Cyclic hydroxamic acid as metalloproteinase inhibitors

• US 6,858,626 B2
• Filed: 06/20/2002
• Issued: 02/22/2005
• Est. Priority Date: 06/17/1998
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Inventors: Xue, Chu-Biao, Decicco, Carl P., He, Xiaohua
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US10/177,235
• Publication Number:
  US 20030139597A1
• Time in Patent Office: 978 Days
• Field of Search: 514/330, 514/346, 514/312, 514/613, 546/225, 546/298, 546/153, 564/163
• US Class Current: 514/312
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07C 259/08 having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07D 211/16 : with acylated ring nitrogen atom
• CPC Class Codes: C07D 211/22 : by oxygen atoms
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/40 : Acylated substituent nitrogen atom
• CPC Class Codes: C07D 215/20 : Oxygen atoms
• CPC Class Codes: C07D 215/233 : only one oxygen atom which is attached in position 4
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The present application describes novel cyclic hydroxamic acids of formula I:
or pharmaceutically acceptable salt forms thereof, wherein ring B is a 5-7 membered cyclic system containing from 0-2 heteroatoms selected from O, N, NR^a, and S(O)_p, and 0-1 carbonyl groups and the other variables are defined in the present specification, which are useful as metalloprotease inhibitors.

Claims

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;

A is selected from —

COR⁵, —

CO₂H, CH₂CO₂H, —

CO₂R⁶, —

CONHOH, —

CONHOR⁵, CONHOR⁶, —

NHR^a, —

N(OH)COR⁵, —

SH, —

CH₂SH, —

SONHR^a, and —

SN₂H₂R^a;

ring B is a 5-6 membered non-aromatic ring with 0-1 carbonyl groups;

R¹ is —

U—

X—

Y—

Z—

U^a—

X^a—

Y^a—

Z^a;

U is selected from;

C(O) and C(O)NR^a′

;

X is absent or selected from C_1-10 alkylene, C_2-10 alkenylene, and C_2-10 alkynylene;

Y is absent;

Z is selected from a C_3-13 carbocyclic residue substituted with 0-5 R^b, piperidinyl substituted with 0-5 R^b, and pyridyl substituted with 0-5 R^b;

U^a is absent or is O;

X^a is absent or is selected from C_1-10 alkylene, C_2-10 alkenylene, and C_2-10 alkynylene;

Y^a is absent or is O;

Z^a is selected from a C_3-13 carbocyclic residue substituted with 0-5 R^c, pyridyl substituted with 0-5 R^c, and quinolinyl substituted with 0-5 R^c;

provided that U, Z, U^a, Y^a, and Z^a do not combine to form an N—

N—

N—

O, O—

N, or O—

O group;

R² is selected from H, C_1-6 alkylene-Q, C_2-6 alkenylene-Q, C_2-6 alkynylene-Q, (CR^aR^a′

)_r′

O(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

NR^a(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_rC(O)(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_rC(O)O(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

OC(O)(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_rC(O)NR^a(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

NR^aC(O)(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

OC(O)O(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

OC(O)NR^a(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

NR^aC(O)O(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

NR^aC(O)NR^a(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

S(O)_p(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

SO₂NR^a(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

NR^aSO₂(CR^aR^a′

)_r—

Q, and (CR^aR^a′

)_r′

NR^aSO₂NR^a(CR^aR^a′

)_r—

Q;

Q is selected from H, a C_3-13 carbocyclic residue substituted with 0-5 R^d and a 5-14 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 R^d.

R³ is selected from H, C_1-6 alkylene-Q′

, C_2-6 alkenylene-Q′

, C_2-6 alkynylene-Q′

, (CR^aR^a′

)_r′

O(CH₂)_r—

Q′

, (CR^aR^a′

)_r′

NR^a(CR^aR^a′

) _r—

Q′

, (CR^aR^a′

)_r′

NR^aC(O)(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)^r′

C(O)NR^a(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_rC(O)(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_rC(O)O(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

₂)_r′

S(O)_p(CR^aR^a′

)_r—

Q′

, and (CR^aR^a′

)_r′

SO₂NR^a(CR^aR^a′

)_r—

Q′

;

Q′

is selected from H, phenyl substituted with 0-3 R^d, naphthyl substituted with 0-3 R^d and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 R^d.

alternatively, R² and R³ combine to form a fused benzo ring substituted with R^3′

;

R^3′

is selected from H, (CR^aR^a′

)_r—

Q′

, C_2-6 alkenylene-Q′

, C_2-6 alkynylene-Q′

, (CR^aR^a′

)_r′

O(CH₂)_r—

Q′

, (CR^aR^a′

)_r′

NR^a(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_r′

NR^aC(O)(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_r′

C(O)NR^a(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_rC(O)(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_rC(O)O (CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_r′

S(O)_p(CR^aR^a′

)_r—

Q′

, and (CR^aR^a′

)_r′

SO₂NR^a(CR^aR^a′

)_r—

Q′

;

R^a, at each occurrence, is independently selected from H, C_1-4 alkyl, phenyl and benzyl;

R^a′

, at each occurrence, is independently selected from H and C_1-4 alkyl;

alternatively, R^a and R^a′

taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R^a″

, at each occurrence, is independently selected from C_1-4 alkyl, phenyl and benzyl;

R^b, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, I, ═

O, —

CN, NO₂, NR^aR^a′

, C(O)R^a, C(O)OR^a, C(O)NR^aR^a′

, R^aNC(O)NR^aR^a, OC(O)NR^aR^a′

, R^aNC(O)O, S(O)₂NR^aR^a′

, NR^aS(O)₂R^a″

, NR^aS(O)₂NR^aR^a′

, OS(O)₂NR^aR^a′

, NR^aS(O)₂R^a″

, S(O)_pR^a″

, CF₃, and CF₂CF₃;

R^c, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, I, ═

O, —

CN, NO₂, NR^aR^a′

, C(O)R^a, C(O)OR^a, C(O)NR^aR^a′

, R^aNC(O)NR^aR^a′

, OC(O)NR^aR^a′

, R^aNC(O)O, S(O)₂NR^aR^a′

, NR^aS(O)₂R^a″

, NR^aS(O)₂NR^aR^a′

, OS(O)₂NR^aR^a′

, NR^aS(O)₂R^a″

, S(O)_pR^a″

, CF₃, CF₂CF₃, C_3-10 carbocyclic residue and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^d, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, I, ═

O, —

CN, NO₂, NR^aR^a′

, C(O)R^a, C(O)OR^a, C(O)NR^aR^a′

, R^aNC(O)NR^aR^a′

, OC(O)NR^aR^a′

, R^aNC(O)O, S(O)₂NR^aR^a′

, NR^aS(O)₂R^a″

, NR^aS(O)₂NR^aR^a′

, OS(O)₂NR^aR^a′

, NR^aS(O)₂R^a″

, S(O)_pR^a″

, CF₃, CF₂CF₃, C_3-10 carbocyclic residue and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

R₅, at each occurrence, is selected from C_1-10 alkyl substituted with 0-2 R^b, and C_1-8 alkyl substituted with 0-2 R^e;

R^e, at each occurrence, is selected from phenyl substituted with 0-2 R^b and biphenyl substituted with 0-2 R^b;

R⁶, at each occurrence, is selected from phenyl, naphthyl, C_1-10 alkyl-phenyl-C_1-6 alkyl-, C_3-11 cycloalkyl, C_1-6 alkylcarbonyloxy-C_1-3 alkyl-, C_1-6 alkoxycarbonyloxy-C_1-3 alkyl-, C_2-10 alkoxycarbonyl, C_3-6 cycloalkylcarbonyloxy-C_1-3 alkyl-, C_3-6 cycloalkoxycarbonyloxy-C_1-3 alkyl-, C_3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C_1-3 alkyl-, phenylcarbonyloxy-C_1-3 alkyl-, C_1-6 alkoxy-C_1-6 alkylcarbonyloxy-C_1-3 alkyl-, [5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(R^a)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —

C_1-10 alkyl-NR⁷R^7a, —

CH(R⁸)OC(═

O)R⁹, and —

CH(R⁸)OC(═

O)OR⁹;

R⁷ is selected from H and C_1-10 alkyl, C_2-6 alkenyl, C_3-6 cycloalkyl-C_1-3 alkyl-, and phenyl-C_1-6 alkyl-;

R^7a is selected from H and C_1-10 alkyl, C_2-6 alkenyl, C_3-6 cycloalkyl-C_1-3 alkyl-, and phenyl-C_1-6 alkyl-;

R⁸ is selected from H and C_1-4 linear alkyl;

R⁹ is selected from H, C_1-8 alkyl substituted with 1-2 R^f, C_3-8 cycloalkyl substituted with 1-2 R^f, and phenyl substituted with 0-2 R^b;

R^f, at each occurrence, is selected from C_1-4 alkyl, C_3-8 cycloalkyl, C_1-5 alkoxy, phenyl substituted with 0-2 R^b;

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

,

r′

, at each occurrence, is selected from 1, 2, 3, and 4;

provided that the moiety in ring B adjacent to CH—

A is other than substituted or unsubstituted N—

SO₂-phenyl-O—

Ar and N—

SO₂-phenyl-S—

Ar, wherein Ar is aryl or heteroaryl; and

,

provided that when ring B is cyclopentyl or cyclohexyl, then R¹ is other than a substituted or unsubstituted phenyl-S(O)_p—

group.

2. A compound according to claim 1, wherein the compound is of formula II:

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;

A is selected from COR⁵, —

CO₂H, CH₂CO₂H, —

CONHOH, —

CONHOR⁵, —

CONHOR⁶, —

N(OH)COR⁵, —

SH, and —

CH₂SH;

ring B is a 5-6 membered non-aromatic ring with 0-1 carbonyl groups;

R¹ is —

U—

X—

Y—

Z—

U^a—

X^a—

Y^a—

Z^a;

U is selected from;

C(O) and C(O)NR^a′

;

X is absent;

Y is absent;

Z is selected from a C_3-6 carbocyclic residue substituted with 0-5 R^b, piperidinyl substituted with 0-5 R^b, and pyridyl substituted with 0-5 R^b;

U^a is absent or is O;

X^a is absent or selected from C_1-4 alkylene;

Y^a is absent or is O;

Z^a is selected from a C_3-6 carbocyclic residue substituted with 0-5 R^c, pyridyl substituted with 0-5 R^c, and quinolinyl substituted with 0-5 R^c;

provided that U, Z, U^a, Y^a, and Z^a do not combine to form an N—

N N—

O, O—

N, or O—

O group;

R² is selected from H, C_1-6 alkylene-Q, (CR^aR^a′

)_r′

O(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

NR^a(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_rC(O)(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_rC(O)O(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_rC(O)NR^a(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_r′

S(O)_p(CR^aR^a′

)_r—

Q, and (CR^aR^a′

)_r′

SO₂NR^a(CR^aR^a′

)_r—

Q;

Q is selected from H, a C_3-6 carbocyclic residue substituted with 0-5 R^d, and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 R^d;

R³ is selected from H, C_1-6 alkylene-Q′

, (CR^aR^a′

)_r′

O(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_r′

NR^a(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_r′

C(O)NR^a(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_rC(O)(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_rC(O)O(CR^aR^a′

)_r—

Q′

, (CR^aR^a′

)_r′

S(O)_p(CR^aR^a′

)_r—

Q′

, and (CR^aR^a′

)_r′

SO₂NR^a(CR^aR^a′

)_r—

Q′

;

Q′

is selected from H, phenyl substituted with 0-3 R^d, naphthyl substituted with 0-3 R^d and a 5-6 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 R^d;

R^a, at each occurrence, is independently selected from H, C_1-4 alkyl, phenyl and benzyl;

R^a′

, at each occurrence, is independently selected from H and C_1-4 alkyl;

alternatively, R^a and R^a′

taken together with the nitrogen to which they are attached form a 5 or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R^a″

, at each occurrence, is independently selected from C_1-4 alkyl, phenyl and benzyl;

R^b, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, ═

O, —

CN, NR^aR^a′

, C(O)R^a, C(O)OR^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, and CF₃;

R^c, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, ═

O, —

CN, NR^aR^a′

, C(O)R^a, C(O)OR^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, CF₃, C_3-6 carbocyclic residue and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^d, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, ═

O, —

CN, NR^aR^a′

, C(O)R^a, C(O)OR^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, CF₃, C_3-6 carbocyclic residue and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

R⁵, at each occurrence, is selected from C_1-6 alkyl substituted with 0-2 R^b, and C_1-4 alkyl substituted with 0-2 R^e;

R^e, at each occurrence, is selected from phenyl substituted with 0-2 R^b and biphenyl substituted with 0-2 R^b;

R⁶, at each occurrence, is selected from phenyl, naphthyl, C_1-10 alkyl-phenyl-C_1-6 alkyl-, C_3-11 cycloalkyl, C_1-6 alkylcarbonyloxy-C_1-3 alkyl-, C_1-6 alkoxycarbonyloxy-C_1-3 alkyl-, C_2-10 alkoxycarbonyl, C_3-6 cycloalkylcarbonyloxy-C_1-3 alkyl-, C_3-6 cycloalkoxycarbonyloxy-C_1-3 alkyl-, C_3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C_1-3 alkyl-, phenylcarbonyloxy-C_1-3 alkyl-, C_1-6 alkoxy-C_1-6 alkylcarbonyloxy-C_1-3 alkyl-, [5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(R^a)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —

C_1-10 alkyl-NR⁷R^7a, —

CH(R⁸)OC(═

O)R⁹, and —

CH(R⁸)OC(═

O)OR⁹;

R⁷ is selected from H and C_1-6 alkyl, C_2-6 alkenyl, C_3-6 cycloalkyl-C_1-3 alkyl-, and phenyl-C_1-6 alkyl-;

R^7a is selected from H and C_1-6 alkyl, C_2-6 alkenyl, C_3-6 cycloalkyl-C_1-3 alkyl-, and phenyl-C_1-6 alkyl-;

R⁸ is selected from H and C_1-4 linear alkyl;

R⁹ is selected from H, C_1-6 alkyl substituted with 1-2 R^f, C_3-6 cycloalkyl substituted with 1-2 R^f, and phenyl substituted with 0-2 R^b;

R^f, at each occurrence, is selected from C_1-4 alkyl, C_3-6 cycloalkyl, C_1-5 alkoxy, phenyl substituted with 0-2 R^b;

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

,

r′

, at each occurrence, is selected from 1, 2, 3, and 4;

provided that the moiety in ring B adjacent to CH—

A is other than substituted or unsubstituted N—

SO₂-phenyl-O—

Ar and N—

SO₂-phenyl-S—

Ar, wherein Ar is aryl or heteroaryl; and

,

provided that when ring B is cyclopentyl or cyclohexyl, then R¹ is other than a substituted or unsubstituted phenyl-S(Q)p—

group.

3. A compound according to claim 2, wherein:

A is selected from 13 CO₂H, CH₂CO₂H, —

CONHOH, —

CONHOR⁵, and —

N(OH)COR⁵;

R¹ is —

U—

X—

Y—

Z—

U^a—

X^a—

Y^a—

Z^a;

U is selected from;

C(O) and C(O)NR^a′

;

X is absent;

Y is absent;

Z is selected from a C_5-6 carbocyclic residue substituted with 0-3 R^b and pyridyl substituted with 0-5 R^b;

U^a is absent or is O;

X^a is absent or is selected from C_1-2 alkylene;

Y^a is absent or is O;

Z^a is selected from a C_5-6 carbocyclic residue substituted with 0-3 R^c, pyridyl substituted with 0-5 R^c, and quinolinyl substituted with 0-5 R^c;

provided that U, Z, U^a, Y^a, and Z^a do not combine to form an N—

N N—

O, O—

N or O—

O group;

R² is selected from H, C_1-6 alkylene-Q, (CR^aR^a′

)_rC(O)(CR^aR^a′

)_r—

Q, (CR^aR^a′

)_rC(O)O(CR^aR^a′

)_r—

Q, (CR^aR^a″

)_rC(O)NR^a(CR^aR^a′

)_r—

Q, and (CR^aR^a′

)_r′

S(O)_p(CR^aR^a′

)_r—

Q;

Q is selected from H, a C_3-6 carbocyclic residue substituted with 0-3 R^d and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 R^d;

R³ is selected from H, C_1-6 alkylene-Q′

, (CHR^a)_r′

O(CHR^a)_r—

Q′

, (CHR^a)_r′

NR^a(CHR^a)_r—

Q′

, (CHR^a)_r′

C(O)NR^a(CHR^a)_r—

Q′

, (CHR^a)_rC(O)(CHR^a)_r—

Q′

, and (CHR^a)_r′

S(O)_p(CHR^a)_r—

Q′

;

Q′

is selected from H, phenyl substituted with 0-3 R^d, and a 5-6 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 R^d;

R^a, at each occurrence, is independently selected from H, C_1-4 alkyl, phenyl and benzyl;

R^a′

, at each occurrence, is independently selected from H and C_1-4 alkyl;

R^a″

, at each occurrence, is independently selected from C_1-4 alkyl, phenyl and benzyl;

R^b, at each occurrence, is independently selected from C_1-4 alkyl, OR^a, Cl, F, ═

O, NR^aR^a′

, C(O)R^a, C(O)OR^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, and CF₃;

R^c, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, ═

O, NR^aR^a′

, C(O)R^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, and CF₃;

R^d, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, ═

O, NR^aR^a′

, C(O)R^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, CF₃ and phenyl;

R⁵, at each occurrence, is selected from C_1-4 alkyl substituted with 0-2 R^b, and C_1-4 alkyl substituted with 0-2 R^e;

R^e, at each occurrence, is selected from phenyl substituted with 0-2 R^b and biphenyl substituted with 0-2 R^b;

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

,

r′

, at each occurrence, is selected from 1, 2, 3, and 4;

provided that the moiety in ring B adjacent to CH—

A is other than substituted or unsubstituted N—

SO₂-phenyl-O—

Ar and N—

SO₂-phenyl-S—

Ar, wherein Ar is aryl or heteroaryl; and

,

provided that when ring B is cyclopentyl or cyclohexyl, then R¹ is other than a substituted or unsubstituted phenyl-S(O)_p—

group.

4. A compound according to claim 3, wherein the compound is of formula III:

ring B is a 5-6 membered non-aromatic ring with 0-1 carbonyl groups;

R¹ is —

U—

Z—

U^a—

X^a—

Y^a—

Z^a;

U is selected from C(O) and C(O)NR^a′

;

Z is selected from phenyl substituted with 0-3 R^b and pyridyl substituted with 0-3 R^b;

U^a is absent or is O;

X^a is absent or is CH₂ or CH₂CH₂;

Y^a is absent or is O;

Z^a is selected from phenyl substituted with 0-3 R^c, pyridyl substituted with 0-3 R^c, and quinolinyl substituted with 0-3 R^c;

provided that U, Z, U^a, Y^a, and Z^a do not combine to form a N—

N, N—

O, O—

N, or O—

O group;

R² is selected from H, C_1-6 alkylene-Q, C(O)(CR^aR^a′

)_r—

Q, C(O)O(CR^aR^a′

)_r—

Q, C(O)NR^a(CR^aR^a′

)_r—

Q, and S(O)_p(CR^aR^a′

)_r—

Q;

Q is selected from H, cyclopropyl substituted with 0-1 R^d, cyclopentyl substituted with 0-1 R^d, cyclohexyl substituted with 0-1 R^d, phenyl substituted with 0-2 R^d and a heteroaryl substituted with 0-3 R^d, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;

R^a, at each occurrence, is independently selected from H and CH₃, and CH₂CH₃;

R^a′

, at each occurrence, is independently selected from H and CH₃, and CH₂CH₃;

R^a″

, at each occurrence, is independently selected from H and CH₃, and CH₂CH₃;

R^b, at each occurrence, is independently selected from C_1-4 alkyl, OR^a, Cl, F, ═

O, NR^aR^a′

, C(O)R^a, C(O)OR^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, and CF₃;

R^c, at each occurrence, is independently selected from C_1-6 alkyl, OR_a, Cl, F, Br, ═

O, NR^aR^a′

, C(O)R^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, and CF₃;

R^d, at each occurrence, is independently selected from C_1-6 alkyl, OR^a, Cl, F, Br, ═

O, NR^aR^a′

, C(O)R^a, C(O)NR^aR^a′

, S(O)₂NR^aR^a′

, S(O)_pR^a″

, 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

,

r′

, at each occurrence, is selected from 1, 2, and 3;

provided that the moiety in ring B adjacent to CH—

A is other than substituted or unsubstituted N—

SO₂-phenyl-O—

Ar and N—

SO₂-phenyl-S—

Ar, wherein Ar is aryl or heteroaryl; and

,

provided that when ring B is cyclopentyl or cyclohexyl, then R¹ is other than a substituted or unsubstituted phenyl-S(O)_p—

group.

5. A compound according to claim 1, wherein the compound is selected from the group:

trans-N-Hydroxy-2-[(4-phenyl-1piperidinyl)carbonyl]cyclopentanecarboxamide;

trans-N-Hydroxy-2-{[4-[(4-methylphenoxy)methyl]-1-piperidinyl]carbonyl}cyclopentanecarboxamide;

trans-N-Hydroxy-2-[[4-(2-phenoxyethyl)-1-piperidinyl]carbonyl]cyclopentanecarboxamide;

trans-N-Hydroxy-N′

-[4-(phenylmethoxy)phenyl]-1,2-cyclopentanedicarboxamide;

trans-N-Hydroxy-N′

-[4-(4-pyridinylmethoxy)phenyl]-1,2-cyclopentanedicarboxamide;

trans-N-[4-[(3,5-Dichlorophenyl)methoxy]phenyl]-N′

-hydroxy-1,2-cyclopentanedicarboxamide;

trans-N-Hydroxy-N′

-[4-[4-quinolinyloxy)methyl]phenyl]-1,2-cyclopentanedicarboxamide;

trans-N-Hydroxy-N′

-[4-(4-pyridinylmethyl)phenyl]-1,2-cyclopentanedicarboxamide;

trans-N-Hydroxy-N′

-[4-(phenylmethoxy)phenyl]-1,2-cyclohexanedicarboxamide;

trans-N-Hydroxy-N′

-[4-[(4-quinolinyloxy)methyl]phenyl]-1,2-cyclohexanedicarboxamide;

trans-N-Hydroxy-N′

[4-[(5-quinolinyloxy)methyl]phenyl]-1,2-cyclohexanedicarboxamide; and

,

trans-N-Hydroxy-N′

-[4-[(6-quinolinyloxy)methyl]phenyl]-1,2-cyclohexanedicarboxamide;

or a pharmaceutically acceptable salt form thereof.

6. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.

7. A method for treating an inflammatory disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.

8. A method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, or psoriasis in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.

9. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.

10. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.

11. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.

12. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.

13. A method for treating an inflammatory disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.

14. A method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, or psoriasis in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.

15. A method for treating an inflammatory disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.

16. A method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, or psoriasis in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.

17. A method for treating an inflammatory disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.

18. A method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, or psoriasis in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.

19. A method for treating an inflammatory disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.

20. A method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, or psoriasis in a mammal, comprising:

administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.