The present application describes novel xcex2-amino acid derivatives of formula I:

This invention relates generally to novel xcex2-amino acid derivatives as matrix metalloproteases and TNF-xcex1 inhibitors, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloprotease), which form inactive complexes with the MP""s.
Osteo-and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases which are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloprotease enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently, TNF-xcex1 converting enzyme (TACE), the enzyme responsible for TNF-xcex1 release from cells, were purified and sequenced (Black et al Nature 1997, 385, 729; Moss et al Nature 1997, 385, 733). This invention describes molecules that inhibit this enzyme and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also charactarized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechansisms are involved.
EP 0,780,286 describes MMP inhibitors of formula A:
wherein Y can be NHOH, R1 and R2 can combine to form a cycloalkyl or heterocyclo alkyl group, R3 and R4 can be a variety of groups including H, and R5 can be substituted aryl.
WO 97/20824 depicts MMP inhibitors of formula B:
wherein ring V contains six atoms, Z is O or S, and Ar is an aryl or heteroaryl group. Ar is preferably a monocyclic aryl group with an optional para substituent or an unsubstituted monocyclic heteroaryl group.
EP 0,818,442 illustrates MMP inhibitors of formula C:
wherein Ar is optionally substituted phenyl or naphthyl, Z can be absent and X and Y can be a variety of substituents. Compounds of this sort are not considered to be part of the present invention.
WO 00/63165 relates to MMP and TNF-xcex1 inhibitors of formula D:
wherein X is aryl or heterocyclic and R1 can be a variety of groups including alkoxy, aryl, heterocyclic, aroyl, aryl-oxy, aryl-thio, and heterocyclic-oxy. Compounds of this sort are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular TNF-xcex1, MMPs, and/or aggrecanase. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of aggrecanase, TNF-C, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.
Accordingly, one object of the present invention is to provide xcex2-amino acid derivatives useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPS, TNF, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I):
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, X, Z, Ua, Xa, Ya, Za, R1, R2, R3, R4, and R4a are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I:
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94COR5, xe2x80x94CO2H, xe2x80x94CO2R6, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR5, xe2x80x94C(O)NHOR6, xe2x80x94NHRa, xe2x80x94N(OH)COR5, xe2x80x94N(OH)CHO, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94S(O)(xe2x95x90NH)Ra, xe2x80x94S(xe2x95x90NH)2Ra, xe2x80x94SC(O)Ra, xe2x80x94PO(OH)2, and xe2x80x94PO(OH)NHRa;
X is absent or selected from C1-3 alkylene, C2-3 alkenylene, and C2-3 alkynylene;
Z is absent or selected from a C3-13 carbocycle substituted with 0-5 Rb and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or selected from O, NRa1, S(O)p, and C(O);
Za is selected from H, a C3-13 carbocycle substituted with 0-5 Rc and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q, (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaSO2(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1NRaSO2NRa(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-13 carbocycle substituted with 0-5 Rd and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
R3 is selected from Q1, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, (CRaRa1)r1O(CH2)rxe2x80x94-Q1, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1NRaC(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q1, (CRaRa12)r1S(O)p(CRaRa1)rxe2x80x94Q1, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q1;
Q1 is selected from H, a C3-13 carbocycle substituted with 0-5 Rd and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
R4 is selected from H, C1-6 alkyl substituted with 0-1 Rb, C2-6 alkenyl substituted with 0-1 Rb, and C2-6 alkynyl substituted with 0-1 Rb;
R4a is selected from H, C1-6 alkyl substituted with 0-1 Rb, C2-6 alkenyl substituted with 0-1 Rb, and C2-6 alkynyl substituted with 0-1 Rb;
alternatively, R1 and R2 together with the carbon and nitrogen atoms to which they are attached combine to form a 3-10 membered heterocyclic ring comprising carbon atoms and, in addition to the nitrogen atom to which R1 is attached, 0-2 ring heteroatoms selected from O, N, NRc, and S(O)p and substituted with 0-3 Rc;
alternatively, R1 and R3 together with the carbon and nitrogen atoms to which they are attached combine to form a 4-6 membered heterocyclic ring comprising carbon atoms and, in addition to the nitrogen atom to which R1 is attached, 0-1 ring heteroatoms selected from O, N, NRc, and S(O)p and substituted with 0-1 Rc;
alternatively, R3 and R4a together with the carbon atom to which they are attached combine to form a 3-10 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRc, and S(O)p and substituted with 0-3 Rc;
provided that from 0-2 of R1 and R2, R1 and R3, and R3 and R4a combine to form a ring;
Ra, at each occurrence, is independently selected from H and C1-6 alkyl;
Ra1, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-1 Rc1, C2-6 alkenyl substituted with 0-1 Rc1, C2-6 alkynyl substituted with 0-1 Rc1, and xe2x80x94(CH2)r-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NRc1, O, and S(O)p and substituted with 0-3 Rc1;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle comprising carbon atoms and from 0-1 additional heteroatoms selected from N, NRa2, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl, and benzyl;
Ra3, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-1 Rc1, C2-6 alkenyl substituted with 0-1 Rc1, C2-6 alkynyl substituted with 0-1 Rc1, and xe2x80x94(CH2)r-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NRc1, O, and S(O)p and substituted with 0-3 Rc1;
Rb, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-1 Rc1, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, C(S)NRaRa1, NRaC(O)NRaRa1, OC(O)NRaRa1, NRaC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra3, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra3, S(O)pRa3, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-2 Rc1, C2-6 alkenyl substituted with 0-2 Rc1, C2-6 alkynyl substituted with 0-2 Rc1, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, (CRaRa1)r1NRaRa1, CF3, CF2CF3, (CRaRa1)r1C(xe2x95x90NCN)NRaRa1, (CRaRa1)r1C(xe2x95x90NRa)NRaRa1, (CRaRa1)r1C(xe2x95x90NORa)NRaRa1, (CRaRa1)r1C(O)NRaOH, (CRaRa1)r1C(O)Ra1, (CRaRa1)r1C(O)ORa1, (CRaRa1)r1C(S)ORa1, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1NRaC(O)Ra1, (CRaRa1)r1C(S)NRaRa1, (CRaRa1)r1OC(O)NRaRa1, (CRaRa1)r1NRaC(O)ORa1, (CRaRa1)r1NRaC(O)NRaRa1, (CRaRa1)r1(O)pRa3, (CRaRa1)r1SO2NRaRa1, (CRaRa1)r1NRaSO2Ra3, and (CRaRa1)r1NRaSO2NRaRa1, C3-10 carbocycle substituted with 0-2 Rc1, (CRaRa1)r1xe2x80x94C3-10 carbocycle substituted with 0-2 Rc1, a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1, and (CRaRa1)r1-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
Rc1, at each occurrence, is independently selected from H, C1-4 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CF3, xe2x80x94CN, NO2, C(O)ORa, and C(O)NRaRa;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, C(S)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra3, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra3, S(O)pRa3, CF3, CF2CF3, C3-10 carbocycle and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and, r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[2] In a preferred embodiment, the present invention provides a novel compound, wherein;
A is selected from COR5, xe2x80x94CO2H, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR5, xe2x80x94C(O)NHOR6, xe2x80x94N(OH)COR5, xe2x80x94N(OH)CHO, xe2x80x94SH, and xe2x80x94CH2SH;
X is absent or is C1-3 alkylene;
Z is absent or selected from a C3-11 carbocycle substituted with 0-5 Rb and a 5-11 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, C(O)NRa1, NRa1C(O), S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C3-10 carbocycle substituted with 0-5 Rc and a 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, C1-6 alkylene-Q, C1-6 alkenylene-Q, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocycle substituted with 0-5 Rd, and a 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
R4 is selected from H and C1-6 alkyl;
R4a is selected from H and C1-6 alkyl;
alternatively, R1 and R2 together with the carbon and nitrogen atoms to which they are attached combine to form a 3-10 membered heterocyclic ring comprising carbon atoms and, in addition to the nitrogen atom to which R1 is attached, 0-1 ring heteroatoms selected from O, N, NRc, and S(O)p and substituted with 0-1 Rc;
alternatively, R1 and R3 together with the carbon and nitrogen atoms to which they are attached combine to form a 4-6 membered heterocyclic ring comprising carbon atoms and, in addition to the nitrogen atom to which R1 is attached, 0-1 ring heteroatoms selected from O, N, and NRc, and substituted with 0-1 Rc;
alternatively, R3 and R4a together with the carbon atom to which they are attached combine to form a 3-6 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRc, and S(O)p and substituted with 0-1 Rc;
provided that from 0-2 of R1 and R2, R1 and R3, and R3 and R4a combine to form a ring;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle comprising carbon atoms and from 0-1 additional heteroatoms selected from N, NRa2, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-1 Rc1, C2-6 alkenyl substituted with 0-1 Rc1, C2-6 alkynyl substituted with 0-1 Rc1, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, CF3, (CRaRa1)r1C(O)Ra1, (CRaRa1)r1C(O)ORa1, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1S(O)pRa3, (CRaRa1)r1SO2NRaRa1, C3-6 carbocycle and a 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, CF3, C3-6 carbocycle and a 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-C10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-6 alkyl substituted with 1-2 Rf, C3-6 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[3] In a more preferred embodiment, the present invention provides a novel compound, wherein;
A is selected from xe2x80x94CO2H, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR5, xe2x80x94N(OH)CHO, and xe2x80x94N(OH)COR5;
X is absent or is C1-2 alkylene;
Z is absent or selected from a C5-6 carbocycle substituted with 0-3 Rb and a 5-6 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)NRa1, S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C5-6 carbocycle substituted with 0-3 Rc and a 5-10 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, C1-6 alkylene-Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocycle substituted with 0-3 Rd and a 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
R4 is selected from H and C1-4 alkyl;
R4a is selected from H and C1-4 alkyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, CF3, (CRaRa1)r1C(O)Ra1, (CRaRa1)r1C(O)ORa, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1S(O)pRa3, (CRaRa1)r1SO2NRaRa1, and phenyl;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, CF3 and phenyl;
R5, at each occurrence, is selected from C1-4 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[4] In an even more preferred embodiment, the present invention provides a novel compound, wherein;
A is xe2x80x94C(O)NHOH;
X is absent or is methylene;
Z is absent or selected from phenyl substituted with 0-3 Rb and pyridyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R1 is selected from H, CH3, and CH2CH3;
R2 is selected from Q, C1-6 alkylene-Q, C(O)(CRaRa1)rxe2x80x94Q, C(O)O(CRaRa1)rxe2x80x94Q, C(O)NRa(CRaRa1)rxe2x80x94Q, and S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;
R4 is selected from H and C1-2 alkyl;
R4a is selected from H and C1-2 alkyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra2, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, CF3, (CRaRa1)r1C(O)Ra1, (CRaRa1)r1C(O)ORa, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1S(O)pRa3, and (CRaRa1)r1SO2NRaRa1;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, CF3 and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3; and,
r1, at each occurrence, is selected from 0, 1, 2, and 3.
[5] In another preferred embodiment, the present invention provides a novel compound selected from the group:
N-hydroxy-1-[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]acetyl]-3-azetidinecarboxamide
N-hydroxy-1-[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]acetyl]-3-piperidinecarboxamide
2,3-dihydro-N-hydroxy-2-[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]acetyl]-1H-isoindole-1-acetamide
2,3-dihydro-2-[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]acetyl]-1H-isoindole-1-acetic acid
N-hydroxy-1-[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]acetyl]-2-pyrrolidineacetamide
N-hydroxy-xcex1,xcex1-dimethyl-1-[4-(phenylmethoxy)benzoyl]-2-piperidineacetamide
N-hydroxy-2-(2-{4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}-2,3-dihydro-1H-isoindol-1-yl)acetamide
2,3-dihydro-2-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-1H-isoindole-1-acetic acid
1-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-3-piperidinecarboxylic acid
N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-3-piperidinecarboxamide
N-[3-(hydroxyamino)-2-methyl-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-hydroxy-4-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-3-thiomorpholineacetamide
N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-2-pyrrolidineacetamide
N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-2-piperidineacetamide
N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-3-azetidinecarboxamide
N-hydroxy-xcex1-methyl-1-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-2-piperidineacetamide
N-[[1-[(hydroxyamino)carbonyl]-1-cyclopropyl]methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-hydroxy-xcex1,xcex1-dimethyl-1-[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-2-pyrrolidineacetamide
N-[3-(hydroxyamino)-2,2-dimethyl-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
2,2-dimethyl-3-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]propanoic acid
N-[3-(hydroxyamino)-2,2-dimethyl-3-oxopropyl]-N-methyl-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[[1-[(hydroxyamino)carbonyl]-1-cyclohexyl]methyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tetrahydro-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]methyl]-2H-pyran-4-carboxamide
1-[(1,1-dimethylethoxy)carbonyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]methyl]-4-piperidinecarboxamide
N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]methyl]-4-piperidinecarboxamide
1-[2,2-dimethylpropionyl]-N-hydroxy-4-[[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]methyl]-4-piperidinecarboxamide
N4-hydroxy-N1,N1-dimethyl-4-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-1,4-piperidinecarboxamide
N-hydroxy-4-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-1-propyl-4-piperidinecarboxamide
N-hydroxy-4-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-1-(methylsulfonyl)-4-piperidinecarboxamide
N-hydroxy-4-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-1-tetrahydro-2H-pyran-4-yl-4-piperidinecarboxamide
N-[2-amino-3-(hydroxyamino)-2-methyl-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[2-[(2,2-dimethylpropanoyl)amino]-3-(hydroxyamino)-2-methyl-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-hydroxy-2-[[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]methyl]-2-piperidinecarboxamide
tert-butyl 3-[(hydroxyamino)carbonyl]-3-[({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)methyl]-1-piperidinecarboxylate
N-[1-[2-(diethylamino)ethyl]-3-(hydroxyamino)-1-methyl-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(1S)-1-[(dimethylamino)methyl]-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(1S)-3-(hydroxyamino)-3-oxo-1-(1-pyrrolidinylmethyl)propyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(1R)-1-[(dimethylamino)methyl]-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(1S)-3-(hydroxyamino)-1-(methoxymethyl)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(1S,2R)-1-[(dimethylamino)methyl]-2-[(hydroxyamino)carbonyl]pentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(1S,2R)-2-[(hydroxyamino)carbonyl]-1-(methoxymethyl)pentyl]-4-{(2-methyl-4-quinolinyl)methoxy]benzamide
(2R)-N4-hydroxy-N1,N1-dimethyl-2-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)butanediamide
N-{(1R,2S)-1-[(dimethylamino)methyl]-2-[(hydroxyamino)carbonyl]pentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]propionamide
N-hydroxy-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]butyramide
N-hydroxy-2-(1-hydroxyethyl)-3-[[[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]carbonyl]amino]propionamide
N-[(2S)-2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(2R)-2-hydroxy-3-(hydroxyamino)-2-methyl-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(2R)-2-hydroxy-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(2S)-2-hydroxy-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxo-1-phenylpropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-cyclopentyl-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxo-1-(4-pyridinyl)propyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxo-1-(2-pyridinyl)propyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxo-1-(3-pyridinyl)propyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxo-1-(1,3-thiazol-2-yl)propyl]-4-[(2methyl-4-quinolinyl)methoxy]benzamide
N-[1-[4-(dimethylamino)phenyl]-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxo-1-(3-thienyl)propyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxo-1-(2-thienyl)propyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-(3-furyl)-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-1-(1-methyl-1H-imidazol-2-yl)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxo-1-(4-piperidinyl)propyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-1-(1-methyl-4-piperidinyl)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-1-(1-isopropyl-4-piperidinyl)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-(hydroxyamino)-1-[1-(methylsulfonyl)-4-piperidinyl]-3-oxopropyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-(1-acetyl-4-piperidinyl)-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-[1-(2,2-dimethylpropanoyl)-4-piperidinyl]-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-benzyl-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(1R)-3-(hydroxyamino)-3-oxo-1-(4-pyridinylmethyl)propyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-3-oxopropyl]-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamide
or a pharmaceutically acceptable salt form thereof.
[6] In another embodiment, the present invention provides a novel compound of formula I:
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94COR5, xe2x80x94CO2H, xe2x80x94CO2R6, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR5, xe2x80x94C(O)NHOR6, xe2x80x94NHRa, xe2x80x94N(OH)COR5, xe2x80x94N(OH)CHO, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94S(O)(xe2x95x90NH)Ra, xe2x80x94S(xe2x95x90NH)2Ra, xe2x80x94SC(O)Ra, xe2x80x94PO(OH)2, and xe2x80x94PO(OH)NHRa;
X is absent or selected from C1-3 alkylene, C2-3 alkenylene, and C2-3 alkynylene;
Z is absent or selected from a C3-13 carbocycle substituted with 0-5 Rb and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa1, C(O) C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or selected from O, NRa1, S(O)p, and C(O);
Za is selected from H, a C3-13 carbocycle substituted with 0-5 Rc and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 and R4 together with the carbon atom to which they are attached combine to form a 3-10 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRc, and S(O)p and substituted with 0-4 Rc;
R3 is selected from Q1, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, (CRaRa1)r1O(CH2)rxe2x80x94Q1, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1NRaC(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q1, (CRaRa12)r1S(O)p(CRaRa1)rxe2x80x94Q1, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q1;
Q1 is selected from H, a C3-13 carbocycle substituted with 0-5 Rd and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
R4a is selected from H, C1-6 alkyl substituted with 0-1 Rb, C2-6 alkenyl substituted with 0-1 Rb, and C2-6 alkynyl substituted with 0-1 Rb;
Ra, at each occurrence, is independently selected from H and C1-6 alkyl;
Ra1 at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-1 Rc1, C2-6 alkenyl substituted with 0-1 Rc1, C2-6 alkynyl substituted with 0-1 Rc1, and xe2x80x94(CH2)r-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NRc1, O, and S(O)p and substituted with 0-3 Rc1;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle comprising carbon atoms and from 0-1 additional heteroatoms selected from N, NRa2, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl, and benzyl;
Ra3, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-1 Rc1, C2-6 alkenyl substituted with 0-1 Rc1, C2-6 alkynyl substituted with 0-1 Rc1, and xe2x80x94(CH2)r-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NRc1, O, and S(O)p and substituted with 0-3 Rc1;
Rb, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-1 Rc1, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, C(S)NRaRa1, NRaC(O)NRaRa1, OC(O)NRaRa1, NRaC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra3, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra3, S(O)pRa3, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-2 Rc1, C2-6 alkenyl substituted with 0-2 Rc1, C2-6 alkynyl substituted with 0-2 Rc1, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, (CRaRa1)r1NRaRa1, CF3, CF2CF3, (CRaRa1)r1C(xe2x95x90NCN)NRaRa1, (CRaRa1)r1C(xe2x95x90NRa)NRaRa1, (CRaRa1)r1C(xe2x95x90NORa)NRaRa1, (CRaRa1)r1C(O)NRaOH, (CRaRa1)r1C(O)Ra1, (CRaRa1)r1C(O)ORa1, (CRaRa1)r1C(S)ORa1, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1NRaC(O)Ra1, (CRaRa1)r1C(S)NRaRa1, (CRaRa1)r1OC(O)NRaRa1, (CRaRa1)r1NRaC(O)ORa1, (CRaRa1)r1NRaC(O)NRaRa1, (CRaRa1)r1S(O)pRa3, (CRaRa1)r1SO2NRaRa1, (CRaRa1)r1NRaSO2Ra3, and (CRaRa1)r1NRaSO2NRaRa1, C3-10 carbocycle substituted with 0-2 Rc1, (CRaRa1)r1xe2x80x94C3-10 carbocycle substituted with 0-2 Rc1, a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1, and (CRaRa1)r1-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
alternatively, when, on the ring formed by R2 and R4, 2 Rc""s are attached to the same carbon atom they combine to form a 3-7 membered carbocycle substituted with 0-2 Rc1 or a 3-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
alternatively, when, on the ring formed by R2 and R4, 2 Rc""s are attached to adjacent atoms they combine to form a 4-7 membered carbocycle substituted with 0-2 Rc1 or a 4-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
alternatively, when, on the ring formed by R2 and R4, 2 Rc""s are attached to atoms separated by one ring atom they combine to form a 5-7 membered carbocycle substituted with 0-2 Rc1 or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
Rc1, at each occurrence, is independently selected from H, C1-4 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CF3, xe2x80x94CN, NO2, C(O)ORa, and C(O)NRaRa;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, C(S)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra3, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra3, S(O)pRa3, CF3, CF2CF3, C3-10 carbocycle and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[7] In another preferred embodiment, the present invention provides a novel compound, wherein;
A is selected from COR5, xe2x80x94CO2H, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR5, xe2x80x94C(O)NHOR6, xe2x80x94N(OH)COR5, xe2x80x94N(OH)CHO, xe2x80x94SH, and xe2x80x94CH2SH;
X is absent or is C1-3 alkylene;
Z is absent or selected from a C3-11 carbocycle substituted with 0-5 Rb and a 5-11 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, C(O)NRa1, NRa1C(O), S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C3-10 carbocycle substituted with 0-5 Rc and a 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 and R4 together with the carbon atom to which they are attached combine to form a 3-7 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRc, and S(O)p and substituted with 0-2 Rc;
R4a is selected from H and C1-6 alkyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached form a 5 or 6 membered heterocycle comprising carbon atoms and from 0-1 additional heteroatoms selected from N, NRa2, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-1 Rc1, C2-6 alkenyl substituted with 0-1 Rc1, C2-6 alkynyl substituted with 0-1 Rc1, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, CF3, (CRaRa1)r1C(O)Ra1, (CRaRa1)r1C(O)ORa1, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1S(O)pRa3, (CRaRa1)r1SO2NRaRa1, C3-6 carbocycle and a 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, CF3, C3-6 carbocycle and a 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
R5, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-; R7a is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-6 alkyl substituted with 1-2 Rf, C3-6 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[8] In another more preferred embodiment, the present invention provides a novel compound, wherein;
A is selected from xe2x80x94CO2H, xe2x80x94C(O)NHOH, xe2x80x94C(O)NHOR5, xe2x80x94N(OH)CHO, and xe2x80x94N(OH)COR5;
X is absent or is C1-2 alkylene;
Z is absent or selected from a C5-6 carbocycle substituted with 0-3 Rb and a 5-6 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)NRa1, S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C5-6 carbocycle substituted with 0-3 Rc and a 5-10 membered heteroaryl containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 and R4 together with the carbon atom to which they are attached combine to form a 4-7 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, N, NRc, and S(O)p and substituted with 0-1 Rc;
R4a is selected from H and C1-4 alkyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, CF3, (CRaRa1)r1C(O)Ra1, (CRaRa1)r1C(O)ORa, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1S(O)pRa3, (CRaRa1)r1SO2NRaRa1, and phenyl;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, CF3 and phenyl;
R5, at each occurrence, is selected from C1-4 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Re;
Re, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[9] In another even more preferred embodiment, the present invention provides a novel compound, wherein;
A is xe2x80x94C(O)NHOH;
X is absent or is methylene;
Z is absent or selected from phenyl substituted with 0-3 Rb and pyridyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R1 is selected from H, CH3, and CH2CH3;
R2 and R4 together with the carbon atom to which they are attached combine to form a 4-7 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from O, NRc, and S(O)p and substituted with 0-1 Rc;
R4a is selected from H and C1-2 alkyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra2, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, CF3, (CRaRa1)r1C(O)Ra1, (CRaRa1)r1C(O)ORa, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1S(O)pRa3, and (CRaRa1)r1SO2NRaRa1;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa3, CF3 and phenyl;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3; and,
r1, at each occurrence, is selected from 0, 1, 2, and 3.
[10] In another preferred embodiment, the present invention provides a novel compound selected from the group:
tert-butyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-propyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(methylsulfonyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(2,2-dimethylpropanoyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-isopropyl-4-piperidinyl}-4-[2-methyl-4-quinolinyl)methoxy]benzamide
4-[2-(hydroxyamino)-2-oxoethyl]-N,N-dimethyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-methyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[(dimethylamino)carbothioyl]-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-acetyl-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
methyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
N-{1-(2-fluoroethyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl 4-[2-(hydroxyamino)-1-methyl-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
N-{4-[2-(hydroxyamino)-1-methyl-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl (2R)-2-{[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]methyl}-1-pyrrolidinecarboxylate
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-[(2R)-pyrrolidinylmethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(2,2-difluoroethyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(methoxyacetyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-tetrahydro-2H-pyran-4-yl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-ethyl-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl 2-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]-2-methylpropanoate
2-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]-2-methylpropanoic acid
tert-butyl 2-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]ethylcarbamate
N-{1-(2-aminoethyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(dimethylamino)ethyl]-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(dimethylamino)-1,1-dimethyl-2-oxoethyl]-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-propionyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-butyryl-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(3,3-dimethylbutanoyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(2-methoxyethyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-isobutyryl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(1,1-dimethyl-2-propynyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(2-hydroxy-2-methylpropyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(3-methylbutanoyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-tert-butyl-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[(E)-(cyanoimino)(dimethylamino)methyl]-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
methyl 2-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]-2-methylpropanoate
O-phenyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarbothioate
N-{1-{[1-(aminocarbonyl)cyclopropyl]carbonyl}-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[(1-cyanocyclopropyl)carbonyl}-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(2,2-dimethyl-4-pentenoyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(2-hydroxy-2-methylpropanoyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
ethyl 2-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]-2-methylpropanoate
N-{1-(1,1-dimethyl-2-propenyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(1,3-thiazol-2-yl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-(methyl{4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
N-{1-(4,5-dihydro-1,3-thiazol-2-yl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-[2-(methylsulfanyl)ethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(1,3-thiazol-2-ylmethyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(2-propynyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(2-pyridinylmethyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(3-pyridinylmethyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(4-pyridinylmethyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl [4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]acetate
[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]acetic acid
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-[(1-methyl-1H-pyrrol-2-yl)methyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(1H-imidazol-4-ylmethyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-phenyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-benzyl-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(ethylsulfonyl)ethyl]-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-1-methyl-2-oxoethyl]-1-isopropyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-isobutyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(tert-butylsulfonyl)ethyl]-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-neopentyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
N-{4-[2-(hydroxyamino)-1-methyl-2-oxoethyl]-1-propyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(cyclopropylmethyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(cyclohexylmethyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-isopentyl-4-piperidinyl}-4-[(4-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(3,3-dimethylbutyl)-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-(hydroxyamino)-1,1-dimethyl-3-oxopropyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
methyl (2S)-2-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]propanoate
N-{4-[2-(hydroxyamino)-2-oxoethyl]-2-methyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1,2-dimethyl-4-piperidinyl}-4[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{2-tert-butyl-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4xcex1-[2-(hydroxyamino)-2-oxoethyl]-2xcex2,6xcex2-dimethyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4xcex1-[2-(hydroxyamino)-2-oxoethyl]-1,2xcex2,6xcex2-trimethyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-6-methyl-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1,6-dimethyl-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
benzyl 3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-azetidinecarboxylate
N-{3-[2-(hydroxyamino)-2-oxoethyl]-3-azetidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-methyl-3-azetidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl 2-[3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-azetidinyl]-2-methylpropanoate
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-isobutyl-3-azetidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-neopentyl-3-azetidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(tert-butylsulfonyl)ethyl]-3-[2-(hydroxyamino)-2-oxoethyl]-3-azetidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-3-methyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1,3-dimethyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-ethyl-4xcex1-[2-(hydroxyamino)-2-oxoethyl]-2xcex2,6xcex2-dimethylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-acetyl-4xcex1-[2-(hydroxyamino)-2-oxoethyl]-2xcex2,6xcex2-dimethylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4xcex1-[2-(hydroxyamino)-2-oxoethyl]-2xcex2,6xcex2-dimethyl-1-(2-propynyl)piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-1-(2-methyl-2-propenyl)-4-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-fluoro-4-[2-(hydroxyamino)-2-oxoethyl]-1-methyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[amino(imino)methyl]-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{2-(difluoromethyl)-4-[2-(hydroxyamino)-2-oxoethyl]-1-methyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-2-isopropyl-1-methyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1,2-dimethyl-4-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl 4-{[4-(2-butynyloxy)benzoyl]amino}-4-[2-(hydroxyamino)-2-oxoethyl]-1-piperidinecarboxylate
4-(2-butynyloxy)-N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(4-hydroxy-2-butynyl)oxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-{[3-(4-pyridinyl)-2-propynyl]oxy}benzamide
tert-butyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-[({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)amino]-1-piperidinecarboxylate
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetamide
tert-butyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-[(4-{[(2-methyl-4-quinolinyl)methyl]sulfanyl}benzoyl)amino]-1-piperidinecarboxylate
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-{[(2-methyl-4-quinolinyl)methyl]sulfanyl}benzamide
N-{4-(2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-{[(2-methyl-4-quinolinyl)methyl]sulfonyl}benzamide
tert-butyl 4-{[4-(benzyloxy)benzoyl]amino}-4-[2-(hydroxyamino)-2-oxoethyl]-1-piperidinecarboxyl
4-(benzyloxy)-N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}benzamide
tert-butyl 4-({4-[(3,5-dimethylbenzyl)oxy]benzoyl}amino)-4-[2-(hydroxyamino)-2-oxoethyl]-1-piperidinecarboxylate
4-[(3,5-dimethylbenzyl)oxy]-N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}benzamide
tert-butyl 4-({4-[(2,5-dimethylbenzyl)oxy]benzoyl}amino)-4-[2-(hydroxyamino)-2-oxoethyl]-1-piperidinecarboxylate
4-[(2,5-dimethylbenzyl)oxy]-N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-(3-pyridinylmethoxy)benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-(4-pyridinylmethoxy)benzamide
4-[(2,6-dimethyl-4-pyridinyl)methoxy]-N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-3-pyridinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(7-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-{[4-(4-quinolinylmethoxy)benzoyl]amino}-1-piperidinecarboxylate
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-(4-quinolinylmethoxy)benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-{[2-(trifluoromethyl)-4-quinolinyl]methoxy}benzamide
6-(benzyloxy)-N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}nicotinamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-6-[(2-methyl-4-quinolinyl)methoxy]nicotinamide
tert-butyl 4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(4-quinolinyloxy)methyl]benzoyl}amino)-1-piperidinecarboxylate
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(4-quinolinyloxy)methyl]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-3-methyl-4-(4-quinolinylmethoxy)benzamide
4-[(2,6-dimethyl-4-pyridinyl)methoxy]-N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-3-methylbenzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-3-methyl-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]hexahydro-1H-azepin-4-yl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-methylhexahydro-1H-azepin-4-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1-isopropylhexahydro-1H-azepin-4-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
5-(benzyloxy)-N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl)-2-pyridinecarboxamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-5-(1-naphthylmethoxy)-2-pyridinecarboxamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-5-[(2-methyl-4-quinolinyl)methoxy]-2-pyridinecarboxamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]cyclopentyl}-5-[(2-methyl-4-quinolinyl)methoxy]-2-pyridinecarboxamide
N-(4-{[formyl(hydroxy)amino]methyl}-4-piperidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-3-piperidinyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-3-[2-(hydroxyamino)-2-oxoethyl]piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-3-[2-(hydroxyamino)-2-oxoethyl]piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
tert-butyl 3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-methyl-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-3-[2-(hydroxyamino)-2-oxoethyl]-1-methylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-3-[2-(hydroxyamino)-2-oxoethyl]-1-methylpiperidinyl}-4[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-isopropyl-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-3-[2-(hydroxyamino)-2-oxoethyl]-1-isopropylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-3-[2-(hydroxyamino)-2-oxoethyl]-1-isopropylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(2-propynyl)-3-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(3-pyridinylmethyl)-3-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(3R)-3-[2-(hydroxyamino)-2-oxoethyl]-1-(3-pyridinylmethyl)piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(3S)-3-[2-(hydroxyamino)-2-oxoethyl]-1-(3-pyridinylmethyl)piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(2-pyridinylmethyl)-3-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(4-pyridinylmethyl)-3-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-propyl-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-3-[2-(hydroxyamino)-2-oxoethyl]-1-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-3-[2-(hydroxyamino)-2-oxoethyl]-1-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-isobutyl-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-ethyl-3-[2-(hydroxyamino)-2-oxoethyl]-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
Methyl 2-[3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinyl]-2-methylpropanoate
N-{1-benzyl-3-[2-(hydroxyamino)-2-oxoethyl]-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(cyclopropylmethyl)-3-[2-(hydroxyamino)-2-oxoethyl]-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-phenyl-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-acetyl-3-[2-(hydroxyamino)-2-oxoethyl]-3-piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-ethyl-3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(methylsulfonyl)-3-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(phenylsulfonyl)-3-piperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
Isobutyl 3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
Benzyl 3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-piperidinecarboxylate
N-{3-[2-(hydroxyamino)-2-oxoethyl]-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-methyl-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-3-[2-(hydroxyamino)-2-oxoethyl]-1-methylpyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-3-[2-(hydroxyamino)-2-oxoethyl]-1-methylpyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-isopropyl-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(2-propynyl)-3-pyrrolidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(3-pyridinylmethyl)-3-pyrrolidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(2-pyridinylmethyl)-3-pyrrolidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-benzyl-3-[2-(hydroxyamino)-2-oxoethyl]-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-1-benzyl-3-[2-(hydroxyamino)-2-oxoethyl]pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-1-benzyl-3-[2-(hydroxyamino)-2-oxoethyl]pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(cyclopropylmethyl)-3-[2-(hydroxyamino)-2-oxoethyl]-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(3,5-dimethylbenzyl)-3-[2-(hydroxyamino)-2-oxoethyl]-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(3,5-dimethoxybenzyl)-3-[2-(hydroxyamino)-2-oxoethyl]-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2,4-bis(trifluoromethyl)benzyl]-3-[2-(hydroxyamino)-2-oxoethyl]-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-(1-acetyl-3-[2-(hydroxyamino)-2-oxoethyl]-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-(2,2-dimethylpropanoyl)-3-[2-(hydroxyamino)-2-oxoethyl]-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-ethyl-3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(methylsulfonyl)-3-pyrrolidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(3-pyridinylcarbonyl)-3-pyrrolidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-N-phenyl-1-pyrrolidinecarboxamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(phenylacetyl)-3-pyrrolidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-1-(phenylsulfonyl)-3-pyrrolidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
Isobutyl 3-[2-(hydroxyamino)-2-oxoethyl]-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-pyrrolidinecarboxylate
N-{4-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-2H-pyran-4-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4xcex1-[2-(hydroxyamino)-2-oxoethyl]-2xcex2,6xcex2-dimethyltetrahydro-2H-pyran-4-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-2H-pyran-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-2H-pyran-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-2H-pyran-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-2H-thiopyran-4-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-(2-(hydroxyamino)-2-oxoethyl]-1-oxidotetrahydro-2H-thiopyran-4-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]-1,1-dioxidotetrahydro-2H-thiopyran-4-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-2H-thiopyran-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-oxidotetrahydro-2H-thiopyran-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1,1-dioxidotetrahydro-2H-thiopyran-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-3-furanyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-3-furanyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-3-furanyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-2-methyltetrahydro-3-furanyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-2,2,5,5-tetramethyltetrahydro-3-furanyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-3-thienyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3R)-3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-3-thienyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-3-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-3-thienyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1-oxidotetrahydro-3-thienyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-1,1-dioxidotetrahydro-3-thienyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-5-methyltetrahydro-3-thienyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-5-methyl-1-oxidotetrahydro-3-thienyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-5-methyl-1,1-dioxidotetrahydro-3-thienyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]cyclobutyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]cycloheptyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-1-methyl-2-oxoethyl]tetrahydro-2H-pyran-4-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-2,5-dimethyl-tetrahydro-3-furanyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-1-methyl-2-oxoethyl]tetrahydro-2H-pyran-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-5-methyl-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-6-methoxytetrahydro-2H-pyran-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{5-[2-(hydroxyamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-5-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-1-methyl-2-oxoethyl]tetrahydro-3-furanyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[3-[2-(hydroxyamino)-2-oxoethyl]-5-(4-methoxyphenyl)tetrahydro-3-furanyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-hydroxy-4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-2-pyrrolidinecarboxamide
N-{1-benzyl-3-[2-(hydroxyamino)-2-oxoethyl]-5,5-dimethyl-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-5,5-dimethyl-3-pyrrolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1,2-diethyl-4-[2-(hydroxyamino)-2-oxoethyl]-4-pyrazolidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-[2-(hydroxyamino)-2-oxoethyl]tetrahydro-2H-pyran-4-yl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamide
N-4-[2-(hydroxyamino)-2-oxoethyl]-4-piperidinyl}-1-[(2-methyl-4-quinolinyl)methyl]-1H-indole-5-carboxamide
N-[1-[2-(hydroxyamino)-2-oxoethyl]-4-oxocyclohexyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[trans-[4-hydroxy-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[cis-[4-hydroxy-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[trans-[1-[2-(hydroxyamino)-2-oxoethyl]-4-methoxycyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[cis-[1-[2-(hydroxyamino)-2-oxoethyl]-4-methoxycyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[trans-[1-[2-(hydroxyamino)-2-oxoethyl]-4-(methylamino)cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[cis-[1-[2-(hydroxyamino)-2-oxoethyl]-4-(methylamino)cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[trans-[4-(dimethylamino)-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[cis-[4-(dimethylamino)-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[trans[4-amino-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[cis-[4-amino-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[trans-[1-[2-(hydroxyamino)-2-oxoethyl]-4-[(1-methylethyl)amino]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[cis-[1-[2-(hydroxyamino)-2-oxoethyl]-4-[(1-methylethyl)amino]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[trans-[4-[(1,1-dimethylethyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[cis-[4-[(1,1-dimethylethyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[trans-[4-(acetylamino)-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[cis-[4-(acetylamino)-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
carbamic acid, trans-[4-[2-(hydroxyamino)-2-oxoethyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]cyclohexyl]-1,1-dimethylethyl ester
carbamic acid, cis-[4-[2-(hydroxyamino)-2-oxoethyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]cyclohexyl]-1,1-dimethylethyl ester
N-[1-[2-(hydroxyamino)-2-oxoethyl]-4-methylenecyclohexyl]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[4-hydroxy-trans-[1-[2-(hydroxyamino)-2-oxoethyl]-4-(2-propenyl)cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
N-[4-hydroxy-cis-[1-[2-(hydroxyamino)-2-oxoethyl]-4-(2-propenyl)cyclohexyl]]-4-[(2-methyl-4-quinolinyl)methoxy]-benzamide
Methyl 4-cis and trans-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexylcarbamate
Ethyl 4-cis and trans-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexylcarbamate
Propyl 4-cis and trans-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexylcarbamate
Allyl 4-cis and trans-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexylcarbamate
n-Butyl 4-cis and trans-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexylcarbamate
Isobutyl 4-cis and trans-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexylcarbamate
Benzyl 4-cis and trans-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexylcarbamate
N-{4-cis and trans-[(2,2-dimethylpropanoyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-[benzoylamino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-(propionylamino)cyclohexyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-[(3-methylbutanoyl)amino]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-[(cyclopentylcarbonyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-[(cyclopentylacetyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-[(3,3-dimethylbutanoyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexyl]-cis and trans-2-furamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexyl]-cis-2-isonicotinamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexyl]-trans-2-isonicotinamide
N-(1-[2-(hydroxyamino)-2-oxoethyl]-4-{cis and trans-[4-(trifluoromethyl)benzoyl]amino}cyclohexyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{cis and trans-4-[(cyclopropylcarbonyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-[(methoxyacetyl)amino]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-[(phenylacetyl)amino]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-(1-[2-(hydroxyamino)-2-oxoethyl]-4-{[cis and trans-(trifluoromethyl)sulfonyl]amino}cyclohexyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-[2-(hydroxyamino)-2-oxoethyl]-4-(cis and trans-{[4-(trifluoromethyl)phenyl]sulfonyl}amino)cyclohexyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-{[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino}-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-[(methylsulfonyl)amino]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-[(2-thienylsulfonyl)amino]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-[(3-cyclopentylpropanoyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-[(2-ethylbutanoyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-[(2-thienylacetyl)amino]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-[2-(hydroxyamino)-2-oxoethyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)cyclohexyl]-cis and trans-2-thiophenecarboxamide
N-{4-cis and trans-[(cyclobutylcarbonyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-[(anilinocarbonyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-({[(2-phenylethyl)amino]carbonyl}amino)cyclohexyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-(1-[2-(hydroxyamino)-2-oxoethyl]-4-cis and trans-{[(tetrahydro-2H-pyran-2-ylamino)carbonyl]amino}cyclohexyl)-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-{[(ethylamino)carbonyl]amino}-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-{[(allylamino)carbonyl]amino}-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-{(hexylamino)carbonyl]amino}-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-{[(propylamino)carbonyl]amino}-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis and trans-{[(isopropylamino)carbonyl]amino}-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-cis-{4-(benzylamino)-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-trans-{4-(benzylamino)-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-[2-(hydroxyamino)-2-oxoethyl]-4-cis-(1-pyrrolidinyl)cyclohexyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[1-[2-(hydroxyamino)-2-oxoethyl]-4-trans-(1-pyrrolidinyl)cyclohexyl]-4-[2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis-[(3-fluorobenzyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-trans-[(3-fluorobenzyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis-[(4-fluorobenzyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-trans-[(4-fluorobenzyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-cis-[(2,4-difluorobenzyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{4-trans-[(2,4-difluorobenzyl)amino]-1-[2-(hydroxyamino)-2-oxoethyl]cyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-cis and trans-hydroxy-1-[2-(hydroxyamino)-2-oxoethyl]-4-(methoxymethyl)cyclohexyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{8-[2-(hydroxyamino)-2-oxoethyl]-1-oxaspiro[4.5]dec-8-yl}-4-cis-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{8-[2-(hydroxyamino)-2-oxoethyl]-1-oxaspiro[4.5]dec-8-yl}-4-trans-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{8-[2-(hydroxyamino)-2-oxoethyl]-3-methyl-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{6-[2-(hydroxyamino)-2-oxoethyl]-1-azaspiro[2.5]oct-6-yl}-4-cis-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{6-[2-(hydroxyamino)-2-oxoethyl]-1-azaspiro[2.5]oct-6-yl}-4-trans-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[4-hydroxy-1-[2-(hydroxyamino)-2-oxoethyl]-4-(hydroxymethyl)cyclohexyl]-4-cis and trans-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{9-[2-(hydroxyamino)-2-oxoethyl]-1,4-dioxaspiro[5.5]undec-9-yl}-4-cis-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{9-[2-(hydroxyamino)-2-oxoethyl]-1,4-dioxaspiro[5.5]undec-9-yl}-4-trans-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{3-[2-(hydroxyamino)-2-oxoethyl]-8-azabicyclo[3.2.1]oct-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{8-ethyl-3-[2-(hydroxyamino)-2-oxoethyl]-8-azabicyclo[3.2.1]oct-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{8-acetyl-3-[2-(hydroxyamino)-2-oxoethyl]-8-azabicyclo[3.2.1]oct-3-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,4R)-2-allyl-4-[2-(hydroxyamino)-2-oxoethyl]piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,4R)-2-allyl-1-ethyl-4-[2-(hydroxyamino)-2-oxoethyl]piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,4R)-1-acetyl-2-allyl-4-[2-(hydroxyamino)-2-oxoethyl]piperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,4R)-4-[2-(hydroxyamino)-2-oxoethyl]-2-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,4R)-4-[2-(hydroxyamino)-2-oxoethyl]-1-methyl-2-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,4R)-1-ethyl-4-[2-(hydroxyamino)-2-oxoethyl]-2-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,4R)-4-[2-(hydroxyamino)-2-oxoethyl]-1,2-dipropylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2R,9aS)-2-[2-(hydroxyamino)-2-oxoethyl]-6-oxooctahydro-2H-quinolizin-2-yl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2R)-1-ethyl-4-[2-(hydroxyamino)-2-oxoethyl]-2-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-[(2R)-4-[2-(hydroxyamino)-2-oxoethyl]-1-(2-oxopropyl)-2-propylpiperidinyl]-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2R)-4-[2-(hydroxyamino)-2-oxoethyl]-1-[(2Z)-2-(hydroxyimino)propyl]-2-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,3S)-3-[2-(hydroxyamino)-2-oxoethyl]-2-methylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S,3S)-1-acetyl-3-[2-(hydroxyamino)-2-oxoethyl]-2-methylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2S)-1-ethyl-4-[2-(hydroxyamino)-2-oxoethyl]-2-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(3S)-4-acetyl-1-[2-(hydroxyamino)-2-oxoethyl]-3-propylcyclohexyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-{(2R,4R)-1-ethyl-4-[2-(hydroxyamino)-2-oxoethyl]-2-propylpiperidinyl}-4-[(2-methyl-4-quinolinyl)methoxy]benzamide
N-hydroxy-8-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-1,4-dioxaspiro[4.5]decane-8-acetamide
N-hydroxy-3,3-dimethyl-9-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-1,5-dioxaspiro[5.5]undecane-9-acetamide
N-Hydroxy-3-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-5-oxo-3-pyrrolidineacetamide
N-hydroxy-1-methyl-3-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-5-oxo-3-pyrrolidineacetamide
N-hydroxy-3-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-5-oxo-1-(2-propenyl)-3-pyrrolidineacetamide
N-hydroxy-3-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-6-oxo-3-piperidineacetamide
N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-2-oxo-4-piperidineacetamide
Benzamide, N-[hexahydro-3-[2-[(hydroxyamino)oxy]-2-oxoethyl]-1H-azepin-3-yl]-4-[(2-methyl-4-quinolinyl)methoxy]
Benzamide, N-[1-ethylhexahydro-3-[2-[(hydroxyamino)oxy]-2-oxoethyl]-1H-azepin-3-yl]-4-[(2-methyl-4-quinolinyl)methoxy]
Benzamide, N-[1-acetylhexahydro-3-[2-[(hydroxyamino)oxy]-2-oxoethyl]-1H-azepin-3-yl]-4-[(2-methyl-4-quinolinyl)methoxy]
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating, wherein the disease or condition is referred to as acute infection, acute phase response, age related macular degeneration, alcoholism, anorexia, asthma, autoimmune disease, autoimmune hepatitis, Bechet""s disease, cachexia, calcium pyrophosphate dihydrate deposition disease, cardiovascular effects, chronic fatigue syndrome, chronic obstruction pulmonary disease, coagulation, congestive heart failure, corneal ulceration, Crohn""s disease, enteropathic arthropathy, Felty""s syndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis, glucocorticoid withdrawal syndrome, gout, graft versus host disease, hemorrhage, HIV infection, hyperoxic alveolar injury, infectious arthritis, inflammation, intermittent hydrarthrosis, Lyme disease, meningitis, multiple sclerosis, myasthenia gravis, mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis, polymyositis/dermatomyositis, post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis, psoriatic arthritis, pydoderma gangrenosum, relapsing polychondritis, Reiter""s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sepsis syndrome, Still""s disease, shock, Sjogren""s syndrome, skin inflammatory diseases, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener""s granulomatosis.
In another embodiment, the present invention provides novel compounds of the present invention for use in therapy.
In another embodiment, the present invention provides the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example-CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, O, and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a desired metalloprotease in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A variety of compounds of formula (I) wherein A is a hydroxamic acid group are prepared from their corresponding esters via several routes known in the literature (Scheme 1). The methyl ester of 1 (R11=Me) is directly converted to hydroxamic acid 2 by treatment with hydroxylamine under basic conditions such as KOH or NaOMe in solvents such as methanol. The methyl ester of 1 (R11=Me) can also be converted to O-benzyl protected hydroxamic acid with O-benzylhydroxylamine under similar conditions or using Weinreb""s trimethylalluminum conditions (Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12, 989) or Roskamp""s bis[bis(trimethylsilyl)amido]tin reagent (Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101). The benzyl ether is removed by methods well known in the literature such as hydrogenation using palladium on barium sulfate in hydrogen, to give compound 2. Alternatively, 2 can be prepared through carboxylic intermediate 3. Carboxylic acid 3 is converted to 2 via coupling with hydroxylamine, or O-benzylhydroxylamine followed by deprotection.
xcex2-Amidoester 1 can be prepared by coupling the corresponding amine 4 with a carboxylic acid derivative as demonstrated in Scheme 2. When amine 4 is unhindered, direct coupling with carboxylic acid 5 can be accomplished using the BOP reagent or the combination of EDCI/HOBt. For hindered amines, a more activated derivative of 5 such as the acid chloride 6 or acid fluoride 7 may be utilized for the formation of the amide bond.
The xcex2-amino acid moiety in formula (I) can be synthesized following a variety of routes, most of which are found in the literature (see for example, Enantioselective Synthesis of xcex2-Amino Acids, E. Juaristi, Ed., Wiley-VCH, 1997). One approach for the preparation of cyclic xcex2-secondary amines such as 11 involves the reaction of a benzyl protected amine 9 with a bromo-substituted xcex1,xcex2-unsaturated ester 8 (Scheme 3). Removal of the benzyl protecting group gives amine 11 (see for example, J. Org. Chem. 1992, 57, 1727-1733).
Furthermore, xcex1-substitution can be introduced using a synthetic strategy similar to the one shown in Scheme 4. Oxidation of a cyclic amine 12 with aqueous alkaline sodium persulfate in the presence of silver nitrate provides the cyclic amine trimer 13. Reaction of triazine 13 with a silyl ketene acetal 14 and TMSOTf gives the 2-substituted cyclic amine 15 (Chem. Pharm. Bull. 1986, 24, 1579-1583). Amino esters 11 and 15 (Schemes 3 and 4) are transformed intocompounds of formula (I) as demonstrated in Schemes 1 and 2.
xcex1,xcex1-Disubstituted-xcex2-amino esters can be readily prepared as shown in Schemes 5-7. Treatment of chloromethyl methyl ether with lithium hexamethyldisilazide followed by addition of a silyl ketene acetal 17 produces protected amine 18 (Scheme 5). Desilylation of 18 is accomplished by heating in methanol (Chem. Pharm. Bull. 1985, 33, 2228-2234). Amine 19 can be coupled with acid 5 as shown in Scheme 2 or further derivatized by alkylation or reductive amination to provide the secondary amine 20.
Alternatively, esters such as 21 can be alkylated with N-(bromomethyl)phthalimide using LDA to give the xcex2-imide products 22 (Scheme 6). Hydrazine deprotection provides 19.
Another attractive route for the preparation of 19 involves dialkylation of xcex1-cyanoesters followed by reduction of the cyano group as detailed in Scheme 7. When 23 is subjected to sodium hydride/DMF or potassium carbonate/acetone followed by a dihalide 24, cyclization occurs to produce ring B in 25. Amine 19 is obtained by hydrogenation of 25 in the presence of a catalytic amount of platinum oxide. Amino esters 19 and 20 (Schemes 5-7) are transformed into compounds of formula (I) as demonstrated in Schemes 1 and 2.
A series of compounds having xcex2-aminoacid core structure 20 wherein ring B is piperidine are prepared following the sequence outlined in Scheme 8. Methyl cyanoacetate 26 is alkylated with dibromide 27 using sodium hydride in DMF. Protecting group manipulation of 28 followed by reduction of the cyano group provides amine 30. Amide 32 is accessed through BOP coupling of 30 with carboxylic acid 31. At this stage 32 is either converted to tertiary amide 33 or treated with TFA to deprotect the piperidine nitrogen to give 34 where R1 is H. When R1 is not H, 34 is obtained from 33 in a similar manner. The piperidine nitrogen of 34 is functionalized to various analogues through alkylation, reductive amination, sulfonylation, acylation, etc. Ester 35 is transformed into hydroxamic acid as outlined in Scheme 1. Isomers of 19 with piperidine nitrogen transposed to other positions are prepared following a sequence similar to Scheme 6.
xcex2,xcex2-Disubstituted-xcex2-amino esters can be constructed following the synthetic routes outlined in Schemes 9-10. Cyclic ketone 36 is treated with Wittig reagent 37 in refluxing toluene or Horner-Emmons reagent 38 to give xcex1,xcex2-unsaturated ester 39 (Scheme 9). Addition of ammonia to 39 in a Michael fashion provides the xcex2-amino ester 40. Derivatization of the primary amine through alkylation or reductive amination gains access to secondary amine 41.
Another useful method for the preparation of amine 40 involves unsubstituted ester 42 as shown in Scheme 10. This approach allows for incorporation of R4 at a later stage, alleviating the necessity of preparing non-commercially available Wittig reagents such as 37 (Scheme 9). The amine functionality of 42 is protected as a benzyl carbamate and the resulting substrate treated with LDA and an alkyl halide to give ester 44. Hydrogenolysis provides amine 40. Amino esters 40 and 41 (Schemes 9 and 10) are transformed into compounds of formula (I) as demonstrated in Schemes 1 and 2.
A series of compounds having xcex2-aminoacid core structure 40 wherein ring B is piperidine are prepared following the sequence outlined in Scheme 11. Amine 45 (prepared similarly as shown in Scheme 9) is coupled to acid 31 using the BOP reagent to give amide 46. The piperidine nitrogen is unmasked and the resulting amine 47 functionalized to various tertiary amines, amides, carbamides, ureas, sulfonamides, and sulfonyl ureas following procedures well known in the literature. Ester 48 is transformed into hydroxamic acid as outlined in Scheme 1.
A variety of compounds of formula (I) wherein Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za is a functionalized phenyl group can be prepared by methods described in Scheme 12. Intermediate 49, available from schemes described previously, is converted to phenol 50 by hydrogenolysis. Phenol 50 is used as a common intermediate for structure diversification. Reaction of 50 with R10xe2x80x94X provides 51; an alternative is the reaction of 50 with R10xe2x80x94OH under Mitsunobu conditions to produce 51. R10 can be appended directly to the aromatic ring by converting 50 to an aryl triflate then reaction with an organometallic in the presence of a palladium (0) catalyst to give 52. 50 can also be reacted with acyl halides or isocyanates to afford 55. Biaryl ethers 54 can be produced by treatment of 50 with aryl boronic acids in the presence of a copper catalyst. Esters 51-52 and 54-55 are converted to the hydroxamic acids following the sequences outlined in Scheme 1.
A series of substituted cyclohexyl xcex2-aminoacid cores were prepared by the chemistry outlined in Schemes 13 through 15. The sequence began with the Wittig reaction between 1,4-cyclohexanedione mono-ethylene ketal and stabilized ylide 56. 1,4-Addition of ammonia to unsaturated ester 57 provided xcex2-aminoacid 58. Carboxylic acid 31 could be appended to 58 using a variety of amide bond forming reactions. Typical conditions include the use of BOP reagent and N-methylmorpholine. Ethylene ketal 59 was then deprotected using aqueous HCl in THF to provide ketone 60 which is then carried on to the hydroxamic acid 61 under standard conditions.
Ketone 60 was proven to be a very versatile intermediate as seen in Scheme 14. Examples of the chemical transformations that are readily available from 60 include the Wittig reaction (62), reductive ether formation (63), reductive amination (64 and 65), ketallization (66), and synthesis of quaternary alcohols via addition of organometallic reagents (67). In Scheme 15 several of these analogs are also shown to be useful intermediates. For example the Wittig product 62 provides access to aziridine 68 and epoxide 70 that can then be ring opened with a variety of organometallic reagents to afford novel amines 69 and alcohols 71. Olefin 62 can also serve as the alkene component in cycloaddition reactions such as the Diels-Alder reaction and the dipolar cyloaddition of nitrile oxides and nitrones. Illustrated in Scheme 15 is the reaction between 62 and nitrile oxide 72 to provide heterocyclic analog 73.
Scheme 16 illustrates the utility of secondary amine 65 as an intermediate for parallel synthesis. Using either a ninety six well format or shaker tubes, 65 can be reacted with chloroformates to give carbamates 74, acid chlorides to give amides 75, sulfonyl chlorides to give sulfonamides 76 or isocyanates to give ureas 77. All the compounds described in Schemes 14, 15, and 16 can be easily converted to the corresponding hydroxamic acids by standard conditions.
The preparation of lactam xcex2-amino acids cores is included in Schemes 17 and 18. The synthesis of the five membered ring analog (Scheme 17) began with bis alkylation of t-butyl cyanoacetate with methyl bromoacetate to provide triester 78. Reduction of the nitrile group by hydrogenation over raney nickel at 1000 psi was followed by spontaneous cyclization to form lactam 79. Lactam 79 was then converted into the desired xcex2-aminoacid core by acid hydrolysis of the t-butyl ester. Curtius rearrangement using diphenylphosphoryl azide in the presence of benzyl alcohol gave Cbz protected xcex2-aminoacid 80. The protecting group was removed by hydrogenation over 10% Pd on C and lactam 81 was carried forward to the desired hydroxamic acid 83 as described previously.
The synthesis of the six membered ring lactam analogs is shown in scheme 18. The sequence began with the palladium catalyzed cycloaddition reaction between t-butyl-methyl itaconate and 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate to provide exocyclic olefin 84. Ozonolysis gave ketone 85 and ring expansion to the regioisomeric lactams 87 and 88 was accomplished by a Beckmann rearrangement sequence which included formation of oxime 86, treatment with p-toluenesulfonyl chloride, and ring expansion on silica gel. From this point, lactams 87 and 88 were moved forward to final products using the same Curtius rearrangement described in Scheme 17.
The seven membered ring analogs are available from the Beckmann rearrangement of ketone 60 as seen in Scheme 19. The ring nitrogen in the lactam series can be elaborated by careful treatment with base then alkyl halides to give N-alkyl lactams 95 (Scheme 20).
In addition to Schemes 9 and 10, xcex2,xcex2-disubstituted-xcex2-amino esters can also be prepared according to synthetic Schemes 21-22. Cyclic ketone 36 is transformed into olefin 96 by reaction with the in situ generated methylene Wittig reagent (Scheme 21). Treatment of 96 with chlorosulfonyl isocyanate gives the xcex2-lactam 97. Following removal of the sulfonyl group, the xcex2-lactam 98 is reacted with an alcohol to open the lactam ring and provide the xcex2-amino ester 99.
An alternative route to xcex2-amino esters involves an ortho-ester Claisen rearrangement (Scheme 22). Treatment of allylic alcohol 100 with a suitable ortho ester followed by heating gives ester 101. The olefin of 101 is cleaved using either ozone or osmium tetroxide/sodium periodate to provide the corresponding aldehyde 102. Further oxidation with sodium chlorite followed by a Curtius rearrangement gives access to the protected amine 104. Removal of the protecting group affords xcex2-amino ester 105.
A useful method for making compounds having xcex2-amino acid core structure 40 (Scheme 10, R4=H) wherein ring B is a quinolizidinone is outlined in Scheme 23. Ketone 106 (for a preparation of this ketone and similar moieties see Comins, D. L.; Goehring, R. R.; Joseph, S. P.; O""Connor, S. J. Org. Chem. 1990, 55, 2574-2576.) can be transformed into urethane 107 utilizing the three step sequence shown. The secondary amine can be deprotected to provide 108. Acylation of the amine followed by ring closing metathesis provides 109. Amide 109 is a versatile intermediate that can be modified with several existing technologies. One such modification is reduction of the olefin and removal of the protecting group in one synthetic operation followed by amide formation to give 110. Trans-esterification and hydroxamic acid formation yields bicyclic inhibitor 111.
Intermediate 60 can also be used for the synthesis of spirocyclic analogs centered at the ketone carbonyl (Scheme 24). For example, allylation with tin(II) chloride and allyltri-n-butyltin provides alcohol 112 which is hydroborated to diol 113. The mesylate is formed on the less hindered alcohol with methanesulfonyl chloride and triethylamine with spontaneous cyclization occurring overnight at room temperature. The mixture of diastereomeric tetrahydrofurans 114 are then carried on to hydroxamic acids 115 under the standard conditions.
Scheme 25 provides an alternative synthesis of spirocyclic analogues. Epoxide 116 is prepared by the addition of trimethylsulfoxonium ylide to 1,4-cyclohexanedione monoethylene ketal. The epoxide is opened with the sodium salt of allyl alcohol to provide olefin alcohol 117. The double bond is treated with ozone and the ozonide worked up with sodium borohydride. The resulting diol is immediately brominated with carbon tetrabromide and triphenylphospine to give cyclization precursor 118. Dioxalane 119 is formed by deprotonation with sodium hydride in tetrahydrofuran followed by heating the solution to reflux for one hour. Ketal 120 is deprotected with aqueous HCl in tetrahydrofuran then Horner Emmons olefination provides t-butyl ester 121. Michael addition of ammonia gives xcex2-amino ester 122, which is carried on to hydroxamic acid 124 by the usual sequence of attaching acid 31 and conversion to the hydroxamic acid using the standard conditions. Modification of Schemes 24 and 25 can be used to provide spirocylic oxetane, tetrahydropyran, and oxepane analogs.
A series of compounds of formula (I) wherein A is a reverse hydroxamate [xe2x80x94N(OH)CHO] are prepared following the sequence outlined in Scheme 26. Amino Acid 125 is converted to methyl ester 126 by acid catalyzed esterification or reaction with (trimethylsilyl)diazomethane. Coupling of 126 with acid chloride 127 provides amide 128. Compound 128 is reduced with lithium borohydride to give alcohol 129, which is oxidized to aldehyde 130 under Swern conditions. Oximine formation and sodium cyanoborohydride reduction yields hydroxylamine 132. N-formylation is achieved with acetic formic anhydride. Removal of the t-butyl group completes the synthesis of 134.
One diastereomer of a compound of formula (I) may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention.
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).

xcex2-amino acid derivatives as inhibitors of matrix metalloproteases and TNF-xcex1

Abstract: or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, X, Z, Ua, Xa, Ya, Za, R1, R2, R3, R4, and R4a are defined in the present specification, which are useful as metalloprotease and/or as TNF-xcex1 inhibitors.