBME), xylene,
Examples include aromatic compounds such as toluene or benzene, ethyl acetic acid, methyl acetic acid, butyl acetic acid, trichloroethane, methylene chloride, ethylene dichloride (EDC), hexane, heptane, isooctane, and cyclohexane. Examples of the dipolar aprotic solvent include dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea, and N-methylpyrrolidone.

Non-limiting examples of reagents used as part of a solvent or mixed solvent system include organic or inorganic mono- or complex protic acids or bases, such as hydrochloric acid, phosphoric acid, sulfuric acid, Acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohol or amine to form an ester or amide, or the present invention And a thiol for forming a product of the formula (1). Preferred reaction temperatures are room temperature or below, or moderate heating (-10 ° C to 60 ° C). If desired, the reaction temperature can be from about −78 ° C. to the reflux temperature of the reaction solvent or solvents. The preferred solvent for the alkylation reaction is tetrahydrofuran (THF).

Acids are used in many reactions during various syntheses. In addition to the preparative methods in this detailed description, the scheme also describes the use of acids to remove the THF protecting group to form hydroxamic acid, the tert-butoxycarbonyl group, the hydroxylamine / ester exchange, and the like. Acid hydrolysis of carboxylic acid protecting groups or derivatives is known in the art. These methods known in the art can use an acid or acidic catalyst. The acid may be a mono-, di- or tri-protic organic or inorganic acid. Examples of acids include hydrochloric, phosphoric, sulfuric, acetic, formic, citric, succinic, hydrobromic, hydrofluoric, carbonic, phophorus, p-toluenesulfonic, trifluoromethanesulfonic Trifluoroacetic acid, difluoroacetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, 2,6-dimethylbenzenesulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. They also include aluminum chloride, boron trifluoride,
A Lewis acid such as antimony pentafluoride may be used.

Contemplated compounds can include, for example, compounds in which the amine nitrogen is acylated to provide an amino acid carbamate. Non-limiting examples of these carbamates include carbobenzoxycarbonyl (z, CBZ, benzyloxycarbonyl), iso-butoxycarbonyl and tert-butoxycarbonyl (BO
C, t-BOC) compounds. The materials are manufactured at various stages of the synthesis, as described above, using methods known in the art, based on the needs and determinations of those skilled in the art.

Useful synthetic techniques and reagents include those used in protein, peptide and amino acid synthesis, coupling and transformation chemistry. Examples of such protection or synthesis include tert-butoxycarbonyl (BOC), benzyloxycarbonyl (z)
Synthesis and removal and use. The conversion of the amino acids, amino esters, amino acid hydroxamates, amino acid hydroxamate derivatives and amino acid amides of the present invention are described herein and / or shown in the scheme. This includes, for example, active ester or mixed anhydrous coupling, where necessary, where the preferred base is a tertiary amine such as N-methylmorpholine. Reagents for protecting the amino group of protected amino acids include carbobenzoxycyclolide, iso-
Mention may be made of butyl chloroformate, tert-butoxycarbonyl chloride, di-tert-butyl dicarbonate and the like, which react with the amine in an aprotic or dipolar aprotic solvent such as DMF or THF or a mixture of solvents.

The removal of carbamates, silyl groups and benzyl, p-methoxybenzyl, or other substituted benzyl groups, or protecting groups such as diphenylmethyl (benzhydryl) or triphenylmethyl (trityl) is up to the skilled artisan. Can be carried out at different stages of the synthesis of the compounds of the invention as required by the described methods. These methods include amino acid, amino acid coupling, peptide synthesis, peptidomimetic synthesis techniques, and are known in the art. Examples of the removal method include catalytic hydrogenation, base hydrolysis, carbonyl addition reaction, and acid hydrolysis. Protecting group,
For example, both the preparation and removal of carbamates, benzyl groups and / or substituted arylalkyl groups are described in Green, T. et al. , Protecting Groups in Organic Chemistry , 2nd edition. , John Wiley & Sons, New York (1991). The preferred method of removing the BOC group is HCl gas in methylene chloride, which provides, after usual work-up, the HCl salt of the amino acids of the invention directly.

Sulfone compounds in which R ¹ is nitrobenzene can be prepared by the synthesis of thiols, displacement of electrophiles by nucleophilic thiols or thiolates, and oxidation of product thiol ethers to sulfones, such as compounds of the present invention. Can be synthesized.
For example, displacement of an electrophilic group with nitrobenzene thiol can provide compounds where R ¹ is nitrobenzene, which nitro group can be reduced to provide useful amino compounds where R ¹ is aniline. It should be noted that nitrobenzenethiol is an example and should not be regarded as limiting or required. Oxidation of the thioether product can be performed, if desired, as described below.

The reduction of the nitro group to an amine is a preferred method known in the art, hydrogenation. Usually, there are metal catalysts, such as Rh, Pd, Pt, Ni, with or without additional supports such as carbon, barium carbonate. The solvent may be a required protic or aprotic pure solvent or mixed solvent. The reduction can be performed at multiples of atmospheric pressure, from atmospheric pressure to the preferred about 40 pounds per square inch (psi).

The resulting amino groups can be alkylated if desired. The group can also be acylated, for example, with aroyl chloride, heteroaryl chloride or other amine carbonyl forming agents to form the R ₁ amide of the present invention. Amino sulfones or thioethers can also be reacted with carbonate chloride, sulfonyl chloride, carbamoyl chloride or isocyanate to form the corresponding carbamate, sulfonamide, or urea of the present invention. Acylation of amines of this type is known in the art and reagents are well known.

Typically, these reactions are carried out under inert and / or dry air at about 45 ° C to about -10 ° C.
C. in an aprotic solvent. Equivalents of non-competitive bases are usually used with sulfonyl chloride, acid chloride or carbonyl chloride reagents. Subsequent to or prior to this acylation step, the synthesis of the hydroxamic acid products of the present invention can be performed as described.

Other thiol reagents can also be used in making the compounds of the present invention. Examples are fluoroaryl, azidoaryl or azidoheteroaryl, or heteroarylthiol reagents. For these thiols, the nucleophiles described above can be used. Subsequently, oxidation to the corresponding sulfone can be performed.

When a sulfone is replaced by hydrazine or a substituted hydrazine, such sulfone can be oxidized to a hydrazone of the present invention. The fluoro-substituted sulfone can be treated, if desired, with a nucleophile such as ammonia, primary amine, quaternary ammonium or a metal azide salt or hydrazine under pressure to provide an azide, amino, substituted amino or hydrazino. Provide groups. Azides can be reduced to amino groups using, for example, hydrogen with a metal catalyst or metal chelate catalyst, or with an activated hydride transfer reagent. The amine can be acylated as described above.

Methods for making useful amine thiol intermediates include protection of aromatic or heteroaromatic thiols with trityl chloride to form trityl thiol derivatives, aromatic or heteroaromatic acids to form amides Treatment of the amine with a reagent such as chloride, removal of the trityl group with an acid to form a thiol. Acylating reagents include benzoyl chloride, and trityl removal reagents include trifluoroacetic acid and triisopropylsilane.

Fluorine on the fluorosulfones of the invention can also be substituted with other aryl or heteroaryl nucleophiles to form compounds of the invention. Such nucleophiles include phenol salts, thiophenols, -OH groups or -SH containing heteroaryl compounds, including aromatic heterocyclic compounds. Tautomers of groups such as azo, hydrazo, -OH or -SH are included as specifically useful isomers.

A preferred method of preparing intermediates in the substituted sulfone synthesis is to form the corresponding phenol-ether by oxidation of the appropriate acetophenone, for example, from peroxymonosulfuric acid and fluoroacetophenone. The phenol-ether is converted to its dimethylthiocarbamoyl derivative using dimethylthiocarbamoyl chloride, reconverted to the dimethylthiocarbamoyl derivative by heat, and the thiol required to make the thioether intermediate described and / or shown in the scheme. I will provide a.

Compounds of the present invention, including protected compounds or intermediates, are shown in the scheme
And / or can be oxidized to the sulfones described above. One skilled in the art can select alternative synthetic steps to perform this conversion of the sulfide to the sulfone or sulfoxide.

Reagents in non-limiting examples for this oxidation process include peroxymonosulfuric acid (OXONE®) hydrogen peroxide, meta-perchlorobenzoic acid, perbenzoic acid, peracetic acid, peracetic acid, Lactic acid, tert-butyl peroxide, tert-butyl hydroperoxide, tert
-Butyl hypochlorous acid, sodium hypochlorite, hypochlorous acid, sodium meta-periodate, periodic acid, ozone, and the like. As a protic, aprotic, dipolar aprotic solvent, either pure or mixed, for example, methanol / water can be selected. The oxidation can be carried out at a temperature from about -78 ° C to about 50 ° C, and can usually be selected from a range from -10 ° C to about 40 ° C.

The preparation of the sulfone can also be carried out in two steps: oxidation of the sulfide to the sulfoxide, followed by oxidation of the sulfoxide to the sulfone. The reaction may take place in one pot or by isolation of the sulfoxide. The latter oxidation can be carried out in a manner similar to the direct oxidation to the sulfone, except that preferably about one equivalent of the oxidizing agent can be used at a lower temperature, such as about 0 ° C. Preferred oxidizing agents include peroxymonosulfuric acid and meta-chloroperbenzoic acid.

The sulfonamides of the present invention can be made in an analogous manner using the methods and processes described herein. Aryl, substituted aryl, heteroaryl or substituted heteroaryl dicarboxylic anhydrides, imides (eg, phthalic anhydride or imide), their sulfonyl analogs or mixed carboxylic acid-sulfonic amides, imides (eg, , 2-benzenetriazole-3
(2H) -one 1,1-dioxide) or anhydride is a useful starting substrate. Reactions using such substrates can be performed before or after the substitution pattern of the aryl or heteroaryl ring has changed.

Sulfonamides can also be prepared from heterocyclic compounds such as saccharin analogs and saccharin analogs. Such compounds and methods are well-known in the literature. For example, alkylation of saccharin sodium followed by ring opening, or ring opening followed by alkylation, allows coupling, and THP (tetrahydropyranyl)
Or to form a protected hydroxamic acid derivative such as a TMS (trimethylsilyl) derivative. Hydrolysis of the protecting group provides the hydroxamic acid. The sulfonamide nitrogen can be further subjected to alkylation, acylation or other treatment to form various compounds of formula VI, for example, at this stage which favors coupling and deprotection.

As a non-limiting example, treatment of mixed sulfuric acid / carboxylic anhydride, (2-sulfobenzoic cyclic anhydride) with an alcohol or a salt of an alcohol or a protected hydroxamic acid can be carried out as a sulfonic acid or salt. A ring-opened carboxylic acid derivative (ester or anhydride, respectively) is provided. The carboxylic acid derivative so produced is a product of the present invention and can be converted to a sulfonyl halide according to standard methods with reagents such as thionyl chloride, phosphorus pentachloride and the like.

The reaction of a primary amine, secondary amine or ammonia with a sulfonyl halide, with or without the addition of a base, provides the sulfonamides or sulfonimides of the invention, wherein the sulfonamide is alkylated. To yield the sulfonamides of the invention or intermediates to the sulfonamides of the invention. These imides or amides of the sulfonamides can be alkylated as desired before or after ring opening to benzoic acid substituted sulfonamides or phenylacetic acid substituted sulfonamides.

The compounds with protected carboxyl groups prepared as described above can be readily converted to the hydroxamic acids of the invention by an exchange, combined exchange / hydrolysis or hydrolysis-coupling process. The exchange / conversion of esters, amides and protected hydroxylamines (protected hydroxamic acids) to hydroxamic acids is described herein. For example, a sulfonamide-ester can be hydrolyzed to a carboxylic acid, coupled with a THP-hydroxylamine reagent by a benzotriazole active ester, and subsequently deprotected. The phenylacetic acid analogs of the foregoing sulfobenzoic acid compounds can also be used in processes analogous to the previous processes, which are processes for producing the corresponding phenylacetic acid-derived compounds of the present invention.

An aryl or heteroaryl 5- or 6-membered thiolactone or dithiolactone is also a preferred starting material for the preparation of the compounds of the invention. Such thiolactones can be opened before or after altering the aryl or heteroaryl substitution pattern to form protected carboxylic acid derivatives such as esters, amides or hydroxylamides. The thiol group can be oxidized before or after the substitution change depending on the needs and desires of those skilled in the art.
Sulfur compounds can also be directly oxidized to sulfonyl chloride compounds using oxidizing reagents, and such oxidation mechanisms involved putative positive chlorine species. Next, the sulfonic acid derivative thus obtained is converted to the sulfonamide of the present invention as described above.

Changes in the substitution pattern on the ring of the compounds of this invention can be made by methods known in the art. Non-limiting examples of such methods include diazonium chemistry, aromatic ring substitution or addition-elimination sequences, metallation reactions and halogen metal exchange reactions.

The substituted or unsubstituted aryl or heteroaryl sulfonic acids, sulfonic acid derivatives or sulfonamides of the present invention can be prepared by the following starting materials, and can be used as a compound of the present invention or an intermediate compound of the present invention. Form the body.
Starting materials include halo-sulfonic or sulfonic acids, carbonyl compounds, isocyanates, halogenating reagents, alkylating reagents, acylating reagents, protected in such a way that the corresponding anion can react with carbon dioxide. Hydroxylamine isocyanate or isocyanate derivative. Anions can be formed, for example, by direct metallation or metal-halogen exchange. A substituted or unsubstituted aryl or heteroaryl sulfonic acid, sulfonic acid derivative or sulfonamide can be prepared by sulfonation or chlorosulfonation of a substituted or unsubstituted aryl or heteroaryl compound. Metallation reactions as well as metal-halogen exchange to form salts of the corresponding anions or complex anions are performed as described hereinbefore for lithium, sodium, potassium, palladium, platinum or complexes thereof. For example, or a strong base such as tert-butyllithium or sec-butyllithium. These intermediates are quenched by reagents as described herein. The resulting carboxylic acid or carboxylic acid derivative is converted to the sulfonamide of the present invention by the methods and processes well known in the art and described herein.

The salts of the compounds or intermediates of the present invention are prepared in conventional manner, wherein the acidic compound is reacted with a base as described above to produce a metal or nitrogen-containing cation salt. Basic compounds such as amines can be treated with an acid to form an amine salt.

Note that some of the compounds of the present invention can be synthesized by biochemical methods involving mammalian metabolic processes. For example, a methoxy group can be converted by the liver to alcohol and / or phenol in situ. When one or more methoxy groups are present, either or both of those groups can be independently metabolized to hydroxy compounds.

The compounds of the present invention may have one or more asymmetric carbons, and thus can exist in the form of their racemic or non-racemic mixtures as well as in the form of optical isomers. Optical isomers can be obtained by resolving racemic mixtures according to conventional methods known in the art, including, for example, diastereomers by treatment with optically active acids or bases. There is salt formation.

Examples of suitable acids include tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid, which resolve a diastereomeric mixture by crystallization and form an optically active base from these salts. Is released. Different methods for resolution of optical isomers include the use of chiral chromatography, appropriately selected to maximize resolution of enantiomers.

Still other available methods include covalent attachment by reacting a compound of Formula I with an optically active acid, an optically active diol or an optically active isocyanate. Examples include the synthesis of diastereomeric molecules such as esters, amides, acetals, ketals, and the like. The synthesized diastereomers can be resolved by conventional methods such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to give enantiomerically pure compounds. In some cases, hydrolysis to the optically active parent compound is not required before administration to the patient. This is because the compound can behave like a prodrug.
Optically active compounds of the formula I can likewise be obtained using optically active starting materials.

In addition to the optical isomers or potential optical isomers described above, other types of isomers are specifically contemplated as being included herein and in the present invention. Examples include cis isomers, trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers, tautomers, and the like. Aryl, heteroaryl or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substituted isomers are also included as isomers. Solvates or solvated compounds such as hydrates or alcoholates are also specifically included as compounds of the present invention and in dosage forms or pharmaceutical compositions, for example, for drug delivery.

When a substituent is or may be hydrogen, the exact chemical nature of the substituent at that position other than hydrogen, for example, a hydrocarbonyl group or a functional group such as halogen, hydroxy, amino, is It is not important as long as it does not adversely affect the specific activity and / or the synthetic method. For example, it is known that a 2-hydroxyl, 2-amino, 2-thiol or 2-hydrogen-heteroatom group on the same carbon atom is not stable unless protected or derivative.

The chemistry described above generally discloses the preparation of the compounds of the present invention so as to be most widely applicable. Occasionally, reactions may not be applicable as described for each compound falling within the disclosed ranges. Those skilled in the art will readily recognize compounds where this occurs. In all such cases, any reaction can be performed successfully with conventional modifications known to those skilled in the art. Such modifications include, for example, appropriate protection of interfering groups, conversion to alternative conventional reagents,
There are routine modifications of the reaction conditions and the like. Also, other methods disclosed herein or otherwise conventional can be applied to the preparation of the corresponding compounds of the invention.
In all processes, all starting materials are either known or can easily be prepared from known starting materials.

Other compounds of the invention that are acids can also form salts. For example,
Alkali metals such as sodium, potassium, calcium or magnesium,
Or a salt with an alkaline earth metal or an organic base, or a basic quaternary ammonium salt.

In some cases, salts can also be used to assist in isolating, purifying, or dissolving the compound of the present invention.

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Best Mode for Carrying Out the Invention Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following preferred specific embodiments are merely illustrative of the present invention and do not limit the present disclosure in any way.

Example 1 N-hydroxy-2-[[(4-phenoxyphenyl) sulfonyl] methyl ] benzamide

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Part A: To a solution of phthalide (6.30 g, 47.0 mmol) in DMF (100 mL) was added K_TwoCO_Three (10.0 g, 49.4 mmol) and 4- (phenoxy) benzenethiol (9.59 g, 49.4
mmol) was added and the solution was heated to 100 ° C. for 2 hours. Put this solution in H_TwoDiluted with O, 1
 Acidified to pH = 1 with N HCl. The resulting brown solid was collected and H_TwoWashed with O. This fixed
The body is dissolved in ethyl ether and MgSO_FourAnd dried. Concentrate under vacuum, then reconstitute
Crystallization (ethyl ether / hexane) gave the sulfide as a white solid (9
.12 g, 58%). C₂₀H₁₆O_ThreeS MS (CI) MH⁺ Calculated: 337, Observed: 337. C₂₀H₁₆O _Three Elemental analysis for S Calculated: C, 71.41; H, 4.79; S, 9.53. Found: C, 71.28; H, 4
.67; S, 9.19.

Part B: To a solution of the sulfide of Part A (3.00 g, 8.92 mmol) in dichloromethane (28 mL) and DMF (1 drop) was added oxalyl chloride (1.08 mL, 12.4 mmol) and the solution was added. Stir for 1 hour. After concentration under vacuum, the residue was dissolved in dichloromethane (16 mL) and the solution was cooled to 0 ° C. Tetramethylsilylhydroxylamine (2.55 mL, 20.8 mmol) was added and the solution was stirred for 1.5 hours. The solution was diluted with dichloromethane, 1 N HCl, washed with H ₂ O then saturated NaCl, MgSO ₄
And dried. Chromatography (on silica, ethyl acetate / hexane / toluene)
Gave hydroxylamine (970 mg, 31%) as a clear paste.

Part C: Hydroxylamine of Part B (970 m) in dichloromethane (25 mL)
g, 2.76 mmol) in a solution cooled to 0 ° C., 3-chloroperbenzoic acid (60%, 2.14 g, 7
.45 mmol) was added and the solution was stirred at ambient temperature for 3 hours. Ethyl this solution
Diluted with ether, saturated Na_TwoSO_Three, Saturated NaHCO_ThreeThen washed with saturated NaCl, MgSO_Fourso
Dried. Reversed phase chromatography (on silica, acetonitrile / H_TwoO)
The title compound (345 mg, 33%) was obtained as a white solid. C₂₀H₁₇NO_FiveS MS (CI) MH ⁺ Calculated value: 384, measured value: 384. C₂₀H₁₇NO_FiveS0.3H_TwoElemental analysis of O Calculated value: C, 61
.70; H, 4.56; N, 3.60; S, 8.25. Found: C, 61.74; H, 4.42; N, 3.61; S, 8
.31.

Example 2 N-hydroxy-2-[(4-phenoxyphenyl) -sulfonyl] benze
Nacetamide

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Part A: To a solution of 4- (phenoxy) -benzenethiol (6.06 g, 30.0 mmol) and K ₂ CO ₃ (4.55 g, 33.0 mmol) in isopropanol (30 mL) was added 2-fluorobenzaldehyde (3.2 mL, 30.0 mmol) was added. The solution was refluxed for 20 hours. It was added to ice -H ₂ O reaction was quenched and extracted with CHCl _3. The organic layer was dried over MgSO _4. Filtration through a pad of silica gel gave a yellow solid sulfide (
7.43 g, 81%).

Part B: NaH in THF (12 mL) (60% dispersion in mineral oil, washed with hexane, 264 mg
, 6.6 mmol) was cooled to 0 ° C and tetraethyldimethylammonium methylene diphosphonate (1.99 g, 6.0 mmol) was added. The solution was warmed to ambient temperature and part A sulfide (1.84 g, 6.0 mmol) was added. The solution was stirred at ambient temperature for 4 hours. The solution was extracted with ethyl acetate, washed with H ₂ O, the organic layer was dried over MgSO _4. Concentration in vacuo gave a brown oil, which was dissolved in 6 M HCl (10 mL) and the solution was heated to 100 ° C. for 1 hour. This solution was extracted with CHCl ₃ and dried over MgSO ₄ . Concentration under vacuum provided an oily acid (918 mg, 48%).

Part C: To a solution of the acid of Part B (918 mg, 3 mmol) in acetic acid (30 mL) was added 30%
Hydrogen peroxide (1.2 mL, 12 mmol) was added and the solution was heated to 100 ° C. for 40 minutes.
The solution was lyophilized and chromatographed (hexane / ethyl acetate) to give foamy sulfone (697 mg, 63%).

Part D: Sulfone of Part C (695 mg, 1.89 mmol) in acetonitrile (2 mL)
l) in a solution of O-tetrahydropyranylhydroxylamine (270 mg, 2.3 mmol)
) Was added. After 5 minutes, EDC (442 mg, 2.3 mmol) was added and the solution was stirred for 3 hours. The solution was concentrated in vacuo, the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was dried over MgSO _4. Chromatography (on silica gel, ethyl acetate / hexane) provided THP-ether as a white foam (688 mg, 77%).

Part E: THP-ether of Part D (565 mg, 1.2 mmol) in methanol (10 mL)
l) solution of p-toluenesulfonic acid (25 mg) is added to the solution of
Stir for 2 hours. The solution was concentrated under vacuum and chromatographed (chloroform / methanol) to give the title compound as a white solid (339 mg, 74%).

Example 3 N-hydroxy-2-[[4- (phenylmethyl) -1-piperidinyl] sul
Honyl) benzamide

[0326]

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Part A: Nagasawa et al., J. Med. Chem. 1995, 38 in acetonitrile (50 mL).
2-Chlorosulfonyl-benzoic acid ethyl ester prepared according to Vol.
5.80 g, 23.0 mmol) in a solution of 4-benzylpiperidine (4.38 mL, 25 mmol),
Triethylamine (3.78 mL, 27 mmol) and 4-dimethylaminopyridine (50 mg
) Was added. The solution was stirred at ambient temperature for 4 hours and concentrated under vacuum. 1 residue
Dissolved in N HCl and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and filtered through a pad of silica gel to give the oily sulfonamide (7.45 g, 84%).

Part B: To a solution of the sulfonamide of Part A (1.08 g, 2.80 mmol) in methanol (50 mL) and H ₂ O (20 mL) was added KOH (2 g) and the solution was allowed to reach ambient temperature. In 3
Stirred for hours. The solution was concentrated under vacuum and the remaining aqueous solution was acidified with 1 N HCl. The solution was extracted with chloroform, the organic layer was dried over MgSO ₄ and filtered over a pad of silica gel. Concentration in vacuo gave the acid as a white foam (996 mg, quantitative yield).

Part C: To a solution of the acid from Part B (415 mg, 1.2 mmol) in acetonitrile (2 mL) was added O-tetrahydropyranylhydroxylamine (200 mg, 1.7 mmol). After stirring the solution for 5 minutes, EDC (325 mg, 1.7 mmol) was added and the solution was stirred at ambient temperature for 3 hours. The solution was concentrated in vacuo and the residue dissolved in H ₂ O, and extracted with ethyl acetate. The organic layer was dried over MgSO _4. Chromatography (on silica, ethyl acetate / hexane) provided THP-ether as a white solid (437 mg, 82%).

Part D: THP-ether of Part C (437 mg, 0.98 mmo) in methanol (5 mL)
l) p-Toluenesulfonic acid (40 mg) is added to the solution of
Stir for 1 hour. The solution was concentrated under vacuum. Chromatography (ethyl acetate, 1
% NH ₄ OH) gave the title compound as an oil (122 mg, 34%).

Example 4: 2-[([1,1'-biphenyl] -4-ylmethyl) -sulfonyl] -N-hydrido
Roxibenzamide

[0332]

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Part A: Thiosalicylic acid (5.00 g) in ethanol (81 mL) and H ₂ O (40 mL)
, 32.4 mmol) and 4-phenylbenzyl chloride (6.57 g, to a solution of _{32.4 mmol), K 2 CO 3} (4.48 g, were added 32.4 mmol), the solution was under reflux for 2 hours while heating to. Upon cooling to ambient temperature, a white solid formed. To this mixture, add 1 N HCl (200 mL)
Was added and vacuum filtration provided the sulfide as a white solid (7.32 g, 70%).

Part B: The sulfide of Part A (1.00 g, 3 in formic acid (17 mL) heated to 50 ° C.
.12 mmol) was added 30% hydrogen peroxide (1.16 mL). 55 ° C
For 3 hours and then at ambient temperature for 40 hours. The solution was concentrated and subjected to reverse phase chromatography (acetonitrile / H ₂ O) to give a white solid sulfone (500 mg,
45%).

Part C: A solution of the sulfone of Part B (500 mg, 1.42 mmol) in DMF (2.8 mL)
In addition, O-tetrahydropyranylhydroxylamine (173 mg, 1.48 mmol), N-
Droxybenzotriazole (211 mg, 1.56 mmol) and EDC (299 mg, 1.56 mmo
l) was added and the solution was stirred at ambient temperature for 18 hours. Concentrate this solution under vacuum
And the residue is H_TwoDissolved in O. The solution was extracted with ethyl acetate and the organic layer was washed with 1 N HCl,
Saturated NaHCO_Three, H_TwoO then washed with saturated NaCl, MgSO_FourAnd dried. Concentrate under vacuum
Afforded the ester as a white solid (571 mg, 89%). C_{twenty five}H_{twenty five}NO_FiveS MS (CI) MH ⁺ Calculated: 452, Observed: 452.

Part D: Ester of Part C (570 mg, 1.26 mmol) in methanol (10 mL)
P-Toluenesulfonic acid (15 mg) was added to the solution of
Stirred for hours. The solution is concentrated under vacuum and reversed phase chromatography (acetonitrile
/ H_TwoO) afforded the title compound as a white solid (244 mg, 53%). C₂₀H ₁₇ NO_FourS MS (EI) M⁺ Calculated value: 367, measured value: 367. C₂₀H₁₇NO_FourElemental analysis of S Calculation
Values: C, 65.38; H, 4.66; N, 3.81. Found: C, 65.01; H, 4.64; N, 4.04.

Example 5: N-hydroxy-2-[[(4-phenoxyphenyl) -sulfonyl] amido
No) benzamide

[0338]

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Part A: Isatoic anhydride (1.00 g, 6.13 mmol) in acetonitrile (3 mL)
O-tetrahydropyranylhydroxylamine (1.56 g, 6.74 mmol)
Was added and the solution was heated under reflux for 2 hours. The solution was concentrated in vacuo and the residue was recrystallized (ethyl acetate / hexane) to give a white solid THP-ether (760 mg, 5 mg).
2%). C ₁₂ H ₁₆ N ₂ O ₃ of MS (CI) MH ⁺ calculated: 237, found: 237. _{C 1 2 H 16 N 2 O} 3 of Analysis Calculated: C, 61.00; H, 6.83 ; N, 11.86. Measured value: C, 60.8
2; H, 6.95; N, 11.76.

Part B: 4- (phenoxy) benzenesulfonyl chloride (3) prepared by J. Am. Chem. Soc., 1931, 93, 1112-1115 in pyridine (2 mL) cooled to 0 ° C.
To a solution of 41 mg, 1.27 mmol) was added Part B THP-ether (300 mg, 1.27 mmol) and the solution was stirred at 0 ° C. for 3 hours. The solution is concentrated under vacuum and the residue is
Dissolved in N HCl and extracted with ethyl acetate. The organic layer was washed with 1 N HCl, H ₂ O and then saturated NaCl
And dried over MgSO ₄ . Chromatography (on silica gel, ethyl acetate /
Hexanes) provided the sulfone (321 mg, 54%) as a white solid. _{C 24 H 24 N 2 O 6} S of MS (CI) MH ⁺ calculated: 469, found: 469. C ₂₄ H ₂₄ N ₂ O ₆ Analysis Calculated for S: C, 61.53; H, 5.16; N, 5.98; S, 6.84. Found: C, 61.10; H, 4.93; N, 5
.86; S, 6.41.

Part C: The sulfone of Part B (320 mg) in methanol (3 mL) cooled to 0 ° C.
, 0.68 mmol) was sparged with HCl gas for 5 minutes. The solution was concentrated under vacuum and the residue was triturated with ethyl ether. Collected by vacuum filtration to give the title compound (163 mg, 62%) as a pink solid. _{C l9 H l6 N 2 O d} S of MS (CI) MH ⁺ calculated: 385, found: 385. _{C 19 H 16 N 2 O 6} S · 0.2H 2 O of Calcd: C, 58.81; H, 4 .
26; N, 7.22; S, 8.26. Found: C, 58.88; H, 4.37; N, 6.98; S, 7.83.

Example 6: N-hydroxy-2-[[(4-methoxyphenyl) -sulfonyl] methyl
] Benzamide

[0343]

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Part A: In a 500 mL round bottom flask equipped with a magnetic stir bar and N ₂ inlet, 1.5 mL of 4-methoxybenzenethiol (1.7 g, 12.0
mM) and 2.5 g (10.9 mM) of methyl (2-bromomethyl) benzoate.
This solution was treated with 1.8 g (13.1 mM) of potassium carbonate and heated to 55 (C in an oil bath.
The reaction mixture was stirred at 55 ° C. for 17 hours, then concentrated under vacuum. The residue was extracted with EtOAc and H ₂ O
And the layers were separated, the aqueous layer was extracted with EtOAc (1 ×), the organic layers were combined, washed with 5% citric acid solution, saturated sodium bicarbonate solution and then brine, and dried (Na.sub.3). ₂ SO ₄ ) and concentrated in vacuo to give 3.3 g of product suitable for the next reaction.

[0345] Part B: To a 500 mL round bottom flask equipped with a magnetic stir bar and N ₂ inlet was charged with 90 mL of the product from Part A in MeOH 3.1 g (10.8 mM). This solution was treated with 15 mL of water and 13.9 g (22.6 mM) of Oxone®. Add the reaction mixture to 1
Stirred for 7 hours then filtered. The filter cake was washed with MeOH and the filtrate was concentrated under vacuum. The residue was partitioned between EtOAc and H ₂ O, the layers were separated, the aqueous layer was extracted with EtOAc (2 ×). The organic layers were combined, washed with saturated sodium bicarbonate solution then brine, dried (MgSO _4), then concentrated under vacuum, the crude product 3.3 g was obtained. This was chromatographed on silica gel using 25-45% ethyl acetate / hexane to give 2.1 g of pure product. m / z = 321 (M + H).

[0346] Part C: a magnetic stir bar and N 250 mL round bottom flask equipped with a _second inlet, acetate (25 mL) and concentrated HCl solution (25 mL) the product of Part B in 2.1 g (6.6 mM)
And the solution was heated under reflux for a total of 24 hours. The reaction mixture was concentrated in vacuo, then two aliquots of toluene were added, stripped and dried under high vacuum to give 2.0 g of a product suitable for the next reaction.

Part D: A _2- neck 50 mL round bottom flask equipped with an addition funnel, thermometer, magnetic stir bar, and N ₂ inlet was charged with 1.0 mL DMF in 10 mL CH ₂ Cl ₂ . The solution was cooled in an ice bath and then 3.5 mL of a 2.0 M oxalyl chloride solution in CH ₂ Cl ₂ (0.9 g
6.9 mM), followed by a solution of 1.0 g (3.3 mM) of Part C product in 5 mL DMF. The bath was removed and the reaction was stirred for 1 hour. The reaction mixture was added to THF (25
mL) 50% aqueous hydroxylamine 2.1 mL (1.1 g in, addition funnel containing cold solution of 37.7 mM), thermometer, two neck 100 mL round bottom flask equipped with a magnetic stir bar and N ₂ inlet Was added. The bath was removed and the reaction mixture was stirred for 2 hours. The reaction was filtered, the filtrate was concentrated in vacuo, the residue was partitioned with EtOAc / water, the layers were separated,
The aqueous layer was extracted with EtOAc (1 ×), the organic layers were combined, washed with water then brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 1.3 g of crude product . 8
Chromatography on silica gel using 0% ethyl acetate / hexane gave 0.5 g of pure product. m / z = 328 (M + Li).

Example 7: N-hydroxy-2-[(4-methoxyanilino) -sulfonyl] benzure
Mid

[0349]

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Part A: 0.5 g (4.3 mM) of p-anisidine in CH ₂ Cl ₂ (20 mL) in a 3-neck round bottom flask equipped with an addition funnel, thermometer, magnetic stir bar and N ₂ inlet And 1.8 mL of triethylamine (1.3 g, 12.8 mM). The solution was cooled in an ice bath and then 1.0 g of (2-chlorosulfonyl) benzoate in CH ₂ Cl ₂ (10 mL)
(4.3 mM). The reaction solution was stirred for 17 hours, then concentrated under vacuum. The residue was partitioned between EtOAc and H ₂ O, the layers were separated, the solution and the organic layer with 5% citric acid, washed with saturated sodium bicarbonate solution then brine, dried (Na ₂ SO _4), under vacuum Concentration gave 0.9 g of crude product. This was chromatographed on silica gel using 20-30% ethyl acetate / hexane to give 0.77 g of pure product.
g was obtained. m / z = 328 (M + Li).

[0351] Part B: magnetic in stir bar and N 100 mL round bottom flask equipped with a _second inlet, MeOH product 0.7 from Part A in 10 mL g (2.1 mM) and hydroxylamine hydrochloride 0.7 g (10.2 mM). The reaction was cooled to 0 ° C. and
g (16.4 mM). After stirring for 17 hours, the reaction was concentrated in vacuo, the residue slurried in 20 mL of water, and then acidified with 2N HCl solution. Aqueous slurry
Extracted with EtOAc (3x). Combine the organic layers, wash with brine, dry (Na ₂ SO ₄ ),
Concentration under vacuum gave 0.6 g of crude product. When methylene chloride was added to the crude product, an off-white solid precipitated. Filtration provided 0.2 g of crude product. m / z = 323 (M + Li).

Example 8: N-hydroxy-2-[(benzylamino) -sulfonyl] benzamide

[0353]

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Part A: In a three-neck 100 mL round bottom flask equipped with an addition funnel, thermometer, magnetic stir bar and N ₂ inlet, add 0.5 mL (0 mL) of benzylamine in CH ₂ Cl ₂ (20 mL).
.5 g, 4.3 mM) and 1.8 mL of triethylamine (1.3 g, 12.8 mM). The solution was cooled in an ice bath, then treated with a solution of CH ₂ Cl ₂ (10 mL) of methyl (2-chlorosulfonyl) benzoate 1.0 g (4.3 mM). The reaction mixture was stirred for 2 hours, then concentrated under vacuum. The residue was partitioned between EtOAc and H ₂ O, the layers were separated, the solution and the organic layer with 5% citric acid, washed with saturated sodium bicarbonate solution then brine, dried (Na ₂ SO _4), under vacuum Concentration gave 0.9 g of crude product. 20% of this
Chromatography on silica gel using ethyl acetate / hexane provided 0.7 g of pure product. m / z = 312 (M + Li).

[0355] Part B: To a magnetic stir bar and N 100 mL round bottom flask equipped with a _second inlet, MeOH 10 product 0.7 g (2.1 mM) and hydroxylamine hydrochloride 0.7 g (10.6 mM from Part A in mL ). The reaction was cooled to 0 ° C. and
g (17.0 mM). After stirring for 17 hours, the reaction was concentrated in vacuo, the residue slurried in 20 mL of water, and then acidified with 2N HCl solution. Aqueous slurry
Extracted with EtOAc (3x). Combine the organic layers, wash with brine, dry (Na ₂ SO ₄ ),
Concentration under vacuum gave 0.3 g of crude product. When methylene chloride was added to the crude product, a white solid precipitated. Filtration yielded 0.1 g of pure product. m / z = 307 (M + H).

Example 9: N-hydroxy-2-[[4- (phenyl) -1-piperidinyl] sulfonyl
Production of benzamide

[0357]

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Part A: 2-Carboethoxybenzenesulfonyl chloride (3.72 g, 15 mmol)
Was dissolved in methylene chloride (60 mL). 4-phenylpiperidine (2.89 g, 18 mmol
) Was added, followed by triethylamine (2.5 mL, 18 mmol) and 4- (dimethylamino) piperidine (100 mg). After 5 hours, the mixture was diluted with 10% aqueous HCl (10%
0 mL). The organic layer was separated and dried over magnesium sulfate. The solution was filtered through a pad of silica and concentrated to give the ester sulfonamide as an oil (3.27 g, 63%).

Part B: Ester sulfonamide from Part A (938 mg, 2.51 mmol)
Stirred at ambient temperature for 20 hours in the presence of potassium hydroxide (940 mg, 17 mmol), ethanol (15 mL) and water (5 mL). The mixture was diluted with water (20 mL) and acidified to about pH 4 using concentrated HCl. The product was diluted with chloroform (2 × 100 mL) and the combined organic layers were dried using anhydrous magnesium sulfate. Concentration provided the carboxylic acid (768 mg, 89%), which was used in the next step.

Part C: Acid from Part B (764 mg, 2.2 mmol) in acetonitrile (15 mL)
O-tetrahydropyranyl hydroxylamine (351 mg, 3.0
mmol) and N-hydroxybenzotriazole (405 mg, 3.0 mmol) followed by 1- (
3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (600 mg, 3 mmol
) Was added. The reaction was stirred for 16 hours and then concentrated. The residue was washed with half-saturated brine (1
5 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried using magnesium sulfate, concentrated, the residue was purified by chromatography on silica gel and concentrated to give the desired THP-protected hydroxamate as a white foam (833 mg,
82%).

Part D: THP-protected hydroxamate from Part C (833 mg, 1.8 mmol)
Dissolved in anhydrous methanol (3 mL). Add acetyl chloride (0.28 mL, 4 mmol) dropwise
Was added. After 3 hours, the reaction was concentrated and the residue was purified by chromatography.
Upon application, the title compound was obtained as a white foam (430 mg, 66%). C₁₈H₂₀N_TwoO_FourS (H _Two Elemental analysis for O) Calculated: C, 57.08; H, 5.81; N, 7.40. Found: C, 57.02; H
, 5.61; N, 6.90.

Example 10: N, 2-dihydroxy-2-methyl-2-[(4-phenyl-1-piperidinyl) -sulfonyl ] benzeneacetamide

[0363]

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Part A: 2-Bromobenzenesulfonyl chloride (2.56 g, 10 mmol) was added to 4-phenylpiperidine (1.61 g, 10 mmol), triethylamine (2.0 mL, 14 mmol)
, 4-dimethylaminopyridine (75 mg) and acetonitrile (20 mL). After 24 hours, water (100 mL) was added. The mixture was extracted with ethyl acetate (100 ml then 50 ml). The combined organic layers were dried over magnesium sulfate, filtered through silica, and concentrated to give a white solid, bromosulfonamide (3.47 g).
, 96%).

Part B: This bromosulfonamide (359 mg, 1 mmol) was dissolved in dry tetrahydrofuran (2 mL) and cooled to -78 ° C. t-Butyllithium (0.68 mL, 1.7 M in pentane) was added dropwise and the anion was formed in 15 minutes. Ethyl pyruvate (0.11 mL, 1.15 mmol) was added. The cooling bath was removed. When the reaction reached ambient temperature, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate, filtered through silica, concentrated,
Chromatography gives the desired hydroxyester in glassy form (163 mg
, 40%).

Part C: The hydroxyester from Part B (134 mg, 0.33 mmol) was stirred in the presence of potassium hydroxide (134 mg, 2.4 mmol) in ethanol (1 mL) and water (1 mL). After 4 hours, the mixture was heated at 50 ° C. for 1 hour, then cooled, neutralized with dilute hydrochloric acid, concentrated, and azeotroped with acetonitrile to give the crude hydroxy acid, which was used directly as it was. The hydroxy acid was diluted with acetonitrile (1 mL). O-tetrahydropyranylhydroxylamine (117 mg, 1.0 mmol) and N-hydroxybenzotriazole (135 mg, 1.0 mmol) were added, followed by 1- (
3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (191 mg, 1 mmol
) Was added. The reaction was stirred overnight (about 18 hours), diluted with water (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over ethyl acetate, concentrated and chromatographed to give a glassy THP-protected hydroxamate (80 mg, 4 mg).
8%).

Part D: The THP-protected hydroxamate from Part C (80 mg) was diluted with anhydrous methanol (4 mL) and toluenesulfonic acid (6 mg) was added. After 3 hours, the reaction mixture was concentrated and the residue was chromatographed using 1: 1 hexane: ethyl acetate 1% NH ₄ OH. The title compound was isolated as a white foam (40 mg, 6
0%). _{C 20 H 24 N 2 O 5} S (1.33H 2 O) Elemental analysis Calculated: C, 53.75; H, 5.90 ; N, 6
.27. Found: C, 53.80; H, 5.65; N, 5.84.

[0368] Example 11: N-hydroxy-2 - [[3 - [(4-methoxybenzoyl) amino] -1-pin Rorijiniru 1- sulfonyl] benzamide

[0369]

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Part A: 3-Aminopyrrolidine (636 mg, 4 mmol), triethylamine (2.7 m
L, 20 mmol) and 4- (dimethylamino) pyridine (75 mg) were suspended in acetonitrile. After 10 minutes, the reaction was cooled to 0 ° C. 4-Methoxybenzoyl chloride (0.54 mL, 4 mmol) was added dropwise. After 30 minutes, 2-carbethoxybenzenesulfonyl chloride (0.996 g, 4.0 mmol) was introduced dropwise via syringe. The mixture was stirred at 0 ° C. for 1 hour, then at ambient temperature for 2 hours. Water (50 mL) was added. This mixture was extracted using ethyl acetate (2 × 50 mL). The organic layer was dried over magnesium sulfate, filtered through silica and concentrated. 1: 1 ethyl acetate as eluent:
The residue was purified using silica gel chromatography using hexane to ethyl acetate. The desired amidosulfonamide was isolated as a foam (282 mg, 16%).

Part B: Amidosulfonamide from Part A (272 mg, 0.63 mmol) was mixed with potassium hydroxide (156 mg, 2.8 mmol), ethanol (3 mL) and water (2 mL) and refluxed . After 40 minutes, the reaction was cooled. Acetic acid (0.1 mL) and absolute ethanol (20 mL) were added. Concentration followed by chromatography (9: 1 ethyl acetate:
Methanol to methanol; 20 g silica gel) provided the desired acid as a crystalline solid (229 mg, 96%). This acid (229 mg, 0.57 mmol) was dissolved in acetonitrile (1 mL). O-tetrahydropyranyl hydroxylamine (117 mg, 1.
0 mmol) and N-hydroxybenzotriazole (135 mg, 1.0 mmol) followed by 1-
(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (191 mg, 1 mmo
l) was added. The mixture is stirred at ambient temperature overnight (about 18 hours), then concentrated and chromatographed (ethyl acetate to 9: 1 ethyl acetate: methanol) to give a THP-protected hydroxamate as a white crystalline solid (98 mg, 33%) was obtained.

Part C: This THP-protected hydroxamate (76 mg, 0.15 mmol) was dissolved in methanol (2 mL). Acetyl chloride (0.01 mL, 1 mmol) was added. After 30 minutes, the solution was concentrated then azeotroped with chloroform / acetonitrile to give the title compound as a solid (65 mg, quantitative). _{C 19 H 21 N 3 O 6} S of MS (EI) MH ⁺ calculated: 420, found: 420.

Example 12: N-hydroxy-2-[[4- [4- (trifluoromethoxy) phenoxy]
1-piperidinyl] sulfonyl] benzamide

[0374]

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Part A: Diethyl azodicarboxylate (4.11 g, 23.6 mmol) was added in a nitrogen atmosphere.
N- (tert-butyloxycarbonyl) -4 in THF (200 mL) at ambient temperature under ambient
-Piperidinol (4.31 g, 21.4 mmol) (Wells, Kenneth M. et al., Tetrahedron L
ett., 1996, 37, 6439-6442), 4-trifluoromethoxyphenol (4.2
0 g, 23.6 mmol) and a mixture of triphenylphosphine (6.19 g, 23.6 mmol)
Was added. After 1.5 hours, the reaction mixture was concentrated. Dilute the residue with ethyl ale
And filtered, then chromatographed (on silica, methyl tert-butyl ether).
Ter / hexane) to give impure BOC-amine (5.23 g) as a white solid.
Was. To an off-white solid cooled to 0 ° C under a nitrogen atmosphere, add dioxane (36.1 mL
, 145 mmol) was added. After 2 hours, the reaction mixture was concentrated.
Upon dilution with ethyl ether, a white solid was obtained. This white solid is H_TwoO (15
NaHCO in water (10 mL)_Three(1.68 g, 20.0 mmol) solution was added
. The precipitate was extracted into ethyl ether. The organic layer was washed with brine and dried over MgSO_FourDry
Drying and concentration then gave the amine as a white solid (1.93 g, 34%). C₁₂H ₁₄ NO_TwoF_ThreeMS MH⁺ Calculated: 262, Observed: 262.

Part B: The amine of Part A (1.90 g, 7.28 mmol) in acetonitrile (20 mL)
), Ethyl 2-chlorosulfonylbenzoate (1.70, 6.85 mmol), triethylamine (1.15 mL, 8.22 mmol) and 4-dimethylaminopyridine (10 mg) were stirred at ambient temperature under a nitrogen atmosphere for 18 hours. The solution was concentrated and the residue was diluted with H ₂ O, and extracted into ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O, then brine, dried over MgSO ₄ and concentrated to a yellow oil. Chromatography (on silica, ethyl acetate / hexane) provided the sulfonamide (1.59 g, 51%) as a white solid. MS MH ⁺ calcd _{C 21 H 22 NO 6 F 3} S: 474
, Found: 474.

Part C: Part in a mixture of MeOH (30 mL), H ₂ O (10 mL) and THF (10 mL)
B sulfonamide (1.45 g, 3.17 mmol) and potassium hydroxide (1.77 g, 31.7 m)
mol) was heated under reflux for 1.5 hours. The solution was concentrated in vacuo and the residue triturated with ethyl ether, dissolved in H ₂ O, acidified with concentrated HCl, and extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO _4, and concentrated under vacuum, the acid as a clear oil (1.04 g, 74%) was obtained. Elemental analysis of C ₁₉ H ₁₈ NO ₆ F ₃ S Calculated value: C
H, 4.07; N, 3.14; S, 7.20. Found: C, 51.34; H, 3.78; N, 3.15;
S, 7.30.

Part D: Part C acid (0.97 g, 2.18 mmol), N-hydroxybenzotriazole (0.89 g, 6.50 mmol), 4-methylmorpholine (0.71 mL, DMF (19 mL)
6.50 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.51 g
, 4.36 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.25 g, 6.50 mmol) were stirred at ambient temperature under a nitrogen atmosphere for 20 hours. The mixture was concentrated under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O, then brine, then dried over MgSO ₄ and concentrated in vacuo to give a white solid THP-protected hydroxamate (1.05 g, 88 %
)was gotten. _{C 24 H 27 N 2 O 7} F 3 Analysis Calculated for S: C, 52.94; H, 5.00; N, 5.1
4; S, 5.89. Found: C, 52.80; H, 4.84; N, 5.23; S, 6.14.

Part E: The THP-protected hydroxamate of Part D (1.01 g, 1.86 mmol) was dissolved in methanol (10 mL). Acetyl chloride (0.36 mL, 5.0 mmol) was added. After 1 hour, the solution was concentrated and the residue chromatographed (1: 1 hexane: ethyl acetate; 1% NH ₄ OH~ ethyl acetate; 1% NH ₄ OH) When the applied foam-like title compound (
643 mg, 75%). Analysis Calculated for _{C 19 H 19 F 3 N 2} O 6 S: C, 49.56; H,
4.13; N, 6.09. Found: C, 49.27; H, 3.72; N, 5.87.

Example 13 Preparation of N-hydroxy-2-[[4- [4- (trifluoromethyl) phenoxy] -1 -piperidinyl] sulfonyl] benzamide

[0381]

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Part A: N- (tert-butoxycarbonyl) -4-piperidinol (5.00 g, 2.48 mmol), 4-fluorobenzo-trifluoride (3.46 mL, 2.73) in DMF (60 mL)
mmol) and cesium carbonate (12.1 g, 3.72 mmol) at 120 ° C under a nitrogen atmosphere.
Heated for 2 days. The mixture was concentrated, diluted with H ₂ O, and extracted with ethyl acetate. The organic layer was washed with H ₂ O then brine, dried over MgSO _4, and concentrated in vacuo. Chromatography (on silica, ethyl acetate / hexane) provided BOC-aminoether (6.97 g, 81%) as a white solid. Analysis Calculated for _{C 17 H 22 NO 3 F 3} : C,
59.12; H, 6.42; N, 4.06. Found: C, 59.29; H, 6.47; N, 3.99.

Part B: BOC-amino ether of Part A in CH ₂ Cl ₂ (30 mL) (4.00 g, 11.6
mmol) and p-toluenesulfonic acid (6.61 g, 34.7 mmol) was stirred at ambient temperature under a nitrogen atmosphere for 3 hours, then concentrated in vacuo. The residue was partitioned between aqueous NaHCO ₃ and ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated,
The free amine (1.57 g, 55%) was obtained as a clear yellow oil. C ₁₂ H ₁₄ NOF _3: the MS MH
+ Calculated: 246, found: 246.

Part C: Part B amine (1.57 g, 6.40 mmol) in acetonitrile (20 mL)
), Ethyl 2-chlorosulfonylbenzoate (1.57 g, 6.03 mmol), a solution of triethylamine (1.00 mL, 7.24 mmol) and 4-dimethylaminopyridine (10 mg) were stirred at ambient temperature under a nitrogen atmosphere for about 1.5 hours. . After concentrating this solution,
The residue was diluted with H ₂ O, and extracted into ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated Na
HCO _3, washed with H ₂ O then brine, dried over MgSO _4, and concentrated to give sulfonamides of clear yellow oil (2.52 g, 92%) was obtained. MS MH for C ₂₁ H ₂₂ NO ₅ F ₃ S ⁺ calculated: 4
58, found: 458.

Part D: A solution of the sulfonamide of Part C (2.50 g, 5.46 mmol) and potassium hydroxide (3.06 g, 54.6 mmol) in a mixture of MeOH (49 mL) and H ₂ O (24 mL) Heat under reflux for 4 hours. After concentrating the solution under vacuum, the residue was triturated with ethyl ether, dissolved in H ₂ O, acidified with concentrated HCl and extracted into ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , H ₂ O, then brine, dried over MgSO ₄ and concentrated in vacuo to give an oily acid (2.17 g, 93%). MS MH ⁺ calcd _{C 19 H 18 NO 5 F 3} S: 430, found: 430.

Part E: Part D acid (2.10 g, 4.89 mmol), N-hydroxybenzotriazole (1.97 g, 14.6 mmol), 4-methylmorpholine (1.61 mL, DMF (43 mL)
14.6 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.15 g
, 9.79 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.80 g, 14.6 mmol) were stirred at ambient temperature under a nitrogen atmosphere for about 18 hours. The mixture was concentrated under vacuum, diluted with water and extracted into ethyl acetate. The organic layer was washed with 1.0 N KHSO _4, H ₂ O then brine, dried over MgSO _4, and concentrated in vacuo. Chromatography (on silica, ethanol / CHCl ₃ ) gives a white solid
THP-protected hydroxamate (2.09 g, 81%) was obtained. C ₂₄ H ₂₇ N ₂ O ₆ F ₃ S MS
MH ⁺ calc: 529, found: 529.

Part F: THP-protected hydroxamate of Part C in methanol (24 mL) (1
Acetyl chloride (0.73 mL, 10.2 mmol) was added to a solution of .80 g (3.41 mmol).
The solution was stirred at ambient temperature under a nitrogen atmosphere for 1.5 hours. The solution was concentrated under vacuum and chromatographed (on silica, MeOH / CHCl ₃ ) to give the title compound as an off-white solid (1.18 g, 78%). _{C 19 H 19 N 2 O 5} F 3 S · 0.2% H 2 O Elemental analysis Calculated: C, 50.94; H, 4.36 ; N, 6.25; S, 7.16. Found: C, 50.88; H
, 4.31; N, 6.20; S, 7.43. MS MH + calcd _{C 19 H 19 N 2 O 5} F 3 S: 445. Measured value: 4
45.

Example 14: N-hydroxy-2-[[4-[[4- (trifluoromethyl) phenyl]
Preparation of [methoxy] -1-piperidinyl] sulfonyl] benzamide

[0389]

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Part A: 4- (trifluoromethyl) benzyl bromide (2.00 in THF (6 mL)
 mL, 12.9 mmol) of N- (tert-butyloxycarbonate) in THF (15 mL).
Le) -4-piperidinol (2.85, 14.9 mmol) and 60% sodium hydride (0.600
g, 14.9 mmol) was added dropwise under a nitrogen atmosphere to the mixture cooled to -52 ° C.
Stirred at ambient temperature for about 20 hours. The reaction mixture is brought to saturated NH_FourQuench with Cl solution,
Concentrate under vacuum, H_TwoDiluted with O and extracted with ethyl acetate. 1.0 N HC
l, saturated NaHCO_ThreeSolution, H_TwoO then washed with brine, MgSO_FourAnd concentrated under vacuum
This gave BOC-aminoether as an off-white solid (3.35 g, 72%). C₁₈H _{twenty four} NO_ThreeF_ThreeMS MH⁺ Calculated: 360, Observed: 360.

Part B: BOC-amino ether of Part A in ethyl acetate (40 mL) (3.35 g, 9
.32 mmol) at 0 ° C. was saturated with HCl (gas) and stirred at ambient temperature for 1 hour. After concentration in vacuo, triturated with ethyl ether and the crude free base was partitioned between aqueous NaHCO ₃ and ethyl ether. The organic layer was washed with H ₂ O then brine, dried over MgSO ₄ and concentrated in vacuo to give the amine as a clear yellow oil (2.11 g, 87%
)was gotten. This was consistent with the proton NMR spectrum of the desired product.

Part C: Part B amine (2.11 g, 8.14 mmol) in acetonitrile (25 mL)
), Ethyl 2-chlorosulfonylbenzoate (2.65 g, 10.7 mmol), a solution of triethylamine (1.75 mL, 12.6 mmol) and 4-dimethylaminopyridine (50 mg) were stirred at ambient temperature under a nitrogen atmosphere for about 18 hours. . After concentrating the solution, the residue is
Diluted with 1.0 N KHSO _4, and extracted into ethyl acetate. The organic layer is saturated with 1.0 N KHSO ₄ ,
Washed with NaHCO ₃ , H ₂ O then brine, dried over MgSO ₄ and concentrated to a yellow oil. Chromatography (on silica, ethyl acetate / hexane) provided a clear oil of the sulfonamide (2.48 g, 65%). MS MH ⁺ calcd _{C 22 H 24 NO 5 F 3} S: 472, found: 472.

Part D: MeOH (40 mL), H_TwoPart C in a mixture of O (20 mL) and THF (4 mL)
Of sulfonamide (2.10 g, 4.45 mmol) and potassium hydroxide (2.49 g, 44.5 mm)
ol) was heated under reflux for 1.5 hours. After concentrating the solution under vacuum, the remaining
Triturate the residue with ethyl ether and add H_TwoDissolve in O, acidify with concentrated HCl and add ethyl acetate
Extracted. This organic layer is transferred to 1.0 N KHSO_Four, H_TwoWashed with O and brine, MgSO_FourDry in
And concentrated in vacuo to give the acid as a white solid (2.08 g, 1.06%). C₂₀H₂₀NO _Five F_ThreeElemental analysis for S Calculated: C, 54.17; H, 4.55; N, 3.16; S, 7.23. Measured value: C,
54.29; H, 4.68; N, 3.11; S, 7.19.

Part E: Part D acid (2.00 g, 4.51 mmol) in NMF (40 mL), N-hydroxybenzotriazole (1.83 g, 13.5 mmol), 4-methylmorpholine (1.48 mL,
13.5 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.06 g
, 9.02 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.59 g, 13.5 mmol) were stirred under an atmosphere of nitrogen at ambient temperature for about 20 hours. The mixture was concentrated under vacuum, diluted with water and extracted into ethyl acetate. The organic layer was washed with saturated NaHCO ₃ , H ₂ O then brine, then dried over MgSO ₄ and concentrated in vacuo to give a white solid THP-protected hydroxamate (2.01 g, 82%). Was. _{C 25 H 29 N 2 O 6} F 3 Analysis Calculated for S: C, 55.34; H, 5.39; N, 5.16; S, 5.91
. Found: C, 55.36; H, 5.63; N, 5.20; S, 6.12.

Part F: To a solution of the THP-protected hydroxamate of Part E in methanol (25.9 mL) (2.00 g, 3.69 mmol) was added acetyl chloride (0.78 mL, 11.1 mmol) and the solution was added. The mixture was stirred at ambient temperature under a nitrogen atmosphere for 1.5 hours. The solution was concentrated in vacuo and chromatographed (on silica, MeOH / CHCl ₃ ) to give the title compound as an off-white solid (1.07 g, 63%). _{C 20 H 21 N 2 O 5} F 3 Analysis Calculated for S: C, 52.40; H, 4.62; N, 6.11; S, 6.99. Found: C, 52.53; H, 4.74
N, 6.25; S, 7.16. MS MH + calcd _{C 20 H 21 N 2 O 5} SF 3: 459, Found: 459.

Example 15: N-hydroxy-2-[[(4-phenoxyphenyl) amino] sulfoni
Production of benzamide

[0397]

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Part A: 4-phenoxyaniline (3.43 g, 18.5) in acetonitrile (40 mL)
 mmol), ethyl 2-chlorosulfonylbenzoate (4.25 g, 17.1 mmol),
Ethylamine (2.81 mL, 20.1 mmol) and 4-dimethylaminopyridine (50 mg)
Was stirred at ambient temperature under a nitrogen atmosphere for about 18 hours. After concentrating this solution
, 1.0 N KHSO residue_FourAnd extracted into ethyl acetate. 1.0 N KH
SO_Four, H_TwoO then washed with brine, MgSO_FourAnd concentrated in vacuo. Chromatog
Raffy (on silica, ethyl acetate / hexane) gives a brown solid
(4.94 g, 73%). C_{twenty one}H₁₉NO_FiveElemental analysis of S Calculated: C, 63.46; H
, 4.82; N, 3.52; S, 8.07. Found: C, 63.36; H, 4.78; N, 3.45; S, 8.31. C _{twenty one} H₁₉NO_FiveS MS M⁺ Calculated value: 397, actual value: 397.

Part B: Part A in a mixture of MeOH (68 mL), THF (8 mL) and H ₂ O (33 mL)
Of sulfonamide (3.00 g, 7.55 mmol) and potassium hydroxide (4.23 g, 75.5 mm
ol) was heated under reflux for 2 hours. After concentrating the solution under vacuum, the residue was triturated with ethyl ether, dissolved in H ₂ O, acidified with concentrated HCl and extracted into ethyl acetate. The organic layer was washed with 1.0 N HCl, H ₂ O, then brine, dried over MgSO ₄ ,
Concentration under vacuum provided the acid as a brown solid (2.31 g, 83%). C ₁₉ H ₁₅ NO ₅ Elemental Analysis Calculated S: C, 61.78; H, 4.09; N, 3.79; S, 8.68. Obtained value: C, 61.66
H, 4.22; N, 3.73; S, 8.70. MS M ⁺ calcd for _{C 19 H 15 NO 5 S:} 369, found: 36
9.

Part C: Part B acid (2.30 g, 6.23 mmol), N-hydroxybenzotriazole (2.52 g, 18.6 mmol), 4-methylmorpholine (2.04 mL, DMF (55 mL)
18.6 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.46 g
, 12.5 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.57 g, 18.6 mmol) were stirred at ambient temperature under a nitrogen atmosphere for about 18 hours. The mixture was diluted with water and extracted into ethyl acetate. The organic layer is saturated NaHC
Washed with O ₃ , H ₂ O then brine, dried over MgSO ₄ and concentrated in vacuo to give the saccharin compound as a white solid (2.13 g, 97%). C ₁₉ H ₁₃ NO ₄ Elemental analysis Calculated S: C, 64.95; H, ; 3.73; N, 3.99; S, 9.13. Found: C, 64.98; H, 3.82; N, 4
.17; S, 9.07. MS MH ⁺ calcd _{C 19 H 13 NO 4 S:} 352, found: 352.

Part D: Saccharin from Part C (0.500 g, 1.42 mmol) in dioxane (2 mL)
) And O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.183 g, 1.56
mmol) was stirred at ambient temperature under a nitrogen atmosphere for 6 days, then at 50 ° C. for 1 day. The solution was concentrated and chromatographed to give THP-protected hydroxamate as a white solid (0.285 g, 43%). MS MH ⁺ calcd _{C 24 H 24 N 2 O 6} S: 469, found: 469.

Part E: THP-protected hydroxamate of Part D (0.5 mL) in methanol (5 mL)
Acetyl chloride (0.150 mL, 2.13 mmol) was added to a solution of 275 g (0.587 mmol) and the solution was stirred under a nitrogen atmosphere at ambient temperature for 2 hours. The solution was concentrated under vacuum and chromatographed (on silica, MeOH / CHCl ₃ ) to give the title compound as an off-white solid (1.18 g, 78%). Proton NMR was consistent with that of the desired product.

Example 16 Preparation of N-hydroxy-2,3-dimethoxy-6-[[4- [4- (trifluoromethyl ) phenoxy] -1-piperidinyl) sulfonyl] benzamide

[0404]

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Part A: Piperidine of Example 13, Part B (as hydrochloride) (1.12 g, 4.0 mm
ol) with acetonitrile (6 ml), triethylamine (1.3 mL, 9.0 mmol) and N,
Dissolved in a mixture of N-dimethylaminopyridine (80 mg). 3,4-Dimethoxybenzenesulfonyl chloride (947 mg, 4.0 mmol) was added and the mixture was stirred at ambient temperature for 6 hours.
Stirred for hours. The reaction mixture was concentrated and the residue was taken up in ethyl acetate (100, then 25 mL
). The combined organic layers were dried over magnesium sulfate, filtered through silica, and concentrated to give the desired sulfonamide as a white solid (1.05 g, 59%).

Part B: The sulfonamide of Part A (1.05 g, 2.38 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 ° C. t-butyllithium (1.7 M in pentane
, 2.8 mL) was added dropwise. 15 minutes after the base addition was complete, the solution was quickly saturated with dry carbon dioxide gas. After an additional 15 minutes, the solution was acidified with a minimal amount of concentrated hydrogen chloride. The reaction mixture is concentrated, azeotroped with absolute ethanol and the residue is diluted 8: 1.
Ethyl acetate: Chromatography on silica gel using methanol gives
The glassy desired acid (279 mg, 24%) was obtained.

Part C: The acid from Part B (231 mg, 0.47 mmol) was dissolved in methylene chloride (4 mL). N, N-dimethylformamide (2 drops) was added, followed by oxalyl chloride (0.35 mL, 4 mmol). The reaction was stirred at ambient temperature for 1.5 hours, during which time gas evolved. The reaction mixture was concentrated and dried under vacuum to give the crude acid chloride, which was used as it was. To this acid chloride, add acetonitrile (2-3 mL)
A solution of O-tetrahydropyranylhydroxylamine (234 mg, 2.0 mmol) and pyridine (0.5 mL, 6.0 mmol) in was added. The reaction was stirred at ambient temperature for 16 hours, then diluted with water (3 mL). The mixture is added to ethyl acetate (100 mL, then 50 mL
mL). The combined organic layers were dried over magnesium sulfate and filtered through a pad of silica to give 376 mg of crude THP-protected hydroxamate.
This THP-protected hydroxamate was used directly without purification and was treated with anhydrous methanol (10
mL). Acetyl chloride (0.36 mL, 5.0 mmol) was added dropwise. After 2.5 hours, mixture was concentrated and the residue chromatographed: subjected to (ethyl acetate 1% NH ₄ OH). The desired hydroxamate (121 mg, 51% from acid) was obtained as a glass. MS MH ⁺ calcd _{C 21 H 23 F 3 N 2} O 7 S: 505, found: 505.

Example 17 Preparation of N-hydroxy-2-[[3- [4- (trifluoromethyl) phenoxy] -1 -pyrrolidinyl] sulfonyl] benzamide

[0409]

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Part A: Diethyl azodicarboxylate (2.03 mL, 12.9 mmol) was treated with 1- (tert-butoxycarbonyl) -3-hydroxypyrrolidine (2.31 g, 12.3) in anhydrous THF (40 mL) under a nitrogen atmosphere. mmol), p-trifluoromethylphenol (2.09 g
, 12.9 mmol) and triphenylphosphine (3.38 g, 12.9 mmol) at ambient temperature. After stirring for 2 hours, the reaction was concentrated in vacuo. The residue was diluted with ether, filtered through a bed of silica gel, concentrated and purified by flash chromatography (ethyl acetate / hexane on silica) to give the BOC-protected amine (1.85 g, 45%) as a white solid. Was. Analysis Calculated for _{C 16 H 20 NO 3 F 3} : C, 58
.00; H, 6.08; N, 4.23. Found: C, 57.86; H, 6.17; N, 3.92.

Part B: To the BOC-protected amine of Part A (1.75 g, 5.28 mmol) was added a solution of 4 N HCl in dioxane (13.2 mL, 52.8 mmol). After 1 hour, the reaction mixture was concentrated, diluted with ethyl ether, and concentrated to an oil. The oil was dissolved in water and a saturated NaHCO ₃ solution was added until the pH value was 8. The mixture was extracted with ethyl acetate. The organic layer was washed with H ₂ O then brine, dried over MgSO _4, and concentrated under vacuum, amine clear yellow oil (0.75 g, 61%) was obtained. C ₁₁ H ₁₂ NOF ₃
MS MH ⁺ calc .: 231; found: 232.

Part C: Part B amine (0.680 g, 2.94 mmol) in acetonitrile (10 mL)
l), a solution of ethyl 2-chlorosulfonylbenzoate (0.688, 2.77 mmol), triethylamine (0.46 mL, 3.3 mmol) and 4-dimethylaminopyridine (10 mg) was stirred at ambient temperature under a nitrogen atmosphere for 18 hours. After concentration in vacuo, the residue was diluted with H ₂ O, and extracted with ethyl acetate. The organic layer was washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O, then brine, dried over MgSO ₄ and concentrated to a yellow oil. Chromatography (on silica, ethyl acetate / hexanes) provided a clear, colorless, oily sulfonamide (0.95 g, 76%). _{C 20 H 20 NO 5 F 3} S of MS MH ⁺ calculated: 443
, Found: 444. C ₂₀ H ₂₀ NO ₅ F ₃ Analysis Calculated for S: C, 54.17; H, 4.55; N, 3.1
6; S, 7.23. Found: C, 53.82; H, 4.35; N, 3.13.

Part D: A solution of the sulfonamide of Part C (0.85 g, 1.9 mmol) and potassium hydroxide (1.07 g, 19.2 mmol) in a mixture of MeOH (17 mL) and H ₂ O (8 mL) Four
Heat under reflux for hours. After concentrating the solution under vacuum, the residue was dissolved in H ₂ O, acidified with concentrated HCl and extracted into ethyl acetate. The organic layer was washed with H ₂ O then brine, dried over MgSO ₄ and concentrated in vacuo to give a clear waxy acid (0.74 g, 93%). MS MH ⁺ calcd _{C 1 8 H 16 NO 5 F} 3 S: 415, found: 416.

Part E: Part D Acid (0.690 g, 1.56 mmol), N-Hydroxybenzotriazole (0.629 g, 4.65 mmol), 4-Methylmorpholine (0.51 mL, 4.7 mmol), O-
Tetrahydro-2H-pyran-2-yl-hydroxylamine (0.340 g, 2.90 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.891 g,
A solution of 4.65 mmol) in DMF (13 mL) was stirred at ambient temperature under a nitrogen atmosphere for 3 days. The mixture was concentrated in vacuo, diluted with 1.0 N KHSO _4, and extracted with ethyl acetate.
The organic layer 1.0 N KHSO ₄ and washed with saturated NaHCO _3, H ₂ O then brine, dried over MgSO _4,
Concentrated under vacuum. Chromatography on silica using ethyl acetate / hexane as the eluent gave a white foam of the THP-protected hydroxamate (0.575 g, 7
1.6%). _{C 23 H 25 N 2 O 6} F 3 Analysis Calculated for S: C, 53.69; H, 4.90; N
, 5.44; S, 6.23. Found: C, 53.48; H, 4.95; N, 5.37; S, 6.35.

Part F: THP-protected hydroxamate of Part E in methanol (6 mL) (0.
Acetyl chloride (0.24 mL, 3.5 mmol) was added to a solution of 500 g (0.972 mmol).
The solution was stirred at ambient temperature under a nitrogen atmosphere for 4.5 hours. The solution was concentrated in vacuo and chromatographed (on silica, MeOH / CHCl ₃ ) to give the title compound as a white solid (0.325 g, 77.8%). MS MH + calcd _{C 18 H 17 N 2 O 5} SF 3: 4
30, found: 431.

[0416] Example 18: N-alpha - preparation of [[4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] benzene acetamide - dihydroxy -2

[0417]

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Part A: 4-[(4-trifluoromethyl) -phenoxy] piperidine hydrochloride (hydrochloride from the product of Example 13, Part B) in acetonitrile (25 mL) (2.50
g, 8.87 mmol), 2-bromobenzenesulfonyl chloride (2.16 g, 8.45 mmol)
, A mixture of triethylamine (2.51 mL, 18.0 mmol), and 4- (dimethylamino) pyridine (20 mg) were stirred at ambient temperature under a nitrogen atmosphere for 18 hours, concentrated in vacuo, and H ₂ O and ethyl acetate And distributed between. The organic layer is treated with 1.0 N KHSO ₄ , saturated NaHC
O _3, washed with H ₂ O then brine, dried over MgSO _4, and concentrated in vacuo. The oil was purified by chromatography (on silica, ethyl acetate / hexane) to give a clear oil, bromide (3.38 g, 82.8%). _{C 18 H 17 NO 3 SF 3} Br of MS + calcd: 464, found: 464.

Part B: Sulfonamide from Part A (3.68 g, 7.93) in anhydrous THF (40 mL)
mmol) at −78 ° C. under a nitrogen atmosphere under 1.7 M tert-butyllithium (9.35
mL, 15.9 mmol) was added. The reaction was held at -78 ° C for 1 hour, warmed to -30 ° C, and then cooled to -78 ° C. While maintaining the reaction mixture at a temperature below -50 ° C, a 50% solution of ethyl glyoxalate in toluene was added dropwise. The solution was slowly warmed to ambient temperature, stirred for 2 days at ambient temperature, poured into saturated NH ₄ Cl solution, diluted with H ₂ O, and extracted with ethyl acetate. The organic layer was washed with H ₂ O then brine, dried over MgSO _4, and concentrated in vacuo. Chromatography on silica using ethyl acetate / hexane as the eluent provided the ester as a yellow oil (1.55 g, 40%).
Analysis Calculated for _{C 22 H 24 NO 6 F 3} S: C, 54.20; H, 4.96; N, 2.87. Measured value: C, 5
4.18; H, 4.72; N, 2.77. _{C 22 H 24 NO 6 F 3} S of MS MH ⁺ calcd 487, found 488.

Part C: A solution of the ester of Part B (1.35 g, 2.77 mmol) and potassium hydroxide (1.55 g, 27.7 mmol) in a mixture of MeOH (24.5 mL) and H ₂ O (14.7 mL) was stirred at ambient temperature. Stirred at temperature for 1 hour. The solution was concentrated in vacuo, and dissolved in a mixture of H ₂ O and acetonitrile, acidified with concentrated HCl, and extracted with ethyl acetate. 1.0 NK of organic layer
Washed with HSO ₄ , H ₂ O then brine, dried over MgSO ₄ and concentrated in vacuo to give a waxy acid (1.09 g, 85.8%). C ₂₀ H ₂₀ NO ₆ F ₃ Analysis Calculated for S: C, 52.29;
H, 4.39; N, 3.05; S, 6.98. Found: C, 52.06; H, 4.41; N, 2.90; S, 7.11.

Part D: Part C acid (1.00 g, 2.18 mmol), N-hydroxybenzotriazole (0.876 g, 6.48 mmol), 4-methylmorpholine (0.712 mL) in DMF (15 mL)
, 6.48 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.474
g, 4.05 mmol) and a solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.24 g, 6.48 mmol) were stirred at ambient temperature under a nitrogen atmosphere for 18 hours. The mixture was concentrated under vacuum, diluted with water and extracted with ethyl acetate. Organic layer
Washed with 1.0 N KHSO ₄ , saturated NaHCO ₃ , H ₂ O, then brine, dried over MgSO ₄ and concentrated in vacuo. Chromatography on silica using ethyl acetate / hexane as eluent provided THP-protected hydroxamate as a white solid (0.81 g, 66%). _{C 25 H 29 N 2 O 7} F 3 Analysis Calculated for S: C, 53.76; H, 5.23; N, 5.02; S,
5.74. Found: C, 53.73; H, 5.39; N, 4.85; S, 5.72.

Part E: THP-protected hydroxamate of Part D in methanol (15 mL) (0
A solution of .800 g (1.43 mmol) and acetyl chloride (0.36 mL, 5.2 mmol) was stirred at ambient temperature under a nitrogen atmosphere for 1.5 hours. The solution was concentrated in vacuo and purified by preparative _{HPLC (CH 3 CN / H 2} O), the title compound as a white solid (0.310 g, 45%) was obtained. _{C 20 H 21 N 2 O 6} SF 3 · 0.2% H 2 O Elemental analysis Calculated: C, 50.25; H, 4.51 ; N, 5.8
6; S, 6.71. Found: C, 50.18; H, 4.52; N, 5.82; S, 6.58.

[0423] Example 19: 2-Fluoro -N- hydroxy-6 - [[4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] benzamide

[0424]

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Part A: Piperidine of Example 13, Part B (as hydrochloride) (2.0 g, 6.72 mmol), 3-fluorobenzenesulfonyl chloride (10 mL) in acetonitrile (10 mL)
A solution of 1.19 g, 6.11 mmol), triethylamine (2.13 mL, 15.3 mmol) and 4-dimethylaminopyridine (10 mg) was stirred under an argon atmosphere at ambient temperature for 18 hours. The solution was concentrated and the residue was diluted with H ₂ O, and extracted into ethyl acetate.
The organic layer was washed with saturated NaHSO ₄ , H ₂ O, then brine; dried over MgSO ₄ and concentrated to an oil. Chromatography (on silica, 20% ethyl acetate / hexane) provided the viscous oily sulfonamide (2.35 g, 95%). MS H + calcd for C ₁₈ H ₁₇ NSO ₃ F ₄ : 404, found: 404.

Part B: t-Butyllithium (3.5 mL, 5.96 mmol) was added to a solution of the sulfonamide of Part A (1.2 g, 2.98 mmol) in dry THF (10 mL) at 0 ° C. The solution was stirred at this temperature for 15 minutes. Carbon dioxide was bubbled into the reaction mixture at 0 ° C. for 7 minutes and the mixture was stirred for 0.5 hours. Water is added to the solution and the mixture is
Acidified to pH = 1.0 with HCl and concentrated in vacuo to give an oil. Chromatography (on silica, 1% acetic acid / 5% methanol / ethyl acetate) provided the acid as a white powder (0.970 mg, 73%). MS H + for C ₁₉ H ₁₆ NSO ₅ F ₄ Calculated: 448, found: 448.

Part C: Part B acid (880 mg, 1.97 mmol), N-hydroxybenzotriazole (319 mg, 2.36 mmol), 4-methylmorpholine (0.649 mL) in DMF (10 mL)
, 5.91 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (346 m
g, 2.95 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (528 mg, 2.76 mmol) were stirred at ambient temperature under an atmosphere of argon for 18 hours, followed by 60 ° C. Stirred for 24 hours. The mixture was concentrated under vacuum, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO _4, and concentrated in vacuo to give a solid. C-18 reverse phase column chromatography eluting with acetonitrile / water yielded a white solid of THP-protected hydroxamate (240 mg
, 30%).

Part D: THP-protected hydroxamate of Part C in dioxane (5 mL) (23
(0 mg, 0.422 mmol) was added 4 N HCl (1 mL) and the solution was stirred under an argon atmosphere at ambient temperature for 1 hour. The solution was concentrated under vacuum to give an oil. Chromatography on a C-18 reverse phase column, eluting with acetonitrile / water, provided the title hydroxamate as a white foam (180 mg, 92%).

[0429] Example 20: 2-Chloro -N- hydroxy-6 - [[4- [4- (trifluoromethyl) Fe phenoxy] -1-piperidinyl] sulfonyl] benzamide

[0430]

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Part A: Amine of the piperidine from Example 13, Part B (as hydrochloride) (2.00 g, 6.72 mmol), 3-chlorobenzenesulfonyl chloride (1.29 g, 6.11 mmol) in acetonitrile (10 mL), A solution of triethylamine (2.2 mL, 15.3 mmol) and 4-dimethylaminopyridine (10 mg) was stirred under an argon atmosphere at ambient temperature for 18 hours. The solution was concentrated and the residue was diluted with H ₂ O, and extracted into ethyl acetate. The organic layer was washed with saturated NaHSO ₄ , H ₂ O, then brine, dried over MgSO ₄ and concentrated to an oil. Chromatography (on silica, 20% ethyl acetate /
Hexane) provided the viscous oily sulfonamide (2.44 g, 95%). _{C 1 8 H 17 NSO 3 F} 3 Cl of MS H + calculated: 419, found: 419.

Part B: t-Butyllithium (3.4 mL, 5.7 mmol) was added to a solution of the sulfonamide of Part A (1.2 g, 2.9 mmol) in dry THF (10 mL) at 0 ° C. The solution was stirred at this temperature for 15 minutes. Carbon dioxide was bubbled through the reaction mixture at 0 ° C. for 7 minutes, then the reaction was stirred for 1.5 hours. Water is added to this solution, then 1 NH
Acidification with Cl to pH = 1.0 and then concentration under vacuum gave an oil. Chromatography (on silica, 1% acetic acid / 5% methanol / ethyl acetate) provided the acid as a white powder (320 mg, 24%).

Part C: Oxalyl chloride (0.154 mL) is added to a solution of the acid of Part B (410 mg, 0.88 mmol) in methylene chloride (4 mL) at ambient temperature and the solution is added under argon atmosphere for 1 hour. Stirred for hours. The solution was concentrated under vacuum to give the acid chloride. D
To this acid chloride in MF (5 mL) was added 4-methylmorpholine (0.200 mL, 1.77 mmol
), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (155 mg, 1.30 mmo
l) was added and the solution was stirred at ambient temperature under an atmosphere of argon for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under vacuum to give an oil. Chromatography on a C-18 reverse phase column, eluting with acetonitrile / water, gave a white foam of THP-protected hydroxamate (
260 mg, 52%).

Part D: To a solution of the THP-protected hydroxamate of Part C in dioxane, add 4
N HCl was added and the solution was stirred at ambient temperature under an argon atmosphere for 1 hour. The solution was concentrated under vacuum to give a semi-solid. Chromatography (on silica, 60% ethyl acetate / hexane) provided the title compound.

Example 21: Production of N-hydroxy-2-[[4- (4-pyridinyloxy) -1-piperidinyl] sulfonyl] -benzamide , monohydrochloride

[0436]

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Part A: To a solution of N-BOC-4-hydroxypiperidine (3.00 g, 14.9 mmol) in dimethyl sulfoxide (10 mL) was added 4-chloropyridine hydrochloride (2.35 g, 15.6 mmol)
) Then potassium-t-butoxide (30.5 mL of a 1.0 M solution in tetrahydrofuran, 3
0.5 mmol). After 16 hours at ambient temperature, the reaction mixture was diluted with diethyl ether (100 mL), washed with water (3 ×), then brine, and then dried over sodium sulfate. Concentration of the organic solution provided the desired 4-pyridyloxypiperidine (4.24 g, 100%) as a white solid. Analysis Calculated for _{C 15 H 22 N 2 O 3} : C, 64.73
H, 7.97; N, 10.06. Found: C, 64.48; H, 8.14; N, 9.82.

Part B: A solution of hydrogen chloride in 1,4-dioxane (20 mL of 4 N solution, 80 mmol)
Pyridyloxypiperidine from Part A in 1,4-dioxane (28 mL) (3.81 g, 13
.7 mmol) at ambient temperature. After 1 hour, the suspension was concentrated and the residue was triturated with hot isopropanol. The resulting solid was dried under vacuum at 50 ° C. to give the desired piperidine hydrochloride as a white powder (3.03 g, 88%). C ₁₀ H ₁₄ N ₂ O.2HCl
Elemental analysis for Calculated: C, 47.82; H, 6.42; N, 11.15. Found: C, 47.40; H, 6.
64; N, 11.04.

Part C: The solid piperidine hydrochloride from Part B (450 mg, 1.79 mmol) was treated with acetoacetate.
2-carboxyethoxy-benzenesulfonyl chloride (580 in nitrile (5 mL)
 mg, 2.33 mmol), followed by neat triethylamine (0.95 mL, 7
.16 mmol) and dimethylaminopyridine (10 mg, 0.08 mmol) were added. Further
Add acetonitrile (10 mL) together with methylene chloride (3 mL) to dissolve
Made it easier. After 16 hours at ambient temperature, water (100 mL) is added and the mixture is quenched with ethyl acetate.
Extracted twice. Wash the combined organic extracts sequentially with water (3x), then with brine,
Dried with sodium. Concentration gave a residue (0.49 g), which was
Chromatography on silica gel eluting with ethyl acetate / ethyl acetate (4/96) gives
The desired arylsulfonamide (462 mg, 66%) was obtained as a pale yellow foam. C₁₉H _{twenty two} N_TwoO_FiveS. 3 / 4H_TwoElemental analysis of O Calculated: C, 56.49; H, 5.86; N, 6.93. Measured value: C
, 56.36; H, 5.88; N, 6.68.

Part D: Sodium hydroxide (10 equivalents) is added to a solution of the aryl sulfonamide of Part C in ethanol, water and tetrahydrofuran, and the solution is heated to 60 ° C.
For 24 hours. The solution was cooled and diluted with water followed by 10% aqueous hydrochloric acid to a pH of 3. The resulting solution was extracted with ethyl acetate. The organic extracts were combined, washed with water then brine, and dried over sodium sulfate to give the desired carboxylic acid.

Part E: To a solution of the carboxylic acid of Part D in N, N-dimethylformamide was added 4-methylmorpholine (6.0 equiv), N-hydroxybenzotriazole (1.2 equiv), then 1- [3- (dimethyl Amino) propyl] -3-ethylcarbodiimide hydrochloride (1.3
Equivalents), followed by O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (1.3
Eq.) Was added. After stirring for 2 days at ambient temperature, the solution was concentrated. Water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with water and then with brine and dried over sodium sulfate. Concentration gave a residue, which was eluted with ethyl acetate.
Chromatography on silica gel eluting with / hexane (20 / 80-90 / 10) provided the THP-protected hydroxamate derivative.

Part F: To a solution of the THP-protected hydroxamate of Part E in 1,4-dioxane, add 4 N HCl in 1,4-dioxane (10 eq) and allow the solution to reach ambient temperature. For 3 hours. Concentration gave a residue, which was triturated with ethyl ether to give the title compound.

[0443] Example 22: N-hydroxy-2,3-dimethoxy-6 - [[4 - [(2'-methoxy [1,1'-biphenyl] -4-yl) - 1- piperidinyl] Sulfonyl] benzamide
Construction

[0444]

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Part A: N-BOC-4-hydroxypiperidi in 1 Methyl-2-pyrrolidinone (20 mL)
To a solution of hexane (25 mmol, 5.0 g) was added hexane-washed sodium hydride (26 mmol, 1.
01 g) was added. The reaction mixture is stirred at ambient temperature for 15 minutes, then at 65 ° C. for 30 minutes
Heated. Bromo-4-fluorobenzene (25 mmol, 4.38 g) was added and the solution was
Heated at 0 ° C. for 24 hours. Cool the reaction mixture to ambient temperature and wash with water (100 mL).
, And extracted with ethyl acetate (150 mL). The organic layer is washed with brine (50 mL),
Dried over magnesium and concentrated in vacuo to give an oil, which was washed with ethyl acetate.
Further purification through a silica pad eluting. 7.28 g (82%) were obtained. C₁₆H _{twenty two} NO_ThreeMS calculated for Br: 356; found: 356.

Part B: To a solution of the bromide of Part A (20 mmol, 7.2 g) in dioxane (20 mL) was added 4 N HCl (50 mL). The solution was stirred at ambient temperature for 2 hours, then concentrated to give a solid. Trituration of the solid with diethyl ether provided the desired piperidine hydrochloride (5.8 g, 99%).

Part C: To a solution of 3,4-dimethoxybenzenesulfonyl chloride (18 mmol, 4.26 g) in acetonitrile (75 mL), hydrochloride salt from Part B (20 mmol, 5.8 g)
Followed by triethylamine (36 mmol, 7.5 mL) and N, N-dimethylaminopyridine (100 mg). The solution was stirred at ambient temperature for 75 hours. Mix the water (
(200 mL) and extracted with ethyl acetate (300 mL). The ethyl acetate layer was washed with brine (100 mL) and dried over magnesium sulfate. Concentrate and chromatograph (1: 1 hexane: ethyl acetate) to give the solid desired sulfonamide (5.
45 g, 66%). MS calcd for _{C 19 H 22 BrNSO 5: 456} , Found: 456.

Part D: To a solution of the compound of Part C (2.96 g, 6.49 mmol) in ethylene glycol dimethyl ether (30 mL) under a nitrogen atmosphere at ambient temperature was added tetrakis (
Triphenylphosphine) palladium (0) (0.375 g, 0.325 mmol) was added. After stirring for 5 minutes, 2-methoxyphenylboronic acid (1.18 g, 7.7
9 mmol) was added, followed by a solution of sodium carbonate (0.954 g, 9.00 mmol) in water (18 mL). The mixture was refluxed for 1.5 hours and then stirred at ambient temperature overnight (about 18 hours). The mixture was diluted with water (50 mL) and extracted with methylene chloride (50 mL). The solution was filtered through a bed of silica and concentrated under vacuum to give a black solid. Chromatography (on silica, acetone / hexane) provided biphenyl (2.69 g, 86% yield) as a white solid. Analysis Calculated for C ₂₆ H ₂₉ NO ₆ S:
C, 64.58; H, 6.04; N, 2.90; S, 6.63. Found: C, 64.30; H, 6.16; N, 2.86
S, 6.90. C ₂₆ H ₂₉ NO ₆ S of MS (EI) MH + calculated: 484, found: 484.

Part E: To a solution of the biphenyl of Part D (2.85 g, 5.89 mmol) in THF (80 mL) at −80 ° C. under a nitrogen atmosphere, 1.6 M in hexane (5.17 mL, 8.27 mmol). n
A solution of -butyllithium was added. After stirring for 30 minutes at ambient temperature, the solution is
Cooled to 80 ° C. and bubbled carbon dioxide into this solution for 7 minutes. The solution was diluted with 1 N HCl (50
mL) and extracted with ethyl acetate (3 × 50 mL). Water the organic layer (2 × 50 mL)
It was then washed with brine (50 mL), dried over MgSO ₄ and concentrated in vacuo to give the carboxylic acid as a brown solid (3.00 g, 96% yield). C ₂₇ H ₂₉ NO ₈ Analysis Calculated for S: C, 61.47; H, 5.54; N, 2.65; S, 6.08. Found: C, 61.46; H, 5.94; N, 2.4
8; S, 5.70. C ₂₇ H ₂₉ NO ₈ S of MS (EI) MH + calculated: 528, found: 528.

Part F: Carboxylic acid of Part E (2.92 g, 5 in 1,2-dichloroethane (50 mL)
Oxalyl chloride (4.07 mL, 46.7 mmol) in a solution of .53 mmol) and DMF (2 drops, catalytic)
mmol) was added. After stirring at ambient temperature under a nitrogen atmosphere for 1.5 hours, the solution was concentrated in vacuo to a yellow oil. Add N-methylmorpholine (1.57 m
L, 14.2 mmol), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (1
.66 g, 14.2 mmol) and 1,2-dichloroethane (19 mL) were added. After stirring for about 20 hours at ambient temperature under a nitrogen atmosphere, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 50 mL). Organic layer with 1 N HCl (50 mL), saturated NaHCO ₃ (50 mL)
Washed with water (50 mL) then brine (50 mL), dried over MgSO ₄ and concentrated in vacuo to give a brown solid. Chromatography (on silica, ethyl acetate / hexane) provided the O-protected hydroxamate as a white solid (2.41 g, 69% yield). _{C 32 H 38 N 2 O 9} S of MS (EI) MH + calculated: 627, found: 627.

Part G: To a solution of acetyl chloride (2.61 mL, 38.1 mmol) in MeOH (39 mL)
Add Part F O-protected hydroxamate (2.39 g, 3.81 mmol) and add a nitrogen atmosphere
The mixture was stirred at ambient temperature for 1.5 hours. Concentrate the solution, grind with ether and concentrate
Shrinking and drying gave a white solid. Chromatography (on silica, MeOH
/ CHCl_Three) Yielded the title compound as a white solid (1.36 g, 66% yield). C₂₇H ₃₀ N_TwoO₈Elemental analysis for S Calculated: C, 59.77; H, 5.57; N, 5.16; S, 5.91. Measured value:
C, 57.60; H, 5.17; N, 5.04; S, 5.67. C₂₇H₃₀N_TwoO₈MS (EI) MH + for S Calculated: 5
43.

Example 23: N-hydroxy-2- (2-methoxy-ethoxy) -6-[[4- [4- (trif
Ruoromechiru) - phenoxy] -1-piperidinyl] sulfonyl] benzamide Made in Concrete

[0453]

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Part A: 1-[(3-Fluorophenyl) -sulfonyl] -4- [4 (trifluoromethyl) phenoxy] piperidine (7.00) in 1-methyl-2-pyrrolidinone (10 mL)
g, 17.4 mmol), 60% sodium hydride (1.13 g, 28.2 mmol) and 2-methoxy-
A solution of l-ethanol (2.19 mL, 27.7 mmol) was heated at 120 C for 5 hours. The solution was diluted with water (300 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with water (2 × 10
0 mL) then diluted with brine (100 mL), dried over MgSO ₄ and concentrated in vacuo to give a brown paste. Recrystallization from methyl tert-butyl ether / hexane provided ether as a white solid (6.59 g, 83% yield). Proton NMR spectrum was consistent with the desired ether.

Part B: A solution of 1.7 M t-butyllithium in pentane (16.8 g) in a solution of the ether of Part A (6.59 g, 14.3 mmol) in THF (120 mL) under nitrogen at -10 ° C.
mL, 26.8 mmol) was added. After stirring at −60 ° C. for 30 minutes, carbon dioxide was bubbled into the solution for 7 minutes, the resulting solution was poured into a solution of 1 N HCl (100 mL) and water (500 mL), and ethyl acetate (3 × 100 mL). The organic layer was washed with 1 N HCl (100 mL), water (
(2 × 100 mL) then washed with brine (100 mL), dried over MgSO ₄ and concentrated in vacuo. Chromatography (acetic acid / MeOH / CHCl ₃ ) gave a yellow oily carboxylic acid (4.6
7 g, 64% yield). Analysis Calculated for _{C 22 H 24 NO 7 F 3} S: C, 52.48; H,
4.80; N, 2.78; S, 6.37. Found: C, 52.49; H, 4.70; N, 2.69; S, 6.31. _{C 22 H 24 NO 7 F 3} S of MS (EI) MH + calculated: 504, found: 504.

Part C: Part B carboxylic acid (5.45 g, 10.8 in dichloromethane (99 mL)
oxalyl chloride (8.03 mL, 92.0 mmol) in a solution of
) Was added. After stirring at ambient temperature for 2 hours, the solution was concentrated in vacuo to a dark brown mixture. To this mixture was added N-methylmorpholine (4.76 mL, 43.3 mmol),
O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (5.07 g, 43.3 mmol
) And dichloromethane (77 mL) were added. After stirring at ambient temperature for about 4 hours, the solution was washed with water, 1.0 N HCl, saturated NaHCO ₃ , water then brine, dried over MgSO ₄ and concentrated in vacuo to give a paste. Chromatography (on silica, MeOH / ethyl acetate) gave O-protected hydroxamate as a pink solid (5.23 g, 80% yield)
)was gotten. _{C 27 H 33 N 2 O 8} F 3 Analysis Calculated for S: C, 53.81; H, 5.52; N, 4.6
5; S, 5.32. Found: C, 53.67; H, 5.43; N, 4.77; S, 5.17. Of _{C 27 H 33 N 2 O 8} F 3 S
MS (EI) MH + calc .: 603, found: 603.

Part D: A solution of acetyl chloride (5.90 mL, 86.3 mmol) in MeOH (89 mL)
Added to Part C O-protected hydroxamate (5.20 g, 8.63 mmol) and stirred at ambient temperature for 3 hours. The solution was concentrated, triturated with ether and concentrated to give an off-white solid. Chromatography (on silica, MeOH / methylene chloride)
Gave the title compound as a white solid (2.25 g, 50% yield). C ₂₂ H ₂₅ N ₂ O ₇ Analysis Calculated for S: C, 50.96; H, 4.86; N, 5.40; S, 6.18. Obtained value: C, 50.57
H, 4.91; N, 5.37; S, 6.08. _{C 22 H 25 N 2 O 7} S of MS (EI) MH + calculated: 519, found: 519.

Example 24: N-hydroxy-2,3-dimethoxy-6-[[4- (phenylthio) -1-pipe
Preparation of [Ridinyl] -sulfonyl] benzamide

[0459]

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Part A: 4-Hydroxypiperidine (55 mmol, 5.56 g) was added to acetonitrile (10
0 mL), triethylamine (55 mmol, 7.7 mL) and N, N-dimethyl-aminopyridine (500 mg). 3,4-dimethoxy-benzenesulfonyl chloride (50 mm
ol, 11.84 g) was added. The mixture was stirred overnight (about 18 hours) and then concentrated by rotary evaporation. The residue was diluted with water (100 mL) and extracted with dichloromethane (2 × 150 mL). The combined organic phases are dried using magnesium sulphate, filtered through a plug of silica and concentrated to give the desired alcohol in the form of a foam (
(7.31 g, 51%).

Part B: The alcohol from Part A (6.39 g, 22.4 mmol) was treated with methylene chloride (65 mL).
) And triethylamine (3.46 mL, 25 mmol). This solution was cooled to 0 ° C. Methanesulfonyl chloride (1.79 mL, 23 mmol) was added. The reaction was stirred at ambient temperature for 4 hours, then diluted with additional methylene chloride to 150 ml and water (2 × 2
5 mL). The organic phase was dried over magnesium sulfate, filtered through silica and concentrated to give mesylate (3.51 g, 41%) as a white solid.

Part C: 60% sodium hydride in mineral oil (324 mg, 8.1 mmol) was washed with hexane. Cover the washed hydride with N, N-dimethylformamide (12 mL),
And cooled. Thiophenol (0.83 mL, 8.1 mmol) was added and the mixture was stirred for 20 minutes. The solid mesylate from Part B above (3.0 g, 7.9 mmol) was added.
The mesylate displacement was slow at ambient temperature; the reaction was warmed at 55 ° C. for 3 hours.
Azeotropic removal of DMF with toluene followed by chromatographic workup of the residue yielded 1.45 g (44%) of the sulfide as a white foam.

Part D: This sulfide was dissolved in tetrahydrofuran (24 mL) and cooled to 0 ° C. T-BuLi (1.7 M in pentane, 4.1 mL) was added in 1 minute. After 15 minutes, the reaction was quenched with carbon dioxide gas. After 10 minutes, the mixture was acidified with concentrated HCl, concentrated and chromatographed to give the desired acid as a foam (1.067 g, 70%).

Part E: The acid from Part C was diluted with methylene chloride (15 mL). Three drops of N, N-dimethylformamide were added, followed by oxalyl chloride (0.35, 4 mmol). The reaction was stirred at ambient temperature for 2 hours, then concentrated. The crude acid chloride was treated with tetrahydropyran-hydroxylamine (0.47
g, 4 mmol), pyridine (0.47 ml, 6 mmol) and acetonitrile (3 mL). The mixture was stirred overnight (about 18 hours) and then subjected to aqueous extraction (50 mL methylene chloride / 50 mL water). The organic phase was dried over magnesium sulfate, concentrated, and chromatographed to give O-THP hydroxamate as foam (619 mg).

The O-THP hydroxamate (614 mg) was diluted with dry methanol (20 mL). Acetyl chloride (0.6 mL, 8 mmol) was added. After 1 hour, the mixture was concentrated and chromatographed to give the desired hydroxamate as a foam (428 mg, 31%)
was gotten. _{C 20 H 24 N 2 O 6} S 2 of MS (EI) MH + calculated: 453, found: 453.

The following analogs could be prepared in excellent yield using a similar method. Example 25: 6 - [[4 - [(3'-dimethoxy [1,1'-biphenyl] -4-yl) -1-piperazinyl lysinyl] sulfonyl] -N-hydroxy-2,3-dimethoxy-benzamide

[0467]

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MS (EI) MH + for C ₂₈ H ₃₂ N ₂ O ₉ S Calculated: 573, found: 573. Example 26: N-hydroxy-2,3-dimethoxy-6-[[4- [4- (trifluoromethyl ) phenyl] -1-piperazinyl] sulfonyl] benzamide

[0469]

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[0470] _{C 20 H 22 F 3 N 3} O 6 S of MS (EI) calcd: 490, found: 490. Example 27: N-hydroxyl-2,3-dimethoxy-6-[[4-[[3 ′-(trifluoro
Methyl) [1,1'-biphenyl] -4-yl] oxy] -1-piperidinyl] sulfonyl
] Benzamide

[0471]

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[0472] _{C 27 H 27 F 3 N 2} O 7 S of MS (EI) calcd: 581, found: 581. Example 28: 6-[[4- (1,1'-biphenyl] -4-yloxy) -1-piperidinyl]
Sulfonyl] -N-hydroxy-2,3-dimethoxybenzamide

[0473]

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Example 29: 2-[[4- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] -sulfonyl] -N-hydroxybenzamide

[0475]

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[0476] _{C 19 H 20 N 4 O 5} S of MS (EI) calcd: 417, found: 417. Example 30: 2,3-dihydro-N-hydroxy-6-[(4-methoxy-1-piperidinyl)
Sulfonyl] -1,4-benzodioxin-5-carboxamide

[0477]

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MS (EI) for C ₁₅ H ₂₀ N ₂ O ₇ S Calculated: 372, found: 373. Example 31: 2,3-dihydro-N-hydroxy-6-[[4- [4- (trifluoromethyl) phenoxy-1-piperidinyl] sulfonyl-1,4-benzodioxin-5-carboxa
Mid

[0479]

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MS (EI) for C ₂₁ H ₂₁ F ₃ N ₂ O ₇ S Calculated: 502, found: 503. Example 32: 2,5-Dichloro-N-hydroxy-4-[[4- [4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] -3-thiophenecarboxamide

[0481]

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[0482] Example 33: N-hydroxy-2,3-dimethoxy-6 - [[4- [4- (trifluoromethyl methoxyethanol) phenoxy] -1-piperidinyl] sulfonyl] benzamide

[0483]

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Example 34: N-hydroxy-2,3-dimethoxy-6-[[4- (2-methoxyphenoxy) -1-piperidinyl] -sulfonyl] benzamide

[0485]

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Elemental analysis for C ₂₁ H ₁₆ N ₂ O ₈ S Calculated: C, 50.07; H, 5.62; N, 6.00. Observed value: C, 53
.77; H, 5.64; N, 5.79. Example 35: N-hydroxy-3,6-dimethoxy-2 - [[4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] benzamide

[0487]

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Example 36: N-hydroxyl-5-[[4- [4- (trifluoromethyl) -phenoxy -1-piperidinyl] sulfonyl-1,3-benzodioxole-4-carboxamide

[0489]

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[0490] _{C 20 H 19 F 3 N 2} O 7 S of MS (EI) calcd: 489, found: 489. Example 37: 6 - [[4 - [(2 ', 5'-dimethoxy [1,1'-biphenyl] -4-yl) Oki shea] -1-piperidinyl] sulfonyl] -N- hydroxy-2,3 -Dimethoxybenzami
Do

[0490]

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Elemental analysis for C ₂₈ H ₃₂ N ₂ O ₉ S Calculated: C, 58.73; H, 5.63; N, 4.89. Measured value: C, 58
.55; H, 5.82; N, 4.81. Example 38: N-hydroxy-2,3-dimethoxy-6-[[4-[[2 '-(trifluorometh
Tyl) [1,1'-biphenyl] -4-yl] oxy] -1-piperidinyl] sulfonyl]
Benzamide

[0493]

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Elemental analysis for C ₂₇ H ₂₇ F ₃ N ₂ O ₇ S Calculated: C, 55.86; H, 4.69; N, 4.83. Measured value: C,
55.77; H, 4.75; N, 4.77. Example 39: N-hydroxy-2,3-dimethoxy-6-[[4-[[2 ′-(trifluorometh
Tyl) [1,1'-biphenyl] -4-yl] oxy] -1-piperidinyl] sulfonyl]
Benzamide

[0495]

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Elemental analysis for C ₃₀ H ₃₆ N ₂ O ₈ S Calculated: C, 61.63; H, 6.21; N, 4.79. Measured value: C, 61
.36; H, 6.29; N, 4.64. Example 40: 6-[[4-[(2'-ethoxy [1,1-biphenyl] -4-yl) oxy-1-
Piperidinyl] sulfonyl] -N-hydroxyl-2,3-dimethoxybenzamide

[0497]

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Elemental analysis for C ₂₈ H ₃₂ N ₂ O ₈ S Calculated: C, 60.42; H, 5.79; N, 5.03. Measured value: C, 60
.30; H, 5.94; N, 4.88. Example 41: N-hydroxy-2,3-dimethoxy-6-[[4- (4-methoxyphenyl) -1 -piperazinyl] sulfonyl] -benzamide, monohydrochloride

[0499]

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[0500] _{C 20 H 25 N 3 O 7} S ( free base) MS (EI) MH + calculated: 452, found: 452. Example 42: N-hydroxyl-2-[[4- (2-pyridyloxy) -1-piperidinyl] sulfonyl] benzamide, monohydrochloride

[0501]

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C ₁₇ H ₁₉ N ₃ O ₇ S (free base) MS (EI) MH + calc .: 378, found: 378. Example 43: 5-[(4-butoxy-1-piperidinyl) sulfonyl] -N-hydroxy -1,3-benzodioxole-4-carboxamide

[0503]

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[0504] C ₁₇ H ₂₄ N ₂ O ₇ Analysis Calculated for S: C, 50.99; H, 6.04; N, 7.00. Measured value: C, 50
.97; H, 6.27; N, 6.88. Example 44: 5 - [(4-heptyloxy-1-piperidinyl) sulfonyl] -N- hydro carboxymethyl-1,3-benzodioxol-4-carboxamide

[0505]

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Elemental analysis for C ₂₀ H ₃₀ N ₂ O ₇ S Calculated: C, 54.28; H, 6.33; N, 6.33. Observed value: C, 53
.91; H, 7.10; N, 6.25. Example 45: N-hydroxy-2,3-dimethoxy-6-[[4- (4-methoxyphenoxy-1 -piperidinyl] -sulfonyl] benzamide

[0507]

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Elemental Analysis for C ₂₁ H ₂₆ N ₂ O ₈ S Calculated: C, 54.07; H, 5.62; N, 6.00. Observed value: C, 53
.69; H, 5.87; N, 5.79. Example 46: 6-[[4- (4-chlorophenoxy) -1-piperidinyl] -sulfonyl] -N-hydroxy-2,3-dimethoxybenzamide

[0509]

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Elemental analysis for C ₂₀ H ₂₃ ClN ₂ O ₈ S Calculated: C, 51.01; H, 4.92; N, 5.95. Measured value: C,
50.62; H, 4.93; N, 5.92. Example 47: N-hydroxy-2,3-dimethoxy-6-[(4-phenoxy-1-piperidini
Ru) sulfonyl] benzamide

[0511]

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MS (EI) for C ₂₀ H ₂₄ N ₂ O ₇ S Calculated: 436, found: 437. Example 48: N-hydroxy-2 - [(tetrahydro -2H- pyran-4-yl) oxy] -6 - [[4- (trifluoromethyl) phenoxy] -1-piperidinyl] sulfonyl] Baie Nzuamido

[0513]

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[0514] _{C 24 H 27 F 3 N 2} O 7 Analysis Calculated for S: C, 52.94; H, 5.00; N, 5.14. Measured value: C,
52.64; H, 4.92; N, 5.02. Example 49: 5 - [[4 - ((1,3-benzodioxol] -5-yloxy) -1-Piperi Jiniru] sulfonyl] -N- hydroxy-1,3-benzodioxol-4 Carboxami
Do

[0515]

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[0516] Example 50: 6 - [[4- (1,3-benzodioxol-5-yloxy) -1-piperidin le] sulfonyl] -N- hydroxy-2,3-dimethoxy-benzamide

[0517]

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MS (EI) for C ₂₁ H ₂₄ N ₂ O ₉ S Calculated: 481, found: 481. Example 51: 2 - [(4-benzoyl-1-piperazinyl) sulfonyl] -N- hydroxy benzamide

[0519]

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MS (EI) MH + for C ₁₈ H ₁₉ N ₃ O ₅ S Calculated: 390, found: 390. Example 52: N-hydroxy-2,3-dimethoxy-6-[[4- (phenylmethyl) -1-pi
Perazinyl] sulfonyl] -benzamide, monohydrochloride

[0521]

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[0522] _{C 20 H 25 N 3 O 6} S MS (EI) MH + calculated values of (free base): 436, Found: 436. Example 53: N-hydroxy-2,3-dimethoxy-6 - [[4 - [[4- (trifluoromethyl meth) phenyl] methyl] -1-piperazinyl] sulfonyl] benzamide, monosalt
Acid salt

[0523]

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MS (EI) MH + for C ₂₁ H ₂₄ F ₃ N ₃ O ₇ S Calculated: 520, found: 520. Example 54: 6-[[4- (4-butoxyphenoxy) -1-piperidinyl] -sulfonyl ] -N-hydroxy-2,3-dimethoxybenzamide

[0525]

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MS (EI) MH + for C ₂₄ H ₃₂ N ₂ O ₈ S Calculated: 509, found: 509. Example 55: N-hydroxy-2-[[4- (4-pyridinyloxy) -1-piperidinyl] sulfonylbenzamide, monohydrochloride

[0527]

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C ₁₇ H ₁₉ N ₃ O ₅ S (free base) MS (EI) MH + Calculated: 378, found: 378. Example 56: 6 - [[4- (4-butoxy-3-methylphenyl) -1-piperazinyl] sul Honiru] -N- hydroxy-2,3-dimethoxy-benzamide, monohydrochloride

[0529]

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[0530] _{C 24 H 33 N 3 O 7} S ( free base) MS (EI) MH + calculated: 508, found: 508. Example 57: N-hydroxy-2,3-dimethoxy-6-[[4- (3-methoxyphenoxy-1 -piperidinyl] sulfonyl] benzamide

[0531]

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Elemental analysis of C ₂₁ H ₂₆ N ₂ O ₈ S Calculated: C, 54.07; H, 5.62; N, 6.00. Measured value: C,
53.77; H, 5.64; N, 5.79. Example 58: In vitro metalloprotease inhibition Compounds prepared as described in the above examples were evaluated in an in-vitro assay.
Knight et al., FEBS Lett. 296 (3): 263 (1992). Briefly, mercuric 4-aminophenylacetate (APMA) or trypsin-activated MMP,
Incubated with various concentrations of inhibitor compound for 5 minutes at room temperature.

More specifically, human recombinant MMP-13, MMP-1 and MMP-2 enzymes were produced in the assignee's lab according to routine lab procedures. MMP-13 derived from the full-length cDNA clone is V.
A. Luckow, Insect Cell Expression Technology, pp. 183-218, Protein Enginee ring: Principles and Practice , edited by JLCleland et al., Wiley-Liss, Inc., (1996)
) Was expressed as a proenzyme using the baculovirus described in For details using the baculovirus expression system, see Luckow et al., J. Virol., 67: 4566.
Page -4579 (1993); O'Reilly et al., Baculovirus Expression Vectors: A Laborat ory Manual, WHFreeman and Company, New York, (1992 years); and King et al, T he Baculovirus Expression System: A Laboratory Guide, Chapman & Hall, Lo
See also ndon (1992). The expressed enzyme is transferred to a heparin agarose column,
Then, it was purified by a zinc chloride column for chelation. This proenzyme was activated with APMA for use in this assay.

[0534] MMP-1 expressed in transfected HT-1080 cells was isolated from Washington Unive.
Courtesy of Dr. Harold Welgus of rsity, St. Louis, MO. The enzyme was activated using APMA and then purified on a hydroxamic acid column. Welgus also provided transfected HT-1080 cells that expressed MMP-9. MMP-2
Transfected cells that expressed E. coli were from Gregory G at Washington University.
Provided by Dr. oldberg. MMP in the presence of 0.02% 2-mercaptoethanol
Experiments using -2 are indicated with an asterisk in the table below. Detailed examples of the production and use of these enzymes can be found in the scientific literature describing these enzymes. For example, Enzyme Nomenclature , Academic Press, San Die
go, Ca (1992) and references therein and Frije et al . , J. Biol. Chem. , 26 (24).
Volume: pages 16766-16773 (1994).

The enzyme substrate has the following sequence: MCA-ProLeuGlyLeuDpaAlaArgNH ₂ [where MCA is methoxycoumarin and Dpa is 3- (2,4-dinitrophenyl) -L-2,3-diaminopropionylalanine And a methoxycoumarin-containing polypeptide. This substrate is commercially available from Baychem as product M-1895.

The buffer used in the assay was 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl ₂
And 0.05 percent polyethylene glycol (23) lauryl ether, pH 7.5
Was contained. Assays were performed at room temperature and 1% final concentration of dimethyl sulfoxide (DMSO) was used to dissolve inhibitor compounds.

The assay inhibitor compound in DMSO / buffer solution was Microfluor ™ White Pla
tes (Dynatech) was used to compare to an equal volume of DMSO / buffer without inhibitor as a control. The inhibitor or control solution was kept in the plate for 10 minutes and the substrate was added to a final concentration of 4 μM.

In the absence of inhibitory activity, g of a fluorogenic peptide
Cleavage at the ly-leu peptide bond separates the highly fluorine-producing peptide from the 2,4-dinitrophenyl quencher, resulting in a higher spontaneous fluorescence intensity (excitation 328n
m / emission 415 nm). Inhibition was measured as a decrease in fluorescence intensity as a function of inhibitor concentration using a Perkin Elmer L550 plate reader. IC ₅₀ values were calculated from these values. The results are shown in the following Inhibitions Tables A and B with respect to the IC ₅₀ with three significant figures where appropriate.

[0539]

[Table 1]

[0540]

[Table 2]

Example 59 In Vivo Angiogenesis Assay Angiogenesis experiments are governed by a reliable and reproducible model for stimulating and inhibiting the angiogenic response. The corneal micropocket assay provides a model for such angiogenesis in the mouse cornea. “A Model of Angioge
nesis in the Mouse Cornea ”, Kenyon, BM, etc., Investigative Ophthalmology &
See Visual Science, July 1996, Volume 37, Issue 8.

In this assay, a uniformly sized Hydron containing bFGF and sucralfate was used.
™ pellets were prepared and surgically implanted into the stromal mouse cornea adjacent to the temporal limbus. The pellet was formed by preparing a suspension of 20 μL sterile saline containing 10 μg recombinant bFGF, 10 mg sucralfate and 10 μL of 12 percent Hydron ™ in ethanol. The slurry was then deposited on a 10 × 10 mm piece of sterile nylon mesh. After drying, the mesh nylon fibers were separated, and the pellets were taken out.

A corneal pocket was created by anesthetizing a 7 week old C57B1 / 6 female mouse and then protruding the eyes using jeweler's tweezers. Using a dissecting microscope, a medial stromal linear keratotomy about 0.6 mm in length was performed with a # 15 surgical blade to equilibrate with the point of lateral rectus muscle. The lamellar micropocket was dissected toward the temporal limbus using a modified linear sword. This pocket extends 1.00 mm inside the temporal limbus. One pellet was placed on the corneal surface at the base of the pocket using jeweler tweezers. The pellet was then advanced to the temporal end of the pocket.
An antibiotic ointment was then applied to the eyes.

Mice were dosed on a daily basis for the duration of the assay. Animal doses were based on the bioavailability and overall strength of the compound. As an example of administration, 50 mg / kg bid.p
There is o. Corneal stroma angiogenesis started around day 3 and continued under the influence of the assay compound until day 5. On day 5, the degree of inhibition of angiogenesis was evaluated by observing the progress of angiogenesis with a slit lamp microscope.

The mice were anesthetized and the observed eyes protruded again. Marginal vascular network (limbal v
The maximum vascular length of the angiogenic portion extending from the ascular plexus toward the pellet was measured. In addition, the area around the vascularized area was measured as time (clock hour). Here, an arc of 30 degrees is equal to one hour. The angiogenesis area was calculated as follows.

[0546]

(Equation 1)

The observed mice were then compared to control mice and recorded differences in the area of neovascularization. Compounds of the invention typically show about 25-75 percent inhibition, while
Vehicle control showed 0 percent inhibition.

Various modifications and changes may be made without departing from the spirit and scope of the novel concept of the invention. The specific examples shown here do not limit the invention. The present disclosure includes such modifications, all of which are included in the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4184 A61K 31/4184 4C206 31/445 31/445 4H006 31/4525 31/4525 31/4545 31 / 4545 31/495 31/495 A61P 9/00 A61P 9/00 17/06 17/06 19/02 19/02 25/00 25/00 29/00 29/00 31/00 31/00 35/00 35 / 00 37/00 37/00 37/06 37/06 43/00 111 43/00 111 C07C 311/17 C07C 311/17 311/21 311/21 311/29 311/29 317/44 317/44 C07D 207 / 48 C07D 207/48 211/96 211/96 295/22 295/22 A 309/10 309/10 401/04 401/04 401/12 401/12 405/12 405/12 405/14 405/14 409 / 12 409/12 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG) , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA , CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU , SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, U G, US, UZ, VN, YU, ZA, ZW (72) Inventor Bata, Thomas E. Maple Avenue, 1133, Evanston, Illinois, United States 60202, No. 3 Double (72) Inventor Becker, Daniel P. United States of America Maplewood Lane, Glenview, IL 60025, Illinois 1800 (72) Inventor Lao, Shasidal N. Beralibu Manor Drive, St. Louis, Missouri, United States 63141, United States 736 (72) Inventor Frescos, John N. Missouri, United States of America State, 63105, Clayton, York 7572 (72) Inventor Misk, Brent Buoy 63341, Missouri, United States of America 63341, Defiance, White River Lane 25 (72) Inventor Getman, Daniel P. Missouri, United States 63017, Chester Field, Sunny Hill Court 66 (72) Inventor Decresenzo, Gary A. 63304, Missouri, USA, Scent Charles, Spruce Hill Coat 7345 (72) Inventor Villamill, Clara Eye, Glenview, Long Road, 60025, Illinois, United States of America 813 F-term (Reference) 4C054 AA02 CC08 DD01 EE01 FF05 FF08 4C062 AA17 4C063 AA01 AA03 BB02 BB08 CC10 CC12 CC26 CC81 CC82 CC92 DD10 EE01 4C069 AA23 BC18 4C086 AA01 AA02 AA03 GA07 GA07 Z02 ZA89 ZA96 ZB02 ZB11 ZB26 ZB31 ZB35 ZC20 4C206 AA01 AA03 JA13 JA19 KA01 MA01 MA04 NA14 ZA02 ZA07 ZA36 ZA89 ZA96 ZB02 ZB11 ZB26 ZB31 ZB35 ZC20 4H006 AA01 AA03 AB20 TA02 TB61

Claims (118)

[Claims] 1. A compound corresponding to formula C or a pharmaceutically acceptable salt thereof: Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; R ¹ is a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical which is directly bonded to the described SO ₂ — group Which is approximately longer than that of a hexyl group and shorter than that of an eicosyl group,
R ¹ defines a three-dimensional volume, the 1- and 4-positions to which SO _{2 of the} 6-membered ring radical is bonded
Rotating around an axis drawn through the position, or an axis drawn through the center of the 1-position and the 3,4-bond where the SO _{2 of the} 5-membered ring radical binds, its widest width transverse to the axis of rotation Is from about one furanyl ring to about two phenyl rings; R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituents, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R ^b R ^{c is} independently selected from the group consisting of aminoalkyloxy substituents; or R ⁵ and R ⁶ together with the atoms to which they are attached further form a 5- to 7-membered aliphatic or aromatic carbocycle or heterocycle. And R ²⁰ is (a) —OR ²¹ , wherein R ²¹ is a hydride, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl group, and pharmaceutically acceptable Selected from the group consisting of cations), (b) -NR ¹³ -OR ²² , wherein R ²² is a selectively removable protecting group, and R ^{1 3} is hydride, C ₁ -C ₆ -alkyl, or benzyl group), (c) -NR ¹³ -OR ^{14 wherein} R ¹³ is as described above, R ¹⁴ is hydride, pharmaceutically acceptable Cation, or C (V) R ¹⁵ , wherein V is O or S, and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl-C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl -C ₁ -C ₆ - alkyl, aryloxy, ar-C ₁ -C ₆ - alkoxy, ar-C ₁ -C ₆ - alkyl, heteroaryl, And an amino C ₁ -C ₆ -alkyl group,
Wherein the amino C ₁ -C ₆ -alkyl nitrogen is (i) unsubstituted or (ii) C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -Cycloalkyl-C ₁ -C ₆ -alkyl,
ar-C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, and C ₁ -C _6-
Substituted with one or two substituents independently selected from the group consisting of alkanoyl radicals, or (iii) when the amino C ₁ -C ₆ -alkyl nitrogen and the two substituents attached thereto are from 5 to 5 (Forming an 8-membered heterocyclic or heteroaryl ring), or (d
) -NR ²³ R ²⁴ (R ²³ and R ²⁴ are hydride, C ₁ -C ₆ -alkyl, amino C ₁ -C ₆ -alkyl, hydroxy C ₁ -C ₆ -alkyl, aryl, and ar-C ₁ -C Is independently selected from the group consisting of ₆ -alkyl groups, or R ²³ and R ²⁴ are zero or one further heteroatom together with the stated nitrogen atom, which is oxygen, nitrogen, or sulfur. Wherein R ^b and R ^c are hydride, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxy Alkyl, alkoxyalkyl,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Is independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii)
) A heterocyclo group which is independently substituted with one or two R ^d radicals or in which the substituent on the amino group is saturated or partially unsaturated with the amino nitrogen (optionally independently from the R ^d substituent A heteroaryl group (substituted with 1, 2, or 3 groups optionally selected independently from the R ^f substituent) or a heteroaryl group (substituted with 1, 2, or 3 groups selected) R ^d and R ^e are independently selected from the group consisting of hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; and , R ^f is nitro, hydroxy, alkyl, halogen, aryl, alkoxy is selected from the group consisting cyano, and R ^d R ^e amino groups, Serial compound or salt. 2. The compound or salt according to claim 1, wherein R ¹ is a (i) -NR ⁷ R ⁸ group (
Wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydride, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and substituted arylhydrocarbyl), or (ii) R ⁷ and R ⁸ is hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, independently from the group consisting of heteroarylalkyl, and heterocyclo substituents And each substituent is optionally substituted with an -AREY substituent; in said -AREY substituent, A is: (1) -O-; (2) -S-; (3) -NR ^k -; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C-; (10) -N = N-; (11) -NH-NH- (12) -CS-N (R ^k )-or -N (R ^k ) -CS-; (13) -CH _2- ; (14) -O-CH ₂ -or -CH ₂ -O-; 15) -S-CH ₂ - or _{-CH 2 -S-; (16) -SO-} ; and (17) -SO ₂ -; or (18) A is absent, R represents R ⁷ or R ^8, Or directly bonded to both R ⁷ and R ⁸ ; selected from the group consisting of: wherein the moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cyclo Selected from the group consisting of alkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, where aryl , The teloaryl, cycloalkyl, or heterocycloalkyl substituent can be (i) unsubstituted or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy , C ₁ -C ₂ -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino,
And alkoxy substituted by one or two radicals selected from the group consisting of a carbonyl group; E group the following: (1) -COR ^g - or ^{-R g CO-; (2) -CON} (R k) - Or-(R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k )-; or (7) E is absent and R is directly bonded to Y; The moiety Y is absent or hydride , alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl , Alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is either (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; or R ⁷ and R ⁸ are Forms a -GAREY group with a nitrogen atom, wherein G is an N-heterocyclo group, and substituent A is (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5)- (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C- ; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R k) - or ^{-N (R k) -CS-; (} 13) -CH 2 -; (14) -O-CH ₂ - or _{-CH 2 -O-; (15) -S} -CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and (17) -SO ₂ -; Or (18) A is absent and R is directly bonded to the N-heterocyclo group G; the moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl , Heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl , Cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) halo, Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, 1 or 2 selected from the group consisting of alkanoylamino and alkoxycarbonyl groups
Moiety E is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO -; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k ) Or; (7) E is absent and R is directly attached to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cyclo alkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is (i) unsubstituted or substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; wherein ^Ra is hydride, alkyl, alkenyl, alkenyl, aryl Alkyl, aryl, alkanoyl, aroyl, ant Le alkylcarbonyl, R ^b R ^c aminoalkanoyl, halo alkanoyl, R ^b R ^c aminoalkyl, alkoxyalkyl, selected from the group consisting haloalkyl, and aryl alkyl group; R ^g is hydrido, aryl, heteroaryl, heterocyclo, Aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehyde, hydroxy, amino,
Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ -amino, alkoxyalkyl, alkylenedioxy, aryloxy Alkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -amino carbonyloxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ - Minosuruhoniru, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethylsulfonyl (R ^h) amino, heteroarylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino R ^h is selected from the group consisting of carbonyl, alkylsulfonyl (R ^h ) amino, arylcarbonyl (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, Alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted Amino alkanoyl, selected from the group consisting of halo alkanoyl, and hydroxyalkyl groups, each group similar to the substituent of the aminoalkyl and substituted aminoalkanoyl groups substituted, are independently selected from R ^j substituent R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl , Arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl,
Selected from the group consisting of aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each group optionally substituted with one or two R ^j substituents; R ^j is arylalkyl, aryl , Heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted amino Selected from the group consisting of alkanoyl, haloalkanoyl, and hydroxyalkyl groups, wherein the substituted aminoalkyl and substituted aminoalkanoyl group substituents are alkyl, alkenyl, Alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
R ^k is selected from the group consisting of aryloxycarbonyl and alkyloxycarbonyl groups; and R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl,
Selected from alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl, R ^c R ^d aminoalkanoyl, and R ^c R ^d aminoalkylsulfonyl,
The above compound or salt. Wherein said R ⁵ and R ⁶ are hydride, hydrocarbyl, hydroxyl hydrocarbyl, selected hydroxyl, amino, dihydrocarbylamino, heterocyclo, heterocycloalkyl hydrocarbyl, independently from the group consisting of heterocyclooxy, and heterocycloalkyl thio group 2. The compound or salt according to claim 1, wherein 4. The 5- or 6-membered aromatic or heteroaromatic ring W is 1,2-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 4,5-pyridinylene, 2,3-pyrazinylene, 4 The compound and salt according to claim 1, wherein the compound and salt are selected from the group consisting of a 5,5-pyrimidinylene, and a 5,6-pyrimidinylene group. 5. The compound or salt according to claim 1, wherein said R ²⁰ is —NR ¹³ —OR ¹⁴ . 6. The compound or salt according to claim 1, wherein said R ²⁰ is —NR ¹³ —OR ²² . 7. The compound or salt according to claim 1, wherein the compound has a structure corresponding to formula C1. Such a compound or salt wherein W, R ¹ , R ⁵ , R ⁶ , R ¹³ , and R ¹⁴ are as defined above. 8. The compound or salt according to claim 1, wherein the compound has a structure corresponding to the formula C2. Wherein W, R ⁵ , R ⁶ , and R ¹⁴ are as defined above, Ph is phenyl substituted at its 4-position with a substituent R ⁴ , wherein R ⁴ is 3 to about 14 carbons The above compound or salt, which is a substituent having an atom chain length. 9. The compound or salt according to claim 8, wherein said R ⁴ substituent is phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamide, nicotinamide, isonicotinamide, Picolinamide group, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarbylhydrocarbyl,
Arylhydrocarbylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl The above compound or salt selected from the group consisting of: an arylhydrocarbylamino, a heteroarylhydrocarbylamino, and a heteroarylthio group. 10. The compound or salt of claim 9, wherein said R ⁴ substituent is itself halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy,
Mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio , Heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl,
Hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbylyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl , Hydroxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbyl, hydrocarbyl hydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexyl Locarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Substituted with one or more substituents selected from the group consisting of heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and N-monosubstituted or N, N-disubstituted aminohydrocarbyl groups; The above substituents are hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl Selected from the group consisting of bil, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or the nitrogen and the two substituents attached thereto forming a 5- to 8-membered heterocyclic or heteroaryl ring group The above compound or salt. 11. The compound or salt according to claim 1, wherein the compound has a structure corresponding to Formula D3. Such a compound or salt wherein R ⁵ , R ⁶ , and R ²⁰ are as defined above, and R ⁴ is a substituent having a chain length of 3 to about 14 carbon atoms. 12. The compound or salt according to claim 11, wherein said R ⁴ substituent is phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamide, nicotinamide, isonicotinamide, Picolinamide group, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarbylhydrocarbyl, arylhydrocarbylhydrocarbyl, arylcarbonyl Hydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydroca Building thioaryloxy, arylthio hydrocarbyl,
The above compound or salt selected from the group consisting of heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio groups. 13. The compound or salt of claim 12, wherein said R ⁴ substituent is itself halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy,
Mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio , Heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl,
Hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbylyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl , Hydroxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbyl, hydrocarbyl hydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexyl Locarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Substituted with one or more substituents selected from the group consisting of heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and N-monosubstituted or N, N-disubstituted aminohydrocarbyl groups; The above substituents are hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl Selected from the group consisting of bil, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or the nitrogen and the two substituents attached thereto forming a 5- to 8-membered heterocyclic or heteroaryl ring group The above compound or salt. 14. The compound or salt according to claim 1, wherein the compound has a structure corresponding to Formula VI-1. Wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ²⁰ are each as defined above, and A, B, C
, And D are each carbon, nitrogen, sulfur, or oxygen, which is present or absent, and wherein the described ring is a 5- or 6-membered ring. 15. A compound corresponding to formula C4, or a pharmaceutically acceptable salt thereof: Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; R ¹ is a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical which is directly bonded to the described SO ₂ — group Which is approximately longer than that of a hexyl group and shorter than that of an eicosyl group,
R ¹ defines a three-dimensional volume, the 1- and 4-positions to which SO _{2 of the} 6-membered ring radical is bonded
Rotating around an axis drawn through the position, or an axis drawn through the center of the 1-position and the 3,4-bond where the SO _{2 of the} 5-membered ring radical binds, its widest width transverse to the axis of rotation Is from about one furanyl ring to about two phenyl rings; R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituents, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R ^b R ^{c is} independently selected from the group consisting of aminoalkyloxy substituents; or R ⁵ and R ⁶ together with the atoms to which they are attached further form a 5- to 7-membered aliphatic or aromatic carbocycle or heterocycle. formed; R ^b and R ^c are hydrido, alkanoyl, arylalkyl, aroyl, bis alkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethyl alkyl, perfluoroalkoxy alkyl, alkoxyalkylene ,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thioalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two R ^d radicals, or A substituent on the group is a saturated or partially unsaturated heterocyclo group together with an amino nitrogen (optionally substituted by one, two or three groups independently selected from R ^d substituents) or heteroaryl based on (R ^f location, if necessary To form a 1,2 is independently selected from groups or substituted with three groups); R ^d and R ^e are hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, aryl Independently selected from the group consisting of alkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; and R ^f comprises nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^{d Re} amino groups The above compound or salt selected from the group. 16. The method of claim 15, wherein the 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical of R ¹ is substituted with a substituent R ⁴ having a chain length of 3 to about 14 carbon atoms. Or a salt of 17. The compound or salt according to claim 16, wherein said R ⁴ substituent is phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamide, nicotinamide, isonicotinamide, Picolinamide group, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarbylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonyl Hydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydroca Building thioaryloxy, arylthio hydrocarbyl,
The above compound or salt selected from the group consisting of heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio groups. 18. The compound or salt of claim 17, wherein said R ⁴ substituent is itself halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy,
Mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio , Heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl,
Hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbylyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl , Hydroxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbyl, hydrocarbyl hydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexyl Locarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Substituted with one or more substituents selected from the group consisting of heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and N-monosubstituted or N, N-disubstituted aminohydrocarbyl groups, wherein And the substituent on the nitrogen is hydrocarbyl, aryl, arylhydrocarbyl, Selected from the group consisting of locarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or the nitrogen and the two substituents attached thereto forming a 5- to 8-membered heterocyclic or heteroaryl ring group The above compound or salt. 19. The compound or salt of claim 18, wherein said R ¹ substituent is itself another monocyclic cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl group, a C ₃ -C ₁₄ hydrocarbyl group, A group consisting of C ₂ -C ₁₄ hydrocarbyloxy, phenoxy, thiophenoxy, 4-thiopyridyl, phenylazo, phenylureido, nicotinamide, isonicotinamide, picolinamide, anilino, and benzamide groups substituted with a substituent R ⁴ selected from the above compound or salt. 20. The compound or salt according to claim 19, wherein the R¹The substituent is PhR^Four And Ph is R in 4th place^FourIs phenyl substituted with^FourIs phenyl,
Phenoxy, thiophenoxy, phenylazo, benzamide, anilino, nicotine
Amide, isonicotinamide, picolinamide, or phenylureido groups
It may be halogen, C or para at the meta or para position, or both, if necessary.₁-C ₉ Hydrocarbyloxy group, C₁-C_TenHydrocarbyl group, di-C₁-C₉Hydrocarbyl
Amino group, carboxyl C₁-C₈Hydrocarbyl group, C₁-C_FourHydrocarbyloxyca
Rubonil C₁-C_FourHydrocarbyl group, C₁-C_FourHydrocarbyloxycarbonyl C₁-C_Four
Hydrocarbyl group, and carboxamide C₁-C₈Group consisting of hydrocarbyl groups
Or two methyl or methyl groups at the meta and para positions.
The above compound or a compound selected from the group consisting of
salt. 21. The compound or salt of claim 15, wherein said R ¹ substituent is longer than that of an octyl group and shorter than that of a stearyl group. 22. A compound corresponding to formula D or a pharmaceutically acceptable salt thereof: Wherein A, B, C, and D are each carbon, nitrogen, sulfur, or oxygen, which is present or absent, and the described ring is a 5- or 6-membered ring; R ⁵ and R ⁶ are Hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituents, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and And R ⁵ and R ⁶ are independently selected from the group consisting of R ^b R ^c aminoalkyloxy groups; and or R ⁵ and R ⁶ together with the atoms to which they are attached, a further 5 to 7 membered aliphatic or aromatic carbocyclic or heterocyclic ring In the -AREY substituent, A is: (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or- N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH- (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k )-or -N (R ^k ) -CS-; (13) -CH _2- ; (14) -O-CH ₂ - or _{-CH 2 -O-; (15) -S} -CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and (17) -SO ₂ -; or (18) A is present R is directly attached to the described ring; R is selected from the group consisting of: alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkyl Selected from the group consisting of alkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, where aryl A heteroaryl, cycloalkyl, or heterocycloalkyl substituent is (i) unsubstituted Or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C _l -C ₂ - alkylenedioxy, Hydroxycarbonylalkyl, hydroxycarbonyl alkylamino , Nitro, hydroxy, hydroxyalkyl, alkanoylamino,
And the group E is substituted with one or two radicals selected from the group consisting of an alkoxycarbonyl group; and the E group is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )- Or-(R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ - or ^{_{-SO 2 -N (R k) -}} ; or (7) E is absent, R represents directly attached to Y; is selected from the group consisting of; and moiety or Y is absent, or hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl Alkyl, alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; or wherein ^Ra is hydride, alkyl, alkenyl , Alkenyl, arylalkyl, aryl, alkanoyl, Royle, arylalkyl carbonyl, R ^b R ^c aminoalkanoyl, halo alkanoyl, R ^b R ^c aminoalkyl, alkoxyalkyl, selected haloalkyl, and from the group consisting of arylalkyl group; R ^b and R ^c are hydrido, alkanoyl, Arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Is independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii)
) A heterocyclo group which is independently substituted with one or two R ^d radicals or in which the substituent on the amino group is saturated or partially unsaturated with the amino nitrogen (optionally independently from the R ^d substituent A heteroaryl group (substituted with 1, 2, or 3 groups optionally selected independently from the R ^f substituent) or a heteroaryl group (substituted with 1, 2, or 3 groups selected) R ^d and R ^e are independently selected from the group consisting of hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; and R ^f is selected nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino group; R ^g is Hydride, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehyde, hydroxy, amino,
Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ -amino, alkoxyalkyl, alkylenedioxy, aryloxy Alkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -amino carbonyloxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ - Minosuruhoniru, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethylsulfonyl (R ^h) amino, heteroarylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino R ^h is selected from the group consisting of carbonyl, alkylsulfonyl (R ^h ) amino, arylcarbonyl (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, Alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl Is selected from the group consisting of halo alkanoyl, and hydroxyalkyl groups, 1 or 2 are selected each group similar to the substituent of the aminoalkyl and substituted aminoalkanoyl groups substituted, independently from R ^j substituent R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxy Carbonyl, carboxyalkyl, haloalkyl, alkanoyl,
Aroyl, substituted or unsubstituted aminoalkanoyl, is selected from the group consisting of halo alkanoyl and a hydroxyalkyl group, each substituted group is one or two R ^j substituents if necessary; wherein, R ^j is an aryl Alkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl,
Selected from the group consisting of substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, wherein The substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups. And R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl. ,
Selected from alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl, R ^c R ^d aminoalkanoyl, and R ^c R ^d aminoalkylsulfonyl,
The above compound or salt. 23. A compound corresponding to Formula VIA: or a pharmaceutically acceptable salt thereof.
And:Where R^FourIs a substituent having a chain length of 3 to about 14 carbon atoms;^TwoIs a 5- or 6-membered heterocycle and R^FourIs
, W^TwoIs a 6-membered ring, at the 4-position with respect to the described nitrogen atom, W^TwoIs described when is a 5-membered ring
A substituent attached at the 3- or 4-position with respect to the nitrogen atom; R^FiveAnd R⁶Is hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy
Si, hydroxyalkyl, R^bR^cAminoalkyl substituent, thiol, alkylthio
, Arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy
, Perfluoroalkyl, haloalkyl, heterocyclooxy, and R^bR^cA
Independently selected from the group consisting of minoalkyloxy substituents; or R^FiveAnd R⁶Is an additional 5- to 7-membered aliphatic if the atoms to which they are attached
Or form an aromatic carbocyclic or heterocyclic ring; and R²⁰Is (a) -O-R^{twenty one}(Where R^{twenty one}Is hydride, C₁-C₆-Alkyl, aryl, ar-C₁-C ₆ -Selected from the group consisting of alkyl groups, and pharmaceutically acceptable cations)
, (B) -NR¹³-O-R^{twenty two}(Where R^{twenty two}Is a selectively removable protecting group, R¹³Is a mist
C₁-C₆-Alkyl or benzyl group), (c) -NR¹³-O-R¹⁴(Where R¹³
Is as described above, and R¹⁴Is hydride, a pharmaceutically acceptable cation, or C (V
) R¹⁵Where V is O or S and R¹⁵Is C₁-C₆-Alkyl, aryl, C₁-
C₆-Alkoxy, heteroaryl-C₁-C₆-Alkyl, C_Three-C₈-Cycloalkyl-C₁-C₆ -Alkyl, aryloxy, ar-C₁-C₆-Alkoxy, ar-C₁-C₆-Alkyl, Hete
Lower aryl, and amino C₁-C₆-Selected from the group consisting of alkyl groups, where
Mino C₁-C₆The alkyl nitrogen is (i) unsubstituted or (ii) C₁-C₆-Alkyl, a
Reel, ar-C₁-C₆-Alkyl, C_Three-C₈-Cycloalkyl-C₁-C₆-Alkyl, ar-C₁-C₆ -Alkoxycarbonyl, C₁-C₆-Alkoxycarbonyl, and C₁-C₆-Alkano
Substituted with one or two substituents independently selected from the group consisting of yl radicals
Or (iii) amino C₁-C₆-The alkyl nitrogen and the two substituents attached thereto are 5
To form an 8-membered heterocyclic or heteroaryl ring); or (d) -NR^{twenty three}R^{twenty four}(R ^{twenty three} And R^{twenty four}Is hydride, C₁-C₆-Alkyl, amino C₁-C₆-Alkyl, hydroxy C ₁ -C₆-Alkyl, aryl, and ar-C₁-C₆-Independently of the group consisting of alkyl groups
Selected or R^{twenty three}And R^{twenty four}Represents 0 or 1 additional
5- to 8-membered ring containing a heteroatom (which is oxygen, nitrogen, or sulfur)
Where R is^bAnd R^cIs hydride, alkanoyl, arylalkyl, aroyl,
Bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl,
Trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyal
Kill, cycloalkyl, heterocycloalkyl, heterocycloalkyl carbonyl
, Aryl, heterocyclo, heteroaryl, cycloalkylalkyl, ant
Oxyalkyl, heteroaryloxyalkyl, heteroarylalkoxy
Sialkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoy
, Alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl,
Alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl,
Aryliminocarbonyl, heterocycloiminocarbonyl, arylthioal
Kill, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl
, Heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl,
All alkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy
Cicarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydro
Xyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl
Independently selected from the group consisting of: wherein the amino nitrogen is (i) unsubstituted or
Or (ii) one or two Rs^dIndependently substituted with a radical, or a position on an amino group
When the substituent is a saturated or partially unsaturated heterocyclo group together with the amino nitrogen (necessary
More R^dSubstituted with 1, 2 or 3 groups independently selected from substituents)
Is a heteroaryl group (optionally R^f1, 2, or independently selected from substituents
Substituted with three groups); R^dAnd R^eIs hydride, alkyl, alkenyl, alkenyl, arylalkyl
, Aryl, alkanoyl, aroyl, arylalkylcarbonyl, alk
Selected from the group consisting of xycarbonyl and arylalkyloxycarbonyl groups
Standing and selected; R^fIs nitro, hydroxy, alkyl, halogen, aryl, alkoxy, shea
No, and R^dR^eThe above compound or salt selected from the group consisting of an amino group. 24. The compound or salt according to claim 23, wherein said R ⁴ substituent is phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamide, nicotinamide, isonicotinamide, Picolinamide group, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarbylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonyl Hydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydroca Building thioaryloxy, arylthio hydrocarbyl,
The above compound or salt selected from the group consisting of heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio groups. 25. The compound or salt of claim 24, wherein said R ⁴ substituent is itself halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy,
Mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio , Heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl,
Hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbylyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl , Hydroxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbyl, hydrocarbyl hydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohexyl Locarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Substituted with one or more substituents selected from the group consisting of heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and N-monosubstituted or N, N-disubstituted aminohydrocarbyl groups; The above substituents are hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl Selected from the group consisting of bil, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or the nitrogen and the two substituents attached thereto forming a 5- to 8-membered heterocyclic or heteroaryl ring group The above compound or salt. 26. The compound or salt according to claim 23, wherein said R ²⁰ is —NR ¹³ —OR ¹⁴ . 27. The compound or salt according to claim 26, wherein said R ¹³ is hydride. 28. The compound or salt of claim 23, wherein said R ²⁰ is -NR ¹³ -OR ²² . 29. The compound or salt according to claim 28, wherein R ¹³ is hydride and R ²² is 2-tetrahydropyranyl, benzyl, p-methoxybenzyl, C _1-.
C ₆ alkoxycarbonyl, tri-substituted silyl group, o- nitrophenyl group, and is selected from the group consisting of peptide synthesis resin, wherein the trisubstituted silyl group is C ₁ -C ₆ - alkyl,
Substituted with an aryl, or an ar-C ₁ -C ₆ alkyl group, or a mixture thereof,
The above compound or salt. 30. The compound or salt according to claim 23, wherein the structure of the compound corresponds to formula VIA-1: 31. A compound corresponding to Formula VIIC or a pharmaceutically acceptable salt thereof: Wherein R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R ^b R ^{c is} independently selected from the group consisting of aminoalkyloxy substituents; and or R ⁵ and R ⁶ together with the atoms to which they are attached are further 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic The ring structure W ² containing a nitrogen atom described above is a 5- or 6-membered heterocyclic ring, and the substituent —AR
-EY is attached at the 4-position with respect to the stated nitrogen atom when W ² is a 6-membered ring, or at the 3- or 4-position with respect to the stated nitrogen when W ² is a 5-membered ring; Is: (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C -; (10) -N = N- ; (11) -NH-NH-; (12) -CS-N (R k) - or ^{-N (R k) -CS-; (} 13) -CH 2 - _{; (14) -O-CH 2} - or _{-CH 2 -O-; (15) -S} -CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and (17) -SO ₂ - ; or (18) a is absent, R is directly bonded to the ring structure W ^2; is selected from the group consisting of; moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl , Heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocyclo Selected from the group consisting of alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, where aryl, heteroaryl, cycloalkyl, or heteroaryl. or cycloalkyl substituents is unsubstituted (i), or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C _l -C ₂ - Alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino,
And the group E is substituted with one or two radicals selected from the group consisting of an alkoxycarbonyl group; and the E group is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )- Or-(R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ - or ^{_{-SO 2 -N (R k) -}} ; or (7) E is absent, R represents directly attached to Y; is selected from the group consisting of; and moiety or Y is absent, or hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl Alkyl, alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; wherein ^Ra is hydride, alkyl, alkenyl, Alkenyl, arylalkyl, aryl, alkanoyl, alloy , Arylalkyl carbonyl, R ^b R ^c aminoalkanoyl, halo alkanoyl, R ^b R ^c aminoalkyl, alkoxyalkyl, selected haloalkyl, and from the group consisting of arylalkyl group; R ^b and R ^c are hydrido, alkanoyl, aryl Alkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Is independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii)
) A heterocyclo group which is independently substituted with one or two R ^d radicals or in which the substituent on the amino group is saturated or partially unsaturated with the amino nitrogen (optionally independently from the R ^d substituent A heteroaryl group (substituted with 1, 2, or 3 groups optionally selected independently from the R ^f substituent) or a heteroaryl group (substituted with 1, 2, or 3 groups selected) R ^d and R ^e are independently selected from the group consisting of hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; ^f is selected nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino group; R ^g is hydrido De, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehyde, hydroxy, amino,
Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ -amino, alkoxyalkyl, alkylenedioxy, aryloxy Alkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -amino carbonyloxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ - Minosuruhoniru, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethylsulfonyl (R ^h) amino, heteroarylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino R ^h is selected from the group consisting of carbonyl, alkylsulfonyl (R ^h ) amino, arylcarbonyl (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, Alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl Is selected from the group consisting of halo alkanoyl, and hydroxyalkyl groups, 1 or 2 are selected each group similar to the substituent of the aminoalkyl and substituted aminoalkanoyl groups substituted, independently from R ^j substituent R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxy Carbonyl, carboxyalkyl, haloalkyl, alkanoyl,
Aroyl, substituted or unsubstituted aminoalkanoyl, is selected from the group consisting of halo alkanoyl and a hydroxyalkyl group, each substituted group is one or two R ^j substituents if necessary; wherein, R ^j is an aryl Alkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl,
Selected from the group consisting of substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, wherein The substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, and alkyloxycarbonyl groups. And R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl. ,
Selected from alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl, R ^c R ^d aminoalkanoyl, and R ^c R ^d aminoalkylsulfonyl,
The above compound or salt. 32. A compound corresponding to Formula VIIB or a pharmaceutically acceptable salt thereof: Wherein R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R ^b R ^{c is} independently selected from the group consisting of aminoalkyloxy substituents; and or R ⁵ and R ⁶ together with the atoms to which they are attached are further 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic G is an N-heterocyclo group; Substituent A is: (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N ( (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; ( (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k )-or -N (R ^k ) -CS-; (1 _{3) -CH 2 -; (14} ) -O-CH 2 - or _{-CH 2 -O-; (15) -S} -CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and ( 17) -SO ₂ -; or (18) a is absent, R is directly attached to the N- heterocyclo groups G; is selected from the group consisting of; moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cyclo Alkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, And a heterocycloalkylthioalkyl group, wherein aryl or heteroaryl or cycloalkyl or hetero Black alkyl substituent be unsubstituted (i), or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C _l -C ₂ - 1 or 2 selected from the group consisting of alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups
Moiety E is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO -; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k ) Or; (7) E is absent and R is directly bonded to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl , heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; wherein ^Ra is hydride, alkyl, alkenyl, Alkenyl, arylalkyl, aryl, alkanoyl, alloy , Arylalkyl carbonyl, R ^b R ^c aminoalkanoyl, halo alkanoyl, R ^b R ^c aminoalkyl, alkoxyalkyl, selected haloalkyl, and from the group consisting of arylalkyl group; R ^b and R ^c are hydrido, alkanoyl, aryl Alkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Is independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii)
) A heterocyclo group which is independently substituted with one or two R ^d radicals or in which the substituent on the amino group is saturated or partially unsaturated with the amino nitrogen (optionally independently from the R ^d substituent A heteroaryl group (substituted with 1, 2, or 3 groups optionally selected independently from the R ^f substituent) or a heteroaryl group (substituted with 1, 2, or 3 groups selected) R ^d and R ^e are independently selected from the group consisting of hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; ^f is selected nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino group; R ^g is hydrido De, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehyde, hydroxy, amino,
Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ -amino, alkoxyalkyl, alkylenedioxy, aryloxy Alkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -amino carbonyloxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ - Minosuruhoniru, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethylsulfonyl (R ^h) amino, heteroarylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino R ^h is selected from the group consisting of carbonyl, alkylsulfonyl (R ^h ) amino, arylcarbonyl (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, Alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl Is selected from the group consisting of halo alkanoyl, and hydroxyalkyl groups, 1 or 2 are selected each group similar to the substituent of the aminoalkyl and substituted aminoalkanoyl groups substituted, independently from R ^j substituent R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxy Carbonyl, carboxyalkyl, haloalkyl, alkanoyl,
Selected from the group consisting of aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each group optionally substituted with one or two R ^j substituents; R ^j is arylalkyl, aryl , Heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted amino Selected from the group consisting of alkanoyl, haloalkanoyl, and hydroxyalkyl groups, wherein the substituted aminoalkyl and substituted aminoalkanoyl group substituents are alkyl, alkenyl, Alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
R ^k is selected from the group consisting of aryloxycarbonyl and alkyloxycarbonyl groups; and R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl,
Selected from alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl, R ^c R ^d aminoalkanoyl, and R ^c R ^d aminoalkylsulfonyl,
The above compound or salt. 33. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 34. The compound or salt of claim 32, wherein the compound corresponds to the following formula: Embedded image 35. The compound or salt according to claim 32, wherein the compound corresponds to the following formula: Embedded image 36. The compound or salt according to claim 32, wherein the compound corresponds to the following formula: Embedded image 37. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 38. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 39. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 40. The compound or salt according to claim 32, wherein the compound corresponds to the following formula: Embedded image 41. The compound or salt of claim 32, wherein the compound corresponds to the following formula: Embedded image 42. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 43. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 44. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 45. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 46. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 47. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 48. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 49. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 50. The compound or salt according to claim 32, wherein the compound corresponds to the following formula: Embedded image 51. The compound or salt of claim 32, wherein the compound corresponds to the following formula: Embedded image 52. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 53. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 54. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 55. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 56. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 57. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 58. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 59. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 60. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 61. The compound or salt of claim 32, wherein the compound corresponds to the following formula: Embedded image 62. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 63. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 64. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 65. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 66. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 67. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 68. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 69. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 70. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 71. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 72. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 73. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 74. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 75. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 76. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 77. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 78. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 79. The compound or salt according to paragraph 32, wherein the compound corresponds to the formula: Embedded image 80. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 81. The compound or salt according to paragraph 32, wherein the compound corresponds to the formula: Embedded image 82. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 83. The compound or salt according to claim 32, wherein the compound corresponds to the formula: 84. The compound or salt of claim 32, wherein the compound corresponds to the formula: Embedded image 85. The compound or salt according to claim 32, wherein the compound corresponds to the formula: Embedded image 86. A compound corresponding to Formula VIIE or a pharmaceutically acceptable salt thereof: Wherein R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R ^b R ^{c is} independently selected from the group consisting of aminoalkyloxy substituents; and or R ⁵ and R ⁶ together with the atoms to which they are attached are further 5- to 7-membered aliphatic or aromatic carbocyclic or heterocyclic G is an N-heterocyclo group; Substituent A is: (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N ( (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC = CH-; ( (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R ^k )-or -N (R ^k ) -CS-; (1 _{3) -CH 2 -; (14} ) -O-CH 2 - or _{-CH 2 -O-; (15) -S} -CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and ( 17) -SO ₂ -; or (18) a is absent, R is directly attached to the N- heterocyclo groups G; is selected from the group consisting of; moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cyclo Alkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, And a heterocycloalkylthioalkyl group, wherein aryl or heteroaryl or cycloalkyl or hetero Black alkyl substituent be unsubstituted (i), or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C _l -C ₂ - 1 or 2 selected from the group consisting of alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl groups
Moiety E is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO -; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k ) Or; (7) E is absent and R is directly bonded to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl , heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; wherein ^Ra is hydride, alkyl, alkenyl, Alkenyl, arylalkyl, aryl, alkanoyl, alloy , Arylalkyl carbonyl, R ^b R ^c aminoalkanoyl, halo alkanoyl, R ^b R ^c aminoalkyl, alkoxyalkyl, selected haloalkyl, and from the group consisting of arylalkyl group; R ^b and R ^c are hydrido, alkanoyl, aryl Alkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Is independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii)
) A heterocyclo group which is independently substituted with one or two R ^d radicals or in which the substituent on the amino group is saturated or partially unsaturated with the amino nitrogen (optionally independently from the R ^d substituent A heteroaryl group (substituted with 1, 2, or 3 groups optionally selected independently from the R ^f substituent) or a heteroaryl group (substituted with 1, 2, or 3 groups selected) R ^d and R ^e are independently selected from the group consisting of hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; ^f is selected nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^d R ^e amino group; R ^g is hydrido De, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehyde, hydroxy, amino,
Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ -amino, alkoxyalkyl, alkylenedioxy, aryloxy Alkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -amino carbonyloxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ - Minosuruhoniru, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethylsulfonyl (R ^h) amino, heteroarylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino R ^h is selected from the group consisting of carbonyl, alkylsulfonyl (R ^h ) amino, arylcarbonyl (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, Alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl Is selected from the group consisting of halo alkanoyl, and hydroxyalkyl groups, 1 or 2 are selected each group similar to the substituent of the aminoalkyl and substituted aminoalkanoyl groups substituted, independently from R ^j substituent R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxy Carbonyl, carboxyalkyl, haloalkyl, alkanoyl,
Selected from the group consisting of aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each group optionally substituted with one or two R ^j substituents; R ^j is arylalkyl, aryl , Heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted amino Selected from the group consisting of alkanoyl, haloalkanoyl, and hydroxyalkyl groups, wherein the substituted aminoalkyl and substituted aminoalkanoyl group substituents are alkyl, alkenyl, Alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
R ^k is selected from the group consisting of aryloxycarbonyl and alkyloxycarbonyl groups; and R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl,
Selected from alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl, R ^c R ^d aminoalkanoyl, and R ^c R ^d aminoalkylsulfonyl,
The above compound or salt. 87. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 88. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 89. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 90. The compound of para 86, wherein said compound corresponds to the formula: Embedded image Embodiment 91. The compound of embodiment 86 wherein said compound corresponds to the formula: Embedded image 92. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 93. The compound of claim 86, wherein said compound corresponds to the formula: Embedded image 94. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 95. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 96. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 97. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 98. The compound of para 86, wherein said compound corresponds to the formula: Embedded image 99. The compound according to claim 86, wherein the compound corresponds to the formula: Embedded image 100. A process for treating a host mammal having a pathological matrix, a condition associated with metalloprotease activity, wherein a compound having the structure of Formula C or a pharmaceutically acceptable salt thereof is inhibited by MMP enzyme inhibition. Comprising administering to a mammalian host having such conditions in an effective amount: Wherein the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring; R ¹ is a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl radical which is directly bonded to the described SO ₂ — group Which is approximately longer than that of a hexyl group and shorter than that of an eicosyl group,
R ¹ defines a three-dimensional volume, the 1- and 4-positions to which SO _{2 of the} 6-membered ring radical is bonded
Rotating around an axis drawn through the position, or an axis drawn through the center of the 1-position and the 3,4-bond where the SO _{2 of the} 5-membered ring radical binds, its widest width transverse to the axis of rotation Is from about one furanyl ring to about two phenyl rings; R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituents, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and R ^b R ^{c is} independently selected from the group consisting of aminoalkyloxy substituents; or R ⁵ and R ⁶ together with the atoms to which they are attached further form a 5- to 7-membered aliphatic or aromatic carbocycle or heterocycle. And R ²⁰ is (a) —OR ²¹ , wherein R ²¹ is a hydride, C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl group, and pharmaceutically acceptable Selected from the group consisting of cations), (b) -NR ¹³ -OR ²² , wherein R ²² is a selectively removable protecting group, and R ^{1 3} is hydride, C ₁ -C ₆ -alkyl, or benzyl group), (c) -NR ¹³ -OR ^{14 wherein} R ¹³ is as described above, R ¹⁴ is hydride, pharmaceutically acceptable Cation, or C (V) R ¹⁵ , wherein V is O or S, and R ¹⁵ is C ₁ -C ₆ -alkyl, aryl, C ₁ -C ₆ -alkoxy, heteroaryl-C ₁ -C ₆ - alkyl, C ₃ -C ₈ - cycloalkyl -C ₁ -C ₆ - alkyl, aryloxy, ar-C ₁ -C ₆ - alkoxy, ar-C ₁ -C ₆ - alkyl, heteroaryl, And an amino C ₁ -C ₆ -alkyl group,
Wherein the amino C ₁ -C ₆ -alkyl nitrogen is (i) unsubstituted or (ii) C ₁ -C ₆ -alkyl, aryl, ar-C ₁ -C ₆ -alkyl, C ₃ -C ₈ -Cycloalkyl-C ₁ -C ₆ -alkyl,
ar-C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, and C ₁ -C _6-
Substituted with one or two substituents independently selected from the group consisting of alkanoyl radicals, or (iii) when the amino C ₁ -C ₆ -alkyl nitrogen and the two substituents attached thereto are from 5 to 5 (Forming an 8-membered heterocyclic or heteroaryl ring), or (d
) -NR ²³ R ²⁴ (R ²³ and R ²⁴ are hydride, C ₁ -C ₆ -alkyl, amino C ₁ -C ₆ -alkyl, hydroxy C ₁ -C ₆ -alkyl, aryl, and ar-C ₁ -C Is independently selected from the group consisting of ₆ -alkyl groups, or R ²³ and R ²⁴ are zero or one further heteroatom together with the stated nitrogen atom, which is oxygen, nitrogen, or sulfur. Wherein R ^b and R ^c are hydride, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxy Alkyl, alkoxyalkyl,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Is independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii)
) A heterocyclo group which is independently substituted with one or two R ^d radicals or in which the substituent on the amino group is saturated or partially unsaturated with the amino nitrogen (optionally independently from the R ^d substituent A heteroaryl group (substituted with 1, 2, or 3 groups optionally selected independently from the R ^f substituent) or a heteroaryl group (substituted with 1, 2, or 3 groups selected) R ^d and R ^e are independently selected from the group consisting of hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; and , R ^f is nitro, hydroxy, alkyl, halogen, aryl, alkoxy is selected from the group consisting cyano, and R ^d R ^e amino groups, The serial process. 101. The process of claim 100, wherein said R ¹ is a (i) -NR ⁷ R ⁸ group wherein R ⁷ and R ⁸ are hydride, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl and whether it is independent is selected) from the group consisting of substituted aryl hydrocarbyl, or (ii) R ⁷ and R ⁸ are hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, Independently selected from the group consisting of cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclo substituents, each substituent optionally substituted with an -AREY substituent; In the AREY substituent, A is: (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO -; (5) -CO-O- or -O- (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C-; (10) -N = N -; (11) -NH-NH- ; (12) -CS-N (R k) - or ^{-N (R k) -CS-; (} 13) -CH 2 -; (14) -O-CH 2 -Or -CH ₂ -O-; (15) -S-CH ₂ -or -CH ₂ -S-; (16) -SO-; and (17) -SO _2- ; or (18) A is present Wherein R is directly attached to R ⁷ or R ⁸ , or both R ⁷ and R ⁸ ; wherein the moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloa Selected from the group consisting of a quinthioalkyl group, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl substituent is (i) unsubstituted or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy. , perfluoroalkyl thio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ - alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonyl alkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino,
And alkoxy substituted by one or two radicals selected from the group consisting of a carbonyl group; E group the following: (1) -COR ^g - or ^{-R g CO-; (2) -CON} (R k) - Or-(R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k )-; or (7) E is absent and R is directly bonded to Y; The moiety Y is absent or hydride , alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl , Alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is either (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; or R ⁷ and R ⁸ are Forms a -GAREY group with a nitrogen atom, wherein G is an N-heterocyclo group, and substituent A is (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5)- (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C- ; (10) -N = N-; (11) -NH-NH-; (12) -CS-N (R k) - or ^{-N (R k) -CS-; (} 13) -CH 2 -; (14) -O-CH ₂ - or _{-CH 2 -O-; (15) -S} -CH 2 - or _{-CH 2 -S-; (16) -SO-} ; and (17) -SO ₂ -; Or (18) A is absent and R is directly bonded to the N-heterocyclo group G; the moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl , Heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl , Cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) halo, Alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, 1 or 2 selected from the group consisting of alkanoylamino and alkoxycarbonyl groups
Moiety E is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO -; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k ) Or; (7) E is absent and R is directly attached to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cyclo alkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is (i) unsubstituted or substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; wherein ^Ra is hydride, alkyl, alkenyl, alkenyl, aryl Alkyl, aryl, alkanoyl, aroyl, ant Le alkylcarbonyl, R ^b R ^c aminoalkanoyl, halo alkanoyl, R ^b R ^c aminoalkyl, alkoxyalkyl, selected from the group consisting haloalkyl, and aryl alkyl group; R ^g is hydrido, aryl, heteroaryl, heterocyclo, Aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehyde, hydroxy, amino,
Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ -amino, alkoxyalkyl, alkylenedioxy, aryloxy Alkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -amino carbonyloxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ - Minosuruhoniru, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethylsulfonyl (R ^h) amino, heteroarylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino R ^h is selected from the group consisting of carbonyl, alkylsulfonyl (R ^h ) amino, arylcarbonyl (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, Alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted Amino alkanoyl, selected from the group consisting of halo alkanoyl, and hydroxyalkyl groups, each group similar to the substituent of the aminoalkyl and substituted aminoalkanoyl groups substituted, are independently selected from R ^j substituent R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl , Arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl,
Selected from the group consisting of aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each group optionally substituted with one or two R ^j substituents; R ^j is arylalkyl, aryl , Heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted amino Selected from the group consisting of alkanoyl, haloalkanoyl, and hydroxyalkyl groups, wherein the substituted aminoalkyl and substituted aminoalkanoyl group substituents are alkyl, alkenyl, Alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
R ^k is selected from the group consisting of aryloxycarbonyl and alkyloxycarbonyl groups; and R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl,
Selected from alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl, R ^c R ^d aminoalkanoyl, and R ^c R ^d aminoalkylsulfonyl,
The above process. 102. The process according to claim 100, wherein said compound has a structure corresponding to formula C1: Wherein W, R ¹ , R ⁵ , R ⁶ , R ¹³ , and R ¹⁴ are as defined above. 103. The process according to claim 100, wherein said compound has a structure corresponding to formula C2: Wherein W, R ⁵ , R ⁶ , and R ¹⁴ are as defined above, Ph is phenyl substituted at its 4-position with a substituent R ⁴ , wherein R ⁴ is 3 to about 14 carbon atoms The above process, wherein the substituent has a chain length of 104. The process of claim 103 wherein said R ⁴ substituent is phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamide, nicotinamide, isonicotinamide, picolinamide Group, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarbylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, Arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthio The process selected from the group consisting of oaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio groups . 105. The process of claim 104, wherein said R ⁴ substituent is itself
Halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino , Heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl Hydrocarbylamino Arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxy Hydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydro Carbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbyl Sulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and N-
1 selected from the group consisting of monosubstituted or N, N-disubstituted aminohydrocarbyl groups
Substituted with one or more substituents, wherein the substituent on the nitrogen is selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or nitrogen and The above process, wherein the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group. 106. The process according to claim 100, wherein said compound has a structure corresponding to Formula D4: Wherein R ⁵ and R ⁶ are as defined above, and R ⁴ is a substituent having a chain length of 3 to about 14 carbon atoms. 107. The process of claim 106 wherein said R ⁴ substituent is phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido, benzamide, nicotinamide, isonicotinamide, picolinamide Group, heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, hydrocarbylhydrocarbyl, arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, Arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthio The process selected from the group consisting of oaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio groups . 108. The process of claim 17 wherein said R ⁴ substituent is itself halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryl Oxy, arylthio, arylamino,
Arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, Cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclo, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbylyl, ali Ylcarbonyl, aryl hydrocarbyl acryloyl, hydrocarbyloxy Boyle oxy, aryl hydrocarbyloxy Boyle oxy, hydroxyhydrocarbyl,
Hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, Arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy Hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and N-monosubstituted or N, N-disubstituted aminohydrocarbyl groups Substituted with one or more substituents selected from the group consisting of: wherein the substituent on the nitrogen is from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl. Selected or the nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group The above process. 109. The process of claim 100, wherein said R1 substituent is longer than that of an octyl group and shorter than that of a stearyl group. 110. The process of claim 100, wherein said compound or salt is administered multiple times. 111. A process of treating a host mammal having a pathological matrix, a condition associated with metalloprotease activity, wherein the compound having the structure of Formula VIB-2 or a pharmaceutically acceptable salt thereof is treated with an MMP enzyme: Administering to a mammalian host having such a condition in an amount effective for inhibition, including: Wherein R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and Or R ⁵ and R ⁶ are independently selected from the group consisting of R ^b R ^c aminoalkyloxy substituents; or R ⁵ and R ⁶ together with the atoms to which they are attached, a further 5 to 7 membered aliphatic or aromatic carbocyclic or heterocyclic compound forming a; and the R ⁷ and R ⁸ are hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, R ^a oxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, het Independently selected from the group consisting of arylalkyl, and heterocyclo substituents, each of which is optionally substituted with an -AREY substituent; in which -A is: (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO -; (6) -O-CO-O-; (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C-; (10) -N = N- ; (11) -NH-NH-; (12) -CS-N (R k) - or ^{-N (R k) -CS-; (} 13) -CH 2 -; (14) -O-CH 2 - Or -CH ₂ -O-; (15) -S-CH ₂ -or -CH ₂ -S-; (16) -SO-; and (17) -SO _2- ; or (18) A is not present , R is directly attached to R ⁷ or R ⁸ , or to both R ⁷ and R ⁸ ; wherein the moiety R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl , Heteroaralkyl, heterocycloalkyl, cycloa Selected from the group consisting of alkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, where aryl , A heteroaryl, cycloalkyl, or heterocycloalkyl substituent is (i) unsubstituted or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl , alkoxy, C ₁ -C ₂ - alkylenedioxy, Hydroxycarbonylalkyl, hydroxycarbonyl alkylamino, nitro, hydroxy, hydroxy Alkyl, alkanoylamino,
And the group E is substituted with one or two radicals selected from the group consisting of an alkoxycarbonyl group; and the E group is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )- Or-(R ^k ) NCO-; (3) -CO-; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k )-; or (7) E is absent and R is directly bonded to Y; Y is absent or hydride, Alkyl, alkoxy, haloalkyl,
Aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl, Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl, halo. , Nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy,
And one or two radicals independently selected from the group consisting of: and an amino group, wherein the amino nitrogen is (i) unsubstituted or (ii) independent of hydride, alkyl, and aralkyl groups. Substituted with one or two groups selected as:
Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a -GAREY group, wherein G is an N-heterocyclo group, and the substituent A is: (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; ( (7) -HC = CH-; (8) -NH-CO-NH-; (9) -C≡C-; (10) -N = N-; (11) ) -NH-NH-; (12) -CS-N (R k) - or ^{-N (R k) -CS-; (} 13) -CH 2 -; (14) -O-CH 2 - or -CH ₂ -O-; (15) -S-CH ₂ -or -CH ₂ -S-; (16) -SO-; and (17) -SO _2- ; or (18) A is absent and R is Wherein the moiety R is selected from the group consisting of: an alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, Cycloalkoxyalkyl, heterocycloalkoxy Selected from the group consisting of alkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, wherein aryl or heteroaryl or cycloalkyl or heterocycloalkyl The substituents are (i) unsubstituted or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ -C ₂ -alkylenedi Oxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl It is selected from the group consisting of group 1 or 2
Moiety E is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO -; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k ) Or; (7) E is absent and R is directly attached to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cyclo alkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is (i) unsubstituted or substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; ^Ra is hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl , Alkanoyl, aroyl, arylua Kill carbonyl, R ^b R ^c aminoalkanoyl, halo alkanoyl, R ^b R ^c aminoalkyl, alkoxyalkyl, selected haloalkyl, and from the group consisting of arylalkyl group; R ^b and R ^c are hydrido, alkanoyl, arylalkyl, Aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Is independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii)
) A heterocyclo group which is independently substituted with one or two R ^d radicals or in which the substituent on the amino group is saturated or partially unsaturated with the amino nitrogen (optionally independently from the R ^d substituent A heteroaryl group (substituted with one, two, or three groups optionally selected independently from the R ^f substituents) or a heteroaryl group (substituted with one, two, or three groups selected). R ^d and R ^e are independently selected from the group consisting of hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; and , R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^{d Re} amino groups; R ^g Is hydride, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehyde, hydroxy, amino,
Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ -amino, alkoxyalkyl, alkylenedioxy, aryloxy Alkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -amino carbonyloxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ - Minosuruhoniru, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethylsulfonyl (R ^h) amino, heteroarylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino R ^h is selected from the group consisting of carbonyl, alkylsulfonyl (R ^h ) amino, arylcarbonyl (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, Alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted Amino alkanoyl, selected from the group consisting of halo alkanoyl, and hydroxyalkyl groups, each group similar to the substituent of the aminoalkyl and substituted aminoalkanoyl groups substituted, are independently selected from R ^j substituent R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl , Arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl,
Selected from the group consisting of aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each group optionally substituted with one or two R ^j substituents; R ^j is arylalkyl, aryl , Heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted amino Selected from the group consisting of alkanoyl, haloalkanoyl, and hydroxyalkyl groups, wherein the substituted aminoalkyl and substituted aminoalkanoyl group substituents are alkyl, alkenyl, Alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
R ^k is selected from the group consisting of aryloxycarbonyl and alkyloxycarbonyl groups; and R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl,
Selected from alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl, R ^c R ^d aminoalkanoyl, and R ^c R ^d aminoalkylsulfonyl,
The above process. 112. The process of claim 111, wherein the structure of said compound corresponds to formula VIB-3: 113. The process of claim 111, wherein the structure of said compound corresponds to Formula VIII or VIII-B: 114. The process of claim 111, wherein said NR ⁷ R ⁸ substituent is longer than that of an octyl group and shorter than that of a stearyl group. 115. The process of claim 114, wherein said NR ⁷ R ⁸ is a substituent -GAREY. 116. The process of claim 111, wherein said compound or salt is administered multiple times. 117. A process of treating a host mammal having a pathological matrix, a condition associated with metalloprotease activity, wherein a compound having the structure of Formula VIIB or a pharmaceutically acceptable salt thereof is used to inhibit MMP enzyme inhibition. Comprising administering to a mammalian host having such conditions in an effective amount: Wherein R ⁵ and R ⁶ are hydride, alkyl, cycloalkyl, acylalkyl, halo,
Nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, R ^b R ^c aminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy, and Or R ⁵ and R ⁶ are independently selected from the group consisting of R ^b R ^c aminoalkyloxy substituents; or R ⁵ and R ⁶ together with the atoms to which they are attached, a further 5 to 7 membered aliphatic or aromatic carbocyclic or heterocyclic compound And G is an N-heterocyclo group in the substituent -GAREY; the substituent A is: (1) -O-; (2) -S-; (3) -NR ^k- ; (4) -CO-N (R ^k ) or -N (R ^k ) -CO-; (5) -CO-O- or -O-CO-; (6) -O-CO-O-; (7) -HC (8) -NH-CO-NH-; (9) -C≡C-; (10) -N = N-; (11) -NH-NH-; (12) -CS-N ( R ^k )-Or -N (R ^k ) -CS-; (13) -CH _2- ; (14) -O-CH ₂ -or -CH ₂ -O-; (15) -S-CH ₂ -or -CH _And (17) -SO _2- ; or (18) A is absent and R is directly attached to the N-heterocyclo group G; ₂ -S-; Part R is alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl , Arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl groups, wherein aryl or heteroaryl or cyclo Or alkyl or heterocycloalkyl substituent is unsubstituted (i), or (ii) halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, amino, alkoxycarbonylalkyl, alkoxy, C ₁ - C ₂ - alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonyl alkylamino, nitro, hydroxy, hydroxyalkyl, 1 or 2 is selected from the group consisting alkanoylamino, and alkoxycarbonyl group
Moiety E is: (1) -COR ^g -or -R ^g CO-; (2) -CON (R ^k )-or-(R ^k ) NCO-; (3) -CO -; (4) -SO ₂ R ^g -or -R ^g SO _2- ; (5) -SO _2- ; (6) -N (R ^k ) -SO ₂ -or -SO ₂ -N (R ^k ) Or; (7) E is absent and R is directly attached to Y; and the moiety Y is absent or hydride, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cyclo alkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, R ^a oxyalkyl, perfluoroalkoxy, perfluoroalkyl thio, trifluoromethyl alkyl, alkenyl, heterocycloalkyl,
Selected from the group consisting of cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl groups, wherein the aryl, heteroaryl, aralkyl, or heterocycloalkyl group is (i) unsubstituted or (ii) alkanoyl , Halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, perfluoroalkyl, perfluoroalkoxy, and one or two radicals independently selected from the group consisting of amino groups, wherein the amino nitrogen Is (i) unsubstituted or substituted with one or two groups independently selected from hydride, alkyl, and aralkyl groups; wherein ^Ra is hydride, alkyl, alkenyl, alkenyl, aryl Alkyl, aryl, alkanoyl, aroyl, ant Le alkylcarbonyl, R ^b R ^c aminoalkanoyl, halo alkanoyl, R ^b R ^c aminoalkyl, alkoxyalkyl, selected haloalkyl, and from the group consisting of arylalkyl group; R ^b and R ^c are hydrido, alkanoyl, arylalkyl , Aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl,
Cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralcanoyl, alkylsulfonyl, Heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl,
Alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl Is independently selected from the group consisting of aminosulfonyl, wherein the amino nitrogen is (i) unsubstituted or (ii)
) A heterocyclo group which is independently substituted with one or two R ^d radicals or in which the substituent on the amino group is saturated or partially unsaturated with the amino nitrogen (optionally independently from the R ^d substituent A heteroaryl group (substituted with 1, 2, or 3 groups optionally selected independently from the R ^f substituent) or a heteroaryl group (substituted with 1, 2, or 3 groups selected) R ^d and R ^e are independently selected from the group consisting of hydride, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkylcarbonyl, alkoxycarbonyl, and arylalkyloxycarbonyl groups; and , R ^f is selected from the group consisting of nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and R ^{d Re} amino groups; R ^g Is hydride, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehyde, hydroxy, amino,
Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, R ^h R ⁱ -amino, alkoxyalkyl, alkylenedioxy, aryloxy Alkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, R ^h R ⁱ -amino carbonyloxy, R ^h R ⁱ - aminocarbonyl, R ^h R ⁱ - aminoalkanoyl, hydroxyaminocarbonyl, R ^h R ⁱ - Minosuruhoniru, R ^h R ⁱ - aminocarbonyl (R ^h) amino, trifluoromethylsulfonyl (R ^h) amino, heteroarylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino, arylsulfonyl (R ^h) amino R ^h is selected from the group consisting of carbonyl, alkylsulfonyl (R ^h ) amino, arylcarbonyl (R ^h ) aminosulfonyl, and alkylsulfonyl (R ^h ) aminocarbonyl substituents; R ^h is arylalkyl, aryl, heteroaryl, heterocyclo, Alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted Amino alkanoyl, selected from the group consisting of halo alkanoyl, and hydroxyalkyl groups, each group similar to the substituent of the aminoalkyl and substituted aminoalkanoyl groups substituted, are independently selected from R ^j substituent R ⁱ is arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl , Arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl,
Selected from the group consisting of aroyl, substituted or unsubstituted aminoalkanoyl, haloalkanoyl, and hydroxyalkyl groups, each group optionally substituted with one or two R ^j substituents; R ^j is arylalkyl, aryl , Heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted amino Selected from the group consisting of alkanoyl, haloalkanoyl, and hydroxyalkyl groups, wherein the substituted aminoalkyl and substituted aminoalkanoyl group substituents are alkyl, alkenyl, Alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
R ^k is selected from the group consisting of aryloxycarbonyl and alkyloxycarbonyl groups; and R ^k is hydride, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl,
Selected from alkyloxycarbonyl, R ^c R ^d aminocarbonyl, R ^c R ^d aminosulfonyl, R ^c R ^d aminoalkanoyl, and R ^c R ^d aminoalkylsulfonyl,
The above process. 118. The process of claim 117, wherein said compound or salt is administered multiple times.